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New Technologies in HER2 Testing
BY HUNTERDON REGIONAL BREAST CARE PROGRAM, FLEMINGTON, NEW JERSEY
he treatment of breast cancer begins by identifying the molecular and genetic features of breast cancer cells to determine the best approach to treatment. In July 2008, the US Food and Drug Administration (FDA)
approved two new technologies to identify patients with breast cancer who would benefit from accurate determination of the human epidermal growth factor receptor 2 (HER2) status of breast cancer tumors and to provide prognostic
information to assist in the selection of patients most likely to benefit from trastuzumab (Herceptin) therapy. The HERmark Breast Cancer Assay by Monogram Biosciences, Continued on page 27
The Oncology Nursing Society held its 10th National Conference on Cancer Nursing Research in Orlando, Florida, February 12-14, 2009.
page 13 COMPLIMENTARY CE CREDIT
Nurse Navigator at Helm of Multidisciplinary Program for Upper GI Cancer
NCCN Updates Guidelines for NSCLC
PROGRAM #09CE 036
SAN FRANCISCO—The management of patients with newly diagnosed upper gastrointestinal (GI) cancers typically involves a number of specialists, which can make for fragmented and inefficient care. The Vermont Cancer Center in Burlington has met the challenge by creating a multidisciplinary program that places a nurse navigator at the helm. The program was described at the 2009 Gas-
o keep pace with the advances being made in non–small-cell lung cancer (NSCLC), the National Comprehensive Cancer Network (NCCN) recently updated its guidelines. The new guidelines were the topic of a presentation at the NCCN’s 13th annual conference by David S. Ettinger, MD, the Alex Grass Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. “The future is looking brighter for lung cancer
Continued on page 16
Continued on page 21
Reimbursement for Expensive Cancer Therapies: The Role of Cost-effectiveness Analysis
College of Nursing Continuing Nursing Education
YOU COULD BE HOLDING YOUR LAST ISSUE! Register online at © 2009 Green Hill Healthcare Communications, LLC
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When treating patients with HER2+ breast cancer
No one touches their HER2-positive status is associated with more aggressive disease and poorer outcomes than HER2-negative breast cancer. Women who received 1 year of Herceptin had a lower risk of HER2+ breast cancer returning. We applaud you for playing such a critical role in helping patients with HER2+ breast cancer complete the full course of treatment with Herceptin.
Adjuvant indications Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer: s As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel s With docetaxel and carboplatin s As a single agent following multi-modality anthracyclinebased therapy *High-risk features for patients with ER/PR+ breast cancer include: tumor size >2 cm, age <35 years, and histologic and/or nuclear grade 2/3.
Metastatic indications Herceptin is indicated: s In combination with paclitaxel for ﬁrst-line treatment of HER2-overexpressing metastatic breast cancer s As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease ©2009 Genentech USA
Boxed WARNINGS and Additional Important Safety Information Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF). The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclinecontaining chemotherapy regimens. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer who develop a clinically signiﬁcant decrease in left ventricular function. Patients should undergo monitoring for decreased left ventricular function before Herceptin treatment, and frequently during and after Herceptin treatment. More frequent monitoring should be employed if Herceptin is So. San Francisco, CA
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lives like you
withheld in patients who develop signiďŹ cant left ventricular cardiac dysfunction. In one adjuvant clinical trial, cardiac ischemia or infarction occurred in the Herceptin-containing regimens. Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically signiďŹ cant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Exacerbation of chemotherapy-induced neutropenia has also occurred. Herceptin can cause oligohydramnios and fetal harm
when administered to a pregnant woman. The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Please see brief summary of full Prescribing Information, including Boxed WARNINGS and additional important safety information, on the following pages.
Brief Summary For full Prescribing Information, see package insert.
WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, and PULMONARY TOXICITY Cardiomyopathy Herceptin can result in sub-clinical and clinical cardiac failure manifesting as CHF and decreased LVEF. The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin treatment in patients with metastatic breast cancer for clinically significant decrease in left ventricular function. [see Warnings and Precautions and Dosage and Administration] Infusion Reactions; Pulmonary Toxicity Herceptin administration can result in serious infusion reactions and pulmonary toxicity. Fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. [see Warnings and Precautions] INDICATIONS AND USAGE Adjuvant Breast Cancer Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/ PR negative or with one high risk feature [see Clinical Studies/1A40BC20=24AKB?0AC>50CA40C<4=CA468<4= consisting of doxorubicin, Cyclophosphamide, and either ?02;8C0G4;>A3>24C0G4;K,8C73>24C0G4;0=320A1>?;0C8= KB0B8=6;4064=C5>;;>F8=6<D;C8<>30;8CH0=C7A02H2;8=4 based therapy. Metastatic Breast Cancer Herceptin 8B 8=3820C43 K = 2><18=0C8>= F8C7 ?02;8C0G4; 5>A 58ABC ;8=4 CA40C<4=C >5 ' >E4A4G?A4BB8=6 <4C0BC0C82 1A40BC 20=24A K B 0 B8=6;4 064=C 5>A CA40C<4=C >5 ' >E4A4G?A4BB8=6 1A40BC 20=24A 8= ?0C84=CB F7> have received one or more chemotherapy regimens for metastatic disease. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Cardiomyopathy Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy]. Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4â€“6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is 03<8=8BC4A43F8C70=0=C7A02H2;8=4,8C77>;34A24?C8= for 01B>;DC4342A40B48="+5A><?A4CA40C<4=C values or an LVEF value below institutional limits of normal and 01B>;DC4 342A40B4 8= "+ 5A>< ?A4 treatment values. [see Dosage and Administration] The safety of continuation or resumption of Herceptin in ?0C84=CBF8C74A24?C8=8=3D243;45CE4=CA82D;0A20A3802 dysfunction has not been studied. Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, and determination >5 "+ 1H 427>20A38>6A0< >A #* B20= )74 5>;;>F8=6 B2743D;4 8B A42><<4=343 K 0B4;8=4 "+ measurement immediately prior to initiation of Herceptin K "+ <40BDA4<4=CB 4E4AH <>=C7B 3DA8=6 0=3 D?>= 2><?;4C8>=>54A24?C8=K'4?40C"+<40BDA4<4=C0C 4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration/ K "+ <40BDA4<4=CB 4E4AH <>=C7B for at least 2 years following completion of Herceptin as a component of adjuvant therapy. In Study 1, 16% >5 ?0C84=CB 38B2>=C8=D43 4A24?C8= 3D4 C> clinical evidence of myocardial dysfunction or significant 342;8=48="+ =(CD3H C74=D<14A>5?0C84=CBF7> discontinued Herceptin due to cardiac toxicity was
= (CD3H 0 C>C0; >5 ?0C84=CB8=C74)0A<3DA8=6C74274<>C74A0?H ?70B40=33DA8=6C74<>=>C74A0?H?70B40=3 ?0C84=CB 8= C74 ) 0A< 3DA8=6 C74 chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity. <>=6 ?0C84=CB A4248E8=6 039DE0=C 274<>C74A0?H (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy and all other patients F4A4 A4248E8=6 20A3802 <43820C8>= 0C ;0BC 5>;;>FD? ??A>G8<0C4;H70;5>5C74BDAE8E8=6?0C84=CB703A42>E4AH to a normal LVEF (defined as >=2>=C8=D8=6<43820; <0=064<4=C 0C C74 C8<4 >5 ;0BC 5>;;>FD? =2834=24 of congestive heart failure is presented in Table 1. The safety of continuation or resumption of Herceptin in ?0C84=CBF8C74A24?C8=8=3D243;45CE4=CA82D;0A20A3802 dysfunction has not been studied. Table 1 =2834=24>5>=64BC8E440AC08;DA48=39DE0=C A40BC0=24A(CD384B
Study Regimen 1 & 2a ACbJPaclitaxel+ Herceptin 3 ChemoJHerceptin monotherapy 4 ACbJDocetaxel+ Herceptin 4 Docetaxel+Carbo+ Herceptin
Incidence of CHF Herceptin Control 2% (32/1677)
Includes 1 patient with fatal cardiomyopathy. =C7A02H2;8=43>G>AD1828=0=32H2;>?7>B?70<834
Table 2 Incidence of Cardiac Dysfunctiona in Metastatic A40BC0=24A(CD384B
Study 5 (AC)b 5 (paclitaxel) 6
Event Cardiac Dysfunction Cardiac Dysfunction Cardiac Dysfunctionc
Incidence NYHA I-IV NYHA III-IV Herceptin Control Herceptin Control 28%
Congestive heart failure or significant asymptomatic decrease in LVEF. b=C7A02H2;8=43>G>AD1828=>A4?8AD1828= and cyclophosphamide. cIncludes 1 patient with fatal cardiomyopathy. a
Infusion Reactions Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. [see Adverse Reactions]. In postmarketing reports, serious and fatal infusion reactions have been reported. Severe reactions which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable including progressive worsening, initial improvement 5>;;>F43 1H 2;8=820; 34C4A8>A0C8>= >A 34;0H43 ?>BC infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered, which may include: epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions. There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion A402C8>=F4A4?A4<43820C43F8C70=C878BC0<8=4B0=3 >A 2>AC82>BC4A>83B,78;4B><4?0C84=CBC>;4A0C434A24?C8= infusions, others had recurrent severe infusion reactions 34B?8C4?A4<43820C8>=BExacerbation of ChemotherapyInduced Neutropenia In randomized, controlled clinical CA80;B8=F><4=F8C7<4C0BC0C821A40BC20=24AC74?4A ?0C84=C8=2834=24B>5$ )A034 =4DCA>?4=800=3 of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was not significantly increased. [see Adverse Reactions]. Pulmonary Toxicity Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, ?;4DA0; 455DB8>=B =>=20A38>64=82 ?D;<>=0AH 434<0 pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been B7>F=BB4BB<4=C5>A' >E4A4G?A4BB8>=0=3>5' gene amplification should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, 20= ;403 C> D=A4;801;4 A4BD;CB (4E4A0; 0??A>E43 commercial assays are available to aid in the selection of patients for Herceptin therapy. These include HercepTestTM and Pathway ÂŽ ' =4D 0BB0HB 0=3 &0C7+HB8>=ÂŽ and HER2 FISH pharmDxTM (FISH assays). Users should refer to the package inserts of specific assay kits for information on the validation and performance of each assay. Limitations in assay precision (particularly for the IHC method) and in the direct linkage between assay result and overexpression of the Herceptin target (for the FISH method) make it inadvisable to rely on a single <4C7>3C>AD;4>DC?>C4=C80;4A24?C8=14=458C=460C8E4 FISH result does not rule out HER2 overexpression and potential benefit from Herceptin. Treatment outcomes 5>A <4C0BC0C82 1A40BC 20=24A (CD3H 0B 0 5D=2C8>= >5 0=3 ( C4BC8=6 0A4 ?A>E8343 8= )01;4 )A40C<4=C >DC2><4B5>A039DE0=C1A40BC20=24A(CD384B 0=3 0B a function of IHC and FISH testing are provided in Table 7. HER2 Protein Overexpression Detection Methods HER2 protein overexpression can be established by measuring HER2 protein using an IHC method. HercepTest ÂŽ, one test approved for this use, was assessed for concordance with C74 ;8=820; )A80; BB0H ) DB8=6 CD<>A B?428<4=B collected and stored independently from those obtained in Herceptin clinical studies in women with metastatic breast cancer. Data are provided in the package insert for HercepTest ÂŽ. HER2 Gene Amplification Detection Method The presence of HER2 protein overexpression and gene amplification are highly correlated, therefore the use of FISH to detect gene amplification may be employed for selection of patients appropriate for Herceptin therapy. PathVysionÂŽ, one test approved for this use, was evaluated in an exploratory, retrospective assessment >5 0E08;01;4 ) >A CD<>A B?428<4=B 2>;;42C43 0B part of patient screening for clinical studies in metastatic 1A40BC20=24A(CD384B0=30C00A4?A>E83438=C74 package insert for PathVysionÂŽ. Embryo-Fetal Toxicity (Pregnancy Category D) Herceptin can cause fetal harm F74=03<8=8BC4A43C>0?A46=0=CF><0=&>BC<0A:4C8=6 case reports suggest that Herceptin use during pregnancy increases the risk of oligohydramnios during the second and third trimesters. If Herceptin is used during pregnancy
or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard to a fetus. [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater 34C08; 8= >C74A B42C8>=B >5 C74 ;014; K 0A38><H>?0C7H [see Warnings and Precautions/ K =5DB8>= A402C8>=B [see Warnings and Precautions / K G024A10C8>= >5 274<>C74A0?H8=3D243 =4DCA>?4=80 .see Warnings and Precautions/ K &D;<>=0AH C>G828CH .see Warnings and Precautions] The most common adverse reactions in patients receiving Herceptin are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, 0=3 <H0;680 3E4AB4 A402C8>=B A4@D8A8=6 8=C4AAD?C8>= or discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration]. Clinical Trials Experience 420DB4 2;8=820; CA80;B 0A4 2>=3D2C43 D=34A F834;H varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Breast Cancer Studies The data below reflect exposure to 4A24?C8=02A>BBC7A44A0=3><8I43>?4=;014;BCD384B (CD384B 0=3 F8C7= >AF8C7>DC= trastuzumab in the adjuvant treatment of breast cancer. )74 30C0 BD<<0A8I43 8= )01;4 14;>F 5A>< (CD3H A45;42C 4G?>BDA4 C> 4A24?C8= 8= ?0C84=CB C74 <4380= CA40C<4=C 3DA0C8>= F0B F44:B 0=3 <4380= =D<14A >5 8=5DB8>=B F0B <>=6 C74 ?0C84=CB 4=A>;;438=(CD3H C74<4380=064F0BH40ABA0=64
C> H40AB >5 ?0C84=CB F4A4 0D20B80= 0=3 F4A4B80= Table 3 3E4AB4'402C8>=B5>A(CD3H ;;A034Ba :
MedDRA (v. 7.1) 1 Year Herceptin (n= 1678) Adverse Event Preferred Term Cardiac Hypertension 64 (4%) Dizziness 60 (4%) Ejection Fraction Decreased 58 (3.5%) 48 (3%) Palpitations Cardiac Arrhythmiasb 40 (3%) Cardiac Failure Congestive 30 (2%) Cardiac Failure 9 (0.5%) Cardiac Disorder 5 (0.3%) Ventricular Dysfunction 4 (0.2%) Respiratory Thoracic Mediastinal Disorders Nasopharyngitis 135 (8%) Cough 81 (5%) Influenza 70 (4%) Dyspnea 57 (3%) URI 46 (3%) Rhinitis 36 (2%) Pharyngolaryngeal Pain 32 (2%) Sinusitis 26 (2%) Epistaxis 25 (2%) Pulmonary Hypertension 4 (0.2%) Interstitial Pneumonitis 4 (0.2%) Gastrointestinal Disorders Diarrhea 123 (7%) Nausea 108 (6%) Vomiting 58 (3.5%) Constipation 33 (2%) 30 (2%) Dyspepsia Upper Abdominal Pain 29 (2%) Musculoskeletal & Connective Tissue Disorders Arthralgia 137 (8%) Back Pain 91 (5%) Myalgia 63 (4%) Bone Pain 49 (3%) Muscle Spasm 46 (3%) Nervous System Disorders Headache 162 (10%) Paraesthesia 29 (2%) Skin & Subcutaneous Tissue Disorders Rash 70 (4%) Nail Disorders 43 (2%) Pruritus 40 (2%) General Disorders Pyrexia 100 (6%) Edema Peripheral 79 (5%) Chills 85 (5%) Asthenia 75 (4.5%) Influenza-like Illness 40 (2%) Sudden Death 1 (0.06%) Infections Nasopharyngitis 135 (8%) UTI 39 (3%) Immune System Disorders Hypersensitivity 10 (0.6%) Autoimmune Thyroiditis 4 (0.3%)
Observation (n= 1708) 35 (2%) 29 (2%) 11 (0.6%) 12 (0.7%) 17 (1%) 5 (0.3%) 4 (0.2%) 0 (0%) 0 (0%) 43 (3%) 34 (2%) 9 (0.5%) 26 (2%) 20 (1%) 6 (0.4%) 8 (0.5%) 5 (0.3%) 1 (0.06%) 0 (0%) 0 (0%)
C74 5>;;>F8=6 8=E4BC860C>A0CCA81DC43 CA40C<4=CA4;0C43 03E4AB4A402C8>=B$ )A0340=374<0C>;>682 C>G828C84BA034 J=>=74<0C>;>682C>G828C84BB4;42C43 A034 J C>G828C84B 0BB>280C43 F8C7 C0G0=4B <H0;680 arthralgias, nail changes, motor neuropathy, sensory =4DA>?0C7H0=3A034J20A3802C>G828C84B>22DAA8=6 during chemotherapy and/or Herceptin treatment. The 5>;;>F8=6 =>=20A3802 03E4AB4 A402C8>=B >5 A034 J occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (11% vs. <H0;680 EB=08;270=64BEB 0=33HB?=40 EB )74<09>A8CH>5C74B44E4=CB were Grade 2 in severity. Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose >5 BCD3H CA40C<4=C .) = ) = / )74 >E4A0;; <4380= CA40C<4=C 3DA0C8>= F0B F44:B 8= 1>C7 C74 ) 0=3 ) 0A<B )74 <4380= =D<14A >58=5DB8>=BF0B 8=C74)0A<0=3 8=C74) arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy ?4A8>3 <>=6 C74B4 ?0C84=CB C74 <4380= 064 F0B years (range 22 to 74 years). In Study 4, the toxicity ?A>58;4F0BB8<8;0AC>C70CA4?>AC438=(CD384B 0=3 with the exception of a low incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The data below A45;42C4G?>BDA4C>4A24?C8=8=>=4A0=3><8I43>?4= ;014; BCD3H (CD3H >5 274<>C74A0?H F8C7 = >A F8C7>DC= CA0BCDID<018=?0C84=CBF8C7<4C0BC0C82 1A40BC 20=24A 0=3 >=4 B8=6;40A< BCD3H (CD3H =
8= ?0C84=CB F8C7 <4C0BC0C82 1A40BC 20=24A 0C0 8=)01;40A410B43>=(CD384B0=3<>=6C74 ?0C84=CBCA40C438=(CD3HC74<4380=064F0B H40AB A0=64 J H40AB 867CH=8=4 ?4A24=C F4A4 ,78C4 ;02:B80=0=3>C74AA0280; 4C7=826A>D?B ;; ?0C84=CB A4248E43 <6 :6 8=8C80; 3>B4 >5 4A24?C8= followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for 6 months and <>=C7B F4A4 0=3 A4B?42C8E4;H <>=6 C74 ?0C84=CB CA40C43 8= B8=6;4 064=C BCD384B ?0C84=CB 5A>< (CD3H C74 <4380= 064 F0B H40AB A0=64 J H40AB
703 1A40BC 20=24A F4A4 ,78C4 F4A4 ;02: F4A4 B80= 0=3 in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for 6 months and <>=C7BF4A4 0=3A4B?42C8E4;H Table 4 &4A&0C84=C =2834=24 >5 3E4AB4 '402C8>=B Occurring in >5&0C84=CB8=*=2>=CA>;;43(CD384B>A 0C =2A40B43 =2834=248=C744A24?C8=A<(CD384B and 6) (Percent of Patients)
Herceptin Single + Paclitaxel Herceptin ACb a Agent Paclitaxel Alone + ACb Alone n = 352 n = 91 n = 95 n = 143 n = 135 Body as a Whole 47 61 62 57 42 Pain Asthenia 42 62 57 54 55 Fever 36 49 23 56 34 Chills 32 41 4 35 11 Headache 26 36 28 44 31 Abdominal pain 22 34 22 23 18 Back pain 22 34 30 27 15 Infection 20 47 27 47 31 Flu syndrome 10 12 5 12 6 Accidental injury 6 13 3 9 4 Allergic reaction 3 8 2 4 2 Cardiovascular Tachycardia 5 12 4 10 5 Congestive heart failure 7 11 1 28 7 Digestive Nausea 33 51 9 76 77 Diarrhea 25 45 29 45 26 Vomiting 23 37 28 53 49 Nausea and 8 14 11 18 9 vomiting Anorexia 14 24 16 31 26 Heme & Lymphatic Anemia 4 14 9 36 26 Leukopenia 3 24 17 52 34 Metabolic Peripheral edema 10 22 20 20 17 Edema 8 10 8 11 5 Musculoskeletal Bone pain 7 24 18 7 7 Arthralgia 6 37 21 8 9 Nervous Insomnia 14 25 13 29 15 Dizziness 13 22 24 24 18 Paresthesia 9 48 39 17 11 Depression 6 12 13 20 12 Peripheral neuritis 2 23 16 2 2 Neuropathy 1 13 5 4 4 Respiratory Cough increased 26 41 22 43 29 Dyspnea 22 27 26 42 25 Rhinitis 14 22 5 22 16 Pharyngitis 12 22 14 30 18 Sinusitis 9 21 7 13 6 Skin Rash 18 38 18 27 17 Herpes simplex 2 12 3 7 9 Acne 2 11 3 3 <1 Urogenital Urinary tract infection 5 18 14 13 7
16 (1%) 19 (1%) 10 (0.6%) 17 (1%) 9 (0.5%) 15 (1%) 98 (6%) 58 (3%) 17 (1%) 26 (2%) 3 (0.2%) 49 (3%) 11 (0.6%) 10 (0.6%) 0 (0%) 10 (0.6%) 6 (0.4%) 37 (2%) 0 (0%) 30 (2%) 3 (0.2%) 0 (0%) 43 (3%) 13 (0.8%) 1 (0.06%) 0 (0%)
a )748=2834=24>5A034 03E4AB4A402C8>=BF0B8= both arms for each listed term. b Higher level grouping term.
The data from Studies 1 and 2 were obtained from
?0C84=CB4=A>;;43>5F7827 ?0C84=CBA4248E43 4A24?C8=C74<4380=CA40C<4=C3DA0C8>=F0B F44:B )74 <4380= 064 F0B H40AB A0=64 >5 ?0C84=CB F4A4 ,78C4 0=3 F4A4 ;02: F4A4 8B?0=820=3F4A4B80= =(CD3H>=;HA034 J 03E4AB4 4E4=CB CA40C<4=CA4;0C43 A034 4E4=CB 0=3 A034 J3HB?=40F4A42>;;42C433DA8=60=35>AD?C> <>=C7B 5>;;>F8=6 ?A>C>2>;B?4285843 CA40C<4=C )74 5>;;>F8=6 =>=20A3802 03E4AB4 A402C8>=B >5 A034 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as 2><?0A43 C> 274<>C74A0?H 0;>=4 0AC7A0;680 EB
EB7>C 5;0B74BEB0=4<80 EB3HB?=40 vs. 4%), rash/desquamation (11% vs. 7%), neutropenia EB74030274EB0=38=B><=80 EB )74 <09>A8CH >5 C74B4 4E4=CB F4A4 A034 in severity. In Study 2, data collection was limited to
Data for Herceptin single agent were from 4 studies, 8=2;D38=6 ?0C84=CB 5A>< (CD3H b=C7A02H2;8=4 (doxorubicin or epirubicin) and cyclophosphamide.
The following subsections provide additional detail regarding adverse reactions observed in clinical
For Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment. For Study 4, events are counted from the date of randomization. bStudies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (ACJT) or paclitaxel plus Herceptin (ACJTH). c Study 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (ACJT) or docetaxel plus Herceptin (ACJTH); docetaxel and carboplatin plus Herceptin (TCH). a
Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event
Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy. Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event
Time 0 is the date of randomization. Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event
Time 0 is the date of randomization. The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I–IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials the probability of cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclines. Infusion Reactions During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusional toxicity was required in <1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional toxicity occurred in 21% and 35% of patients, and was
she should be apprised of the potential hazard to a fetus. In the post-marketing setting, oligohydramnios was reported in women who received Herceptin during pregnancy, either alone or in combination with chemotherapy. In half of these women, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin was resumed after the amniotic fluid index improved, and oligohydramnios recurred. Women using Herceptin during pregnancy should be monitored for oligohydramnios. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and consistent with community standards of care. Additional intravenous (IV) hydration has been helpful when oligohydramnios has occurred following administration of other chemotherapy agents; however, the effects of additional IV hydration with Herceptin treatment are not known. Reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended weekly human dose of 2 mg/kg trastuzumab have revealed no evidence of harm to the fetus. However, HER2 protein expression is high in many embryonic tissues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation. Placental transfer of trastuzumab during the early (Days 20-50 of gestation) and late (Days 120-150 of gestation) fetal development period was observed in monkeys. [See Nonclinical Toxicology] Because animal reproduction studies are not always predictive of human response, Herceptin should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Nursing Mothers It is not known whether Herceptin is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 mg/kg of Herceptin. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not accurately reflect human breast milk levels. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Herceptin, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of trastuzumab and the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Herceptin in pediatric patients has not been established. Geriatric Use Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment. OVERDOSAGE There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested. PATIENT COUNSELING INFORMATION K3E8B4?0C84=CBC>2>=C02C0740;C720A4 professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Warning: Cardiomyopathy]. K 3E8B4 F><4= F8C7 A4?A>3D2C8E4 ?>C4=C80; C> DB4 effective contraceptive methods during treatment and for a minimum of six months following Herceptin [see Pregnancy/ K =2>DA064 ?A46=0=C F><4= F7> 0A4 DB8=6 Herceptin to enroll in the Cancer and Childbirth Registry [see Pregnancy].
HERCEPTIN® [trastuzumab] Manufactured by: 4839802 Genentech, Inc. Initial US Approval: Sept. 1998 1 DNA Way Revision Date: May 2008 South San Francisco, CA LK0726 7172910 94080-4990 9317800 ©2008 Genentech USA
News Notes ■ ASCO Guide on Managing Costs of Care In a report presented at the American Association for Cancer Research’s Science of Cancer Health Disparities conference in February, National Cancer Institute researchers showed that an estimated 2 million cancer survivors go without needed medical care because of economic considerations. Another report by the Kaiser Family Foundation and American Cancer Society, Spending to Survive: Cancer Patients Confront Holes in the Health Insurance System, highlights how many patients amass high debt, file for personal bankruptcy, or postpone or forgo necessary care. Now a new American Society of Clinical Oncology (ASCO) guide, Managing the Cost of Cancer Care, can help patients and clinical staff to communicate about the costs of cancer care. The guide can help patients understand what costs to expect, a crucial step in preparing for their disease’s financial impact. Included in the guide is a list of questions patients can ask their providers about healthcare costs. Information on resources for employment or health insurance problems is also included, along with tips for organizing bills and expenses, a list of financial resources available to people with cancer, and a glossary of cancer treatment and financial terms. The guide can be downloaded at www.cancer. net/managingcost ofcare.
LVEF <50% and Absolute Absolute LVEF Decrease from Baseline Decrease LVEF 10% 16% <20% and <50% decrease decrease 10% 20% Studies 1 & 2b 22.8% 18.3% 11.7% 33.4% 9.2% ACJTH (n=1606) (366) (294) (188) (536) (148) ACJT 9.1% 5.4% 2.2% 18.3% 2.4% (272) (36) (n=1488) (136) (81) (33) Study 3 Herceptin 8.6% 7.0% 3.8% 22.4% 3.5% (376) (59) (n=1678) (144) (118) (64) Observation 2.7% 2.0% 1.2% 11.9% 1.2% (204) (21) (n=1708) (46) (35) (20) Study 4c TCH 8.5% 5.9% 3.3% 34.5% 6.3% (n=1056) (90) (62) (35) (364) (67) ACJTH 17% 13.3% 9.8% 44.3% 13.2% (n=1068) (182) (142) (105) (473) (141) ACJT 9.5% 6.6% 3.3% 34% 5.5% (n=1050) (100) (69) (35) (357) (58)
severe in 1.4% and 9% of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the postmarketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2–5 anemia (12.5% vs. 6.6% [Study 1]), and of anemia requiring transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was <1%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4–5 neutropenia (2% vs. 0.7% [Study 2]) and of selected Grade 2–5 neutropenia (7.1% vs. 4.5 % [Study 1]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Infection The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2–5 infection/febrile neutropenia (22% vs. 14% [Study 1]) and of selected Grade 3–5 infection/febrile neutropenia (3.3% vs. 1.4%) [Study 2]), were higher in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In Study 4, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC grade 3-4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer: Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2–5 pulmonary toxicity (14% vs. 5% [Study 1]) and of selected NCI-CTC Grade 3–5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 1% [Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI CTC Grade 2–5: 12% vs. 4% [Study 1]; NCI-CTC Grade 2–5: 2.5% vs. 0.1% [Study 2]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In Study 3, there were 4 cases of interstitial pneumonitis in Herceptin-treated patients compared to none in the control arm. Metastatic Breast Cancer: Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions. Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies (3.0% vs. 1.3% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCICTC Grade 2–5 diarrhea (6.2% vs. 4.8% [Study 1]) and of NCI-CTC Grade 3–5 diarrhea (1.6% vs. 0% [Study 2]), and of Grade 1–4 diarrhea (7% vs. 1% [Study 3]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3–4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1–4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer. Glomerulopathy In the postmarketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of Herceptin therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human antihuman antibody (HAHA) to Herceptin was detected in one patient using an enzyme-linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Herceptin with the incidence of antibodies to other products may be misleading. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category D [see Warnings and Precautions] Herceptin can cause fetal harm when administered to a pregnant woman. Post-marketing case reports suggest that Herceptin use during pregnancy increases the risk for oligohydramnios during the second and third trimester. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin,
■ Nurse Assumes ACCC Presidency Luana Lamkin, RN, MPH, assumed the presidency of the American Association of Community Cancer Centers at its 35th Annual Meeting. During her year as president, she says, “I hope to shine a light on the coming professional workforce shortage in oncology, particularly oncology nursing.” To attract more people into the oncology workforce, she suggests developing new staffing strategies and advocating for more federal funding for education. Lamkin is administrator for St. Luke’s Mountain States Tumor Institute at St. Luke’s Boise Medical Center, Idaho. ■ Reminders Increase Colorectal Cancer Screening Rates Reminders mailed to patients increase colorectal cancer (CRC) screening rates, according to a study by Sequist and associates. The findings also showed that electronic reminders to physicians may increase screening among adults with frequent primary care visits. In the study of patients at 11 ambulatory healthcare centers, 21,860 patients 50 to 80 years of age who were overdue for CRC screening were randomly assigned to receive mailings containing an educational pamphlet, a fecal occult blood test, and instructions on scheduling flexible sigmoidoscopy or colonoscopy. In addition, 110 primary care physicians were randomly selected to receive electronic reminders during visits with patients who were overdue for CRC screening. Screening rates were Continued on page 9
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trials of adjuvant breast, metastatic breast cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); and in Studies 1 and 2, 23 months in the AC-T arm, 24 months in the AC-TH arm. In Studies 1 and 2, 6% of patients were not permitted to initiate Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF < 50% or 15 point decline in LVEF from baseline to end of AC). Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving Herceptin monotherapy compared to observation in Study 3 (see Table 5, Figures 1 and 2). Table 5 a Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4
A Letter from the Editor T
he article reprinted from the Wall Street Journal in this issue discusses the challenges that our nation may face when attempting to provide universal healthcare to all citizens of the United States. Three years ago under then-Governor Mitt Romney, a law was passed in Massachusetts in an attempt to provide healthcare coverage to all residents of the state. Current Governor Deval Patrick and his state are now seeking ways to manage the costs of the program. The Massachusetts model is similar to the one being considered by President Obama and his administration in order to provide healthcare across the country. With many people with little or no income, providing healthcare for all seems like a good solution—doesn’t it? Universal healthcare is the standard for countries like Canada and much of Europe. How would this work in the United States? According to the Wall Street Journal article, since the pilot program in Massachusetts began in 2006, the state’s overall costs on health programs have increased by 42%. In addition, not everybody is taking advantage of the services that have become available. Why would a program directed at providing healthcare for everyone, one that is supposed
to reduce costs, actually lead to an increase in dollars spent? The program was designed to address needs on a state level, yet state-driven model costs were not considered. Employers pay into Medicare and Medicaid, but the current Medicare and Medicaid systems are not designed to accommodate this type of healthcare model and thus become cost-ineffective. To have a state try to run a budget for healthcare without certain types of reform may not work, and state solutions may not be successful if run independently. But what if this was expanded to the entire US population and not just Massachusetts? Would expanding to the larger population have a negative effect our nation’s deficit? In a government-run program, one of the hazards is that the decision-making may rest with the bureaucrats and not with the providers. One may argue that if the appropriate staff were employed to review medical needs on a case-by-case basis in a new system, health costs may be kept down and people would receive appropriate medical care. Think of the challenges we as nurses face in trying to obtain prior authorizations for tests or procedures; this may be even more difficult if our healthcare system becomes gov-
CE article: Treatment of Advanced Non–Small Cell Lung Cancer: Gefitinib vs Docetaxel
New Technologies in HER2 Testing, Part II Cancer-treatment Related Bone Loss and Osteoporosis Recent Advances in Colorectal Cancer Creating a Healthy Work Environment Increasing Oncology Patient Participation in Clinical Trials: The Coalition of Cancer Cooperative Groups
Reports from NCCN 14th Annual Conference, Scripps Cancer Center’s 29th Annual Conference on Clinical Hematology and Oncology
For a free subscription go to
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ernment run. A trickle-down effect may occur, and this may impact medical malpractice complaints. Providers may be more at risk for lawsuits as they are limited by the services they can recommend. Universal coverage is not a panacea in the United States. Although we might like to model our healthcare after places like Canada, we do not currently have the system in place to make it happen, and we run the risk of rationing care and making cost control issues worse if we go that route. The universal coverage model may be more successful if directed by reforms in our healthcare system, and if significant changes in insurance and reimbursement are enacted. Cost containment is ineffective at the state level, as seen in the current Massachusetts pilot, and universal healthcare may not be successful if reforms to our other programs are not made, as Medicare and Medicaid are driving much of our healthcare costs. Medical malpractice concerns must also be addressed if providers are limited by the government in regard to the services they can recommend. We are looking to President Obama and his administration with optimism to find a balance and address these issues as we move forward with his plan.
EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Nurse™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: karen@greenhill hc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in The Oncology Nurse™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Nurse™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. ISSN #1944-9798. The Oncology Nurse™ is published 7 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2009 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Nurse™ logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.
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Vol. 2, No. 2
Feature Articles 13
19 22 25 26 28 35 38 40
ONS 10th National Conference on Cancer Nursing Research
Patient Support Programs
Spotlight on NexConnect
Lung Cancer Alliance seeks to overcome stigma associated with the disease
Lymphoma survivor turns entrepreneur
Puget Sound Oncology Nursing Society promotes excellence
Preventing skin toxicity from EGFR inhibitors Colorectal screening guidelines not always followed Octreotide LAR blunts disease progression in midgut neuroendocrine tumors
Statin use may significantly lower the risk of death from prostate cancer
Superfoods: a realistic approach?
Pediatric cancer survivors shun screening Non-Hodgkin’s lymphomas, Part 4: Evidence-based treatment selection
Recognizing structural oncologic emergencies
Reimbursement for expensive cancer therapies: the role of cost-effectiveness analysis
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For patients 55 years and older with AML following induction chemotherapy...
Which CSF is proven to help prevent early death* by ﬁghting fungal infections?
Goes beyond neutrophil recovery to reduce the incidence of fatal infections1,2
▲ Reduces the incidence of early death associated with fungal infections, including deaths due to Aspergillus and Candida*1-3 ▲ Reduces the incidence of life-threatening, severe, and fatal infections1,2 ▲ Shortens time to neutrophil recovery1,2 ▲ Adverse event proﬁle similar to placebo1 *During and within 30 days of study completion.2
LEUKINE is indicated for use following induction chemotherapy in older adults with AML to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death.
Important Information In controlled clinical trials across all indications, no signiﬁcant differences were observed between LEUKINE- and placebo-treated patients in the type or frequency of adverse events with the exception of an increase in skin-associated events in the LEUKINE group in the pivotal AML trial. There were occasional reports of ﬂuid retention, dyspnea, supraventricular tachycardia, and laboratory abnormalities (increases in creatinine, bilirubin, and liver enzymes). Other adverse events have been reported; please see full Prescribing Information, which contains a more complete listing of indications, contraindications, warnings, precautions, adverse events, and dosage and administration guidelines. Please see adjacent brief summary of full Prescribing Information.
References: 1. LEUKINE® (sargramostim) [package insert]. Seattle, Wash: Bayer HealthCare Pharmaceuticals Inc.; 2007. 2. Rowe JM, Rubin A, Mazza JJ, et al. Incidence of infections in adult patients (> 55 years) with acute myeloid leukemia treated with yeast-derived GM-CSF (sargramostim): results of a double-blind prospective study by the Eastern Cooperative Oncology Group. In: Hiddemann W, et al, eds. Acute Leukemias V: Experimental Approaches and Management of Refractory Diseases. Berlin, Germany: Springer-Verlag; 1996:178-184. 3. Rowe JM. Treatment of acute myeloid leukemia with cytokines: effect on duration of neutropenia and response to infections. Clin Infect Dis. 1998;26:1290-1294.
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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE LEUKINE is Use Following Induction Chemotherapy in Acute Myelogenous Leukemia indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of LEUKINE have not been assessed in patients with AML under 55 years of age. The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification. Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progenitor Cells LEUKINE is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of LEUKINE following peripheral blood progenitor cell transplantation. Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation LEUKINE is indicated for acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin’s disease undergoing autologous bone marrow transplantation (BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin’s disease, LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential cell counts performed twice per week. Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation LEUKINE is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization. Use in Bone Marrow Transplantation Failure or Engraftment Delay LEUKINE is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. LEUKINE has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay, no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF) score ≤ two (see CLINICAL EXPERIENCE). Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential performed twice per week. CONTRAINDICATIONS LEUKINE is contraindicated: 1) in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%); 2) in patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product; 3) for concomitant use with chemotherapy and radiotherapy. Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received LEUKINE and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without LEUKINE. The patients randomized to LEUKINE had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.11 WARNINGS Pediatric Use Benzyl alcohol is a constituent of liquid LEUKINE and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Fluid Retention Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies using LEUKINE at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention (LEUKINE vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed LEUKINE, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINE may aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has been reversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure. Sequestration of granulocytes in the pulmonary circulation has been Respiratory Symptoms documented following LEUKINE infusion12 and dyspnea has been reported occasionally in patients treated with LEUKINE. Special attention should be given to respiratory symptoms during or immediately following LEUKINE infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during LEUKINE administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. LEUKINE should be administered with caution in patients with hypoxia. Cardiovascular Symptoms Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of LEUKINE. LEUKINE should be used with caution in patients with preexisting cardiac disease. Renal and Hepatic Dysfunction In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of LEUKINE administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between LEUKINE (250 mcg/m2/day by 2-hour IV infusion) and placebotreated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during LEUKINE administration. PRECAUTIONS General Parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, LEUKINE therapy should immediately be discontinued and appropriate therapy initiated. A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of LEUKINE in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment. Stimulation of marrow precursors with LEUKINE may result in a rapid rise in white blood cell (WBC) count. If the ANC exceeds 20,000 cells/mm3 or if the platelet count exceeds 500,000/mm3, LEUKINE administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within three to seven days following cessation of LEUKINE therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts. Growth Factor Potential LEUKINE is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that LEUKINE can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics. Should disease progression be detected during LEUKINE treatment, LEUKINE therapy should be discontinued. LEUKINE has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolled studies without evidence of increased relapse rates.13, 14, 15 Controlled studies have not been performed in patients with MDS.
Use in Patients Receiving Purged Bone Marrow LEUKINE is effective in accelerating myeloid recovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to LEUKINE. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 x 104/kg), a beneficial effect of LEUKINE on myeloid engraftment has been reported.16 Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy In patients who before autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of LEUKINE on myeloid reconstitution may be limited. Use in Patients with Malignancy Undergoing LEUKINE-Mobilized PBPC Collection When using LEUKINE to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released and reinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied and the data are inconclusive. Information for Patients LEUKINE should be used under the guidance and supervision of a health care professional. However, when the physician determines that LEUKINE may be used outside of the hospital or office setting, persons who will be administering LEUKINE should be instructed as to the proper dose, and the method of reconstituting and administering LEUKINE (see DOSAGE AND ADMINISTRATION). If home use is prescribed, patients should be instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, drug product, and diluent. A puncture resistant container should be used by the patient for the disposal of used needles. Patients should be informed of the serious and most common adverse reactions associated with LEUKINE administration (see ADVERSE REACTIONS). Female patients of childbearing potential should be advised of the possible risks to the fetus of LEUKINE (see PRECAUTIONS, Pregnancy Category C). Laboratory Monitoring LEUKINE can induce variable increases in WBC and/or platelet counts. In order to avoid potential complications of excessive leukocytosis (WBC >50,000 cells/mm3; ANC >20,000 cells/mm3), a CBC is recommended twice per week during LEUKINE therapy. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least biweekly during LEUKINE administration. Body weight and hydration status should be carefully monitored during LEUKINE administration. Drug Interaction Interactions between LEUKINE and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of LEUKINE, such as lithium and corticosteroids, should be used with caution. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted with LEUKINE to evaluate the carcinogenic potential or the effect on fertility. Pregnancy (Category C) Animal reproduction studies have not been conducted with LEUKINE. It is not known whether LEUKINE can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. LEUKINE should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether LEUKINE is excreted in human milk. Because many drugs are excreted in human milk, LEUKINE should be administered to a nursing woman only if clearly needed. Pediatric Use Safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that LEUKINE does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with LEUKINE in clinical trials at doses ranging from 60-1,000 mcg/m2/day intravenously and 4-1,500 mcg/m2/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see WARNINGS). Geriatric Use In the clinical trials, experience in older patients (age ≥65 years), was limited to the acute myelogenous leukemia (AML) study. Of the 52 patients treated with LEUKINE in this randomized study, 22 patients were age 65-70 years and 30 patients were age 55-64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65-70 yrs) vs younger patients (55-64 yrs). Greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Autologous and Allogeneic Bone Marrow Transplantation LEUKINE is generally well tolerated. In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral blood progenitor cell transplantation, events reported in at least 10% of patients who received IV LEUKINE or placebo were as reported in Table 6. No significant differences were observed between LEUKINE and placebo-treated patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS). In addition, there was no significant difference in relapse rate and 24 month survival between the LEUKINE and placebotreated patients. In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients who received IV LEUKINE or placebo were as reported in Table 7. There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the LEUKINE and placebo-treated patients. Adverse events observed for the patients treated with LEUKINE in the historically-controlled BMT failure study were similar to those reported in the placebo-controlled studies. In addition, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with LEUKINE in the graft failure study. In uncontrolled Phase I/II studies with LEUKINE in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, and rash. Reports of events occurring with marketed LEUKINE include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities. In patients with preexisting edema, capillary leak syndrome, pleural and/or pericardial effusion, administration of LEUKINE may aggravate fluid retention (see WARNINGS). Body weight and hydration status should be carefully monitored during LEUKINE administration. Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients. Acute Myelogenous Leukemia Adverse events reported in at least 10% of patients who received LEUKINE or placebo were as reported in Table 8. Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between LEUKINE and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the LEUKINE group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the LEUKINE and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate. In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the LEUKINE treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two LEUKINE treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when LEUKINE was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).15 Antibody Formation Serum samples collected before and after LEUKINE treatment from 214 patients with a variety of underlying diseases have been examined for immunogenicity based on the presence of antibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving LEUKINE by continuous IV infusion (three patients) or subcutaneous injection (SC)(two patients) for 28 to 84 days in multiple courses. All five patients had impaired hematopoiesis before the administration of LEUKINE and consequently the effect of the development of anti-GM-CSF antibodies on normal hematopoiesis could not be assessed. Antibody studies of 75 patients with Crohn’s disease receiving LEUKINE by subcutaneous injection with normal hematopoiesis and no other immunosuppressive drugs showed one patient (1.3%) with detectable neutralizing antibodies. The clinical relevance of the presence of these antibodies are unknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of the therapeutic effect of LEUKINE secondary to formation of neutralizing antibody remain a theoretical possibility. Serious allergic and anaphylactoid reactions have been reported with LEUKINE but the rate of occurrence of antibodies in such patients has not been assessed. Overdosage The maximum amount of LEUKINE that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of LEUKINE. In case of overdosage, LEUKINE therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.
Percent of AuBMT Patients Reporting Events LEUKINE Placebo Events by Body System (n=79) (n=77) Body, General Fever 95 96 Mucous membrane disorder 75 78 Asthenia 66 51 Malaise 57 51 Sepsis 11 14 Digestive System Nausea 90 96 Diarrhea 89 82 Vomiting 85 90 54 58 Anorexia GI disorder 37 47 27 33 GI hemorrhage Stomatitis 24 29 Liver damage 13 14 Skin and Appendages 73 74 Alopecia Rash 44 38
LEUKINE Placebo Events by Body System (n=79) (n=77) Metabolic, Nutritional Disorder Edema 34 35 Peripheral edema 11 7 Respiratory System Dyspnea 28 31 Lung disorder 20 23 Hemic and Lymphatic System Blood dyscrasia 25 27 Cardiovascular System Hemorrhage 23 30 Urogenital System Urinary tract disorder 14 13 Kidney function abnormal 8 10 Nervous System 11 16 CNS disorder
Percent of Allogeneic BMT Patients Reporting Events LEUKINE Events by Body System (n=53) Body, General 77 Fever Abdominal pain 38 Headache 36 25 Chills Pain 17 Asthenia 17 Chest pain 15 Back pain 9 Digestive System Diarrhea 81 Nausea 70 Vomiting 70 62 Stomatitis Anorexia 51 Dyspepsia 17 Hematemesis 13 Dysphagia 11 11 GI hemorrhage 8 Constipation Skin and Appendages Rash 70 Alopecia 45 Pruritis 23 Musculo-skeletal System Bone pain 21 Arthralgia 11 Special Senses Eye hemorrhage 11 Cardiovascular System Hypertension 34 Tachycardia 11
Placebo (n=56) 80 23 36 20 36 20 9 18 66 66 57 63 57 20 7 7 5 11 73 45 13 5 4 0 32 9
LEUKINE Placebo Events by Body System (n=53) (n=56) Metabolic/Nutritional Disorders Bilirubinemia 30 27 Hyperglycemia 25 23 Peripheral edema 15 21 Increased creatinine 15 14 Hypomagnesemia 15 9 Increased SGPT 13 16 Edema 13 11 Increased alk. phosphatase 8 14 Respiratory System Pharyngitis 23 13 Epistaxis 17 16 Dyspnea 15 14 11 14 Rhinitis Hemic and Lymphatic System Thrombocytopenia 19 34 Leukopenia 17 29 6 11 Petechia Agranulocytosis 6 11 Urogenital System Hematuria 9 21 Nervous System 11 13 Paresthesia Insomnia 11 9 Anxiety 11 2 Laboratory Abnormalities* High glucose 41 49 27 36 Low albumin 23 17 High BUN Low calcium 2 7 High cholesterol 17 8
*Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratory measurements.
Percent of AML Patients Reporting Events LEUKINE Events by Body System (n=52) Body, General Fever (no infection) 81 Infection 65 37 Weight loss 8 Weight gain Chills 19 Allergy 12 Sweats 6 Digestive System Nausea 58 Liver 77 Diarrhea 52 Vomiting 46 Stomatitis 42 Anorexia 13 Abdominal distention 4 Skin and Appendages Skin 77 Alopecia 37
Placebo (n=47) 74 68 28 21 26 15 13 55 83 53 34 43 11 13 45 51
LEUKINE Placebo Events by Body System (n=52) (n=47) Metabolic/Nutritional Disorder Metabolic 58 49 Edema 25 23 Respiratory System Pulmonary 48 64 Hemic and Lymphatic System Coagulation 19 21 Cardiovascular System Hemorrhage 29 43 Hypertension 25 32 Cardiac 23 32 Hypotension 13 26 Urogenital System GU 50 57 Nervous System Neuro-clinical 42 53 Neuro-motor 25 26 Neuro-psych 15 26 Neuro-sensory 6 11
REFERENCES 11. Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colonystimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the southwest oncology group. JCO 1995; 13(7):1632-1641. 12. Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocyte-macrophage colonystimulating factor in cancer patients: A phase Ib clinical study. In Behring Institute Research Communications, Colony Stimulating Factors-CSF. International Symposium, Garmisch-Partenkirchen, West Germany. 1988; 83:107-118. 13. Estey EH, Dixon D, Kantarjian H, et al. Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with Ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1990; 75(9):1766-1769. 14. Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. NEJM 1987; 317:1545-1552. 15. Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte-macrophage colony stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78(5):1190-1197. 16. Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood 1989; 73(3):849-857. © 2008, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496. Licensed under Research Corporation Technologies U.S. Patent No. 5,602,007, and under Novartis Corporation U.S. Patent Nos. 5,942,221; 5,908,763; 5,895,646; 5,891,429; and 5,720,952. Manufactured by:
Bayer HealthCare Pharmaceuticals, LLC. Seattle, WA 98101 US License No. 1791
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higher among patients who received reminders than in those who did not, and the effect increased with age. Screening rates for patients of physicians who received electronic reminders and those who did not were similar. Electronic reminders did, however, tend to increase screening rates among patients who saw their primary care physician three or more times per year. Detection of adenomas increased with patient mailings (Arch Intern Med. 2009;169:364-371).
■ Targeted Therapies Used More Often Among Informed Patients Patients with colorectal cancer who search for health information on the Internet and in the news media are more likely to be aware of and receive the latest treatments for their disease. Researchers from the NCI Center of Excellence in Cancer Communication Research at the University of Pennsylvania Annenberg School used a retrospective analysis to determine if patient awareness of bevacizumab and cetuximab correlated to use of these drugs. Although they found an association between the two, patients did not always understand which treatments were appropriate or inappropriate. Given their findings, the researchers emphasized the importance of exploring patient influence on physician prescribing patterns and understanding the impact of information seeking on cancer outcomes (Gray SW, et al. Cancer. 2009;115:1424-1434).
■ Medicare Expands Coverage of PET Scans as Cancer Diagnostic Tools The Centers for Medicare & Medicaid Services (CMS) issued a final national coverage determination (NCD) to expand coverage for initial testing with positron-emission tomography (PET) for Medicare beneficiaries who are diagnosed with and treated for most solid tumor cancers. It also expands coverage of PET scans for subsequent follow-up testing in beneficiaries who have cervical or ovarian cancer, or who are being treated for myeloma. This NCD removes the clinical study requirement for PET scan use in patients with solid tumors. Since 2005, Medicare coverage of PET scans for diagnosing some forms of cancer and guiding treatment required that providers collect clinical information about how the scans have affected treatment decisions. It is important to note that the NCD still requires providers to report data when using PET scans to monitor the progress of treatment or remission of cancer in some cases. Currently, scientific evidence is not as strong in showing that PET scans are as useful in making subsequent treatment decisions for some types of cancer. More information about the types of cancer covered by this new policy is available in CMS’ final decision memorandum (www.cms.hhs.gov/mcd/viewdecision memo.asp?id=218). G REEN H ILL H EALTHCARE C OMMUNICATIONS
New Genomic Test May Help Personalize Breast Cancer Treatment John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute. He can be reached at email@example.com.
A set of 50 genes can be used to reliably identify the four known types of breast cancer, according to researchers at Washington University School of Medicine. By using this 50gene set it may be possible to predict the most effective therapy for each breast tumor type and thereby personalize breast cancer treatment for all patients. “Unlike a widely used genomic test that applies only to lymph-node–negative, estrogen receptor–positive breast cancer, this new genomic test is broadly applicable for all women diagnosed with breast cancer,” said Matthew Ellis, MD, PhD, a breast cancer specialist at the Siteman Cancer Center at Washington University School of Medicine, St. Louis, Missouri. “Our test is the first to incorporate a molecular profile for the basallike–type breast cancers. That’s important because these breast cancers are arguably the most aggressive, yet the most sensitive to chemotherapy. By identifying them, we can ensure they are treated adequately.” Breast cancer results from genetic abnormalities in breast tissue, but not all breast cancers have identical genetic alterations. Ellis and his colleagues have analyzed the gene activity of more than 1000 breast tumors to identify and validate the genetic signature of each of the four types of breast cancer. These tumor types have been previously defined and are known as luminal A,
luminal B, HER2-enriched, and basal-like. The latter three types are generally considered the types with a poor prognosis. Using this new 50-gene set test, the researchers studied how well 133 breast cancer patients responded to standard chemotherapy. They found that their genetic test was highly sensitive and very predictive of chemotherapy response. The test was more predictive than typically used clinical molecular markers, such as estrogen receptor status, progesterone receptor status, or HER2 gene expression status. The investigators found that luminal A was not sensitive to chemotherapy, suggesting that patients with this good-prognosis tumor type can forgo chemotherapy in favor of hormonebased therapy. Among the poor-prognosis tumor types, basal-like breast cancer was the most sensitive to chemotherapy and luminal B the least. “Luminal B tumors are a very poor prognosis group, and none of the current conventional therapies are particularly effective against it,” Ellis explained. “The ability to identify luminal B tumors accurately makes it possible to develop better therapies for this type.” Currently, there are more than 20 drugs available for treating breast cancer, and the researchers are now investigating how each tumor type responds to these drugs to help determine the best treatment for each.
MRI and PET/CT May Improve Chances for Optimal Therapy for Cervical Cancer Pretreatment magnetic resonance imaging (MRI) and positron- expensive. Further study of these long-term consequences is needemission tomography/computed tomography (PET/CT) for cervical ed to more precisely consider the cost implications of up-front MRI cancer may direct more women to optimal therapy choices and spare and PET/CT.” She said currently there are no specific guidelines that prescribe many women potential long-term morbidity and complications from trimodality therapy (surgery followed by chemoradiation), according to MRI or PET/CT for determining a plan of action for the treatment researchers at the Institute for Technology Assessment (ITA), Boston. of stage IB cervical cancer patients. They have developed a decision-analytic model to determine the value of pretreatment imaging with MRI and/or PET/CT in patients with FIGO stage IB cervical cancer (Pandharipande P, et al. AJR Am J Roentgenol. 2009;192:802-814). Some men taking folic acid supplements on 643 men who were randomly assigned to 1-mg “Stage IB cervical cancer, in the a daily basis may want to rethink it. A study by daily folic acid supplements or placebo absence of pretreatment imaging, is researchers at the University of Southern (Figueiredo J, et al. J Natl Cancer Inst. treated with surgery. As surgery cannot California (USC) has found that men who 2009;101:432-435). They found that the cancompletely resect the cancer in many of took a folic acid supplement of 1 mg daily had cer risk was 9.7% at 10 years for the men these patients, they receive postsurgical more than twice the risk of prostate cancer assigned to folate compared with just 3.3% in chemoradiation,” said lead study author compared with men who took a placebo. The men assigned to placebo. Pari Pandharipande, MD, an oncology finding comes from a secondary researcher at ITA. “The goal of pre“We know that adequate analysis of the Aspirin/ Folate treatment imaging is to identify these folate levels are important in Polyp Prevention (AFPP) patients noninvasively, spare them surthe prevention of several study, a placebo-controlled rangery, and have them treated with cancer types, and cardiovasdomized trial to determine the chemoradiation alone.” cular and neurological disShe said study results showed that impact of aspirin and folic acid eases. However, little has while imaging does not improve survival, on colon polyps in men and been known about its role in PET/CT resulted in the highest percentwomen who were at high risk prostate cancer,” said lead age of patients receiving correct primary for the disease. study author Jane Figueiredo, therapy (89%); also, use of both MRI and The AFPP study was conPhD, who is an assistant proPET/CT spared the most patients of triducted between 1994 and fessor of preventive medicine modality therapy (95%). 2006, and it found that aspirin at the Keck School of Med“Pretreatment imaging can triage reduced the risk of colon polyps icine at the University of patients to optimal primary treatment whereas folic acid has a negative effect and Southern California, Los Angeles. choices that minimize the risk of increased the risk of advanced and multiple Folic acid (folate) is a B vitamin found in long-term complications and morbidpolyps. The first analysis did not address the many vegetables, beans, fruits, and whole ity while preserving chances for surimpact of folic acid supplements on prostate grains. Its ability to reduce neural tube defects vival,” Pandharipande explained. cancer risk. Previous observational studies in infants when taken by the mother before or “MRI and PET/CT are expensive, but have been inconsistent. during pregnancy has been well documented. long-term consequences of trimodaliIn the secondary analysis, the researchers However, the effects of taking folate supplety therapy can severely affect longlooked at prostate cancer incidence among ments on other conditions are unclear. term quality of life and are also
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Folic Acid Supplements Linked to Higher Risk of Prostate Cancer
G REEN H ILL H EALTHCARE C OMMUNICATIONS
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For F or more more information, informa o tion,, call 866-478-8274 86 66-478-8274 or visit our website websitte at at www.totect.com w ww.ttotect.com for for full f prescribing prescribing information i ormation inf Visit V isit our exhibit exhiibit at the ONS Natio National nal Confer Conference C onference in SSan an A ntonio o, April April 30 3 - May 2, 2009 Antonio,
Mouridsen HT et al. al. Treatment Treatment of an anthracycline thracycline extravasation extravasation with savene savene ((dexrazoxane). dexrazoxane). Results frfrom om two two pr ospective clinic al multic entre studies nn OOncol ncol 2007; 18: :546-550. prospective clinical multicentre studies.. AAnn 18:546-550. Totect® Totect® pack package age inser insert.t. 2009 TopoTarget TopooTarget USA. All All rights rights rreserved. eserved. TTOT0077/02-09 OT0077/02-09 TTotect otect and its logo mark are are rregistered egistered tr trademarks ademarks of TTopoTarget opoTTarget USA, Inc Inc.,., Ro Rockaway, ckaway, NJ NJ,, USA. SA
To T o or order der T Totect®, o otect®, ccontact ontact one of our authoriz authorized orized distribut distributors: ors: ASSD Healthcare ASD Healthcare Cardinal Cardinal Specialt Specialty cialty McKesson/OTN McKesson/OTN Oncology Onccology Supply (800) (8 800) 746-6273 (866) 677-4844 844 (800) 482-6700 (800) (80 00) 633-7555
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Totect® – Brief prescribing information Please refer to the package insert for full prescribing information. Each Totect carton contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent. Indication: Treatment of extravasation resulting from IV anthracycline chemotherapy. Dosage and administration: Administration of Totect should begin as soon as possible and within 6 hours following the anthracycline extravasation. Totect should be given as an intravenous (IV) infusion once daily for 3 consecutive days. The dose of Totect is based on the patient’s body surface area: day one, 1000 mg/m2; day two, 1000 mg/m2; day three, 500 mg/m2. For patients with a body surface area of > 2 m2, a dose of 2000 mg should be given on days 1 and 2, and a dose of 1000 mg should be given on day 3. The Totect dose should be reduced 50% for patients with creatinine clearance values of <40 mL/minute. Cooling procedures such as ice packs should be removed from the affected area at least 15 minutes prior to Totect administration. Totect (dexrazoxane for injection) must be reconstituted with diluent, supplied in the carton. The patient’s Totect dose is diluted in 0.9% 1000 mL NaCl prior to administration. Contraindications: None known. Warnings: Pregnancy Category D. Dexrazoxane was toxic to pregnant rats at doses of 2 mg/kg (1/80 the human dose on a mg/m2 basis) and embryotoxic and teratogenic at 8 mg/kg when given daily during the period of organogenesis. Teratogenic effects in the rat included imperforate anus, microphthalmia, and anophthalmia. In offspring allowed to develop to maturity, fertility was impaired in the male and female rats treated in utero during organogenesis at 8 mg/kg. In rabbits, doses of 5 mg/kg daily during the period of organogenesis caused maternal toxicity and doses of 20 mg/kg were embryotoxic and terato-
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genic. Teratogenic effects in the rabbit included several skeletal malformations such as short tail, rib and thoracic malformations, and soft tissue variations including subcutaneous, eye and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the intermediate lobe of the lung. There is no adequate information about the use of Totect in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Precautions: Totect is a cytotoxic drug. When administered to patients receiving anthracycline-containing cytotoxic therapy, additive cytotoxicity may occur. Treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Reversible elevations of liver enzymes may occur. Blood counts and liver enzymes should be monitored. Greater exposure to dexrazoxane may occur in patients with compromised renal function. The Totect dose should be reduced by 50% in patients with creatinine clearance values <40 mL/min. Dimethyl sulfoxide (DMSO) should not be used in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation. Women who have the potential to become pregnant should be advised that Totect might cause fetal harm. There are no known drug interactions. No carcinogenicity studies have been done with Totect in animals. The carcinogenic potential of dexrazoxane has not been investigated. Long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in
Rx only Totect® is a registered trademark of TopoTarget A/S US Patent No. 6,727,253B2
NDC 38423-110-01 TOT0077/02-09 ©2009 TopoTarget USA
Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Hameln Pharmaceuticals GmbH 31789 Hameln Germany
mice. Dexrazoxane is mutagenic and clastogenic. The possible adverse effects of Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs. The effect of dexrazoxane on labor and delivery in humans has not been studied. It is not known whether dexrazoxane or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dexrazoxane, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The safety and effectiveness of Totect in pediatric patients have not been established. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older patients has been observed. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse reactions: Adverse reactions of nausea/vomiting, diarrhea, stomatitis, bone marrow suppression (neutropenia, thrombocytopenia), altered liver function (increased AST/ALT), and infusion site burning have been observed. These adverse reactions have been reversible.
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Single-surgery Lymph Node Biopsy Associated with Less Arm Morbidity in Breast Cancer Patients Canada. “When women are Hack and his colleagues receiving both surgeries and looked at predictor variables they’re not done concurrentsuch as surgery type, node dissecly, and there’s a delay, then tion type, stage of disease, presence of postoperative infections, they’re having more invasion body mass index (BMI), and to their lymph node area and partner status. The dependent more arm morbidity as a result.” variables included pain, funcHack, who presented the tional disability (of arm, shoulfindings, said that this study der, and hand), range of motion, should be of special interest to and lymphedema. breast oncology nurses, as Tom Hack, PhD The researchers found that they frequently counsel pain was significantly worse for women on arm problems after surgery. those who received both SNB and axil“These findings can better prepare them lary node dissection, as well as for those for advising patients about the risk fac- without a partner, those with stage III disease, and those with a high BMI. tors associated with the surgery.” In this multicenter study, a total of Functional disability was significant316 women (mean age, 54.3 years) with ly predicted by disease stage, postopera nonmetastatic primary diagnosis of ative infections, and BMI. Patients cancer were accrued from four Canadian who had a mastectomy and postoperacities. Patients were assessed 6 to 12 tive infections had significantly less months postsurgery. range of motion. Lymphedema was also
Education Crucial in Decreasing Barriers to Pain and Fatigue Management for Cancer Patients ORLANDO—Providing structured especially important for nurses to patient and professional education, keep in mind. “When it comes to along with a systems change inter- how they treat patients, for pain, vention, can lead to a lessening of they’ve got it down. But fatigue is pain and fatigue symptoms in tricky. There were a couple of openoncology patients, according to ended questions on our questiondata from a phase 2 trial presented naire and patients said things like, at the 2009 National Conference ‘Fatigue is anguish,’ and ‘Fatigue means I have no life.’ So I would on Cancer Nursing Research. While investigating specific barri- tell nurses to have patients not just rate their fatigue, but ask ers to pain and fatigue manthem: how does this affect agement, researchers noted your life? Ask what this 3 or that patients were especial8 out of 10 means because ly in need of information that is still objective.” In on ways to deal with addition, she stressed that fatigue. “Many patients in nurses should encourage this study were afraid to patients to exercise as much mention fatigue symptoms as they safely can. to their doctors because Borneman and her colthat would mean that leagues compared symptom they’re either a complainer, the treatment isn’t work- Tami Borneman, RN, management in 187 outpatient oncology patients ing, or their cancer is get- MSN, CNS experiencing pain and/or ting worse,” said Tami Borneman, RN, MSN, CNS, a sen- fatigue based on whether they ior research specialist/clinical nurse received usual care (n = 83) or the specialist with City of Hope, an preselected intervention (n = 104). NCI-designated Comprehensive Of these, 39% had breast cancer, Cancer Center in Duarte, Cali- 25% lung cancer, 21% colon cancer, fornia. “They also think that dealing and 16% prostate cancer. The intervention included a with fatigue is not nearly as important as dealing with cancer. They four-part patient education prodon’t realize that all these symptoms gram, professional education, and are part of taking care of them as a strategies to integrate symptoms management into routine oncolowhole person.” In an interview with The gy practice. Patients were assessed Oncology Nurse, she said that this is at baseline and 1 and 3 months
after the intervention. The intervention group had an immediate beneficial effect on anxiety, depression, and social support (P = .007, .006, and .048, respectively), compared with those who received usual care. In addition, barriers to pain management decreased significantly and knowledge of pain increased significantly in the intervention sample (P <.001), whereas knowledge of pain decreased in the usual care group. Although fatigue decreased significantly in those who received the intervention (P = .006-<.001), it often increased for those who received usual care. Plus, knowledge of fatigue increased significantly for the intervention group (P <.001), but fell in the usual care group. “We still deal with the same old pain issues, such as fear of addiction, and medication issues, such as around-the-clock dosing,” said Borneman. “With these and the fatigue issues, it’s just really important to help patients learn and to overturn their misconceptions.” She concluded, “The number one takeaway of this study is that you can make a difference for your patients.” —DB
significantly predicted by stage of disease, surgery type, dissection type (for the dual procedure and axillary node dissection alone), and BMI. “I’m hopeful that studies like ours and those of other researchers around the world will quicken the rate at which [SNBs] are taken up and considered the gold standard, as opposed to dual surgeries,” said Hack during an interview with The Oncology Nurse. “I think it’s really important to help reduce the morbidity that these women have so they can get back to living their lives.” “For all of us, it’s basically looking beyond just taking care of the immediate problem. It’s also realizing that we want to get these patients back to having the quality of life that they had before,” he concluded. —Deborah Brauser
New Palliative Care Intervention Improved Survival and Quality of Life for Advanced Cancer Patients ORLANDO—Findings from the Educate, Nurture, Advise Before Life Ends (ENABLE) II randomized trial showed a survival increase of almost 6 months and improved quality of life (QOL) when palliative care was introduced upon diagnosis of life-limiting cancer. These results were presented at the 2009 National Conference on Marie Bakitas, DNSc, ARNP, FAAN Cancer Nursing Research. “We clearly found that the introduction of palliative care at the time of a diagnosis is feasible, advisable, and can only benefit these patients,” said coinvestigator Marie Bakitas, DNSc, ARNP, FAAN, who is a research assistant professor in the Section of Palliative Medicine at the Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, in an interview with The Oncology Nurse. In this study, Bakitas and her colleagues evaluated quality of life, mood, symptom intensity, and survival in an advanced practice nurse–led, early identification, psycho-educational intervention, which was based on the World Health Organization continuum of palliative care model. Following informed consent, 322 patients Continued on page 14
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ORLANDO—Patients with breast cancer experience significantly greater arm morbidity after receiving axillary node dissection, both alone and with sentinel lymph node biopsy (SNB) surgeries, compared with those who receive SNB alone, according to a new Canadian study presented at the 2009 National Conference on Cancer Nursing Research. While evaluating demographics, disease, and treatment-related predictors of arm morbidity, the researchers found that pain and lymphedema were both significantly increased for those who received dual (SNB and axillary node dissection) surgeries. “We need to facilitate the adoption of [SNB] procedures only,” said study investigator Tom Hack, PhD, an associate professor with the Faculty of Nursing/Cancer Nursing Research at the University of Manitoba, Winnipeg,
Conference News Continued from page 13
New Palliative Care Intervention continued
with newly diagnosed advanced gastrointestinal (41%), lung (36%), genitourinary (12%), or breast (10%) cancer were randomized to either an intervention (INV) or usual care (UC) group. The mean age of all group members was 65 years, with 58% of them men. The study intervention consisted of four weekly educational sessions focused on problem-solving, communication, symptom management, and advance care planning plus monthly follow-up calls. The researchers used the Functional Assessment of Chronic Illness Therapy-Palliative (FACIT-Pal), Center for Epidemiological StudiesDepression (CES-D), and Edmonton Symptom Assessment Scale (ESAS) at baseline, 1 month after diagnosis, and then every 3 months until death. Survival was determined using KaplanMeier analysis, while the hazard ratio was estimated using the Cox proportional hazards model. Patients in the INV group experienced both higher QOL (FACIT-Pal 7 months P <.01; 10 months P = .03; predeath P = .002) and mood (CES-D 7 months P = .03; 10 months P = .06; predeath P <.001) than those in the UC group. However, the ESAS differed only at 1 month after baseline (P = .3). The INV group also had longer survival at 14.0 months versus 8.5 months for the UC group. The estimated hazard ratio for those in INV versus UC was 0.71 (P = .026) for up to 1 year after enrollment. “The interesting thing is we were not attempting to influence survival,” Bakitas explained. “So this was a surprising outcome. And we have a lot more work to do to figure out what the reason is for such a huge difference in survival between those two groups. As one of our oncologists said, there isn’t a chemo drug out there that increases survival by up to 6 months for this type of patient. So we need to figure out exactly what we have here.” —DB
Increased Pain Found in Advanced Cancer Patients with Both Anxiety and Depression Patients with both anxiety and depression have the highest level of pain, followed by those with depression only, and then those with anxiety alone.
ORLANDO—Patients with advanced cancer with both anxiety and depression experience greater pain than those who have either mood symptom alone, according to a study presented at the 2009 National Conference on Cancer Nursing Research. The investigators found that patients with both mood disturbances also had increased interference in their typical activities. “With 44% of our study patients reporting both anxiety and depression, oncology nurses have to be aware of this co-occurrence and not just look for one or the other,” said Inger Utne, RN, Cand San, Dipl EEd, assistant professor, Faculty of Nursing Research and Development Unit, Oslo University College, Norway. “We need to look at the impact this causes and then develop appropriate interventions to manage these symptoms.” Utne, who presented the findings at this meeting, said that though mood disturbances and pain are highly prevalent symptoms in patients with advanced cancer, little is known about the pain effects from having both mood disorders at the same time. The purpose of this study was to examine the differences in pain severity, pain’s interference with Inger Utne, RN, Cand normal activities, and quality of life San, Dipl EEd (QOL) in oncology patients categorized into separate mood groups. A total of 225 Norwegian patients receiving regularly scheduled opioid treatment for cancer pain were enrolled. Based on their answers from the Symptom Severity Checklist, the patients were placed into one of four mood groups: those experiencing anxiety only (A, 12.0%), depression only (D, 12.4%), both anxiety and depression (A + D, 44.0%), or neither anxiety nor depression (NA/ND, 31.6%). Other patient-reported instruments included the
Brief Pain Inventory (BPI) and the European Organization for Research and Treatment of Cancer QLQ-C30. The researchers found that younger patients and women were more likely to report having both mood symptoms. In addition, while only minimal differences were found among the four mood groups on pain intensity scores, significant differences were found on all of the BPI interference items, except walking ability and daily activity. For four of the other six items evaluated (mood, work relations, sleep, and enjoyment of life), patients in the A + D and D groups reported significantly higher interference scores than those in the NA/ND or A groups (all groups, P <.05). In the QOL category, patients in the NA/ND group reported significantly higher emotional and social function, and those in the A group reported significantly higher emotional functioning compared with patients in the A + D group. Patients in the A + D group reported significantly poorer overall QOL scores. “The takeaway is that patients with both anxiety and depression have the highest level of pain, followed by those with depression only, and then those with anxiety alone,” said Utne. She concluded, “I think the next step is the development of interventions.” —DB
Diagnosis a Predictor of Altered Time Perception for Patients Using Virtual Reality During Chemotherapy CONFERENCE NEWS
ORLANDO—When using virtual re- cost-effective intervention that can ality (VR) as a distraction during chem- make chemotherapy treatments more otherapy, a patient’s diagnosis can be the tolerable,” said the studies’ lead investigator Susan Schneider, RN, greatest influence on their time PhD, AOCN, who is a direcperception, according to a sector and associate professor at ondary analysis study presented Duke University School of here at the 2009 National ConNursing, Durham, North ference on Cancer Nursing Carolina. Research. For the new study, investiIn three previous studies, gators reexamined the data researchers demonstrated a sigfrom the previous studies to nificant elapsed time compresexplore which factors influsion for patients using headenced the effectiveness of VR mounted VR devices during chemotherapy. “From that re- Susan Schneider, RN, as a distraction. With a sample size of 137 participants, search, we know that VR is an innovative, noninvasive, and PhD, AOCN the researchers evaluated age, 14
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We know that VR is an innovative, noninvasive, and cost-effective intervention that can make chemotherapy treatments more tolerable. sex, state of anxiety, fatigue, and diagnosis in predicting the difference, in minutes, between the actual elapsed time of chemotherapy versus the time patients thought they were receiving treatment while immersed in a VR scenario. Because two of the three previous studies included only breast cancer patients,
that diagnostic group had the most subjects (66.4%), with colon cancer (13.1%) and lung cancer (20.5%) patients completing the study population. The total sample had a mean age of 52.4 years, with 81.7% women. Continued on page 18
Patient Support Coordinator Program A dedicated, central point of contact helping providers and patients who rely on Celgene products Trained professionals providing personal assistance concerning: • Reimbursement assistance, insurance claims, and appeals • Medicare Issues • Locating co-pay assistance programs and services • Identifying pharmacies that are registered to dispense Celgene products • Determining the status of a prescription • Inquiries regarding Celgene’s patient assistance program • Providing information regarding Celgene products and their restricted distribution programs (RevAssist ® or S.T.E.P.S.®) or appropriate contacts for other questions
To contact a PSC: Call 1-800-931-8691 Email firstname.lastname@example.org Fax 1-800-822-2496 www.CelgenePSC.com Available to answer questions Monday – Friday from 8:00 AM to 7:00 PM ET RevAssist® S.T.E.P.S.®, Patient Support Coordinator®, and PSC® are registered trademarks of Celgene Corporation. © 2008 Celgene Corporation
Nurse Navigator at Helm Continued from cover
trointestinal Cancers Symposium by nurse navigator Nicole Messier, RN, along with Laurence E. McCahill, MD, associate professor of surgery at the University of Vermont, Burlington. The Upper GI Cancer Multidisciplinary Program at the Vermont Cancer Center has three key components: (1) a multidisciplinary clinic comprised of gastroenterologists, pathologists, radiologists, and medical, radiation, and surgical oncologists; (2) a treatment planning conference (which takes the place of traditional “tumor boards”) that meets three times a month, immediately prior to the clinic, and is attended by the above physicians; and (3) a dedicated subspecialty cancer nurse navigator. The structured approach to the management of patients with pancreatic, esophageal, gastric, liver, and biliary tract cancers has allowed for more timely evaluation and treatment in a highly coordinated fashion, thanks mainly to the nurse navigator. The Institute of Medicine has reported that the delivery of cancer care in this country is often quite poor. In some parts of Europe, by contrast, a more focused multidisciplinary approach that revolves around a coordinating nurse has been shown to facilitate assessment and evidence-based treatment, McCahill noted in an interview with The Oncology Nurse. “In the public health system in the United Kingdom, patients must be seen within 2 weeks of their diagnosis. At Vermont Cancer Center, we are trying to move toward that model,” he said. Messier, who has experience in both inpatient oncology nursing as well as general surgical oncology nursing, said that before initiating the program, “It was not uncommon to see patients who were diagnosed 6 weeks earlier just coming in to discuss surgery. It took weeks to complete imaging studies and all appropriate consultations because so many different people were involved. “We saw that the nurse navigator program was working well for the breast cancer program, and Dr McCahill asked, ‘Why can’t we do that for our GI cancer patients?’” The two not only got the program up and running, but took it a step further by providing outcomes data to demonstrate its worth. “We are measuring everything we do,” McCahill added, which he anticipates will be part of an emerging mandate to meet benchmarks of quality cancer care.
At the center of care: dedicated nurse navigator Messier is responsible for coordinating all aspects of the patient’s medical care and for serving as a patient educator and advocate. She starts by obtaining the patient’s history and medical records, which she uses for the initial determination of the disease stage, and scheduling diagnostic tests. “We follow NCCN [National Comprehensive Cancer Network] guidelines to make
Table. Comparison of Outcomes by Treatment Period Group 1 (N = 78)
Group 2 (N = 55)
Staging evaluation (days) Days to last pretreatment visit Days until first cancer treatment
7.9 21.1 25.2
11.3 24.3 32.3
.07 .39 .05
Treatment planning conference
See all physicians in single day Number of pretreatment hospital/clinic visits
sure we are working up the patient appropriately, and not ordering inappropriate tests or overutilizing radiology services,” she added. She then books appointments—attempting to have patients complete several visits in 1 day—and organizes the treatment planning conference, all before the patient is seen by the first and most appropriate physician (which she determines). “Initial testing and consults are accomplished within 2 weeks of my first contact with the patient, and treatment is initiated within 30 days. We are trying to tighten this up even more,” Messier said. She also serves as a liaison with the patient throughout the diagnostic and treatment course, transitions the patient from postoperative to outpatient care, and coordinates postoperative visits. “The patients have me to look out for the loose ends, and to keep things moving smoothly. They have their oncologists and their surgeons and their primary nurses to deal with the nitty-gritty, but I am always in the background, looking at the whole picture,” she said.
Cancer Center, Nashville, Tennesse commented that having a nurse navigator to coordinate multidisciplinary care is especially valuable in GI oncology. “Many patients come for a second opinion and have already had tests done. Getting the correct data on them is important, which nurse navigators can do. They also can ensure that patients see the right subspecialist first, which in GI oncology is not always the case. Patients are often scheduled to see the medical oncologist when what they really need is the surgeon.”
The numbers prove it McCahill and Messier evaluated the impact of this new approach on the efficiency of healthcare by comparing patients referred during the first 6 months of the new program (Group 1), with those treated under the traditional system (Group 2). Patients seen within the multidisciplinary program had significantly shorter time between their first visit and initiation of treatment, required significantly fewer hospital or clinic visits prior to treatment, and were significantly more likely to receive a multidisciplinary evaluation (Table). Commenting on the increase in patient numbers, McCahill said, “I think patients sense that we have coordinated care here. And once they come, they really like the fact that they are not coming in for an average of six visits before treatment, but more like three visits. That is a really big change.” “A lot of our patients travel over 2 ½ hours to come here,” added Messier, “so this is very important to them.” Running the program requires tremendous organization on her part, she acknowledged. “I have developed strategies to keep my patients organized, and it is not only for current patients but those who have finished treatment and still call me. Close to 300 patients have my phone number!”
“Initial testing and consults are accomplished within 2 weeks of my first contact with the patient, and treatment is initiated within 30 days.”
Physicians’ jobs made easier Richard Zubarik, MD, chief of endoscopy, said the new program has not only streamlined patient care, moving it beyond an ad hoc situation, but also has improved communication and collaboration between the physicians involved in the care. “I am on the front end of putting the patients into the system. After I receive referrals from the primary physician, I hand the patient over to the nurse navigator to arrange everything else. Because of her, at the planning conference we have all the data
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we need when we discuss the case,” he said. He also thanks Messier for updating the referring physician—formerly his responsibility. Messier has observed that her efforts and the collaboration that occurs during the planning conference make patient care simpler for all providers. “Before, physicians were always paging each other about the patients. It was very inefficient,” she said. Jordan Berlin, MD, clinical director of GI Oncology at Vanderbilt-Ingram
STRONG. FROM THE START.
HELP ESTABLISH A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When your patients experience acute chemotherapy-induced nausea and vomiting (CINV) during their ﬁrst cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3
ALOXI®: Starts strong to prevent CINV4 A single IV dose lasts up to 5 days after MEC4,5* Can be used with multiple-day chemotherapy regimens6† * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.
ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy. Important Safety Information ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. Most commonly reported adverse reactions include headache (9%) and constipation (5%). Please see the following brief summary of prescribing information. REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapyinduced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved Prevention of Moderately Emetogenic Chemotherapy-induced Nausea and Vomiting with Palonosetron, a Pharmacologically Novel 5-HT3 Receptor Antagonist: Results of a Phase III, Single-Dose Trial Versus Dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.
ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2008 Eisai Inc. All rights reserved. Printed in USA. AL348 A 10/08
Conference News Continued from page 14
Diagnosis a Predictor of Altered Time Perception continued The results showed that diagnosis was the strongest predictor of altered time perception. Schneider reported that the average mean time difference was 17 minALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE
Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates reported in practice. In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and ﬂatulence.
utes for all patients, 23 minutes for those with breast cancer, 12 minutes for patients with colon cancer, and 3.5 minutes for those with lung cancer. Age and sex were not significant
factors, while anxiety had a slight influence. Schneider said that results of the current study are consistent with those of other studies. “Breast cancer patients are
General: 1%: weakness, < 1%: fatigue, fever, hot ﬂash, ﬂu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte ﬂuctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Postmarketing Experience The following adverse reactions have been identiﬁed during postapproval use of ALOXI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting. DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically signiﬁcant drug interactions with palonosetron appears to be low. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not signiﬁcantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no signiﬁcant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the ﬁve chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efﬁcacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efﬁcacy in geriatric patients has not been adequately evaluated. Renal Impairment Mild to moderate renal impairment does not signiﬁcantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. Hepatic Impairment Hepatic impairment does not signiﬁcantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg ﬁxed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information]. • Patients should be instructed to read the patient insert.
G REEN H ILL H EALTHCARE C OMMUNICATIONS
Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.
ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2008 Eisai Inc. All rights reserved. Printed in USA. AL350 10/08
often more open to various distractions and guided imagery.” Lung cancer patients, she said, may not be as distractible “because they’re the ones displaying the most symptoms. They may just be too sick to participate in something like this.” She cited concerns with the study’s retrospective design, as well as the large percentages of breast cancer patients and women. “However, gender was not a significant factor in the regression model,” she said. In an interview with The Oncology Nurse, Schneider said that VR should be viewed as one more tool in the toolbox of distractions. “I’m not sold that it has to be VR that helps people out,” she said. “Maybe a book, or movie, or music would work. So I think we should look at individual factors and tailor interventions to individual needs. And VR is one of those options.” She continued, “When I started looking at virtual reality 10 or 12 years ago, it seemed pretty bizarre to others. But people are more comfortable with technology now. I’m finding that VR is starting to be more acceptable and people are starting to use it more clinically.” —DB Continued on page 36
Approvals • Everolimus for Advanced Renal Cell Cancer
The US Food and Drug Administration has approved everolimus (Affinitor, Novartis) for treatment of advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Approval was based on the results of a phase 3 trial, which showed that compared with placebo, everolimus more than doubled the time without tumor growth or death (4.9 vs 1.9 months) and reduced the risk of disease progression or death by 67%. The trial also showed that approximately 25% of patients had no tumor growth after 10 months of treatment. Everolimus inhibits mammalian target of rapamycin, a protein that controls tumor cell division and blood vessel growth.
Spotlight on NexConnect™ An interview with Beth Manchen, RN, MS, OCN University of Chicago Medical Center, Illinois
What is the NexConnect program? NexConnect is a program sponsored by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals for patients with liver or kidney cancer who are taking their oral multiple kinase inhibitor sorafenib. It is manned by nurses and serves as a sort of extension of the clinic nurses by providing educational materials for patients. Let me explain how it works. Patients who are starting on sorafenib fill out a form (available online www. nexavar-us.com) that includes the prescription and insurance information. If their insurance doesn’t cover it or if there are issues about getting the coverage, the REACH® (Resources for Expert Assistance and Care Helpline) program, which is another arm of the NexConnect, will do all the research into getting the authorization or patient assistance for the nurse in the clinic. Unless the patient checks a box on the application opting out of the NexConnect program, a nurse will call the patient and provide information about the drug and the side effects that he or she may experience. This information reinforces what the patient has heard from the clinic nurse or other healthcare provider. When the drug is ready to ship, written material is included in the package too. There’s a patient starter kit, which includes lotions, a pill dispenser box, pamphlets on side effect management, and a drug calendar with which the patients can keep track of any side effects. This might seem like overload, but I think patients and their caregivers get a lot of benefit from it. Why do patients need the support and guidance of NexConnect during the first 30 days of therapy? Side effects, such as hand-foot skin
reaction, high blood pressure, and skin rashes, usually occur within the first 6 weeks of therapy. The NexConnect nurse will call the patient on programmed days—at days 10, 17, and 28 and ask about side effects he or she is experiencing. If there is a problem, the
NexConnect nurse will advise the patient to call his or her healthcare provider. NexConnect nurses triage and offer suggestions on the management of the side effects for the patient, but the total management is left in the healthcare provider’s hands.
The program provides valuable reinforcement of the information patients get from the clinic staff. They get printed educational materials, which complement the information the nurse provides. Continued on page 20
In moderate-risk* chemotherapy regimens
Start every cycle with confidence by helping reduce the risk of febrile neutropenia
Neulasta® is given once per chemotherapy cycle and should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Important Safety Information Splenic rupture (including fatal cases), acute respiratory distress syndrome, and sickle cell crises have been reported. Allergic reactions, including anaphylaxis, have also been reported. The majority of these reactions occurred upon initial exposure. However, in rare cases, allergic reactions, including anaphylaxis, recurred within days after discontinuing anti-allergic treatment. In a placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta®-treated patients as compared to placebotreated patients (31% vs. 26%). The most common adverse events reported in either placebo- or active-controlled trials were consistent with the underlying cancer diagnosis and its treatment with chemotherapy, with the exception of bone pain. Please refer to brief summary of Neulasta® Prescribing Information. © 2009 Amgen. All rights reserved. MC45637 03-09 Class I www.neulasta.com
PATIENT SUPPORT PROGRAMS
iven the complexity and cost of many cancer therapies, major pharmaceutical companies offer patient assistance programs to help patients take their medications properly, prevent and manage side effects, and deal with insurance and reimbursement issues. This series will profile the patient assistance programs offered for various cancer drugs to familiarize nurses with the available resources for themselves and their patients. In this interview, Beth Manchen, RN, MS, OCN, research nurse associate in the Genitourinary Oncology division at the University of Chicago Medical Center, Illinois, discusses her experience in referring her patients with renal cell cancer to Bayer HealthCare Pharmaceuticals’ and Onyx Pharmaceuticals’ NexConnect program for patients taking sorafenib (Nexavar).
PATIENT SUPPORT PROGRAMS
Patient Support Programs
Consequences of febrile neutropenia, such as hospitalization, may impact patient care ■ In a prospective registry study (N = 2,692), febrile neutropenia affected more than 1 in 10 patients overall (10.7%) in the first 3 cycles of chemotherapy in select tumor types.1
First- and subsequent-cycle Neulasta® achieved significant results in patients receiving moderate-risk* regimens: ■ 94% reduction in febrile neutropenia vs. placebo (17% vs. 1%).2,3 ■ 93% reduction in febrile neutropenia–related hospitalization vs. placebo (14% vs. 1%).2,3 *Regimens associated with ≥ 17% risk of febrile neutropenia.
Start with support
G REEN H ILL H EALTHCARE C OMMUNICATIONS
PATIENT SUPPORT PROGRAMS
Spotlight on NexConnect Continued from page 19
What role does the oncology nurse counselor play in the NexConnect program? I find that patients are often hesitant to bother their nurse. Beth Manchen, The program counRN, MS, OCN selors provide another ear that the patient can turn to with problems and questions. Taking care of patients nowadays
and making sure they continue on their therapy is a team effort that requires collaboration by the patient, the healthcare staff, dietary counselors, and others. The nurse counselor is another team member who can contribute to this effort.
Do you find the patient support materials helpful and are the mailings/outreach calls timed to reach patients during critical periods in their therapy? Yes, I do. As I mentioned, patients receive calls at 10, 17, and 28 days, which are critical times in the treat-
ment. If a patient is experiencing a side effect, the nurse counselor will explain that the problem can be treated, refer the patient to the handouts and mailings provided, such as the booklet on managing skin toxicities, give little tricks of the trade to help him or her stay on treatment, and encourage the patient to call his or her healthcare provider.
I view it as an extension of me. The counselors can tease out the potential dose-limiting side effects before they get out of hand because they are proactive in making the phone calls at predetermined dates. They give patients advice right then and there and encourage them to follow up with their healthcare providers.
How helpful is the NexConnect program in educating your patients about their sorafenib therapy and managing side effects?
Are your patients in NexConnect more likely to take their sorafenib therapy as directed compared with patients not in the program? I don’t know if there is a difference between taking it as directed, but, anecdotally, it does seem that they have a tendency to stay on the drug longer because we are able to capture bothersome side effects earlier and treat them before they get out of hand. This avoids having to reduce doses or withhold the drug.
References: 1. Crawford J, et al. J Natl Compr Canc Netw. 2008;6:109-118. 2. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 3. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen.
Start with support
PATIENT SUPPORT PROGRAMS
BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. CONTRAINDICATIONS Neulasta is contraindicated in patients with known hypersensitivity to E coli-derived proteins‚ pegfilgrastim‚ Filgrastim, or any other component of the product. WARNINGS General The safety and efficacy of Neulasta for peripheral blood progenitor cell (PBPC) mobilization has not been evaluated in adequate and well-controlled studies. Neulasta should not be used for PBPC mobilization. Splenic Rupture SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEULASTA AND ITS PARENT COMPOUND, FILGRASTIM. PATIENTS RECEIVING NEULASTA WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE. Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) has been reported in patients receiving Neulasta, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving Neulasta who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Neulasta should be discontinued and/or withheld until resolution of ARDS and patients should receive appropriate medical management for this condition. Allergic Reactions Allergic reactions to Neulasta, including anaphylaxis, skin rash, urticaria, and erythema/flushing have been reported in postmarketing experience. The majority of reported events occurred upon initial exposure. In some cases, symptoms recurred with rechallenge, suggesting a causal relationship. In rare cases, allergic reactions including anaphylaxis, recurred within days after initial anti-allergic treatment was discontinued. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Neulasta should be permanently discontinued in patients with serious allergic reactions. Sickle Cell Disorders Severe sickle cell crises have been associated with the use of Neulasta in patients with sickle cell disorders. Severe sickle cell crises, in some cases resulting in death, have also been associated with Filgrastim, the parent compound of pegfilgrastim. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe Neulasta for such patients, and only after careful consideration of the potential risks and benefits. PRECAUTIONS General Use With Chemotherapy and/or Radiation Therapy Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see DOSAGE AND ADMINISTRATION) because of the potential for an increase in sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy. The use of Neulasta has not been studied in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas, mitomycin C). The administration of Neulasta concomitantly with 5-fluorouracil or other antimetabolites has not been evaluated in patients. Administration of pegfilgrastim at 0, 1, and 3 days before 5-fluorouracil resulted in increased mortality in mice; administration of pegfilgrastim 24 hours after 5-fluorouracil did not adversely affect survival. The use of Neulasta has not been studied in patients receiving radiation therapy. Potential Effect on Malignant Cells Pegfilgrastim is a growth factor that primarily stimulates neutrophils and neutrophil precursors; however, the G-CSF receptor through which pegfilgrastim and Filgrastim act has been found on tumor cell lines, including some myeloid, T-lymphoid, lung, head and neck, and bladder tumor cell lines. The possibility that pegfilgrastim can act as a growth factor for any tumor type cannot be excluded. Use of Neulasta in myeloid malignancies and myelodysplasia (MDS) has not been studied. In a randomized study comparing the effects of the parent compound of Neulasta, Filgrastim, to placebo in patients undergoing remission induction and consolidation chemotherapy for acute myeloid leukemia, important differences in remission rate between the two arms were excluded. Disease-free survival and overall survival were comparable; however, the study was not designed to detect important differences in these endpoints.* Information for Patients Patients should be informed of the possible side effects of Neulasta and be instructed to report them to the prescribing physician. Patients should be informed of the signs and symptoms of allergic drug reactions and be advised of appropriate actions. Patients should be counseled on the importance of compliance with their Neulasta treatment, including regular monitoring of blood counts. If it is determined that a patient or caregiver can safely and effectively administer Neulasta (pegfilgrastim) at home, appropriate instruction on the proper use of Neulasta (pegfilgrastim) should be provided for patients and their caregivers, including careful review of the “Information for Patients and Caregivers” insert. Patients and caregivers should be cautioned against the reuse of needles, syringes, or drug product, and be thoroughly instructed in their proper disposal. A puncture-resistant container for the disposal of used syringes and needles should be available. Laboratory Monitoring To assess a patient’s hematologic status and ability to tolerate myelosuppressive chemotherapy, a complete blood count and platelet count should be obtained before chemotherapy is administered. Regular monitoring of hematocrit value and platelet count is recommended. Drug Interaction No formal drug interaction studies between Neulasta and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils;
patients receiving lithium and Neulasta should have more frequent monitoring of neutrophil counts. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential of pegfilgrastim has not been evaluated in long-term animal studies. In a toxicity study of 6 months duration in rats given once weekly subcutaneous injections of up to 1000 mcg/kg of pegfilgrastim (approximately 23-fold higher than the recommended human dose), no precancerous or cancerous lesions were noted. When administered once weekly via subcutaneous injections to male and female rats at doses up to 1000 mcg/kg prior to, and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected. Pregnancy Category C Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when administered subcutaneously every other day during gestation at doses as low as 50 mcg/kg/dose (approximately 4-fold higher than the recommended human dose). Decreased maternal food consumption, accompanied by a decreased maternal body weight gain and decreased fetal body weights were observed at 50 to 1000 mcg/kg/dose. Pegfilgrastim doses of 200 and 250 mcg/kg/dose resulted in an increased incidence of abortions. Increased post-implantation loss due to early resorptions was observed at doses of 200 to 1000 mcg/kg/dose, and decreased numbers of live rabbit fetuses were observed at pegfilgrastim doses of 200 to 1000 mcg/kg/dose, given every other day. Subcutaneous injections of pegfilgrastim of up to 1000 mcg/kg/dose every other day during the period of organogenesis in rats were not associated with an embryotoxic or fetotoxic outcome. However, an increased incidence (compared to historical controls) of wavy ribs was observed in rat fetuses at 1000 mcg/kg/dose every other day. Very low levels (< 0.5%) of pegfilgrastim crossed the placenta when administered subcutaneously to pregnant rats every other day during gestation. Once weekly subcutaneous injections of pegfilgrastim to female rats from day 6 of gestation through day 18 of lactation at doses up to 1000 mcg/kg/dose did not result in any adverse maternal effects. There were no deleterious effects on the growth and development of the offspring and no adverse effects were found upon assessment of fertility indices. There are no adequate and well-controlled studies in pregnant women. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Nursing Mothers It is not known whether pegfilgrastim is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised when Neulasta is administered to a nursing woman. Pediatric Use The safety and pharmacokinetics of Neulasta were studied in 37 pediatric patients with sarcoma. The mean (± Standard Deviation) systemic exposure (AUC 0-inf) of Neulasta after subcutaneous administration at 100 mcg/kg was 22.0 (±13.1) mcg·hr/mL in the 6–11 years age group (n = 10), 29.3 (±23.2) mcg·hr/mL in the 12–21 years age group (n = 13) and 47.9 (±22.5) mcg·hr/mL in the youngest age group (0–5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (±11.3) hours, 21.2 (±16.0) hours and 30.1 (±38.2) hours, respectively. The most common adverse reaction was bone pain. The 6 mg fixed dose single-use syringe formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. ADVERSE REACTIONS (See WARNINGS, Splenic Rupture, Acute Respiratory Distress Syndrome (ARDS), Allergic Reactions, and Sickle Cell Disorders.) Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Neulasta cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to Neulasta use and for approximating rates. The data described below reflect exposure to Neulasta in 932 patients. Neulasta was studied in placebo- and active-controlled trials (n = 467, and n = 465, respectively). The population encompassed an age range of 21 to 88 years. Ninety-two percent of patients were female. The ethnicity of the patients was as follows: 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with solid tumors (breast [n = 823], lung and thoracic tumors [n = 53]) or lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. In the placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta-treated patients as compared to placebo-treated patients. The incidence of other commonly reported adverse events were similar in the Neulasta- and placebo-treated patients, and were consistent with the underlying cancer diagnosis and its treatment with chemotherapy. The data in Table 1 reflect those adverse events occurring in at least 10% of patients treated with Neulasta in the placebo-controlled study. Table 1. Adverse Events Occurring in ≥ 10%a of Patients in the Placebo-Controlled Study Event Alopecia Bone Painb Diarrhea Pyrexia (not including febrile neutropenia) Myalgia Headache Arthralgia Vomiting Asthenia Peripheral Edema Constipation
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Neulasta (n = 467) 48% 31% 29%
Placebo (n = 461) 47% 26% 28%
21% 16% 16% 13% 13% 12% 10%
18% 14% 13% 11% 11% 10% 6%
Events occurring in ≥ 10% of Neulasta-treated patients and at a higher incidence as compared to placebo-treated patients Bone pain is limited to the specified adverse event term “bone pain”
In the active controlled studies, common adverse events occurred at similar rates and severities in both treatment arms (Neulasta, n = 465; Filgrastim, n = 331). These adverse experiences occurred at rates between 72% and 15% and included: nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever. Bone Pain The analysis of bone pain described below is based on a composite analysis using multiple, related, adverse event terms. In the placebo-controlled study, the incidence of bone pain was 57% in Neulasta-treated patients compared to 50% in placebo-treated patients. Bone pain was generally reported to be of mild-to-moderate severity. Among patients experiencing bone pain, approximately 37% of Neulasta-and 31% of placebo-treated patients utilized non-narcotic analgesics and 10% of Neulasta- and 9% of placebo-treated patients utilized narcotic analgesics. In the active-controlled studies, the use of non-narcotic and narcotic analgesics in association with bone pain was similar between Neulasta-and Filgrastimtreated patients. No patient withdrew from study due to bone pain. Laboratory Abnormalities In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. Leukocytosis was not associated with any adverse effects. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Cytopenias resulting from a neutralizing antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia. This has not been observed in clinical studies of Neulasta. Postmarketing Experience The following adverse reactions have been identified during postapproval of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • splenic rupture (see WARNINGS: Splenic Rupture) • acute respiratory distress syndrome (ARDS) (see WARNINGS: Acute Respiratory Distress Syndrome) • allergic reactions (including anaphylaxis, skin rash, urticaria, erythema/flushing) (see WARNINGS: Allergic Reactions) • sickle cell crisis (see WARNINGS: Sickle Cell Disorders) • injection site pain • Sweet’s syndrome (acute febrile dermatosis) OVERDOSAGE The maximum amount of Neulasta that can be safely administered in single or multiple doses has not been determined. Single subcutaneous doses of 300 mcg/kg have been administered to 8 healthy volunteers and 3 patients with non-small cell lung cancer without serious adverse effects. These patients experienced a mean maximum ANC of 55 x 109/L, with a corresponding mean maximum WBC of 67 x 109/L. The absolute maximum ANC observed was 96 x 109/L with a corresponding absolute maximum WBC observed of 120 x 109/L. The duration of leukocytosis ranged from 6 to 13 days. Leukapheresis should be considered in the management of symptomatic individuals. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see PRECAUTIONS). The 6 mg fixed-dose formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg. No dosing adjustment is necessary for renal dysfunction. Neulasta should be visually inspected for discoloration and particulate matter before administration. Neulasta should not be administered if discoloration or particulates are observed. Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 4,810,643; 4,999,291; 5,582,823; 5,580,755, as well as other patents or patents pending. REFERENCE *Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebocontrolled, phase III study of Filgrastim in remission induction and consolidation therapy for adults with de novo Acute Myeloid Leukemia. Blood. 1997;90:4710-4718. v.10 Issue Date: 11/2008
Manufactured by: Amgen Manufacturing, Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 © 2002–2009 Amgen Inc. All rights reserved. MC45288
What are the benefits of patients staying on therapy longer? They get greater efficacy. We’re not curing renal cell cancer yet, but if we can keep them on drug therapy longer, we can prolong time to progression, keep them alive longer, and help them get to the next milestone, such as their son or daughter’s wedding or graduation. What do you find most satisfying about the NexConnect program? It saves me a lot of work. The counselors do a wonderful job of educating patients and reinforcing what I’ve told them. Hearing it more than once sometimes makes it sink in a little bit better. Some doctors will have their office staff fill out the application for the program as soon as they write the prescription for sorafenib versus just leaving the patient with “Just take these pills and call me in a month.” This way, patients get immediate reinforcement for everything the doctor has told them. Patients enroll in the NexConnect program and access the REACH application online. That saves a lot of time and is particularly convenient for small practices that do not have the personnel with a lot of time to spend on the phone checking on a patient’s insurance coverage. I find the program provides good collaboration with the clinic staff and helps ensure continuity of care.
Call 1-866-NEXAVAR (1.866.637.2827)
Lung Cancer the epidermal growth factor receptor (EGFR), and the use of pemetrexed is dependent upon nonsquamous histology. Cetuximab/vinorelbine/cisplatin is also an option for PS 2 patients with EGFR positivity. Cetuximab/vinorelbine/cisplatin is included in the guidelines based on efficacy shown in the FLEX study, which randomized 1125 patients to cisplatin/ vinorelbine with and without cetuximab (Pirker R, et al. J Clin Oncol. 2008;26(20 suppl):Abstract 3). The use of cetuximab was associated with a 23% reduction in mortality. According to Ettinger, the addition of pemetrexed/cisplatin to the recommended options was based largely on a phase 3 trial comparing pemetrexed/ cisplatin to gemcitabine/cisplatin in 1725 patients (Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551). With pemetrexed/cisplatin, median survival was improved but only in patients with adenocarcinoma and large cell-histologies, and toxicity was worse. The guidelines no longer support the use of gemcitabine/carboplatin, docetaxel/carboplatin or gemcitabine/doc-
Key Updates • Cetuximab/vinorelbine/cisplatin is a new first-line option for appropriately selected patients • Bevacizumab can be given to patients with treated brain metastases and those on blood thinners • For patients with nonsquamous histology, pemetrexed is an option for first-line treatment, preferably with cisplatin, and for maintenance therapy • The staging system has been revised • A survivorship care section has been added
ab, they also had significantly more toxicity than younger patients and no corresponding increase in median survival, 1-year survival, or PFS, compared with paclitaxel/carboplatin. “The story with bevacizumab is not finished yet,” Ettinger predicted. Activity has also been shown when bevacizumab is combined with pemetrexed and carboplatin. The NCCN guidelines were updated to allow bevacizumab in patients with treated brain metastases and those on blood thinners.
New first-line options For advanced and metastatic disease, the guidelines have added information regarding the use of cetuximab and pemetrexed. Specifically, the updated guidelines added cetuximab/vinorelbine/cisplatin and cisplatin/pemetrexed as first-line options for performance status (PS) 0-1 patients, in addition to chemotherapy with or without bevacizumab. The use of cetuximab is dependent upon positive staining for
etaxel in patients who cannot tolerate chemotherapy, he added.
Maintenance therapy As maintenance, the updated guidelines now allow patients with nonsquamous histology to receive single-agent pemetrexed until disease progression. Alternatively, patients responding to chemotherapy can continue chemotherapy for four to six cycles. The use of pemetrexed as maintenance therapy is based on a 2008 study (Ciuleanu T, et al. J Clin Oncol. 2008;26(20 suppl):Abstract 8011), in which chemotherapy responders were randomized to maintenance with pemetrexed or placebo. Those receiving pemetrexed had a doubling in PFS, from < 2 months to 4 months, for a 41% highly significant reduction in risk. Most benefit was seen in patients with nonsquamous and adenomatous tumors. In patients with nonsquamous histology, survival was increased from 9.4 months to 14.4 months. “These studies illustrate the new
concept that we must know the histology to select treatment. When we get a pathology report that says ‘carcinoma, not otherwise specified,’ that is now a problem,” Ettinger suggested. The NCCN panel also reiterated the preference for a two-drug regimen, with the exception of three-drug regimens containing bevacizumab and cetuximab. They also indicate that patients having reactions to paclitaxel or docetaxel can be treated with albumin-bound paclitaxel. After disease progression, second-line agents include docetaxel, pemetrexed, and erlotinib for PS 0-2 patients. Best supportive care is suggested for PS 3-4 patients.
Molecular diagnostic studies in NSCLC The presence of EGFR-activating mutations is of true biological relevance for patient selection. There is a significant association between EGFR mutations, especially exon 19 and 21 deletions, and response to tyrosine kinase inhibitors. Mutations in exon 18 are associated with resistance to treatment. And mutations in Kirsten rat sarcoma (KRAS), which is a critical downstream effector of the EGFR pathway, are also associated with intrinsic resistance to tyrosine kinase inhibitors. “In many institutions now, patients are automatically getting tested for EGFR and KRAS status,” Ettinger noted. In patients with an EGFR mutation or gene amplification, or never smokers, clinicians can consider erlotinib with or without chemotherapy, the guidelines state. If the patient has a KRAS mutation, treatment other than erlotinib should be considered. Guidelines for survivorship care The NCCN has recognized the need for structured recommendations on caring for cancer survivors, and these have been incorporated into the NSCLC guidelines. Surveillance recommendations include obtaining a history and physical examination, with a contrast-enhanced chest computed tomography (CT) scan every 4 to 6 months for 2 years, then history and physical examination, with a noncontrast-enhanced chest CT scan annually. Smoking status should be assessed at each visit, with counseling and referral for cessation as needed. Patients should receive annual flu and pneumococcal vaccinations with revaccination as appropriate. Survivorship care also includes counseling regarding health promotion and wellness, additional health monitoring, cancer screenings and so forth in accordance with recommendations for all cancer survivors. Updates in evaluation and staging The new guidelines have changed all references to positron-emission tomograph (PET) scan to “PET/CT scan,” reflecting the higher resolution and bet-
ter correlation with this modality, and have added endobronchial ultrasound biopsy to the evaluation of stage IIIB patients. Changes were also made to the staging of NSCLC, especially the T and M descriptors, to better reflect the way that clinicians practice, Ettinger explained. The new staging recognizes the impact of the primary tumor size on prognosis, recognizes the lack of impact of the same lobe nodules (ie, T4 to T3), eliminates “wet 3B,” and adds M1a and M1b to the lexicon. N2 descriptors remain the same (see ST-1 in guidelines).
Predicting future advances Ettinger predicted that ongoing studies will identify means of optimizing the delivery of chemoradiation. Concurrent carboplatin, paclitaxel, cetuximab, and radiation therapy followed by carboplatin, paclitaxel with cetuximab in unresectable stage III disease is being evaluated in Radiation Therapy Oncology Group (RTOG) 0324 (Blumenschein GR, et al. J Clin Oncol. 2008;26(20 suppl):Abstract 7516). Early study data show a disease control rate of 78%, overall survival of 22.7 months, and 2-year survival of 49.3%. Another study, RTOG 0617, will evaluate conventional versus highdose radiotherapy with and without cetuximab to determine the value of the higher doses of radiotherapy and the addition of the targeted agent. Finally, individualization of NSCLC treatment will eventually come, he predicted, as “the era of markers is here.” The recent Iressa Pan-Asia Study (IPASS) demonstrated how one agent specifically benefits a particular subset of patients. The study showed that benefits of gefitinib 250 mg/day given first-line, versus carboplatin/paclitaxel, reduced risk of progression by 26% in a group of patients selected for certain clinical characteristics: never or light smoking, adenocarcinoma histology, female gender, and Asian ethnicity (Mok T, et al. Ann Oncol. 2008;19(suppl 8):Abstract LBA 2). The findings suggest that perhaps, in selected patients, targeted therapy without chemotherapy may be sufficient, Ettinger said. Future management will also benefit from refinements in the use of EGFR mutations for predictions. In genetically enriched populations, response rates to gefitinib and erlotinib exceed 50%, and PFS had reached 12 months, Ettinger said. Other markers and genetic strategies will also be informative, including KRAS mutations (associated with lack of response to EGFR inhibitors and chemotherapy), low ERCC1 expression (associated with a favorable response to cisplatin), and multiple “metagene” sets and proteomic patterns. For the complete guidelines go to www.nccn.org.
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patients,” said Ettinger, who chairs the NCCN panel on NSCLC. “We have made strides, and I am optimistic we can go further.” The addition of bevacizumab to the armamentarium has increased the median survival of advanced NSCLC to 12+ months. In the European Avastin in lung (AVAiL) trial (Manegold C, et al. Ann Oncol. 2008;19(suppl 8):Abstract LBA1), advanced-disease patients who received first-line treatment with bevacizumab in addition to gemcitabine/ cisplatin had significantly improved response rates, duration of response, and progression-free survival (PFS) compared with chemotherapy alone; however, overall survival was not improved. Ettinger estimated that, approximately 20% of eligible patients do not receive bevacizumab because of concerns about side effects. Risks in the elderly were confirmed in a 2008 analysis of the landmark Eastern Cooperative Oncology Group (ECOG) 4599 trial (Ramalingam SS, et al. J Clin Oncol. 2008;26:60-65). Although elderly patients ( 70 years) did have increased response rates with bevacizum-
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Lung Cancer Alliance Seeks to Overcome Stigma Associated with the Disease An interview with Laurie Fenton Ambrose
ung cancer remains the leading cause of cancer deaths in the United States, but receives less public attention and research funding support than other forms of cancer, and treatment options are limited. A recent survey of oncologists and adults with and without cancer revealed pervasive negative attitudes toward lung cancer among both healthcare professionals and the general public, which may negatively affect funding for research and the care and support provided for patients. The Lung Cancer Stigma Study was conducted by Russell Research on behalf of the Lung Cancer Alliance and AstraZeneca. A total of 1481 adults were interviewed: 1071 adults who were not cancer patients, survivors, or caretakers, 204 patients with lung cancer, and 206 oncologists. The Oncology Nurse recently spoke with Laurie Fenton Ambrose, president and CEO of the Lung Cancer Alliance, about the findings of the study and what needs to be done to remove the stigma associated with this deadly disease.
What were the major findings? In a broad context, the survey validated what we have known, and that is that there is a stigma associated with lung cancer. Itâ€™s real and itâ€™s pervasive, not just among the patient population but also among the caregiver community. A majorityâ€”59%â€”of the general population surveyed felt that patients with lung cancer were at least partly to blame for their disease; 54% of patients and 60% of oncologists surveyed agreed that there is a stigma associated with lung cancer. In addition, the results showed that a patient with lung cancer does not receive the same level of compassion and support as other cancer patients. In our survey, 31% of patients with lung cancer felt that strangers or acquaintances had said or done things that blamed patients for their cancer, and 21% said that friends or family members had said or done things that blamed them for their cancer. Furthermore, 13% of patients thought that members of their treatment team had said or done things that blamed them for their cancer. For patients, feelings of guilt and blame can lead to depression and make them less adherent to therapy. Negative feelings also place a burden on family members and other caregivers, who may have ambivalent feelings toward the disease. Do these negative feelings affect support for lung cancer research? The stigma associated with lung cancer has led to the underfunding of research dollars to support those who are 22
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donate money to breast cancer organizations as to lung cancer organizations.
What is the Lung Cancer Alliance doing to provide support for patients with lung cancer? The Lung Cancer Alliance is the only national organization that provides a robust portfolio of patient support services and advocacy for those living with or at risk for lung cancer. The services include a clinical trial matching service, a toll-free information line, an active online support community, and a peer-
to-peer support program. In addition, the alliance provides free educational materials tailored to individual needs. We work closely with the Oncology Nursing Society (ONS) and other professional groups to develop a new platform of looking at lung cancer compassionately and comprehensively. No one deserves lung cancer, and advocates and caregivers have to come together and work to ensure that this community gets better support, both in the care they receive and the research that is funded. We need to do exactly
what other diseases have done for their stakeholders. We work with nurses directly to make sure that they have the tools, support materials, and information they need to guide the caregiver community as well as patient communities to seek help and support.
What are the challenges in combating lung cancer and the stigma associated with it? Our challenge is to promote the understanding that lung cancer is a disContinued on page 24
providing care and services to the lung cancer community. Both patients and oncologists expressed dissatisfaction with the amount of lung cancer research, and 64% of oncologists said they do not have adequate treatment options for their patients with advanced lung cancer. The stigma has prevented the development of a robust research pipeline for lung cancer. It affects not only funding for basic research, but also funding for the care and support initiatives. For example, people are nearly twice as likely to volunteer their services or
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Lung Cancer Alliance Continued from page 23
ease, not just the result of a tobacco addiction. The majority—more than 60%—of those being diagnosed with this illness are former smokers who quit decades ago or who have never smoked. Certainly we work hard to do all we can to support cessation and prevention initiatives. But that’s only one leg of the three-legged stool. Ways to detect lung
cancer earlier and better treatment options are also needed. We have to make people aware that lung cancer is a tsunami that’s hit our shores. It’s a public health epidemic. It is very complex; it’s misunderstood; and it is stigmatized. Forty years ago when the war on cancer was launched, lung cancer was the leading cause of cancer
death, and it remains so today. If we are going to see a decrease in cancer mortality overall, we need to address lung cancer as a disease, not just as a tobacco addiction. Our organization is here to help educate people about lung cancer and ensure that patients are treated with compassion and that there is adequate support for research.
For more information about lung cancer and the Lung Cancer Alliance, call or log on to .
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G REEN H ILL H EALTHCARE C OMMUNICATIONS
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ari Ugent is a good example of the old adage, â€œWhen life hands you lemons, make lemonade.â€? Diagnosed with non-Hodgkinâ€™s lymphoma at the age of 21 just before her
senior year in college, she was in and out of the hospital for 9 years before receiving an allogenic stem cell transplant at the age of 30. â€œI celebrated my 30th birthday in the hospital,â€? she recalls. During the
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time between relapses, Cari started a career as a journalist and was awaiting publication of her third book when she received the transplant. Cari received her transplant at
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Northwestern Memorial Hospital in Chicago. Her doctors and nurses encouraged her to take daily laps around the hospital, which helped her avoid complications like blood clots and pneumonia that often result from prolonged bed rest. But she found her mobility and independence were limited by the cumbersome intravenous (IV) pole that was her constant companion. â€œIt is there from the moment you step in to the moment you leave,â€? and she found it â€œwas counterproductive to many of the things that I was being encouraged to do that I knew were beneficial for my health.â€? During her long weeks of recovery, Cari talked to her doctors and nurses about the drawbacks of the standard IV pole, and they shared ideas about how it could be improved for greater patient safety and convenience. â€œIt became a nice pastime to brainstorm how the pole should look,â€? she says, and it gave her a sense of purpose. â€œThe process kept me going.â€? After her recovery, Cari worked with industrial designers to develop a safer, more convenient IV pole, known as Safepole. The new pole has features that make it attractive to both patients and caregivers, such as a tip-resistant design, an integrated power strip, and a covered dome to prevent tripping and tangling of tubes. Because the poleâ€™s design allows patients greater mobility and independence, nurses have more time to attend to other matters. â€œWhat is good for the patient, is good for the nurse,â€? Cari says. Grateful to those who helped her during her illness and recovery and wanting to give back to patients, doctors and nurses, and charities, Cari now shares her story with other survivors and works with organizations such as the Lymphoma Research Foundation of America and the Bone Marrow Transplant Information Network (www. bmtinfonet.org). Safepole is sold directly to hospitals, but individuals can also purchase a pole to be donated to a hospital or clinic, customized with a plaque engraved with the donorâ€™s name and inspirational messages or words of wisdom if they wish. Cari is a healthy cancer survivor and a successful entrepreneur. One key to her success is her own positive attitude. Another is open communication with her doctors, nurses, and other caregivers. They listened to her complaints about the standard IV pole and worked with her to design an improved model. Cariâ€™s story shows how important it is for patients to take a proactive role in Continued on page 39
G REEN H ILL H EALTHCARE C OMMUNICATIONS
Lymphoma Survivor Turns Entrepreneur
The Puget Sound Oncology Nursing Society Promotes Excellence in Nursing An interview with chapter president Renita Vance, MSN, RN
egional chapters of the Oncology Nursing Society (ONS) provide a variety of resources and services for their members in addition to those offered by the national organization. In this interview, Renita Vance, MSN, RN, president of the Puget Sound Oncology Nursing Society (PSONS), describes the activities of her chapter and how they are adapting to changes within the profession and within the pharmaceutical industry. Vance is an oncology clinical coordinator at Genentech, Inc.
When was PSONS founded? How many members do you now have? PSONS was founded as the Regional (Northwest/Alaska) Oncology Nursing Society in 1978. Its goals were to promote excellence in cancer nursing, to create opportunities for professional growth, and to provide personal support centers to care for people with cancer. In 1985, the group became large enough to meet the criteria to become a chapter of ONS. Currently, PSONS averages between 300 and 325 members. How often do you meet and what kinds of programs do you offer? We hold a monthly educational program and two other big programs. One is a symposium that we do every year, and the other is the Fundamentals of On-
cology Nursing course. Traditionally, the sources and develop a course. We created monthly educational programs have a contract that individual institutions been in Seattle. We are also sign. When they sign that constarting to offer programs in tract, they agree to provide other parts of the region. This somebody to participate on the year our goal is to post slides planning committee and to on our web site and, with teleprovide 2 hours of lectures in conference capabilities, allow the 4-day course. They also people in individual instituagree to provide a major servtions to call in to the educaice, such as arranging for CE tional programs and particiaccreditation or putting the sylpate remotely. One thing labus together. It is a big comthat I mandated as president mitment, but, in exchange, is that every educational Renita Vance, MSN, everyone in their institution program will offer continu- RN can attend the course for free. ing education (CE) credits. The course is offered twice a That needs to be our commitment to year, and it averages 125 people at each our membership. course. The first day covers the basics of cancer. The second day covers solid Where do you get funding for tumors, and there is also a tumor the CE programs and other board–type session, where participants activities? learn what happens at the tumor In the past, the CE programs have board. The third day is devoted to liqbeen mostly industry sponsored. We also uid tumors and how to care for have a fair amount of money in our treas- immunocompromised patients. There ury because of the Fundamentals of is a patient panel too, in which two or Oncology Nursing program. three patients talk about what nurses The Fundamentals of Oncology have said or done with them that has Nursing is a 4-day course that is geared to been helpful or not helpful. The fourth the nurse who is new to oncology nurs- day reviews oncologic emergencies, ing, whether an experienced nurse or a psychosocial issues, pain management, new nurse. About 7 or 8 years ago, a and end-of-life care. Participants get group of mostly clinical nurse specialists 32 CE credits for attending the course. got together and realized we were all try- PSONS offers vendor opportunities for ing to duplicate the same efforts in our exhibiting. Vendors pay a fee to exhibfacilities. We decided to pool our re- it and often also provide sponsorship of
Serving ~ Leading ~ Sharing ~ Educating ~ Networking The Puget Sound Chapter of the Oncology Nursing Society History
Learning ~ Renewing
In 1978, with financial support from the Fred Hutchinson Cancer Research Center an intrepid band of oncology nurses formed a special interest group called the Regional (Northwest/Alaska) Oncology Nurses (RONs). RONs included cancer nurses from Washington, Alaska, Montana, Idaho, and British Columbia, who wanted to promote excellence in cancer nursing, create opportunities for professional growth, and provide personal support to nurses who care for people with cancer. These nurses traveled hundreds of miles along the I-5 corridor and across international borders to meet quarterly. In 1985, RONs, now a large active and successful special interest group, became the Pugent Sound Chapter of the Oncology Nursing Society (PSONS). PSONS has matured into an organization deeply committed to the professional and personal development of its member. It has maintained organizational flexibility and is responsive to charges in the helathcare community. Individual members have received honors for research, writing. and community service. PSONS has provided national leadership and helped ONS to grow.
Award-winning Quartely Newsletter
The mission of the Chapter is to promote Th excellence in oncology nursing and quality cancer care
McCorkle Lecture Recognizes a Member who has made a significant contribution to Oncology Nursing
Biannual Fundamental of Oncology Nursing Class
the food. Participants from nonmember institutions pay a fee of about $400 for the 4 days. We also have an annual symposium, which is a 2-day event that averages about 150 participants. Often, we have nationally known speakers who are sponsored by a pharmaceutical company. The bulk of the PSONS budget has come from vendor support in the past, as well as the 300 members who pay their $35 dues every year. As of this January, however, because of the changes in PhRMA regulations, vendors are not able to provide the same kind of support as they have in the past, so we are shifting our priorities and will have to do things differently in terms of our educational programs. We will have to start charging a fee for educational programs.
What are some of the most pressing concerns of your members, with regard to their careers/professional opportunities and oncology nursing practice/patient care? The most pressing concern is probably that resources are scarce. Everybody is being asked to work harder and smarter with fewer resources. The nursing shortage reached this area later than it hit other parts of the country, but clearly there is a nursing shortage. People worry about how much more they are being asked to do. Recruiting nurses and physicians to the Seattle area can be difficult because the cost of living is high. Regulatory agencies are making more demands too, such as electronic medical records and safety changes. These are good, but there is not any more staff to do the work. With all they have to do, nurses feel they are losing touch with the patients. People are also very concerned about the cost of healthcare and about lack of access to healthcare. Another concern is generational Caring differences between older and newer nurses, which can ~ present challenges in the workplace. Teaching —Karen Rosenberg
• To promote quality in oncology nursing practice through education, communication, and research.
• To promote networking among oncology nurses served by PSONS • To foster service to our communitites.
Breathing ~ Resting ~ Laughing ~ Hugging ~ Growing ~ Collaborating
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Would you like to see your local chapter of ONS featured in our paper? Write to email@example.com.
New Technologies in HER2 Testing since 2001, there is no test that is recognized as the “gold standard.” Neither IHC, nor FISH, is considered 100% accurate in determining HER2 overexpression.3,5 Wolff and colleagues reported that up to 20% of HER2 testing may be inaccurate and urge the use of uniform operating procedures and rigorous laboratory accreditation standards.5
Breast cancer and HER2 Breast cancer remains the leading cause of cancer among women in the United States,1 with approximately 26% of American women being at risk for developing the disease.2 Examination of the cellular biology that is associated with breast cancer has revealed that the biologic marker, HER2, is linked with prognosis and aggressiveness of tumor growth. HER2 is present in all cells, but an excess of HER2 causes increased signaling and prolific cellular division.3 It is reported that the 25% to 30% of patients who have an overexpression of HER2 protein caused by gene amplification (HER2+) have aggressive tumors and a poorer prognosis.2,4 Recent data have also shown that there is a correlation between HER2 overexpression and response to chemotherapy and hormonal therapy.2,3,5 Once a woman is diagnosed with an invasive breast cancer, the American Society of Clinical Oncology (ASCO) practice guidelines advise that all tumor samples be evaluated for expression of HER2.2 The crucial component in directing the care of a woman with breast cancer with an overexpression of HER2 is the potential benefit from the anti-HER2 antibody, trastuzumab.
New HER2 tests HERmark Breast Cancer Assay. In July 2008, Monogram Biosciences introduced a new technology for measuring HER2. The HERmark Breast Cancer Assay is promoted by Monogram as providing accurate quantitative measurement of HER2 total protein and HER2 homodimer levels rather than the semiquantitative HER2 measurement of conventional testing by IHC and FISH. HERmark is a protein-protein assay using electrophoresis technology. The HERmark data are based on a sample size of 1090 specimens that were compared with IHC and/or FISH specimens embedded in formalin-fixed paraffin. Monogram purports that the HERmark assay can more accurately determine HER2 levels with improved specificity and sensitivity compared with conventional testing by IHC or FISH. Patients who had been deemed HER2-negative (HER2-) on conventional testing were shown to be HER2+ by HERmark, and, conversely, patients who were HER2+ by IHC or FISH were found to be HER2- by HERmark. Additionally, HERmark technology stratifies patients by predicting the degree of benefit from trastuzumab in relation to their HER2 expression. Patients are still categorized as HER2negative, equivocal, or positive. Data on HERmark were initially reported in June 2007 at the annual meeting of ASCO. In a multicenter study by Bates and colleagues,7 HER2 semiquantitative measurements were compared with quantitative HER2 measurements using the HERmark assay in 71 patients with metastatic breast cancer who had had at least two prior courses of chemotherapy. The study showed that among patients selected by FISH or IHC to receive trastuzumab, higher HER2 expression correlated with better outcomes. Patients with high HER2 expression who received trastuzumab did not benefit from concomitant chemotherapy, whereas patients with low HER2 expression had a significant benefit when chemotherapy was added to trastuzumab. Another multicenter study presented at ASCO in 2007, by Toi and colleagues,8 involved patients (n = 75) with metastatic breast cancer who were eligible for trastuzumab by IHC testing for HER2 overexpression. The study demonstrated a correlation between quantitative HER2 expression and overall survival. The patients who had true overexpression of HER2 by HERmark assay and were treated with trastuzumab had greater overall survival.
Guidelines and current testing The two most commonly used tests for determining HER2 are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) (Table). IHC testing6 involves measuring HER2 protein on the surface of the tumor cells using polyclonal or monoclonal antibodies. The results are scored on a scale of 0 to 3+, indicating the degree and percentage to which the cells absorb staining. The scores are classified as 0 to 1+ (negative), 2+ (equivocal), and 3+ (positive). Guidelines from ASCO, the College of American Pathologists (CAP), and the National Comprehensive Cancer Network recommend additional testing by FISH for values of 2+ (Figure). Considered to be a more sensitive test, FISH measures HER2 gene amplification using fluorescently labeled probes. FISH is not a replacement for IHC, but is complementary to IHC. The FISH test counts the gene copies and quantifies them in a ratio with chromosome 17 (CEP 17). The CEP 17 is used as an internal control; HER2 is located in CEP 17. A positive result is a ratio of >2.2 or more than 6 HER2 gene copies.1,4,6 Although ASCO has recommended HER2 testing as part of a diagnostic and metastatic evaluation for breast cancer
Equivocal (IHC 2+)
Retest with FISH
Positive, eligible for trastuzumab
Positive, eligible for trastuzumab
IHC indicates immunohistochemistry; FISH, fluorescence in situ hybridization.
Identification of patients eligible for treatment with trastuzumab. At the 44th annual ASCO meeting in 2008, Leitzel and colleagues9 presented a study evaluating the ability of the HERmark assay to predict response to trastuzumab in patients with metastatic breast cancer (n = 106). Patients who were eligible for trastuzumab therapy by positive result from IHC and FISH testing were retested with HERmark assay. The result of the study, using multivariate Cox proportional hazards models, indicated that the HERmark assay levels were a statistically significant predictor of response to trastuzumab therapy in terms of both time to progression and overall survival. Monogram Biosciences is currently enrolling patients in a retrospective, multicenter Collaborative Biomarker Study to collect data on HER1, HER2, and HER3 proteins. There are three objectives of the study: (1) to continue comparison between HERmark and conventional HER2 testing; (2) to investigate HER1 and HER3, proteins that may cause a resistance to trastuzumab therapy; (3) and to show a relationship between HER proteins and disease characteristics and clinical outcomes. To date, the HERmark assay is not incorporated in many insurance plans; patients will have to pay $3350 for the test.10 Monogram Biosciences will work with patients concerning coverage. Testing is performed at Monogram Biosciences, a Clinical Laboratory
Improvement Amendments–certified clinical reference laboratory. There is a 7-day turnaround time. The HERmark assay is approved by CAP but has not been recognized or approved by the FDA. SPOT-Light test. In July 2008, a second laboratory product was introduced to measure HER2 overexpression. The genetics-based test developed by Invitrogen Corporation, called the SPOTLight HER2 CISH kit, uses chromogenic in situ hybridization (CISH) to measure the strength of HER2 gene amplification quantitatively. The CISH method uses paraffinembedded tissue, which is stained and heat treated. The process of chemical staining using fluorescent tagged antibodies causes any HER2 genes in the sample to change color and be visually counted using a standard light microscope.11 Similar to FISH, CISH uses DNA probes to measure the number of copies of HER2 genes on CEP 17.12 According to Invitrogen, the advantages of CISH and the SPOT-Light kit are that (a) it is a less expensive, easily available light microscope; (b) tissue morphology can be evaluated at the same time as gene status; and (c) staining is long-lasting, allowing slides to be stored for extended periods of time.11,13 In their approval summary, the FDA Continued on page 28
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Inc, and the SPOT-Light HER2 CISH kit by Invitrogen Corporation were developed to improve the current testing technologies of HER2 expression and determine which patients with breast cancer are good candidates for treatment with trastuzumab. This article will discuss and compare these two technologies.
Continued from cover
New Technologies in HER2 Testing Continued from page 27
Table. Immunohistochemistry and Fluorescence In Situ Hybridization Tests to Determine HER2 Status Immunohistochemistry • Polyclonal or monoclonal antibodies recognize and bind to HER2 protein in the tissue section, which allows the tester to visualize the location and relative amount of HER2 protein • Semiquantitative scoring system 0: no circumferential membrane staining (negative) 1+: partial staining in >10% of cells (negative) 2+: thin circumferential staining in >10% of cells (ambiguous) 3+: intense thick circumferential membrane staining (positive)
Fluorescence in situ hybridization • Fluorescent-labeled probes recognize and bind to the HER2 gene in cell nuclei, which allows the tester to visualize and count the copies of HER2 per cell • Result is positive for HER2 amplification if the ratio of HER2 signals to chromosome 17 centromeres is >2 HER2 indicates human epidermal growth factor receptor 2. Reprinted with permission from Hicks D, Tubbs R. Assessment of the HER2 status in breast cancer by fluorescence in situ hybridization: a technical review with interpretive guidelines. Hum Pathol. 2005;36:250-261.
stated that concordance between FISH and CISH was more than 95%,12 demonstrating that the use of CISH is a reliable alternative to FISH testing. Additional studies have demonstrated similar results. In a study conducted by Hanna and Kwok,14 254 breast cancer samples were tested using CISH and FISH to calculate concordance between the two testing methods. The results showed a high level (>95%) of concordance and suggested that CISH is a convenient method that is widely available in diagnostic pathology laboratories. A separate, retrospective study by Pothos and colleagues15 used 100 samples from confirmed cases of invasive ductal breast cancer to compare IHC, FISH, and
CISH. The results showed a 100% concordance between FISH and CISH.15 A multicenter, international, ring study had similar results to the above studies. A total of 211 invasive breast cancer specimens were tested. The five laboratories involved in the study tested for CISH, FISH, and IHC with their own samples and also sent unstained, blinded samples to the remaining four laboratories for additional testing by CISH. CISH was determined to be accurate and reliable, and the researchers concluded that CISH can be used as an alternative to FISH.16 The cost of the SPOT-Light CISH kit by Invitrogen (approximately $70) is similar to that of IHC and FISH.10 Insurance companies should cover the
cost, and a Current Procedural Technology code has been assigned. The turnaround time for CISH testing is 2 days compared with the standard of 5 to 7 days for conventional IHC and FISH.
Conclusion The HERmark Assay and SPOTLight HER2 CISH kit offer clinicians two options to identify patients who will most benefit from trastuzumab therapy. The HERmark Assay focuses on the HER2 protein and homodimerization levels; SPOT-Light HER2 CISH targets DNA through its gene amplification, and no direct comparison of these technologies has been documented thus far. Through further studies, we will better understand the biology of these cancers and be able to more accurately select patients for whom trastuzumab treatment would be most beneficial. References
1. Dowsett M, Hanna W, Kockx M, et al. Standardization of HER2 testing: results of an international proficiency testing ring study. Mod Pathol. 2007;20:584-591. 2. American Cancer Society. Cancer facts and figures for 2008. Atlanta, GA: American Cancer Society; 2008:10. 3. Bilous M, Dowsett M, Hanna W, et al. Current perspectives on HER2 testing: a review of national testing guidelines. Mod Pathol. 2003;16:173-182. 4. Hicks D, Kulkarni S. Trastuzumab as adjuvant therapy for early breast cancer. Arch Pathol Lab Med. 2008;132:1008-1015. 5. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/ College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118-144. 6. Dendukuri N, Khetani K, McIsaac M, et al. Testing for HER2-positive breast cancer: a systematic review and cost-effectiveness analysis. CMAJ. 2007;176:1429-1434. 7. Bates M, Desmedt C, Sperinde J, et al. HER2 expression and HER2-HER2 dimerization identifies subpopulations of metastatic breast cancer
patients with different probabilities of longterm survival following trastuzumab treatment and with different requirements for concomitant chemotherapy. Poster presented at the American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, IL. Poster 10577. 8. Toi M, Sperinde J, Huang W, et al. Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2: HER2 dimerization in a clinic-based cohort of patients with metastatic breast cancer. J Clin Oncol. 2007;25:18S. Poster 1025. 9. Leitzel K, Lipton A, Koestler W, et al. Total HER2 and HER2 homodimer levels predict response to trastuzumab. Presented at the American Society of Clinical Oncology Annual Meeting; June 2, 2008; Chicago, IL. 10. Ray T. Two new HER2 assays poised to challenge IHC, FISH standard tests in breast cancer. Pharmacogenomics Reporter. July 16, 2008. www.pgxreporter.com/issues/6_29/features/ 148218-1.html. Accessed October 15, 2008. 11. Invitrogen. CISH technology overview. www. invitrogen.com/site/us/en/home/Products-andServices/Applications/Clinical-and-DiagnosticApplications/Clinical-Pathology/CPMisc/SPOT-Light-HER2-CISH-Kit/CISH-Techn ology-Overview.html. Accessed October 17, 2008. 12. US Food and Drug Administration Center for Devices and Radiologic Health. Invitrogen SPOT-Light HER2 CISH Kit-P050040. www. fda.gov/cdrh/mda/docs/P050040.html. Accessed October 15, 2008. 13. Bilous M, Orey A, Armes J, et.al. Chromogenic in situ hybridization testing for HER2 gene amplification in breast cancer produces highly producible results concordant with fluorescence in situ hybridization and immunohistochemistry. Pathology. 2006;38:120-124. 14. Hanna W, Kwok K. Chromogenic in-situ hybridization: a viable alternative to fluorescence in-situ hybridization in HER2 testing algorithm. Modern Pathol. 2006;19:481-487. 15. Pothos A, Plastira K, Plastiras A, et al. Comparison of chromogenic in situ hybridization with fluorescence in situ hybridization and immunohistochemistry for the assessment of Her-2/neu oncogene in archival material of breast carcinoma. Acta Histochem Cytochem. 2008;41:59-64. 16. Dowsett M, Hanna W, Kockx M, et al. Chromogenic in situ hybridization for the assessment of HER2 status in breast cancer: an international validation ring study. Mod Pathol. 2007;20:584-591.
Pediatric Cancer Survivors Shun Breast Cancer Screening NEW YORK CITY—Most young women who are at risk of breast cancer because of chest radiation for a childhood cancer are not adhering to breast cancer screening recommendations, researchers reported in the January 28 issue of the Journal of the American Medical Association. Women treated with chest radiation for a pediatric malignancy have a significantly increased risk of breast cancer at a young age and are advised to start
ERRATUM Erratum: In the article titled “Nonanthracycline Regimens Provide Alternatives for HER2-positive Breast Cancers” in the January/February issue of The Oncology Nurse, the TCH regimen was incorrectly identified as paclitaxel, carboplatin, and trastuzumab. It should be docetaxel, carboplatin, and trastuzumab. 28
annual screening mammography at 25 years of age or 8 years after radiation therapy has been completed, whichever occurs last, Kevin C. Oeffinger, MD, of Memorial Sloan-Kettering Medical Center, and colleagues elsewhere, pointed out in their article. His team examined responses to questionnaires completed by 551 female pediatric cancer survivors treated with chest radiation and found that about two thirds (63.5%) of survivors between 25 and 39 years of age had not had a mammogram within the prior 2 years. In addition, 23.5% of survivors aged 40 through 50 years had not had a mammogram to check for breast cancer within the past 2 years. “A key to increasing screening rates among this high-risk population is education, and oncology nurses are an integral part of educating cancer survivors regarding their health risks and encouraging them to have recommended risk-based screening,”
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Oncology nurses are an integral part of educating cancer survivors regarding their health risks and encouraging them to have recommended risk-based screening. Oeffinger told The Oncology Nurse in an interview. In the United States, about 20,000 to 25,000 women who are 25 years of age or older were treated for a childhood cancer with moderate- to highdose chest radiation, the authors commented in their article. By the time these women are 45 years old, roughly 12% to 20% of them will be diagnosed with breast cancer. The researchers looked at breast cancer surveillance practices in women aged 25 through 50 years who had survived pediatric cancer and who were participating in the ongoing Childhood Cancer Survivor Study (CCSS). The CCSS has
enrolled long-term survivors from the United States and Canada who had been diagnosed between 1970 and 1986. “We were surprised to find that almost half of women under the age of 40 had never had a mammogram,” Oeffinger said. “What’s more, even for the women ages 40 to 50, about half were not being regularly screened.” The investigators said that their results underscore the importance of a physician recommendation for screening; screening rates have been shown to be three times higher in women whose physicians have recommended screening. Continued on page 48
In the treatment of higher-risk MDS*. . .
* MDS, myelodysplastic syndromes; higher-risk MDS, Intermediate-2- and High-risk MDS per International Prognostic Scoring System (IPSS).
Please see Important Safety Information and Brief Summary of full Prescribing Information on following pages.
Proven Results. Extended Survival.
S U R V I V A L
VIDAZA is the first and only agent proven to extend overall survival vs conventional care regimens (CCR) in patients with higher-risk MDS s Monitor liver chemistries and serum creatinine prior to initiation of therapy and with each cycle
VIDAZA nearly doubled the 2-year overall survival rate1
Study 4, the Survival Study (AZA-001), was a phase 3, prospective, international, multicenter, randomized, controlled, parallel-group, non-crossover study of 358 adult (*18 years) patients with higher-risk MDS (IPSS Intermediate-2 or High), and FAB*-defined refractory anemia with excess blasts (RAEB), or RAEB in transformation (RAEB-T†), or dysplastic-type chronic myelomonocytic leukemia (CMMoL), using modified FAB criteria. Patients were randomized to receive either VIDAZA (75 mg/m2 SC daily for 7 days each 28-day cycle) + best supportive care (BSC; transfusions, antibiotics, G-CSF for neutropenic infection), or 1 of 3 conventional care regimens (CCR). CCR treatments included BSC alone; low-dose cytarabine (L-DAC; 20 mg/m2 SC daily for 14 days every 28 to 42 days); or 7+3 chemotherapy (induction with cytarabine 100-200 mg/m2/d by continuous IV infusion over 7 days plus an anthracycline days 1-3 [plus a maximum of 2 consolidation cycles]). CCR were pre-selected by study investigators. The primary end point of the study was overall survival.1 * French-American-British classification for MDS. † Bone
marrow blast count*20% is classified by the WHO as AML. The investigators in the Survival Study (AZA-001) classified RAEB-T as blasts 21%-29%.1
VIDAZA® is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). Please see Important Safety Information and Brief Summary of full Prescribing Information on following pages.
For proven survival in higher-risk MDS
Thereâ€™s only VIDAZA
VIDAZA significantly extended median overall survival vs CCR s 24.5 months for patients on VIDAZA vs 15 months for patients on CCR (P =.0001; HR=0.58 [95% CI, 0.43-0.77])
VIDAZA nearly doubled the 2-year overall survival rate vs CCR s 51% survival for VIDAZA vs 26% survival for CCR [24.6% difference, 95% CI, 13.1-36.1]1
Patients continued treatment until disease progression, relapse after response, or unacceptable toxicity s To optimize patient benefit, investigators aimed to treat patients with VIDAZA for at least 6 cycles1 s Patients receiving VIDAZA were treated for a median of 9 cycles (range 1-39) sPatients should be monitored for hematologic response and renal toxicities, with dosage delay or reduction as appropriate
Important Safety Information s6)$!:!ISCONTRAINDICATEDINPATIENTSWITHAKNOWNHYPERSENSITIVITYTOAZACITIDINEORMANNITOLANDINPATIENTSWITH advanced malignant hepatic tumors s)N3TUDIESAND THEMOSTCOMMONLYOCCURRINGADVERSEREACTIONSBY3#ROUTEWERENAUSEA ANEMIA (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%), and ecchymosis (30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), and malaise (10.9%). In Study 3, the most common adverse reactions by IV route also included petechiae (45.8%), weakness (35.4%), rigors (35.4%), and hypokalemia (31.3%) s)N3TUDY THEMOSTCOMMONLYOCCURRINGADVERSEREACTIONSWERETHROMBOCYTOPENIA NEUTROPENIA anemia (51.4%), constipation (50.3%), nausea (48.0%), injection site erythema (42.9%), and pyrexia (30.3%). The most commonly occurring Grade 3/4 adverse reactions were neutropenia (61.1%), thrombocytopenia (58.3%), leukopenia (14.9%), anemia (13.7%), and febrile neutropenia (12.6%) s"ECAUSETREATMENTWITH6)$!:!ISASSOCIATEDWITHANEMIA NEUTROPENIA ANDTHROMBOCYTOPENIA COMPLETEBLOODCOUNTS should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle s"ECAUSEAZACITIDINEISPOTENTIALLYHEPATOTOXICINPATIENTSWITHSEVEREPREEXISTINGHEPATICIMPAIRMENT CAUTIONIS needed in patients with liver disease. In addition, azacitidine and its metabolites are substantially excreted by the kidneys and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function s6)$!:!MAYCAUSEFETALHARMWHENADMINISTEREDTOAPREGNANTWOMAN7OMENOFCHILDBEARINGPOTENTIALSHOULD be apprised of the potential hazard to the fetus. Men should be advised not to father a child while receiving VIDAZA s.URSINGMOTHERSSHOULDBEADVISEDTODISCONTINUENURSINGORTHEDRUG TAKINGINTOCONSIDERATIONTHEIMPORTANCE of the drug to the mother Please see Brief Summary of full Prescribing Information on following pages. Reference: 1. Data on file, Celgene Corporation.
VIDAZAÂŽ is a registered trademark of Celgene Corporation. ÂŠ 2009 Celgene Corporation 04/09 VID09009T
Proven Results. Extended Survival.
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Unraveling the Complexities of Non-Hodgkin’s Lymphomas. Part 4
The Challenge of Evidenced-based Treatment Selection BY ARIZONA CANCER CENTER, UNIVERSITY OF ARIZONA, TUCSON apies have been tested and shown to have activity in DLBCL; however, most have not been found to be equal in efficacy and safety to CHOP. It is important to analyze these newer agents in the context of established regimens with more than 10 years of efficacy, safety, and survival data.
The watch-and-wait approach is an option in this disease because early treatment in asymptomatic disease has not yet shown an overall survival advantage.
Treatment of DLBCL On February 10, 2006, the US Food and Drug Administration granted approval for use of rituximab for first-line treatment of patients with DLBCL in combination with CHOP (R-CHOP) or other anthracyclinebased chemotherapy regimens. The approval of rituximab has revolutionized the treatment of DLBCL. Safety and efficacy were demonstrated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1854 patients.3 R-CHOP has now become the standard first-line regimen for treatment of DLBCL. More recent trials have focused on patients previously treated with rituximab-containing chemotherapy regimens (relapsed) or those thought to have failed rituximab therapy (refractory). What is not certain is if this previous therapy in any way changes the characteristics of the disease or response to future therapy. Elderly individuals (median age, 67-68 years) represent the largest population of DLBCL patients.4 Fiveyear overall survival for patients aged 60 years and older is approximately 41%. Hershman and colleagues evaluated 9438 patients more than 65 years of age who were diagnosed with DLBCL from 1991 to 2002.4 Only 42% of patients (3164) received doxorubicin-based chemotherapy, such as CHOP. Any doxorubicin use was associated with a 29% increase in risk of congestive heart failure (CHF). The risk of CHF increased with increasing age, cumulative doses of
doxorubicin, comorbidities, diabetes, and hypertension. Only hypertension intensified the effect of doxorubicin on risk of CHF (hazard ratio [HR] = 1.8; P <.01). In the 8 years after diagnosis, the adjusted CHF-free survival rate was 74% in the doxorubicin-treated patients versus 79% in patients not treated with doxorubicin. Many patients were not offered doxorubicin based solely on age. Given the increased incidence of NHL in older patients and the key role of CHOP chemotherapy in improving survival for elderly patients with DLBCL, the authors suggested the survival effect may outweigh the risk of cardiotoxicity.4 Careful pretreatment screening, aggressive concurrent management of hypertension and other co-morbidities, administration of cardioprotective agents, and continued surveillance during treatment may provide more effective therapy in elderly patients.
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Treatment of FL The standard first-line treatment for patients with FL is less clear. FL is characterized by an indolent course with median survival of 8 to 12 years.5 Many patients have extended survival without ever receiving treatment. The disease is thought to be incurable but highly treatable in most cases. Therefore, the benefit of treatment must be weighed against any potential toxicity. The watch-andwait approach is an option in this disease because early treatment in asymptomatic disease has not yet shown an overall survival advantage.6 A recent multicenter, longitudinal, observational trial evaluating 2728 FL patients enrolled at 265 different clinical sites throughout the United States between 2004 and 2007 found wide disparities in treatment approaches for FL.7 The most common initial therapy was chemotherapy plus rituximab (51.8%), CHOP (55%), cytoxan, vincristine, prednisone (23.1%), and fludarabine-based regimens (15.5%) being the most common. Significant differences in treatment approaches
were noted among regions of the United States (P <.01). The authors suggested that the variable approaches to initial treatment for FL create a heterogeneous group of patients at relapse, further complicating analysis of trials specific to relapsed or refractory disease. The role of rituximab in the initial treatment of FL is well established. The role of maintenance therapy using rituximab to extend progression-free survival has been the focus of many recent trials. A recent meta-analysis of five trials totaling 985 patients with FL found that patients treated with maintenance rituximab had improved overall survival compared with patients in the observation arm or patients treated at relapse (HR = 0.60, 95% confidence interval [CI]).8 The rate of infectionrelated adverse events was higher with rituximab maintenance treatment (HR = 1.99, 95% CI). The authors suggested that maintenance therapy with rituximab, either as four weekly infusions every 6 months or as a single infusion every 2 to 3 months, should be added to standard therapy for patients with relapsed or refractory FL after successful initial therapy. The recommended duration of maintenance therapy is 2 years, but the higher rates of infections must be considered.
Implications for clinical practice The challenge going forward for scientists and clinicians will be to refine the molecular signature of individual subtypes of NHL to allow selection of therapies based on the specific disease phenotype or recognized adverse risk attributes. Validation of these new criteria is difficult because of the number of trials required and the limited number of patients with NHL who are eligible or interested in clinical trial participation. Comparison with historical trials is flawed because of differences in the definitions used for each disease. As a result, leading clinical experts continue to disagree about when to initiate treatContinued on page 36
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on-Hodgkin’s lymphomas (NHLs) represent a group of heterogeneous lymphoid malignancies with variable clinical presentations, pathologic characteristics, prognoses, and recommended treatments. The diseases arise from either B or T lymphocytes at different stages of maturation. The two most common subtypes of NHL are follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), both B-cell malignancies. Successful treatment of NHL is based on complete evaluation of the disease and the individual patient, including an adequate tissue diagnosis, location and extent of organ involvement, complete laboratory and diagnostic evaluation, and a thorough history and physical examination. The specific elements of the diagnostic evaluation have been discussed in detail in previous articles in this series. Treatment guidelines for FL and DLBCL have been developed by the National Comprehensive Cancer Network1 as well as other oncology specialty groups. Wide variations in approaches to treatment of NHL continue, however, and these guidelines are updated frequently. Both diseases have established prognostic grading systems, the International Prognostic Index (IPI) for DLBCL, and the Follicular Lymphoma International Prognostic Index for FL. These tools provide a framework for risk-adapted therapy in these two diseases. The IPI originated out of the national High Priority Lymphoma Study, a randomized phase 3 intergroup trial (n = 3273) published in 1993.2 The results of this trial indicated that patient selection based on key risk factors was a more important criterion for treatment selection than a specific regimen and reconfirmed that cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) was the most effective and least toxic regimen for DLBCL. Since these data were published, many chemotherapy regimens and novel ther-
Conference News Continued from page 18
Smoking History Affects Efficacy, Toxicity of EGFR-TKI Agents for Lung Cancer Patients ORLANDO—A patient’s smoking his- dependence, especially in patients with tory can significantly influence the smoking-related malignancies undergoeffectiveness of treatment with epider- ing cancer treatment.” mal growth factor receptor tyrosine Cooley explained that continuous kinase inhibitors (EGFR-TKIs), ac- smoking may have detrimental effects cording to an analysis presented at the on the effectiveness of targeted agents 2009 National Conference on Cancer because of mechanisms such as an Nursing Research. interaction between nicotine and the Focusing specifically on EGFR-TKI– metabolism of targeted agents. “The targeted agents, researchers examined effects of smoking on the efficacy of the relationship between smoking histo- targeted treatments have been underry at diagnosis and length studied. It’s absolutely essential of survival and drug toxicito incorporate smoking cessaty level among never, fortion into clinical care to ensure mer, and current smokers. better outcomes during cancer They also sought to identitreatments.” fy predictors of survival Drug toxicity was defined as among those who had quit diarrhea, rash, nausea/vomiting, smoking. and shortness of breath. Rash is The investigative team one of the most prominent side found that current smokeffects of EGFR-TKIs, and can ers, and to a lesser degree act as a surrogate marker for former smokers, had more Mary Cooley, PhD, RN treatment response, explained toxicity compared with Cooley. “It’s a marker of efficanever smokers. “These findings suggest cy.” Compared with the other study that smoking history influences out- groups, current smokers showed the comes associated with cancer treat- least amount of rash. ment,” said Mary Cooley, PhD, RN, Cooley and her colleagues evaluated who is a nurse scientist at Dana-Farber data on 187 patients with non–small-cell Cancer Institute, Boston. “Oncology lung cancer treated with EGFR-TKIs nurses can play an important role in the from the Dana-Farber/Harvard Cancer assessment and treatment of tobacco Center Thoracic Oncology Program’s
NHL Part 4
Continued from page 35
ment, treatment sequencing and treatment duration, methods for evaluation of response, and the role of bone marrow transplantation. The integration of new agents into the treatment algorithm will create additional complexity. These differences create particular challenges for patients who may have seasonal residences and travel between treatment sites. The development, implementation, and continuous updating of evidenced-based practice guidelines is essential for building a more consistent approach to therapy. With the robust pace of scientific discovery, perhaps the most pressing challenge for clinicians is to preserve future treatment options while effectively managing what in most cases represents a chronic disease. Therefore, continued enrollment of patients in clinical trials will be necessary to capture late effects of therapy that may limit future therapies. Regular review of scientific updates and changes to practice guidelines will be necessary for clinicians to provide optimal patient care. 36
1. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas. V.1. 2009. www.nccn. org/professionals/physician_gls/PDF/nhl.pdf. Accessed March 19, 2009. 2. A predictive model for aggressive non-Hodgkin’s lymphoma: the International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994. 3. Pazdur R. FDA approval for rituximab. October 2006. www.cancer.gov/cancertopics/druginfo/fda rituximab. Accessed March 19, 2009. 4. Hershman D, McBride R, Eisenberger A, et al. Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26:3159-3165. 5. Ansell S, Armitage J. Non-Hodgkin lymphoma: diagnosis and treatment. Mayo Clin Proc. 2005;80:1087-1097. 6. Tan D, Rosenberg SA, Levy R, et al. Survival in follicular lymphoma: the Stanford experience, 1960-2003. Blood. 2007;110:Abstract 3428. 7. Friedberg J, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the national LymphoCare study. J Clin Oncol. 2009;27:1202-1208. 8. Vidal L, Gafter-Gvili A, Leibovici L, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009;101:248-255.
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In addition, the presence of rash was the strongest predictor associated with longer survival among former smokers. several questions. There are former smokers from 20 years ago, 10 years ago, and yesterday. We need a really firm identification of what a former smoker is and we need to answer: How long do they have to have quit before it makes a difference?” In an interview with The Oncology Nurse, Cooley said that this is the first time that smoking status has become such an important marker. “It’s been generally accepted ∋# ! # ∃#&∀ that never smokers are going clinical research information system. to best respond to treatment. So in a The total sample had a mean age of 67 lot of older trials, that’s what people years, with 106 former smokers, 33 never had to be. Now, there’s evidence that smokers, and 48 current smokers. former smokers can respond and that The primary end points were toxic- some smokers may also have the mutaity and survival, measured from the tion. The next step for me will be intefirst day of treatment with the target- grating biological outcome measures ed agent. The researchers also looked into my research. And I think it’s at gender, race, histology, smoking important to have a core set of tobachistory, and the presence of rash as co-related questions integrated into all possible identifiable factors associ- of our research.” ated with survival among former When Cooley was asked during the smokers. question and answer session if she’d They used the stratified log-rank consider sharing her rather dire statistest, the Fisher’s exact test, and the tics with her currently smoking Cox proportional hazards modes to patients, she replied, “I don’t think I analyze patient chart and patient- would be comfortable with that since reported tobacco questionnaires. they’re already under so much stress. Presenting the study’s results, But we should share with them that Cooley reported a median survival smoking cessation is absolutely essenof 13.9 months for never smokers, 6 tial to outcomes. I just don’t think months for former smokers, and 4.9 patients understand that smoking months for current smokers. impacts so significantly whether their “Never smokers had the highest treatment is effective or not. And prevalence of rash at 27%, followed again, nurses can play a really imporby former and current smokers, and tant role in explaining that.” the least shortness of breath,” said Cooley. —DB In addition, the presence of rash was the strongest predictor associated with longer survival among former smokers. Factors associated with shorter survival were number of cigarettes smoked per day and male gender. In a post-hoc analysis looking only at those who received first-line EGFR-TKI treatment, the median survival was 19.8, 10.6, and 4.9 According to a report from the Pharmonths for never, former, and curmaceutical Research and Manufacturers rent smokers, respectively. of America (PhRMA), a record 861 new At the end of the presentation, drugs and vaccines for cancer are being panel moderator Linda Sarna, RN, tested in clinical trials or are awaiting DNSc, FAAN, AOCN, a professor at UCLA School of Nursing, comapproval by the US Food and Drug mented that the analysis of the forAdministration. Source: www.phrma.org. mer smoker “is interesting, but raises
EÐis]hgejcl]ej)bnaa]c]ej* Tom Callaghan Attorney, Age: 58 Diagnosis: Multiple myeloma-induced fracture
Tom Callaghan experienced debilitating pain due to spinal fractures caused by multiple myeloma. “I couldn’t stand for more than a couple of minutes without pain.” Tom underwent a minimally invasive procedure, Balloon Kyphoplasty, to treat his collapsed vertebrae. “It was truly remarkable,” he says. “Within two days of being discharged from the hospital, I was back on the golf course and playing tennis with my son. I could stand up straight and walk pain-free. It was as though it never happened.” Tom’s cancer is in remission and he remains pain-free to this day.
A vertebral compression fracture (VCF) occurs when the vertebral body collapses because the bone is too weak due to primary bone cancer, metastatic bone disease, and cancer and chemotherapy-related osteoporosis.
To learn more about Balloon Kyphoplasty, visit our website at www.kyphon.com. Although the complication rate with Balloon Kyphoplasty has been demonstrated to be low, as with most surgical procedures, there are risks associated with Balloon Kyphoplasty, including serious complications. For complete information regarding indications for use, warnings, precautions, adverse events and methods of use, please reference the devices’ Instructions for Use. Kyphon and KyphX are registered trademarks and Ahead of the Curve is a trademark of Kyphon Inc. © 2007 Kyphon Inc. All rights reserved. 16000846-01
Structural Emergencies Structural Oncologic Emergencies: Recognizing These Uncommon But High-risk Situations
tructural emergencies in oncology occur infrequently but can be devastating. These anatomic or “structural” disruptions to normal function, such as increased intracranial pressure (ICP), superior vena cava syndrome, cardiac tamponade, and spinal cord compression, are therefore “low-volume, high-risk” situations. The Acute and Critical Care Special Interest Group of the Oncology Nursing Society presented a session at their 33rd Annual Congress in Philadelphia in May to help nurses identify patients at high risk, to recognize structural emergencies, and to intervene quickly. “Getting involved, recognizing [a problem] early, and doing something about it—that’s what it’s all about,” according to Cyndi Cramer, BA, RN, OCN, PCRN, clinical administrative supervisor and oncology educator, Critical Care and Pediatrics at Tampa General Hospital, Florida.
Increased intracranial pressure Cramer explained that the skull defines a fixed volume so any swelling or growth in brain tissue or increase in blood or cerebrospinal fluid will compress the brain against the skull. Normal pressure is 0 mm Hg to 15 mm Hg. Although pressure fluctuates and a transient increase may be benign, any sustained increase can be life-threatening within minutes, even without symptoms. Some risk factors for a rise in ICP are brain tumor, intracranial bleeding, central nervous system infections, internal jugular vein obstruction, hydrocephalus, and whole brain radiation > 6000 rads. Signs and symptoms are headache (especially in the early morning after being recumbent), papilledema, sudden and projectile vomiting not related to eating, ocular and visual changes, labile temperature, changes in mentation or activity, restlessness, and subtle personality changes. Diagnostics include brain imaging and cerebral angiography. Late signs may include Cushing’s triad: wide pulse pressure, bradycardia, and slow, irregular respiration. When staff or a family member says that a patient is “just not acting right, that’s when the hairs on the back of your neck should stand up,” Cramer advised. A patient may describe the headache as “the worst I’ve ever had,” she said. Interventions include hourly neurologic assessments; elevating the head of the bed 30º to 45º; maintaining an airway and ventilation; ICP monitoring; and surgery, radiation, or chemotherapy to treat the cause of the increased ICP. Useful medications include osmotic and loop diuretics, glucocorticoids, barbiturates, possible paralytics, anticonvulsants, antihypertensives, and antipyretics. Intracranial hemorrhage must be considered. 38
Superior vena cava syndrome The superior vena cava receives blood from the head, neck, arms, and upper thorax and drains into the right atrium. It has thin walls and low pressure and is encased in the thorax, surrounded by lymph node chains, so it does not have room to move and cannot resist compression from mediastinal masses. Increased pressure in the superior vena cava shunts blood to collateral pathways, mainly the azygos vein. Venous stasis may occur as a tumor grows locally. Decreased cardiac output and third spacing may occur, as well as pleural and pericardial effusions. Risk factors for superior vena cava syndrome are malignant tumors of the chest, especially right-sided lung tumors; lymphomas; esophageal, thyroid, and breast cancers; and Kaposi’s sarcoma. Nonmalignant causes include central venous catheters, benign tumors, radia-
When staff or a family member says that a patient is “just not acting right, that’s when the hairs on the back of your neck should stand up.”
tion-induced fibrosis, infections, and aortic aneurysms. Among early signs and symptoms are shortness of breath, facial and neck swelling (a patient may complain that his collar is “getting a little tight”), arm swelling, cough, chest pain, dysphagia, and vocal cord paralysis. Symptoms are usually worse on arising because of the recumbent position during sleep. Later, cyanosis of the face and upper torso, decreased peripheral pulses, hypotension, congestive heart failure, tachycardia, tachypnea, and syncope may occur. Horner’s syndrome (sinking of eyes with ptosis) may be present. Radiation is the gold standard treatment for a mediastinal mass, with good to excellent relief in the case of most lung cancers and lymphomas. Chemotherapy may be used, but a central venous catheter needs to be placed in the inferior vena cava via the femoral vein and not in the subclavian vein. “This is
patient in Fowler’s or semi-Fowler’s position to enhance venous drainage. Patients should avoid Valsalva maneuvers, bending, or stooping.
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because venous stasis can cause a local increase in concentration of the drug,” Cramer warned. Oxygen, analgesics and tranquilizers for chest pain, furosemide (being careful to avoid shock from reduced lower extremity volume), and steroids may be indicated, along with a fibrinolytic if an superior vena cava thrombus is present. Nursing interventions are maintenance of an airway; monitoring of oxygen saturation, vital signs, daily weights, and intake/output; and placing the
Cardiac tamponade Excessive accumulation of fluid in the pericardial sac increases venous pressure, reduces stroke volume, and decreases cardiac output and systemic perfusion. Compensatory mechanisms can lead to shock and cardiac arrest. The prognosis in this life-threatening condition depends on how fast fluid accumulates, the amount of pressure in the sac, and the promptness of diagnosis and intervention. In her presentation on cardiac tamponade, Linda Johnson, RN, BSN, OCN, unit manager at Huntsman Cancer Hospital in Salt Lake City, Utah, noted that risk factors are primary tumors of the heart, metastatic tumors of the pericardium, radiation
pericarditis, viral or bacterial pericarditis, uremia, collagen vascular disease, AIDS-related Kaposi’s sarcoma, and certain medications (eg, some chemotherapies, anticoagulants, procainamide, and hydralazine). Early symptoms are chest pain, dyspnea, and cough, as well as anxiety, agitation, fatigue, and hoarseness from nerve compression. Early signs are muffled heart sounds and weak or absent pulses. Late signs include tachycardia, tachypnea, peripheral edema, narrow pulse pressure, increased central venous pressure, pulsus paradoxus (inspiratory fall of systolic blood pressure > 10 mm Hg), fever, oliguria, cyanosis, and a change in mental status. The most definitive diagnostic study is echocardiography. Electrical alternans may be present on electrocardiogram, and chest imaging may show an enlarged cardiac silhouette related to fluid accumulation. Pharmacologic treatment consists of fluid administration to increase venous pressure and blood flow into the heart, pericardial sclerosing agents, corticosteroids, and chemotherapy to treat mediastinal masses. Pericardiocentesis can be both diagnostic and therapeutic. Low-dose radiation over 3 to 4 weeks may be helpful, and surgical interventions can relieve pressure in the pericardial sac. Oxygen administration can increase tissue oxygenation. Immediate nursing interventions include frequent vital sign, cardiac, hemodynamic, respiratory, and intake/output monitoring. The patient should be in a semi-Fowler’s position. On an ongoing basis, one should monitor for respiratory distress, decreased tissue perfusion, pulsus paradoxus, diminishing level of consciousness, electrocardiogram changes, hepatojugular reflux, and new onset of chest pain. A palliative care consultation may be a good idea.
Spinal cord compression Cramer gave the final talk of the session, focusing on spinal cord compression, which she said occurs in 2% to 5% of patients with cancer. Compression results directly from tumor, metastasis, or vertebral collapse, and effects may be minor or as severe as paralysis. Death from respiratory paralysis may result if the compression is at C4 or above. Patients may shrug off back pains as related to some recent activity such as lifting or to normal aging. “You’ve got to
Lymphoma Survivor Continued from page 25 their own care and for their healthcare providers to listen to their ideas and treat them as partners in their treatment. Commenting on Cari’s experience, Karen Haller, vice president, Nursing and Patient Care Services, Johns
Hopkins Hospital and associate dean for clinical affairs at the School of Nursing, recommended considering including patient representatives on hospital committees. She wrote, “Patients, especially those who stay in hospitals for long peri-
ods, are motivated to solve safety problems. Whenever possible, we should harness their wisdom” (Johns Hopkins Magazine. Summer 2006). For more information on Safepole, visit their Web site www.safepole.net.
get people to stop thinking that way,” Cramer said, because early intervention is key to preserving function. Primary tumors account for 1% to 3% of cases, with the rest from metastatic disease. Metastases seem to show a preference for the spinal level affected depending on the tissue of origin: cervical for breast; thoracic for breast, lung, prostate, and renal tumors; and lumbosacral for gastrointestinal tumors. Cancer treatments themselves can lead to lytic lesions of vertebrae. Spinal cord compression presence and extent is diagnosed by spinal radiographs, computed tomograph, magnetic resonance image, bone scan, and myelograms. The strongest indicator for a good prognosis is detection and intervention within 24 hours. Even then, most patients do not regain lost function. Up to 95% of patients first present with pain, ranging from dull or aching to severe, burning, or shooting. Most have central back pain, which may or may not radiate. Lying down provides no relief. Other early signs and symptoms are weakness; affecting mobility and coordination; and sensory loss to pain, temperature, and light touch. Later, muscle atrophy, paralysis, and bowel and bladder incontinence may ensue. Spinal shock, an extreme outcome with lesions at T6 and above, manifests as autonomic dysreflexia with hypertension, heart rate changes, and respiratory distress. Caregivers have to decide between palliative care and treatment. Depending on the cause of the spinal cord compression, interventions may include radiation, surgery, and medication, such as high-dose steroids, analgesics, lowmolecular-weight heparin, chemotherapy, bisphosphonates, and a bowel regimen. Whereas laminectomy or spinal fusion are not generally used to treat vertebral compression fractures, “kyphoplasty is a big player,” Cramer said. Patients “can have immediate relief” of pain. It involves inserting a balloon into one or more collapsed vertebrae and expanding the balloon with a quick-hardening cement to approximate the normal anatomy of the vertebra. Patients should be immobilized and log-rolled. Monitoring and assessment should focus on sensory (pinprick) and motor function (ataxia), pain, airway maintenance, good circulation to avoid deep-vein thrombosis, and bowel and bladder function. Cramer recommends maintaining urine pH < 7.0 and voiding every 2 to 3 hours or catheterizing as needed. Spinal rehabilitation may be appropriate for some patients. “Any patient with cancer who complains of new back pain, suspect something is going on,” Cramer warned, since early intervention can provide “time with quality” of life.
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Program #09CE 036 • RELEASE DATE: April 15, 2009 • EXPIRATION DATE: April 14, 2010
Reimbursement for Expensive Cancer Therapies: The Role of Cost-effectiveness Analysis BY #)& College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska To receive continuing education credit, learners must: • Read the article in its entirety • Take the CE self-assessment test and complete the evaluation test: 1. Log on to www.theoncologynurse.com. 2. Click on UNMC logo on homepage. 3. Register to participate. 4. Enter program number #09CE 036 • Complete and submit the evaluation form online (enter program number #09CE 036). Nurses must answer at least 70% of the questions on the post-test correctly. If Internet access is not available, please fax a request for an evaluation form to 402-559-6379, Attn: Anji Wittman (please include return fax number) or e-mail firstname.lastname@example.org. • The estimated time to complete this activity is 1 hour. Your continuing education certificate can be printed by following the directions online after successful completion of the post-test. The opinions or views expressed in this continuing education activity are those of the faculty and do not necessarily reflect the opinions or recommendations of the University of Nebraska Medical Center College of Nursing Continuing Nursing Education.
ue to changes in the US Food and Drug Administration (FDA) approval process for cancer drugs, many new cancer drugs have been approved over the past 10 to 15 years. Although the availability of these new drugs has improved survival for many cancer patients, there is increasing concern over the cost of these agents.1 The global oncology market is predicted to increase 12% to 15% each year, from $48 billion in 2008 to $75 billion to $80 billion in 2012.2 About 70% of all sales of cancer drugs in North America and the European Union are of agents introduced in the past 10 years. Although purchasers and payers have always been concerned about healthcare costs, recently concerns have been raised by providers (ie, hospitals and oncologists) and patients. In an effort to control the utilization of expensive specialty drugs, many insurers have added a fourth tier to their pharmacy benefit plans.3 In contrast to the modest copayments required for other tiers, the fourth tier usually requires that patients pay a percentage of the drug cost (ie, coinsurance). Coinsurance payments, which generally range from 20% to 33% of the All planners and faculty participating in continuing education activities provided by the University of Nebraska Medical Center, College of Nursing Continuing Nursing Education are expected to disclose to the audience any significant support or substantial relationship(s) with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporters of the activity. In addition, all faculty are expected to openly disclose any off-label, experimental, or investigational use of drugs or devices discussed in their presentation. The planners and faculty have been advised that this activity must be free from commercial bias and based upon all the available scientifically rigorous data from research that conforms to accepted standards of experimental design, data collection, and analysis.
While the University of Nebraska Medical Center College of Nursing Continuing Nursing Education is an ANCC accredited organization, this does not imply endorsement by the UNMC or ANCC of any commercial products affiliated with this activity. After completing this activity, the reader should be better able to: • Describe the types of cost analyses used in making decisions about reimbursement for cancer drugs. • Explain the role of cost-effectiveness in reimbursement decisions in the United States compared with the United Kingdom and Canada. • Provide an example of how cost-effectiveness analysis may affect decisions about coverage of a new cancer therapy. Advanced practice nurses, registered nurses, and other interested healthcare professionals, especially those caring for cancer patients. This program is complimentary for all learners.
drug cost, can sometimes exceed $10,000 each year. Elderly patients with Medicare coverage who receive their chemotherapy in the clinic setting are subject to similar coinsurance payments. As a result, many patients cannot afford the coinsurance payments.4 With declining reimbursement, private oncology offices and hospital-based clinics are caught in the middle, and many now require up-front payment before chemotherapy administration.5 In a recent survey, 23% of oncologists responded that costs influenced their treatment decisions, and 16% said that they omit discussion of very expensive treatments when they know that cost would place a great strain on patient resources.6 In this review, a recently published cost-effectiveness analysis will be used to illustrate how these types of analyses may be used by policy makers to make reimbursement decisions concerning cancer drugs.
Case study: sunitinib for first-line treatment of metastatic renal cell carcinoma Sunitinib malate is a recently approved, orally administered small
The authors, reviewers, and planning committee members listed below have stated they have no significant or substantial relationship with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporter of this activity. • Lisa Anzai, RN, MA • Catherine Bevil, RN, EdD • Carole R. Chambers, BSc (Pharm), MBA • Susan Goodin, PharmD, FCCP, BCOP • Dawn Lagrosa • Emily Lauritzen • Lara J. Reiman • Karen Rosenberg The following author has stated that she has the following financial relationships: • Lyssa Friedman, RN, MPA, OCN, is an employee of Veracyte, Inc.
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• Gary C. Yee, PharmD, FCCP, BCOP, serves on the utilization management and national pharmacy & therapeutics committees for a large pharmacy benefits manager. The University of Nebraska Medical Center College of Nursing Continuing Nursing Education is accredited as a provider of conCollege of Nursing Continuing Nursing Education tinuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. This activity is provided for 1.0 contact hour under ANCC criteria. Provided for 1.2 contact hours under Iowa Provider #78. Provider Approved by the California Board of Registered Nursing, Provider #13699 for 1.2 contact hours.
EDITORIAL BOARD )(%!#&!)∗#)& Director of Pharmacy Alberta Cancer Board 1331-29th Street NW Edmonton, Alberta T2N 4 N2 Canada /∗∗)∃! &∋ Senior Director, Clinical Programs Veracyte, Inc. 7000 Shoreline Court South San Francisco, CA 94080 ,∗∋(( ∃∋#)& Director, Division of Pharmaceutical Sciences Cancer Institute of New Jersey 195 Little Albany Street New Brunswick, NJ 08903-2681 )/!!#)& Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center 986405 Nebraska Medical Center Omaha, NE 68198-6045 PLANNING COMMITTEE ∃∗∋0∃ Nurse Planner University of Nebraska Medical Center College of Nursing 985330 Nebraska Medical Center Omaha, NE 68198-5330 +#!)∃∋!!−∃% Director, Continuing Nursing Education and Evaluation University of Nebraska Medical Center College of Nursing 985330 Nebraska Medical Center Omaha, NE 68198-5330 .∋∀)(∗ Associate Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 &∃%/,)∃+0!∋ University of Nebraska Medical Center College of Nursing 985330 Nebraska Medical Center Omaha, NE 68198-5330 )!∃&∋ Managing Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 )!∋(∗!∋!)∀ Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831
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Table. Cost-effectiveness of Targeted Agents for Renal Cell Carcinoma Treatment
Base-Case ICER (Cost [£] per QALY) NICE Manufacturer
First-line treatment, suitable for immunotherapy Sunitinib IFN Bevacizumab plus IFN IFN
First-line treatment, poor prognosis Temsirolimus IFN
Second-line treatment Sorafenib
BSC indicates best supportive care; ICER, incremental cost-effectiveness ratio; IFN, interferon; NICE, National Institute for Health and Clinical Excellence; QALY, qualityadjusted life-year. Adapted with permission from Coon JT, Hoyle M, Green C, et al; Peninsula Technology Assessment Group. Bevacizumab, sorafenib tosylate, sunitinib, and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation. Exeter, UK: Peninsula Medical School; May 2008.
molecule with antitumor activity against renal cell carcinoma, gastrointestinal stromal tumors, and other solid tumors. The annual cost of sunitinib in the United States is $50,000 to $60,000. A recently published large multicenter, randomized, phase 3 trial showed that
sunitinib was superior to interferon alfa in patients with previously untreated metastatic renal cell carcinoma.7 Sunitinib-treated patients had a significantly higher objective response rate (31% vs 6%, P <.001) and longer median progression-free survival (11 vs 5
months, P <.001) than those treated with interferon alfa. In a recent update of that trial, patients in the sunitinib group had longer median overall survival than those in the interferon alfa group (26.4 vs 21.8 months), although the difference was of borderline significance (P = .051).8 Based on the results of that phase 3 trial, a Pfizer-supported cost-effectiveness analysis was conducted, and the results of that analysis were recently published.9 A Markov model was developed to evaluate the costeffectiveness and cost-utility of sunitinib (as compared with interferon alfa or interleukin-2) in a hypothetical cohort of 1000 patients with metastatic renal cell carcinoma receiving first-line treatment of sunitinib. The analysis was done from a US societal perspective. Model parameters were obtained from trial results, published literature, government sources, and expert opinion. A 10-year time horizon was assumed to represent a lifetime horizon, because the model predicted that fewer than 1% of patients would still be alive at 10 years. Utilities were derived from quality-of-life data collected with the EuroQoL (EQ-5D) instrument in clinical trials. Only direct medical costs were included. Sunitinib was more effective and more costly than interferon alfa. Both sunitinib and interferon alfa dominated interleukin-2 (ie, more effective and less costly). The incremental cost-effectiveness or cost-utility ratio of sunitinib versus interferon alfa was $18,611 per progression-free year gained, $67,215 per life-year gained, or
Reimbursement for Expensive Cancer Therapies: The Role of Cost-effectiveness Analysis: Implications for Nurses BY Senior Director, Clinical Programs, Veracyte, Inc, South San Francisco, California
he economic news is abysmal. Unemployment has skyrocketed; home values and retirement savings accounts have plummeted. Start saving, the pundits advise; ease spending. Even President Obama counseled, “Our economy is badly weakened, a consequence of greed and irresponsibility on the part of some, but also our collective failure to make hard choices and prepare the nation for a new age.”1 Nowhere is the downturn felt more than in healthcare. According to the Centers for Medicare and Medicaid Services (CMS), total US health expenditures reached $2.2 trillion in 2007, which equals about $7421 per person or 16.2% of the nation’s gross domestic product (GDP).2 In the accompanying article, Yee notes that the United Kingdom controls healthcare costs by using cost-effectiveness to decide which therapies are approved. Britain’s National Institute for Health and Clinical Excellence (NICE), under fire for denying high-cost drugs such as sunitinib for patients with metastatic renal cell carcinoma, has support from health policy experts in countries around the globe, including the United States. Here, however, efforts by CMS to apply such controls meet with considerable backlash and have been unsuccessful.3 “Why does U.S. health care cost so much?” asked Princeton University economist Uwe E. Reinhardt. He noted that although high healthcare costs are common in
wealthy countries (as defined by high GDP), healthcare spending is considerably higher per capita in the United States than elsewhere in the developed world. Reinhardt attributed what health services researchers call “excess spending” to several factors, such as4: • Higher prices for healthcare goods and services than those paid in other countries for the same goods and services • Higher administrative overhead costs than those incurred in other countries with simpler health insurance systems • More use of high-cost, high-technology equipment and procedures than are used in other countries • Higher healthcare utilization related to American tort laws, in which tests and procedures are used as a defense against possible future malpractice litigation. Oncology nurses who see themselves as patient advocates may find it difficult to support the NICE model in the United States. The Oncology Nursing Society 20092012 strategic plan lists advocacy as its primary strategic area, with efforts targeted at increasing cancer services reimbursement, promoting legislation to ensure access to care and clinical trials, and advocating for medically underserved populations.5 Health services policy experts may view healthcare at the population level, but in the United States, nurse advocates evaluate healthcare one patient at a time. Yee describes cost-effectiveness and
cost-utility ratios, which lead to rationing of costly therapies. To nurses, rationing may seem acceptable in the abstract yet untenable when applied to an individual patient or family member. Yee suggests that the United States is at a crossroads; society has postponed the use of cost models to drive reimbursement, yet society can no longer bear cancer care’s rising cost. Perhaps an ethical society cannot justify denying care from an individual, but if healthcare breaks down population-wide, the healthcare system no longer benefits even one person. Perhaps ethically we cannot afford to withhold a single dose of sunitinib; system-wide, however, can we afford not to? References
1. Obama B. Transcript: Barack Obama’s inaugural address. New York Times. January 20, 2009. 2. Centers for Medicare and Medicaid Services. National health expenditures 2007 highlights. www.cms.hhs.gov/NationalHealthExpendData/ downloads/highlights.pdf. Accessed February 9, 2009. 3. Harris G. The evidence gap: British balance benefit vs. cost of latest drugs. New York Times. December 2, 2008. 4. Reinhardt UE. Why does U.S. health care cost so much (part 1)? Economix/New York Times Blog. November 14, 2008. http:// economix.blogs.nytimes.com/2008/11/14/why-does-us-health-carecost-so-much-part-i/?scp=2&sq=health%20care%20cost&st=cse. Accessed February 2, 2009. 5. Oncology Nursing Society strategic plan pillar description document (2009-2012). April 15, 2008. http://onsopcontent.ons.org/Corporate Reports/strategic.shtml. Accessed February 2, 2009.
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$52,593 per quality-adjusted life-year (QALY) gained (2006 US dollars; costs and outcomes discounted at 5%). A probabilistic sensitivity analysis showed that the model was most sensitive to utility values during treatment, sunitinib cost, and the cost of best supportive care. The authors concluded that sunitinib is a cost-effective alternative to interferon alfa as first-line treatment for metastatic renal cell carcinoma because the costeffectiveness (or cost-utility) ratios were in the range of values that society (in the United States) is willing to pay for health benefits.
NICE declines drugs for metastatic renal cell carcinoma In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE), a government agency, advises the National Health Service (NHS) on coverage for medicines and technologies.10 Details on its appraisal process are available online on the NICE web site (www.nice.org.uk). NICE usually hires an academic group to prepare its appraisals, which include an economic evaluation that estimates the incremental cost-effectiveness (or cost-utility) ratio of the new drug. These appraisals can sometimes take 2 to 3 years after a drug has been approved. The NHS then considers these analyses when it makes decisions concerning reimbursement for that new drug or technology.
In August 2008, NICE issued draft guidance that rejected the use of four drugs, including sunitinib, for metastatic renal cell carcinoma.11 Although the report concluded that the four drugs were effective, NICE rejected them because its analysis showed that they were “not cost-effective use of NHS resources” based on its usual threshold of £30,000 per QALY (Table). It is interesting to note that estimates of the cost-effectiveness ratios of the four drugs from the manufacturers differed considerably from the estimates from the independent academic group hired by NICE. The estimated cost-utility ratio for sunitinib in the setting of first-line treatment in the Pfizer model submitted to NICE was about 25% lower than the value reported in the study published by Remák and associates,9 which is about the same as the difference in sunitinib cost between the United States and Britain. That decision angered patients and physicians, because the drugs are widely available in other European countries. Furthermore, British patients were angered by the NHS guidelines, which state that they would lose all of their NHS benefits if they decided to pay for the cancer drugs with their personal funds. In response to this outcry, the British government announced in November 2008 that it would not withdraw NHS benefits from patients who choose to pay out-of-pocket for cancer drugs and issued new guidelines to NICE that encourage greater flexibil-
ity when NICE appraises high-cost drugs for patients with rare and serious conditions. Some reports indicate that NICE will increase the threshold to as high as £80,000 per QALY for these selected drugs. In a final ruling announced March 25, 2009, NICE recommends sunitinib for the first-line treatment of renal cancer.
Role of cost-effectiveness analysis in reimbursement decisions In the United States, the single largest payer of healthcare for cancer patients is the Centers for Medicare and Medicaid Services. The long-standing Medicare policy is to not consider cost-effectiveness analyses in its reimbursement decisions.12 Private insurers also have been reluctant to formally consider costeffectiveness analyses in its reimbursement decisions. Although cancer drugs usually have been viewed as “off limits” for utilization management strategies, the high cost of these agents has prompted private insurers to apply these strategies to cancer drugs.13,14 Some insurers are limiting the use of these agents to FDAapproved indications, which can be problematic because cancer drugs are often used for “off-label” indications and because some drugs are approved based on limited evidence. Others are applying step-therapy protocols to cancer drugs, which require that patients fail one or more less expensive options before they are eligible to
Reimbursement for Expensive Cancer Therapies: The Role of Cost-effectiveness Analysis: A Canadian Pharmacist’s Perspective BY Pharmacy Director, Alberta Cancer Board, Edmonton, Alberta
he role of cost-effectiveness analysis in expensive cancer therapies is a timely topic, with the recent release of the updated National Institute for Health and Clinical Excellence (NICE) guidance document for cancer drugs in the United Kingdom and the studies on the new therapies for treating renal cell carcinoma. However, funding decisions continue to challenge us. Although many of the new tyrosine kinase inhibitors (TKIs) for the treatment of renal cell carcinoma have been available for more than 2 years, funding questions have not resolved. The incorporation of cost-effectiveness in the evaluation of new drugs and technologies is anticipated in certain countries, such as Canada.1 Our provincial oncology program annually identifies those cancer agents that consume 80% of the cancer drug program resources. Thirteen agents consumed 80% of the resources for the calendar year 2008; nine (70%) of these agents did not exist in the marketplace 10 years ago. Should we perform economic evaluations as a pharmaceutical is undergoing clinical trials? The National Cancer Institute of Canada (NCIC) Working Group on Economics recommends that at least one of the following criteria be met before an economic analysis is undertaken alongside a clinical trial2: • The new intervention is anticipated to have only a modest therapeutic benefit in a potentially large population • The new therapy is potentially very costly
• There is a high degree of uncertainty about the economic impact of the treatment of interest • An economic evaluation associated with equivalence trials may yield information of importance in the determination of routine practice • Economic data will assist future economic evaluation of new therapies. Because of the controlled environment of a clinical trial, the result of the economic analysis is the intervention’s cost efficacy; after it is released into the market, we can learn its true cost-effectiveness. A novel idea being discussed in the literature is “coverage with evidence development,” which explores funding approvals for promising technologies and drugs for which the evidence remains uncertain.3,4 One-time decisions regarding funding may become history as evidence continues to accumulate during the early stages of drug market entry, and this new concept provides for earlier access to the new therapy but ongoing scrutiny. Economic evaluation is one of many tools that can be used by decision makers, but it cannot serve alone to make such value-based decisions.5 As Yee explains, NICE came to different conclusions over time. The use of cost-effectiveness by panels such as NICE does not guarantee that similar decisions are made as values are implicitly or explicitly a part of the recommendations for funding. In Canada, we have a Common Drug Review (CDR) for review of all new pharmaceuticals. CDR did not support the use of public funds for
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the TKIs in renal cell carcinoma in the spring of 2007. On March l, 2007, a new oncology-focused panel called the Joint Oncology Drug Review (JODR) was formed.6 JODR, which uses both clinical and pharmacoeconomic review tools in its decision-making, is similar to NICE and the new panel under consideration for the United States. JODR has supported the use of sunitinib for renal cell carcinoma as well as sorafenib for second-line therapy. Access to cancer drugs is an evolving area that is not yet resolved and is an important consideration for all those involved in the decision-making process. References
1. Guideline for the Economic Evaluation of Health Technologies: Canada. 3rd ed. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health; 2006. 2. Evans WK, Goyle D, Gafni A, Walker H; NCIC Working Group on Economic Analysis. Which cancer clinical trials should be considered for economic evaluation? Selection criteria from the National Cancer Institute of Canada’s Working Group on Economic Analysis. Chronic Dis Can. 2003;24:102-107. 3. Hutton J, Trueman P, Henshall C. Coverage with evidence development: an examination of conceptual and policy issues. Int J Technol Assess Health Care. 2007;23:425-432. 4. Tunis SR, Pearson SD. Coverage options for promising technologies: Medicare’s ‘coverage with evidence development.’ Health Aff (Millwood). 2006;25:1218-1230. 5. Browman GP, Manns B, Hagen N, et al. 6-STEPPPs: a modular tool to facilitate clinician participation in fair decisions for funding new cancer drugs. J Oncol Pract. 2008;4:2-7. 6. Jeffcott G. New initiatives in managing access to cancer drugs. Provincial Reimbursement Advisor. May 2007:43-48.
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receive the more expensive agent. One innovative approach is a “pay-for-performance” strategy, which means that the manufacturer agrees to lower the price its drug by providing a rebate if the drug fails to perform.15,16 Several manufacturers have already agreed to that strategy in Britain, and at least one large private insurer in the United States is exploring it. Many policy experts support an expanded role of cost-effectiveness analyses in determining reimbursement decisions, including the creation of a new federally funded, independent entity (modeled after NICE) to produce comparative effectiveness and cost-effectiveness information.1,12,17-19 Some argue that payers already make these comparisons, either implicitly or explicitly. Creation of such a formal entity was recently predicted to yield savings of $368 billion to the healthcare system over the next 10 years.19 Although cost-effectiveness analyses can be useful to decision makers, healthcare professionals and the public are skeptical of the use of these types of information and are uncomfortable with efforts to allocate resources based on the economic value of a person’s life.20 Ideally, the public (ie, society) should determine how societal resources are allocated. Private employers, however, are major purchasers of healthcare in the United States. The outcry in Britain over NICE’s decision concerning drugs to treat renal cell carcinoma suggests that the public views cancer drugs differently from other drugs. In response, NICE has adjusted its cost-effectiveness threshold for certain cancer
drugs. Similarly, some experts suggest Americans do not want to consider cost when making decisions concerning new cancer treatments.20
Summary The rising cost of cancer drugs is of concern to society, particularly patients with cancer, who often cannot afford the newer agents. Although decision makers have been reluctant to consider cost-effectiveness analyses in reimbursement decisions, there is increasing support for an expanded role of these types of analyses, including the creation of a new federally funded entity to produce these analyses. As illustrated by the experiences in Britain, however, application of cost-effectiveness analyses to reimbursement decisions for cancer drugs can be controversial because of the societal burden of cancer. Disclosure Dr. Yee serves on the utilization management and national pharmacy & therapeutics committees for a large pharmacy benefits manager. References 1. Sinha G. Expensive cancer drugs with modest benefit ignite debate over solutions. J Natl Cancer Inst. 2008;100:1347-1349. 2. Gavel SJ. The oncology pipeline: maturing, competitive, and growing? Oncology Business Review. Sept 2008. www.imshealth.com/im shealth/ Global/Content/Web%20Article/The_Oncology_Pipeline3.pdf. Accessed February 6, 2009. 3. Kolata G. Co-payments soar for drugs with high prices. New York Times. April 14, 2008.
4. Kolata G, Pollack A. Costly cancer drug offers hope, but also a dilemma. New York Times. July 6, 2008. 5. Chase M. Pricey drugs put squeeze on doctors. Wall Street Journal. July 8, 2008. 6. Schrag D, Hanger M. Medical oncologists’ views on communicating with patients about chemotherapy costs: a pilot survey. J Clin Oncol. 2007;25:233-237. 7. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2008;356:115-124. 8. Figlin RA, Hutson TE, Tomczak P, et al. Overall survival with sunitinib versus interferon-alfa as first-line treatment of metastatic renal cell carcinoma [abstract]. J Clin Oncol 2008;26(suppl)Abstract 5024. 9. Remák E, Charbonneau C, Négrier S, et al. Economic evaluation of sunitinib malate for the first-line treatment of metastatic renal cell carcinoma. J Clin Oncol. 2008;26:3995-4000. 10. Steinbrook R. Saying no isn’t NICE—travails of Britain’s National Institute for Health and Clinical Excellence. N Engl J Med. 2008;359:1977-1981. 11. Harris G. British balance benefit vs. cost of latest drugs. New York Times. December 2, 2008. 12. Neumann PJ, Rosen AB, Weinstein MC. Medicare and cost-effectiveness analysis. N Engl J Med. 2005;353:1516-1522. 13. Anand G. As costs rise, new medicines face pushback. Wall Street Journal. September 18, 2007. 14. Chase M. Payers aim to rein in specialty-drug spending. Wall Street Journal. March 20, 2008. 15. Pollack A. Pricing pills by the results. New York Times. July 14, 2007. 16. Garber AM, McClellan MB. Satisfaction guaranteed—“payment by results” for biologic agents. N Engl J Med. 2007;357:1575-1577. 17. Emanuel EJ, Fuchs VR, Garber AM. Essential elements of a technology and outcomes assessment initiative. JAMA. 2007;298:1323-1325. 18. American College of Physicians. Information on cost-effectiveness: an essential product of a national comparative effectiveness program. Ann Intern Med. 2008;148:956-961. 19. Davis K. Slowing the growth of health care costs—learning from international experience. N Engl J Med. 2008;359:1751-1755. 20. Berenson A. Pinning down the money’s value of a person’s life. New York Times. June 11, 2007.
Reimbursement for Expensive Cancer Therapies: The Role of Cost-effectiveness Analysis: A US Pharmacist’s Perspective BY Cancer Institute of New Jersey, New Brunswick
magine if you can, buying your dream home at today’s median price of $198,6001 and then being told you can only live in it 2.4 months of the year, or 20% of the time. We all would understand the ramifications of such a decision and, as long as there were other alternatives, this is not an agreement we would enter into from a financial standpoint. Similarly, although the newest cancer drugs offer improvements over older therapies, they often cost thousands of dollars more a month with response rates around 20%. It is a similar type decision, payers, providers, and patients struggle with every day to decide which drugs are worth the increased costs. While there are patients dying of cancer every minute of every day, we must be smart about drug selection, because the direct medical costs of cancer are $89 billion a year2 and continue to rise. Genetic testing has been shown to boost efficacy in cancer care, and reduce costs, but we are still a long way from having a test to predict for response with every new drug. An example of how this could reduce drugs costs is testing for Kirsten rat sarcoma (KRAS) mutations before prescribing cetuximab, which was approved by the US Food and Administration in 2004. Patients with KRAS mutations do not respond to cetuximab, and it has been estimated that limiting cetuximab to patients without these mutations will save the country up to $604 million a year.3 Putting this savings in perspective, if the lack of a KRAS
mutation had been identified at the time of approval as a predictor for the pool of patients who may have benefited from cetuximab, a healthcare savings of approximately $2.4 billion may have occurred. As many of the newly approved agents do not have a biomarker for prediction of response, cost is becoming the “biomarker” used by policy makers for coverage decisions. Yee discusses a recently published cost-effectiveness analysis that could be used in making these policy decisions, instead of the evaluation of these agents based on cost alone. Pharmacists must be familiar with cost-effectiveness analyses that have been performed and the methodology behind their calculations. In addition to understanding the recent literature on cost-effective analyses, pharmacists in the ambulatorycare setting must be familiar with the recent changes to the Centers for Medicare and Medicaid Services (CMS) “off-label” reimbursement and the current compendia for coverage, because cost-effectiveness analyses are not currently a part of the reimbursement decision. At my own institution, a policy has been in place since 1993 that requires the prescribed regimen be a nationally accepted treatment regimen, as defined in standard textbooks or documented in a peer-reviewed publication or multi-institutional trial that is published as an abstract, but the final decision is left with the dispensing pharmacist. This policy was not developed because
of reimbursement issues but because we support evidence-based care. It has made the transition to the new CMS guidelines easy, because compendia follow similar rules for “off-label” reimbursement. I urge all pharmacists to evaluate their institutional policies regarding “off-label” use and base their decisions on evidence, not solely on reimbursement, whether the payer is CMS or another third-party payer. If we “police” ourselves regarding these decisions, we will not have payers dictating therapy. Healthcare costs, and ultimately payers, eventually will drive down prices of pharmaceuticals, and the pharmaceutical industry will have to be more efficient in drug development and identification of the appropriate patient population. Until this goal is attained, pharmacists must be at the table with the appropriate understanding of cost-effectiveness when making decisions regarding formularies, reimbursement, and patient care. References
1. Freedman R. 2009 economic outlook. January 2009. www.realtor.org/ rmonews_and_commentary/articles/2009/0901_residentialoutlook2009. Accessed February 3, 2009. 2. Schwartz K, Claxton G, Martin K, Schmidt C; Kaiser Family Foundation, American Cancer Society. Spending to Survive. February 2009. www.cancer.org/downloads/accesstocare/Spending_to_Survive. pdf. Accessed February 9, 2009. 3. Gardner A. Researchers zero in on GI cancers. USA Today. January 14, 2009.
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Gastrointestinal Cancers Preventing Skin Toxicity from EGFR Inhibitors SAN FRANCISCO—Skin toxicity associated with the use of epidermal growth factor receptor (EGFR) inhibitors for colorectal cancer can be prevented with an upfront “preemptive” treatment regimen, according to investigators who presented their findings at the 2009 Gastrointestinal Cancers Symposium. Skin toxicity—mainly, a severe acneiform rash—is the main side effect of the EGFR inhibitors cetuximab and panitumumab. These agents have become key components in the treatment of metastatic colorectal cancer and are being evaluated in other tumors. The prophylactic approach is new, as management of skin toxicity is usually driven by symptoms that emerge during chemotherapy. In many cases, treatment must be delayed or even discontinued while the rash is treated. “I have had patients completely refuse to be treated with these drugs because they don’t want to look like another patient they know,” said Edith Mitchell, MD, of Thomas Jefferson University, Philadelphia, who presented the findings. The lead author was Mario E. Lacouture, MD, director of the Cancer Skin Care Program at Northwestern University, Chicago. The preemptive regimen consisted of moisturizers, paraaminobenzoic acid (PABA)–free sunscreen rated sun protective factor (SPF) ≥ 15, topical steroid cream (hydrocortisone 1%), and doxycy-
Table. Commonly Observed Skin Toxicities Preemptive skin treatment (N = 48) Toxicity
Any grade, N (%)
Grade 4, N (%)
Any grade, N (%)
Grade 3, N (%)
Grade 4, N (%)
cline 100 mg twice daily. Use of this preemptive regimen reduced by half the occurrence of skin toxicity in the study presented at the meeting. The study randomized 95 patients to preemptive therapy starting 24 hours before the first scheduled dose of panitumumab (with folinic acid, fluorouracil, irinotecan [FOLFIRI]) and continued for 6 weeks, or to “reactive” therapy administered after toxicity occurred. The primary end point was the incidence of grade 2 or higher skin toxicity. At 6 weeks, patients randomized to preemptive skin therapy had a 29% incidence of protocol-specified grade 2 or higher skin toxicity, compared with 62% among patients in the reactive treatment arm, Mitchell reported. Specifically, grade 2 skin toxicity
Skin reactions to EGFR inhibitor, before and after treatment of the eruption. Reprinted with permission from Lacouture ME, Basti S, Patel J, Benson A III. An interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol. 2006;4:236-238 (top); and Boone SL, Rademaker A, Liu D, et al. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology. 2007;72:152-159 (bottom). 44
Grade 3, N (%)
Reactive skin treatment (N = 47)
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occurred in 23% and 40%, respectively, and grade 3 toxicity occurred in 6% and 21%, respectively. Manifestations of this toxicity are shown in the Table. Median time to first occurrence of grade ≥ 2 skin toxicity was 2.1 weeks in the reactive treatment arm, but has not been reached in the preemptive arm. Preemptive therapy also helped patients stay on treatment, with 155 total panitumumab doses given compared with 141 doses in the reactive group. Dose delays occurred in 1% and 6% of the arms, respectively. Clinical response and other outcome measures were not negatively impacted by the treatments. Interestingly, adverse events other than skin toxicity were also reduced in the prophylactic arm, including diarrhea, neutropenia, hypomagnesemia, and dehydration. The reason for this is unclear, Mitchell said. “Patients in the prophylactic treatment group also reported improved quality of life, especially during weeks 2 to 3, when half the reactive treatment patients had first experienced a grade 2 or higher event,” she added. Preemptively treated patients, however, did not discontinue treatment at a lower rate than reactively treated patients, Mitchell explained, “We were seeing all patients weekly, and we think this enhanced compliance in both arms.” Robert Mayer, MD, professor of medicine at Dana-Farber Cancer Center, Boston, said the findings are important because skin toxicity is the reason that many patients discontinue treatment with EGFR inhibitors. “The antitumor response rates were the same, and there was less toxicity with preemptive treatment. That’s the good news,” he said. “The bad news is that this was not shown to impact patients in terms of therapeutic outcomes of panitumumab (ie, preemptively treated patients had no additional improvement in clinical outcomes).” —Caroline Helwick
Colorectal Screening Guidelines Not Always Followed
lder adults with a life expectancy of < 5 years and significant comorbidities who visit their doctor four or more times a year are as likely to be screened for colorectal cancer (CRC) as healthier patients with fewer doctor visits, according to a study of Veterans Affairs (VA) medical center patients. VA, American Cancer Society, and the American Geriatrics Society guidelines recommend CRC screening for older adults only if they have a life expectancy of ≥ 5 years and do not have significant comorbidities. In a study of 27,068 VA patients 70 years or older, Louise C. Walter, MD, and associates found that overall, 46% of patients 70 years or older who had an outpatient visit at a VA medical center in 2001 or 2002 and were due for screening were screened. Of those with no comorbidity and life expectancy of ≥ 5 years, 47% were screened. Screening rates decreased with age and worsening comorbidity, but nonetheless, 41% of patients with severe comorbidity and life expectancy < 5 years were screened. The authors concluded that the findings indicate that more attention to comorbidities is needed to better target CRC screening to older patients with substantial life expectancies and to avoid it in those with limited life expectancies (Ann Intern Med. 2009; 150:465-473).
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Gastrointestinal Cancers Octreotide LAR Blunts Disease Progression in Patients with Midgut Neuroendocrine Tumors SAN FRANCISCO—The somatostatin analog octreotide long-acting release (LAR) can slow disease progression in patients with metastatic neuroendocrine midgut tumors, according to the results of a phase 3b study conducted at 18 cancer sites in Germany.
The data, released at the American Society of Clinical Oncology’s 2009 Gastrointestinal Cancers Symposium, showed that octreotide LAR was associated with a statistically significant 66% reduction in the risk of disease progression compared with placebo after 6 months of treatment.
“We believe that our study will change the way this disease is treated, with the study drug offering a ‘first-drug option’ for patients who can’t be cured by surgery,” said principal investigator Rudolf Arnold, MD, with Philipps University in Marburg, Germany. Arnold and his colleagues random-
NEXAVAR (sorafenib) tablets, oral Initial U.S. Approval: 2005 BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 1.1 1.2 4
CONTRAINDICATIONS NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR.
WARNINGS AND PRECAUTIONS Risk of Cardiac Ischemia and/or Infarction In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in NEXAVAR patients compared with 1.3% in the placebo group and in RCC Study 1, the incidence of cardiac ischemia/infarction was higher in the NEXAVAR group (2.9%) compared with the placebo group (0.4%). Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. Temporary or permanent discontinuation of NEXAVAR should be considered in patients who develop cardiac ischemia and/or infarction. Risk of Hemorrhage An increased risk of bleeding may occur following NEXAVAR administration. In the HCC study, an excess of bleeding regardless of causality was not apparent and the rate of bleeding from esophageal varices was 2.4% in NEXAVAR patients and 4% in placebo patients. Bleeding with a fatal outcome from any site was reported in 2.4% of NEXAVAR patients and 4% in placebo patients. In RCC Study 1, bleeding regardless of causality was reported in 15.3% of patients in the NEXAVAR group and 8.2% of patients in the placebo group. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR patients, and 1.3% and 0.2%, respectively, in placebo patients. There was one fatal hemorrhage in each treatment group in RCC Study 1. If any bleeding necessitates medical intervention, permanent discontinuation of NEXAVAR should be considered. Risk of Hypertension Blood pressure should be monitored weekly during the first 6 weeks of NEXAVAR therapy and thereafter monitored and treated, if required, in accordance with standard medical practice. In the HCC study, hypertension was reported in approximately 9.4% of NEXAVAR-treated patients and 4.3% of patients in the placebo group. In RCC Study 1, hypertension was reported in approximately 16.9% of NEXAVAR-treated patients and 1.8% of patients in the placebo group. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. In cases of severe or persistent hypertension, despite institution of antihypertensive therapy, temporary or permanent discontinuation of NEXAVAR should be considered. Permanent discontinuation due to hypertension occurred in 1 of 297 NEXAVAR patients in the HCC study and 1 of 451 NEXAVAR patients in RCC Study 1. Risk of Dermatologic Toxicities Hand-foot skin reaction and rash represent the most common adverse reactions attributed to NEXAVAR. Rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of treatment with NEXAVAR. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of NEXAVAR, or in severe or persistent cases, permanent discontinuation of NEXAVAR. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 of 297 NEXAVAR HCC patients and 3 of 451 NEXAVAR RCC patients. Risk of Gastrointestinal Perforation Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking NEXAVAR. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, NEXAVAR therapy should be discontinued. Warfarin Co-Administration Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on NEXAVAR therapy. Patients taking concomitant warfarin should be monitored regularly for changes in prothrombin time, INR or clinical bleeding episodes. Wound Healing Complications No formal studies of the effect of NEXAVAR on wound healing have been conducted. Temporary interruption of NEXAVAR therapy is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of NEXAVAR therapy following major surgical intervention. Therefore, the decision to resume NEXAVAR therapy following a major surgical intervention should be based on clinical judgment of adequate wound healing. Interactions with UGT1A1 Substrates Sorafenib can cause increases in plasma concentrations of drugs that are substrates of UGT1A1. Caution is recommended when administering NEXAVAR with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan) [see Drug Interactions (7.1)**].
INDICATIONS AND USAGE Hepatocellular Carcinoma NEXAVAR is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC). Renal Cell Carcinoma NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
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ized 85 patients to octreotide LAR 30 mg or placebo given by intramuscular administration every 4 weeks. Treatment was continued for 18 months or until there was evidence of tumor progression or the patient died. All participants were treatmentnaïve and had histologically confirmed
Interaction with Docetaxel Sorafenib can cause increases in plasma concentrations of docetaxel. Caution is recommended when NEXAVAR is co-administered with docetaxel [see Drug Interactions (7.2)**]. 5.10 Interaction with Doxorubicin Sorafenib can cause increases in plasma concentrations of doxorubicin. Caution is recommended when NEXAVAR is co-administered with doxorubicin [see Drug Interactions (7.3)**]. 5.11 Pregnancy: Pregnancy Category D Sorafenib may cause fetal harm when administered to a pregnant woman. In rats and rabbits, sorafenib has been shown to be teratogenic and to induce embryo-fetal toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight). The effects occurred at doses considerably below the recommended human dose of 400 mg twice daily (approximately 500 mg/m2/day on a body surface area basis). Adverse intrauterine development effects were seen at doses ≥1.2 mg/m2/day in rats and 3.6 mg/m2/day in rabbits (approximately 0.008 times the AUC seen in cancer patients at the recommended human dose). A NOAEL (no observed adverse effect level) was not defined for either species, since lower doses were not tested. There are no adequate and well-controlled studies in pregnant women using NEXAVAR. Women of childbearing potential should be advised to avoid becoming pregnant while on NEXAVAR. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 5.12 Hepatic Impairment Hepatic impairment may reduce plasma concentrations of sorafenib. Comparison of data across studies suggests that sorafenib levels are lower in HCC patients than in non-HCC patients (without hepatic impairment). The AUC of sorafenib is similar between HCC patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. The optimal dose in non-HCC patients with hepatic impairment is not established [see Use in Specific Populations (8.6**) and Clinical Pharmacology (12.3)**]. 6
ADVERSE REACTIONS The following risks are discussed in greater detail in the WARNINGS AND PRECAUTIONS section (5): • Cardiac ischemia, infarction [see Warnings and Precautions (5.1)] • Hemorrhage [see Warnings and Precautions (5.2)] • Hypertension [see Warnings and Precautions (5.3)] • Hand-foot skin reaction and rash [see Warnings and Precautions (5.4)] • Gastrointestinal perforation [see Warnings and Precautions (5.5)] • Wound healing complications [see Warnings and Precautions (5.7)] • Teratogenicity and embryofetal toxicity [see Warnings and Precautions (5.11)] The data described in sections 6.1 and 6.2 reflect exposure to NEXAVAR in 748 patients who participated in placebo controlled studies in hepatocellular carcinoma (N=297) or advanced renal cell carcinoma (N=451). The most common adverse reactions (≥20%), which were considered to be related to NEXAVAR, in patients with HCC or RCC are fatigue, weight loss, rash/desquamation, handfoot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions in HCC Study Table 2 shows the percentage of HCC patients experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in the NEXAVAR arm than the placebo arm. CTCAE Grade 3 adverse reactions were reported in 39% of patients receiving NEXAVAR compared to 24% of patients receiving placebo. CTCAE Grade 4 adverse reactions were reported in 6% of patients receiving NEXAVAR compared to 8% of patients receiving placebo.
Table 2 Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in NEXAVAR Arm than the Placebo Arm – HCC Study NEXAVAR N=297
Adverse Reaction NCI- CTCAE v3 Category/Term
All Grades %
Grade 3 %
Grade 4 %
All Grades %
Grade 3 %
Grade 4 %
Any Adverse Reaction
Constitutional symptoms Fatigue
research has shown that chemotherapy and radiation are not effective. The primary end point in the trial was the median time to disease progression. After 6 months of treatment, disease progression was reduced in 69% of octreotide LAR–treated patients and 39% of placebo-treated patients, Arnold said. The median time to disease progression was 14.3 months in the
Table 2 continued:
6.2 NEXAVAR N=297
Adverse Reaction NCI- CTCAE v3 Category/Term Dermatology/skin Rash/desquamation Pruritus Hand-foot skin reaction Dry skin Alopecia Gastrointestinal Diarrhea Anorexia Nausea Vomiting Constipation Hepatobiliary/ pancreas Liver dysfunction Pain Pain, abdomen
All Grades %
Grade 3 %
Grade 4 %
All Grades %
Grade 3 %
Grade 4 %
19 14 21 10 14
1 <1 8 0 0
0 0 0 0 0
14 11 3 6 2
0 <1 <1 0 0
0 0 0 0 0
55 29 24 15 14
10 3 1 2 0
<1 0 0 0 0
25 18 20 11 10
2 3 3 2 0
0 <1 0 0 0
Hypertension was reported in 9% of patients treated with NEXAVAR and 4% of those treated with placebo. CTCAE Grade 3 hypertension was reported in 4% of NEXAVAR treated patients and 1% of placebo treated patients. No patients were reported with CTCAE Grade 4 reactions in either treatment group. Hemorrhage/bleeding was reported in 18% of those receiving NEXAVAR and 20% of placebo patients. The rates of CTCAE Grade 3 and 4 bleeding were also higher in the placebo group (CTCAE Grade 3 - 3% NEXAVAR and 5% placebo and CTCAE Grade 4 - 2% NEXAVAR and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in NEXAVAR treated patients and 4% of placebo treated patients. Renal failure was reported in <1% of patients treated with NEXAVAR and 3% of placebo treated patients. The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the NEXAVAR and placebo groups (32% of NEXAVAR patients and 35% of placebo patients). Laboratory Abnormalities The following laboratory abnormalities were observed in HCC patients: Hypophosphatemia was a common laboratory finding, observed in 35% of NEXAVAR-treated patients compared to 11% of placebo patients; CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 11% of NEXAVAR-treated patients and 2% of patients in the placebo group; there was 1 case of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in the placebo group. The etiology of hypophosphatemia associated with NEXAVAR is not known. Elevated lipase was observed in 40% of patients treated with NEXAVAR compared to 37% of patients in the placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 9% of patients in each group. Elevated amylase was observed in 34% of patients treated with NEXAVAR compared to 29% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 2% of patients in each group. Many of the lipase and amylase elevations were transient, and in the majority of cases NEXAVAR treatment was not interrupted. Clinical pancreatitis was reported in 1 of 297 NEXAVAR-treated patients (CTCAE Grade 2). Elevations in liver function tests were comparable between the 2 arms of the study. Hypoalbuminemia was observed in 59% of NEXAVAR-treated patients and 47% of placebo patients; no CTCAE Grade 3 or 4 hypoalbuminemia was observed in either group. INR elevations were observed in 42% of NEXAVAR-treated patients and 34% of placebo patients; CTCAE Grade 3 INR elevations were reported in 4% of NEXAVAR-treated patients and 2% of placebo patients; there was no CTCAE Grade 4 INR elevation in either group. Lymphopenia was observed in 47% of NEXAVAR-treated patients and 42% of placebo patients. Thrombocytopenia was observed in 46% of NEXAVAR-treated patients and 41% of placebo patients; CTCAE Grade 3 or 4 thrombocytopenia was reported in 4% of NEXAVAR-treated patients and less than 1% of placebo patients.
He added that the study was the first to compare octreotide LAR with placebo for the treatment of malignant neuroendocrine tumors. —Jill Stein
Approximately 67% of drugs dispensed in the United States in 2007 were generics, up from 63% in 2006. Source: www. therapeuticsdaily.com.
Adverse Reactions in RCC Study 1 Table 3 shows the percentage of RCC patients experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in the NEXAVAR arm than the placebo arm. CTCAE Grade 3 adverse reactions were reported in 31% of patients receiving NEXAVAR compared to 22% of patients receiving placebo. CTCAE Grade 4 adverse reactions were reported in 7% of patients receiving NEXAVAR compared to 6% of patients receiving placebo.
Table 3: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in NEXAVAR Arm than the Placebo Arm – RCC Study 1
Adverse Reactions NCI- CTCAE v3 Category/Term Any Adverse Reactions Cardiovascular, General Hypertension Constitutional symptoms Fatigue Weight loss Dermatology/skin Rash/desquamation Hand-foot skin reaction Alopecia Pruritus Dry skin Gastrointestinal symptoms Diarrhea Nausea Anorexia Vomiting Constipation Hemorrhage/bleeding Hemorrhage – all sites Neurology Neuropathy-sensory Pain Pain, abdomen Pain, joint Pain, headache Pulmonary Dyspnea
NEXAVAR N=451 All Grade Grade Grades 3 4 % % % 95 31 7
Placebo N=451 All Grade Grade Grades 3 4 % % % 86 22 6
40 30 27 19 11
<1 6 <1 <1 0
0 0 0 0 0
16 7 3 6 4
<1 0 0 0 0
0 0 0 0 0
43 23 16 16 15
2 <1 <1 <1 <1
0 0 0 0 0
13 19 13 12 11
<1 <1 1 1 <1
0 0 0 0 0
11 10 10
2 2 <1
0 0 0
9 6 6
2 <1 <1
0 0 0
locally inoperable or metastasized welldifferentiated neuroendocrine tumors and a Karnofsky index greater than 60. Their median age was 65 years. The standard treatment for patients with metastatic midgut neuroendocrine tumors is surgery, Arnold noted. Additional options include hepatic embolization in the event of liver metastases or radioligand therapy, but both approaches produce significant side effects, he said. Previous
octreotide LAR group and 6 months in the placebo group. Patients who benefited most were newly diagnosed and had a tumor load that was less than or equal to 10%. Arnold said that because most patients enrolled in the trial are still alive, it is not yet possible to ascertain the median overall survival. The side effects of octreotide LAR use were consistent with those found in previous studies of the drug in patients with neuroendrocrine tumors and included diarrhea, fatigue, fever, and bile stones. Based on the study results, Arnold said that octreotide LAR should be considered the treatment standard in patients with newly diagnosed, functionally active or inactive, well-differentiated metastatic midgut neuroendocrine tumors and a low hepatic tumor load.
The median time to disease progression was 14.3 months in the octreotide LAR group and 6 months in the placebo group.
The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the NEXAVAR and placebo groups (10% of NEXAVAR patients and 8% of placebo patients). Laboratory Abnormalities The following laboratory abnormalities were observed in RCC patients in Study 1: Hypophosphatemia was a common laboratory finding, observed in 45% of NEXAVARtreated patients compared to 11% of placebo patients. CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 13% of NEXAVAR-treated patients and 3% of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in either NEXAVAR or placebo patients. The etiology of hypophosphatemia associated with NEXAVAR is not known. Elevated lipase was observed in 41% of patients treated with NEXAVAR compared to 30% of patients in the placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the NEXAVAR group compared to 7% of patients in the placebo group. Elevated amylase was observed in 30% of patients treated with NEXAVAR compared to 23% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 1% of patients in the NEXAVAR group compared to 3% of patients in the placebo group. Many of the lipase and amylase elevations were transient, and in the majority of cases NEXAVAR treatment was not interrupted. Clinical pancreatitis was reported in 3 of 451 NEXAVARtreated patients (one CTCAE Grade 2 and two Grade 4) and 1 of 451 patients (CTCAE Grade 2) in the placebo group.
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Statin Use May Significantly Lower the Risk of Death from Prostate Cancer ORLANDO—Taking a statin medication may significantly reduce a man’s risk of dying from prostate cancer, according to data presented at the 2009 Genitourinary Cancers Symposium. Researchers analyzed data from the New Jersey Cancer Registry on men who died of prostate cancer in New Jersey from 1989 through 2001. They found that over this 12-year period, the use of a statin cut the risk of death due
metabolic syndrome to advanced prostate cancer. Because obesity and other elements of the metabolic syndrome are indications for the use of a statin, any protective effect of a statin may be underestimated without adjusting for these possible confounders, according to the researchers from the University of Medicine and Dentistry of New Jersey (UMDNJ). Their study, therefore, examined the risk of death
They found that on unadjusted analysis, exposure to a statin cut a man’s odds of dying of prostate cancer in half compared with a control’s. to prostate cancer in half. This finding was consistent regardless of adjustment for possible confounders, such as obesity, number of chronic comorbidities, and hypertension. Previous results from four prospective studies showed a decreased risk of advanced or metastatic prostate cancer in men exposed to statins. New studies, however, have linked obesity and the
from prostate cancer with statin exposure and also accounted for some of the underlying indications for their use in a state-wide, population-based study. The investigators identified men who died from prostate cancer in New Jersey from 1989 to 2001 from the New Jersey Vital Statistics and verified cause of death from medical records. Each man in the study was matched by age and
Lymphopenia was observed in 23% of NEXAVAR-treated patients and 13% of placebo patients. CTCAE Grade 3 or 4 lymphopenia was reported in 13% of NEXAVAR-treated patients and 7% of placebo patients. Neutropenia was observed in 18% of NEXAVAR-treated patients and 10% of placebo patients. CTCAE Grade 3 or 4 neutropenia was reported in 5% of NEXAVAR-treated patients and 2% of placebo patients. Anemia was observed in 44% of NEXAVAR-treated patients and 49% of placebo patients. CTCAE Grade 3 or 4 anemia was reported in 2% of NEXAVAR-treated patients and 4% of placebo patients. Thrombocytopenia was observed in 12% of NEXAVAR-treated patients and 5% of placebo patients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of NEXAVAR-treated patients and 0% of placebo patients. 6.3
Additional Data from Multiple Clinical Trials The following additional drug-related adverse reactions and laboratory abnormalities were reported from clinical trials of NEXAVAR as monotherapy (very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than 1%): Cardiovascular: Uncommon: hypertensive crisis*, myocardial ischemia and/or infarction*, congestive heart failure* Dermatologic: Very common: erythema Common: exfoliative dermatitis, acne, flushing Uncommon: folliculitis, eczema, erythema multiforme, keratoacanthomas/squamous cell cancer of the skin Digestive: Very common: increased lipase, increased amylase Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia Uncommon: pancreatitis, gastrointestinal reflux, gastritis, gastrointestinal perforations* Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values General Disorders: Very common: hemorrhage (including gastrointestinal* & respiratory tract* and uncommon cases of cerebral hemorrhage*), asthenia, pain (including mouth, bone, and tumor pain) Common: decreased appetite, influenza-like illness, pyrexia Uncommon: infection Hematologic: Very common: leukopenia, lymphopenia Common: anemia, neutropenia, thrombocytopenia Uncommon: INR abnormal Hypersensitivity: Uncommon: hypersensitivity reactions (including skin reactions and urticaria) Metabolic and Nutritional: Very common: hypophosphatemia Common: transient increases in transaminases Uncommon: dehydration, hyponatremia, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hypothyroidism, cholecystitis, cholangitis Musculoskeletal: Common: arthralgia, myalgia Nervous System and Psychiatric: Common: depression Uncommon: tinnitus, reversible posterior leukoencephalopathy* Renal and Genitourinary: Common: renal failure Reproductive: Common: erectile dysfunction Uncommon: gynecomastia Respiratory: Common: hoarseness Uncommon: rhinorrhea *adverse reactions may have a life-threatening or fatal outcome. In addition, the following medically significant adverse reactions were uncommon during clinical trials of NEXAVAR: transient ischemic attack, arrhythmia, thromboembolism, acute renal failure. For these adverse reactions, the causal relationship to NEXAVAR has not been established. ** See specific section in full prescribing information. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions (5.11)].
race to a population-based control. Cases and controls were matched oneto-one for a total of 760 subjects (380 cases, 380 controls). The researchers abstracted medical records to determine statin use, and they used conditional logistic regression for matched analysis. They found that on unadjusted analysis, exposure to a statin cut a man’s odds of dying of prostate cancer in half compared with a control’s. After adjusting for exposure to any hypertensive medication, the odds decreased further to 0.4; adjustment for comorbidity, indices of obesity (waist size, body mass index), and education, provided no additional change. “Our results show that any exposure to a statin cuts the risk by 50%,” said lead study investigator Stephen Marcella, MD, PhD, who is an assistant professor of epidemiology at the School of Public Health at the UMDNJ, Piscataway, New Jersey. “We were very surprised by the extent of the risk reduction.” He said high-potency statins seem to have more of an effect, a fact that is in keeping with the hypothesis that the extent of cholesterol lowering is one of the mechanisms in prevention of pro-
Nursing Mothers It is not known whether sorafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from NEXAVAR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Following administration of radiolabeled sorafenib to lactating Wistar rats, approximately 27% of the radioactivity was secreted into the milk. The milk to plasma AUC ratio was approximately 5:1. Pediatric Use The safety and effectiveness of NEXAVAR in pediatric patients have not been studied. Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the femoral growth plate at daily sorafenib doses ≥ 600 mg/m2 (approximately 0.3 times the AUC at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 mg/m2/day (approximately 0.1 times the AUC at the recommended human dose), and alterations of the dentin composition at 600 mg/m2/day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less. Geriatric Use In total, 59% of HCC patients treated with NEXAVAR were age 65 years or older, and 19% were 75 and older. In total, 32% of RCC patients treated with NEXAVAR were age 65 years or older, and 4% were 75 and older. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment In vitro and in vivo data indicate that sorafenib is primarily metabolized by the liver. Comparison of data across studies suggests that patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment have sorafenib AUCs that may be 23- 65% lower than subjects with normal hepatic function. Systemic exposure and safety data were comparable in HCC patients with Child-Pugh A and B hepatic impairment. NEXAVAR has not been studied in patients with Child-Pugh C hepatic impairment [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3)]. Patients with Renal Impairment NEXAVAR has not been studied in patients undergoing dialysis. No dosage adjustment is necessary when administering NEXAVAR to patients with mild, moderate or severe renal impairment not undergoing dialysis [see Clinical Pharmacology (12.3)]. Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.
Manufactured by: Bayer HealthCare AG, Leverkusen, Germany Manufactured for: Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ 07470 Onyx Pharmaceuticals, Inc., 2100 Powell Street, Emeryville, CA 94608 Distributed and marketed by: Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ 07470 Marketed by: Onyx Pharmaceuticals, Inc., 2100 Powell Street, Emeryville, CA 94608 80771372BS, R.2 Revised: 10/2008 ©2008 Bayer HealthCare Pharmaceuticals Inc.
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gression of prostate cancer. He noted that high-potency statins are about 2.5 times more effective in lowering cholesterol than of low-potency statins. “The take-home message is that if you have a man with abdominal obesity, being put on a statin may not only help with his cardiovascular risk factors, but also his potential risk of dying from prostate cancer,” said Marcella in an interview with The Oncology Nurse. “This study makes sense, because if you are going to prevent advanced prostate cancer, then it stands to reason that you are also eventually going to prevent mortality from prostate cancer.” He noted that this study is important because it is a very large study as well as one of the few that looked at mortality from prostate cancer rather than just advanced disease. He said the strength of the study is that it is populationbased, with no referral patterns that may have led to a potential bias. He cautioned, however, that the study is limited, in part, because it is retrospective and the medical conditions were abstracted from charts. —John Schieszer
Pediatric Cancer Survivors Continued from page 28
Several potential caveats must be considered when analyzing the study results, they noted. For example, a history of mammography was provided by self-report that was not confirmed by medical records. They were quick to note, however, that mammography self-report has been shown to be highly correlated with confirmed radiology reports. In addition, the study cohort was mostly white, non-Hispanic, and thus the results may not necessarily apply to ethnic or minority populations. The authors also pointed out that trial participants have been enrolled in the longitudinal CCSS cohort study for nearly a decade and have been receiving regular health-oriented newsletters that included information on cancer screening. It is possible that the pres-
ent study’s estimates of breast cancer screening rates may actually “overestimate” the screening rates for high-risk women who are not participating in the longitudinal study. Finally, Oeffinger and his group maintain that their study has yielded information that may be useful for developing targeted interventions for women at risk of breast cancer after chest radiation. For example, women in their study who had a positive view of screening mammography were more likely to undergo screening irrespective of their age. Of note, they said they believe that their investigation is the first to offer a comprehensive assessment of the breast cancer surveillance practices of young women, from 25 through 50 years of age, in this high-risk population.
Is peripheral neuropathy holding them back? Intervene early to preserve quality of life Peripheral neuropathy (PN) can have a devastating effect on patients with multiple myeloma (MM). These patients have an increased risk since both MM and some of its treatments can cause PN.1-4 Even though PN symptoms are mild at the outset, eventually they can have an impact on patients’ lives, limiting their ability to do the activities they enjoy. And these effects may cause permanent damage.5,6 That is why it is so important to identify symptoms early.2
Assessing PN is critical to optimizing myeloma management A baseline assessment is the first step in preventing or controlling the symptoms of PN.2 Patients with MM may have pre-existing conditions, such as diabetes, that can lead to PN.7 By identifying pre-existing PN early on, you can better monitor patients throughout treatment. Identifying and assessing symptoms can be challenging. The sensations caused by PN are subjective, and patients may be hesitant to share these symptoms since it may lead to changes in their treatment plan.5,8 Therefore, it is important to encourage your patients to report any symptoms they may be experiencing.7 Here are some questions to start the dialogue: • “Do you have any unusual sensations (pins and needles, shooting pain like electric current) in your feet, legs, or hands?” • “Would you describe these sensations as tingling, numbness, burning, or pain?” • “Do any of these sensations or feelings keep you from doing things like buttoning your shirt or using a fork and knife?” • “Have your legs or arms been weak? Does this weakness keep you from taking part in the activities you enjoy, like needlework or golﬁng?”
Discuss PN with your patients early and often Multiple myeloma treatments may cause PN symptoms and the damage may be permanent.3,4 By identifying patients at risk and assessing their symptoms, you can: • Help them overcome their fears: assure your patients that a change in treatment plan in response to PN does not have to compromise efﬁcacy • Assess PN at baseline and throughout treatment to help guide treatment decisions2
Your intervention can help ensure your patients’ treatment allows them to pursue the things they love References: 1. Asbury AK. Approach to the patient with peripheral neuropathy. In: Kasper DL, Braunwald E, Hauser SL, Longo DL, Jameson JL, Fauci AS, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill Medical Publishing Division; 2004:2500-2510. 2. Armstrong T, Almadrones L, Gilbert MR. Chemotherapy-induced peripheral neuropathy. Oncol Nurs Forum. 2005;32(23):305-311. 3. Ghobrial IM, Rajkumar SV. Management of thalidomide toxicity. J Support Oncol. 2003;1(3):194-205. 4. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24(19):3113-3120. 5. Hausheer FH, Schilsky RL, Bain S, Berghorn EJ, Lieberman F. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol. 2006;33(1):15-49. 6. Stillman M, Cata JP. Management of chemotherapy-induced peripheral neuropathy. Curr Pain Headache Rep. 2006;10(4):279-287. 7. Lavoie Smith EM, Beck SL. The total neuropathy score: a tool for measuring chemotherapy-induced peripheral neuropathy. Oncol Nurs Forum. 2008;35(1):96-102. 8. Markman M. Chemotherapy-induced peripheral neuropathy: underreported and underappreciated. Curr Pain Headache Rep. 2006;10(9):275-278. ©2008 Celgene Corporation 10/08
Oncology Nutrition Superfoods: A Realistic Approach? BY AMANDA SALDIVAR, MS, RD, LD TAUSSIG CANCER INSTITUTE, CLEVELAND, OHIO
hear the praises of acai (pronounced ah-sigh-ee) berries or mangosteen at least once a day from patients and other healthcare professionals who use products containing these ingredients. It seems that these “superfoods” are achieving rock-star status and are promoted everywhere, even by celebrities. These fruits are marketed as having unique abilities to cure any ailment, including cancer. With these claims as well as the enticing attribute of being imported from exotic countries
that they will compensate for unhealthy habits or cure any disease. In addition, many other foods can provide similar benefits and can be found at neighborhood grocery stores, where they are readily available and are less costly. Both the acai berry and mangosteen have been shown to contain antioxidants in the form of phytochemicals,1 but so have many other fruits and vegetables. The acai berry also contains several fatty acids, monounsaturated (heart-healthy) fats being the most abundant; this type of fat also is found in high concentrations in olive oil. And while both of these fruits have been shown to have many antioxidant properties and benefits in in vitro studies, there has yet to be a large-scale human study showing the same benefits.2,3 Because of the extremely high antioxidant content of these foods, it is important to advise patients who are receiving chemotherapy that they must be taken in moderation. It is still unknown whether or not excessive antioxidant intake during treatment interferes with the effective∋∃!∀!∃!! ∃& !!% ness of treatment. Therefore, advocating that patients obtain nutrients from diet should remain the standard message. It is important to advise patients that with these fruits or other high antioxidant foods, variety is important. If patients rely on these high antioxidant foods as “magic bullets,” they auté onion, marjoram, and might believe that more is better. thyme in large saucepan until Even with foods, there is potenonion is tender, about 5 mintial to obtain a large amount of an utes. Stir in stock, peas, lettuce, and individual phytonutrient if its heat until boiling. Bring to simmer, source is consumed in large quancovered until peas are tender, 5 to 8 tities. Thus, a varied diet allows for consumption of various phyminutes. Cool soup for 10 minutes. tonutrients and even distribution Process soup in food processor or throughout the diet. Although blender until smooth. Refrigerate there is no clear recommendation until chilled, 3 to 4 hours. Stir sour as to how much is too much, my cream into soup; pour into individual rule of thumb is to advise patients bowls and sprinkle with paprika. to consume no more than a stanSource: www.cdc.gov dard serving based on MyPyramid guidelines (a serving of fruit is 4 ounces of juice or 1 cup of raw What’s Your Favorite fruit) per day. Research on and promotion of Healthy Recipe? phytonutrients that come from With a little creativity, healthy foods can be fruits and vegetables continues to delicious as well as nutritious. Do you have a increase. Diet in relation to health, favorite healthy recipe that you would like to more specifically cancer, is the prishare with your colleagues and patients? Send mary focus of the American your recipe and its source (family recipes are Institute for Cancer Research welcome) to Karen@greenhillhc.com. (AICR). This nonprofit organization provides funding for
and their overall novelty, people are lining up to buy these products at any price. Some juices containing these ingredients are sold for more than $30 per 25-ounce bottle. It is no wonder. These foods have been shown to have high antioxidant values, and people continue the quest to find that “magic bullet.” Although there is no reason to discourage consumption of these fruits or juices, people should be educated about incorporating these foods into a healthy lifestyle rather than believing
Creamy Chilled Pea Soup Recipe Summary:
Preparation Time: 4 hours 30 minutes Number of Servings: 4 Cups of Fruits and Vegetables Per Person: 1.00
1 cup chopped onion 1/2 tsp dried marjoram leaves 1/2 tsp dried thyme leaves 1-1/2 cups low-sodium vegetable stock 1 cup water 2 packages (20 oz) frozen peas 2 cup sliced romaine lettuce 1 cup fat-free sour cream 1 tsp paprika (garnish)
G REEN H ILL H EALTHCARE C OMMUNICATIONS
research and makes recommendations based on this and other research. The AICR has collaborated with the World Cancer Research Fund to produce a report entitled Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. This 517-page report, based on global research, involved a three-step process to help reduce bias in the interpretation of literature. The report recommendations include the following4: • Maintain a healthy weight • Perform regular physical activity for at least 30 minutes per day • Limit intake of high-calorie foods • Eat a plant-based diet (including five servings each of nonstarchy vegetables and fruits) • Limit intake of red and processed meats • Limit alcohol consumption • Limit intake of dietary salt • Obtain nutrients through diet rather than supplements. When patients approach me about use of one of the exotic foods or beverages, I encourage them to focus on the goals set by the AICR. I explain that they may consume these products if they wish, but I stress that if they are not following the other recommendations, it may not be worthwhile to continue use of these products because they may not have as much benefit as they believe. The overall message I try to convey is this: There is no harm in consuming these products in moderation, but try not to focus on the idea that they are miracle foods and that they will cure disease.
1. Pozo-Insfran D, Percival SS, Talcot ST. Acai (Euterpe oleracea Mart.) polyphenolics in their glycoside and aglycone formas induce apoptosis of HL-60 leukemia cells. J Agric Food Chem. 2006;54:1222-1229. 2. Natural Standard Inc. Mangosteen (Garcinia mangostana). 2008. www.naturalstandard. com/naturalstandard/monographs/monoframe set.asp?monograph=/monographs/herbssupple ments/mangosteen.asp&patientVersion=/mo nographs/herbssupplements/patient-mangos teen.asp. Accessed January 6, 2009. 3. Natural Standard Inc. Acai (Euterpe oleracea). 2008. www.naturalstandard.com/natu ralstandard/monographs/monoframeset.asp? monograph=/monographs/herbssupplements/ acai.asp&patientVersion=/monographs/herb ssupplements/patient-acai.asp. Accessed January 6, 2009. 4. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. 2007. www.dietandcancerreport.org/downloads/summary/english.pdf?J ServSessionIdr006=83ta19h2j2.app46a. Accessed January 7, 2009.
Calling All Navigators
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AONN membership is for Oncology Nurses—AND all Oncology Caregivers, including Nurse Navigators, Practice Managers, and Nursing Administrators, devoted to the complexities of the cancer care treatment continuum. Information on patient care and treatment strategies, side effect management, patient outreach and navigation programs, and much more is thoroughly covered in AONN’s vast resources. AONN membership provides you with:
• A subscription to the journal, The Oncology Nurse (TON) (a $150 value), and the bimonthly Journal of Multidisciplinary Cancer Care.
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• Free patient brochures on a range of issues impacting cancer patients (eg, Treatment Guidelines, CINV, Pain Management, DVT, Chemotherapy Toxicities, Skin Reactions, Reimbursement Information, Coding Updates) will soon be available. • An online web portal with enhanced members-only sections with clinical resources, a special section for educators, and continuing updates on grant opportunities for researchers, in addition to AONN’s searchable membership directory. • Advocacy for initiatives to increase the number of professionals entering the field of oncology; to provide fair and adequate reimbursement for clinical services; and to increase funding for research.
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Presents The Second Annual 2009 Curriculum for
CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, will proudly offer the multidisciplinary cancer team at your center a series of newsletters focusing on the challenges in treating patients with multiple myeloma.
SAGAR LONIAL, MD
Associate Professor of Hematology and Oncology Emory University
★ Earn Continuing Education Credits ★ Eight part newsletter series
• Retreatment Settings • Maintenance Therapy • Do CRs Correlate to a Clinical Benefit?
• Perspectives on Relevant Endpoints of Clinical Trials • Stem Cell Mobilization • Cytogenic Testing in the MM Patient
• To Transplant or Not to Transplant…That is the Question • Sequencing Strategies in MM: Treatment with Case Studies
Each newsletter will feature:
• Contributions from thought-leading physicians, pharmacists, and nurses
• Continuing Education credits available to physicians, pharmacists, and nurses
TO REQUEST FREE COPIES
Call 732-992-1899 or visit www.coexm.com
Retreatment Settings Newsletter Statement of Need The purpose of this activity is to enhance knowledge concerning the treatment of patients with relapsed and refractory multiple myeloma (MM). Target Audience This activity was developed for physicians, nurses, and pharmacists. Learning Objectives At the completion of this educational activity, participants should be able to: • Describe how standard therapy may be improved with novel agents and treatment approaches for patients with relapsed and refractory multiple myeloma (MM) • Summarize new data from clinical trials in relapsed/refractory MM as reported at the 2008 American Society ofHematology annual meeting • Review the side effect profiles of novel agents for MM • Identify effective strategies for the management of common toxicities associated with MM therapies Physician Accreditation This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Medical Learning Institute, Inc. (MLI). Global is accredited by the ACCME to provide continuing medical education for physicians.
Physician Credit Designation Global designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Registered Nurse Designation MLI is accredited as a provider of continuing nursing education by the American Nurses Credentialing Centerís Commission on Accreditation through the California Board of Registered Nursing, Provider #15106. This continuing nursing education activity for 1.0 contact hour is provided by MLI. Registered Pharmacy Designation MLI is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal program number for this activity is 468-999-09-008-H01-P. Estimated time to complete this activity: 1 hour Date of original release: March 31, 2009 Valid for CME credit through: March 31, 2010
This activity is jointly sponsored by
This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.
he American Society of Clinical Oncology (ASCO) has launched Cancer.net (www.cancer.net) as a comprehensive resource for people living with cancer. With content developed by its oncologists, the site offers information on more 120 kinds of cancer and cancerrelated syndromes, including risk factors, symptoms, diagnosis, staging, and treatment. It suggests questions to ask the doctor as well as clinical research advances. A Spanish-language section discusses types of cancer, tobacco and cancer prevention, clinical trials, management of side effects of treatment and of the disease, and a series of patient guides. The English-language portion of the site is more comprehensive, containing the usual coverage of diagnosis and treatment, coping, survivorship, and resources. But it also has feature articles, op-ed pieces, and podcasts. Cancer.net Bulletin, formerly called PLWC (People Living With Cancer) Bulletin, a monthly emailed electronic newsletter, is available from the site. The ASCO Resources section has information about choosing an oncologist and obtaining second opinions (and a database of oncologists); Cancer Advances, news for patients from the ASCO annual meeting, journals, and Meet the Experts events; Patient Guides based on ASCO’s Clinical Practice Guidelines for physicians; and news on clinical advances derived from ASCO reports, meetings, symposia, and virtual lectures. Expert Perspectives give context opinion on a variety of clinical developments. A very extensive list of organizations and other web sites available in the Frequently Asked Questions section should allow people living with cancer to find more information relevant to their specific diseases or concerns (eg, descriptions, trials, risk factors, cancer prevention, fertility, coping, survivorship, psychological issues, self image, advocacy, complementary medicine, palliative care and hospice, and much more). Also available for download are ASCO Cancer Education slides. These oncologistapproved PowerPoint slide decks are designed for oncology professionals to present to patients and community groups. Although the site is mainly designed for cancer patients, survivors, and families, it should be a good resource for oncology nurses as well. First, they can familiarize themselves with the site so they can recommend it in whole or in part to the target audience, either in general or to help answer specific questions or address concerns. Second, it can provide solid information for them to pass on in lay language. Third, it provides good background information. A section containing good, clear drawings of anatomical sites and organ systems may facilitate patient teaching. Overall, the Cancer.net site is well laid out and easy to navigate. It is packed with
information, generally arranged in an easy-to-find manner. Although any information is probably in a logical place, it is not entirely obvious where to look for it starting out. Therefore, a bit of exploring of the site can help in RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].
INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some
familiarizing the user with where to look on future visits and can reveal the wealth of information that exists on the site. Unfortunately, there is no link to a map of the entire site, but a good way to find one is to type “site map” in the
search box on the upper right of the home page. Click on the first result, which says “Page Not Found” and which allows users to see a site map to help find what they are looking for, which is this site map!
cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses. Table 1 Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b
Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, activecontrolled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) greater. No overall differences in effectiveness were observed between these Respiratory System Any Adverse Events 99 57 38 4 patients and younger patients. Cardiac adverse reactions, mostly supraventricular Body as a Whole Increased Cough 13 1 86 10 Rhinitis 12 1 Fever 53 1 arrhythmias, occurred more frequently among elderly patients. Serious pulmonary Bronchospasm 8 1 Chills 33 3 adverse reactions were also more common among the elderly, including Dyspnea 7 1 Infection 31 4 Sinusitis 6 0 Asthenia 26 1 pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Metabolic and Nutritional Headache 19 1 Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 B-cell NHL did not include sufficient numbers of patients aged 65 and over to Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 determine whether they respond differently from younger subjects. Flushing 5 0 LDH Increase 7 0 OVERDOSAGE There has been no experience with overdosage in human clinical Heme and Lymphatic System 67 Digestive System 48 37 2 Lymphopenia 48 40 Nausea 23 1 trials. Single doses of up to 500 mg/m2 have been given in dose-escalation Leukopenia 14 4 Diarrhea 10 1 Neutropenia 14 6 Vomiting 10 1 clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, 12 2 Thrombocytopenia Nervous System 32 1 Impairment of Fertility No long term animal studies have been performed to Anemia 8 3 Dizziness 10 1 Skin and Appendages Anxiety 5 1 44 2 establish the carcinogenic or mutagenic potential of Rituxan or to determine Musculoskeletal System Night Sweats 15 1 26 3 Rash 15 1 Myalgia 10 1 potential effects on fertility in males or females. PATIENT COUNSELING Pruritus 14 1 Arthralgia 10 1 INFORMATION Patients should be provided the Rituxan Medication Guide and Urticaria 8 1 Cardiovascular System 25 3 Hypotension 10 1 provided an opportunity to read prior to each treatment session. Because caution Hypertension 6 1 should be exercised in administering Rituxan to patients with active infections, it is a Adverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by important that the patient’s overall health be assessed at each visit and any NCI-CTC criteria. questions resulting from the patient’s reading of the Medication Guide be In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and discussed. Rituxan is detectable in serum for up to six months following up to 6 months after Rituxan infusion. Rituxan in Combination With completion of therapy. Individuals of childbearing potential should use effective Chemotherapy Adverse reactions information below is based on 1250 patients contraception during treatment and for 12 months after Rituxan therapy. who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions Revised 9/2008 (4835505) were reported more frequently (≥5%) in patients receiving Rituxan following CVP Jointly Marketed by: compared to patients who received no further therapy: fatigue (39% vs. 14%), Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With ©2008 Biogen Idec Inc. and Genentech, Inc. 7140917 October 2008
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Leading patients toward improved outcomes
You help patients reach their treatment goals RITUXAN is a proven path for many patients battling non-Hodgkin’s lymphoma (NHL), but they can’t complete the journey alone. Oncology nurses are central members of a cancer care team—working together to achieve improved outcomes. Your guidance and leadership help patients reach their treatment goals. We recognize your commitment and support your continued efforts with innovative patient-education materials and services.
RITUXAN is indicated for the treatment of patients with: • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent • Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
To learn more, ask a RITUXAN representative or visit
BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.1
Reference: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.
Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.
PROVE N. POWE R FU L.
©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved. 9231900 April 2008
The Oncology Nurse