Highlights of the
March 9 – 13
NCCN2011 NCCN 16th Annual Conference:
CliniCal PraCtiCe Guidelines & Quality CanCer Care ™
NCCN.org - For Clinicians • NCCN.com - For Patients
TREANDA速 is her chemo.
This is her therapy.
Single-agent TREANDA tripled median PFS in patients with CLL*
Survival distribution function
PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREANDA (n=153)
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
18 months median PFS
6 months median PFS
P<.0001 HR†=0.27 (95% CI‡: 0.17, 0.43)
• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles • TREANDA was generally well tolerated in the pivotal phase 3 trial • The most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%),lymphopenia (68%),and leukopenia (61%) (n=150)
Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). † HR=hazard ratio. ‡ CI=confidence interval.
Single-agent TREANDA produced a 74% ORR§ in patients with indolent B-cell NHL that had progressed ORR§: INDOLENT B-CELL NON-HODGKIN’S LYMPHOMA (NHL) THAT HAS PROGRESSED
(95% CI: 64.3, 82.3)
Patients responding (%) Overall response rate (ORR) was defined as a best response of a complete response (CR), unconfirmed complete response (CRu), or partial response (PR) during the study (ORR=CR+CRu+PR). Independent Review Committee assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be ≥20 mm.
• TREANDA was evaluated in a single-arm pivotal study of 100 patients with indolent B-cell NHL that had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were scheduled to receive TREANDA 120 mg/m2 on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles • TREANDA was generally well tolerated in 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176) • The most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%) (N=176). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%)
TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Selected Safety Information •Seriousadversereactions,includingmyelosuppression,infections,infusionreactionsandanaphylaxis,tumorlysissyndrome,skinreactionsincludingSJS/TEN,other malignancies,andextravasation,havebeenassociatedwithTREANDA.Somereactions,suchasmyelosuppression,infections,andSJS/TEN(whenTREANDAwasadministered concomitantlywithallopurinolandothermedicationsknowntocauseSJS/TEN),havebeenfatal.Patientsshouldbemonitoredcloselyforthesereactionsandtreatedpromptly if any occur •AdversereactionsmayrequireinterventionssuchasdecreasingthedoseofTREANDA,orwithholdingordelayingtreatment.Myelosuppressionisfrequentlysevereandshould be expected when treating patients with TREANDA •TREANDAiscontraindicatedinpatientswithaknownhypersensitivitytobendamustineormannitol.WomenshouldbeadvisedtoavoidbecomingpregnantwhileusingTREANDA
Discover the elements of efficacy and safety LEARN MORE AT TREANDA.COM Please see accompanying brief summary of full Prescribing Information. ©2011Cephalon,Inc.Allrightsreserved.TRE-2214January2011PrintedinUSA.
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Brief Summary of Prescribing Information INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0
Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued) Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study
Laboratory Abnormality Hemoglobin Decreased Platelets Decreased Leukocytes Decreased Lymphocytes Decreased Neutrophils Decreased
TREANDA (N=150) All Grades Grade 3/4 n (%) n (%) 134 (89) 20 (13) 116 (77) 16 (11) 92 (61) 42 (28) 102 (68) 70 (47) 113 (75) 65 (43)
Chlorambucil (N=141) All Grades Grade 3/4 n (%) n (%) 115 (82) 12 (9) 110 (78) 14 (10) 26 (18) 4 (3) 27 (19) 6 (4) 86 (61) 30 (21)
In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two singlearm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) System organ class Preferred term Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain
Number (%) of patients* All Grades Grade 3/4 176 (100) 94 (53) 13 (7)
132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)
7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0
101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)
19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0
Table 3: Non-Hematologic Ad Treated With TREAN (continued)
System organ class Preferred term Infections and infestations Herpes zoster Upper respiratory tract infectio Urinary tract infection Sinusitis Pneumonia Febrile Neutropenia Oral Candidiasis Nasopharyngitis Investigations Weight decreased Metabolism and nutrition diso Anorexia Dehydration Decreased appetite Hypokalemia Musculoskeletal and connecti Back pain Arthralgia Pain in extremity Bone pain Nervous system disorders Headache Dizziness Dysgeusia Psychiatric disorders Insomnia Anxiety Depression Respiratory, thoracic and me Cough Dyspnea Pharyngolaryngeal pain Wheezing Nasal congestion Skin and subcutaneous tissue Rash Pruritus Dry skin Night sweats Hyperhidrosis Vascular disorders Hypotension
*Patients may have reported m NOTE: Patients counted only o organ class category.
Hematologic toxicities, based o single arm studies combined values that were new or worse in NHL patients treated in bot creatinine (2%), hyponatremia
Table 4: Incidence of Hemato TREANDA in the NHL Hematology Variable Lymphocytes Decreased Leukocytes Decreased Hemoglobin Decreased Neutrophils Decreased Platelets Decreased
In both studies, serious advers receiving TREANDA. The most febrile neutropenia and pneum trials and/or post-marketing e skin reactions, pulmonary fibr reactions reported in clinical t syndrome, and infusion reacti less frequently but possibly disorder, atypical pneumonia, s Marketing Experience. The fo use of TREANDA. Because the size, it is not always possi relationship to drug exposur pruritus, irritation, pain, and sw TREANDA was administered cause these syndromes. [See
OVERDOSAGE: The intravenou Toxicities included sedation, tr experience, the reported maxi treated at this dose showed EC These changes included QT pr wave deviations (two patients), ejection fractions remained no known. Management of over monitoring of hematologic par
DOSAGE AND ADMINISTRAT recommended dose is 100 mg a 28-day cycle, up to 6 cycles.
domized CLL Clinical Study of patients Chlorambucil (N=143)
All Grades Grade 3/4 8 (6) 8 (6) 6 (4) 1 (<1)
2 (1) 0 0 0
12 (8) 1 (<1) 7 (5)
0 1 (<1) 0
7 (5) 2 (1)
3 (2) 0
group in the randomized CLL myelosuppressive effects seen were administered to 20% of g chlorambucil.
ients Who Received al Study Chlorambucil (N=141) All Grades Grade 3/4 n (%) n (%) 115 (82) 12 (9) 110 (78) 14 (10) 26 (18) 4 (3) 27 (19) 6 (4) 86 (61) 30 (21)
bin elevations, some without ed bilirubin occurred in 3% of to 1% and 3% of patients, s in their creatinine levels. If be continued to ensure that in NHL. The data described cell NHL treated in two single, and 40% female. The race nd <1% Asian. These patients nd 2 for up to 8 21-day cycles. s, regardless of severity, are actions (≥30%) were nausea a (34%). The most common ue (11%), febrile neutropenia in 5% of patients.
st 5% of NHL Patients rred Term (N=176) of patients* Grade 3/4 94 (53) 0 7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0 19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0
Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) (continued) System organ class Number (%) of patients* Preferred term All Grades Grade 3/4 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile Neutropenia 11 (6) 11 (6) Oral Candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0 Psychiatric disorders Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category. Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients All Grades Grade 3/4 99 94 94 56 88 11 86 60 86 25
Hematology Variable Lymphocytes Decreased Leukocytes Decreased Hemoglobin Decreased Neutrophils Decreased Platelets Decreased
TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/ mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.
In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. PostMarketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. 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: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 50
DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:
Manufactured by: Pharmachemie B.V. The Netherlands
Manufactured for: Cephalon, Inc. Frazer, PA 19355
TREANDA is a trademark of Cephalon, Inc., or its affiliates. ©2008-2011 Cephalon, Inc., or its affiliates. TRE-2263 (Label Code: 00016287.03) This brief summary is based on TREANDA full Prescribing Information.
March 2011 All rights reserved.
Highlights of the NCCN 16th Annual Conference is jointly published by the National Comprehensive Cancer Network and Harborside Press®, LLC. Copyright © 2011 by the National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission from the NCCN. Correspondence Inquiries should be addressed to NCCN Conference Highlights, National Comprehensive Cancer Network, 275 Commerce Drive, Suite 300, Fort Washington, PA 19034; tel: (215) 690-0235; fax: (215) 690-0283. Editorial correspondence should be addressed to Kimberly Callan, e-mail: email@example.com. Advertising For information on advertising rates, reprints, or supplements, contact David Horowitz, tel: (631) 935-7652, e-mail: firstname.lastname@example.org. 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Highlights of the NCCN 16th Annual Conference
National Comprehensive Cancer Network®
Highlights of the NCCN 16th Annual Conference
Clinical Practice Guidelines & Quality Cancer Care™ March 9–13, 2011, Hollywood, Florida
NCCN Staff Editorial Staff
Kimberly Callan, MS, ELS
William T. McGivney, PhD
Senior Director, Professional and Patient Publications
Chief Executive Officer
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John A. Gentile, Jr. Publisher © 2011 NCCN. All rights reserved.
Clinical Practice Guidelines & Quality Cancer Care™
Welcome from William T. McGivney, PhD, NCCN’s Chief Executive Officer
Roundtable Many Faces of Caregivers
Roundtable Molecular Testing
Breast Cancer NCCN Guidelines™ Update
Non–Small Cell Lung Cancer NCCN Guidelines™ Update
Non-Hodgkin’s Lymphomas NCCN Guidelines™ Update
Hepatitis B Screening and Chemotherapy
Prostate Cancer NCCN Guidelines™ Update
Ovarian Cancer NCCN Guidelines™ Update
Myeloid Growth Factors NCCN Guidelines™ Update
Multiple Myeloma NCCN Guidelines™ Update
Chronic Myelogenous Leukemia NCCN Guidelines™ Update
29 Melanoma NCCN Guidelines™ Update 30
Head and Neck Cancers NCCN Guidelines™ Update
New Techniques in Radiation Oncology
Soft Tissue Sarcoma NCCN Guidelines™ Update
New Techniques in Imaging
© 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
Dear Colleague: Welcome to the Highlights of the NCCN 16th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care™. Once again, the National Comprehensive Cancer Network® (NCCN®) is pleased to provide you with a synopsis of the proceedings of our annual flagship event, held March 9–13 in Hollywood, Florida. The NCCN Annual Conference attracted more than 1,400 physicians and other oncology medical professionals from around the country and the world. The program included presentations of NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™), the latest information about new cancer therapies and quality initiatives, and emerging issues in oncology business management, including a new reimbursement resource center. These NCCN Highlights communicate the most pertinent and significant presentations of what is new in oncology as presented by internationally recognized authorities. Again this year, we were pleased to have ABC News veteran and anchor Sam Donaldson moderating a roundtable discussion. “The Many Faces and Challenges of Caregivers” featured notable cancer caregivers, including Sam Silver, MD, PhD, Director of the University of Michigan Cancer Center Network and a survivor of lymphoma; Bill Cowher, sports analyst and former coach of the Pittsburgh Steelers; Suzanne Daulerio, daughter of a long-time NCCN employee who died of lung cancer; Charlie “Chaz” Ebert, wife of renowned film critic Roger Ebert; Priscilla Mack, wife of Senator Connie Mack, who has lived with malignant melanoma; Jai Pausch, cancer research advocate and widow of acclaimed Carnegie Mellon University professor and author Randy Pausch, PhD; Mary Beth Reardon, RN, MS, Vice President of Patient Care Services at the H. Lee Moffitt Cancer Center & Research Institute; Liz Scott, mother of the late Alex Scott, founder of Alex’s Lemonade Stand Foundation; and Jill Ellen Snow, wife of the late Tony Snow, former White House Press Secretary, who died of colon cancer. Other presentations summarized in these Highlights include “Hepatitis B Screening and Chemotherapy,” “New Techniques in Radiation Oncology,” and “New Techniques in Imaging,” and presentation of updated NCCN Guidelines™ on breast cancer, small cell lung cancer, non-Hodgkin’s lymphoma, and others. This year also featured a roundtable discussion on “Molecular Testing: Implications for Practice and Policy,” with candid discussion by nationally recognized experts focusing on 4 main topics: 1) who makes decisions on testing; 2) what is the evidence on molecular testing; 3) how is testing translated into practice; and 4) is there value for money. Other NCCN programs also continue to grow. The seminal NCCN Guidelines, covering 97% of all patients with cancer and continually updated by expert panels, remain the most widely used guidelines in oncology practice and are increasingly recognized not just in the U.S. but as the global standard in oncology. NCCN continues to collaborate with international organizations to create and distribute translations of the NCCN Guidelines, which may include region-specific modifications. For example, NCCN responded to demand for a Latin America initiative and held initial meetings in Brazil to develop the first 2 NCCN Guidelines adaptations for that region. Further, the MENA Coordinating Office for NCCN Collaboration was established last year to coordinate activities for current and future programs. In addition, more than 1,800 Chinese oncologists attended the NCCN 4th Annual Asia Scientific Congress in Shanghai, China. NCCN also continues to partner with U.S. organizations to improve patient care. In December 2010, the National Business Group on Health, a non-profit association of more than 300 large U.S. employers, announced the launch of a major, 3-year project, conducted in collaboration with NCCN to help employers address cancer in the workplace. NCCN is also partnering with informatics companies to provide oncologists with expert recommendations and evidence facilitating the delivery of high-quality, individualized patient care. To further improve access to the latest information on cancer treatment recommendations, NCCN launched the NCCN Guidelines App for iPhone and Android, which are free to download through the iTunes store and Android Market and allow registered users on NCCN.org to view the NCCN Guidelines from smartphones. Another important step was the launch of new NCCN Guidelines for Patients™, which translate the NCCN Guidelines for professionals in a clear, step-by-step manner that patients can use in discussing options and making decisions with their physicians. The NCCN Guidelines for Patients™ are available free of charge at NCCN.com, which also features informative articles for patients and caregivers, as well as videos such as the roundtable described above. NCCN Guidelines for Patients currently available include breast, melanoma, multiple myeloma, nonsmall cell lung cancer, ovarian cancer, and prostate cancer. With the support of the NCCN Foundation, NCCN’s philanthropic affiliate, more NCCN Guidelines for Patients will be available soon. Finally, in 2010, JNCCN–The Journal of the National Comprehensive Cancer Network continued to be among the top 5 most read oncology publications, according to a national independent review of medical journals. It is thanks to the interest and support of individuals and organizations that NCCN continues to grow in our efforts to improve cancer care. We encourage you to participate in NCCN activities and programs. Please visit www.NCCN.org for more information on our many programs, only some of which are mentioned here, and to access the NCCN Guidelines, NCCN Compendium, and Chemotherapy Order Templates, or contact us with any questions at 215.690.0300. Your interest and support are what help drive NCCN programmatic development in a collaborative effort to improve the effectiveness and quality of care available to the patients whom we serve. I thank you, and I look forward to seeing you in Florida on March 14–18, 2012, for our seventeenth annual NCCN conference. Sincerely,
William T. McGivney, PhD Chief Executive Officer National Comprehensive Cancer Network
© 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
The Many Faces and Challenges of Cancer Caregivers Panelists offer insights into the caregiver experience and advice for oncology providers
o a person stricken with cancer, it means so much to have someone who cares, whether it is a family member or just a wonderful nurse or oncologist, or someone in the cancer community,” said Sam Donaldson, ABC News veteran and Chair of the National Comprehensive Cancer Network® (NCCN®) Foundation Board of Directors, the philanthropic affiliate of NCCN. Mr. Donaldson, who moderates a roundtable each year at the NCCN Annual Conference, knows something about this year’s topic—the challenges faced by caregivers— having survived a diagnosis of stage III melanoma in 1995. “My wife Jan was a caregiver once. She told me long after the diagnosis Mr. Donaldson that she cried at some points. Thank goodness she didn’t show me that,” Mr. Donaldson said as he introduced the topic to a panel of individuals who had cared for loved ones with cancer. Bringing their personal stories to the table, the participants gave insight into the unique caregiver experience.
Initial Reaction Is Shock and “Terror” The first reaction to a cancer diagnosis is part shock, part terror, and part helplessness, said panelists, who recounted these moments for the audience. Liz Scott, whose daughter Alex, founder of Alex’s Lemonade Stand Foundation, was diagnosed with neuroblastoma before her first birthday, said her first reaction was “absolute panic…I thought I was going to completely lose control.” Priscilla Mack, wife of Senator Connie Mack, a melanoma survivor, said, “It’s not fear, it’s not just scary—it’s absolute terror, to hear your loved one has cancer.” She also wondered how she was supposed to help. “CaregivMs. Mack ers will do anything,” she said, “but we have no idea what the needs of the patient are.” © 2011 NCCN. All rights reserved.
Jai Pausch, wife of the late Randy Pausch, PhD, acclaimed Carnegie Mellon University professor and author of The Last Lecture, said Ms. Pausch she “collapsed” upon hearing the diagnosis. “I had been struggling for weeks to keep our household together, to keep our children’s lives normal while Randy was sick. I thought, ‘Oh, my God, if you die and I have to keep doing this on my own, I just can’t.’ ”
Caregiving Can Be Exhausting As shocking and terrifying as the diagnosis is, caregivers must pull themselves together. The need to “be strong” for the cancer patient as well as the extended family must kick in immediately. There is little time to consider one’s own needs and concerns. In the words of Suzanne Daulerio, daughter of the late Patricia Daulerio, a longtime employee of NCCN, “My needs, and things that were going on in my own life, just didn’t seem valid anymore.” Ms. Mack, who had already lost her brother-inlaw to melanoma, thought, “I know how this is going to end and I don’t want any part of it” before reminding herself, “It’s not Ms. Ebert about me, it’s about my husband, and what I have to do to help him.” The need for super-human strength, steadiness, and stamina seems neverending, the panelists added. Chaz Ebert, wife of film critic Roger Ebert, who has survived advanced salivary and thyroid cancers, remembered the advice from her husband’s physician as she slept yet another night by the hospital bed. “I was becoming so exhausted that I would just fall asleep anywhere. I wasn’t eating. The doctor told me, ‘This is a marathon, not a sprint. You need to be prepared. Go home, get some sleep, and take care of yourself because if you have nothing, you will have nothing to give to
Meet the Panel Sam Donaldson, moderator, ABC News veteran and anchor, and Chair of the NCCN Foundation Board of Directors, who survived stage III melanoma Bill Cowher, analyst on The NFL Today and former head coach of the Pittsburgh Steelers, whose wife Kaye recently died of melanoma Suzanne Daulerio, daughter of the late Pat Daulerio, a longtime employee of NCCN Jai Pausch, wife of the late Randy Pausch, PhD, acclaimed Carnegie Mellon University professor and author of The Last Lecture, written when he was terminally ill with pancreatic cancer Charlie “Chaz” Ebert, wife of Roger Ebert, who has been treated for salivary gland cancer, and Executive Producer of Ebert Presents at the Movies Priscilla Mack, breast cancer survivor and wife of Senator Connie Mack, who has lived with malignant melanoma Mary Beth Reardon, RN, MS, Vice President of Patient Care Services at the H. Lee Moffitt Cancer Center & Research Institute in Tampa Bay Liz Scott, mother of the late Alex Scott, founder of Alex’s Lemonade Stand Foundation, who died from neuroblastoma Samuel M. Silver, MD, PhD, Director of the University of Michigan Cancer Center Network, Ann Arbor, and a survivor of lymphoma Jill Ellen Snow, wife of the late Tony Snow, former White House Press Secretary, who died of colon cancer
him.’ That’s when I realized it was much more serious than I thought. Roger ended up hospitalized for a year, in 3-month segments at four different times, and I needed my strength.” Jill Ellen Snow, wife of the late Tony Snow, former White House Press Secretary, said that during her husband’s final days she “had nothing left.” She told a friend, “I’m walking in the deep sand, and it’s exhausting.”
It seemed like all my answers were failing and I was just watching somebody die. — Bill Cowher Bill Cowher, analyst of The NFL Today and former head coach of the Pittsburgh Steelers, cared for his wife Kaye after dual diagnoses of advanced melanoma and atypical Alzheimer’s disease. He added, “When you sit down by yourself, you think, man, this is exhausting. Everyone is looking to me for answers, but who do I go to for my answers? It seemed like all my an-
swers were failing and I was just watching somebody die,” he remembered.
How Do You Break the News? Telling a loved one he or she has cancer is understandably one of the worst moments in a caregiver’s journey. Several of the panelists were in this unenviable situation. Each tried to Mr. Cowher offer hope when all seemed lost. “She didn’t think she was going to wake up and find out she had cancer,” said Mr. Cowher. “Finding the right words—that was the toughest part. Kaye looked to me for reassurance, to say, ‘Everything’s going to be okay.’ I tried to stay very positive, and I talked about the power of the mind and the need to remain hopeful. I told her, ‘Listen, there are no guarantees, but we are going to get the best care and utilize every resource to find a way.’ At the same time, I felt very overwhelmed with being asked to do this.” Ms. Ebert faced the heartbreaking
Highlights of the NCCN 16th Annual Conference
Key Points Caregivers face fear, worry, sorrow, and exhaustion all at once.
task of relaying her husband’s prognosis to him. “He loved life so much. He loved eating, and he was a great public speaker. After a series of surgeries, it became apparent that perhaps he would lose his ability to speak, and might live the rest of his life on a Gtube and take nothing by mouth again. How could I tell him this?” she said. She somehow summoned the courage to talk to her husband in a way that was honest, even frank, but hopeful. “You’re going to get through this, but there will be some changes. There will be a new normal for you,” she told him. “Maybe you won’t speak or eat the way you once did. But if you will find the will to live, I will find a way to make life interesting to you.” She promised him, “If you have the will, I will have the way.” She got the help he needed, and 5 years later she reported, “We are very happy, and we are very grateful for each day.” Roger is working again and helping other cancer survivors.
Researching the Options Ms. Ebert relied on research to help her find “the way.” But for many caregivers, research proves futile. Bill Cowher spent time deciphering experimental treatments for melanoma. “I felt my biggest challenge was Ms. Daulerio to find a way to beat this,” he said. “But I was listening to the [survival] percentages and thinking, ‘This is not real good.’” Upon hearing her mother’s diagnosis of non–small cell lung cancer with brain metastases, Ms. Daulerio said she also “went into research mode,” filling her mother’s living room with “piles of articles, information about clinical trials and holistic alternatives.” She said, “My reaction was to rally the family around what we should do next.” Her mother underwent many experimental treatments, but none saved her life. Looking back, one of the things the family did not explore with her mother—and a source of regret now—were her preferences for her final days and her funeral. “We didn’t discuss what would happen if things didn’t go so well. We should have taken time to discuss this as well, early on, while she was still clear-headed,” she said. “The problem is that later on, you don’t want
Breaking the bad news to a loved one is one of the hardest parts of the caregiver role. Children are very sensitive to illness in the home; it is difficult to be honest with them, as the tendency is to protect them from distress. The oncology team should be candid, though gentle, with the family when conveying a poor prognosis, and can be emotionally supportive of the family in a number of ways.
to discuss these things because it will be so sad, now that there’s no hope.”
When the Patient Gives Up In advanced cancer, even the most encouraging experimental treatment usually fails, and at some point the cancer patient may lament, “I can’t go on like this. I’m ready for this to end.” This is usually a request to withdraw life-prolonging measures, but it may also mean, “Help me die.” Several of the panelists faced this terrible moment. One was Ms. Ebert, who knew her husband could survive his cancer, though with great obstacles. Her response was to try to instill a will to live in her husband. Ms. Pausch experienced a similar moment, and when her husband brought up euthanasia, she staunchly refused. They both urged caregivers to anticipate these words and have their responses prepared.
When the Patient Is a Child Alex Scott, in her brief 8 years of life, started a lemonade stand to raise money for pediatric cancer research. This modest act inspired Alex’s Lemonade Stand, which has taken in $41 million for cancer-related causes. According to Alex’s mother, children with cancer “develop a great sense of what is going on around them…and spend a lot of time listening and observing.” Adults, including health care providers, should realize this when children are within earshot, Ms. Scott suggested. Alex seemed to understand Ms. Scott the concept of death but preferred not to talk about it. “She channeled a lot of her concerns into her lemonade stand,” her mother noted, and toward the end of
her life “she took it to the next level… she wanted more time.” In retrospect, Ms. Scott acknowledged that Alex’s siblings probably needed more preparation for the inevitable outcome. Her instinct was to couch the sad reality in terms that kept hope alive. But when children expect a loved one to die, she decided, they can create opportunities to spend more meaningful time with them.
Preparing the Children Caring for the unique emotional needs of the children of cancer patients is another caregiver challenge. Panelists spoke of their uncertainty about what to say, how to say it, and when to tell the children a parent is dying. Ms. Pausch was advised by a counselor to delay this conversation until
It’s absolute terror, to hear your loved one has cancer — Priscilla Mack her husband was obviously ill, and to wait for the children to broach the topic. When this time came, she found it difficult to be honest. “I lied to my son because I didn’t want him to look at his father and think that Daddy is going to die today. This happened a month before Randy passed away,” she said. Ms. Snow said being in the public eye made it hard to hide the truth from her chilMs. Snow dren. “We were trying to protect the children, but I think they had to hear more than they needed to,” she said. “What they most needed to know was that Tony and I were being honest with them the whole time.” Initially, her husband had assured her he could “take care of the cancer” if she could take care of the children, but metastasis of his colon cancer soon rendered him less independent. “That’s when the second part of my caregiving started. I was no longer just watching the children,” she said, “I was taking care of Tony and also taking care of the children.” She expressed gratitude that, when her husband became very ill, Tony’s oncologist offered to talk to her children about their father’s illness and,
in a sense, prepare them for his death. “He was willing to take the time,” Ms. Snow said. “He came off as loving Tony, and it showed the children he had done everything he could do.”
When Oncology Professionals Are Patients and Caregivers Themselves Mary Beth Reardon, RN, MS, of H. Lee Moffitt Cancer Center & Research Institute, is a certified oncology nurse. However, witnessing her close friend’s battle with brain canMs. Reardon cer made her a better “professional caregiver,” she told the audience. “To be with Linda to the end was eye-opening as to what caregivers go through. While I also had tons of sympathy for the patients, I developed more empathy for the families,” she said. Although she was trained as a nurse, Ms. Reardon felt oddly insecure in her role as caregiver, especially when asked to help make decisions— both important decisions, such as what treatment to choose, and small ones, such as when to call the doctor. “There are so many decisions facing caregivers, and to be in that position is a tremendous challenge.” Samuel M. Silver, MD, PhD, of the University of Michigan Comprehensive Cancer Center, developed lymphoma and found himself straddling the line between oncology professional and patient. Finally, he acknowledged, “I need an oncologist and it shouldn’t be me,” he said.
What Caregivers Need from the Oncology Team “What do oncologists owe patients and caregivers?” Mr. Donaldson asked the panel. He prefaced the question by sharing how one oncologist answered a similar question: “When you know the odds are terrible, what do you say to the patient?” “If I said you have a 26% chance of survival, the patient would be devastated,” the oncologist said. “But if I can say to them honestly, ‘I know Dr. Silver people who have had exactly what you have and they are healthy today,” they will say, ‘God bless you, doctor.’” Dr. Silver responded that patients are due “a forthright discussion,” but © 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
what he prefers to add is this: “‘I can give you percentages, but that’s statistics based on a population. We are talking about an individual here. Let’s talk about how you’re different.’ I emphasize their individuality rather than statistics,” he said. Mr. Cowher said he appreciated optimism from oncologists, but he also wanted to know the score and to understand when the end was near. “We
are trying to prepare ourselves and prepare others. I appreciated the nurses and doctors who gave me candid answers,” he said. Ms. Snow was grateful to the nurses who had a compassionate way of communicating the odds. “My wake-up call was when one nurse gently asked if I knew where my will was, and if I knew about hospice. They would quietly sit and talk with me, and I took
my cues from them many times.” Ms. Pausch wanted oncology nurses to appreciate her lack of medical training. “Caregivers are asked to do medically technical things without any medical background—clean the PICC line, push heparin, take blood pressures,” she pointed out. “It comforted Randy for me to take care of him at home, but the stress it placed on me was tremendous.”
Ms. Reardon suggested that oncologists simply listen more and determine what the family understands. “It might influence how physicians communicate with patients and caregivers,” she said.
Molecular Testing: Implications for Practice and Policy The growing excitement over molecular testing is tempered with cautious optimism, as further evidence-based data and regulatory standards are still needed
etection/analysis of genetic mutations, better known as molecular testing, has rapidly emerged as one of the hottest topics in the new era of personalized medicine in oncology. Although the ultimate treatment goal in cancer care hinges on the ability to predict a patient’s response to a specific therapy, molecular testing is still in its infancy, and many questions remain to be answered. With this in mind, Clifford Goodman, PhD, Senior Vice President at The Dr. Goodman Lewin Group in Falls Church, Virginia, moderated a roundtable on the practice and policy implications of molecular testing. Members of the distinguished panel, including oncologists, patient advocates, and third-party payers, voiced their opinions in an attempt to distill the challenging issues at stake before molecular testing can reach its true potential.
Regulatory Standards: ‘Bringing Order Out of Chaos’ Not all molecular tests are performed in the same way or by laboratories with the same experience. “Highcomplexity tests need to be performed in a high-complexity lab,” stated Scott Gottlieb, MD, practicing physician and resident fellow at the American Enterprise Institute in Washington, DC. Test kits may be performed in a community hospital, and simpler tests, such as those for hepatitis C virus and human immunodeficiency virus or CLIA (Clinical Laboratory Improvement Amendments)–waived tests, may be performed in a physician’s of© 2011 NCCN. All rights reserved.
fice. “If a test is marketed as a kit, it is regulated by the US Food and Drug Administration [FDA],” added Dr. Gottlieb. “All tests used to screen the blood supply are FDAregulated.” The panel agreed that regulatory standards and platforms are needed for Dr. Gottlieb these new genetic tests. “One of the major problems we’re facing is the heterogeneity and variability of these tests,” admitted Andrew von Eschenbach, MD, President of Samaritan Health Initiatives, Inc. “We are laying a foundation here, and it is important that we get it right because we are going to have to build on it,” he added. Because of the diversity in the performance of these tests, the accuracy of current test results may come into question. For instance, Lee Newcomer, MD, MHA, Senior Vice President of Oncology Services with UnitedHealth Group, mentioned that 30% of the results from the original HER2 drug trial were inaccurate when compared with reference lab testing. “If you have an overexpressed gene that was wrong, you would be getting a year’s worth of therapy that would not be helpful for you; if you have an underexpressed Dr. Newcomer gene that was wrong, you would be missing a year of very valuable therapy that could save your life,” he explained. “You want the oncologist and the woman to be completely assured that the report they are
Meet the Panel Clifford Goodman, PhD, moderator: Senior Vice President at The Lewin Group, a healthcare policy consulting firm based in Falls Church, Virginia. With more than 25 years of experience in healthcare evaluation, Dr. Goodman is also Director of the Evidence-based Practice Centers Coordinating Center at The Lewin Group. Scott Gottlieb, MD: Practicing physician and resident fellow at the American Enterprise Institute, a private, nonpartisan, nonprofit institution dedicated to research and education on issues of government, economics, and social welfare. Dr. Gottlieb served as FDA Deputy Commissioner from 2005−2007. Louis B. Jacques, MD: Director of the Coverage and Analysis Group of the Centers for Medicare & Medicaid Services, which reviews evidence and develops Medicare national coverage policy. Prior to his arrival at CMS, Dr. Jacques was Associate Dean for Curriculum at Georgetown University School of Medicine, where he retains a faculty appointment. Michael Kolodziej, MD: Chief of Oncology at St. Peter’s Hospital, Albany, New York. An active member of the US Oncology Pharmacy and Therapeutics Committee, Dr. Kolodziej has served as Chairman for the past 4 years and as Medical Director for Oncology Services for the past 3 years. Mark G. Kris, MD: Chief of the Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York City, and Professor of Medicine, Weill Medical College of Cornell University. As a specialist in lung cancer, Dr. Kris is particularly interested in molecular testing to guide treatment strategies. Lee N. Newcomer, MD, MHA: Senior Vice President of Oncology Services with UnitedHealth Group, where his focus is the creation of a new business unit that uses a clinical perspective to improve affordability, Clifford quality, and access to oncology services to its enrollees. Dr. Newcomer is Chairman of the Board at Park Nicollet Health Services in Minneapolis, Minnesota. Elizabeth Thompson: President of Susan G. Komen for the Cure®. A highly respected leader in the global cancer community with expertise in formulating educational and public policy initiatives focused on quality and outcomes, Ms. Thompson serves as Komen’s voice on numerous external boards, review panels, and committees. Andrew von Eschenbach, MD: President of Samaritan Health Initiatives, Inc, in Montgomery, Texas, where he leads a consulting firm in the field of healthcare policy and practice. Dr. von Eschenbach is the former Commissioner of Food and Drugs for the FDA.
getting is accurate.” The panel agreed that regulatory standards for molecular testing may improve the confidence that clinicians
and cancer patients have in the test results. “We need to bring order out of chaos. One entity that is prepared to do that, at least from the point of
Highlights of the NCCN 16th Annual Conference
view of its scientific and analytical infrastructure, is the FDA,” proposed Dr. von Eschenbach. Dr. Gottlieb agreed: “The reality is that a new regulatory scheme will be applied to these tests
in the next 12–24 months. The FDA is working on some regulations and if they don’t act unilaterally, the Hill is working on legislation that will be attached to the reauthorization of the Medical Device User Fee Act in 2013.” Although the consensus was that a regulatory authority should be overseeing the analytic validity of molecular testing, “the keystone of the debate is
whether or not a regulatory authority should be regulating the clinical validity and the clinical utility,” stressed Dr. Gottlieb. “Determining how
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important the test result is to the clinical decision-making process is best left to the clinical community,” he added.
Clinical Utility: Show Me the Data
“How do we know that these molecular tests work, and how effectively are the results being translated into clinical practice?” Dr. Goodman asked the panel. As an advocate of the use of molecular testing in guiding treatment decisions, Mark Kris, MD, Chief of the Thoracic Oncology Service, Division of Solid Tumor Oncology in the Department of Medicine at Memorial Sloan-Kettering Cancer Center in New York, shared two examples in which DNA-based testing has been shown to predict whether or not a certain treatment will work in a given patient: KRAS gene mutations in colorectal cancer and EGFR mutations in advanced lung cancer. Strong evidence shows that if you have the KRAS mutation, there is “virtually a 0% chance” of tumor shrinkage with cetuximab (Erbitux) or panitumumab (Vectibix), whereas there is a “decent chance” of tumor shrinkage with these drugs if you do not have the mutation, explained Dr. Kris. “That is now part of standard guidelines and labeling for these Dr. Kris two drugs,” he added. In addition, according to the IPASS study (Mok TS et al. N Engl J Med 2009;361:947–957), more than 70% of those who had the EGFR mutation responded to treatment with gefitinib (Iressa), versus only 1% of those who did not. Defining evidence in another way, Dr. Newcomer stated that it comprises three points: analytic validity (do you get the same result 99 times out of 100), clinical validity (does the gene you are measuring truly correlate with the result you want), and clinical utility (does the result affect a decision leading to a difference in patient outcome). According to Dr. Kris, “Clinical utility is the job of the clinical research community to provide that data.” However, Dr. Kris admitted that only one of the eight molecular tests performed at Memorial Sloan-Kettering Cancer Center has phase III supporting evidence. For many members of the panel, the evidence-based data for many tests are immature, and this remains a concern. “There is evidence, evidence with practical hurdles, and © 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
inadequate evidence. EGFR mutational analysis is evidence, but we will not order other tests without good evidence, New Ms. Thompson England Journal of Medicine evidence,” declared Michael Kolodziej, MD, Chief of Oncology at St. Peter’s Hospital in Albany. Elizabeth Thompson, President of Susan G. Komen for the Cure®, echoed a similar sentiment: “Although the United States is leading the world in terms of what molecular testing means
Clearly, a new system is needed for billing, as the coding system is antiquated. — Dr. Newcomer for patient care and outcomes, we still don’t have enough information.” Even in light of these reservations, the reality is that molecular testing is guiding treatment decisions in such areas as colorectal, lung, and breast cancer. For example, according to Dr. Newcomer, when Oncotype DX is used in breast cancer, 94% of low-risk patients do not receive chemotherapy, in line with the recommendation of the test. “Cancer treatment at NCCN institutions centers on a group of
people looking at a wide variety of factors, and the test is one part of the decision-making module,” added Ms. Thompson. “At the end of the day,” concluded Dr. Kolodziej, “I am a cautious optimist. There will prove to be value in some molecular testing, and it will prove to be predictive of response to a specific therapy.” Dr. Gottlieb agreed: “If there wasn’t inherent value in these tests, I don’t think they would exist.”
The Price of Testing: Spending Money to Reduce Costs The final question Dr. Goodman posed to the panel was whether the value of the results obtained with these molecular tests is worth the price tag. Although some of the molecular tests are inexpensive, EGFR testing is about $800, stated Dr. Kris. Louis Jacques, MD, Director of the Coverage and Analysis Group of the Centers for Medicare & Medicaid Services, tried to put the cost issue in perspective: “Everything about cancer is expensive. Although molecular testing may be expensive, so is chemotherapy, so is hospitalization, and so are serious adverse events.” Dr. von Dr. von Eschenbach Eschenbach presented another view on the price of molecular testing. “There is no question that these tests are a methodology for saving
money in health care from both a theoretic and an emerging practical perspective,” he said. “When you give the right treatment at the right dose for the right reason, you get the right outcome.” It may be possible to eliminate unnecessary spending for insufficient or inappropriate therapy through the application of molecular testing. “As we integrate diagnostic molecular testing into our therapeutic models, we will reduce costs,” predicted Dr. von Eschenbach. Two additional factors to consider in this value-for-money discussion center on the system of reimbursement for genetic testing and the logistic challenge of access to speciKey Points Because of the diversity in the performance of molecular testing, the accuracy of current test results may come into question. Not all molecular tests are performed in the same way or by laboratories with the same experience, and the panel agreed that regulatory standards are needed. Although KRAS gene mutations in colorectal cancer and EGFR mutations in lung cancer are examples of evidence-based testing, the data supporting other genetic tests are immature. Integrating diagnostic molecular testing into therapeutic models may reduce the costs and serious adverse events associated with inappropriate treatment.
mens. According to Dr. Newcomer, “clearly, a new system is needed for billing. The current system does not itemize the tests, and the coding system is antiquated.” From the perspective of third-party payers, Drs. Jacques and Newcomer agree that the clinical utility of these tests must be clear and that a better understanding of the specifics of testing parameters is necessary. “I have no idea what I am spending for genetic care or what I am actually getting when we reimburse for genetic testing,” revealed Dr. Newcomer. “Frankly, anything short of clinical utility casts a giant pall of uncertainty over whether I ought to be paying for this,” concurred Dr. Jacques. Dr. Gottlieb predicts that the payment scheme will dramatically change over the next few years, with a move to a flat fee–based approach rather than one based on the complexity of the test. The other challenging issue is to get the specimen from the pathology department to the lab performing the test, explained Dr. Kris. “The lab turnaround is days, but getting it to the molecular lab is the tough part.” Dr. Gottlieb believes that some of this difficulty may be lessened by the emergence of more integrated entities. In some cases, “anatomical pathologists are consolidating themselves and also purchasing these molecular diagnostic companies,” he concluded.
Breast Cancer NCCN Guidelines™ Update New drugs included for treating metastatic disease
his year’s update of the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Breast Cancer includes several key changes, announced Panel Chair Robert W. Carlson, MD, of Stanford Comprehensive Cancer Center in Stanford. The updates stemmed from pivotal research presented at major oncology meetings in 2010, he said, Dr. Carlson and will be immediately applicable to daily oncology practices.
© 2011 NCCN. All rights reserved.
Based on the landmark ACOSOG Z0011 study (Giuliano AE et al. JAMA 2011;305:569–575), which included 177 institutions, the Panel maintained that there is no need for a complete axillary lymph node dissection (ALND) in women with clinically node-negative T1–T2 tumors and fewer than three involved sentinel lymph nodes who undergo surgery and radiation therapy. The study found no difference in locoregional recurrences, disease-free survival (DFS), or overall survival (OS) between patients who underwent ALND versus those who had a sentinel lymph node dissection (SLND) only. At a median follow-up of 6.3 years, locoregional recurrences were noted in 4.1% of the ALND cohort (n = 420) and 2.8% of the
SLND patients (n = 436) (P = .11). Median OS was approximately 92% in each group. “In absolute terms, the ALND group actually had a slight increase in recurrence rates,” Dr. Carlson noted. “The Panel, in reviewing the data, declined to add the recommendation to the main guidelines based on this single randomized trial.”But there was substantial discussion, he added, since Z0011 was initially designed for 1,900 patients but only 45% of the target was accrued. At least one NCCN institution is abandoning ALND for this subset of patients, while another NCCN center has not altered its recommendation. On the basis of these data, the Panel added a footnote: “Data from a single randomized trial
suggest that complete axillary lymph node dissection in women with clinically node-negative T1–T2 tumors, fewer than three involved sentinel lymph nodes, and undergoing breastconserving surgery and whole breast radiation results in more morbidity, no improvement in locoregional recurrence rates, and no difference in overall survival compared with sentinel lymph node procedure alone.”
New Drugs for Metastatic Disease Based on robust trial results, eribulin mesylate (Halaven), a synthetic analog of halichondrin B that blocks microtubule polymerization, was added to the list of preferred chemotherapy regimens for metastatic breast
Highlights of the NCCN 16th Annual Conference
cancer (MBC). In the EMBRACE study (Twelves C et al. J Clin Oncol 2010;28;[Suppl 18]:Abstract CRA 1004), 762 patients with MBC were randomized to treatment of physicians’ choice (TPC) or to eribulin 1.4 mg/m2 on days 1 and 8 every 3 weeks. The primary endpoint was OS, “a high hurdle in this arena,” Dr. Carlson noted. One-year OS was 53.9% for patients receiving eribulin versus 43.7% for the TPC arm, and median OS was 13.12 versus 10.65 months, representing a 19% statistically significant risk reduction (P = .041). Time to progression was numerically greater with eribulin: 3.7 versus 2.2 months with TPC (P =.14).“This is a good example of the value of the NCCN review process,” Dr. Carlson noted. “Eribulin became
Key Points Eribulin (Halaven) was added as an option for treating metastatic disease. Denosumab was added as an option for preventing skeletalrelated events in patients with bone metastases. Bevacizumab (Avastin) in combination with paclitaxel was reaffirmed as an option for metastatic disease. Hormonal and HER2 status should be determined in patients with metastatic disease.
FDA-approved in November, and by December we had reviewed the data and incorporated it into our published guidelines.” Greater bone protection with denosumab compared with zoledronic acid was reported at the 2010 American Society of Clinical Oncology Annual Meeting, as well (Stopeck A et al. J Clin Oncol 2010;28[Suppl 15]:Abstract 1024). While OS and DFS were similar between denosumab and zoledronic acid in the trial, skeletal-related events were reduced by 23% with denosumab (P = .001; Stopeck et al. J Clin Oncol 28:5132-5139, 2010). Denosumab, therefore, joins zoledronic acid and pamidronate as a treatment option for MBC with bone involvement.
Issues with Biomarkers Due to growing interest in the need for biomarkers—and the necessity that they be accurate—the Panel reviewed recent reports of discordance between primary and recurrent disease in estrogen receptor (ER) status and HER2 status. In as many as 31% of patients, the primary tumor is ERpositive but metastatic disease tests negative; in up to 60% of patients the primary tumor is ER-negative, becoming positive with metastatic disease; and there is a change in HER2 status in up to 8% of patients. For this reason the Panel recommended that the metastatic disease workup include the determination of hormonal and HER2 status “if unknown, originally negative or not overexpressed at the time of first recurrence in MBC.” “This recommendation is likely to get stronger as these data are formally published,” Dr. Carlson predicted.
Also of recent interest—and possibly practical significance—is the relationship between CYP2D6 polymorphisms and benefit from tamoxifen. A large retrospective study of 1,325 patients found that time to disease re-
The metastatic disease workup should include the determination of hormonal and HER2 status, and this recommendation is likely to get stronger as data are formally published. — Dr. Carlson currence was significantly shortened in patients who were classified as poor metabolizers of the drug (Schroth W et al. JAMA 2009;302:1429–1436). However, a retrospective study presented at the 2010 San Antonio Breast Cancer Symposium reached a different conclusion. In a subset of patients in the BIG 1-98 trial, which compared tamoxifen with letrozole, poor metabolizers actually had a 42% reduction in risk compared with women who were extensive metabolizers, although the difference did not reach statistical significance (LeylandJones B et al. Cancer Res 2010;70[Suppl 5]:Abstract S1-8).The available studies, therefore, are inconsistent on
this issue, Dr. Carlson noted. “Even if the genotype is predictive of outcome with tamoxifen, we don’t know how to [use this information], especially in treating ER-positive premenopausal women in the absence of tamoxifen,” he said. “The current NCCN Guidelines are silent on this issue. Oncologists should interpret this as a recommendation not to perform CYP2D6 testing at this time.”
Bevacizumab Remains in the Recommendations In the wake of the FDA’s pending withdrawal of the breast cancer indication for bevacizumab (Avastin), the Panel stood firm in its inclusion of bevacizumab plus paclitaxel as a preferred regimen, although the issue was heavily debated. “We met three times in 6 months and the end result was a unanimous vote to retain the indication in combination with paclitaxel. The E2100 trial data have not changed since the time of bevacizumab’s approval, and we decided that if it was compelling enough to include this regimen 2 years ago, it still is today.” The Panel did, however, include a footnote stating, “The addition of bevacizumab to some first- or secondline chemotherapy agents modestly improves time to progression and response rates but does not improve OS. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.” A replication trial of this regimen is underway “to get a handle on whether E2100 demonstrated a drug effect or was a statistical variation among the trials,” Dr. Carlson added.
Non–Small Cell Lung Cancer NCCN GuidelinesTM Update Panel recommends using EGFR mutations and histologic subtype to tailor treatment, but use of surgery for N2 disease remains controversial
ersonalized medicine through the use of molecular markers in non–small cell lung cancer (NSCLC) has arrived, and the use of epidermal growth factor receptor (EGFR) mutations and histologic subtype to tailor therapy plays a Dr. Ettinger key role in the updated 2011 National Comprehensive Cancer Network® (NCCN®)
Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Panel Chair David S. Ettinger, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins School of Medicine, presented the major updates to the NCCN Guidelines for NSCLC. He focused on the role of molecular diagnostics (particularly for EGFR, KRAS, and now EML4-ALK); the category 1 recommendation for EGFR testing for adenocarcinoma, large cell carcinoma, and NSCLC not otherwise specified (NOS), and its implications for tailoring treatment of advanced
A Small cell lung cancer (13%) Other NSCLC
EGFR mutated (10% of NSCLC) KRAS mutated (25% of adenocarcinoma)
KRAS-mutated NSCLC 36,000 cases/year
EGFR-mutated NSCLC 18,000 cases/year
EML4-ALK NSCLC CML 9000 cases/year 5000 cases/year
(A) New lung cancer cases in the United States in 2010. (B) Yearly incidence of lung cancers with driver mutations. © 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
Key Points EGFR testing is a category 1 recommendation for adenocarcinoma, large cell carcinoma, and NSCLC NOS but is not recommended for squamous cell carcinoma. Platinum doublets, chemotherapy with bevacizumab (Avastin), histology-directed therapy, and newer targeted agents are improving outcomes in advanced NSCLC. Mutational status, particularly for EGFR and KRAS, and the presence of the EML4-ALK fusion gene are now affecting the choice of effective treatment options. Patients with a single lymph node < 3 cm can be considered for a multimodality approach that includes surgical resection.
Ettinger. Furthermore, all patients who have adenocarcinoma, large cell carcinoma, and NSCLC NOS should undergo studies for molecular mutations, he stressed. Currently, there is no standard method for detecting EML4‑ALK–positive NSCLC, but polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization are being evaluated.
The Era of Mutation-Driven Therapy According to the 2011 NCCN Guidelines, the evaluation process for systemic therapy for advanced, recurrent, or metastatic disease has changed to first establish the histologic subtype and then recommend EGFR testing based on that subtype.
The recommendations for treatment of advanced NSCLC are based on these relevant determinations. “We are heading toward the era of mutation-driven therapy, and this is ex-
ERBITUX Increased Overall Survival in Both: Squamous Cell Carcinoma of the Head and Neck (SCCHN) in Combination With RT in Locoregionally Advanced Disease
EGFR-Expressing Metastatic Colorectal Cancer (mCRC) after Irinotecan and Oxaliplatin Failure as a Single Agent
disease; and the Panel’s lack of consensus regarding the use of pneumonectomy after induction therapy for stage N2 disease.
Molecular Diagnostics: Focus on EGFR, KRAS, and EML4-ALK One major change to the 2011 NCCN Guidelines for NSCLC appears in the Principles of Pathologic Review. Updated information on EGFR and KRAS as well as a new addition on EML4-ALK (echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase) are included under Molecular Diagnostic Studies in Lung Cancer. Featured are incidence data for these mutations and their emerging importance as predictors of patient response to treatment. In the United States, more than 60,000 new cases of NSCLC per year are estimated to contain driver mutations, explained Dr. Ettinger: 25% of adenocarcinomas are KRAS-mutated, 10% of NSCLC are EGFR-mutated, and about 5% of NSCLC are EML4‑ALK−mutated (see figure). In the updated Guidelines, EGFR testing is a category 1 recommendation for adenocarcinoma, large cell carcinoma, and NSCLC NOS but is not recommended for squamous cell carcinoma. Tissue acquisition for such testing is critical, emphasized Dr. Ettinger. The sampling target should be the lesion that will establish the highest disease state. The pathologic evaluation should include the World Health Organization histologic classification. “Histology matters, and NOS is unacceptable in 2011,” pronounced Dr. © 2011 NCCN. All rights reserved.
ERBITUX Indications Head and Neck Cancer ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck
Metastatic Colorectal Cancer ■ ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations
ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX EGFR=epidermal growth factor receptor; RT=radiation therapy.
Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.
SOLUTION FOR INTRAVENOUS INFUSION
tremely important for our patients,” stated Dr. Ettinger. Therapeutic options for advanced NSCLC have progressed from single-agent platinum to platinum doublets and now
Highlights of the NCCN 16th Annual Conference
to bevacizumab (Avastin) plus chemotherapy doublets. He shared the relevant supporting data for NCCNrecommended therapy for advanced NSCLC.
First-Line Therapy The combination of pemetrexed and cisplatin was compared with gemcitabine and cisplatin as first-line
Histology matters, and NSCLC NOS is unacceptable in 2011. — Dr. Ettinger
therapy in a phase III study of more than 1,700 patients with advanced NSCLC (nearly half with adenocarcinoma) (Scagliotti GV et al. J Clin Oncol 2008;26:3543−3551). Pemetrexed/cisplatin proved to be the better regimen for patients with adenocarcinoma, whereas gemcitabine/ cisplatin was best for squamous cell carcinoma.
ERBITUX Significantly Increased SCCHN
in Combination With RT in Locoregionally Advanced Disease Survival in Combination With RT (N=424)*1,2 ERBITUX (cetuximab) + RT (n=211)
Median overall survival 49.0 months
RT alone (n=213)
HR: 0.74; 95% CI: 0.57-0.97; P=0.03
3-year overall survival rate 55%
P=0.05 RT=radiation therapy; HR=hazard ratio; CI=confidence interval. multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 Median follow-up=54 months.2
■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1
ERBITUX Safety Information for SCCHN ■ The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms © 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
Bevacizumab plus paclitaxel/carboplatin is an effective first-line therapy for non–squamous cell tumors but not for squamous cell tumors. In a phase III study of 855 patients with non–squamous cell NSCLC (Sandler A et al. N Engl J Med 2006;355:2542−2550), bevacizumab plus paclitaxel/carboplatin improved overall survival (OS) over the two-drug combination alone, although there was
more toxicity with bevacizumab. “Previously, we never talked about 2-year survival in stage IV disease, so we are making some inroads here with bevacizumab,” concluded Dr. Ettinger. The IPASS study compared gefitinib (Iressa) versus carboplatin/paclitaxel as first-line therapy in patients with advanced adenocarcinoma (Mok TS et al. N Engl J Med 2009;361;947−957).
Even more impressive than the overall response rate with gefitinib was the response rate based on EGFR mutation status. Of those who had the EGFR mutation, more than 70% responded to gefitinib, versus only 1% of those who did not. “The KRAS mutation may be a negative predictor for chemotherapy and EGFR tyrosine kinase inhibitors,” stated Dr. Ettinger.
Overall Survival in Both: EGFR-Expressing mCRC
after Irinotecan and Oxaliplatin Failure as a Single Agent Median Overall Survival, All Patients (N=572)†1 6.14 months ERBITUX + BSC (n=287)
4.57 months BSC alone (n=285)
HR: 0.77; 95% CI: 0.64-0.92; P =0.0046
BSC=best supportive care. CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome measure of the trial was overall survival.1
■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1
ERBITUX Safety Information for EGFR-Expressing mCRC ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/ desquamation (12%), and other-gastrointestinal (10%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.
Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889). © 2011 NCCN. All rights reserved.
SOLUTION FOR INTRAVENOUS INFUSION
Maintenance Therapy In the SATURN study (Cappuzzo F et al. Lancet Oncol 2010;11:521−529), which assessed erlotinib as maintenance therapy
for patients with advanced NSCLC, “overall survival was statistically significant in favor of erlotinib in patients with adenocarcinoma and squamous cell carcinoma,” re-
Highlights of the NCCN 16th Annual Conference
vealed Dr. Ettinger. Another study showed that maintenance therapy with pemetrexed improved OS in patients with non–squamous cell NSCLC (ie, adenocarcinoma, large cell carcinoma, or NSCLC NOS) but not squamous cell carcinoma (Belani CP et al. J Clin Oncol 2009;27[Suppl 18]:Abstract CRA8000). Thus, data show that
maintenance therapy is valuable. In addition, the ATLAS study recently showed promising progressionfree survival with maintenance therapy using bevacizumab and erlotinib versus bevacizumab alone in patients who had received chemotherapy/bevacizumab as first-line therapy (Miller VA et al. J Clin Oncol 2009;27[Suppl 18]:Abstract LBA8002).
Second-Line Therapy Docetaxel, pemetrexed, and erlotinib are listed as second-line treatments for advanced NSCLC. A new second-line treatment was added this year: bevacizumab plus a platinum doublet (for patients who received first-line erlotinib and have adenocarcinoma), which currently
Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions
Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy
Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed
Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects
ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events © 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
holds a category 2B ranking. Dr. Ettinger briefly mentioned a recent clinical trial of patients with EML4-ALK–positive adenocarcinoma. Preliminary results with crizotinib as second-line therapy show dramatic response rates (70%) in patients with advanced NSCLC (Kwak EL et al. N Engl J Med 2010;363:1693−1703). “If you have
either the KRAS or EGFR mutation, you’re not going to have the EML4ALK translocation,” noted Dr. Ettinger.
The Controversial Use of Surgery for N2 Disease New pages were added to “Surgical Principles for NSCLC,” including the debate surrounding the use
of surgery after induction therapy for patients with stage IIIA (N2) disease. Multidisciplinary evaluation including a board-certified thoracic surgeon with experience in thoracic oncology is recommended prior to the initiation of any therapy. Although there is no proven OS benefit to surgery in this patient population, the Panel believes that trials
Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary
Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms
Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX
Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)
Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).
©2010, ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb, Princeton, NJ, 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US10AB08608
© 2011 NCCN. All rights reserved.
SOLUTION FOR INTRAVENOUS INFUSION
have not sufficiently evaluated the nuances present with the heterogeneity of N2 disease and the likely oncology benefit of surgery in specific clinical situations.
To assess practice patterns when approaching this difficult clinical
Highlights of the NCCN 16th Annual Conference
problem, the NCCN submitted a questionnaire to its institutions. More than 90% of respondents indicated they would consider surgery in patients with one N2 lymph node station involved by a lymph node smaller than 3 cm. However,
less than half (48%) of respondents said they would consider surgery with more than one N2 lymph node station involved, even if no lymph node was bigger than 3 cm. Based on this consensus of expert opinion, the NCCN states that patients with
eRbITUx® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: seRIOUs INFUsION ReACTIONs and CARDIOPULMONARY ARResT Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.] INDICATIONs AND UsAGe squamous Cell Carcinoma of the Head and Neck (sCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information]. CONTRAINDICATIONs None. WARNINGs AND PReCAUTIONs Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.] Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.] Use of erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.
a single lymph node smaller than 3 cm can be considered for a multimodality approach that includes surgical resection. “The pneumonectomy issue is not resolved in the NCCN institutions,” concluded Dr. Ettinger.
epidermal Growth Factor Receptor (eGFR) expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADveRse ReACTIONs The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials experience 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 below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:
Incidence of selected Adverse events (≥10%) in Patients with Locoregionally Advanced sCCHN erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) body system Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fever1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 Chills1 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 0 9 1 Dyspepsia 14 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 3 Alanine Transaminase, high 43 2 21 1 3 38 1 24 1 Aspartate Transaminase, high 3 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 skin/Appendages 87 17 10 1 Acneiform Rash4 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2
Includes cases also reported as infusion reaction. Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.
The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.
© 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
Update on Non-Hodgkin’s Lymphomas A new guideline for PTLD and upgraded therapies for FL take center stage
he most significant changes to the updated National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guide-
lines in Oncology (NCCN Guidelines™) for Non-Hodgkin’s Lymphomas (NHL) center on the addition of a new guideline for posttransplant
Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 2:
Incidence of selected Adverse events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with erbitux Monotherapy erbitux plus bsC bsC alone (n=288) (n=274) body system Any Grades Any Grades 2 Preferred Term Grades 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation Dry Skin Pruritus Other-Dermatology Nail Changes body as a Whole Fatigue Fever Infusion Reactions3 Rigors, Chills Pain Abdominal Pain Pain-Other Headache Bone Pain Pulmonary Dyspnea Cough Gastrointestinal Constipation Diarrhea Vomiting Stomatitis Other-Gastrointestinal Mouth Dryness Infection Infection without neutropenia Neurology Insomnia Confusion Anxiety Depression
89 49 40 27 21
12 0 2 1 0
16 11 8 6 4
<1 0 0 1 0
89 30 20 13
33 1 5 <1
59 51 33 15
14 16 4 3
52 34 11 7
16 7 0 2
46 39 37 25 23 11
4 2 6 1 10 0
38 20 29 10 18 4
5 2 6 <1 8 0
30 15 14 13
1 6 2 1
15 9 8 6
1 2 1 <1
Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. Adverse events were graded using the NCI CTC, V 2.0. Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated. BSC = best supportive care 1 2 3
The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and 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 Erbitux with the incidence of antibodies to other products may be misleading. Postmarketing experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. • Aseptic meningitis DRUG INTeRACTIONs A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.
lymphoproliferative disorder (PTLD) and the upgrading of two therapeutic regimens for follicular lymphoma (FL) to category 1 designations, announced
Use IN sPeCIFIC POPULATIONs Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, 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. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OveRDOsAGe The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOxICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIeNT COUNseLING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA
Copyright © 2004–2011 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved. 1236886A8
© 2011 NCCN. All rights reserved.
Rev March 2011
Panel Chair Andrew D. Zelenetz, MD, PhD, of Memorial SloanKettering Cancer Center (MSKCC), New York. OthDr. Zelenetz er highlighted topics include the role of PET scans in both the assessment and response evaluation in FL and the prognostic value of the proliferation index (PI) in mantle cell lymphoma (MCL).
A New Guideline for PTLD PTLD has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation. Understanding the pathogenesis and risk factors of PTLD has helped to identify high-risk patients (Jacobson CA et al. Oncology [Williston Park] 2010;24:936−944). “The single biggest risk factor for PTLD is if there is an Epstein-Barr virus [EBV] mismatch between the recipient and the donor,” explained Dr. Zelenetz (see table). The recommendations in the NCCN Guidelines for PTLD pertaining to diagnosis and workup are similar to those for other NHLs. Recommendations for tests are labeled as either “essential” or “useful in selected Key Points Recommended treatment options for posttransplant lymphoproliferative disorder include reduction of immunosuppression, use of ganciclovir for Epstein-Barr virus– positive disease, single-agent rituximab (Rituxan), and chemoimmunotherapy. Category 1–recommended treatments for follicular lymphoma (FL) now include the combination of bendamustine (Treanda) and rituximab for firstline treatment, and rituximab maintenance for post–first remission treatment. Posttreatment PET-CT is highly predictive of progression-free survival in FL. Patients with mantle cell lymphoma who have a low proliferation index and are treated aggressively are potentially curable.
cases.” Among the essential tests to establish diagnosis are histopathology and immunophenotyping as well as the EBER-ISH (EBV-encoded RNA in situ hybridization). For cases of EBVpositive disease, measurement of EBV viral load during workup becomes important in directing therapy. Depending on the PTLD subtype, “the first line of therapy is typically reduction of immunosuppression, when possible,” said Dr. Zelenetz. “Between a quarter and half of patients will have a sustained response to reduction in immunosuppression, but completely removing immunosuppression runs the risk of loss of the transplanted organ,” he cautioned. Single-agent rituximab (Rituxan) is an effective treatment as well, particularly for early and polymorphic lesions, with response rates as high as 90% (Jacobson CA et al. Oncology [Williston Park] 2010;24:936−944). “I would reserve chemoimmunotherapy for patients in whom other simpler maneuvers have failed,” he added.
Two Therapeutic Strategies for FL Upgraded Important changes were made in the FL section of the NCCN Guidelines. Two therapeutic strategies were upgraded from lower-level to category 1 recommendations: the combination of bendamustine (Treanda) and rituximab (B-R) for first-line treatment and rituximab maintenance for post–first remission treatment. In the trial comparing B-R with standard therapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab (R-CHOP) for previously untreated patients with FL, MCL, and other lymphomas (Rummel MJ et al. Blood 2009;114:Abstract 405), B-R significantly improved progression-free survival (PFS) and complete response rates versus R-CHOP. However, there was no difference in overall survival (OS) between treatments. Recent randomized studies of radioimmunotherapy and rituximab
Highlights of the NCCN 16th Annual Conference
maintenance indicate significant improvements in PFS with post–first remission therapy. In a trial comparing radioimmunotherapy consolidation with observation (Hagenbeek A et al. Blood 2010;116:Abstract 594), radioimmunotherapy (with 90Y ibritumomab tiuxetan [Zevalin]) improved response quality in 78% of patients and resulted in a 3-year prolongation of median PFS. However, only a small percentage of patients in this trial received rituximabcontaining induction therapy, which may limit the applicability of these results. In addition, there was “no hint of improvement in OS at 5.5 years,” stated Dr. Zelenetz. “There is a suggestion of an increased risk of myelodysplastic syndrome with 90Y ibritumomab tiuxetan, which is not statistically significant but is clinically concerning,” he added. The PRIMA study (Salles G et
tion without compromising survival outcomes. Dr. Zelenetz emphasized the importance of individualized treatment planning for patients with FL. Characteristics such as patient age, symptoms, comorbidities, disease stage, sites of involvement, and time from prior therapy, as well as the treatment goals of individual patients and the desire to preserve future treatment options, should be considered when making treatment decisions. Observation is appropriate for patients with advanced-stage FL, no symptoms, and a low tumor burden. However, for those with advanced-stage FL who have symptoms and a high tumor burden, treatment is warranted. “If a patient is symptomatic, that is the number-one indication for treatment of FL,” stated Dr. Zelenetz.
PTLD Risk Factors Risk Factor
EBV seronegative recipient
24 × average risk
Younger age at transplant
4–8 × adult risk
Type of immunosuppression Tacrolimus OKT3 and/or ATG
2–5 × cyclosporine risk 3–4 × without these agents
Type of organ transplant Kidney Liver Heart Heart-lung Lung Small bowel
1%–3% 1%–3% 1%–6% 2%–6% 4%–10% 20%
Time from transplant < 1 year
5–10 x risk vs ≥ 1 year
CMV (recipient –/donor +)
4–6 x risk of CMV+ recipient
Adapted with permission. Jacobson CA and LaCasce AS. Oncology 2010;24:936-944.
al. Lancet 2011;377:42−51) showed a dramatic improvement in PFS with 2 years of rituximab maintenance following remission-induction therapy with rituximab-containing regimens; again, no impact on OS was seen with current follow-up. Observation is still an appropriate option in the NCCN Guidelines algorithms for management of FL following remission-induction therapy, stressed Dr. Zelenetz. “No maintenance strategy in FL has yet demonstrated a benefit in overall survival,” suggesting that delayed treatment remains a viable op-
Special Topics: PET in FL, PI in MCL Two special topics were explored by Dr. Zelenetz: the value of PET scans in both the assessment and response evaluation of patients with FL, and the role of PI as a critical biomarker in patients with MCL. “Assessment of PET in Hodgkin’s lymphoma and diffuse large B-cell lymphoma has become completely standard both at induction and at response evaluation, but the role of routine PET scanning in FL is still a matter of investigation,”
No maintenance strategy in FL has yet demonstrated a benefit in overall survival. — Dr. Zelenetz stated Dr. Zelenetz. The outcomes of two studies (Schöder H et al. J Clin Oncol 2005;23:4643−4651; Noy A et al. Ann Oncol 2009;20:508−512) indicate that PET imaging can help to distinguish between indolent and aggressive histologies, because the latter typically have a much higher standard uptake value. This may be particularly useful in detecting cases of transformation. “Transformation is typically associated with a poor prognosis, so identifying patients who have transformed is important clinically,” said Dr. Zelenetz. PET imaging may also be useful in identifying patients with FL who have poor-risk disease after initial induction therapy. Based on the findings of the PRIMA study, the predictive power of post-treatment PET on PFS outcomes appeared to be stronger than and independent of other prognostic factors. “PET positivity at the end of treatment indicates poor outcome,” Dr. Zelenetz stated. PI is an important indicator of clinical outcomes in patients with MCL, but its use has been limited by variability in measurements between observers. The results of a recent study (Schaffel R et al. Ann Oncol 2010;21:133−139) suggest that a PI of less than 30%, as measured by quantitative image analysis (QIA), is a clinically meaningful cutoff, identifying patients with a favorable outcome. “This is a group of patients with a low proliferation fraction treated aggressively who are potentially curable,” said Dr. Zelenetz. Determination of PI by QIA is more reproducible than estimation by a pathologist and is easier than manually counting 1,000 cells. This information may be particularly helpful in tailoring the intensity of therapy in future clinical trials.
Hepatitis B Screening and Chemotherapy Although the supporting data are imperfect, antiviral prophylaxis for hepatitis B reactivation can save lives and prevent delays in cancer treatment
ne-third of the world has been exposed to hepatitis B, making it an enormous problem,” announced Emmy Ludwig, MD, of Memorial Sloan-
Kettering Cancer Center (MSKCC) in New York. Reactivation of the hepatitis B virus (HBV) can have a significant negative impact on the outcomes of many patients treated
with chemotherapy for cancer, both hematologic malignancies and solid tumors. Furthermore, “depending on how it’s defined, between 5% and 40% of people who have an acute
reactivation will die of liver failure,” added Dr. Ludwig. The good news is that this problem can be prevented with the prophylactic use of effective antiviral agents. © 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
Focus on Cancer Patients
Many patients being treated for cancer are at risk for HBV reactivation. Although reactivation can occur spontaneously, it is more typically triggered by immunosuppressive therapies for cancer, autoimmune disease, or organ transplantation (Hoofnagle JH. Hepatology 2009;49[Suppl 5]:S156−165). The risk of HBV reactivation persists for at least 6 months after chemotherapy ends. However, Dr. Ludwig added, this risk may be longer in stem cell transplant patients and in those receiving rituximab (Rituxan). The risk of liver failure from HBV reactivation has been linked to the use of rituximab, which led the FDA to issue a black-box warning about this problem. Therefore, patients receiving rituximab should be evaluated for HBV. Dr. Ludwig shared the retrospective experience regarding HBV reactivation in cancer patients being treated at MSKCC from 2003 to 2009. Twenty-three patients experienced reactivation of HBV while being treated with multiple different chemotherapeutic and immunosuppressive agents, including steroids alone. Although about one-third of these patients had hematologic cancers, the others had an assortment of solid tumors. Of these 23 patients, 19 (86%) required hospitalization for HBV reactivation and 4 died of liver failure. Dr. Ludwig emphasized that 4 Dr. Ludwig patients experienced clinically significant delays in chemotherapeutic treatment or surgery.
Recommendations for Screening and Prophylaxis
Antiviral prophylaxis has been shown to prevent chemotherapyrelated HBV reactivations, stated Dr. Ludwig. For instance, a systematic review of 14 studies (Loomba R et al. Ann Intern Med 2008;148:519−528) evaluated the use of lamivudine in patients who tested positive for the hepatitis B surface antigen (HBsAg) and were receiving chemotherapy.
© 2011 NCCN. All rights reserved.
Of 108 patients who received lamivudine prophylactically, none developed HBV reactivation or HBVrelated hepatic failure. Another study explored the use of lamivudine prophylaxis in patients with lymphoma who were HBV-positive (Lau GK et al. Gastroenterology 2003;125:1742−1749). Again, there were no cases of HBV reactivation in patients treated with prophylaxis, compared with 8 cases (53%) in those who were not. Furthermore, there were no lapses in chemotherapy in those who received prophylaxis. In March 2009, MSKCC implemented a standard to perform screening for HBV in all new patients receiving immunosuppressive
Antiviral prophylaxis works and prevention is better than treatment. — Dr. Ludwig therapy. From May 2009 to September 2010, almost 10% of the 4,065 chemotherapy patients screened for HBV at MSKCC tested positive for either the HBsAg or the hepatitis B core antibody (HBcAb). All of these patients were treated with antiviral prophylaxis, and there were no cases of HBV reactivation. Based on the potential benefits of HBV screening in patients receiving immunosuppressive therapy, many medical groups have joined MSKCC in endorsing it. For instance, organizations such as the American, European, and Asian-Pacific Associations for the Study of Liver Diseases; the Infectious Disease Society of America; the American and World Gastroenterology Association; the American College of Rheumatology; and the Centers for Disease Control and Prevention all support universal screening. The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Prevention and Treatment of Cancer-Related Infections recommend HBV screening in patients undergoing hematopoietic stem cell transplant or other intensive immunosuppressive therapy. The Guidelines also
Key Points Many patients being treated for cancer with immunosuppressive therapies are at risk for hepatitis B virus (HBV) reactivation. Limited data suggest that antiviral prophylaxis is 100% safe and effective in preventing chemotherapy-related HBV reactivation. Many medical groups recommend universal screening for HBV, although ASCO is not one of them. The optimal antiviral agent and duration of prophylaxis remain unresolved issues.
state that, based on limited data, antiviral therapy should be strongly considered in this group of patients. In addition, the NCCN Guidelines for non-Hodgkin’s lymphomas also recommend HBsAg and HBcAb screening for all patients receiving rituximab. On the other hand, the American Society of Clinical Oncology (ASCO) does not recommend routine screening for HBV. According to ASCO, “the evidence is insufficient to determine the net benefits and harms of routine screening for chronic HBV infection in individuals with cancer who are about to receive cytotoxic or immunosuppressive therapy or who are already receiving therapy” (Artz AS et al. J Clin Oncol 2010;28:3199−3202). Dr. Ludwig acknowledged this, admitting, “The data honestly are imperfect, and there are no large, randomized trials. However, if I had hepatitis B and were getting chemotherapy, I would put myself on this [antiviral] medication.” Screening is straightforward and cost-effective,
antiviral prophylaxis for hepatitis B works, and prevention is better than treatment, she pronounced.
Unanswered Questions Several issues require further consideration. First and foremost is the need to increase awareness of HBV reactivation in the oncology community. Oncologists need to understand that “HBV reactivation is potentially fatal but completely preventable (with appropriate prophylaxis),” as they make treatment decisions for their patients, advised Dr. Ludwig. The second issue centers on the optimal choice of antiviral agent. Lamivudine, used in many of the earlier studies, is an effective option; however, 65% of patients will become resistant to lamivudine at 5 years, Dr. Ludwig explained. “We do not recommend lamivudine because of the high resistance rate,” she added. Newer agents such as entecavir (Baraclude) are extremely effective and have a low resistance profile. “MSKCC uses entecavir, because there appears to be no resistance at 5 years, and we have had no problems with interactions with medications,” she said. The third issue addresses the optimal duration of antiviral prophylaxis. “For patients who are not getting rituximab or a bone marrow transplant, we have been stopping at 6 months, and people have been doing well,” stated Dr. Ludwig. However, there have been a few recent reactivations after a year, which she calls “disturbing.” Therefore, she adds, bone marrow transplant recipients may require longer antiviral prophylaxis compared with other patients.
HBV Reactivation at MSKCC from 2003–2009 Summary of findings ■■
Cancer patients may die from fulminant hepatic failure secondary to HBV reactivation
No association was seen with a specific treatment or malignancy
“Profiling” patients by country of birth misses patients
Screening is straightforward
Antiviral prophylaxis for HBV is effective
Prevention works better than treatment
Highlights of the NCCN 16th Annual Conference
NCCN GuidelinesTM for Prostate Cancer Update Panel recommends more rigorous monitoring of men undergoing active surveillance and new category 1 therapies for advanced disease
verybody knows we have been overtreating men for prostate cancer,” declared James L. Mohler, MD, of Roswell Park Cancer Institute, Buffalo, who is Chair of the National Comprehensive Cancer Network® (NCCN®) Panel for Prostate Cancer. The Panel remains concerned about overdetection and overtreatment. Although the development of the prostatespecific antigen (PSA) blood test has played some role in the declining mortalDr. Mohler ity from prostate cancer over the past 20 years, it is also partly responsible for so many men with early prostate cancer receiving unnecessary treatment. With this in mind, the major modifications in the 2011 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Prostate Cancer focus on more rigorous monitoring of men undergoing active surveillance and the rationale behind the changes for this controversial approach. In addition, the complete reorganization of the Guidelines for advanced prostate cancer features several new category 1 options: sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC), cabazitaxel (Jevtana) for docetaxel failure, and denosumab (Xgeva) for prevention of skeletal-related events (SREs).
The Controversy Over PSA Screening Conflicting study data about the benefits of PSA screening are at the heart of the overdetection controversy, and this in turn leads to the overtreatment problem. In 2009, two large screening studies sparked the debate. The European study (Schröder FH et al. N Engl J Med 2009;360:1320−1328) concluded that 1,410 men need to be screened and 48 PSA-detected cancers treated to prevent one prostate cancer death. The American study (Andriole GL et al. N Engl J Med 2009;360:1310−1319) reported no survival benefits from PSA screening, although the control arm was heavily PSA-tested. The best informa-
tion on the true performance of PSA screening, according to Dr. Mohler, may come from a subset analysis of the European study (Hugosson J et al. Lancet Oncol 2010;11:725−732). “The chance of dying of prostate cancer was reduced by 40% with PSA screening,” reported Dr. Mohler. In this study, 12 men need to be treated to prevent one death. The American Cancer Society and the NCCN generally agree that the use of PSA screening for early detection of prostate cancer is most appropriate for high-risk groups: African Americans, men whose father or brother has prostate cancer, and men with the BRCA1 mutation.
The Continuing Debate Over Active Surveillance Adding and refining recommendations for active surveillance is the NCCN response to overtreat-
We need to learn how to select patients who may do well with sipuleucel-T. — Dr. Mohler ment. “We clearly don’t need to treat everyone in whom we can diagnose prostate cancer,” revealed Dr. Mohler, but who can be spared treatment is less clear. Another question is when to switch to treatment. “A major problem is that we do not want to have someone with curable prostate cancer convert to incurable prostate cancer during a period of active surveillance,” he added. Large patient series on active surveillance from Johns Hopkins (Ross AE et al. J Clin Oncol 2010;28:2810−2816), the University of California at San Francisco (Cooperberg MR et al. J Clin Oncol 2011;29:228−234), and Toronto (Klotz L et al. J Clin Oncol 2010;28:126−131) shed some light on this issue while raising more questions. PSA kinetics were found to be unreliable in determining disease progression, but the studies conflict in the enrollment criteria. The current NCCN Guidelines recommend
active surveillance for men with low-risk prostate cancer and a life expectancy of less than 10 years, and for those with very low–risk prostate cancer and a life expectancy of less than 20 years. The UCSF group stated that less-restrictive guidelines will not increase progression risk, but the Toronto group cautioned that curative treatment may not be possible for men whose disease progresses on active surveillance. “The panel remains perplexed by these conundrums,” admitted Dr. Mohler. “We make a plea for more support for clinical research in the active surveillance population.” In an attempt to clarify the appropriate use of active surveillance, the NCCN reworked its 2011 Guidelines to include more aggressive monitoring for men undergoing observation. PSA levels should be measured at least every 6 months, prostate examination should be performed at least every 12 months, and repeat prostate biopsies should be considered as often as every 12 months. However, biopsies are not without risk. Patients may suffer urosepsis or failure of nerve preservation during future prostatectomy. “We could just biopsy everybody annually, but that is fraught with danger,” commented Dr. Mohler. Interestingly, anxiety is often associated with active surveillance. “Based on the North American experience, one-third of men who convert to treatment do so because of anxiety, with no evidence of disease progression at all,” he observed.
Newer Therapies for Advanced Disease The NCCN completely reorganized its 2011 Guidelines for treatment of advanced prostate cancer, especially for CRPC. The major changes center on the addition of three new category 1 therapeutic options supported by phase III trials: sipuleucel-T, cabazitaxel, and denosumab. Immunotherapy with sipuleucelT is an alternative for patients with CRPC who do not have symptomatic or visceral disease. This recommendation is based on data from two phase III trials—the D9901 study (Small EJ et al. J Clin Oncol 2006;24:3089−3094) and the IMPACT trial (Kantoff PW et al. N Engl J Med 2010;363:411−422). Both studies demonstrated an improvement in overall survival (OS) of
a little more than 4 months with sipuleucel-T, but it did not prolong time to progression. “We need to learn how to select patients who may do well with this agent,” Dr. Mohler stated. “Unfortunately, PSA responses are few so we have no early biomarker of response.” Cabazitaxel has been added as a second-line option for men with CRPC that fails to respond to docetaxel. The supporting data for this recommendation derive from the phase III TROPIC study (de Bono JS et al. Lancet 2010;376:1147−1154). In this trial, cabazitaxel and prednisone produced an OS benefit of 2.4 months over the standard of care (mitoxantrone and prednisone), which Dr. Mohler calls statistically significant but perhaps not clinically relevant. It carries a significant risk of granulocytopenia, and therefore growth factor support should be considered. Denosumab has been included as an alternative to zoledronic acid for the prevention of SREs in men with CRPC who have metastases. In a phase III study of approximately 1,900 patients (Fizazi K et al. Lancet 2011;377:813−822), denosumab delayed the time to the first on-study SRE (fracture, spinal cord compression, and the need for surgery or radiation therapy to bone) and reduced the rate of multiple SREs compared with zoledronic acid, although there was no difference in OS and time to disease progression. Key Points The prostate-specific antigen blood test has played some role in the declining mortality from prostate cancer but is also partly responsible for overdetection and overtreatment. Active surveillance with rigorous monitoring is recommended for men with low-risk or very low– risk prostate cancer and a life expectancy of < 10 years or < 20 years, respectively. More research on active surveillance is needed to optimize the criteria for enrollment and progression. Sipuleucel-T (Provenge), cabazitaxel (Jevtana), and denosumab (Xgeva) are now category 1 treatment options for men with advanced disease. © 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
NCCN Guidelines™ for Ovarian Cancer Update Steady progress is being made with surgery and platinum-based chemotherapy as preliminary data emerge on the role of bevacizumab
Fertility-Sparing Surgery In the 2011 NCCN Guidelines, fertility-sparing surgery (ie, unilateral salpingo-oophorectomy preserving the uterus and contralateral ovary) in combination with comprehensive staging is an option for women with early-stage epithelial ovarian cancer (EOC) (eg, stage IA). Fertility-sparing surgery plus comprehensive staging is also an option for patients with EOC of low malignant potential (ie, borderline EOC), a rare type of ovarian cancer. If fertility is not desired, standard surgery with comprehensive staging is recommended for both types of cancer.
Initial Therapy for Advanced Disease For primary treatment of advanced EOC/fallopian tube cancer (FTC)/primary peritoneal cancer (PPC), two revisions center on tumor-reductive surgery and intra© 2011 NCCN. All rights reserved.
peritoneal (IP) chemotherapy. For advanced-stage disease, tumor-reductive surgery is recommended for suspected potentially resectable residual disease, because a recent meta-analysis has shown better survival with aggressive surgical procedures. After tumor-reductive surgery, chemotherapy is needed. “There is not a surgeon in the world who can remove the microscopic disease in ovarian cancer,” said Dr. Morgan. Four category 1 chemotherapy regimens are recommended: (1) the
There is not a surgeon in the world who can remove the microscopic disease in ovarian cancer. — Dr. Morgan Armstrong regimen (paclitaxel IV, cisplatin IP, paclitaxel IP); (2) paclitaxel IV, then carboplatin IV; (3) docetaxel IV, then carboplatin IV; and (4) dose-dense paclitaxel IV and carboplatin IV (Katsumata N et al. Lancet 2009;374:1331−1338). However, the IP chemotherapy regimen is only recommended for less than 1 cm optimally debulked stage II disease and for debulked stage III disease (category 1 for stage III).
Dr. Morgan discussed the Armstrong regimen (Armstrong DK et al. N Engl J Med 2006;354:34−43). At 5-year follow-up, patients treated with the IP regimen had a 16-month improvement in median overall survival (OS) compared with those who received the IV regimen (65.6 months vs. 49.7 months). “I have to confess, I am a believer in IP chemotherapy,” declared Dr. Morgan, although he admitted it is associated with more short-term toxicity. Only 42% of patients completed this treatment, with catheter-related problems being the most common reason for discontinuation. Dr. Morgan offered 3 key points about IP chemotherapy: (1) nurses must know how to administer it; (2) it should be given in institutions familiar with potential problems; and 3) appropriate hydration for 5 days after IP cisplatin can markedly improve patients’ ability to tolerate it.
Emerging Data on Bevacizumab In the 2011 guideline for primary chemotherapy for EOC/FTC/ PPC, the NCCN added the following statement about bevacizumab: “The NCCN Ovarian Cancer Panel recognizes that data for first-line and maintenance bevacizumab are becoming available and encourages participation in clinical trials… Until there are more mature results from GOG-0218 and ICON7, the NCCN Ovarian Cancer Panel does not recommend the routine addition
Respiratory Throat tightness
80 Percentage of Patients (%)
ewer treatment options are slowly improving the outcomes of women with ovarian cancer, declared Robert J. Morgan, MD, of City of Hope Comprehensive Cancer Center, Los Angeles, who is Chair of the National Comprehensive Cancer Network® ( N C C N ®) Ovarian Cancer Panel. Although detecting ovarian cancer at an earlier stage would improve survival, effective screening Dr. Morgan tools are not yet available. Therefore, most patients present with advanced ovarian cancer, and aggressive therapy with surgery and chemotherapy is recommended in most cases. The major modifications to the 2011 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Ovarian Cancer focus on the use of fertility-sparing surgery, recommended chemotherapy options, the emerging data on bevacizumab (Avastin) in upfront and maintenance settings, and the importance of desensitization procedures for patients with drug reactions.
70 60 50 40 30 20 10 0
Paclitaxel Chemotherapeutic Agents
Frequency of symptoms and signs during initial hypersensitivity reactions. Adapted from Castells MC et al. J Allergy Clin Immunol 2008;122:574–580, with permission from Elsevier.
Key Points Premenopausal women with borderline epithelial ovarian cancer (EOC) or early-stage EOC may be treated with fertilitysparing surgery. Intraperitoneal chemotherapy has shown an improvement in overall survival over intravenous chemotherapy but is associated with more short-term toxicity. Routine use of bevacizumab (Avastin) in upfront or maintenance therapy is not yet recommended, but early results show improved progression-free survival. For patients who have had drug reactions, desensitization is an effective way to continue treatment.
of bevacizumab to upfront therapy with carboplatin/paclitaxel or as maintenance therapy at this time.” Dr. Morgan offered a glimpse at the emerging preliminary data from the GOG-0218 trial (Burger RA et al. J Clin Oncol 2010;28[Suppl 18]:Abstract LBA1). In this phase III study of bevacizumab plus carboplatin/ paclitaxel in the primary treatment of advanced EOC/FTC/PPC, there was a significant progression-free survival benefit of 3.8 months with upfront and maintenance bevacizumab. However, OS and quality-oflife data have not yet been reported.
Desensitization for Drug Reactions to Chemotherapy “Drug reactions can occur in patients who have been pre-exposed to carboplatin or cisplatin,” warned Dr. Morgan. These reactions can also occur to paclitaxel, docetaxel, oxaliplatin, and liposomal doxorubicin (Doxil). Although most drug reactions are mild, life-threatening (ie, anaphylactic) reactions can occur. Symptoms include rash, shortness of breath, wheezing, chest pain, back pain, itching, changes in blood pressure, and severe anxiety. Reactions may occur immediately during the first exposure or even at the second or third exposure (eg, > 1 year after initial treatment). “Most common reactions are cutaneous, but cardio-
NCCN 6th Annual Congress:
Hematologic Malignancies™ September 9 – 10, 2011
New York Marriott® Marquis • 1535 Broadway • New York, New York Treatment of hematological malignancies is increasingly complex. Issues relating to pathology, transplantation, and various new therapies require oncologists and hematologists to stay abreast of breakthrough advances. In addition, targeted therapies and oral treatments bring the latest benefits to patients. This Congress will focus on the new approaches that have been incorporated into patient management, including the use of drugs, biologics, and diagnostics. The agenda will address Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Infections, Lymphomas, Multiple Myeloma, Transplantation, and Supportive Care.
Exhibiting Opportunities Available
For more information, contact Jennifer Tredwell, 215.690.0274 or firstname.lastname@example.org.
NCCN.org to register or for additional information about this educational event.
NCCN Live Webinars
REGISTER TODAY! These educational initiatives are designed to provide CE opportunities to nursing professionals who were unable to attend the NCCN 2011 Nursing Program at the NCCN 16th Annual Conference. Register now for one or more of the following: Recognition and Treatment of Depression in Patients with Cancer Wednesday, May 25, 2011, 3:00 - 4:00 PM EDT
All sessions are approved for AMA PRA Category 1 Credit(s)™. Nursing (ANCC) hours and pharmacy (ACPE) credits are also provided for all sessions. Register now for one or more of the following*: Adjuvant Therapy for Locoregional Disease Thursday, May 26, 2011, 3:00 - 4:00 PM EDT Metastatic Disease Management of ER-PR+ Disease Monday, June 20, 2011, 12:00 - 1:00 PM EDT
Updates in the Management of Venous Thromboembolism Friday, May 27, 2011, 2:30 - 3:30 PM EDT
Metastatic Disease Management of ER-PR- Disease Thursday, May 26, 2011, 9:00 - 10:00 AM EDT (or) Friday, June 17, 2011, 10:00 - 11:00 AM EDT
Management of Cardiac Complications from Cancer Therapy Friday, June 3, 2011, 3:00 - 4:00 PM EDT
Radiation Therapy in the Management of Locoregional Disease Tuesday, June 14, 2011, 2:30 - 3:30 PM EDT (or) Thursday, June 30, 2011, 10:00 - 11:00 AM EDT
A Multidisciplinary Approach to Prostate Cancer Tuesday, June 7, 2011, 12:00 - 1:00 PM EDT Nursing Considerations in the Treatment of Pancreatic Cancer Monday, June 13, 2011, 3:00 - 4:00 PM EDT
Diagnosis, Staging, and Initial Therapy Tuesday, June 14, 2011, 1:30 - 2:30 PM EDT (or) Friday, July 8, 2011, 2:00 - 3:00 PM EDT *Although each session is being offered twice, CME/CE credits will only be awarded to attendees once per session. AC-N-0932-0311
Highlights of the NCCN 16th Annual Conference
vascular side effects occur 60%–70% of the time with platinum or paclitaxel reactions, so you cannot be blasé about this,” he urged. Therefore, NCCN recommends desensitization procedures for patients with hypersensitivity reactions (Castells MC et al. J Allergy Clin Immunol 2008;122:574−580). During
desensitization, very small doses are administered and the doses are slowly increased; the infusion time is also increased (from about 1 hour to nearly 6–12 hours), often under intensive care unit surveillance. “Platinum is still so important in the overall treatment of ovarian cancer that regimens have
been worked out to try to desensitize patients so you can continue treating with platinum,” Dr. Morgan explained. For example, patients with recurrent disease—who previously had complete responses (> 6 months) to primary therapy with platinum agents—can often achieve remission with more platinum therapy;
therefore, desensitization is very useful for these patients. “In my experience, desensitization works about 95%–98% of the time.”
Guidelines for Myeloid Growth Factors Updated Benefits of granulocyte colony-stimulating factors outweigh risk of MDS/AML
olid evidence supports the use of prophylactic myeloid growth factors to prevent neutropenic complications and improve survival in patients at high risk for febrile neutropenia (FN), announced Panel Chair Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, North Carolina, who presented recent findings at the National Comprehensive Cancer Network® (NCCN®) Annual Conference. Benefits substantially outweigh any risks associated with the granulocyte colony-stimulating factors Key Points Granulocyte colony-stimulating factors (G-CSFs) prevent febrile neutropenia (FN) and its complications and improve survival. Outcomes with filgrastim and the longer-acting pegfilgrastim are similar. Patients should be assessed for risk, and those with > 20% FN risk should receive prophylactic G-CSF starting at the first cycle. Risk of myelodysplasia and acute myeloid leukemia with G-CSF is real, but it is small and greatly offset by a 5% reduction in allcause mortality.
Although reducing chemotherapy dose intensity might also be preventative, Dr. Crawford strongly cautioned against this. The delivery of standard doses of chemotherapy is associated with overall survival benefits, and when myelosuppression occurs with adjuvant chemotherapy, it actually predicts for survival, because it indicates that the most effective dose has been delivered (LyDr. Crawford man GH. J Natl Compr Canc Netw 2009;7:99–108).
stitutes the only major change to the Guidelines in 2011.
Growth Factors Backed by Body of Data Myeloid growth factors are the primary means of preventing chemotherapy-induced neutropenia and therefore FN. Most FN events occur during the first cycle of chemotherapy, regardless of tumor type, and thus, preemptive measures should be taken from the start in patients deemed to have at least a 20% risk for this side effect. In a study conducted by Dr. Crawford’s group, FN developed during the first 3 cycles in 11% of patients (Crawford J et al. J Natl Compr Canc Netw 2008:6;109–118). Furthermore, based on a database of over 40,000 indivuduals, 10% of such patients die once hospitalized for FN (Kuderer NM et al. Cancer 2006;106:2258–2266). Prophylactic antibiotics can supplement G-CSF in selected settings, but widespread use increases the development of resistant bacteria. “Routine application of prophylactic antibiotics is limited to high-risk inpatients with hematologic malignancies and stem cell transplantation,” said Dr. Crawford.
Evidence Supporting G-CSF Use Most of the data available for chemotherapy-induced neutropenia focused on lineage-specific G-CSFs instead of multilineage granulocyte macrophage colony-stimulating factors (GM-CSFs). The timing of filgrastim affects neutrophil recovery. “Our window for starting prophylaxis is not big. We should start 24–72 hours after chemotherapy is completed,” Dr. Crawford noted. When adminis-
(G-CSFs) filgrastim (Neupogen) and pegfilgrastim (Neulasta) when initiated at the first cycle of chemotherapy and given in all subsequent cycles, Dr. Crawford emphasized. However, he called special attention to the possible increased risk of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) in patients receiving G-CSF. Due to recent concerns about MDS/AML, the Panel included a discussion of this topic in the update to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Myeloid Growth Factors. This con© 2011 NCCN. All rights reserved.
MDS/AML Risk Not a Major Concern
tration is delayed, the duration of grade 4 neutropenia may be longer and the risk of FN greater, he added. Concurrent CSF prophylaxis during chemotherapy or radiation is not recommended, however, due to possible interference with the treatment effects. In contrast, pegfilgrastim has a unique neutrophil-regulated clearance and is a longer-lasting drug, due to sustained high serum levels in patients, he said. Clinical outcomes for a single dose of pegfilgrastim and multiple daily doses of filgrastim are comparable, with a meta-analysis showing an approximately 46% reduction in FN risk, 45% reduction in infection-related mortality, and 40% reduction in early mortality (Kuderer NM et al. J Clin Oncol 2007;25:3158–3167). The impact of pegfilgrastim on overall and disease-free survival has been apparent in all major prognostic subgroups, including patients who receive at least 85% of their planned chemotherapy and patients with lung cancer, liver dysfunction, or poor performance status (Lyman GH et al. J Clin Oncol 2008;26[Suppl 15]:Abstract 6552). “The data suggest that what we do in the very first cycle of treatment makes a big difference,” Dr. Crawford emphasized. Sargramostim (Leukine), a GMCSF, received a category 2B recommendation in the NCCN Guidelines as it is associated with more toxicity, he noted.
Risk ratio (95% CI)
All-cause mortality by tumor type in patients receiving G-CSF vs no GCSF. Adapted from Lyman GH et al. J Clin Oncol 2010;28:2914–2924. Abbreviations: G-CSF = granulocyte colony-stimulating factor; HD = Hodgkin disease; NHL = non-Hodgkin’s lymphoma; SCLC = small-cell lung cancer.
MDS/AML risk was clearly elevated in a recent meta-analysis, regardless of tumor type or the specifics of the treatment regimen (Lyman GH. J Clin Oncol 2010;28:2914– 2924). However, all-cause mortality was significantly lower among patients who received growth factor support (see figure). This was seen in all regimen categories. “There was an increase in MDS
and leukemia, but the all-cause mortality analysis showed a significant reduction in deaths. The rise in absolute leukemia risk was around 0.5%, but the survival benefit was 5%. This amounts to an almost 10fold difference in probabilities,” Dr. Crawford pointed out. “There clearly is an overall net benefit.”
Selecting Patients for Prophylaxis When selecting patients for primary G-CSF prophylaxis, the NCCN Guidelines recommend that clinicians consider the chemotherapy regimen (a detailed but nonexhaustive list is in the guidelines),
Highlights of the NCCN 16th Annual Conference
patient risk factors, and treatment intent (curative vs palliative), and to then determine whether risk is high (> 20%), intermediate (10%– 20%), or low (< 10%). High-risk patients should receive growth factors, regardless of treatment intent; low-risk patients should not receive them; and intermediate-risk patients should be considered for treatment based on risk factors. “But remember that the type of chemotherapy regimen is only one component of the risk assessment,” Dr. Crawford reminded attendees. Type of malignancy, age, previous treatment, preexisting conditions, performance status, and other factors are also very relevant. Lyman and colleagues described a predictive model based on a combination of factors in a recent article (Cancer. November 29,
There was an increase in MDS and leukemia, but the all-cause mortality analysis showed a significant reduction in deaths…. There clearly is an overall net benefit. — Dr. Crawford 2010 [ePub ahead of print]). Patients should be reevaluated prior to the second and each subsequent cycle. If patients have developed FN or a dose-limiting neu-
tropenic event, they are classified according to prior use of growth factors. Those with prior use can be considered for chemotherapy dose reductions or alternative regimens. Patients with no prior use can be considered for prophylaxis. The value of myeloid growth factors in the therapeutic setting has not been well studied, noted Dr. Crawford. If patients develop FN during the current cycle, those on filgrastim or sargramostim can continue these drugs, whereas those who have received pegfilgrastim are unlikely to benefit further from additional CSF since they already have high levels of the long-lasting drug in their body. Those without prior prophylactic growth factors are assessed for risk factors for infection, and if at high risk, they are considered for growth factor support.
Multiple Myeloma NCCN Guidelines™ Update Based on unprecedented rates of response and survival, novel targeted agents are now included as upfront, maintenance, and relapsed/refractory options
here has been a very rapid bench-to-bedside translation with targeted agents in multiple myeloma [MM],” declared Kenneth C. Anderson, MD, from Dana-Farber Cancer Institute in Boston, and they are now included throughout the National Comprehensive Cancer Network® ( N C C N ®) Clinical Practice Guidelines in Oncology Dr. Anderson (NCCN Guidelines™) for MM (alone or in combination) in upfront, maintenance, and relapsed/refractory therapies. There is now evidence that these novel drugs in initial treatment improve response rates, event-free survival, and progression-free survival (PFS). Although in the past, patients with MM were encouraged to participate in clinical trials to help people in the future, “now we are expecting to see responses in the earliest-phase trials, and these will hopefully benefit the patients who need our help today,” Dr. Anderson stated.
Upfront Targeted Therapy for Transplant-Eligible Patients
The updates in the 2011 NCCN Guidelines for MM feature the inclusion of new regimens under primary induction therapy. Category 1 options
for initial treatment of transplant candidates include bortezomib (Velcade)/ dexamethasone, bortezomib/doxorubicin/dexamethasone, bortezomib/ thalidomide (Thalomid)/dexamethasone, and lenalidomide (Revlimid)/ dexamethasone. This year, joining these recommendations for transplant candidates is the combination of bortezomib, cyclophosphamide, and dexamethasone, which holds a category 2A designation. Another promising treatment option for primary induction therapy in the transplant setting is lenalidomide, bortezomib, and dexamethasone (RVD). Although RVD is currently
ranked as a category 2B option, emerging data demonstrate “unprecedented responses” with this combination in early-phase studies (Richardson PG et al. Blood 2010;116:679−686). More than half of patients receiving upfront RVD had a complete response (CR) or a near CR, and 100% achieved at least a partial response (PR) (see table). The benefits of RVD were also seen in the EVOLUTION study (Kumar S et al. Blood 2010;116:Abstract 621). “For the first time, we now have achieved molecular CRs in MM when using novel agents in combination upfront,” pronounced Dr. Anderson. Based on the updated NCCN
Upfront Lenalidomide, Bortezomib, Dexamethasone Best response, n (%)
All patients (n = 66)
Phase II (n = 35)
CR+nCR (90% CI)
26 (39) (29, 50)
20 (57) (42, 71)
CR+nCR+VGPR (90% CI)
44 (67) (56, 76)
26 (74) (59, 86)
At least PR (90% CI)
66 (100) (96, 100)
35 (100) (92, 100)
Response improvement seen in 42/56 patients (75%) from C4–8 and 0/38 patients (53%) beyond C8 Median (range) time to best overall response was 2.1(0.6,20) months
Abbreviations: CR = complete response; nCR = near-complete response; PR = partial response; VGPR = very good partial response. Adapted from Richardson PG et al. Blood 2010;116:679−686.
Guidelines, patients with active (symptomatic) myeloma who respond to induction therapy can either continue induction chemotherapy to plateau or undergo stem cell transplant and then move on to maintenance therapy. The addition of lenalidomide as maintenance therapy is a new option, with supporting phase III data from two studies (McCarthy PL et al. Blood 2010;116:Abstract 37; Attal M et al. Blood 2010;116:Abstract 310). Both the American study (McCarthy) and the French study (Attal) arrived at similar conclusions: The median PFS was nearly twice as long (approximately 4 years vs 2 years) with lenalidomide maintenance after autologous transplantation than without it. “Although there was no overall survival difference yet,” added Dr. Anderson, “it is expected to be reported shortly.” The slight increase in secondary malignancies with lenalidomide maintenance in both studies was briefly mentioned by Dr. Anderson. The rate of both hematologic and nonhematologic malignancies was higher with lenalidomide maintenance than without it. “We need to watch carefully this concern for secondary malignancy,” he cautioned. In the HOVON trial (Sonneveld P et al. Blood 2010;116:Abstract 40), the use of bortezomib maintenance produced better CR, near CR, and PR rates, as well as PFS and overall survival (OS), than did conven© 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
For the first time, we now have achieved molecular complete responses in MM when using novel agents in combination upfront. — Dr. Anderson tional treatment in newly diagnosed transplant candidates. In addition, unlike lenalidomide, bortezomib appears to overcome adverse prognosis caused by del 13/13q− and partially overcomes adverse prognosis caused by t(4;14) and 17p−.
Upfront Targeted Therapy for Transplant-Ineligible Patients
Category 1 options for primary induction therapy for nontransplant candidates include lenalidomide/lowdose dexamethasone, melphalan/prednisone/bortezomib, and melphalan/ prednisone/thalidomide. Two new options included in the 2011 Guidelines are melphalan/prednisone/lenalidomide (MPR) and bortezomib/dexamethasone, both carrying a category 2A ranking.
For elderly patients with newly diagnosed MM, Dr. Anderson’s current preference is MPR followed by lenalidomide maintenance. The supporting data for this selection come from a recent phase III study (Palumbo A et al. Blood 2010;116:Abstract 622). PFS was significantly improved with the use of MPR plus lenalidomide maintenance compared with MPR alone or melphalan/prednisone (31 months vs 14 months and 13 months, respectively), but there is no OS advantage yet. Interestingly, unlike the previously mentioned American and French clinical trials of lenalidomide maintenance, there was a low rate of secondary malignancies in this study. Another possible treatment option for elderly patients with newly diagnosed MM is bortezomib-based induction therapy. The supporting data for this approach (Niesvizky R et al. Blood 2010;116:Abstract 619) suggest that three different bortezomib regimens were active. The study also showed that bortezomib maintenance was well tolerated and resulted in increased rates of very good PRs in all three arms.
Advances in Relapsed/ Refractory Therapies Two category 2A salvage treatment options were added to the 2011 Guidelines: cyclophosphamide/bortezomib/
dexamethasone and cyclophosphamide/lenalidomide/dexamethasone. Category 1 alternatives include bortezomib, bortezomib/liposomal doxorubicin (Doxil), and lenalidomide/dexamethasone. Novel agents, alone and in combination, are garnering attention, and Dr. Anderson highlighted a few of them: carfilzomib, pomalidomide, and bortezomib/panobinostat. Carfilzomib has been tested in patients with progressive, refractory disease. In one study (Jagannath S et al. J Clin Oncol 2009;27[Suppl 15]:Abstract 8504), patients achieved a 24% overall response rate with carfilzomib, with a duration of response of 8.3 months. “The Key Points New bortezomib (Velcade)- and lenalidomide (Revlimid)-based regimens have been added as options for induction therapy in the transplant and nontransplant setting as well as for salvage treatment options. Lenalidomide maintenance, which has been reported by two randomized phase III studies to nearly double PFS, has been added as an option. Carfilzomib, pomalidomide, and panobinostat are promising novel agents in clinical development for relapsed/refractory disease.
remarkable thing about this proteasome inhibitor is the very low incidence of peripheral neuropathy [overall, 12%; grade 3/4, 0.8%],” reported Dr. Anderson. Pomalidomide in combination with low-dose dexamethasone appears to be an effective treatment alternative with a favorable side-effect profile for patients with relapsed/ refractory MM. In one clinical trial of heavily pretreated patients (including those who were refractory to bortezomib and lenalidomide; Richardson PG et al. Blood 2010;116:Abstract 864), there was a greater than 25% PR rate and a 50% or better minimal response rate. “In my opinion, pomalidomide will meet an unmet medical need in MM,” predicted Dr. Anderson. The combination of bortezomib and panobinostat represents another promising treatment option, “perhaps the most important one,” according to Dr. Anderson. Early results have shown an overall response rate of 70%, including a 60% response rate in patients with bortezomib-refractory disease (San-Miguel JF et al. J Clin Oncol 2010;28[Suppl 15]:Abstract 8001).
Chronic Myelogenous Leukemia: NCCN Guidelines™ Revised New treatment options are approved, and more are on the way
econd-generation tyrosine kinase inhibitors (TKIs), now approved for first-line therapy of chronic myelogenous leukemia (CML), offer newly diagnosed patients an expanded range of treatment options, announced Susan O’Brien, MD, of The University of Texas MD Anderson Cancer Center, Houston. The inclusion of nilotinib (Tasigna; 300 mg twice Dr. O’Brien daily) and dasatinib (Sprycel; 100 mg daily) as initial treatment options in addition to imatinib (400 mg daily) is the major update to the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in © 2011 NCCN. All rights reserved.
Oncology (NCCN Guidelines™) for CML, noted Dr. O’Brien, who chairs the CML panel. In two separate randomized studies, dasatinib and nilotinib were associated with significantly higher response rates and reductions in the 12-month incidence of accelerated or blast phase CML in newly diagnosed patients compared with imatinib. This led to the FDA approval of these drugs, which were previously reserved for patients with resistance or intolerance to imatinib. Updates of these pivotal studies were presented at the 2010 American Society of Hematology (ASH) Annual Meeting. In the ENESTnd study, major molecular response (MMR) was achieved at 24 months in over 60% of patients treated with nilotinib versus 37% in those receiving imatinib (P < .0001). Fewer than 2% of
patients treated with nilotinib progressed to accelerated or blast phase, versus 4%–6% with imatinib (Hughes TP et al. Blood 2010;116:Abstract 207). “These are the most clinically relevant short-term data, because transformation confers a very, very poor prognosis,” Dr. O’Brien noted. Similarly, in the updated results of the DASISION trial (Shah N et al. Blood 2010;116:Abstract 206), the likelihood of achieving a confirmed complete cytogenetic response (CCyR) or MMR at any time was 1.5-fold or 1.8-fold higher, respectively, with dasatinib than with imatinib (see figure). In another randomized trial of dasatinib versus imatinib presented at ASH (SWOG 0325), dasatinib was associated with a more robust MMR (Radich JP et al. Blood 2010;116:Abstract LBA-6). “If we look at the toxicity profile, grade 3–4 [toxicities] are rare with all
of these drugs,” Dr. O’Brien pointed out. But some of the grade 2 toxicities, such as nausea and vomiting, that can really impact a patient’s tolerance to Key Points Nilotinib (Tasigna) and dasatinib (Sprycel) were added as frontline treatment options. In randomized clinical trials, nilotinib and dasatinib resulted in higher response rates and lower rates of disease progression compared with imatinib. Complete cytogenetic response remains the gold standard for monitoring response; molecular responses do not define treatment failure. New agents now in clinical trials show promising activity, particularly for patients with T315I mutation.
FREE On-line Resources Take advantage of these resources and stay current with new information that will help you provide the best care to your patients.
Educational Opportunities on NCCN.org NCCN Congress Series: Genitourinary Cancers™ Kidney and Prostate Cancers Webcasts of select sessions from the live program are available for accreditation. NCCN.org/professionals/meetings/congress
NCCN Guidelines Update Webinar Series™: Non-Hodgkin’s Lymphoma Four separate presentations from the live webinar series are available for accreditation. NCCN.org/professionals/meetings/webinars
JNCCN Task Force Supplements NCCN convenes experts from within and beyond NCCN Member Institutions to expand on issues discussed in the NCCN Guidelines™ and to discuss issues outside the scope of the NCCN Guidelines™. • NCCN Task Force Report: Tyrosine Kinase Inhibitor Therapy Selection in the Management of Patients With Chronic Myelogenous Leukemia • NCCN Task Force Report: Optimizing Treatment of Advanced Renal Cell Carcinoma With Molecular Targeted Therapy NCCN.org/JNCCN/supplements
Regist e NCCN. r on for thi org s progralive m
NCCN CONGRESS SERIES
Respiratory Tract ™ Cancers Covering Head and Neck, Small Cell Lung, and Non-Small Cell Lung Cancers June 29, 2011 Durham, NC
NCCN Oncology Case Management Program™ Webinars Continuing Education credits (CEU, CCM, and CME) will be provided. NCCN.org/professionals/managed_care_live_ programs AC-N-0932-0311
Highlights of the NCCN 16th Annual Conference
CCyR is the gold standard for response. If you can’t get there, the patient fails. — Dr. O’Brien cologists. “You can either start new patients on a second-generation TKI or, since the salvage rates with these drugs are so good, you can start with imatinib up front and then just salvage the patients who don’t reach the endpoints, as outlined by the guidelines,” Dr. O’Brien pointed out. However, the optimal approach is not yet clear.
P = .0366
P = .0086 100 Confirmed CCyR, %
long-term therapy were more common with imatinib, she added. Dr. O’Brien concluded that early data from recent trials that suggest superior outcome with secondgeneration TKIs, including higher CCyR and MMR rates and lower rate of transformation. However, longer follow-up is needed before the impact on event-free and overall survival can be established. Nevertheless, she concurred that dasatinib, nilotinib, and imatinib are all effective and well-tolerated first-line options available for on-
Dasatinib 100 mg QD Imatinib 400 mg QD
20 0 12 Mos
DASISION Study: Dasatinib vs imatinib in patients with newly diagnosed CML in chronic phase. Confirmed CCyR rates (intent-to-treat population). Adapted with permission from Shah N et al. Blood 2010;116:Abstract 206. Abbreviations: CCyR = complete cytogenic response; CML = chronic myelogenous leukemia.
CCyR Best for Monitoring Treatment Response Adequate monitoring will optimize outcomes of TKI therapy. Quantitative polymerase chain reaction is the most sensitive technique, can be done on peripheral blood, is evaluable in CCyR, and is predictive of relapse. However, tests are not standardized, and there is lab-to-lab variability. “You need to use the same laboratory for each patient,” she advised. CCyR is associated with improved survival, and it remains the gold standard for monitoring re-
sponse. MMR (ie, a 3-log reduction from baseline or < 0.1% on the International scale) is associated with a low rate of relapse; however, it has not yet been shown to improve survival, she noted. “Molecular monitoring is useful, but MMR does not, by itself, constitute a failure,” Dr. O’Brien clarified. If BCR-ABL transcript levels continue to rise (> 1 log without MMR), bone marrow cytogenetics is recommended. If there is cytogenetic relapse, mutation analysis is advised before changing treatment.
“Results should be interpreted in the context of alternative options.”
Future Outlook Is Exciting “Several new agents in clinical trials are looking very promising, particularly for patients with T315I who don’t respond to any of the currently available drugs,” Dr. O’Brien concluded. Ponatinib (AP24534), an oral multikinase inhibitor, has shown efficacy in patients with treatment-resistant T315I mutations; in a study presented at the 2010 ASH Annual Meeting, all 9 patients with this mutation achieved a major cytogenetic response (MCyR) and 8 patients achieved CCyR (Cortes J et al. Blood 2010;116:Abstract 210). Bosutinib is active against all imatinib-resistant mutants of BCRABL except T315I, and as third-line treatment yielded 2-year survival rates of 66%–100% in patients resistant to prior TKI therapy (Khoury HJ et al. Blood 2010;116:Abstract 892). And in patients relapsing on at least two TKIs, omacetaxine, was associated with a median-duration MCyR of 7.4 months and median survival of 30 months (Cortes J et al. Blood 2009;114;Abstract 644).
Melanoma NCCN Guidelines™ Updated Focus is on mitotic index, with less routine imaging
urvival is improving in advanced melanoma with the advent of new therapies that will be incorporated into future treatment paradigms as randomized controlled trials establish their role. While oncologists await changes to the National Comprehensive Can-
Mitotic index is the single most important predictor of survival in the patient with a thin melanoma. — Dr. Coit cer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines™) to accommodate these advances, other up© 2011 NCCN. All rights reserved.
dates to the 2011 recommendations have refined the standard of care of melanoma. Panel Chair Daniel G. Coit, MD, of Memorial Sloan-Kettering Cancer Center, New York, presented the update, as well as a discussion of emerging agents. “The Panel wrestled with the appropriateness of preoperative staging and postoperative follow-up, and we reached unanimity on several important issues,” he said. Mitotic index of the lesion has replaced Clark level in defining clinical stage IB disease. “Mitotic index is the single most important predictor of survival in the patient with a thin melanoma,” he noted (Balch CM et al. J Clin Oncol 2009;27:6199– 6206). The presence of any mitosis (mitotic rate ≥ 1 per mm2) in a thin melanoma (≤ 1 mm) upstages the patient to stage IB and has implications for sentinel lymph node biopsy
(SLNB). Clark level is now considered an optional factor in the pathologic description. The Panel emphasized that the biopsy be read by a pathologist experienced in pigmented lesions, who should provide at least the following information: • Breslow thickness • Ulceration • Mitotic rate/mm2 • Margins • Microsatellitosis
Early-Stage Workup Reevaluated For patients with clinical stage 1B and IIA melanoma, the suggested workup is complete history and physical examination, with particular attention to the skin and regional nodes. Chest x-ray is an option for patients with thicker lesions (IIB to IIC). Routine imaging with computed tomography, positron emission tomography, and magnetic
resonance imaging (MRI) is not recommended for stage I and II disease, and is advised only when clinically indicated (ie, to evaluate particular signs and symptoms of early-stage melanoma). “The yield Dr. Coit of true positives is so low in stage IIA patients that imaging cannot be recommended,” Dr. Coit explained.
Margins up to 2 cm Adequate Many large studies with adequate follow-up have evaluated surgical margin width and failed to show improved locoregional and overall survival (OS) benefits for margins wider than 2 cm, Dr. Coit noted. Current NCCN recommendations
for wide excision are 1-cm margins for melanomas 1 mm or thinner, 1–2 cm for melanomas 1.01–2 mm thick, and 2 cm for lesions thicker than 2 mm. “These are very conservative estimates from the clinical trials,” he stated. He acknowledged, however, that studies comparing 2-cm versus 1-cm margins for melanomas thicker than 2 mm are still needed, as are studies of margin requirements in lesions thicker than 4 mm or in situ.
Recommendations for Sentinel Node Biopsy SLNB should be discussed and offered to patients with stage IB or II melanomas. In patients with intermediate-thickness melanomas, SLNB can provide important prognostic information and can improve disease-free survival, though not melanoma-specific survival (Morton et al. N Engl J Med 2006;355:1307– 1317). “This is principally a staging tool,” Dr. Coit commented. The final follow-up of the pivotal MSLT-1 trial may help confirm these findings. Only thickness and mitotic index predict for the finding of positive sentinel lymph nodes (SLNs). Thin melanomas (≤ 1 mm) are associated with positive nodes in less than 5% of cases, studies have affirmed, including a recent meta-analysis of 3,651 patients (Warycha MA et al. Cancer 2009;115:869–879). Among the 1,135 patients who had completion lymph node dissection (CLND), only one was found to have a posi-
Highlights of the NCCN 16th Annual Conference
tive nonsentinel node. “This is a uniquely favorable population, with a very low nodal recurrence rate,” Dr. Coit noted. “We are still sorting out the role of SLNB in these patients.” Considering these factors, clinicians should consider SLNB in patients with a risk of nodal positivity of around 7%, the Panel concluded. Helpful prognostic information can be obtained at http://www.melanomaprognosis.org.
Evaluating the Cost of SLNB in Thin Melanomas Although the NCCN does not consider the cost of treatment when determining recommendations, Dr. Coit performed an economic exercise that justified the Panel’s recommendations for the SLNB threshold. Based on published outcomes for thin melanomas extrapolated to 120
patients undergoing SLNB at a cost of $10,000 each, he determined that the cost of identifying one excess unpreventable death from melanoma would be $1.2 million. “As an organization we have to get our arms around this as we counsel about the use of technology in our patients,” he said.
Lymphadenectomy and Beyond A positive SLN is an indication for CLND or, preferably, referral to the MSLT-II clinical trial comparing CLND to observation with nodal basin ultrasound surveillance. The principles of CLND, in particular, what defines an adequate dissection, were discussed by the Panel. “We ultimately felt a description of the anatomic area was the best surrogate,” Dr. Coit reported. After CLND, patients can be of-
Key Points Mitotic index replaces Clark level in defining clinical stage IB. Sentinal lymph node biopsy provides prognostic information and improves disease-free survival for patients with melanoma of intermediate thickness. Routine cross-sectional imaging is not recommended as workup for early melanoma. Clinical trial is the preferred option for stage III adjuvant treatment. Newer targeted agents and immunotherapy strategies will change the treatment paradigm for advanced melanoma.
fered participation in a clinical trial, observation, or a course of high-dose interferon-alfa (a category 2B recommendation). Adjuvant high-dose interferon-alfa has been shown to improve relapse-free survival though not OS. “If the patient and physician value relapse-free survival, high-dose interferon is perfectly appropriate, but if the goal is OS, there is no statistically significant impact of this adjuvant treatment,” Dr. Coit reiterated.
Molecular Markers and New Therapies
2 weeks on PLX4032
Response to PLX4032 in 52-year-old patient with metastatic melanoma, BRAF mutation.
Recent elucidation of genetic alterations in melanoma is resulting in promising treatments. Based on alterations in BRAF, c-KIT, and NRAS, four major genetic subgroups of melanoma have become apparent: chronic sun-damaged skin, nonchronic sun-damaged skin, acral, and mucosal.
Head and Neck NCCN Guidelines™ Update Guidelines streamlined, include suggestions for HPV-associated tumors and locoregionally advanced disease
evisions to the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Head and Neck Cancer included changes to streamline and refine the care of patients with these challenging tumors. The updates, and a discussion of state-of-the-art management, were presented Dr. Pfister by Panel Chair
David G. Pfister, MD, of Memorial Sloan-Kettering Cancer Center, New York.
Streamlining the Recommendations Several parts of the guidelines were clarified, simplified, and made more consistent, which should make them easier for clinicians to use, Dr. Pfister said. Staging now reflects the 2010 edition of the American Joint Committee on Cancer staging manual across all head and neck cancer subtypes. The order of the primary site algorithms was revised, sections pertaining to the
The role of induction chemotherapy is hugely controversial. — Dr. Pfister workup of patients were made more consistent, “complete response” was made more explicit as being “complete clinical response,” and follow-up recommendations were consolidated on one page, as was neck management after primary treatment with chemora-
diation or radiation. A new “Principles of Surgery” section was added, and the “Principles of Radiation Therapy” section was revised to be concordant with latest advances.
Mucosal Melanoma Recognized Head and neck cancers have included upper aerodigestive tract cancers and salivary gland cancers. The updated Guidelines add a third group, mucosal melanomas, which are relatively uncommon, poorprognosis tumors. “We added this because the surgical management is © 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
typically done by head and neck specialists,” Dr. Pfister said. The new algorithm in the NCCN Guidelines emphasizes that mucosal melanoma occurs in different sites (mainly in the paranasal sinuses and nasal cavity but also in the oral cavity), and that treatment differs depending on the site.
Growing Interest in HPV The role of human papillomavirus (HPV) in oropharyngeal cancer, both as a risk factor and a prognostic factor, is becoming better understood, and the latest NCCN Guidelines reflect this. High-risk HPV subtypes (especially HPV16) can facilitate the development of oropharyngeal cancer, independent of tobacco and alcohol use, the traditional risk factors. The Guidelines include a suggestion that the workup for oropharyngeal cancer and occult primary cancer include testing for HPV, either with fluorescent in situ hybridization, which looks for the high-risk subtypes (particularly HPV16), or by immunohistochemistry, which looks for p16 antibody expression and is more widely available. HPV-associated tumors are commonly found in the oropharynx and have a propensity for very bulky cystic adenopathy and basaloid histology. Also unique to HPV-associated cancers is their better prognosis; however, the Panel considered it premature to alter the treatment paradigm accordingly. “We don’t have enough data to change how we manage these patients, but trials limited to HPV-positive head and neck cancer are being designed,” Dr. Pfister said.
Locoregionally Advanced Disease About 30% of head and neck cancers are T1N0–1 or T2N0 tumors, for which surgery or radiotherapy are both recommended. “The treatment you choose depends on the anticipated functional outcome,” he noted. Most patients, however, have locoregionally advanced disease (T2N1, T3-4, or N2-3) at presentation, and combined-modality therapy (primary surgery and postoperative radiation or combined-modality chemoradiation) is indicated for this group (see figure). The Panel preferred primary surgical management for locoregionally advanced cancer of the oral cavity. “Functional outcomes with stateof-the-art reconstruction are quite good now. Also, giving high-dose radiation near the mandible can create some morbidity concerns,” Dr. © 2011 NCCN. All rights reserved.
Pfister pointed out. For the advanced patient group (T4a, N0-3), the Panel also recommended surgery because the likelihood of chemoradiation failing tends to be much higher than for other tumor-node-metastasis (TNM) staging groups. “As tumor bulk increases, the odds of controlling it with a radiation-based treat-
ment decrease. In addition, should chemoradiation not be effective and surgery then be indicated, the outcome will be poorer in tissue that has been irradiated.” For patients with resectable disease, surgery plus radiation is indicated, but the evidence backs the integration of concurrent chemotherapy with postoperative radia-
tion if poor-risk features are present. The addition of chemoradiation after surgery seems to be most beneficial in patients with these poorrisk factors: extracapsular nodal
Highlights of the NCCN 16th Annual Conference
extension and/or positive surgical margins (Bernier J et al. Head Neck 2005;27:843–850). “These two factors figure prominently in the algorithm in terms of selecting therapy after surgery,” he added. For unresectable tumors, data support the integration of chemotherapy with radiation, which is reflected in the NCCN Guidelines. For patients with resectable disease who want to avoid surgery, chemoradiation for organ preservation is supported by randomized trial data. The value of integrating chemotherapy with locoregional treatment (ie. surgery and/or radiotherKey Points A new “Principles of Surgery” section was added. An algorithm for mucosal melanoma was added. Staging was updated to reflect the 2010 American Joint Committee on Cancer staging manual (7th edition). Concurrent chemoradiation is preferred over induction chemotherapy in many disease settings. Components of the guidelines were clarified, simplified, and made more consistent to be more user-friendly.
RT ± chemotherapy RT ± chemotherapy Surgery + RT
Surgery + RT ± chemotherapy
Comorbidity Low PS
Combined-modality therapy for patients with locoregionally advanced head and neck cancer. apy) versus locoregional treatment alone was upheld in an important meta-analysis (Pignon JP et al. Lancet 2000;355:949–955) that found that chemotherapy given concomitantly with locoregional treatment offered the greatest survival benefit (8%) and risk reduction (19%); no significant benefit was shown with adjuvant and induction chemotherapy approaches. The updated metaanalysis confirmed the earlier results for concomitant (ie, concurrent) chemoradiation (6.5%; HR = 0.81, P < .0001) (Pignon JP et al. Radiother Oncol 2009;92:4–14). Single-agent cisplatin is considered an adequate concurrent regimen. There is growing support for cetuximab (Erbitux), but since no studies have compared cisplatin and cetuximab, the Panel recommended cisplatin. The Radiation Therapy Oncology Group trial 0522 will evaluate these
agents in combination. For recurrent disease that is amenable to a locoregional treatment, either surgery or radiation has curative potential. Chemotherapy by itself is generally viewed as palliative and should be evaluated in the context of the patient’s performance status.
Closer Look at Induction Chemotherapy The role of induction chemotherapy is “hugely controversial,” Dr. Pfister noted. Although induction chemotherapy has its advocates, induction did not improve survival in the aforementioned meta-analysis by Dr. Pignon and colleagues (Radiother Oncol 2009;92:4–14). “Looking at patients who got a platinum-based concurrent program with radiation, the mortality reduction was still three times higher compared with induction. Concurrent chemoradio-
therapy is backed by the strongest evidence,” he said. Induction chemotherapy also extends the duration of treatment, although it does allow for less overall morbidity and improves disease control and organ preservation. It may, however, be the optimal approach in several situations: when there is the possibility of distant metastases, a delay in initiating radiotherapy, or an anticipated airway problem. “By giving induction [chemotherapy] and getting a response, you will decrease the likelihood of a local problem,” Dr. Pfister noted, “but be mindful that you could use concurrent treatment even in those settings.” While awaiting definitive studies, the Panel felt there were sufficient data to incorporate induction chemotherapy as an option, although it still preferred concurrent chemoradiation, he said.
Which Radiotherapy Approach? Based on published data, concurrent chemoradiation most commonly uses conventional fractionation with single-agent cisplatin. Other fractionation schemes, multiagent chemotherapy, and nonstandard cisplatin schedules are also efficacious, and there is no consensus on the optimal approach. The Panel maintained that “it is still appropriate to go with standard fractionation in 2011,” Dr. Pfister said. The Guidelines’ “Principles of Radiation Therapy” section has been updated to clarify the acceptable altered fractionation schemes.
Newer Techniques in Radiation Oncology Improvement in quality of life is one major benefit of SBRT, proton therapy, and IMRT
tereotactic body radiation therapy (SBRT), proton therapy, and intensity-modulated radiation therapy (IMRT) are among the success stories in radiation oncology. All represent effective ways to treat select patients with certain types of cancer while minimizing the effects on other nearby organs and improving Dr. Kuettel patients’ quality of life. A panel met at the National Comprehensive Cancer Network® (NCCN®) 16th Annual Conference to provide an update on the status of
these newer techniques. The members of the panel included Michael Kuettel, MD, MBA, PhD, from Roswell Park Cancer Institute, Buffalo; Quynh-Nhu Nguyen, MD, from The University of Texas MD Anderson Cancer Center, Houston; and Andy Trotti, MD, from H. Lee Moffitt Cancer Center & Research Institute, Tampa.
SBRT for Lung and Liver Tumors SBRT uses multiple narrow radiation beams to target small areas with precision. Traditional radiation therapy may take in excess of 2 months, whereas SBRT is given in one to five sessions, usually over 1–2 weeks. Another advantage of SBRT is that its precise focus makes it pos-
We now have high-level evidence that IMRT in head and neck cancer reduces toxicity and improves quality of life by sparing the salivary gland. — Dr. Trotti sible to deliver high doses of radiation while minimizing the effect on nearby organs. SBRT is only advised for patients with small, inoperable
tumors. “Current NCCN guidelines state that if a patient is medically operable, surgery is still the first option,” declared Dr. Kuettel. Small non–small cell lung cancer (NSCLC) tumors (< 5 cm), lung metastases, hepatocellular carcinoma, and liver metastases can be treated with SBRT. Initial study findings with SBRT in patients with medically inoperable lung tumors were “quite spectacular,” stated Dr. Kuettel. In RTOG 0236 (Timmerman R et al. JAMA 2010;303:1070−1076), the estimated 3-year primary tumor control rate was 98%, with a 3-year overall survival rate of 56%. “We’ve seen tumors that would actually melt away with stereotactic radiotherapy, and these were patients who really didn’t have much © 2011 NCCN. All rights reserved.
Highlights of the NCCN 16th Annual Conference
in the way of other options,” he added. The optimal dose fractionation for SBRT is being studied in randomized trials (eg, RTOG 0915). The only two sites that are approved by the NCCN for use of SBRT are the lungs and the liver. The section on Principles of Radiation Therapy in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for NSCLC states that SBRT is a well-established treatment for inoperable stage I NSCLC patients. In the treatment algorithm for hepatocellular carcinoma, SBRT is considered a category 2B recommen dation for patients with unresectable tumors who are not candidates for transplant. “There are many facilities throughout the country that are Dr. Nguyen [using SBRT for tumors in the] pancreas, head and neck, prostate, spinal cord, as well as retreatment,” admitted Dr. Kuettel. He noted, however, that until further data are available, use of SBRT outside the lungs and liver should be limited to clinical trials.
Proton Therapy for Pediatric Tumors Proton therapy has emerged as a useful alternative to standard radiation therapies in childhood cancer. Dr. Nguyen explored the rationale behind the use of proton beams for pediatric cancers as an effective way to minimize the occurrence of late morbidities, including the increased risk of secondary malignancy associated with craniospinal radiation (Miralbell R et al. Int J Radiat Oncol Biol Phys 2002;54:824−829; Newhauser WD et al. Phys Med Biol 2009;54:2277−2291). According to the Newhauser study, three-dimensional conformal photon therapy was linked to a 12-fold increased risk of secondary malignancy compared with proton therapy, whereas IMRT had a 7-fold increased risk. Furthermore, “the unique dose distribution of protons has the ability to potentially allow increased dose to be delivered to the target volume, which may result in improved local control
© 2011 NCCN. All rights reserved.
Key Points Inoperable lung and liver tumors are currently the only two NCCNapproved indications for SBRT. Used to treat pediatric tumors, proton therapy can deliver an increased dose to the target volume while decreasing the dose to normal tissue, thereby reducing morbidity while improving local tumor control. IMRT has a proven benefit in reducing dry mouth in patients with head and neck cancer and in improving associated quality of life. In head and neck cancer, the rate of HPV-associated cancers is increasing and the rate of smoking-related cancers is decreasing.
in certain patients and translate to improved probability of survival,” Dr. Nguyen stated. Dr. Nguyen shared her experiences at MD Anderson with proton therapy for rhabdomyosarcoma, retinoblastoma, Ewing’s sarcoma, and medulloblastoma. With conventional photon therapy, patients with tumors along the orbit, such as rhabdomyosarcoma or retinoblastoma, may experience loss of vision, bony growth abnormalities, and secondary malignancies. With proton therapy, there was a significant dose reduction to the brain stem, the optic nerve, the pituitary, the temporal lobe, and the contralateral orbit and nerves. When two-field intensitymodulated proton beam therapy was used to treat a patient with Ewing’s
sarcoma, there was a significant decrease in dose to the liver, small bowel, spinal cord, and contralateral kidney. Similarly, the use of proton therapy for medulloblastoma resulted in a reduced interval dose to the oropharynx, neck, chest, abdomen, and pelvis, “which can significantly decrease acute as well as long-term toxicities,” Dr. Nguyen added.
IMRT for Head and Neck Cancer “Dry mouth has been the bane of our existence, our legacy, in head and neck cancer,” admitted Dr. Trotti. The good news is that randomized trials now support reduction of dry mouth with IMRT. One phase III trial of nearly 100 patients with oropharyngeal/hypopharyngeal cancer (Nutting C et al. J Clin Oncol 2009;27[Suppl 18]:Abstract LBA6006) showed a definite reduction in salivary gland outcomes, including patient-reported dry mouth and measurable salivary flow, with IMRT compared with conventional radiotherapy. On the other hand, a new pattern of toxicity with IMRT has been noticed: hair loss on the back of the head. “This hair usually does grow Dr. Trotti back,” Dr. Trotti reassured, but this side effect is being studied in clinical trials. “We now have high-level evidence that IMRT in head and neck cancer reduces toxicity and im-
proves quality of life by sparing the salivary gland,” stated Dr. Trotti. Furthermore, over the past 5 years or so, there has been wide adoption
We’ve seen tumors that would actually melt away with SBRT, and these were patients who really didn’t have much in the way of other options. – Dr. Kuettel of IMRT, with more than 90% of the RTOG membership using it as a standard platform in clinical trials, he added. With this success, “our attention now is being turned to other toxicities, including the global burden of toxicity, swallowing, and taste disorders,” Dr. Trotti indicated. The recent recognition of human papillomavirus (HPV)-related oral cancer has given rise to a new focus of attention in head and neck cancer. Incidence trends for HPVassociated cancers of the head and neck show that HPV-related cancers are increasing and HPV-unrelated cancers, which include smokingrelated cancers, are decreasing (Chaturvedi AK et al. J Clin Oncol 2008;26:612−619). “This shifts the type of cancers we are seeing in the clinic and the type of research that we will be doing,” revealed Dr. Trotti. Furthermore, HPV-positive patients tend to have a much better survival than do HPV-negative patients. A new trial (RTOG 1016) is comparing the less toxic cetuximab (Erbitux) with more toxic chemotherapy in combination with radiotherapy in this better prognostic population. All patients in this trial are receiving IMRT as a standard platform, which shows how well accepted this type of radiation therapy has become, Dr. Trotti concluded.
Highlights of the NCCN 16th Annual Conference
NCCN Guidelines™ for Soft Tissue Sarcoma Update Observation is now an acceptable option for patients with resectable desmoid tumors
he major change to the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Soft Tissue Sarcoma pertains to the management of desmoid tumors, revealed Margaret von Mehren, MD, of Fox Chase Cancer Center, Philadelphia, who is the new Chair of the Soft Tissue Sarcoma Panel. “Desmoid tumors can be difficult to manage, and you need a mulDr. von Mehren tidisciplinary team with sarcoma expertise,” she said. Desmoid tumors, or desmoid fibromatosis (DF), are defined as clonal fibroblastic proliferation marked by an infiltrative growth. DF does not metastasize but often increases in size. In the past, standard treatment has been complete macroscopic surgical resection. With this management, local recurrence rates have ranged from 20%–60% in major retrospective studies (Fiore M et al. Ann Surg Oncol 2009;16:2587–2593). “The issue with resection is the high rate of recurrence,” Dr. von Mehren said. “This has led the field to ask whether we are serving our patients well by doing surgery.” In the aforementioned retrospective analysis, Fiore and colleagues reported that observation did not increase the risk of recurrence (Ann Surg Oncol 2009;16:2587–2593). “There didn’t seem to be a statistically significant difference [in 5-year progressionfree survival] between patients in the two arms who were either watched or offered medical therapy,” Dr. von Mehren observed. Large tumors that were at least 10 cm in size and tumors
located on the trunk were associated with a high risk of recurrence. Based largely on this pivotal study, the Panel concluded that patients with DF can be managed appropriately with a careful “watch and wait” approach if their tumors are not causing morbidity, pain, or functional limitation; if the tu-
If you have a sarcoma, it might be worth getting a second pathologic opinion to make sure that you understand the nature of that tumor and that you can get your patient the best treatment that is available. — Dr. von Mehren mors are small and not on the trunk; and if a surgical approach would lead to excess morbidity. The Guidelines have included observation as an option for patients with resectable tumors. Patients experiencing disease progression can be treated with surgery and/or radiotherapy and/or systemic therapy.
Other Changes to the Guidelines The staging system was revised according to the new American Joint Committee on Cancer staging. “Lymph node involvement in the past had been considered metastatic disease, and this has been changed to now being stage III,” Dr. von Mehren pointed out.
Moving on to the low-grade (stage IA–IB) tumors of the extremity or those located on the trunk, Dr. von Mehren noted that “a majority of these patients are treated with surgery as their first option.” The Panel also concluded that in patients with lowgrade extremity tumors, observation is a reasonable option after surgery if the final surgical margins are larger than 1 cm, irrespective of the size of the tumor. However, if the final margins are smaller than 1 cm, “observation may be less appropriate for those with larger tumors, even if they are low-grade,” Dr. von Mehren explained. For patients with metastatic disease (stage IV), treatment options are dependent on whether it is limited or diffuse disease. Surgery in association with chemotherapy, radiation, or observation were included as options for those with limited metastatic disease, whereas for those with diffuse metastatic disease, “we are really looking at palliative therapy,” she stated. For retroperitoneal and intraabdominal sarcomas, surgery with or without intraoperative radiation therapy (IORT) is the primary treatment. However, the use of IORT must be accompanied by a clear pathologic diagnosis to exclude DF and gastrointestinal stromal tumors (GIST),” Dr. von Mehren emphasized.
Promising Future Directions Although sarcomas are most amenable to local techniques, emerging data suggest that various subtypes also benefit from chemotherapy. “Thinking about what your tumor is when you’re making chemotherapy decisions is important,” Dr. von Mehren pointed out. Beyond imatinib, small studies suggest some promise for sorafenib (Nexavar), dasatinib (Sprycel), nilotinib (Tasigna), and sunitinib (Sutent) in GIST and possibly other subtypes.
Better understanding of the molecular profiles of the many sarcoma subtypes will help guide treatment in the future. “There are 50–70 histologies within sarcoma, and markers will help us in the diagnosis and in choosing appropriate treatments,” Dr. von Mehren predicted. For example, a retrospective molecular analysis of patients with DF in the MD Anderson database (Lazar AJ et al. Am J Pathol 2008;173:1518– 1527) found that patients with the 45F mutation in exon 3 of the CTNNB1 gene had significantly impaired 5-year recurrence-free survival (23%) compared with patients having no mutations (65%) or the 41A mutation (57%). “This may be a way of selecting patients who need more aggressive treatment,” Dr. von Mehren said. Finally, recent studies have identified several germline mutations in the succinate dehydrogenase subunit in patients with wild-type GIST (Janeway KA et al. Proc Natl Acad Sci 2011;108:314–318; Ricketts CJ et al. Hum Mutat 2010;31:41–51). “This underscores the need to perform mutation testing in GIST tumors,” Dr. von Mehren suggested, “and perhaps to consider some of these patients for genetic counseling.” Key Points Patients with desmoid tumors can be observed carefully if the tumors are small and not located on the trunk and if surgery would lead to excessive morbidity. Lymph node involvement is no longer considered a stage IV disease. Molecular markers are becoming increasingly important in the diagnosis, prognosis, and treatment of patients with sarcoma.
New Techniques in Imaging The radiologist, now a vital member of the oncology team, has a wide spectrum of data-analysis tools
nnovations in computed tomography (CT) have made the workup of suspected malignancies a much more exact science, providing information that oncologists can use not only in diagnosis, but also in treatment © 2011 NCCN. All rights reserved.
planning, declared Elliot Fishman, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who provided a look at what can be accomplished with modern CT techniques.
CT imaging has an important role in oncology in detecting disease, staging disease, and assisting with patient management. The radiologist is now a vital member of the medical team, he said. “In radiology, a big part of what
we do is consultation, really working with the medical oncologist, surgical oncologist, or radiation therapist in optimizing the information necessary for the patient.” He referred to this as radiology
“asset management,” that is, obtaining the right data on the right device and getting it to the right people, at the point of care. Because imaging is “mission critical information” that guides patient management, “the acquisition, analysis, and interpretation of imaging need to be done correctly and in a very timely manner,” he said.
The CT Journey Over the past 30 years, “CT has gone from a study that took 30 minutes and gave you about 30 slices, to a study that typically takes under a minute and gives us anywhere between hundreds and thousands of slices,” Dr. Fishman noted. Using axial CT alone limDr. Fishman its the capability of using state-of-the-art CT in patients with cancer. A volumetric approach, which includes 3D imaging and display, is now routinely possible. In addition, with CT angiography, CT moves from being a study focused on detection of masses to one that focuses on the complete picture of malignancy. “We now have an entire spectrum of data analysis tools to work with,” he pointed out, including multiplanar reconstruction (MPR), curved planar reconstruction, volume rendering techniques, and maximum intensity projection. Using these tools, radiologists can quickly acquire computer-generated images that can be viewed from any plane or perspective to obtain information about lesion texture, vascularity, the presence and extent of neovascularity, perfusion, and potential resectability. Volume visualization has replaced looking only at classic axial slices. “Instead of looking slice by slice, I’m looking at 1,500 slices in a volume,” Dr. Fishman explained. Volume visualization gives a more comprehen-
Highlights of the NCCN 16th Annual Conference
sive view and is more accurate, he said, providing a look at abnormal enhancement, strictures, increased blood flow, and other such characteristics within anatomic structures. For example, in renal tumors, surgical approach is determined by tumor type. Radiologists can distinguish a papillary renal cell carcinoma from a clear cell renal carcinoma using quantitative CT enhancement parameters, including attenuation values and vascularity. In the corticomedullary phase, attenuation values of renal clear cell carcinoma are significantly higher than those of renal papillary carcinoma (Ruppert-Kohlmayr AJ et al. AJR Am J Roentgenol 2004;183:1387– 1391). “The extent of neovascularity will define the aggressiveness of the tumor. With aggressive tumors, you do not want to be doing partial nephrectomies,” he said.
Accuracy Depends on Several Factors The accuracy of CT in oncology depends on a number of factors: ■■ Scanner used for study ■■ Scan protocol (single vs. dual phase acquisition) ■■ Rate of injection of iodinated contrast material ■■ Image display used (axial vs. MPR vs. 3D) ■■ Skill of interpreting physician Complex visualization is valuable in improving accuracy, Dr. Fishman said, describing a study that suggests that, with the addition of coronal and sagittal MPR images, parenchymal-phase and portal venous-phase imaging may help in evaluating pan-
CT has gone from a study that took 30 minutes and gave you about 30 slices, to a study that typically takes under a minute and gives us anywhere between hundreds and thousands of slices. — Dr. Fishman creatic tumors (Ichikawa T et al. AJR Am J Roentgenol 2006;187:1513– 1520). Axial images have been the backbone of CT but are potentially limited when analyzing complex anatomy or attempting surgical planning.
Focusing on Pancreatic Cancer With recent advances in imaging and surgical techniques, a distinct subset of pancreatic tumors is emerging that blurs the distinction between resectable and locally advanced disease: tumors of “borderline resectability.” The borderline resectable lesion is characterized by encasement of a short segment of the hepatic artery without celiac artery involvement; tumor abutment of the superior mesenteric artery involving less than 180 degrees of the circumference of
the artery; or short-segment occlusion of the superior mesenteric vein, portal vein, or their confluence. A multidisciplinary approach to these lesions is very important, he emphasized. At the multidisciplinary clinic at Hopkins, 38 of 203 pancreatic patients (18.7%) had a change in the status of their clinical stage, based on either new imaging studies with 3D mapping or reinterpretation of the original imaging (Pawlik TM et al. Ann Surg Oncol 2008;15:2081–2088). Review by pathologists accounts for some additional staging changes that can result in management changes. The detection of a pancreatic mass is based on size, change in enhancement (solid vs cystic; hypovascular vs hypervascular), pancreatic and common bile duct transition/obstruction or dilation, and the effect Key Points Multidetector computed tomography (CT) allows the radiologist to serve as a consultant to the oncology team, as the interpretation of CT images is key to treatment planning. New data analysis tools provide information about a tumor’s texture, vascularity, neovascularity, perfusion, and resectability. Volume visualization has replaced standard analysis of axial slices.
of the mass on adjacent structures (see figure). Vascular mapping can define the anatomic location of the vessel; determine whether the vessel is patent, occluded, or encased/narrowed; and show collateral vessels as a guide to vessel encasement. This information is critical for determining whether a patient is resectable for cure, he said.
The Future of CT
Tumor in body of pancreas with duct cutoff. Dilation of the pancreatic duct suggests the presence of a small pancreatic adenocarcinoma.
Dr. Fishman anticipates even more sophisticated technology in the future, including dual-energy CT, higher resolution and lower radiation doses, tumor volumetrics, computerassisted diagnosis of colon polyps and lung nodules, and closer integration of imaging into medical records.
© 2011 NCCN. All rights reserved.
AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]
AVASTIN® (bevacizumab) Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience 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 below reflect exposure to Avastin in 2661 patients with mCRC, non‑squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21‑88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first‑ and second‑line mCRC patients who received a median of 11 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 7, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus‑IFL plus Avastin as compared to patients receiving bolus‑IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra‑abdominal venous thrombosis (10 vs. 5 patients). Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%. Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3‑4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.
1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2‑negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. 1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Table 1 Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with NCI‑CTC Grade 3−4 Adverse Events in Study 1 appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control) monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated Arm 1 Arm 2 hypertension after discontinuation of Avastin. IFL + Placebo IFL + Avastin Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive (n = 396) (n = 392) encephalopathy. [See Dosage and Administration (2.4).] NCI‑CTC Grade 3‑4 Events 74% 87% 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms Body as a Whole Asthenia 7% 10% occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder Abdominal Pain 5% 8% which can present with headache, seizure, lethargy, confusion, blindness and other visual and Pain 5% 8% neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Cardiovascular Hypertension 2% 12% Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of Deep Vein Thrombosis 5% 9% reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Intra‑Abdominal Thrombosis 1% 3% Dosage and Administration (2.4).] Syncope 1% 3% 5.8 Proteinuria Digestive The incidence and severity of proteinuria is increased in patients receiving Avastin as Diarrhea 25% 34% compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in Constipation 2% 4% clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a Hemic/Lymphatic published case series, kidney biopsy of six patients with proteinuria showed findings Leukopenia 31% 37% consistent with thrombotic microangiopathy. 14% 21% Neutropeniaa Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine aCentral laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. dipstick reading should undergo further assessment with a 24‑hour urine collection.
AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving Table 4 bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. NCI‑CTC Grades 1−5 Adverse Events in Study 9 Grade 1–4 adverse events were collected for the first approximately 100 patients in each of (Occuring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin (n = 304) (n = 337) Preferred terma Table 2 Gastrointestinal disorders NCI‑CTC Grade 1‑4 Adverse Events in Study 1 Diarrhea 16% 21% (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) General disorders and administration Arm 1 Arm 2 Arm 3 site conditions IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin Fatigue 27% 33% (n = 98) (n = 102) (n = 109) Investigations Weight decreased 15% 20% Body as a Whole Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders Weight Loss 10% 15% 16% Hypertension 9% 28% Dry Mouth 2% 7% 4% a Adverse events were encoded using MedDRA, Version 10.1. Colitis 1% 6% 1% Hemic/Lymphatic The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Thrombocytopenia 0% 5% 5% Avastin arm compared to IFN‑α alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) Respiratory and pulmonary embolism (5 vs. 1). Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected. Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second‑line mCRC The following adverse reactions have been identified during post‑approval use of Avastin. Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 always possible to reliably estimate their frequency or establish a causal relationship to non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence drug exposure. (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving Body as a Whole: Polyserositis FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Eye disorders (reported from unapproved use for treatment of various ocular disorders): hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection to under‑estimate the true adverse event rates due to the reporting mechanisms used including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual in Study 2. disturbances; Ocular hyperemia; Ocular pain and/or discomfort Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected Hemic and lymphatic: Pancytopenia in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension Respiratory: Nasal septum perforation, dysphonia (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), 7 DRUG INTERACTIONS febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 A drug interaction study was performed in which irinotecan was administered as part of the or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. (3% vs. 0%). In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to Metastatic Breast Cancer (MBC) Only Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were collected in be a difference in the mean exposure of either carboplatin or paclitaxel when each was Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving administered alone or in combination with Avastin. However, 3 of the 8 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% In Study 9, there was no difference in the mean exposure of interferon alfa administered in vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation combination with Avastin when compared to interferon alfa alone. (3% vs. 0.3%) and proteinuria (3% vs. 0%). 8 USE IN SPECIFIC POPULATIONS Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in 8.1 Pregnancy the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. Pregnancy Category C Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in abdominal, and pain/weakness/hypotension (2). teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Avastin is not approved for use in combination with capecitabine or for use in second or third Adverse fetal outcomes were observed at all doses tested. Other observed effects included line treatment of MBC. The data below are presented to provide information on the overall decreases in maternal and fetal body weights and an increased number of fetal resorptions. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, [See Nonclinical Toxicology (13.3).] controlled study in which all adverse events were collected for all patients. All patients in Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for from the mother to the developing fetus, and has the potential to cause fetal harm when metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients administered to pregnant women. Because of the observed teratogenic effects of known inhibitors receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential in Table 3. benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers Table 3 It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. NCI‑CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone) substantial amounts. Because many drugs are secreted in human milk and because of the potential for Capecitabine serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab Capecitabine + Avastin (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical (n = 215) (n = 229) Pharmacology (12.3).] Body as a Whole 8.4 Pediatric Use Asthenia 47% 57% The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Headache 13% 33% been established. Pain 25% 31% Antitumor activity was not observed among eight children with relapsed glioblastoma treated Cardiovascular with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Hypertension 2% 24% Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Digestive to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and Stomatitis 19% 25% exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially Metabolic/Nutrition reversible upon cessation of treatment. Weight loss 4% 9% 8.5 Geriatric Use Musculoskeletal In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 Myalgia 8% 14% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Respiratory hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, Dyspnea 18% 27% leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Epistaxis 1% 16% survival was similar in elderly patients as compared to younger patients. Skin/Appendages In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk Exfoliative dermatitis 75% 84% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. Urogenital In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Albuminuria 7% 22% Precautions (5.8).] In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received the overall adverse events profile was different in the elderly as compared with younger patients. Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of cough, and voice alteration. any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two incidence of arterial thromboembolic events was increased in all patients receiving Avastin with deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions Avastin‑related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (5.5).] (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), 10 OVERDOSAGE arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 16 patients and with severe headache in three of 16 patients. 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin Avastin® (bevacizumab) compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), 02/11 AVA0000306600 asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including Manufactured by: 10127309 hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Initial U.S.Approval: February 2004 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Genentech, Inc. haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract A Member of the Roche Group Code Revision Date: February 2011 hemorrhage, and traumatic hematoma). 1 DNA Way Avastin® is a registered trademark of Genentech, Inc. Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN‑α plus South San Francisco, CA 94080‑4990 ©2011 Genentech, Inc. Avastin compared to the IFN‑α plus placebo arm are presented in Table 4.
In first-line metastatic NSCLC and first- and second-line MCRC
To reach beyond convention…
Indications Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.
Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.
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