Clinical Oncology News Digital Edition - June 2012

Oncology Edition 4 0th A N N IV E RSA RY

Independent News on Advances in Cancer Care clinicaloncology.com • June 2012 • Vol. 7, No. 6

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A new biomarker to guide treatment for esophagogastric cancer treatment.

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A more pragmatic approach to Phase II trials.

Clinical Conundrums: A quiz for the practicing hematologist/ oncologist.

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Addressing the needs of young adults with cancer.

EXPERT COMMENTARIES FROM CLEVELAND CLINIC

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A n introduction to the Taussig Cancer Institute.

One institution’s 29-year experience with intraoperative radiation therapy.

Kevin Stephans, MD

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Adjuvant

chemotherapy for non-small cell lung cancer.

Metastatic NSCLC: Palliative Care at Diagnosis ASCO provisional opinion says palliative care at diagnosis leads to better patient outcomes

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ll patients with metastatic nonsmall cell lung cancer (NSCLC) should be offered palliative care along with standard cancer therapy, beginning at the time of diagnosis, according to a provisional clinical opinion (PCO) issued by the American Society of Clinical Oncology (ASCO).

The statement, published Feb. 6 in the Journal of Clinical Oncology (2012;30:880-887, PMID: 22312101), was initiated by a recent Phase III randomized clinical trial that demonstrated the benefits of concurrent palliative see NSCLC, page 11 

Significant Bone Changes with Exemestane Unclear whether bone density drop leads to increased fractures

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Nathan Pennell, MD, PhD

EDUCATIONAL REVIEW

The Systemic Treatment of Metastatic Melanoma Access at clinicaloncology.com

here is a significant drop in bone density with two years of use of the aromatase inhibitor exemestane (Aromasin, Pfizer) at a dosage of 25 mg per day, according to a new study.

In a substudy of a randomized controlled trial of healthy postmenopausal women taking exemestane to prevent breast cancer, the medication was associated with an average 6.1% reduction in bone mineral density (BMD) at the distal radius using quantitative see CHANGES, page 10 

The Underreported Cardiac Toxicity of Anticancer Drugs T

here appears to be a signifi­cant disconnect between the cardiac effects of cancer drugs and how they are reported in clinical trials.

The problem may be so prevalent that some oncologists are calling for revamping how cardiovascular side effects are reported during clinical trials of newer chemotherapeutic agents.

“Th ere are signals that many of the tyrosine kinase inhibitors are an issue,” said Ronald Witteles, MD, an assistant professor of cardiovascular medicine at Stanford University School of Medicine in Stanford, Calif. “However, there is no way to know how widespread the

Anticancer Agents Associated With LV Dysfunction Anticancer agents causing permanent damage Doxorubicin

Daunorubicin

Epirubicin

Idarubicin

Mitoxantrone

Cyclophosphamide

Anticancer agents causing reversible damage Trastuzumab

Sunitinib

Lapatinib (tyrosine kinase inhibitor)

see CARDIOTOXICITY, page 17 

Heterogeneity of Gastric Cancers Poses Challenges San Francisco—A growing body of evidence demonstrates that stomach cancer is an extremely heterogeneous disease, so much so that researchers are questioning whether clinical trials need to be restructured to reflect the myriad differences.

“Gastric cancer isn’t one disease but many diseases,” said Manish Shah, MD, the director of Gastrointestinal Oncology at Weill Cornell Medical College in New York City, speaking at the 2012 Gastrointestinal Cancers Symposium (ASCO-GI).

“This is supported by epidemiology, risk factors, response to therapy and even molecular analyses.”

Teasing Out the Differences Although gastric cancer is more prevalent in Asia, there is more advanced disease in the United States and the West in general.

“Then there is the question of whether there is different underlying biology. That see CHALLENGES, page 29 

McMahonMedicalBooks.com To order cancer therapeutic regimens or agents pocket guides, go to http://www. clinicaloncology.com/ PocketGuides.

New Drugs for Malignancy, An Issue of Hematology/ Oncology Clinics of North America Franco Muggia, MD See page 31.

Adapted from Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know.” Nat Rev Cardio. 2010;7:564-575.

SOLID TUMORS

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CLINICAL ONCOLOGY NEWS

Clinical Oncology News • June 2012

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Prostate Cancer

Susan K. Seo, MD

AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

Cleveland State University Cleveland, OH

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Maura N. Dickler, MD

Harry Erba, MD, PhD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

University of Michigan Ann Arbor, MI

University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Richard Stone, MD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Lung, and Head and Neck Cancers Edward S. Kim, MD University of Texas, MD Anderson Cancer Center Houston, TX

Lung Cancer, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Policy and Management Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Cindy O’Bryant, PharmD University of Colorado Cancer Center Denver, CO

Rhonda M. Gold, RN, MSN The Pritchard Group Rockville, MD

Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Steven Vogl, MD Medical Oncologist New York, NY

Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

University of Texas, MD Anderson Cancer Center Houston, TX

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Genitourinary Cancer Ronald M. Bukowski, MD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Pharmacy Mayo Clinic Rochester, MN

Leonard Saltz, MD

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

Shaji Kumar, MD

Edward Chu, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Oncology Nursing

Hematologic Malignancies

Andrew Seidman, MD

Cathy Eng, MD

Bioethics

Michael A. Carducci, MD

Jennifer R. Brown, MD, PhD

Gastrointestinal Cancer

Infection Control

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

Charles F. von Gunten, MD University of California, San Diego, CA

Mission Statement

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he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

Editorial Philosophy The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published.

Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Additionally, all news articles that appear in Clinical Oncology News are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

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Clinical Oncology News • June 2012

Evidence-based Medicine

Randomized Phase II trials:

A Pragmatic Way To Inform Clinical Practice The crisis in clinical cancer research has been well described. From the extremely small percentage of patients that elect to enter a cancer trial, to the time required for the activation of studies, to the high failure rate by cooperative groups to complete accrual, and the increasingly questionable ethical justification of “placebo” or “no crossover” studies, there is much in clinical cancer research that desperately requires fixing.

We should add the need for more pragmatic clinical trials that address, even if not definitively, issues of considerable relevance to individual patient management, but for which there is little recognized interest from either the “scientific community” or potential financial sponsors.

Consider, for example, the recent report on the biological activity of single-agent, nanoparticle albumin-bound paclitaxel in the second-line treatment of epithelial ovarian cancer.1 This nonrandomized study, conducted by the

simply be unknown because any suggested “superior” outcomes may solely reflect the inadvertent selection bias resulting from the favorable baseline clinical features inherent in all nonrandomized studies.

And although a definitive answer to this question would admittedly require a rather large Phase III trial, a 100- or 120-patient randomized Phase II study that directly compares the nanoparticle agent with generic paclitaxel may provide sufficient data to adequately inform both individual patient decision making

only a single well-defined question, be easy to explain to prospective research subjects and strictly avoid the largely, if not completely, unnecessary mandates required for regulatory approval—for example, placebo control and independent radiology review.

And wherever clinically appropriate, a crossover design should be strongly considered, permitting patients entering the trial the opportunity to receive and potentially benefit from the investigative regimen. Patients progressing on weekly paclitaxel in the above

‘It can be strongly argued that pragmatic, randomized Phase II trials should be simple in design, address only a single well-defined question, be easy to explain to prospective research subjects and strictly avoid the largely, if not completely, unnecessary mandates required for regulatory approval—for example, placebo control and independent radiology review.’

Gynecologic Oncology Group, revealed an objective response rate of 23%, similar to that previously reported with the far less expensive generic paclitaxel.2,3 But is it possible that this agent is actually superior to paclitaxel in that treatment with nanoparticle albuminbound paclitaxel achieves a similar degree of objective clinical benefit (e.g., degree of tumor shrinkage and delay in time to progression) but with a measurably more favorable toxicity profile that includes a substantially reduced risk for peripheral neuropathy?

Unfortunately, in the complete absence of data from a randomized trial, the answer to this specific question will

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Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2012 McMahon Publishing, New York, NY. All rights reserved.

POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

mucositis—or even time to worsening of cancer-related symptoms.

Finally, although pragmatic, randomized Phase II trials will almost never serve as a definitive test, they may provide genuinely meaningful data in a substantial number of clinical settings that truly inform the decision-making process both for the treating physician and, most importantly, the patient.

References 1. Coleman RL, Brady WE, McMeekin DS, et al. A phase II evaluation of nanoparticle, albumin-bound (nab) paclitaxel in the treatment of recurrent or persistent platinumresistant ovarian, fallopian tube, or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2001;122:111115, PMID: 21497382.

2. Markman M, Blessing J, Rubin SC, et al.

Phase II trial of weekly paclitaxel (80 mg/ m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol Oncol. 2006;101:436-440, PMID: 16325893.

as well as deliberations by third-party insurers asked to pay the cost associated with the more expensive antineoplastic.

As the question being addressed does not relate to drug approval or marketing, there would be no regulatory requirement for a study confirming superiority based on improved survival. Rather, the specific issues addressed by the study relate solely to the decision to both use and pay for the agent in its clinical indication; and the data would be directed at the physician, payer and patient audiences.

It also can be strongly argued that pragmatic, randomized Phase II trials should be simple in design, address

example might cross over to nanoparticle paclitaxel, the argument being that the unique drug formulation may overcome a clinically meaningful degree of paclitaxel resistance. Of course, there can never be any guarantee to patients that crossover will be possible—clinical circumstances at the time of disease progression may demand alternative options that are ultimately in the patient’s best interests.

In pragmatic, randomized Phase II studies, the acceptable end points might include differences in the objective response rate, progression-free survival, clinically relevant toxicity— peripheral neuropathy or stomatitis/

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3. Markman M, Hall J, Spitz D, et al. Phase II trial of weekly single-agent paclitaxel in paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol. 2002;20:23652369, PMID: 11981009.

Comments or feedback on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor Gabriel Miller at

gmiller@mcmahonmed.com

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Indication ZOMETA (zoledronic acid) 4 mg/5 mL Injection is indicated for the treatment of hypercalcemia of malignancy (HCM) and patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Safe and efficacious use of ZOMETA has not been established for use in hyperparathyroidism or non-tumor-related hypercalcemia.

Important Safety Information ZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported.

Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient.

Patients with HCM must be adequately rehydrated prior to use of ZOMETA and loop diuretics (if applicable). Loop diuretics should be used with caution in combination with ZOMETA to avoid hypocalcemia. ZOMETA should be used with caution with other nephrotoxic drugs. Carefully monitor serum calcium, phosphate, magnesium, and serum creatinine following initiation of ZOMETA. Short-term supplemental therapy may be necessary.

In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. Consider individual patient risk/benefit profile before starting ZOMETA therapy in HCM patients with severe renal impairment. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment. Preexisting renal insufficiency and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose.

Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fitting dentures).

Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible, as recovery may be prolonged. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

ZOMETA should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant or plans to breast-feed while taking this drug, the patient should be apprised of the potential harm to the fetus or baby.

In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including ZOMETA. Discontinue use if severe symptoms develop, as a subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. There have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including ZOMETA. These fractures may occur with minimal or no trauma. A number of case reports noted that patients were also receiving treatment with glucocorticoids at time of fracture. Causality with bisphosphonates has not been established. Any patient with a history of bisphosphonate exposure who presents with hip, thigh, or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Drug discontinuation in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit/risk assessment.

Insufficient data exist on how to safely use ZOMETA in HCM patients with hepatic impairment.

Acute-phase reaction symptoms can occur in HCM patients, with fever most commonly reported (44% with ZOMETA vs. 33% with pamidronate). Patients may occasionally experience flu-like syndrome (fever, chills, flushing, bone pain and/or arthralgias and myalgias).

The most common adverse events (≥10%) in HCM clinical trials, regardless of causality, with ZOMETA 4 mg (n=86) were as follows: fever (44%), nausea (29%), constipation (27%), anemia (22%), dyspnea (22%), diarrhea (17%), abdominal pain (16%), progression of cancer (16%), insomnia (15%), vomiting (14%), anxiety (14%), urinary tract infection (14%), hypophosphatemia (13%), confusion (13%), agitation (13%), moniliasis (12%), hypokalemia (12%), coughing (12%), skeletal pain (12%), hypotension (11%), and hypomagnesemia (11%). In controlled HCM clinical trials, adverse events (5-10% frequency) occurring in greater incidence with ZOMETA than pamidronate include: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, non-specific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Injection site reactions (redness, swelling) have been infrequently reported.

The most common adverse events (≥15%) in bone metastases clinical trials, regardless of causality, with ZOMETA 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lower-limb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%), and paresthesia (15%). Patients should also be made aware of the potential for abdominal pain.

Ocular adverse events may occur with bisphosphonates, including ZOMETA. Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Caution is advised when bisphosphonates, including ZOMETA, are administered with aminoglycosides, loop diuretics, and potentially nephrotoxic drugs.

Patients with multiple myeloma and bone metastases due to solid tumors should be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.

Please see full Prescribing Information.

Please see brief summary of full Prescribing Information on the following pages.

References: 1. ZOMETA Prescribing Information. Novartis Pharmaceuticals Corporation. 2. Aredia Prescribing Information. Novartis Pharmaceuticals Corporation.

3. Actonel Prescribing Information. Procter & Gamble Pharmaceuticals. 4. Boniva Prescribing Information. Roche Laboratories Inc. 5. Didronel Prescribing Information. Procter & Gamble Pharmaceuticals. 6. Fosamax Prescribing Information. Merck & Co. 7. Skelid Prescribing Information. sanofi-aventis US LLC. 8. Xgeva Prescribing Information.

Amgen Inc.

© 2012 Novartis

April 2012

ZOM-1040045

Proven efficacy across multiple malignancies1

Indicated across more advanced malignancies than any other approved bone-remodeling agent1-8

Bone metastases from solid tumors

*ZOMETA (zoledronic acid) 4 mg/5 mL Injection should be used in prostate patients with bone metastases that have progressed after treatment with at least one hormonal therapy.

Across multiple advanced malignancies, helps reduce and delay multiple SREs1 • Pathologic fracture • Surgery to bone • HCM

• Spinal cord compression • Radiation to bone

SRE=skeletal-related event.

Highlights from the Important Safety Information • There have been reports of renal toxicity with ZOMETA. Renal toxicity may be greater in patients with renal impairment. Treatment in patients with severe renal impairment is not recommended. Do not use doses greater than 4 mg and monitor serum creatinine before each dose • Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status • A causal relationship between bisphosphonate use and ONJ has not been established Please see full Prescribing Information.

Please see brief summary of full Prescribing Information on the following pages.

Zometa® (zoledronic acid) Injection Ready-to-Use Solution for Intravenous Infusion (For Single Use) Concentrate for Intravenous Infusion Initial U.S. Approval: 2001 BRIEF SUMMARY: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin (g/dL)).

1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established.

4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient or in the Same Drug Class Zometa contains the same active ingredient as found in Reclast® (zoledronic acid).

Patients being treated with Zometa should not be treated with Reclast or other bisphosphonates.

5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs.

Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary.

5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1)]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa.

Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible.

Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine greater than 400 μmol/L or greater than 4.5 mg/dL were excluded.

Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine greater than 265 μmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information].

5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis.

Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment

reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)].

5.5 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2)].

5.6 Atypical subtrochanteric and diaphyseal femoral fractures Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Zometa. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma.

Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of Zometa therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.

5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates.

5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients.

5.9 Use in Pregnancy Bisphosphonates, such as Zometa, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy.

Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Studies 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.

Hypercalcemia of Malignancy The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.

Renal Toxicity Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information].

The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 4).

Table 6: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM

Table 4 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials.

Adverse events are listed regardless of presumed causality to study drug.

Grade 4

Table 4: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

Patients Studied Total No. of Patients Studied Total No. of Patients with any AE Body as a Whole Fever Progression of Cancer Cardiovascular Hypotension Digestive Nausea Constipation Diarrhea Abdominal Pain Vomiting Anorexia Hemic and Lymphatic System Anemia Infections Moniliasis Laboratory Abnormalities Hypophosphatemia Hypokalemia Hypomagnesemia Musculoskeletal Skeletal Pain Nervous Insomnia Anxiety Confusion Agitation Respiratory Dyspnea Coughing Urogenital Urinary Tract Infection

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

86 (100) 81 (94)

103 (100) 95 (92)

38 14

(44) (16)

34 21

(33) (20)

9

(11)

2

(2)

25 23 15 14 12 8

(29) (27) (17) (16) (14) (9)

28 13 17 13 17 14

(27) (13) (17) (13) (17) (14)

19

(22)

18

(18)

10

(12)

4

(4)

11 10 9

(13) (12) (11)

2 16 5

(2) (16) (5)

10

(12)

10

(10)

13 12 11 11

(15) (14) (13) (13)

10 8 13 8

(10) (8) (13) (8)

19 10

(22) (12)

20 12

(19) (12)

12

(14)

15

(15)

The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence.

Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa.

Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias.

Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use.

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 5 and 6.

Table 5: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter

Creatinine1

Serum Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

2/86 1/86 36/70 0/71

(2%) (1%) (51%) —

3/100 2/100 27/81 0/84

(3%) (2%) (33%) —

Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

0/86 0/86 1/70 0/71

— — (1%) —

1/100 0/100 4/81 1/84

(1%) — (5%) (1%)

1Grade

3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) 2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L) Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.

Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)].

Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors.

Table 7 describes adverse events that were reported by 10% or more of patients.

Adverse events are listed regardless of presumed causality to study drug.

Table 7: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%) Patients Studied Total No. of Patients 1031 (100) Total No. of Patients with any AE 1015 (98) Blood and Lymphatic Anemia 344 (33) Neutropenia 124 (12) Thrombocytopenia 102 (10) Gastrointestinal Nausea 476 (46) Vomiting 333 (32) Constipation 320 (31) Diarrhea 249 (24) Abdominal Pain 143 (14) Dyspepsia 105 (10) Stomatitis 86 (8) Sore Throat 82 (8) General Disorders and Administration Site Fatigue 398 (39) Pyrexia 328 (32) Weakness 252 (24) Edema Lower Limb 215 (21) Rigors 112 (11) Infections Urinary Tract Infection 124 (12) Upper Respiratory Tract Infection 101 (10) Metabolism Anorexia 231 (22) Weight Decreased 164 (16) Dehydration 145 (14) Appetite Decreased 130 (13)

Pamidronate 90 mg n (%)

Placebo

556 (100) 548 (99)

455 (100) 445 (98)

175 83 53

(32) (15) (10)

128 35 20

(28) (8) (4)

266 183 162 162 81 74 65 61

(48) (33) (29) (29) (15) (13) (12) (11)

171 122 174 83 48 31 14 17

(38) (27) (38) (18) (11) (7) (3) (4)

240 172 108 126 62

(43) (31) (19) (23) (11)

130 89 114 84 28

(29) (20) (25) (19) (6)

50 82

(9) (15)

41 30

(9) (7)

81 50 60 48

(15) (9) (11) (9)

n (%)

105 (23) 61 (13) 59 (13) 45 (10) (continued)

Table 7: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%) Musculoskeletal Bone Pain Myalgia Arthralgia Back Pain Pain in Limb Neoplasms Malignant Neoplasm Aggravated Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia Psychiatric Depression Anxiety Confusion Respiratory Dyspnea Cough Skin Alopecia Dermatitis

Pamidronate 90 mg n (%)

Placebo n (%)

569 239 216 156 143

(55) (23) (21) (15) (14)

316 143 131 106 84

(57) (26) (24) (19) (15)

284 74 73 40 52

(62) (16) (16) (9) (11)

205

(20)

97

(17)

89

(20)

191 180 166 149 127

(19) (18) (16) (15) (12)

149 91 111 85 65

(27) (16) (20) (15) (12)

50 58 73 35 43

(11) (13) (16) (8) (10)

146 112 74

(14) (11) (7)

95 73 39

(17) (13) (7)

49 37 47

(11) (8) (10)

282 224

(27) (22)

155 129

(28) (23)

107 65

(24) (14)

125 114

(12) (11)

80 74

(14) (13)

36 38

(8) (8)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 8 and 9.

Table 8: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 3 Laboratory Parameter

Zometa 4 mg n/N

Creatinine1*

Serum Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

(%)

7/529 (1%) 6/973 (<1%) 115/973 (12%) 19/971 (2%) 1/971 (<1%)

Pamidronate 90 mg n/N

(%)

4/268 (2%) 4/536 (<1%) 38/537 (7%) 2/535 (<1%) 0/535 —

Placebo n/N

(%)

4/241 (2%) 0/415 — 14/415 (3%) 8/415 (2%) 1/415 (<1%)

1Grade

3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) 5Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L) Table 9: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 4 Laboratory Parameter

Creatinine1*

Serum Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5 1Grade

Zometa 4 mg

Pamidronate 90 mg

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

2/529 7/973 5/973 0/971 2/971

(<1%) (<1%) (<1%) — (<1%)

1/268 3/536 0/537 0/535 1/535

(<1%) (<1%) — — (<1%)

0/241 2/415 1/415 2/415 0/415

— (<1%) (<1%) (<1%) —

3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) 5Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)

Among the less frequently occurring adverse events (less than 15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group.

Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear.

Renal Toxicity In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (less than 1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (greater than or equal to 1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 10).

Table 10: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer Normal Abnormal Total Solid Tumors Normal Abnormal Total Prostate Cancer Normal Abnormal Total

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

27/246 2/26 29/272

(11%) (8%) (11%)

23/246 2/22 25/268

(9%) (9%) (9%)

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

17/154 1/11 18/165

(11%) (9%) (11%)

10/143 1/20 11/163

(7%) (5%) (7%)

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

12/82 4/10 16/92

(15%) (40%) (17%)

8/68 2/10 10/78

(12%) (20%) (13%)

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes.

The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate.

In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose.

6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa.

Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5)].

Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5)].

Atypical subtrochanteric and diaphyseal femoral fractures Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including Zometa [see Warnings and Precautions (5.6)].

Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported.

Additional adverse reactions reported in postmarketing use include: CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: Increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia.

7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug.

7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials.

7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia.

7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs.

7.4 Thalidomide No dose adjustment for Zometa 4 mg is needed when co-administered with thalidomide.

In a pharmacokinetic study of 24 patients with multiple myeloma, Zometa 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of thalidomide with Zometa did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precaution (5.9)] There are no adequate and well-controlled studies of Zometa in pregnant women.

Zometa may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as Zometa, are incorporated into the bone matrix and are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. If this drug is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus.

In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect.

In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study.

In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were

observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.

8.3 Nursing Mothers It is not known whether zoledronic acid is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zometa, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Zoledronic acid binds to bone long term and may be released over weeks to years.

8.4 Pediatric Use Zometa is not indicated for use in children.

The safety and effectiveness of zoledronic acid was studied in a one-year activecontrolled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7).

At one year, increases in BMD were observed in the zoledronic acid treatment group.

However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk.

Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose.

8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.

10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose.

A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known.

In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information].

16 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Manufactured by Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2012-66 March 2012

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Clinical Oncology News • June 2012

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computed tomography (CT), compared to an average 1.8% BMD reduction with placebo (P<0.0001; Lancet Oncol 2012;13:275-284, PMID: 22318095).

This was despite the fact that most of the women were taking calcium and vitamin D supplements.

However, in neither the substudy nor the parent study—known as MAP.3 (Mammary Prevention 3) and funded by the National Cancer Institute of Canada—were there any significant differences between the two groups’ rates of fragility fractures, total fractures, no less than 10% drop in areal BMD, or reduction in height. Hence, the investigators are not recommending against exemestane in any eligible patient populations.

“I have been advising individuals to consider their own risks and benefits when thinking about taking this medication,” lead investigator Angela Cheung, MD, PHD, told Clinical Oncology News.

“For some women, their breast cancer risk is high and accepting the potential risks to bone health is worthwhile because not all women experience BMD loss—in our study, 35% did not have any significant bone loss according to the usual BMD test [dual-energy x-ray

absorptiometry or DXA]. For others, this may not be the case.”

Dr. Cheung—the Lillian Love Chair in Women’s Health and director of the Osteoporosis Program at the University of Toronto in Canada—and her colleagues are conducting an extension study to determine whether their observations are due to an initial adjustment of bone to the lower circulating estrogen levels induced by exemestane or whether continued use results in a continual decline in BMD. The study also will examine whether stopping the medication reverses the BMD drop.

MAP.3 was a large trial of exemestane 25 mg per day in the primary prevention of breast cancer (NEJM 2011;364:23812391, PMID: 21639806). Exemestane significantly reduced the risk for invasive breast cancer but did not increase women’s fracture risk in the trial. (See “Exemestane Reduces Breast Cancer Risk in Postmenopausal Women” in the December 2011 issue of Clinical Oncology News, page 16.)

However, the study was underpowered to unequivocally determine bone health effects. Instead, Dr. Cheung performed a nested substudy of MAP.3 involving CT measurement of BMD at three centers in Canada and two in the United States. The primary end point was the percent change in total volumetric BMD at the distal radius using high-resolution

❖❖ Exemestane worsens age-related bone loss in postmenopausal women

❖❖Although it is unclear whether exemestane-related bone loss translates into an increased risk for fractures, early results indicate that it does not

‘I have been advising individuals to consider their own risks and benefits when thinking about taking this medication.’ peripheral quantitative CT from baseline to two years; 351 women were included in the study and 242 women completed the full, two-year follow-up (exemestane, n=124; placebo, n=118).

The investigators found a significant reduction in the exemestane group compared with placebo with this end point.

They also detected a significantly greater reduction in mean percent change in cortical thickness at that site and a significantly greater drop in total volumetric BMD at the distal tibia with exemestane versus placebo. They also documented significantly greater declines in areal BMD using DXA at the lumbar spine,

Dietary Supplements May Raise Cancer Risk Dietary supplements have little to no effect in preventing cancer and may increase cancer risk, according to a review published in the Journal of the National Cancer Institute (2012;104:732-739, PMID: 22534785).

Restricting their review to supplements that have been researched in sufficiently powered clinical trials or large observational studies, the authors focused on antioxidants, folate and folic acid, vitamin D and calcium.

Despite early evidence suggesting an anticancer benefit from antioxidants, clinical studies have not borne out that promise, the authors argue. For example, b-carotene does not prevent

recurrence of non-melanoma skin cancer (N Engl J Med 1990;323:789-795, PMID: 2202901); b-carotene and vitamin A do not protect against lung cancer (N Engl J Med 1996;334:1150-1155, PMID: 8602180); vitamins C and E do not protect against total cancer incidence (JAMA 2009;301:52-62, PMID: 19066368); and a-tocopherol, vitamin C, and b-carotene do not protect against total cancer or cancer mortality (J Natl

Cancer Inst 2009;101:14-23, PMID: 19116389).

However, several trials have shown evidence of an increased cancer risk from antioxidants, the review authors, led by María Elena Martínez, PhD, at the University of California-San Diego, reported. One such study, conducted in a population at high risk for lung cancer, found a 39% increase in lung cancer incidence in the b-carotene arm compared with the placebo arm (N Engl J Med 1996;334:1150-1155, PMID: 8602180).

Similarly, the authors did not find evidence that folic acid and folate protect against cancer, whereas they did note evidence of increased risk for cancer

—Angela Cheung, MD, PHD hip and femoral neck.

In an accompanying commentary (Lancet Oncol 2012;13:221-222, PMID: 22318094), Jane A. Cauley, DrPH, a professor of epidemiology at the University of Pittsburgh, noted that most of the BMD loss appears to occur in the cortical bone, which “is important because 80% of our bone mass is cortical and 80% of all fractures occur in non-vertebral sites that are mainly cortical.”

–Rosemary Frei, MSc Drs. Cheung and Cauley do not have any conflicts of interest to disclose.

from long-term folic acid supplementation. They found insufficient evidence to draw conclusions about vitamin D, and “diverse results” regarding calcium.

Many expert groups have reached a “general consensus” that “nutritional supplements have little to no benefit in preventing cancer,” the authors wrote. Even so, much of the public continues to use dietary supplements, a fact that the authors attribute in large part to the marketing influence of supplement manufacturers. The authors call for “efforts by scientists and government officials to encourage the public to make prudent decisions based on sound evidence with respect to the use of dietary supplements for cancer prevention.”

—George Ochoa

Article & Review Reprints Reprints of Clinical Oncology News articles & reviews are available.

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Reprints can be ordered in black & white or 4-color.

SOLID TUMORS

Clinical Oncology News • June 2012

Lung

NSCLC continued from page 1 

care and standard oncologic care for patients with metastatic NSCLC. In that study, patients with metastatic NSCLC who received both forms of care early on had both improved quality of life and increased survival compared with patients who received standard cancer care alone (N Engl J Med 2010;363:733-742, PMID: 20818875).

Although the available evidence is strongest for metastatic lung cancer, ASCO also called for palliative care to be considered early in the course of care for patients with other metastatic cancers and for those with a high burden of cancer-related symptoms.

“For patients with advanced cancer, the data are increasingly showing us that palliative care can be incredibly valuable for them and their caregivers from the time patients are diagnosed, not just at the end of life,” said Jamie Von Roenn, MD, co-author of the PCO and a professor of medicine in the Division of Hematology/Oncology at Northwestern University in Chicago.

A panel of oncology and palliative experts convened by ASCO developed the report, which was titled “Integration of Palliative Care into Standard Oncology Care.”

The panel, led by Thomas Smith, MD, director of Palliative Care at Johns Hopkins University in Baltimore, analyzed data from seven recently published randomized clinical trials (RCTs) involving patients with metastatic cancer. All RCTs involved a standard cancer care group and a concurrent care group, comprising patients receiving both standard and palliative care.

Overall, the authors found that “substantial evidence demonstrates that palliative care—when combined with standard cancer care or as the main focus of care—leads to better patient and caregiver outcomes.”

They identified benefits such as comparable or improved survival, better symptom management, reduced depression and improved caregiver and patient quality of life. In some cases, patients can receive palliative care as an outpatient service and as an inpatient service when needed.

No trials to date have demonstrated harm to patients or caregivers, or an

Table. Research Priorities Identified

By ASCO Optimal timing and venue for provision of palliative care (i.e., inpatient vs. outpatient/ community) Evidence-based reimbursement models to support palliative care Assess which components of palliative care have an impact Interventions in other diseases besides lung cancer Evaluate the effect of palliation across the continuum of care, especially during the delivery of antitumor therapy

of the National Palliative Care Research Center and a professor of geriatrics and medicine at Mount Sinai School of Medicine in New York City.

The survival benefit of palliative care shown in the RCT is similar to the survival advantage associated with platinum-based chemotherapy for lung cancer, which has become the gold standard, he noted. “With platinum, you get hair loss, nausea, fatigue. With palliative care, you get a survival benefit and you feel better. So, it should be standard of care just the way platinum appropriately became standard of care.”

Experts caution that the optimal delivery of palliative care to improve patient outcomes is still evolving. More research is needed to look at different

‘For patients with advanced cancer, the data are increasingly showing us that palliative care can be incredibly valuable for them and their caregivers from the time the patients are diagnosed, not just at the end of life.’ excessive increase in health care costs, from early involvement in palliative care.

Experts from both oncology and palliative care welcomed the statement, saying it marks a paradigm shift in palliative care.

“It is wonderful that ASCO is encouraging oncologists to provide supportive care in addition to cancer-directed therapy,” said Jennifer S. Temel, MD, an assistant professor of hematology/oncology at Massachusetts General Hospital in Boston and author of the original Phase III study.

“The main take-home message is that, as oncologists, we can do better than we are currently doing. Palliative care—and other supportive care services—should be used in conjunction with cancer-directed therapy,” she said.

“This sends a strong message that palliative care is about providing highquality care for patients living with cancer and the palliative care team provides an extra layer of support to the patient’s oncologist right from diagnosis,” said R. Sean Morrison, MD, the director

—Jamie Von Roenn, MD strategies of care delivery, as well as the effect on important patient and caregiver outcomes such as quality of life, survival, health care services utilization and costs, they said (Table).

True palliative care is focused on the relief of suffering throughout the course of a patient’s illness, not just at the end, the report authors wrote.

Patients can reap benefits from the ongoing support of palliation services right from the beginning rather than, as often is the case, being enrolled in a hospice three weeks before their death.

“For a long time, patients’ options were seen as being therapy or palliative care but not both,” said F. Amos Bailey, MD, the director of palliative care and an associate professor at the University of Alabama at Birmingham and Birmingham VA Medical Center. “That’s changing now. Oncologists and palliative care consultants can work together as patients receive therapy. Doing this will allow the medical oncologist to focus more on the oncologic treatment and the palliative care consultant can

Visit ClinicalOncology.com for the

Cancer News Review With William Nelson, MD From the director of the Johns Hopkins Kimmel Cancer Center

Key Phase III study on which the opinion was baseda ❖❖ Metastatic NSCLC patients who received early palliative care survived 2.7 months longer than those receiving standard oncology care alone

❖❖They also had significantly higher quality-of-life scores and fewer depressive symptoms a

emel JS, Greer JA, Muzikansky A, et al. Early T palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742, PMID: 20818875.

be available to assist with patient, family and symptom management.”

There are significant barriers that keep patients from palliative care services. One study, presented in 2011 at the ASCO annual meeting, showed that more than half of lung cancer patients do not access supportive care after cancer diagnosis and often cite lack of awareness and lack of physician referral as barriers.

Workforce shortages often are cited as a problem, also. There are not enough oncologists and palliative care physicians for the disease burden in the United States. Clinic- and communitybased palliative services are extremely limited and there are not yet enough to meet the anticipated growing demand, said the study authors.

With limited funding available for patients before they formally enter hospice care, reimbursement is a major issue as well. Future priorities include developing aligned health policy and reimbursement mechanisms to facilitate evidence-based palliative care models, said the report authors.

They noted that PCOs reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision-making and identify questions and settings for further research. PCOs are not continually updated and cannot account for individual variation among patients.

It is the responsibility of the treating physician or other health care provider to determine the best course of treatment for the patient.

—Christina Frangou

Podcast Series

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12

PRN

Clinical Oncology News • JUNE 2012

Community Oncology

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

Spotlight on selected articles from the Journal of Clinical Oncology and Blood

QUESTIONS

1.

True or False. Adopting new therapies based on studies that use an end point that effectively lowers the bar for declaring activity in new drugs— for example, progression-free survival (PFS)—may be of little value to cancer patients.

2.

True or False. The case-cohort study by Vincent Koppelmans, MD, and colleagues at Erasmus Medical Center in Rotterdam, The Netherlands, demonstrated that survivors of breast cancer who received adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate and fluorouracil), an average of 21 years ago, performed on neuropsychological tests comparably to random population controls.

3.

True or False. The randomized, double-blind Phase III ZEPHYR trial [Zactima Efficacy Trial for NSCLC Patients with History of EGFR-TKI and Chemo-Resistance] of vandetanib (Caprelsa, AstraZeneca) versus placebo demonstrated superiority in terms of overall survival (OS) in patients with advanced non–small cell lung cancer (NSCLC) following failure of prior treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and one or two chemotherapy regimens.

4. True or False. Studies by the multicenter European Early Lung Cancer Detection Group (EUELC) project

indicate that high expression of the three key elements in the vascular endothelial growth factor (VEGF) pathway—VEGF, VEGFR1 and VEGFR2 protein expression—is associated with a good prognosis in patients with stage I squamous cell carcinoma (SCC) but not in patients with adenocarcinoma.

5.

but for which the 21-gene Oncotype DX recurrence score is less than 25 to assess the role of adjuvant chemotherapy in this subtype of breast cancer.

9.

True or False. Research on psychosocial interventions indicates that when the caregiver and patient dyad is treated as the unit of care, important synergies are achieved that contribute to the well-being of both members.

True or False. Positron emission tomography (PET) scan is not sufficiently sensitive to detect positive axillary lymph nodes as demonstrated in a study from Ontario in 325 women with newly diagnosed, operable breast cancers.

6.

10. True or False. The TET (ten-

True or False. Research-based psychosocial interventions have profound, positive effects on many aspects of life for cancer patients and their caregivers.

7.

True or False. The risk for breast cancer death after any surgical approach to ductal carcinoma in situ is extremely low, ranging from between 2.3% and 4.7% at 15 years in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 and B-24 trials of breastconserving surgery to less than 1% after mastectomy, and is further decreased by administration of adjuvant endocrine therapy with tamoxifen.

8.

TrueorFalse.TheRxPonder(SWOG S1007) trial is enrolling women with positive axillary nodal breast cancer that is estrogen receptor (ER)-positive

eleven-translocation) oncogene family member 2 (TET2) gene has been identified as mutated in myeloid disorders.

The TET2 protein is an enzyme believed to be involved in the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA.

11.

True or False. In acute myeloid leukemia (AML), azacitidine (Vidaza, Celgene) following reduced intensity conditioning (RIC) and allogeneic stem cell transplantation (allo-SCT) has potential for augmenting the graftversus-leukemia (GVL) effect without increasing the risk for graft-versus-host disease (GVHD).

12. True or False. Testing tumor

V600E is recommended in those cases where immunohistochemistry (IHC) results indicate the absence of MLH1 protein expression, which correlates with sporadic colorectal cancer (CRC) and is rarely found in patients who have Lynch syndrome.

13.

True or False. Thirty percent of patients with low-grade or follicular lymphoma (FL) who responded to initial rituximab (Rituxan, Biogen Idec/ Genentech) therapy failed to respond to repeat rituximab therapy, indicating that initially sensitive patients can acquire rituximab resistance.

14. True

or False. Ofatumumab (Arzerra, GlaxoSmithKline) monotherapy may have greater clinical activity in patients with FL that is refractory to rituximab.

15.

True or False. A large retrospective analysis performed by the Center for International Blood and Marrow Transplant Research (CIBMTR) showed that transplantation from match-related (MRD) and match-unrelated (MUD) donors resulted in similar survival for patients with AML.

DNA for the somatic BRAF mutation

for answers see CONUNDRUMS, page 24 

New Breast Cancer Susceptibility Gene Identified An international team of researchers has identified a new breast cancer susceptibility gene, XRCC2 (Am J Hum Genet 2012;90:734-739, PMID: 22464251).

“We found a gene that when mutated predisposes to breast cancer, and this adds to the small collection of breast cancer susceptibility genes previously identified,” senior author Melissa C. Southey, PhD, the head of the Genetic Epidemiology Laboratory at the University of Melbourne in Australia, told Clinical Oncology News.

By exome sequencing families with multiple individuals affected by breast cancer, the researchers identified two families with XRCC2 mutations.

Subsequently, two further studies were conducted: one, a population-based case-control mutation screening study

of XRCC2 and the other an additional mutation screening of XRCC2 in index cases from multiple-case families and in male breast cancer cases. The researchers identified six distinct, rare variants in the gene that were predicted to severely affect protein function.

Two of these variants were proteintruncating mutations and four resulted in missense changes.

Dr. Southey, also a group leader of Australia’s Victorian Breast Cancer Research Consortium, said the study would be relevant to “clinical oncologists who work with families with multiple cases of breast cancer.

This is another gene they can test for.”

No commercially available tests have yet been developed based on these findings; however, Dr. Southey said, “I imagine there will be [tests] soon, to help women determine their personal risk for breast cancer. Some treatment choices might be influenced by knowing if a woman has a mutation in XRCC2.”

In the paper, the researchers noted that specific targeted treatments such as poly-ADP ribose polymerase (PARP) inhibitors might benefit patients whose breast cancer is associated with homologous-recombination DNA repair dysfunction, as is the case with deleterious XRCC2 mutations.

The study is the first report of massively parallel sequencing being used in the discovery of a breast cancer susceptibility gene, said Dr. Southey,

who called this “one of the really exciting things about this paper.” She added, “We anticipate finding more genes related to susceptibility to breast cancer by applying this methodology.”

Massively parallel sequencing has been used previously to identify the genetic explanation for relatively simple autosomal-dominant diseases, Dr. Southey stated. “This is the first report applying it to a complex disease. Now the world’s our oyster.” Dr. Southey is currently using the technique to study genetic predisposition to prostate and colorectal cancers. “A large number of genetic research groups are applying this technology.”

—George Ochoa Dr. Southey reported no relevant financial disclosures.

SOLID TUMORS

Clinical Oncology News • June 2012

13

Breast

T-DM1: Significantly Better Safety Profile for Breast Cancer San Antonio—New results from a Phase II trial reveal that patients with breast cancer who receive T-DM1 (Genentech) have an improved quality of life (QoL) compared with patients who receive the traditional therapy of trastuzumab (Herceptin, Genentech) and docetaxel.

“This novel delivery system improves the tolerability and limits the toxicity experienced by patients,” said Sara Hurvitz, MD, the director of the Breast Oncology Program at the University of California in Los Angeles, who headed up the study. “I believe this is highly clinically meaningful to patients, especially patients with advanced breast cancer where palliation is a key objective of therapy.”

T-DM1 combines the biological HER2targeted properties of trastuzumab with an anti-microtubule derivative of maytansine called DM1, a highly potent chemotherapy. T-DM1 selectively delivers DM1 to HER2-positive tumor cells; DM1 is released within the tumor cells and thus spares healthy tissue.

In the study, 137 patients with HER2positive locally advanced breast cancer or metastatic breast cancer who had not received prior chemotherapy for metastatic disease were randomized to T-DM1 or docetaxel plus trastuzumab.

At the 2011 European Multidisciplinary Cancer Congress, researchers reported that patients in the T-DM1 arm had a longer median progression-free survival (PFS) than patients in the placebo arm (14.2 vs. 9.2 months; P=0.0353).

At the most recent San Antonio Breast Cancer Symposium, researchers presented data on QoL (poster p1-12-02).

Approximately 30% of patients in the traditional therapy arm stopped one or both drugs because of adverse events compared with 7% of patients in the T-DM1 arm. A total of 132 patients filled out the Functional Assessment of Cancer Therapy-Breast Trial Outcome Index (FACT-B TOI) at baseline and at least once after baseline. Patients receiving trastuzumab and docetaxel had worsening FACT-B TOI scores much earlier than patients receiving T-DM1 (3.5 vs. 7.5 months; hazard ratio, 0.58; P=0.022).

An exploratory analysis showed an average difference of 3.65 in FACT-B TOI scores (P=0.023). This was chiefly driven by improved physical well-being scores (mean difference, 2.28; P=0.002) in the T-DM1 arm, but this was below the five-point change considered clinically meaningful.

Five of the seven physical wellbeing items showed significantly better scores in the T-DM1 arm. These included lack of energy (P=0.011), trouble meeting needs of family (P=0.025), bothered by side effects (P<0.001), feeling ill (P=0.016) and forced to

spend time in bed (P=0.015).

According to Robert Carlson, MD, an oncologist at Stanford Comprehensive Cancer Center in Stanford, Calif., the QoL patient-reported outcomes come as “no surprise” because the drug has not been associated with any nausea, vomiting, alopecia or neutropenia in Phase I/II trials.

“Compared with standard FDAapproved chemo plus trastuzumab in terms of safety, T-DM1 would appear to

be the winner by any measure,” said Dr. Carlson. “The only thing that you may have to be mindful of with T-DM1 is transient and reversible thrombocytopenia, usually not associated with any clinical bleeding features, and reversible transaminase elevation. But apart from those two adverse events, the safety profile appears to be particularly clean and superior to standard chemo and Herceptin.”

Researchers are anxiously awaiting

results from three Phase III trials of T-DM1 currently under way, including EMILIA (Trastuzumab-MCC-DM1 vs Capecitabine + Lapatinib) that is expected to report data during 2012.

—Kate O’Rourke Dr. Hurvitz has received research grants from Genentech and Sanofi. Dr. Carlson disclosed serving as an unpaid advisor/ consultant to Genentech/Roche.

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Dannemiller and Athena Education Group gratefully acknowledge an educational grant from the Cancer Treatment Centers of America® in support of this continuing medical education activity.

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SOLID TUMORS

Clinical Oncology News • June 2012

Lung

Photos and text provided by Cleveland Clinic Taussig Cancer Institute.

14

Cleveland Clinic Taussig Cancer Institute:

Multidisciplinary Care and Breakthrough Research

F

or the next three months, Clinical Oncology News is pleased to provide commentaries on important research affecting oncology from experts at Cleveland Clinic’s Taussig Cancer Institute.

At Cleveland Clinic Taussig Cancer Institute, more than 250 cancer specialists, researchers, nurses and technicians are dedicated to developing and applying the latest and most effective medical techniques to achieve long-term survival and improve the quality of life of more than 10,000 new cancer patients every year. Because of Taussig Cancer Institute’s patientcentered approach to care, leading-edge treatments, innovative research, access to clinical trials and stateof-the-art medical technologies, U.S. News & World Report has ranked Cleveland Clinic among the top 10 cancer centers in the nation for two consecutive years.

Taussig Cancer Institute’s oncologists work closely with multidisciplinary teams of specialists in digestive disease, urology, neurology and women’s health, among others, to provide patients with innovative diagnostic techniques, the latest chemotherapy or anticancer agents, surgical options, access to clinical trials and novel therapies and genetic counseling.

Taussig Cancer Institute’s physicians are nationally and internationally known for their contributions to cancer research and their ability to deliver superior outcomes for their patients. In 2011, 16 Taussig physicians were included in the seventh edition of Castle Connolly’s America’s Top Doctors for Cancer. Taussig staff also authored more than 650 publications in highimpact journals, including results from the pivotal Phase III AXIS 1032 trial published in The Lancet (2011;378:19311939, PMID: 22056247), whose lead author was Brian Rini, MD, staff physician in the Department of Solid Tumor Oncology. In January, the FDA approved axitinib, the drug under investigation in the AXIS 1032 trial, for the treatment of advanced renal cell carcinoma.

Cleveland Clinic has a rich history in oncology research. Since the Clinic’s inception in 1921, Taussig researchers have been at the forefront of cancer breakthroughs. Cleveland Clinic physicians and scientists have developed new surgical techniques, discovered new treatments and uncovered key information about cancer cells that have resulted in significant changes in the way patients are screened, diagnosed and treated.

Providing cancer care close to home is integral to

Taussig Cancer Institute’s mission. In addition to providing care to more than 28,000 patients annually on the main campus, treatment is offered at 12 other locations in northeast Ohio and at Cleveland Clinic Florida. Recently, Taussig Cancer Institute entered into its first adult medical oncology affiliation with Cadence Health in Winfield, Ill. Once the oncology program is fully implemented, Cadence Health patients will have access to treatment protocols, clinical trials and additional research opportunities.

The physicians at Cleveland Clinic Taussig Cancer Institute are inspired by their patients to challenge today’s status quo and develop new ways to treat cancer—with the ultimate goal of eradicating it in the future.

CD26 Expression Is Mesothelioma Therapy Biomarker From Clinical Cancer Research

A

recent study has found that the CD26 glycoprotein is a significant biomarker for predicting chemotherapeutic response for malignant pleural mesothelioma (MPM), a therapy-resistant neoplasm that currently lacks any established indicator of therapeutic responsiveness.

MPM is notoriously aggressive, with most patients succumbing within 10 to 17 months after noticing their first symptoms. CD26 plays a complex role in tumor behavior, which varies depending on tumor type and the microenvironment. For some subsets

of T-cell non-Hodgkin’s lymphomas and leukemias, for example, CD26 is an indicator of aggressive disease. CD26 also is a prognostic marker in B-cell chronic lymphocytic leukemia, as well as a therapeutic target, as reported in recent studies with anti-CD26 monoclonal antibody treatment for lymphoma and renal cell carcinoma.

Keisuke Aoe and colleagues, based largely in Japan, have studied CD26 extensively and felt earlier findings suggested that it may be a clinically significant biomarker for MPM. In this study, published in Clinical Cancer Research (2012;18:1447-1456, PMID: 22261805), the investigators examined tissue

EXPERT INSIGHT Patrick Ma, MD, MS Director, Aerodigestive Oncology Translational Research Cleveland Clinic Taussig Cancer Institute Assistant Professor of Molecular Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

D

r. Keisuke Aoe and his co-workers reported in Clinical Cancer Research their expression analysis of dipeptidyl peptidase IV cell surface glycoprotein CD26 in MPM. The authors retrospectively studied the biopsies or surgical formalinfixed, paraffin-embedded specimens of 79 MPM patients using standard

immunohistochemistry techniques.

They found that 73.4% of MPM expressed CD26 on the surface, the majority of which were epithelioid and biphasic types, whereas the sarcomatoid type was found to lack CD26 surface expression. A higher level of CD26 expression was found to be predictive of better response to

samples from 79 patients with MPM who had undergone surgery or biopsy.

Analysis found that 73.4% of the patients expressed CD26 on the cell membrane. More specifically, although most epithelioid and biphasic types of MPM expressed CD26 on the cell membrane, the sarcomatoid type of MPM did not show surface expression.

A trend was noted of an association between response to chemotherapy and CD26 expression (P=0.053), with greater degree of overexpression indicating better response to chemotherapy.

CD26 expression was associated with improved survival in patients receiving chemotherapy, and CD26

expression also was associated with a better prognosis in those patients whose chemotherapy did not contain pemetrexed (Alimta, Lilly; mean survival time, 14.2 vs. 7.4 months; P=0.0042). The researchers also noted through in vitro and microarray studies that those mesothelioma cells that highly expressed CD26 also were highly proliferative.

The researchers found that CD26 expression is “closely linked to cell cycle regulation, apoptosis and chemotherapy resistance.” They concluded that CD26 overexpression is a biomarker that can help predict response to chemotherapy in patients with MPM.

chemotherapy treatment. However, it was not found to be prognostic of survival, despite its low expression in the sarcomatoid type, which is known to be poorly prognostic.

The authors conducted various survival prognostic analyses among patients treated with different chemotherapeutic regimens (pemetrexed vs. non–pemetrexed-based) and had mixed results. Overall, this study highlights the difficulties in conducting biomarker analysis, especially in a rare malignancy type such as MPM. Ultimately, validation of potential biomarkers needs to be carried out in prospective studies in properly designed randomized treatment arms.

Clear differentiation between whether a biomarker is predictive (of treatment response) versus prognostic (of

survival outcome irrespective of treatment), or both, needs to be made.

In this study, CD26 is thought to have an important role in T-cell biology and overall immune function, and has multifunctional characteristics, with complex biological functions that likely are dependent on tumor type and the stromal microenvironment. These intrinsic complex properties of the molecule might confer more variables and difficulties in biomarker analysis. Although it may be of potential as a biomarker of treatment response in MPM, further studies with larger cohorts, and ideally in prospective trials, would be warranted for establishing its eventual clinical utility.

Dr. Ma reported no financial disclosures relevant to this study.

SOLID TUMORS

Clinical Oncology News • June 2012

Pancreatic

Intraoperative Radiotherapy, Yes; External Beam, No From the International Journal of Radiation Oncology, Biology, Physics

A

Japanese institution’s threedecade-long experience with intraoperative radiation therapy (IORT), administered with or without external beam radiotherapy (EBRT), for pancreatic cancer has demonstrated excellent local control and few cases of severe late toxicity. Additionally, the overall survival (OS) of patients treated with IORT

with or without EBRT significantly improved over time.

The records of 322 patients treated with IORT with or without EBRT from 1980 to 2009 were reviewed. 192 patients who had neither distant organ metastases nor dissemination at the time of surgery were included in the study, led by Keiichi Jingu, MD, of the Tohoku University School of Medicine in Sendai, Japan (Int J Radiat Oncol Biol Phys 2012 Mar 21.

[Epub ahead of print], PMID: 22445002).

Gross total resection was performed on 83 patients (48 patients, R0; 35 patients, R1), biopsy or palliative resection was undertaken on 109 patients, adjuvant EBRT was performed on 53 patients, and adjuvant chemotherapy was administered to 124 patients. Disease recurrence occurred in 163 patients, as did local failure in 35 patients. The two-year local control (LC) and OS rates were 71.0% and 16.9%, respectively. OS improved significantly through the decades (two-year

OS: 25.0% for 2000-2009; 18.8% for 19901999; and 4.2% for 1980-1989; P<0.001).

Analysis showed that the degree of resection and use of adjuvant chemotherapy exerted a significant effect on OS. There were three cases of severe gastrointestinal (GI) bleeding and one ileus.

The authors noted that the second and third duodenal portions may be given high doses of irradiation in patients with unresectable pancreas head cancer.

EBRT did not correlate with any improvements in LC or OS; IORT, on the other hand, has allowed for excellent LC and improvements in OS.

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Submissions should be emailed as a Word document to Clinical Oncology News managing editor Gabriel Miller at gmiller@mcmahonmed.com.

‘Change in Medical Oncology or Hematology/Oncology’.

EXPERT INSIGHT Kevin Stephans, MD Associate Staff Physician, Department of Radiation Oncology Cleveland Clinic Taussig Cancer Institute Associate Professor of Medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

E

BRT for pancreatic cancer has been challenging due to the proximity of sensitive dose-limiting normal tissue, such as the stomach and small bowel. This has limited the deliverable radiation dose and led to both acute and late treatment-related toxicity. IORT is a logical alternative due to the ability to displace the sensitive tissue prior to radiation.

IORT at present, however, remains unproven, with inconsistent and limited supporting level 1 evidence.

Jingu et al’s series is a valuable addition. The 71% rate of two-year LC with IORT is an improvement on historical standards where approximately half of unirradiated patients typically experience local failure as part of recurrence. Interestingly, adding EBRT did not appear to confer additional LC or affect OS. This raises an interesting question of whether IORT might effectively substitute for EBRT, thus simplifying the overall treatment course.

There was a 2.1% rate of grade 4 or 5 late GI toxicity, notably occuring in patients treated without supplemental external beam. Further investigation would be insightful, as toxicity occurred in four patients at doses of 20 to 25 Gy, typically considered safe for intraoperative treatment. The potential effect of recurrent tumor, other cancer-directed therapies and volume of sensitive tissue radiated should be considered.

Dr. Stephans reported no financial disclosures relevant to this study.

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HEMATOLOGIC DISEASE

Clinical Oncology News • June 2012

Myeloma

Bortezomib Regimen Improves Primary Amyloidosis Survival From Blood

A

three-drug regimen of cyclophosphamide, bortezomib (Velcade, Millennium) and dexamethasone (CVD) as initial therapy or upon relapse for amyloid light-chain (AL; primary) amyloidosis has proved effective in improving both two-year progression-free survival (PFS) and overall survival (OS).

Bortezomib previously was found to be effective in treating AL amyloidosis, with and without dexamethasone, as well as myeloma. The London-based researchers, headed by Christopher P. Venner, noted excellent results in myeloma trials in which

EXPERT INSIGHT Jason N. Valent, MD Associate Staff Physician, Department of Regional Oncology Cleveland Clinic Taussig Cancer Institute

A

L amyloidosis treatment regimens that include bortezomib are able to produce rapid and potentially deep hematologic responses.1 Hematologic VGPR or better is a reliable surrogate end point for predicting improved OS in patients with AL amyloidosis.2 The present study by Venner provides more evidence that threedrug combinations, including an alkylating agent, a proteasome inhibitor and a corticosteroid, yield high rates of hematologic response. Complete hematologic response in untreated patients was 65%, which was similar to the 60% reported in another CVD

a steroid/alkylator was used in combination with bortezomib. They decided to attempt a similar strategy against AL amyloidosis, using CVD for initial therapy and upon relapse. The study was published in Blood (2012;119:4387-4390, PMID: 22331187).

This retrospective series included 43 patients from the National Amyloidosis Centre of London. Median age was 54 years; 58% were male. The organs involved were cardiac, 74%; renal, 79%; liver, 23%; and other, 35%; 18% reported peripheral neuropathy and 21% reported autonomic neuropathy. Mayo Clinic staging was available for most patients, of whom 43% were stage III. The CVD regimen was bortezomib, 1 mg/m2 IV, days 1, 4, 8 and 11 (increasing

to 1.3 mg/m2 if tolerated); oral cyclophosphamide, 350 mg/m2, days 1, 8 and 15; and oral dexamethasone, 20 mg, days 1, 4, 8 and 11 (increasing to 20 mg every two days if tolerated). The researchers aimed for a maximum of eight cycles. The maximal hematologic response was defined as the lowest attained involved light-chain value. A reduction in the difference in free light-chain (dFLC) value of 50% to 90% was considered a partial response and a reduction of more than 90% defined a very good partial response (VGPR).

The overall hematologic response rate was 81.4%, of which 41.9% achieved a complete response (CR) and 51.4% achieved a VGPR. Patients who received CVD therapy initially

had a CR rate of 65% and VGPR rate of 66.7%. Two-year PFS was 66.5% in initial patients and 41.4% in relapsed patients. Two-year OS was 97.7%, and was 94.4% for those with Mayo stage III disease.

The authors concluded that CVD was highly effective for AL amyloidosis, and the hematologic responses appeared “durable,” especially in those patients achieving CR or VGPR. Because CVD spares stem cells, the improvement in organ function may possibly allow later stem cell transplant in patients previously deemed ineligible. “The regime is tolerated by stage III patients with possible improvement in outcomes in this poor-risk group,” the investigators wrote.

study by Mikhael.3 Among all patients treated in the Venner study, 51% experienced a hematologic VGPR. The time to maximal response was 4.1 months.

Neurologic toxicity occurred in 30% of the patients, although the grade of neuropathy was not reported. It was reported that 14% of patients discontinued therapy due to the development of neuropathy.

There are several challenges in interpreting results from AL amyloidosis trials. Sample sizes often are small in prospective trials, including novel agents such as bortezomib. Phase II trials have used a variety of bortezomib dosing schedules, complicating toxicity assessment. Furthermore, there is a lack of prospective randomized trials comparing bortezomib-based therapy to alkylating agent–based therapy and comparing three-drug regimens to two-drug regimens. Additionally, the use of high-dose chemotherapy and autologous peripheral blood progenitor cell rescue is beyond the scope of this discussion.

As stated in the Venner article, further study with novel agent combination

therapy in AL amyloidosis is needed. It would be ideal to identify the optimal dosing schedule and route of administration of bortezomib in patients with AL amyloidosis. Weekly and subcutaneous administration of bortezomib minimizes neurologic side effects but subcutaneous administration may be complicated by profound peripheral edema in amyloid patients. Larger trials investigating the role of novel agents before and/or after high-dose chemotherapy and autologous peripheral blood progenitor cell rescue also are warranted in eligible patients with AL amyloidosis.4 The obvious question is whether or not the results and limited toxicity of bortezomib-containing three-drug regimens establish a new “standard” treatment for AL amyloidosis. An ongoing Eastern Cooperative Oncology Group trial comparing melphalan and dexamethasone with or without bortezomib will help answer this question in untreated patients with AL amyloidosis. In the absence of trial participation, the three-drug regimen of bortezomib,

cyclophosphamide and dexamethasone is acceptable treatment for AL amyloidosis, with rapid and high rates of hematologic response documented in the Venner study.

References 1. Reece D, Sanchorawala V, Hegenbart U, et al. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1/2 study. Blood.

2009;114:1489-1497, PMID: 19498019.

2. Palladini G, Dispenzieri A, Gertz M, et al. Validation of the criteria of response to treatment in AL amyloidosis. Blood.

2010;116:1364a.

3. Mikhael J, Schuster S, Jimenez-Zepeda V, et al. Cyclophosphamide-bortezomibdexamethasone (CYBORD) produces rapid and complete hematological response in patients with AL amyloidosis. Blood. doi: 10.1182/blood-2011-11-390930. Feb 13, 2012 [Epub ahead of print].

4. Landau H, Hassoun H, Bello C, et al.

Consolidation with bortezomib and dexamethasone following risk-adapted melphalan and stem cell transplant in systemic AL amyloidosis. Amyloid.

2011;18(suppl 1):130-131, PMID: 21838462.

Dr. Valent reported no financial disclosures relevant to this study.

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On a monthly basis, Clinical Oncology News highlights key studies from the journals and provides guest clinician perspectives to help you stay up to date.

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Clinical Oncology News • June 2012

17

Clinical Trials FilE Slug

CARDIOTOXICITY problem is and how many cancer drugs may be of concern.”

Dr. Witteles and other U.S. physicians are calling for significant changes in how cardiac adverse events (AEs) are reported in clinical trials involving newer chemotherapeutic agents. They have found significant evidence of underreporting of the possible cardiac damage from cancer drugs. They claim the problem is now placing a significant number of oncology patients at an increased risk for heart failure.

In a commentary published online on March 26 in the Journal of Clinical Oncology (doi: 10.1200/JCO.2011.40.4012), Dr. Witteles wrote that urgent reforms are needed to standardize measurements of the potential toxicity of cancer drugs during clinical trials in order to prevent the publication of misleading results, which have already appeared in such prestigious scientific journals as The Lancet and The New England Journal of Medicine. “It’s a major issue when adverse events aren’t being counted in clinical trials, and this has led to a profound underappreciation of the risk for heart failure and other adverse cardiac events,” said Dr. Witteles.

Dr. Witteles, who is a cardiologist at Stanford Hospital & Clinics, and coauthor Melinda Telli, MD, assistant

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PROOF lAyOuT APPROVED PROOF 1: 3/13 EDiTOR: gabe cancers. 1ST What the two authors found in the journal articles.” iniTiAlS AnD DATE ART DiRECTOR: Frank REV 1: 3/16 was a complete REV 2: 3/19 The authors said sunitinib is a good Full name of Senior editor disconnect between project REV 3: 3/21 Editor reported incidences of cardiac toxicities example of how the current method REV 4: continued from page 1  Project no.

Copy editor REV 5: of measuring cardiac side effects durin journal articles on one hand and the REV 6: Revision # Rev 3 Sales professor of oncology at Stanford, FDA’s drug labeling on the other. The ing cancer drug trials is inadequate. layout date/ June 6, 2012 7:50 AM Production became concerned time when they started labeling raised red flags, indicating that Although the commentary focuses soleEditorial date/of patients seeing a surprising number cliniciansCirculation should be aware of the pos- ly on sunitinib, the authors believe that time with heart failure Trim who were being sible sideCOMMEnTS: effects of cardiac damageKEywORDS: in studies of other cancer drugs have simsize treated with sunitinib (Sutent, Pfizpatients using the drug.

This was a very ilar methodologic problems and are Color specs er). “That’s what first raised App@itunes.indd our eye- different picture from what had been prone to the same underreporting of File path brows,” said Dr. Witteles. presented in the journal articles. “It side effects.

Over the past five years, the FDA didn’t make any sense,” said Dr. Wittel“Sunitinib is just the clearest examapproved sunitinib for the treatment of es. “The labeling warned of a high inci- ple, but the same problems can be renal cell carcinoma (RCC) and certain dence of heart failure during the clini- and undoubtedly are present in other see CARDIOTOXIciTY, page 18  types of pancreatic and gastrointestinal cal trials that was not even mentioned Current file:

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Clinical Oncology News • June 2012

Clinical Trials

Table. Potential Cardiovascular Events Associated With Common Chemotherapies

CARDIOTOXICITY continued from page 17 

trials. Some may not be as obvious,” said Dr. Witteles in an interview with Clinical Oncology News. “We saw way too many patients developing heart failure and we started questioning what was going on. The irony is that the data were there from the beginning, but it was just misrepresented.”

For example, in October 2006, the results of the first Phase III study of sunitinib published in The Lancet stated that there was no evidence of a decrease in left ventricular ejection fraction (LVEF) measurements (Lancet 2006;368:13291338, PMID: 17046465). Yet, the FDA’s 2007 labeling of sunitinib for use in RCC treatment, which was based on the same data set from the same trial, stated that 11% of trial subjects on sunitinib and 3% on placebo developed EF measurements below the lower limit of normal.

The underreporting is very worrisome because many clinicians read journal articles on new drugs but few read a drug’s labeling, according to Dr. Witteles. The three sunitinib studies referred to in the article—two in The New England Journal of Medicine (2007;356:115-124, 2011;364:501-513) and one in The Lancet—were all funded by Pfizer, which raises the potential of conflict of interest.

It is clear that these inconsistencies in reporting are partly due to an inadequate method of measuring AEs in clinical trials. The current system allows for too much variability in how individual investigators at different sites can grade possible AEs. For instance, there are inconsistencies in defining what an AE is and whether an AE may be ignored if there are questions as to whether the event was caused by the drug treatment. Additionally, there currently is no requirement that the results from primary data sets— such as an imaging finding or a laboratory test—be reported at all. The system places more reliance on the judgments made by the individual site investigator.

“Some subjective findings, such as the description of a rash or the qualitative assessment of a symptom such as shortness of breath, are necessarily reliant on the site investigator’s judgment. However, in the case of objective findings, such as laboratory findings like decreased platelets or imaging findings like drops in LVEF, it is far more relevant to focus on the actual validated data, which is not dependent on the idiosyncrasies of a site investigator remembering to list and properly categorize the event as an AE,” said Dr. Witteles.

The figures reported by the FDA on sunitinib’s drug label were based on the real decreases in cardiac function as reflected by the primary data, which enabled the agency to come closer to determining the actual number of cardiac

AEs, according to Dr. Witteles. He and Dr. Telli suggest that whenever there has been a signal of heart toxicity in a drug trial, routine cardiac monitoring should be built into the trial. This is one of several recommendations they make to assure reliable, accurate and consistent reporting of cardiac safety in cancer trials (see recommendations sidebar).

“It is a problem with the way toxicity is reported. The way it is graded and listed can vary significantly depending on what the investigator wants to do. The problem is with the reporting system and it has to be much more rigorous, and the objective information should always trump the subjective information,” said Dr. Telli in an interview with Clinical Oncology News. “One doctor may call something one thing and another doctor may call it something else.”

Chemotherapy

Potential Cardiovascular Adverse Events

Anthracyclines and anthraquinolones

Acute myocarditis, arrhythmia, CHF, LVD

Bevacizumab

GI tract bleeding, hypertension, thromboembolism

Capecitabine, 5-fluorouracil, cytarabine

CHF, cardiogenic shock, ischemia, pericarditis

Cyclophosphamide

Mitral regurgitation, neurohumoral activation

COX-2–specific inhibitors

Thromboembolism

Imatinib

Arrhythmias, angioedema, CHF, LVD

Paclitaxel, vinca alkaloids

Atrioventricular block, CHF, sinus bradycardia, hypotension, ischemia, ventricular tachycardia

SERMs

LDL/HDL modulation, thromboembolism

Sorafenib

Arrhythmias, hypertension

Sunitinib

Arrhythmias, hypertension

Thorax irradiation

LVD, myocardial fibrosis, valvular heart disease

Trastuzumab

Arrhythmias, angioedema, CHF, LVD

CHF, congestive heart failure; COX, cyclooxygenase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVD, left ventricular dysfunction; SERMs, selective estrogen receptor modulators

‘The labeling warned of a high incidence of heart failure during the clinical trials that was not even mentioned in the journal articles.’

—Ronald Witteles, MD

‘We need to make sure that we don’t trade the adverse impact of cancer for another disease, the largest killer in the world, heart disease.’

—Greg Hundley, MD

Problems Go Beyond One Drug Current anticancer therapies commonly have unintended cardiotoxic consequences. Newer chemotherapeutic agents are being developed and some may have significant potential for cardiotoxicity, according to Ronald Krone, MD, a cardiologist at Washington University School of Medicine in St. Louis. He claims that current cancer therapies may cause overt damage to the heart and circulation.

Additionally, they may alternately exacerbate or mask existing heart disease.

“We have known for a long time that the breast cancer drugs can cause serious heart problems,” Dr. Krone told Clinical Oncology News. “Tyrosine kinase inhibitors could be involved in the heart. We may need to start monitoring patients on these medications for cardiac effects or start a registry. There may be a very serious problem. We need to know the actual incidence.”

Greg Hundley, MD, a professor of cardiology at Wake Forest Baptist Medical Center in Winston-Salem, N.C., agrees with Dr. Krone. He is currently conducting magnetic resonance imaging (MRI) studies to see if it is possible to predict which patients will suffer heart damage as a result of chemotherapeutic agents.

“Now, the game has changed. The oncologists have become very effective at treating cancer and so we need to start thinking about cardiac issues. We need to make sure that we don’t trade the adverse impact of cancer for another disease, the largest killer in the world, heart disease,” said Dr. Hundley.

He said in breast cancer there is now improved survival and a growing number of clinicians are seeing patients who are eight to 10 years out from treatment and they are having cardiac events. “They are turning up through billing databases and

SOLID TUMORS

Clinical Oncology News • June 2012

Renal

Monitor Thyroid During Sunitinib, Sorafenib Therapy From European Journal of Cancer

A

large German cohort study has better defined the incidence of hypothyroidism as a serious adverse drug reaction in patients with advanced or metastatic renal cell carcinoma taking either sunitinib (Sutent, Pfizer) or sorafenib (Nexavar, Bayer and Onyx). For both of these drugs, the potential for hypothyroidism appears higher than current labeling suggests, and routine monitoring of thyroid functioning is suggested.

The study, whose lead author was Sandra Feldt, PhD, appeared in the European Journal of Cancer (2012;doi:10.1016/j. ejca.2012.01.036). The authors note that both sunitinib and sorafenib are

EXPERT INSIGHT Brian I. Rini, MD Staff Physician, Department of Solid Tumor Oncology Cleveland Clinic Taussig Cancer Institute

I

t is well described that patients receiving inhibitors of the vascular endothelial growth factor receptor, prominently including sunitinib and

it is making us ask questions now about whether we should start doing surveillance for cardiac markers,” said Dr. Hundley in an interview. “Should we start trying to detect subclinical cardiac disease?

The answer appears to be yes.”

He noted that some medical centers are now starting to monitor oncology patients for subclinical cardiac disease. Inexpensive generic therapies can cut cardiovascular risk in high-risk populations and Dr. Hundley’s team is now investigating how MRI imaging may be used to identify those who have damaged heart function and blood vessels following cancer therapy.

“We don’t know yet if this needs to be done in patients with renal cell carcinoma on sunitinib. If you are going to make a clinical recommendation, we need a lot more information,” said Dr. Hundley. “We are starting to realize that there is another frontier and it is called cardio-oncology. We need to merge the expertise of oncologists with the expertise of cardiologists.

They need to be working together to

multikinase inhibitors (MKIs) and represent significant advances in the treatment of renal cell carcinoma. Sunitinib has become the standard therapy for patients receiving first-line treatment of metastatic renal cell carcinoma; likewise, sorafenib is the standard therapy for second-line treatment in these patients. These agents also have been approved for gastrointestinal stromal tumors and hepatocellular carcinoma.

Hypothyroidism can occur early or late during treatment with MKIs. The rates of hypothyroidism requiring therapeutic intervention with a thyroid hormone (TH), usually levothyroxine, have ranged from 14% to 46% in sunitinib studies and 3% to 6% in sorafenib studies, but the number of patients in these trials has been

limited and the methodologic differences have been substantial. The researchers aimed to obtain a more reliable understanding of hypothyroidism in these patients by accessing a larger representative database.

The authors reviewed claims data filed at pharmacies that covered more than 80% of all German prescriptions.

Patients who were identified by filling a new prescription for either sunitinib or sorafenib between June 2006 and December 2007 were followed. If these patients went on to fill a prescription for TH therapy, then that was considered an event of interest. The study found that 178 of 1,295 patients administered sunitinib (13.7%) and 77 of 1,214 patients taking sorafenib (6.3%) received TH therapy. The incidence

rates were 24.2 and 12.1 per 100 personyears, respectively, and the unadjusted hazard ratio for TH therapy for sunitinib compared with sorafenib was 2.0 (95% confidence interval, 1.5-2.6).

The authors concluded that clinicians should obtain baseline and treatment measurements of thyroid function for those taking both sunitinib and sorafenib. They cautioned, however, that TH therapy should not be prescribed for cancer patients with only slightly increased serum thyroid-stimulating hormone (TSH) levels who are asymptomatic to hypothyroidism because TH therapy “leads to fast and complete correction of increased TSH values and should not restrict the use of sunitinib and sorafenib in malignant diseases.”

sorafenib, can experience abnormalities of thyroid function.1,2 This appears most commonly to be hypothyroidism, and has been reported to be more common with sunitinib. The mechanism of this particular toxicity is as yet undefined. Furthermore, whether this toxicity may serve as a predictive biomarker of response to these agents is debated.3 The current report by Feldt et al adds to existing data by reporting from a large German claims database on the receipt of thyroid replacement therapy in patients treated with one of these agents. The true incidence of thyroid

abnormalities from these medications is likely higher, accounting for abnormalities that did not require hormone replacement. Nonetheless, baseline and routine monitoring of thyroid function is indicated (e.g., every two cycles), with clinical judgment prevailing as to when hormone replacement is indicated.

Such vigilance to this potential toxicity may help alleviate the fatigue associated with these agents, and occurrence of thyroid abnormalities do not appear to adversely affect clinical outcome.

Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2007;99:8183, PMID: 17202116.

References 1. Rini BI, Tamaskar I, Shaheen P, et al.

‘I would emphasize … that this underreporting in journal articles has very real consequences.’

—Ronald Witteles, MD see which agents cause problems.”

He said that oncologists have traditionally collaborated closely with surgeons. However, that has not been the case with cardiologists. Historically, they don’t interact and collaborate a great deal during chemotherapy and radiation and surgical treatments.

“Maybe a little bit, but they are not two groups that have gotten together like oncologists and surgeons,” said Dr. Hundley. “We need to blend the two.”

The Clinical Effect Dr. Witteles said that clinicians and cancer patients are being harmed under the current system and there is a need for significant change.

“I would emphasize here that this underreporting in journal articles has

very real consequences,” said Dr. Witteles. “These are exceptionally useful drugs, but clinicians need to know the full array of possible cardiac side effects so that they can monitor cardiac function appropriately and consider starting cardiac medications or holding the anticancer therapy altogether when necessary.”

He said that frequently the appropriate cardiac treatments may not get started because patients are not being monitored for cardiac function. “There is no standard for monitoring for cardiac function for sunitinib and that’s because it was never known that it was needed. No one knew it was a concern,” said Dr. Witteles.

However, Paul Pretruska, MD, a professor of medicine in the Division of Hematology/Oncology at Saint Louis University School of Medicine, in Missouri,

2. Tamaskar I, Bukowski R, Elson P, et al.

Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol.

2008;19:265-268, PMID: 17962201.

3. Rini B. Kidney cancer: Does hypothyroidism predict clinical outcome? Nat Rev Urol. 2011;8:10-11, PMID: 21116300.

Dr. Rini disclosed that he receives consulting and research funding from Pfizer, which makes sunitinib.

❖❖Cardiac adverse events are underreported in anticancer drug trials

❖❖ Longer cancer survival may be leading to an increased incidence of late cardiac events

❖❖ Newer chemotherapeutic agents may have potentially significant cardiotoxic effects

disagrees. He contends that this issue is being far overblown. “Yes, there is some heart failure and yes, it has been known for some time,” said Dr. Pretruska.

He believes there is not enough data to warrant registry development or routine cardiac monitoring during clinical trials with newer chemotherapeutic agents. “I think this is blowing this up quite a bit,” said Dr. Pretruska in an interview. “If the problem is that see CARDIOTOXIciTY, page 20 

19

20

SOLID TUMORS

Clinical Oncology News • June 2012

GIST

Extended Imatinib Rx Improves Survival in GIST From JAMA

I

n patients at high risk for recurrence of gastrointestinal stromal tumor (GIST), the administration of 36 months of adjuvant imatinib therapy improved recurrence-free survival (RFS) and overall survival (OS) compared with 12 months of administration, the current standard, according to a new study published in JAMA (2012;307:1265-1272, PMID: 22453568).

Most GISTs have been found to include an activating mutation in the KIT oncogene, which is essential for tumor pathogenesis, as is a mutation in platelet-derived growth factor receptor-α (PDGFRA), found in

5% to 10% of GISTs. The risk for GIST recurrence is stratified based on these and other factors. Imatinib mesylate often is successful initially in patients with advanced GIST because it inhibits both KIT and PDGFRA, although typically the disease eventually progresses. The administration of adjuvant imatinib for 12 months following surgical resection of a KIT-immunopositive GIST lengthens RFS; however, recurrence of GIST after imatinib discontinuation is common. Thus, the question has been raised whether the administration period of 12 months might be extended.

This randomized, open-label, Phase III study sought to increase the treatment period to 36 months in patients whose risk for GIST recurrence was

EXPERT INSIGHT G. Thomas Budd, MD Staff Physician, Department of Solid Tumor Oncology Cleveland Clinic Taussig Cancer Institute Professor of Medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

I

n 2001, Joensuu and colleagues reported a dramatic response to imatinib mesylate in a 50-year-old woman with advanced GIST.1 The efficacy of this agent was substantiated in Phase III trials,2 leading to an adjuvant study.3 This study, performed in patients with GISTs 3 cm or more in size, showed that imatinib produced a superior diseasefree survival (DFS) at one year compared with placebo. Although follow-up

is ongoing, examination of the DFS curves from this study suggested that relapses occurred after imatinib was discontinued, leading many physicians to hypothesize that a longer duration of treatment would be superior.

The current report by Joensuu et al tests this hypothesis in a group of patients felt to be at high risk for recurrence, defined as patients with tumors larger than 10 cm in size; a mitotic count

CARDIOTOXICITY continued from page 19 

serious, then I would stop the drug.”

Dr. Pretruska contends the information is available and the company sends it all to the FDA. Furthermore, he said it is important to note how the FDA addressed this issue. “It did not give it the black box warning. I am not really sure there is a disconnect. People are aware of it, and the doctors know. I have known about this from day 1,” added Dr. Pretruska.

Right now, the potential collateral damage to the heart by many of the newer chemotherapeutic agents is still unknown.

However, the acquisition of cardiac outcomes data from trials involving

newer chemotherapeutic agents is vital for developing specific evidence-based practice guidelines, according to Dr. Krone. He said more thorough research may be optimal for keeping the heart from interfering with the war on cancer. Additionally, more open reporting also may be beneficial.

“It is a blossoming area of interest.

The oncologists have created a whole new realm of hope for patients. Cancer is becoming a chronic disease like diabetes. Today, patients are living a lot longer and so the landscape has changed,” said Dr. Hundley.

—John Schieszer

estimated to be high. Twenty-four hospitals in Finland, Germany, Norway and Sweden participated in this relatively large study, which was headed

by Heikki Joensuu, MD. Patients with KIT-positive GISTs were given oral imatinib, 400 mg per day, for either 12 or 36 months. The primary end point was RFS, and secondary end points were OS and treatment safety.

Each treatment group consisted of 200 patients. Median follow-up was 54 months. The 36-month cohort had a longer period of RFS than those in the 12-month cohort, with a five-year RFS of 65.6% versus 47.9%, respectively. The authors noted that the five-year RFS in the 36-month group is favorable to the reported five-year RFS of 45% in high-risk GIST patients

treated with surgery alone. The hazard ratio (HR) was 0.46 (95% confidence interval [CI], 0.32-0.65; P<0.001). The 36-month group also experienced longer OS (HR, 0.45; 95% CI, 0.22-0.89; P=0.02; five-year survival, 92% vs. 81.7%). However, discontinuation rates for reasons other than GIST recurrence were higher in the 36-month group (25.8%) than the 12-month group (12.6%). The researchers reported relatively mild adverse events (AEs), however, and noted that although imatinib may have cardiac toxicity, few such AEs were recorded.

The authors added, “Because GIST recurrence is frequent after discontinuation of adjuvant imatinib, studies that evaluate still longer treatments are warranted.”

greater than 10 mitoses per high-power field; a tumor diameter greater than 5 cm and a mitotic count greater than 5; or having tumor rupture before or during surgery. Four hundred patients were randomized to receive imatinib mesylate 400 mg per day for one or three years.

Three years of therapy proved to be significantly better than one year of treatment (five-year relapse-free survival of 65.6% vs. 47.9%). Moreover, a significant survival advantage for patients treated for three years was noted (92% at five years vs. 81.7%). The current study clearly indicates that at least three years of adjuvant imatinib should be recommended for patients with resected highrisk GISTs. Like all good studies, however, this report raises more questions than it answers. Can these results be applied to lower-risk tumors? Should adjuvant therapy be continued for longer than three

years? While we await data that address these issues, physicians must make choices with their patients based on improved prognostic tools and extrapolation from currently available information.

References 1. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052-1056, PMID: 11287975.

2. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472-480, PMID: 12181401.

3. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet.

2009;373:1097-1104, PMID: 19303137.

Dr. Budd reported no financial disclosures relevant to this study.

Recommendations for Accurately Reporting Cardiac Adverse Events • Urgent reform of Common Terminology Criteria for Adverse Events is needed to ensure consistent grading of cardiac adverse events (AEs). At a minimum, this necessitates consolidation of the three terms that can currently be used to grade a left ventricular ejection fraction (LVEF) drop into a single consistent term.

• Objective measures (e.g., laboratory and imaging findings) should be reported when data is available.

• In controlled trials, differences in AE rates should be considered more relevant than differences in treatment-related AE rates.

• Routine LVEF monitoring should be mandatory in clinical trials of any new therapeutics considered to carry risk for cardiac toxicity based on mechanism of action or when a previous cardiac toxicity signal has been present.

• Cardiac events should be adjudicated by a safety committee with access to all primary data (e.g., LVEF measurements) when a potential safety signal is present.

Adapted from Witteles RM, Telli M. Underestimating cardiac toxicity in cancer trials: Lessons learned? J Clin Oncol. 2012 Mar 26. [Epub ahead of print], PMID: 22454419.

HEMATOLOGIC DISEASE

Clinical Oncology News • June 2012

Leukemia

Higher Cumulative Dosing of Gemtuzumab Ozogamicin Key in AML From The Lancet

T

he addition of fractionated-dose gemtuzumab ozogamicin (Mylotarg, Pfizer and Ben Venue Laboratories) to the standard front-line chemotherapy regimen for de novo acute myeloid leukemia (AML) allowed for the safe administration of high cumulative doses that improved outcomes in these patients.

The current standard induction regimen for AML is daunorubicin (5060 mg/m2 per day for three days) plus continuous cytarabine (100200 mg/m2 per day for seven days), the so-called 3+7 regimen. Bettering the results from this regimen has failed, however, as no drug added to the 3+7 regimen has demonstrated a significant improvement. In an

EXPERT INSIGHT Anjali Advani, MD Staff Physician Department of Hematologic Oncology & Blood Disorders Cleveland Clinic Taussig Cancer Institute

earlier Phase II study, gemtuzumab ozogamicin, a humanized anti-CD33 monoclonal antibody, was administered to patients with AML at a dose of 9 mg/m2 on days 1 and 14, resulting in a 26% complete remission rate but also resulting in hematologic and liver toxicity.

A different study used a reduced dose of gemtuzumab ozogamicin, at 3 mg/m2 (maximum, 5 mg) on days 1, 4 and 7 (the so-called 3-3-3 regimen).

Two such Phase II studies using this reduced-dose regimen proved “effective,” after which the authors, in the current study, decided to assess the use of the 3-3-3 regimen in combination with 3+7 induction chemotherapy in patients with de novo AML. This French study, headed by Sylvie Castaigne, MD, was reported in The Lancet (2012;379:1508-1516, PMID:

22482940) and was funded by Wyeth (Pfizer).

In the current Phase III, open-label trial, 280 patients aged 50 to 70 years were assigned to receive either the standard 3+7 regimen (i.e., the control group) or the standard treatment plus the 3-3-3 regimen (i.e., the gemtuzumab group). The primary end point was event-free survival (EFS); secondary end points were relapse-free survival (RFS), overall survival (OS), and safety. Each group consisted of 139, all of whom were included in the analysis.

Complete response was seen in 104 (75%) patients in the control group and 113 (81%) in the gemtuzumab group, with or without incomplete platelet recovery to induction (odds ratio, 1.46; 95% confidence interval [CI], 0.82-2.59; P=0.25). EFS at two years was 17.1% (control) versus 40.8%

(gemtuzumab; hazard ratio [HR], 0.58; 95% CI, 0.43-0.78; P=0.0003); OS was 41.9% (95% CI, 33.1%-53.1%) versus 53.2% (95% CI, 44.6%-63.5%), respectively (HR, 0.69; 95% CI, 0.490.98; P=0.0368); and RFS was 22.7% (95% CI, 14.5%-35.7%) versus 50.3% (41.0%-61.6%), respectively (HR, 0.52; 95% CI, 0.36-0.75; P=0.0003).

Thrombocytopenia and other hematologic toxicity were more common in the gemtuzumab group (16%) than the control group (3%; P<0.0001), although there was no increase in risk for death from this toxicity.

The researchers concluded that lower doses of fractionated gemtuzumab ozogamicin improved outcomes in patients with AML, and the use of gemtuzumab ozogamicin as part of front-line regimen for the disease should be reassessed.

unfavorable cytogenetics. One concern with this trial is the dose of daunorubicin (60 mg/m2), particularly in the control arm. Although no trial has examined the superiority of 90 versus 60 mg/m2 of daunorubicin, two trials have demonstrated a survival benefit

may have led to a higher mortality in a “sicker” group of patients.

Overall, however, Castaigne’s paper is encouraging in that it demonstrates statistically significant EFS and OS advantages to adding gemtuzumab ozogamicin in adult patients

trials included patients predominantly younger than 60 years.

Gemtuzumab ozogamicin currently is not available and the above study suggests that further study of the fractionated schedule in adults with AML is warranted. If the above results are confirmed, this could justify bringing the drug back on the market.

‘Gemtuzumab ozogamicin currently is not available and the above study suggests that further study of

T

he prognosis for adult AML remains poor, and novel treatment strategies are needed. CD33 is highly expressed on the surface of the majority of AMLs. Gemtuzumab ozogamicin is a humanized anti-CD33 monoclonal antibody linked to calicheamicin.

After internalization and intracellular release, this chemotherapeutic agent is targeted to CD33-expressing cells. In this paper, Castaigne et al examine the addition of fractionated gemtuzumab ozogamicin during induction and postremission therapy to adult patients aged 50 to 70 years with de novo AML. This is a large randomized study with well-matched patient characteristics between the two arms. Additional molecular studies (FLT3, NPM and CEBP) are well described. There is a statistically significant improvement in EFS, OS and RFS, by the addition of gemtuzumab ozogamicin; and the percentages are striking (40.8% vs. 17.1% EFS at two years), despite the inclusion of 20% of patients with

the fractionated schedule in adults with AML is warranted.’ to 90 mg/m2 over 45 mg/m2 in AML patients up to 65 years of age.1,2 However, the overall survival of patients aged 60 to 65 years in the “high-dose” daunorubicin group of Löwenberg’s trial is 38%, similar to the control arm in this trial, making this less of a concern.

Castaigne’s trial may also have somewhat limited applicability to the larger group of AML patients in this age range because it excluded secondary AML (which is more common in this age range), and because 80% to 90% of patients had an Eastern Cooperative Oncology Group performance status of 0-1. This latter point is relevant because the addition of gemtuzumab ozogamicin did lead to increased toxicity: persistent thrombocytopenia, prolonged neutropenia and a few cases of veno-occlusive disease, and

—Anjali Advani, MD aged 50 to 70 years of age, where the overall prognosis is poor. Two previous trials have examined the addition of gemtuzumab ozogamicin to standard chemotherapy. The U.K. Medical Research Council trial only demonstrated a survival advantage in patients with favorable cytogenetics, predominantly younger than age 60 years.3 The Southwest Oncology Group trial S0106 demonstrated no improvement in outcomes.4 The major difference between these trials and Castaigne’s is the fractionated use of gemtuzumab ozogamicin, with more frequent dosing during both induction and post-remission treatment, suggesting that such a strategy may be critical to the improved outcome. Additionally, Castaigne’s cohort of patients was older (aged 50-70 years), whereas the other two

References 1. Löwenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361:1235-1248, PMID: 19776405.

2. Fernandez HF, Sun Z, Yao X, et al.

Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361:1249-1259, PMID: 19776406.

3. Burnett AK, Hills RK, Milligan D, et al.

Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29:369-377, PMID: 21172891.

4. Petersdorf S, Kopecky K, Stuart RK, et al.

Preliminary results of Southwest Oncology Group Study S0106: An international intergroup Phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to postconsolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia.

51st ASH Annual Meeting; December 7, 2009; New Orleans, LA. Abstract 790.

Dr. Advani disclosed that she receives consulting and research funding from Pfizer.

21

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Clinical Oncology News • June 2012

Lung

Yearlong Oral Adjuvant Chemotherapy for NSCLC Feasible From Clinical Lung Cancer

S

-1, an oral fluoropyrimidine, proved effective as adjuvant chemotherapy in patients with non-small cell lung cancer (NSCLC) in a Phase II trial. Because the oral therapy is administrable on an outpatient basis, it may effectively reduce both psychological and physiologic burdens on oncology patients and improve their quality of life.

This Japanese study was headed by Tomoshi Tsuchiya, MD, PhD, and published in Clinical Lung Cancer (2012 Mar 14. [Epub ahead of print], PMID:

22424872). The researchers felt that avoiding hospitalization by taking an orally administered adjuvant chemotherapeutic agent might be an important advance if effectiveness proved similar to other methods. S-1 is a novel oral derivative of 5-fluorouracil consisting of tegafur and two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate, and has been the subject of several studies in Japan.

S-1 was administered postoperatively in patients with pathologic stage IB-IIIA NSCLC who had undergone curative resection. The adjuvant chemotherapy entailed eight courses, each

EXPERT INSIGHT Nathan Pennell, MD, PhD Associate Staff Physician, Department of Solid Tumor Oncology Cleveland Clinic Taussig Cancer Institute Assistant Professor Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

A

lthough patients with early-stage (stages I-IIIA) NSCLC are potentially curable with surgery, many will relapse and eventually die of recurrent lung cancer. Since 2004, with the publication of IALT (International Adjuvant Lung Trial),1 we have had evidence that four cycles of cisplatin-based doublet chemotherapy can improve cure rates in patients with stage II or III NSCLC. This was confirmed by the LACE (Lung Adjuvant Cisplatin Evaluation) meta-analysis,2 which indicated approximately a 5% improvement in long-term survival with adjuvant chemotherapy in patients with stage II and III disease. In 2012,

adjuvant chemotherapy with a cisplatin doublet is the accepted standard of care in this population. Adjuvant chemotherapy is generally well tolerated and is finished in only nine weeks, although there is significant toxicity and only about half of patients in Phase III trials completed the prescribed four cycles.

In the present study, Tsuchiya and colleagues report a nonrandomized Phase II study of one year of twice daily S-1, an oral fluoropyrimidine that is not commercially available in the United States, in 50 patients with resected stage IBIIIA NSCLC. This is essentially a feasibility study because it is not randomized

of which required a four-week administration period followed by a two-week withdrawal period, thus totaling 12 months. The S-1 dosing ranged from 80 to 120 mg per day and was delivered in two daily doses.

The study, which was undertaken from 2005 to 2007, was multi-institutional, with 50 patients ultimately being eligible. The primary end point was simply the completion of the adjuvant chemotherapy; secondary end points included the incidence and grade of adverse reactions.

The eight full courses of S-1 administration were completed by 72% (n=36)

of patients. Although no grade 4 adverse effects were recorded, some grade 3 reactions were noted, and included neutropenia (4%), anorexia (4%), and thrombopenia, anemia, elevated total bilirubin, hypokalemia, nausea and diarrhea (all 2%). The overall survival rate at three years was 87.7%; the relapse-free survival rate for the same time period was 69.4%.

Citing acceptable survival rates as well as the low incidence of adverse reactions, the researchers concluded that nonhospitalized, oral adjuvant chemotherapy with S-1 for NSCLC was feasible and deserving of a larger Phase III trial.

and the numbers are much too small to make judgments about improvement in long-term survival. They report that an impressive 72% of the enrolled patients completed eight cycles of therapy over the course of one year, and that overall the regimen was tolerable. The average age of the patients was 71 years, similar to the general population and much older than the average age of patients on prior Phase III adjuvant trials (59 years2), suggesting this may be a more tolerable choice for older patients than standard chemotherapy. The authors suggest that this regimen deserves to be tested in a Phase III trial.

There are several issues with this study, however, that raise concerns. For one, the drug being tested is only available in Japan and is metabolized differently in patients of European descent, making results difficult to generalize outside of Japan. Second, trial data suggests that S-1 is not particularly effective in NSCLC,3 raising the question of why this drug should be used instead of other, proven chemotherapy agents.

Its only real advantage seems to be its

oral formulation. Finally, it is questionable whether patients would prefer one year of therapy, however tolerable, to nine weeks of usual IV chemotherapy.

Despite these concerns, it is likely that this drug will proceed to a Phase III, randomized, head-to-head trial against standard chemotherapy, so that will answer at least some of these questions.

Brachytherapy on Trial in Retrospective Analysis From JAMA

A

large, retrospective study comparing brachytherapy with wholebreast irradiation (WBI) in older women with invasive breast cancer has found no difference in overall survival (OS) at five years, but found worse long-term breast preservation and increased complications among recipients of brachytherapy.

The emergence of brachytherapy as an alternative to WBI has resulted in a substantial increase in women adopting this therapeutic option, despite a lack of randomized trial data to support it.

Long-term randomized prospective trials are ongoing, but these results are years away. The authors of this study, which was reported in the May 2 edition of JAMA (2012;307:1827-1837, PMID: 22550197) and headed by Grace Smith, MD, PhD, MPH, of the University of Texas MD Anderson Cancer Center, in Houston, decided that a nonrandomized comparison, using a cohort of older Medicare patients, would provide useful guidance in the interim.

The study compared breast preservation, infectious and noninfectious complications and OS among 92,735 women, aged 67 years or older, who were

diagnosed and treated between 2003 and 2008. Following lumpectomy, 6,952 of the patients received brachytherapy and the rest received WBI. Results favored WBI in these older patients. Five-year incidence of mastectomy was higher in the brachytherapy group (3.95%) than the WBI group (2.18%; P<0.001). Postoperative complications of all types also were more frequent among those receiving brachytherapy (infectious: 16.20% vs. 10.33%, P<0.001; and noninfectious: 16.25% vs. 9.00%, P<0.001). Additionally, the five-year incidence of breast pain was higher in the brachytherapy cohort

References 1. Arriagada R, Bergman B, Dunant A, et al.

Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351-360, PMID: 14736927.

2. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552-3559, PMID: 18506026.

3. Sandler A, Graham C, Baggstrom M, et al.

An open-label, multicenter, three-stage, phase II study of s-1 in combination with cisplatin as first-line therapy for patients with advanced non-small cell lung cancer.

J Thorac Oncol. 2011;6:1400-1406, PMID: 21673602.

Dr. Pennell reported no financial disclosures relevant to this study.

(14.55% vs. 11.92%; P≤0.01), as were the five-year incidences of fat necrosis (8.26% vs 4.05%; P≤0.01) and rib fracture (4.53% vs 3.62%; P≤0.01). However, five-year OS was 87.66% in patients treated with brachytherapy and 87.04% in those receiving WBI (P=0.26).

The authors believe that the “public health implications of these findings are substantial,” particularly given the continued adoption of brachytherapy, which the researchers note is as many as 10% of patients with breast cancer.

The authors concluded, “Although these results await validation in the prospective setting, they also prompt caution over widespread application of breast brachytherapy outside the study setting.”

SOLID TUMORS

Clinical Oncology News • June 2012

23

Esophageal

Marker for Esophagogastric Cancer Treatment Found With FDG-PET, leptin expression may help determine response to therapy San Francisco—A new tool to guide treatment decisions in patients with esophagogastric junction adenocarcinoma (EGJAc) is on the horizon.

A study has found that leptin expression is associated with chemoresistance and may be a biomarker that can be combined with fluorodeoxyglucose–positron emission tomography (FDG-PET) to determine patient response to chemotherapy.

“Leptin has the potential to be a clinically useful biomarker,” said Russell Petty, MB, PhD, a consultant medical oncologist at the University of Aberdeen in Scotland. He presented the study at the 2012 Gastrointestinal Cancers Symposium (ASCO-GI; abstract 1).

In the past decade, the incidence of EGJAc has risen alarmingly, driven in part by the obesity epidemic.

The disease has a poor prognosis and for patients with resectable disease, it has been recognized that neoadjuvant treatment is beneficial for some but not all patients.

Studies have shown that a 35% or greater decrease in FDG standard uptake value (SUV) after just 14 days of treatment indicates a metabolic responder to chemotherapy, whereas less than 35% indicates a metabolic non-responder. Only 50% of patients who are classified as metabolic responders, however, will go on to have a histopathologic response. Of patients who are metabolic

non-responders, less than 5% will have a histopathologic response.

“There is a need to improve the positive predictive value,” said Dr. Petty. The

‘This is not something that will be incorporated into clinical practice, until further studies.’

—Karyn Goodman, MD researchers hypothesized they could combine molecular biomarkers with FDG-PET to subclassify FDG-PET metabolic responders.

They launched a study that included 28 patients with locally advanced or metastatic EGJAc who received platinumbased chemotherapy. Patients underwent FDG-PET computed tomography (PET-CT) scans at baseline and day 14.

Chemotherapy continued regardless of radiologic response at day 14. Gene expression profiling with an Affymetrix 1.0 ST Exon Genechip was performed

did not respond. Leptin expression was the biggest predictor.

“In those FDG-PET metabolic respondent patients who did not have a subsequent radiologic response, leptin was significantly overexpressed compared to those patients who had a metabolic response and then went on to have a radiologic response as well,” said Dr. Petty.

“This data suggests that leptin expression in tumor is a marker of chemoresistance.”

Somewhat surprisingly, in an IHC analysis of an independent group of 154 patients, high leptin expression was associated with better survival (hazard

‘This data suggests that leptin expression in tumor is a marker of chemoresistance.’

—Russell Petty, MB, PhD on tumor biopsies. A tissue microarray comprising an independent set of 154 patients with EGJAc who underwent surgery, with or without neoadjuvant chemotherapy, was used with immunohistochemistry (IHC) for qualification of the gene expression profile results.

The researchers identified an 86-gene

Rahul Tendulkar, MD Associate Staff Physician, Department of Radiation Oncology Cleveland Clinic Taussig Cancer Institute Assistant Professor, Department of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

n the May 2, 2012 issue of JAMA, Smith and colleagues reported their findings of a Medicare analysis of women undergoing breast conservation therapy comparing the rates of subsequent mastectomy following adjuvant WBI versus brachytherapy. Breast

• Leptin expression is associated with chemoresistance in esophagogastric junction adenocarcinoma • A variety of data suggest multiple associations between leptin and esophagogastric cancer • In the future, leptin expression may be combined with FDG-PET to estimate response to chemotherapy

the results have been validated with

EXPERT INSIGHT

I

signature that could distinguish patients who had a radiologic response on CT after completing their full round of chemotherapy, compared with those who

brachytherapy is a method of delivering accelerated partial breast irradiation (APBI), which has been advocated as being more convenient for patients by completing radiation treatment in just one week. In recent years, brachytherapy utilization has increased despite the

ratio, 0.85; P=0.04). But when the investigators conducted a stratified analysis, they found that patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, and those with leptin-negative tumors fared better if they received chemotherapy.

A variety of data supports leptin’s lack of long-term data or direct comparative analysis with WBI, which remains the current standard of care for early stage breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) and Radiation Therapy Oncology Group (RTOG) are presently conducting a large Phase III trial in which early-stage breast cancer patients are randomized to either WBI or APBI, and accrual to this important trial is ongoing.

Smith et al found that women receiving APBI with brachytherapy were about twice as likely to undergo a mastectomy as women receiving WBI, and were also at increased risk for postoperative complications. The reasons for these patients to have a greater likelihood of mastectomy are not discernible

pathogenic role in EGJAc. It is produced by adipocytes and a strong epidemiologic link between obesity and EGJAc exists. High serum and gastric fundus leptin levels have been associated with an increase in Barrett’s esophagus.

Leptin receptors are expressed in more than 90% of esophageal adenocarcinomas, and in vitro studies show that leptin stimulates esophagogastric cancer cell proliferation and can inhibit apoptosis.

According to Dr. Petty, his study suggests that leptin expression has value as a predictive biomarker and also as a therapy-independent prognostic marker as well. “I would suggest that the paradigm of combining molecular biomarkers and FDG-PET appears to be valuable to predict therapy response, and perhaps should be further investigated,” Dr. Petty said.

Karyn Goodman, MD, a radiation oncologist at Memorial Sloan-Kettering Cancer Center, in New York City, said the study was hypothesis-generating, but not ready for prime time. “This is not something that will be incorporated into clinical practice, until the results have been validated with further studies,” she said.

—Kate O’Rourke Drs. Petty and Goodman have no relevant disclosures.

in such a Medicare claims data analysis, but presumably may be related to either an increased risk for in-breast recurrence or treatment-related toxicity. Unfortunately, only the ongoing NSABP/RTOG randomized trial will adequately address the issue of the relative benefit of APBI versus WBI with regard to these end points, and the long-term results will not be available for at least a decade from now. In the meantime, we may be encouraged that the rates of subsequent mastectomy in the current report were quite low, less than 4% in both groups, with no differences in overall survival at five years.

Dr. Tendulkar reported no financial disclosures related to this study.

24

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Clinical Oncology News • JUNE 2012

Community Oncology

CONUNDRUMS continued from page 12 

ANSWERS

1.

True. It is not prudent to assign clinical meaning to an outcome that is merely measurable, while failing to measure, or failing to make decisions based on, those things that are truly important to the patient, such as quality of life (QOL) and overall survival (OS).

and found that family caregivers’ needs are seldom addressed in clinical practice. Evidence suggests that appropriate interventions geared toward the caregivers of patients with cancer or other chronic illnesses can improve their coping skills, knowledge and quality of life.

Northouse L, Williams AL, Given B, McCorkle R. J Clin Oncol. Psychosocial care for family caregivers of patients with cancer. J Clin Oncol.

2012;30:1227-1234, PMID: 22412124.

Jacobsen PB, Holland JC, Steensma DP. Caring for the whole patient: the science of psychosocial care. J Clin Oncol. 2012;30:1151-1153, PMID: 22412125.

Booth CM, Eisenhauer EA. Progression-free survival: meaningful or simply measurable? J Clin Oncol. 2012;30:1030-1033, PMID: 22370321.

2. False. The women exposed to

efforts can focus on other molecular pathways that permit these cancers to escape endocrine therapy.

Hayes DF. Targeting adjuvant chemotherapy: a good idea that needs to be proven! J Clin Oncol.

2012;30:1264-1267, PMID: 22355050.

9. True. Using axillary lymph node

analysis (ALNA) as the gold standard, sensitivity for PET was 23.7% (95% confidence interval [CI], 15.9%-33.6%), specificity was 99.6% (95% CI, 97.2%99.9%), positive predictive value was 95.8% (95% CI, 76.9%-99.8%), negative predictive value was 75.4% (95% CI, 70.1%-80.1%) and prevalence was 29.8% (95% CI, 25.0%-35.2%). Patients were excluded if they had clinically palpable nodes or metastatic disease.

chemotherapy performed significantly worse than the reference group on cognitive tests of immediate (P=0.015) and delayed verbal memory (P=0.002), processing speed (P<0.001), executive functioning (P=0013) and psychomotor speed (P=0.001).

Pritchard KI, Julian JA, Holloway CM, et al.

Prospective study of 2-[18F] fluorodeoxyglucose positron emission tomography in the assessment of regional nodal spread of disease in patients with breast cancer: an Ontario Clinical Oncology Group study. J Clin Oncol. 2012;30:1274-1279, PMID: 22393089.

Koppelmans V, Breteler MM, Boogerd W, Seynaeve C, Gundy C, Schagen SB. Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy.

J Clin Oncol. 2012;30:1080-1086, PMID: 22370315.

True. Sequencing analysis has revealed that TET2 mutations (TET2mut) are present in 7% to 23% of de novo AML and in 14% to 55% of other myeloid malignancies. It has been shown that TET2mut samples display uniformly low levels of 5hmC compared with normal controls, supporting functional relevance for TET2mut in leukemogenesis.

3. False. Vandetanib is a once-dai-

ly oral inhibitor of VEGFR, EGFR and RET signaling. This agent is FDAapproved for symptomatic or metastatic medullary thyroid cancer (MTC). It did not improve OS in patients with advanced NSCLC who had progressed on prior therapies including an EGFRTKI. There is currently no approved treatment option for this high-risk patient population.

Lee JS, Hirsh V, Park K, et al. Vandetanib versus placebo in patients with advanced non-smallcell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol. 2012;30:1114-1121, PMID: 22370318.

4.

10.

6.

True. Given the centrality of psychosocial issues in cancer care, it is surprising that the formal history of the field in the United States dates only to the 1970s. The emergence of psychosocial care reflects growing public and professional awareness of the potential for cancer and its treatment to have profound effects on many aspects of life in a positive manner.

Jacobsen PB, Holland JC, Steensma DP. Caring for the whole patient: the science of psychosocial care. J Clin Oncol. 2012;30:1151-1153, PMID: 22412125.

7. False. Tamoxifen reduces the inci-

dence of both local recurrence and contralateral breast cancer, but not OS in this particular setting.

True. The combination of high VEGF levels and its receptors VEGFR1 and VEGFR2 protein expression—cumulatively known as the “VEGF signaling score”—was associated with a lower risk for disease progression in stage I SCC. Tumors were classified according to the World Health Organization 2004 classification.

Wapnir IL, Dignam JJ, Fisher B, et al. Longterm outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103:478-488, PMID: 21398619.

Pajares MJ, Agorreta J, Larrayoz M, et al.

Expression of tumor-derived vascular endothelial growth factor and its receptors is associated with outcome in early squamous cell carcinoma of the lung. J Clin Oncol. 2012;30:1129-1136, PMID: 22355056.

Morrow M. Refining the use of endocrine therapy for ductal carcinoma in situ. J Clin Oncol.

2012;30:1249-1251, PMID: 22393104.

5. True.

Laurel Northouse, PhD, RN, and colleagues at the University of Michigan reviewed published evidence, health policy legislation including the Affordable Care Act and the Family Leave Act, and current practice trends,

Lee LA, Silverstein MJ, Chung CT, et al. Breast cancer-specific mortality after invasive local recurrence in patients with ductal carcinoma-insitu of the breast. Am J Surg. 2006;192:416-419, PMID: 16978940.

8. True. The outcome of this tri-

al will definitively demonstrate if the 21-gene Oncotype DX assay can identify a group of ER- and node-positive breast cancer patients who do not benefit from adjuvant chemotherapy, for example, the luminal A subtype. If so, over-treatment with chemotherapy may be avoided in this group, and research

Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468:839843, PMID: 21057493.

Delhommeau F, Dupont S, Della Valle V, et al.

Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289-2301, PMID: 19474426.

Gaidzik VI, Paschka P, Späth D, et al. TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML study group. J Clin Oncol.

2012;30:1350-1357, PMID: 22430270.

11. True. Oliver

Goodyear, PhD, and colleagues in the United Kingdom demonstrated that in AML, azacitidine after RIC allo-SCT can increase the number of regulatory T-cells (T-regs) while inducing a cytotoxic CD8+ T-cell response, suggesting a potential mechanism for augmenting the GVL effect without an increase in GVHD. The optimal dosing, schedule timing and duration of azacitidine administration after RIC allo-SCT are yet to be established.

The use of azacitidine in combination with donor lymphocyte infusion (DLI) may further augment the safety and antitumor effect of DLI (ClinicalTrials. gov Identifier: NCT01541280).

Goodyear OC, Dennis M, Jilani NY, et al.

Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML).

Blood. 2012;119:3361-3369, PMID: 22234690.

Mohty M, Chevallier P. Azacitidine after allo-SCT: the good without the bad? Blood.

2012;119:3199-3200, PMID: 22493216.

12. True. Microsatellite instability (MSI) is a hallmark feature associated with Lynch syndrome, with approximately 15% of sporadic CRCs exhibiting the MSI-high phenotype as a result of somatic MLH1 promoter hypermethylation. BRAF testing in the absence of MLH1 protein expression by IHC should reduce the number of patients that need germline mutation analysis and the associated costs.

Kastrinos F, Syngal S. Screening patients with colorectal cancer for Lynch syndrome: what are we waiting for? J Clin Oncol. 2012;30:1024-1027, PMID: 22355054.

13. False. Sixty percent of patients

with low-grade or FL who responded to initial rituximab therapy failed to respond to repeat rituximab therapy, indicating that initially sensitive patients can acquire rituximab resistance. Several mechanisms have been proposed for rituximab resistance.

With the increasing use of repeated rituximab exposure in clinical practice, acquired resistance has become a growing challenge, highlighting the need for alternative treatment options.

Davis TA, Grillo-Lopez AJ, White CA, et al.

Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and efficacy of retreatment. J Clin Oncol. 2000;18:31353143, PMID: 10963642.

14.

False. Ofatumumab monotherapy might have greater clinical activity in patients with FL in a frontline setting or with those not refractory to chemotherapy. Several trials (ClinicalTrials.gov Identifiers: NCT01190449, NCT01200589, NCT01077518) with this agent, alone or in combination, are under way to define the exact role of ofatumumab in front-line and the relapsed/refractory FL setting.

Czuczman MS, Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood. 2012;119:3698-3704, PMID: 22389254.

15. True. The results of this study

demonstrate that an important clinical question—the suitability of unrelated donors for an accepted hematopoietic stem cell transplantation indication—related to an expensive treatment can be addressed by a federally funded outcomes registry that is charged with systematic data collection and analysis to inform policy makers. The use of resources such as the CIBMTR database allows policy decisions to be formulated in a way that ensures efficient use of resources while maintaining optimal clinical outcomes.

Saber W, Opie S, Rizzo JD, Zhang MJ, Horowitz MM, Schriber J. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood. 2012;119:39083916, PMID: 22327226.

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Clinical Oncology News • June 2012

25

Community Oncology

Young Cancer Patients Getting More Attention FILE SLUG

Current file:

Orlando, Fla.—In recent years, a niche of medicine has sprung up to address the needs of adolescent and young adults (AYA) with cancer.

AYA oncology now has its own society and its own journal, and in March, the National Comprehensive Cancer Network (NCCN) issued its first set of AYA guidelines.

The attention to this group of cancer patients is needed. In the past 40 years of the battle against cancer, survival rates of children and older adults have improved significantly, whereas survival rates among AYAs with cancer have barely budged.

“Improvements in cancer survival among AYA patients definitely have lagged behind other sectors of the population,” said Kerry Parsons, PharmD, pediatric oncology pharmacist at Children’s of Alabama, in Birmingham, who discussed AYA oncology at the annual meeting of the Hematology/Oncology Pharmacy Association.

According to the American Cancer Society, 70,000 AYAs, defined as

MN113_A_ad.indd

1ST PROOF LAYOUT APPROVED INITIALS AND DATE

Full name of project

patients aged 15 to 39 years, are diagnosed with invasive cancer each year Project no.States. (For a breakdown in the United of cancerRevision types, see Table 1.) Some of # rev 1 those malignancies are associated with Layout date/time June 6, 2012 7:50 AM a poorer prognosis due to either more Editorial date/time aggressive or unique biology features, size includingTrim breast cancer, colorectal cancer, soft tissue Color specssarcoma, non-Hodgkin’s lymphoma and acute leukemia, accordFile path MN113_A_ad.indd ing to Leonard Sender, MD, the founder of the Society for Adolescent and Young

FINAL OK INITIALS AND DATE

Cancer Type

Ages 15-39 Years

Adult Oncology (SAYAO), and director Editor of the combined adolescent and young Copy editor adult cancer program at Children’s Hospital of Orange County and UniSales versity of California, Irvine. Dr. SendProduction er added that AYAs often do better on MAX sign-off more rigorous pediatric protocols than COMMENTS: adult protocols, but many doctors are not aware of this.

A 2007 study on AYA cancer trends offers some sobering statistics on just how wide the survival gap has become

Breast cancer

20.4

Thyroid cancer

14.6

Melanoma

9.5

Cervix and uterine cancer

9.1

Hodgkin’s lymphoma

3.7

Colorectal cancer

3.4

Gonadal germ cell tumors

10.1

Melanoma

5.5

Non-Hodgkin’s lymphoma

4.7

Colorectal cancer

3.6

Thyroid cancer

2.9

AD LAYOUT EXPT’D:

REV 3 AD LAYOUT RECEIVED: in this vulnerable patient population.

REV 4 Fourteen inLAYOUT AYAEXPT’D: patients REV 5 cancer typesEDIT EDIT LAYOUT RECEIVED: REV 6 have five-year survival rates that are sigREV 7 EDITOR: Jen Kulpa nificantly lower than ART rates in younger DIRECTOR: Blake REV 8 REV 9 the authors reported (CA Canpatients, 10 cer J REV Clin 57;242-255). Of those, six canREV 11 cer types have survival rates that lag KEYWORDS: behind both younger and older patients.

Moreover, “cancer kills more 20- to 30-year-olds than any other disease except depression-induced suicide,”

see YOUTH, page 26 

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Tailoring Therapy in Metastatic Breast Cancer Novel Clinical Approaches

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This activity is based on a live educational symposium held May 21, 2011, in Philadelphia, Pennsylvania.

Learning Objectives

Co-Chairs

Tessa Cigler, MD, MPH

Assistant Professor of Medicine, Weill Cornell Medical Center Attending Physician, NewYork-Presbyterian Hospital New York, New York

Associate Professor, Clinical Investigator, Section of Breast Oncology Medical Oncology, Fox Chase Cancer Center Philadelphia, Pennsylvania

Target Audience

Oncologists, physicians, physician assistants, and other health care professionals involved in the treatment of patients with metastatic breast cancer (MBC). There are no prerequisites or fees.

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Senior editor

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Table 1. The Most Common AYA Cancers per 100,000 People in the United States

STATUS & HISTORY PROOF 1: 1/17

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1 Review recent studies that may have clinically important therapy implications for patients with locally recurrent breast cancer or MBC. 2 Describe a treatment algorithm that reflects evidence-based management of advanced human epidermal growth factor receptor 2 (HER2)-negative and HER2-positive breast tumors and novel strategies for circumventing treatment resistance.

3 Explain core guideline-recommended approaches to MBC management that take into consideration the heterogeneity of patient and tumor characteristics.

4 Compare the mechanisms, synergies, and evolving roles of current and emerging targeted therapies with activity in MBC, particularly in terms of novel combinations and sequences.

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26

PRN

Clinical Oncology News • June 2012

Community Oncology

‘You need to know that

YOUTH

the term “young adult”

continued from page 25 

needs to be put into a

the authors noted. “Yet cancer in young adults has been under-recognized and frequently not considered” by clinicians who often come into contact with these patients—“including oncologists.”

[PubMed] search when you have a leukemia or a sarcoma.’

Major Culprit: Clinical Trials Access According to Dr. Parsons, the factor most responsible for this lack of progress in AYA oncology is inadequate access to clinical trials. “During the period of 1997 and 2003, approximately 70% of children were enrolled in an NCI-sponsored clinical trial,” she said. Unfortunately, “this level of clinical trial participation drops dramatically as you span into the AYA age range and falls to less than 2% [for patients] between 20 and 39 years of age.”

The new AYA NCCN guidelines strongly advise that AYA patients be placed on clinical trials and referred to cancer centers with experience in treating cancer patients in this age group.

Dr. Parsons said that a 20-year-old Marine with osteosarcoma was recently referred to her hospital because it has been gaining a reputation as a center with AYA expertise. Her hospital was able to place him in a clinical trial. “We don’t need a fancy facility to care for these patients,” she said. “In my practice at the University of Alabama, we don’t necessarily have a formal program, although we are moving that way, but over the past few years, we have had a lot more phone calls and discussions between our physicians and our pharmacy colleagues about managing AYA patients.” Dr. Parsons pointed out that strides are being made in terms of getting AYAs into clinical trials for sarcoma. The percentage of AYA patients enrolled in NCI clinical trials for sarcoma was 5% during 1998 and 1999 and 19% during 2004 and 2005, she said.

In addition to inadequate research opportunities, poor access to health care, delayed diagnosis and treatment and poor adherence to treatment regimens also play a role in the survival rates of AYAs not improving over the years.

She noted that a 2010 Gallup poll identified AYAs as the most underinsured age among all age ranges.

Signs of Progress All is not dire, however, in the field of AYA cancer. Since 2006, the NCI has collaborated with the Lance Armstrong Foundation and published a series of reports on AYAs with cancer, in an effort to bolster awareness.

In 2010, Dr. Sender helped found the SAYAO. In 2011, the quarterly Journal of Adolescent and Young Adult Oncology was launched. The NCCN AYA oncology guidelines released in March are the latest big development in this growing

—Leonard Sender, MD

‘The AYAs represent a unique enough cancer diagnosis that argues for the emergence of AYA oncology as a specialty practice in medicine.’

—Kerry Parsons, PharmD field (Table 2). The guidelines aim to help improve the diagnosis, treatment and survivorship care of AYAs. (Access to the NCCN Guidelines for AYA Oncology or any of the NCCN guidelines is available free of charge at NCCN.org.)

According to Dr. Parsons, physicians can do their part by paying particular attention to toxicity and dosing

considerations in this population because of different pharmacokinetics. The oral clearance of dexamethasone and methotrexate, for example, is twofold greater for young children than for adolescents, and there is an inverse relationship in AYAs between age and clearance of etoposide and busulfan. Pharmacists should be aware that when using dactinomycin,

Table 2. Highlights From the NCCN Adolescent and Young Adult Oncology Guidelines AYA patients usually are more tolerant of intensive therapies than older patients.

Monitoring of cumulative dosing for certain medications (anthracylines, epipodophyllotoxins, cisplatin, ifosfamide) associated with irreversible organ damage may be essential when certain lifetime exposure is encountered.

Fertility preservation should be an essential part in the management of AYAs with cancer.

AYA patients with cognitive dysfunction or other psychiatric symptoms (e.g., depression or anxiety) should be referred to a mental health provider and community-based resources serving AYA patients.

All AYAs should have a survivorship care plan.

AYAs with cancer need long-term follow-up care for monitoring and treatment of late effects long after completion of treatment. This can include screening for pulmonary, thyroid, cardiovascular and audiologic issues; breast, colorectal and bladder cancer; acute myeloid leukemia; myelo­ dysplasia; and kidney disease.

Source: www.nccn.org

the area under the curve is lower in adolescents than in young children, she said.

Through acute lymphoblastic leukemia (ALL) clinical trials run by the Children’s Oncology Group, researchers have found that patients between the ages of 16 and 30 years experience higher rates of toxicities than children aged 1 to 15 when it comes to hyperglycemia (22% vs. 15.4%), hyperbilirubinemia (6.7% vs. 3.7%), oral mucositis during interim maintenance therapy (18.5% vs. 11.3%) and peripheral neuropathy (11.5% vs. 7.4%; Blood, ASH Annual Meeting abstracts, 2011;118: Abstract 1510). Osteonecrosis is far more prevalent in ALL patients 10 years or older than in patients younger than age 10 (19.6% vs. 3.1%; J Clin Oncol 2011;29: Abstract 9504).

Survivorship Issues Need To Be Addressed AYAs have specific survivorship issues that need attention, including financial pressures, psychosocial issues and medical concerns such as fertility. According to Dr. Sender, psychological distress is significantly greater in AYAs than in younger children and older patients with cancer. Thus, health care workers need to focus on managing the psychosocial issues of this particular group of patients. The AYA NCCN guidelines echo the need for specific attention to psychosocial issues.

Dr. Parsons stressed that there still is a need to increase the overall awareness among the medical community as well as the lay community about the specific needs of AYA patients. “The AYAs represent a unique enough cancer diagnosis that argues for the emergence of AYA oncology as a specialty practice in medicine,” she said.

Dr. Sender agreed and said practitioners can dive into the subject matter using online resources. “With Google and PubMed, you can bring yourself up to speed pretty quickly, if you know [how] to look for it. You need to know that the term ‘young adult’ needs to be put into a search when you have a leukemia or a sarcoma,” he said. He hopes the growing awareness of AYA oncology will spur health care providers to specialize in the niche. “There is a really rewarding career in doing young adult medicine,” Dr. Sender said.

—Kate O’Rourke

SOLID TUMORS

Clinical Oncology News • June 2012

Adenocarcinoma

Daily Aspirin Inhibits Metastatic Adenocarcinoma From The Lancet

A

n intriguing meta-analysis of five large, randomized cardiovascular trials has found that patients who take daily aspirin (≥75 mg per day) have a reduction in the risk for cancer with distant metastasis, compared with controls. The finding has several implications for clinical care.

The meta-analysis, undertaken by a group of researchers in the United Kingdom and headed by Peter Rothwell, FMedSci, included 17,285 participants, of whom 987 had received a diagnosis of a new solid cancer during trial follow-up (mean, 6.5 years). The study, published in The Lancet (2012;379:15911601; PMID: 22440947), found that those receiving daily aspirin had a

reduction in incidence of cancer with distant metastasis (all cancers: hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.48-0.84; P=0.001; adenocarcinoma: HR, 0.54; 95% CI, 0.380.77; P=0.0007; other solid cancers: HR, 0.82; 95% CI, 0.53-1.28; P=0.39). The reduction was attributed mostly to the diminished proportion of adenocarcinomas with metastatic compared with local disease (odds ratio, 0.52; 95% CI, 0.35-0.75; P=0.0006).

The meta-analysis found that aspirin reduced the risk for adenocarcinoma with metastasis both at initial diagnosis (HR, 0.69; 95% CI, 0.50-0.95; P=0.02) and at subsequent follow-up in those patients who did not present with metastasis initially (HR, 0.45; 95% CI, 0.28-0.72; P=0.0009). This effect was most pronounced in patients with

EXPERT INSIGHT Dale Shepard, MD, PhD Associate Staff Physician, Department of Solid Tumor Oncology Cleveland Clinic Taussig Cancer Institute Associate Professor of Medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

R

othwell and colleagues have analyzed data from five clinical trials testing the reduction in cardiovascular disease in patients receiving aspirin, and have shown a significant decrease in the incidence of metastatic cancer. The results of this trial are intriguing and offer insight into possible interventions to improve survival in patients with

cancer. With 17,285 participants in the trials, there were 1,101 cancers and 563 deaths due to cancer. There was a 12% reduction in risk for developing cancer in subjects receiving daily aspirin and a 23% reduction in death from cancer.

In the 775 patients with a solid tumor and known metastatic disease status, there was a 36% reduction in known

colorectal cancer (HR, 0.26; 95% CI, 0.11-0.57; P=0.0008).

Patients who took daily aspirin and developed adenocarcinoma had a reduced cancer-related death rate, particularly in those with no metastasis at diagnosis (HR, 0.50; 95% CI, 0.34-0.74; P=0.0006). Therefore, aspirin reduced the overall risk for fatal adenocarcinoma in the five trial populations (HR, 0.65; 95% CI, 0.53-0.82; P=0.0002), although it did not lower the risk for other cancer deaths (HR, 1.06; 95%, CI, 0.84-1.32; P=0.64; difference, P=0.003). The absolute benefit was greatest in smokers, although the beneficial effects of aspirin were independent of age and gender. The researchers noted that a lowdose, slow-release aspirin formulation, which inhibits platelets but has reduced systemic bioavailability, was as effective

as aspirin given in higher doses.

The authors note several implications of this meta-analysis. First, the findings help explain the short-term reduction in cancer fatality in trials comparing daily aspirin with a control. Second, the findings suggest that starting a course of aspirin after diagnosis also has a beneficial effect.

Third, stopping aspirin after a diagnosis of cancer, which is routine clinical practice, may indeed be detrimental.

Fourth, pharmacologic intervention to prevent distant metastasis is a possibility worth further study. They added, “The effects of aspirin on metastasis are likely to be platelet-mediated, raising the prospect that more intensive platelet inhibition with combination treatment might be even more effective.”

metastatic disease in patients receiving aspirin, with a decrease in metastases to the lung, liver and brain, but not bone. The effect was most pronounced in patients with adenocarcinoma.

This data has limitations. These were trials assessing cardiovascular risk, not cancer prevention. It is possible that some tumors may have been missed or not diagnosed in a timely manner because this was not a goal of the trial.

The presence of metastases was unclear in 20% of patients and the necessary dose and duration of aspirin for the effects observed is not known. This does, however, reflect routine clinical use of aspirin.

What are the implications of this trial? Clinically, the reduction in incidence or development of metastatic disease is significant because metastatic disease is associated with increased

morbidity, heightened patient and family anxiety and reduced overall survival.

The possibility of decreasing metastatic disease with aspirin, an inexpensive and easy-to-use therapy, is promising.

Clearly, aspirin is associated with risks, including stroke and gastrointestinal bleeding, and should not be used by patients at this time for cancer prevention due to risk for adverse effects and the unproven benefits in specific clinical trials. The mechanism by which aspirin reduced metastatic disease in the current trial remains unclear, but this offers an interesting area for research to understand how tumors grow and for development of future therapies.

Dr. Shepard reported no financial disclosures relevant to this study.

Brivanib Fails in Phase III Colon Cancer Trial San Francisco—The investigational agent brivanib (Bristol-Myers Squibb [BMS]) has failed in a Phase III trial of patients with colorectal cancer (CRC).

“CO.20 did not meet its primary end point of overall survival,” said Lillian Siu, MD, a senior staff physician in the Division of Medical Oncology and Hematology at Princess Margaret Hospital in Toronto, Ontario, Canada. She presented the study at the Gastrointestinal Cancers Symposium (ASCO-GI; abstract 386).

The NCIC Clinical Trials Group and Australasian Gastro-Intestinal Trials Group CO.20 study was based, in part, on a retrospective analysis of a Phase I/ II trial that demonstrated that brivanib

improved the response rate in CRC patients with KRAS wild-type tumors.

Patients who had not received any prior anti-epidermal growth factor receptor (EGFR) therapy were more likely to benefit (ASCO-GI 2009; abstract 375).

The CO.20 trial randomized patients with metastatic, chemotherapy-refractory, KRAS wild-type CRC to receive cetuximab (Erbitux, BMS) with either brivanib (n=376) or placebo (n=374). To be included in the study, patients had to have KRAS wild-type tumors with prior

thymidylate synthase inhibitor therapy (5-fluorouracil or capecitabine), be intolerant of or refractory to irinotecan and oxaliplatin, and have an Eastern Cooperative Group Study performance status of 0 to 2. One prior anti-vascular endothelial growth factor (VEGF) therapy but no prior EGFR therapy was allowed. The two arms were well balanced in terms of patient characteristics. More than 90% of patients had received more than three lines of prior chemotherapy and 40% had received one prior anti-VEGF therapy.

At a median follow-up of 19 months, an intention-to-treat analysis showed that median overall survival was 8.8 months in the brivanib arm and 8.1 months in the

❖❖ Brivanib did not improve overall survival in metastatic, K-RAS wild-type colorectal cancer

❖❖Grade 3/4 adverse events were 25% higher with brivanib

❖❖The agent is currently being studied in no fewer than six cancer types

control arm, a difference that was not statistically significant (hazard ratio, 0.88; P=0.12). Median progression-free survival (PFS) was 5.0 months in patients who received brivanib compared with 3.4 months in patients who received placebo see BRIVANIB, page 28 

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SOLID TUMORS

Clinical Oncology News • June 2012

Thromboprophylaxis

Thromboembolism Risk Reduced With Semuloparin From The New England Journal of Medicine

S

emuloparin (Sanofi), an investigational antithrombotic agent, reduces thromboembolic events in patients being administered cancer chemotherapy, while not increasing the incidence of major bleeding.

Venous thromboembolism (VTE) increases morbidity, mortality and cost in patients with cancer, requiring surgical interventions, prolongation of hospital length of stay and additional medical care. There are many factors that increase risk for thromboembolism in patients with cancer, including the specifics of the cancer itself, as well as the type of chemotherapy being administered and its intensity, comorbidities and performance status. However, there is little evidence from randomized

EXPERT INSIGHT Christy J. Samaras, DO Associate Staff Department of Hematologic Oncology and Blood Disorders Cleveland Clinic Taussig Cancer Institute

T

he association between malignancy and VTE is well recognized.

Cancer patients receiving chemotherapy in the postoperative setting who experience a VTE are at twice the risk for dying within the first six months of initial hospitalization compared with those who do not.1 A meta-analysis of several large randomized controlled trials concluded that although thromboprophylaxis with LMWH in

BRIVANIB continued from page 27 

(HR, 0.72; P<0.0001), and more patients achieved a partial response with brivanib than placebo (13.6% vs. 7.2%; P=0.004).

The overall incidence of grade 3/4 non-hematologic adverse events was 78% in the brivanib arm and 53% in the control arm.

“There is no difference on the relative effect of brivanib against placebo in any of the subgroups tested,” said Dr. Siu. Herbert Hurwitz, MD, an associate professor of medicine at Duke Cancer Institute in Durham, N.C., who was not involved in the study, noted that there

controlled trials that antithromboembolism prophylaxis should be given to ambulatory patients with cancer who are receiving chemotherapy.

This double-blind trial, undertaken by the SAVE-ONCO study group, sought to ascertain the safety and efficacy of semuloparin, an ultra-low-molecular-weight heparin (ultra-LMWH; 2,000-3,000 Da) with high anti-Xa activity and low antiIIa activity, for prophylaxis against VTE in patients being administered chemotherapy for solid tumors. The lead author was Giancarlo Agnelli, MD, and the report, for which there were 414 collaborators at multiple international sites, was published in The New England Journal of Medicine (2012;366:601-609, PMID: 22335737). The study was funded by Sanofi.

Patients with either metastatic or locally advanced solid tumors were

given subcutaneous semuloparin, 20 mg per day, or placebo for the duration of their existing chemotherapy regimen.

The study recorded any symptomatic deep vein thrombosis, nonfatal pulmonary embolism or death from VTE as its primary efficacy outcome measurement.

The principal safety outcome was any clinically relevant major or non-major bleeding. The median duration of treatment was 3.5 months.

VTE was noted in 20 of 1,608 (1.2%) patients in the semuloparin group and 55 of 1,604 (3.4%) patients in the placebo group (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.210.60; P<0.001). Semuloparin was consistently effective across subgroups defined according to the cancer type and baseline risk for VTE. Clinically relevant bleeding was seen in 2.8% of the semuloparin group and 2% of the

placebo group (HR, 1.40). There was major bleeding in 19 of 1,589 (1.2%) patients receiving semuloparin and 18 of 1,583 (1.1%) patients receiving placebo (HR, 1.05). Adverse events were similar in both groups. When comparing the semuloparin group with the placebo group, findings were any adverse event (AE), 85% versus 84.6%; any AE related to the study drug, 15.2% versus 11.8%; any serious AE, 26.3% versus 25.5%; any AE leading to death, 12.1% versus 11.7%; and any AE leading to the permanent discontinuation of the study drug, 15.2% versus 16.4%.

The study group concluded that semuloparin does reduce the incidence of thromboembolism in ambulatory patients receiving cancer chemotherapy, and does so without a significant effect on the incidence of major bleeding.

ambulatory cancer patients is effective and results in a significant 46% relative risk reduction of VTE, the absolute risk reduction with prophylactic anticoagulation is only 2.6%, with concerns remaining regarding an increase in major bleeding events.2 In the present study, Agnelli and colleagues report on semuloparin, a hemisynthetic, ultra-LMWH, and its use as thromboprophylaxis in cancer patients receiving chemotherapy. They found that during a treatment duration of approximately 3.5 months, fewer patients receiving the study drug had a VTE compared with a control group receiving placebo (1.2% vs. 3.4%; HR, 0.36; P<0.001). The incidence of clinically relevant and major bleeding was comparable between groups.

Hence, this report demonstrates a decreased incidence of VTE in patients receiving thromboprophylaxis during

chemotherapy, without an increase in major bleeding. However, semuloparin has not been compared with other currently available LMWH products.

Moreover, the study was not powered to demonstrate a survival benefit, and whether the lack of major bleeding observed in treated patients would have been realized if it had been is uncertain. Semuloparin, like other LMWHs, is administered subcutaneously, therefore patients receiving this agent would need to be agreeable to a daily injection.

Whether thromboprophylaxis with semuloparin or other LMWHs becomes standard practice for ambulatory cancer patients receiving chemotherapy remains to be seen. VTE in cancer patients and in those receiving chemotherapy remains a significant problem; yet, although risk reduction was demonstrated in this study, the

absolute degree was fairly small. Additional studies will be needed to better risk-stratify this population and identify those persons at highest risk for VTE in whom the risk– and cost–benefit ratios are maximal.

was a higher than expected rate of side effects, which led to patients dropping out of the study and significant dose reductions in both arms. This could have compromised the value not only of the experimental drug but cetuximab as well, he said. Nevertheless, the trial was clearly negative.

“There was a response-rate and PFS benefit, but this did not translate into an overall survival benefit. There was no meaningful crossover to confound these results,” said Dr. Hurwitz. He pointed out that the median PFS did not reflect the overall benefit of the drug in some patients, given that the survival curves splayed around the 50% mark. He called the 5% response rate

References 1. Levitan N, Dowlati A, Remick SC, et al.

Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy.

Risk analysis using Medicare claims data.

Medicine (Baltimore). 1999;78:285-291, PMID: 10499070.

2. Kuderer N, Ortel T, Khorana A, et al. Low molecular weight heparin thomboprophylaxis in ambulatory cancer patients: a systematic review and metanalysis of randomized controlled trials. Blood (ASH Annual Meeting Abstracts). 2009;114:490.

Dr. Samaras reported no financial disclosures relevant to this study.

tested in Phase I/II trials for gastrointestinal, kidney, endometrial, colorectal and cervical cancers.

“A decision on how best to continue the development [of brivanib] in CRC specifically, will be made after a careful review of the CO.20 study data from NCIC and other ongoing studies,” said Ms. Barnett.

—Kate O’Rourke “potentially biologically interesting,” but not clinically significant.

According to Cristi Barnett, a spokeswoman for BMS, the company is currently investigating brivanib in four Phase III hepatocellular carcinoma trials, and a second Phase III trial is ongoing in CRC (NCT00640471). Brivanib also is being

Dr. Siu disclosed research funding from Bristol-Myers Squibb. Dr. Hurwitz disclosed a consultancy or advisory role with BristolMyers Squibb and Genentech/Roche; honoraria from Roche; and research funding from Bristol-Myers Squibb, Cephalon, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi, Threshold and Tracon.

SOLID TUMORS

Clinical Oncology News • June 2012

Stomach

CHALLENGES continued from page 1 

has been a prevalent topic of research over the past five or 10 years,” said Dr. Shah.

The main risk factors for gastric cancer are Helicobacter pylori, whose rates vary worldwide, tobacco use and family history. Several genetic syndromes predispose individuals to the disease (Table 1). Gastric cancer also has different histologic patterns—intestinal versus diffuse—and is found in different digestive locations, such as gastroesophageal (GE) junction and the pyloric antrum.

A recent study compared a database of gastric cancer patients from Memorial Sloan-Kettering Cancer Center in New York City (n=711) with data from a hospital in Korea (n=1,646) from 1995 to 2005 (Ann Surg 2010;251:640-646, PMID: 20224369). “In the U.S., and certainly in the Northeast and probably the West, proximal tumors, GE junction, distal esophagus and cardia tumors are much more prevalent than they are in Asia, about 40% of the population here versus 10% in Korea, whereas middle and lower tumors of the stomach are

more prevalent in Korea,” said Dr. Shah (Table 2).

This study also showed a difference in tumor stage at diagnosis. Nearly half (42%) of the patients in Korea had stage Ia, the earliest tumor stage, and more than half (60%) were stage I. In the United States, there was more of an even split by tumor stage: Ia (28%), Ib (21%), II (20%), IIIa (16%) and IIIb (8%).

Thirty-day postoperative mortality was higher in the United States (2%) than in Korea (0.2%), a difference that

than patients in the United States. After adjusting for all known confounding risk factors, the DSS for Korean gastric cancer patients remained significantly better than that of U.S. patients by roughly 30% (hazard ratio [HR], 1.3; P=0.05).

“The study cannot exclude inherent biologic differences between gastric cancer in the United States and Korea that accounts for superior survival

Table 1. Genetic Syndromes That Predispose Patients to Gastric Cancer Hereditary diffuse gastric cancer syndrome (accounts for 3%-5% of gastric cancers) Lynch syndrome (1%-2%) Familial adenomatous polyposis (1%) Li-Fraumeni syndrome (<1%)

‘Not only do we have epidemiologic

Peutz-Jeghers syndrome (<1%)

evidence that there are different subtypes of gastric cancer, we now have [gene] expression evidence that there are different subtypes of gastric cancer as well.’

—Manish Shah, MD could not be explained by differences in surgical volume or quality of surgical care, said Dr. Shah. Patients in Korea had higher overall survival (OS; 81% vs. 58%; P<0.0001) and disease-specific survival (DSS; 82% vs. 74%; P<0.0001)

in Korean patients,” said Dr. Shah.

In areas where gastric cancer is most prevalent, such as in China and Japan, intestinal gastric cancer, which has a glandular appearance and spreads through the stomach wall as part of a

tumor mass, is the most common type. There is no regional variation in diffuse gastric cancer, which spreads as discohesive individual cells throughout the stomach wall and is less common than the intestinal type.

Dr. Shah pointed out that proximal and distal gastric cancers have two distinct epidemiologies. Cardia and GE junction cancers are five times more common in men than in women, twice as common in blacks than in whites, occur in a see CHALLENGES, page 30 

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SOLID TUMORS

Clinical Oncology News • June 2012

Stomach

CHALLENGES

Table 2. Differences In Pathologic Characteristics

continued from page 29 

wide range of ages and are common in industrialized nations. Non-cardia cancers (distal), which are more frequent in Korea, are twice as prevalent in males as in females, four times more common in blacks than in whites, and the incidence increases with age.

In 2010, investigators devised a classification system for gastric cancer that divided the disease into three types (J Natl Compr Canc Netw 2010;8:437-447, PMID: 20410336). The first type, noncardia gastric cancer, is linked to environmental factors such as high dietary salt, tobacco use and increasing age; clinical factors such as H. pylori infection and use of nonsteroidal antiinflammatory drugs; and genetic factors including immune regulatory singlenucleotide polymorphisms. The second type, diffuse gastric cancer, is associated with CDH1 mutation and family history and has no known environmental or clinical factors. The third, proximal gastric cancer, is caused by tobacco and alcohol use; has no known genetic link; and is associated with obesity, high body mass index and gastroesophageal reflux disease.

Probing the Genes The classification system suggested genetic differences between the disease types, said Dr. Shah. “If you have clinical criteria that define three different diseases, they should have different molecular signatures as well,” he said.

Dr. Shah analyzed gene expression profiles from the primary tumors of 36 patients with gastric cancer and identified gene signatures that could discrim-

United States, %

0.4

18

Upper

9

21

Middle

36

27

Lower

54

33

Whole

0.4

2

Unknown

1

0

GE junction

cancer samples (2011;43:1219-1223, PMID: 22037554). They found that 59% of gastric cancers had an error in chromatin modification; 59% had an error in cell junction organization; and 77% had an error in cell cycle regulation.

In 2011, researchers also published a study analyzing gene expression profiles for 37 gastric cancer cell lines and

GE, gastroesophageal Adapted from Strong VE, Song KY, et al. Comparison of gastric cancer survival following R0 resection in the United States and Korea using an internationally validated nomogram. Ann Surg 2010;251:640-646, PMID: 20224369.

‘Upper GI cancers are complex with multiple genetic and epigenetic alterations. The complexity of signaling networks in cancer cells is a challenge in developing successful therapeutics.’

—Wael El-Rifai, MD, PhD identified two intrinsic subtypes, intestinal (G-INT) or diffuse (G-DIF), that they then validated in the primary tumors of 521 patients (Gastroenterology 2011;141:476-485, PMID: 21684283).

They identified a 171-gene set that robustly classifies tumors into the two subtypes. In univariate and multivariate analyses, these intrinsic subtypes, but not subtypes based on Lauren’s histopathologic classification, were prognostic of survival. The G-INT cell lines were significantly more sensitive to

‘If you accept that there are subtypes of gastric cancer, then you must accept that they might have different molecular drivers and therefore they may respond to different molecular targets. I think that is the future of gastric cancer.’ inate three types of gastric tumors— proximal GE junction tumors, diffuse gastric tumors and distal intestinal type tumors—with 85% accuracy (Clin Cancer Res 2011;17:2693-2701, PMID: 21430069).

“Not only do we have epidemiologic evidence that there are different subtypes of gastric cancer, we now have [gene] expression evidence that there are different subtypes of gastric cancer as well,” Dr. Shah said.

Additional evidence for diverse genetics comes from a Nature Genetics study in which researchers performed exome sequencing with 22 gastric

Korea, %

—Manish Shah, MD

5-fluorouracil (5-FU) and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines. The subtypes were also linked with survival following adjuvant, 5-FU–based therapy.

Restructuring Clinical Trials “The implication of all this is that gastric cancer is not one disease. There are subtypes of gastric cancer and these subtypes may explain the differences in response to therapy and the differences in prognosis,” said Dr. Shah. “If you accept that there are subtypes of gastric cancer, then you must accept that they

might have different molecular drivers and therefore they may respond to different molecular targets, and I think that is the future of gastric cancer.”

According to Wael El-Rifai, MD, PhD, a professor of surgery at Vanderbilt University Medical Center in Nashville, Tenn., a wide range of therapeutic drugs are in the pipeline in Phase I/II clinical trials for upper gastrointestinal (GI) cancer. These include inhibitors of crucial molecular targets and cancer signaling pathways such as EGFR, VEGFR, HER2, HER3, aurora kinases, MET, BCL2, DNA methyltransferases, histone deacetylases, heat shock proteins, AKT, mTOR and MEK. “Upper GI cancers are complex with multiple genetic and epigenetic alterations. The complexity of signaling networks in cancer cells is a challenge in developing successful therapeutics,” said Dr. El-Rifai. Genetic approaches, he argued, are powerful in identifying novel targets that could modulate response to therapy, but given the complexity of signaling networks in cancer cells, single-agent therapies may not work for every patient. “Combined strategies that take into account the molecular and biological features of tumors are the future of personalized medicine in cancer therapy,” said Dr. El-Rifai.

He added that clinical trials need to consider the molecular defects in cancer cells of each patient to allow matching patients to therapies that are likely to block the effects of those specific molecular alterations. However,

because of the complexity of the cancer genome, treatment response could vary from one patient to another.

In a recently reported Phase II trial, Dr. Shah and colleagues tested a modified docetaxel, cisplatin, 5-FU and bevacizumab (Avastin, Genentech) regimen in patients with metastatic gastroesophageal adenocarcinoma (J Clin Oncol 2011;29:868-874, PMID: 21189380). The data was encouraging with a six-month progression-free survival (PFS) of 79%, a median PFS of 12 months and a median OS of 16.3 months.

The results were more intriguing, however, when researchers looked more closely at subtypes. “If you divide by the subtypes we defined—proximal tumors, distal tumors and diffuse tumors—we see quite significant differences,” Dr. Shah said. The response rate was 85% in patients with proximal/GE junction tumors, 38% in diffuse tumors and 56% in patients with distal/intestinal tumors.

According to Dr. Shah, investigators testing agents such as cetuximab (Erbitux, Bristol-Myers Squibb), panitumumab (Vectibix, Amgen), sorafenib (Nexavar, Bayer Healthcare Pharmaceuticals) and trastuzumab (Herceptin, Genentech) have not examined the effectiveness of these agents by subtypes of gastric cancer.

“Many of these [agents] have been studied in gastric cancer, but virtually none have actually defined the diseases they have studied. They [the researchers] have grouped them all together,” said Dr. Shah. He thinks clinical trials should be designed to address or account for disease heterogeneity that occurs within a disease and also globally.

“Understand your target. Understand your disease,” he said. “I think we are approaching that in GI malignancies, and therefore the future is bright.”

—Kate O’Rourke Dr. Shah disclosed receiving research funding from Genentech and Sanofi. Dr. El-Rifai had no relevant disclosures.

❖❖Gastric cancer incidence and stage at diagnosis differ widely by geography

❖❖ Epidemiology, risk factors, response to therapy, and genetic analyses suggest that gastric cancer may be an extremely heterogeneous disease

❖❖Anticancer therapies including cetuximab, panitumumab, sorafenib and trastuzumab have not been well studied in gastric cancer subtypes, although studies suggest response rates may vary widely

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Arthur T. Skarin Elsevier/Mosby, December 23, 2009 This book provides the guidance you need to more accurately diagnose a full range of neoplastic conditions for better patient outcomes. An unrivaled collection of more than 2,500 images and drawings, combined with succinct, clinically focused text, equips you with essential information on pathology, diagnostic studies, staging and clinical manifestations.

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Thomas N. Seyfried John Wiley, June 26, 2012 This book aims to provide evidence, through case studies, that cancer is primarily a metabolic disease requring metabolic solutions for its management and prevention. Support for this position is derived from critical assessment of current cancer theories.

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Franco Muggia Elsevier/Saunders, June 28, 2012 Topics in this issue include targeting IGF-1R, tyrosine kinase inhibitors in lung cancer, targeting mTOR, targeting hedgehog, mitotic inhibitors and topoisomerase I inhibitors.

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Recent Advances and Emerging Therapies In the Systemic Treatment of

Metastatic Melanoma JEFFREY T. YORIO, MD Fellow, Hematology and Oncology

KEVIN B. KIM, MD Associate Professor Department of Melanoma Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

M

elanoma, the malignant transformation of melanocytes, most commonly occurs in the skin but also may arise from the mucosal surfaces or in the choroid of the eyes. Melanoma is the fifth and

sixth most common cancer in men and women, respectively, in the United States.1 In 2012, more than 76,000 people will be diagnosed with malignant melanoma, and more than 9,000 people will die from the disease nationally.1

Although surgery offers a great cure rate for patients with early-stage melanoma, those who have either metastatic disease or a high risk for recurrence are given a much poorer prognosis. In fact, the median overall survival (OS) of patients with stage IV melanoma is only 6 to 9 months.2-4 Dacarbazine remains the only cytotoxic chemotherapy FDA-approved for the treatment of metastatic melanoma. However, dacarbazine has modest clinical efficacy, with a response rate of only about 10%.2,4-6 The FDA also has approved high-dose interleukin-2 (IL-2) for the treatment of advanced melanoma because of the agent’s ability to induce a durable response.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Unfortunately, this response is observed in only a small subset of patients, and IL-2 is associated with significant toxicities, such as capillary leak syndrome, that frequently require intensive monitoring in a dedicated unit or intensive care facility.7,8 Other agents—including temozolomide (Temodar, Schering-Plough), cisplatin, carboplatin, vinblastine, paclitaxel, carmustine, and lomustine (CeeNu, Bristol-Myers Squibb)—are commonly used off-label to treat melanoma, but none of these agents or their various combinations have been found to offer a survival advantage over dacarbazine alone.9 Clearly, more active and less toxic drugs are needed for patients with advanced melanoma. In this article, we

C L I N I C A L O N CO LO GY N E WS • J U N E 2 0 1 2

1

review recent advances and emerging therapeutic approaches in the systemic treatment of metastatic melanoma.

Newly Approved Drugs For Late-Stage Melanoma IPILIMUMAB Immunotherapy has been used to treat melanoma for decades. Cancer cells, such as those that make up melanoma, have tumor-associated antigens that can be recognized by T cells. This recognition leads to a host response that targets the tumor cells.10 The standard immunotherapy, high-dose IL-2, enhances this response but elicits a durable clinical response in only a small subset of patients.8,11,12 Accordingly, researchers have actively sought to identify and develop more effective immunologic agents with better safety profiles.

Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 (CTLA-4), a co-inhibitory receptor molecule found on the surface of activated T cells. T-cell activation begins when the T-cell receptor binds to an antigen presented by a major histocompatibility complex on antigen-presenting cells, such as dendritic cells. Cluster of differentiation 28 (CD28), a co-stimulatory receptor molecule found on T cells, binds to B7 (CD80/CD86) found on antigenpresenting cells, leading to T-cell proliferation and IL-2 production. As T cells become activated, CTLA-4 is upregulated to the cell surface, where it competes successfully with CD28 for B7 to halt further cell proliferation in a self-regulatory mechanism. Ipilimumab blocks CTLA-4 on the cell surface, thereby preventing CTLA-4 from binding to B7 molecules and allowing CD28 to bind to these molecules instead, leading to further T-cell proliferation and IL-2 production.13,14 Ultimately, this can help increase the immune response to cancer cells.

Initial clinical studies revealed that ipilimumab could be a promising new therapy for metastatic melanoma.15,16 A Phase I/II trial of ipilimumab (â&#x2030;¤10 mg/kg every 3 weeks) in 23 patients with metastatic melanoma demonstrated a disease control rate of 39%, with at least 2 patients experiencing a durable response of longer than 21 months.15 These encouraging results led to several Phase III trials of ipilimumab in patients with metastatic melanoma (Table 1).17,18 In the first Phase III study of ipilimumab, 676 previously treated patients with unresectable stage III or IV melanoma were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab with a glycoprotein 100 (gp100) peptide vaccine (n=403), ipilimumab alone (n=137), or the gp100 peptide vaccine alone (n=136).17 Ipilimumab was given at a dose of 3 mg/kg every 3 weeks for 4 doses. The median OS of patients who received ipilimumab alone (10.1 months) was significantly longer than that of patients who received the gp100 vaccine alone (6.4 months; hazard ratio [HR], 0.66; P=0.003).

2

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However, the median OS of patients who received ipilimumab with the gp100 vaccine did not differ significantly from that of patients who received ipilimumab alone. The risk for disease progression in patients who received ipilimumab alone was 36% lower than that for patients who received the gp100 vaccine alone (P<0.001). The median progression-free survival (PFS) durations of the 3 groups were similar (2.76 months in the combination group, 2.86 months in the ipilimumab-alone group, and 2.76 months in the gp100 vaccine-alone group). The results of this trial led to the FDAâ&#x20AC;&#x2122;s approval of the drug for the treatment of metastatic melanoma in March 2011.

In the second Phase III study of ipilimumab, 502 treatment-naive patients with metastatic melanoma were randomized to receive dacarbazine with or without ipilimumab.6 During the induction phase, ipilimumab was given at a dose of 10 mg/kg every 3 weeks for 4 doses.

During the maintenance phase, patients who did not experience severe toxicity during the induction phase were given additional doses of ipilimumab (10 mg/kg every 12 weeks). The median OS duration of the patients who received dacarbazine plus ipilimumab (11.2 months) was significantly longer than that of the patients who received dacarbazine alone (9.1 months; P<0.001). The 3-year OS rates in the dacarbazine plus ipilimumab group and the dacarbazine-only group were 20.8% and 12.2%, respectively. The risk for disease progression in the patients who received dacarbazine plus ipilimumab was 24% lower than that for the patients who received dacarbazine alone (P=0.006).

As with other immune-stimulating agents, ipilimumab induces immune-related adverse events (AEs).

In the first Phase III trial, the most common immunerelated AEs among those receiving ipilimumab alone were diarrhea (28%), pruritus (24%), rash (19%), and colitis (8%).17 Grade 3 or 4 diarrhea and colitis was seen in 5% of the patients. The addition of dacarbazine to ipilimumab in the second Phase III trial also resulted in notable elevations in serum liver enzyme levels. Of the 247 patients receiving the combination, elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in 33% and 27% of the patients, respectively.6 Grade 3 or 4 elevations in ALT and AST were seen in 21% and 17%, respectively.

Endocrine immune-related AEs such as hypothyroidism, hypopituitarism, and adrenal insufficiency were observed but were uncommon.

Patients who develop grade 2 diarrhea should be considered for treatment with oral steroids such as budesonide, whereas patients with grade 3 and 4 diarrhea should discontinue ipilimumab and receive highdose systemic corticosteroids until improvement.18 Infliximab, an anti-tumor necrosis factor-Îą antibody, has been used with some success to treat patients who are unresponsive to high-dose steroids. The use of high-dose IV corticosteroids also has been suggested for grade 3 or 4 elevations in serum liver enzyme levels and endocrinopathies.

Table 1. Clinical Data From Positive Phase III Studies of Melanoma N

Treatment Setting

Primary End Point Results

Hazard Ratio (95% CI)

gp100 vaccine

136

Second-line

OS, 6.4 mo

Reference

Ipilimumab

137

OS, 10.1 mo

0.66 (0.51-0.87)

0.003

Ipilimumab + gp100 vaccine

403

OS, 10.0 mo

0.68 (0.55-0.85)

<0.001

Trial and Regimen

P Value

NCT00094653

NCT00324155 Dacarbazine + placebo

252

Dacarbazine + ipilimumab

250

First-line

OS, 9.1 mo

Reference

OS, 11.2 mo

0.72 (0.59-0.87)

OSa

Reference

<0.001

NCT01006980 Dacarbazine

338

First-line; V600E BRAF mutation

OS

a

Vemurafenib

337

0.37 (0.26-0.55)

Dacarbazine

338

PFS, 1.6 mo

Reference

Vemurafenib

337

PFS, 5.3 mo

0.26 (0.20-0.33)

<0.001

<0.001

CI, confidence interval; gp100, glycoprotein 100; OS, overall survival; PFS, progression-free survival a

Inadequate number of patients in follow-up to provide reliable estimates of the survival curve

VEMURAFENIB The Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway is a key pathway for cell proliferation, particularly in cancer cells (Figure).19 In 2002, Davies et al reported that nearly 60% of melanomas harbor a mutation in BRAF, which codes for a serine-threonine protein kinase involved in the Ras/Raf/MEK/ERK pathway.20 Most BRAF mutations are the result of a single nucleotide substitution in which valine is replaced by glutamic acid at codon 600 (V600E) of exon 15, leading to the constitutive activation of the MEK protein and ERKs, which are essential to melanoma cell proliferation. Melanoma cells with the BRAF mutation do not require Ras activation to proliferate, indicating that the BRAF mutation is a driving force behind melanoma cell growth.

To inhibit the Raf/MEK/ERK pathway, researchers investigated sorafenib (Nexavar, Bayer), an inhibitor of multiple kinases, including BRAF, CRAF, and vascular endothelial growth factor receptor (VEGFR). However, 2 Phase II trials of sorafenib at a dose of 400 mg twice daily revealed that the drug elicited little or no response in patients with metastatic melanoma; additionally, the presence of the BRAF mutation was not correlated with response.21,22 Similarly, 2 large randomized Phase III trials revealed that the addition of sorafenib to front- or second-line carboplatin or paclitaxel yielded no additional clinical benefit in patients with metastatic melanoma.23,24 Despite the underwhelming results with sorafenib, researchers used scaffold-based drug design methods to develop increasingly selective inhibitors of the mutated Raf kinase. One of these new drugs, PLX4032 (later

named vemurafenib [Zelboraf, Roche]), was found to have a high affinity for the mutant BRAF kinase.25 A first-in-human Phase I trial of oral vemurafenib enrolled 55 patients and found the maximum tolerated dose (MTD) of the drug to be 960 mg twice a day.26 Thirty-two patients with metastatic melanoma harboring a BRAF mutation were then enrolled in the dose-extension cohort and received vemurafenib at a dose of 960 mg twice a day. Of these 32 patients, 26 had a partial or complete response (CR), for an overall response rate (ORR) of 81% with a confirmed response rate of 56% per Response Evaluation Criteria in Solid Tumors (RECIST).

Subsequently, a large Phase II study of vemurafenib was conducted in 132 previously treated patients who had metastatic melanoma harboring a V600E BRAF mutation.27 The ORR, which was validated by an independent review committee, was 53%, with a median PFS duration of 6.8 months, thus confirming the promising results of the Phase I study.

A concurrent, large multicenter randomized Phase III trial was then conducted to compare the clinical benefit of vemurafenib with that of dacarbazine in treatment-naive patients with metastatic melanoma harboring a V600E BRAF mutation (Table 1).5 Six hundred seventy-five patients were randomized to receive either vemurafenib or dacarbazine, with the primary end points being OS and PFS. At the time of the interim analysis, the hazard ratio for death in the vemurafenib group was 0.37 (P<0.001), and the estimated median PFS duration of patients in the vemurafenib arm (5.3 months) was significantly longer than that of patients in the dacarbazine arm (1.6 months; HR, 0.26; P<0.001). The study was stopped at the time of

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3

Cell membrane receptor

PI3K

Ras

PTEN AKT

Raf MEK 1/2

mTOR

ERK 1/2

IF4E

Cyclin D1

Transcription factors

p70

MMP-2

Tumor cell survival, proliferation, invasion

Nucleus

Figure. Commonly activated signal transduction pathways in melanoma.

ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin

the interim analysis so that patients in the dacarbazine arm could receive vemurafenib.

Overall, patients in the Phase III trial tolerated vemurafenib fairly well.5 The most common AEs were arthralgias, fatigue, and cutaneous events. Twelve percent of patients experienced grade 2 or 3 photosensitivity reactions, but the use of sunblock helped prevent the blistering typically observed in grade 3 reactions.

Eighteen percent of patients developed either cutaneous squamous cell carcinomas (SqCC) or keratoacanthomas; fortunately, these were all treated by simple excision with no further complications or evidence of SqCC in other organs.

These SqCCs could have been the result of the paradoxical activation of the Ras/Raf/MEK/ERK pathway in premalignant skin lesions that lack a BRAF mutation.28,29 Poulikakos et al demonstrated that the binding of vemurafenib to BRAF, which forms a dimer with another Raf kinase, actually leads to transactivation of adenosine triphosphate (ATP)-bound Raf, causing the downstream activation of MEK and ERK in wild-type BRAF cells.30 Many vemurafenib-induced SqCCs harbor a mutation in Ras that ultimately becomes activated

4

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when vemurafenib binds to wild-type BRAF.28,29 Based on the statistically significant improvement in both OS and PFS and the acceptable safety profile, in summer 2011 the FDA approved vemurafenib for the treatment of metastatic melanoma harboring a V600E BRAF mutation. However, despite the high response rate, a majority of patients will have disease progression within 1 year, and a long-term clinical benefit is expected only in a small subset of patients. Therefore, more effective therapeutic strategies are urgently needed.

Emerging Targeted Therapies SELECTIVE RAF INHIBITORS The successful development of vemurafenib has generated great interest in the clinical evaluation of selective Raf inhibitors in patients with metastatic melanoma harboring a BRAF mutation. One such agent, dabrafenib (GSK2118436, GlaxoSmithKline) is an orally available, highly potent ATP-competitive inhibitor of BRAF.31 In a Phase I/II study in patients with advanced solid tumors, dabrafenib was well tolerated, and the MTD was not reached.32 Dabrafenib inhibited the phosphorylation of

ERK in a dose-dependent manner, and based on the pharmacokinetics and pharmacodynamics of the drug and its early clinical activity in the Phase I study, investigators recommended a dose of 150 mg twice daily for further studies. Of the 16 patients in the study who had metastatic melanoma harboring a V600 BRAF mutation and received at least 150 mg of dabrafenib twice daily, 10 (63%) had a partial response. Interestingly, of the 10 patients in the study who had active brain metastases measuring at least 3 mm at baseline, 7 also had a clinical response in the brain lesions.33 Subsequently, a Phase II study of dabrafenib enrolled 76 patients who had metastatic melanoma harboring a V600E/K BRAF mutation.34 Of these 76 patients, 45 (59%) had a confirmed response to dabrafenib, and the median PFS duration was 27.4 weeks. The common AEs associated with dabrafenib were arthralgia, pyrexia, fatigue, hyperkeratosis, and SqCC of the skin. A Phase III study (NCT01227889) is under way to compare dabrafenib and dacarbazine with respect to PFS in treatment-naive patients with metastatic melanoma who harbor a V600E BRAF mutation (Table 2).

Another promising selective Raf inhibitor is LGX818 (Novartis). The results of a Phase I trial of the drug (NCT01436656) will be available shortly.

MEK INHIBITORS Another approach to treating metastatic melanoma is to inhibit the mitogen-activated protein (MAP) kinase pathway at the level downstream of BRAF kinase. This pathway is commonly activated in melanoma and is induced not only by mutated BRAF, but also by kinaseactivating NRAS mutations or other upstream aberrations, such as receptor kinase phosphorylation. In this signal transduction pathway, the MAP kinase kinase (MEK) protein is the direct substrate of activated BRAF kinase. Therefore, targeting the MEK protein can inhibit the MAP kinase pathway.

The results of clinical trials of first-generation MEK inhibitors were disappointing. For example, CI-1040 (Pfizer) and PD0325901 (Pfizer) had poor clinical activity and caused significant AEs, including retinal vein occlusion, that resulted in the discontinuation of their development.35,36 Selumetinib (AZD6244, AstraZeneca) is an orally available, highly selective, allosteric inhibitor of MEK1/2. Although in vitro studies revealed that melanoma cell lines containing a BRAF mutation were particularly sensitive to selumetinib,37,38 a randomized Phase II study showed that the drug had no clinical benefit over temozolomide in chemotherapy-naive patients with metastatic melanoma.39 The differences in the median PFS duration (78 vs 80 days) and ORR (5.8% vs 9.4%) between the patients who received selumetinib and those who received temozolomide, respectively, were not statistically significant, and the response rates among patients with melanoma containing a BRAF mutation in each group were both the same, at 11%.

Clinical outcomes with the next-generation, hydrogen sulfate (Hyd-sulfate) formulation of selumetinib,

Table 2. Ongoing Phase III Clinical Trials for Metastatic Melanoma Trial and Regimen

Treatment Mutation Setting Criteria

Primary End Point

N

NCT01227889 Dabrafenib (GSK2118436) versus dacarbazine

First-line

V600E BRAF mutation

PFS

249

â&#x2030;¤1 prior systemic chemotherapy

V600E/K BRAF mutation

PFS

322

First-line

C-Kit (juxtamembrane)

OS

200

First-line

Any

OS

700

NCT01245062 Trametinib (GSK1120212) versus dacarbazine or paclitaxel NCT01280565 Masitinib versus dacarbazine NCT01515189 Ipilimumab (3 mg/kg) versus ipilimumab (10 mg/kg)

OS, overall survival; PFS, progression-free survival

which has better oral bioavailability than does the original crystalline formulation, are more promising. A Phase I dose-finding study revealed the MTD of Hyd-sulfate selumetinib to be 75 mg twice daily.40 In a separate Phase I study of combination regimens containing Hyd-sulfate selumetinib, patients with metastatic melanoma with a BRAF mutation had a higher clinical response rate and longer median time to progression than did those without a BRAF mutation, suggesting that BRAF mutation is a positive predictive factor for Hyd-sulfate selumetinib.41 A randomized Phase II study comparing dacarbazine plus Hyd-sulfate selumetinib with dacarbazine alone in treatment-naive patients with BRAF-mutated melanoma (NCT00936221) recently completed patient accrual, and the results of this study are highly anticipated.

Another potent, highly selective, nonâ&#x20AC;&#x201C;ATP-competitive MEK1/2 inhibitor is trametinib (GSK1120212, GlaxoSmithKline). Although a Phase I study revealed the MTD of trametinib to be 3 mg per day, 2 mg per day was chosen as the recommended dose for future studies on the basis of pharmacokinetic, clinical activity, and safety data.42 The results of a recent Phase II study of trametinib (2 mg/d) in 97 previously treated patients with metastatic melanoma harboring a V600 BRAF mutation are encouraging.43 In this study, of the 57 patients who had not been previously treated with a BRAF inhibitor (of whom 81% had a V600E

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5

BRAF mutation and 75% had M1c disease), 14 (25%) had a confirmed response, and the median PFS duration was 4 months (95% confidence interval [CI], 3.5-5.6 months).

However, of the 40 patients who had previously received a BRAF inhibitor, none had a confirmed clinical response, and the median PFS duration was 1.8 months (CI, 1.8-2.0 months). The marked differences in clinical response and PFS between the 2 groups suggest that the mechanisms of resistance to BRAF inhibitors also might confer resistance to MEK inhibitors. The results of an open-label randomized Phase III study (NCT01245062) comparing the PFS associated with trametinib with those associated with dacarbazine or paclitaxel in patients with metastatic melanoma harboring a V600 BRAF mutation will be available shortly (Table 2).

Other MEK inhibitors in the early phases of clinical investigation include AS703026 (EMD/Merck Serono), E6201 (Eisai), MEK162 (Novartis), and GDC-0973 (Genentech).

The common AEs of MEK inhibitors include skin rash, diarrhea, nausea, vomiting, peripheral edema, and fatigue.35,36,39,40,42,43 Visual disturbances, such as blurry vision or flashing lights, are common but generally mild.

Serious ocular toxicity, including central serous retinopathy and retinal vein occlusion, is uncommon. The decreased left ventricular ejection fraction associated with the use of MEK inhibitors is mostly asymptomatic and is reversible upon discontinuation of the drugs.

COMBINATION STRATEGIES USING TARGETED THERAPIES Despite the high response rates observed with Raf inhibitors and the promising clinical activity of MEK inhibitors in patients with advanced melanoma harboring a BRAF mutation, the durations of response to these drugs are relatively short because of acquired drug resistance. Recent studies have elucidated a number of mechanisms of resistance to these drugs, including acquisition of activating NRAS mutations,44 acquisition of activating MEK mutations,45 upregulation of upstream receptor kinases,46 upregulation of CRAF kinase,47 induction of splicing variants of BRAF kinase,48 increased Cot expression,49 and activation of PI3K/AKT signaling pathways.50,51 Loss of BRAF mutations and the development of secondary mutations to the drug-binding domain of BRAF kinase have not been observed at the time of drug resistance, however.44,46 A recent study found that although vemurafenib universally inhibited the phosphorylation of tumoral ERK1/2 protein within 14 days of treatment, the phosphorylated-ERK1/2 was re-upregulated at the time of disease progression in a subset of patients.52 This finding suggests that in at least some patients, the reactivation of the MAP kinase pathway is associated with resistance to the Raf inhibitors and can, at least partially, bypass the inhibition of the BRAF mutations. In vitro studies have shown that the addition of a MEK inhibitor can delay the development of drug resistance to a selective Raf inhibitor.45 On the basis of these encouraging findings, a Phase I

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study of dabrafenib plus trametinib (NCT01072175) was conducted in patients with metastatic melanoma.

The clinical data generated from the studyâ&#x20AC;&#x2122;s interim analysis are promising.53,54 Given at the recommended doses for a Phase II study, the combination of dabrafenib (150 mg twice daily) and trametinib (1-2 mg per day) was well tolerated, with mild AEs, the most common of which were pyrexia, chills, nausea, diarrhea, and fatigue.53 Skin toxicity, including the development of cutaneous SqCC, occurred much less commonly than was anticipated based on the safety data of dabrafenib treatment alone, suggesting that treatment with the selective Raf inhibitor paradoxically activated MAP kinase in the normal skin, and the concurrent treatment with MEK eliminated this paradoxical MAP kinase activation. Of the 65 patients who had metastatic melanoma containing a V600E/K/D BRAF mutation and who had never received a BRAF inhibitor, 43 (66%) had objective responses, including 5 (8%) CRs.53 Additionally, of the 26 patients who previously had been treated with a selective Raf inhibitor, 5 (19%) had partial responses.54

KIT INHIBITORS Preclinical findings demonstrating the essential role of stem cell factor and its receptor, KIT tyrosine kinase, in the proliferation and survival of melanocyte precursors,55,56 and KITâ&#x20AC;&#x2122;s frequent expression in melanoma specimens56,57 led investigators to conduct 3 studies evaluating the use of imatinib (Gleevec, Novartis) in patients with metastatic melanoma in the early 2000s.58-60 Unfortunately, imatinib had minimal clinical activity, with only 1 of 63 patients (who had not been selected on the basis of genomic biomarkers) responding to the drug.

Interest in KIT-targeted therapy in melanoma was renewed when Curtin et al showed that KIT mutation and/or amplification is more common in certain subtypes of melanoma than in others.61 In their analysis of 102 primary melanomas, they used a comparative genomic hybridization assay and found KIT mutations and/or increased copy numbers of KIT in 36% of acral lentiginous melanomas, 39% of mucosal melanomas, and 28% of melanomas that developed in chronically sun-damaged skin. Following this novel discovery, a number of case reports have emerged showing that KIT inhibitors have clinical benefit in patients who have melanoma harboring KIT mutations.62-65 Additionally, the interim analysis of a Phase II study of imatinib in patients with advanced acral lentiginous melanoma, mucosal melanoma, or melanoma in chronic sun-damaged skin revealed that 5 of 10 patients with melanoma harboring a KIT mutation had a clinical response to the drug.66 However, none of 10 patients with KIT amplification without a mutation had a response.

In another Phase II study of imatinib in 43 patients with metastatic melanoma harboring a KIT mutation or amplification, 10 (23%) patients had an overall clinical response, and 9 of the 10 responders had a KIT mutation in exon 11 or 13.67 In a separate Phase II study of

imatinib in a similar population, 4 (16%) of 25 patients had a durable clinical response, including 2 patients who had CRs.68 The response rate among patients who had mutations affecting recurrent hotspots of the KIT gene or a higher KIT mutant-to-wild-type allele ratio (>1) was 40%, whereas the response rate among patients who did not have these features was 0% (P=0.05), suggesting that the presence of a functionally relevant KIT mutation is required for imatinib or other KIT inhibitors to have clinical benefit.

Emerging Immunotherapies ANTI-PD1 ANTIBODY Like CTLA-4, programmed death 1 (PD-1) is a member of the CD28 family. PD-1 is expressed in activated T cells, memory T cells, and regulatory T cells and is involved in T-cell regulation. Upon binding to its ligands, PD-L1 and PD-L2 (which are highly expressed in tumor cells and the antigen-presenting cells found in tumors), PD1 suppresses T-cell effector function. Tumoral PD-L1 expression has been associated with negative prognosis in cancer patients.69,70 MDX-1106 (Bristol-Myers Squibb), a fully human immunoglobulin G4 monoclonal antibody against PD-1, can interrupt the binding of PD-1 with its ligands, thereby reactivating T-cell function.71 In a Phase I dose-escalating study evaluating a single dose of the drug (with 2 additional doses every 4 weeks allowed in patients in whom continued clinical benefit was observed), MDX-1106 was well tolerated with only one serious AE (colitis).72 Of the 39 patients in the study, 3 patients, including one with metastatic melanoma, had a clinical response to MDX-1106.

Another Phase I study evaluated the safety profile of a biweekly dosing schedule of MDX-1106 in patients with refractory metastatic non-small cell lung cancer, renal cell carcinoma, melanoma, or prostate cancer.73 The MTD of the drug was not reached up to a dose of 10 mg/kg every 2 weeks. Common AEs included fatigue, nausea, diarrhea, xerostomia, and pruritus, but grade 3 or 4 AEs were uncommon. In the preliminary response evaluation, 6 (38%) of 16 patients had objective responses; among these patients, 3 patients with metastatic melanoma had a partial response. The clinical investigation of MDX-1106 is ongoing.

ADOPTIVE T-CELL THERAPY In the mid-1980s, Rosenberg et al found that tumorinfiltrating lymphocytes (TILs) isolated from murine sarcomas and colon adenocarcinomas that had been transplanted into syngeneic mice could be expanded with IL-2 in vitro. When infused back into the donor mice, the TILs could mediate the regression of metastatic tumors.74 They later reported the regression of metastatic melanoma lesions in 11 of 20 patients who were treated with the adoptive transfer of TILs and IL-2 infusion following a single dose of cyclophosphamide.75 Other researchers found that when the

adoptive transfer of TILs and IL-2 infusion were preceded by a 7-day regimen of cyclophosphamide and fludarabine, which depleted the number of endogenous regulatory cells and lymphocytes that would compete with the transferred TILs for growth-promoting homeostatic cytokines, 6 of 13 patients had a clinical response.76 Notably, this approach resulted in the persistent clonal repopulation of T cells, which proliferated in vivo and traveled to tumor sites in these patients.

In an expanded Phase II study conducted by the same group of investigators, lympho-depleting chemotherapy followed by TIL transfer and high-dose IL-2 infusion elicited a response rate of 51% among 35 patients with metastatic melanoma.77 When TIL transfer and IL-2 infusion were preceded by myeloablative chemoradiation (lympho-depleting chemotherapy plus 2 or 12 Gy of total-body irradiation), clinical activity of the regimen was even better, with response rates of 52% and 72%, respectively.78 Of 20 patients who had CRs in these trials of adoptive TIL transfer, only 1 patientâ&#x20AC;&#x2122;s disease has relapsed. The other patients continue to have CRs 3 to 7 years following the completion of the treatment.78,79 In another study, CD4-positive T-cell clones targeting the DPB1*0401-restricted epitope of a peptide derived from NY-ESO-1 were isolated from the peripheral blood mononuclear cells of patients with metastatic melanoma and expanded in vitro, and the antigen-specific CD4-positive T cells were infused back into the patient.80 One patient had a complete resolution of lung and nodal metastases that was accompanied by the persistent presence of the NY-ESO-1â&#x20AC;&#x201C;specific CD4-positive T cells and lasted for at least 2 years. This finding suggests that the adoptive transfer of antigen-specific CD4-positive T cells may be used to treat advanced melanoma.

Conclusion After a long drought in the development of successful therapies, recent advances in targeted therapy and immunotherapy have set a new standard of treatment for metastatic melanoma. However, the arrival of ipilimumab and vemurafenib in the clinic has generated more questions and challenges. For example, it is not clear which of these agents, ipilimumab or vemurafenib, should be offered first in patients with metastatic disease, especially in those with limited or slowly progressing metastatic lesions; in addition, the optimal sequencing of high-dose IL-2 with these agents remains unknown. Whether a Raf inhibitor should be added to subsequent therapy following the failure of BRAF inhibition is also unclear. The optimal combination of targeted drugs and/or immunotherapeutic agents will need to be determined to maximize their clinical benefit in patients with metastatic melanoma. We hope that these important questions soon will be addressed with rationally designed clinical studies.

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