Clinical Oncology News Hematology Digital Edition - February 2012 by McMahon Group

Independent News on Advances in Cancer Care

Hematology/Oncology Edition clinicaloncology.com • February 2012 • Vol. 7, No. 2

HematOlogic DISEASE

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

A pplying clinical trials to ‘real-world’ cancer care.

Actively recruiting Phase II/III trials started in the past 30 days. SOLID TUMORS

Mounting evidence on the connection between painkillers and malignancy.

14 22

Finding an Avastin Biomarker: An Elusive Target For a decade, investigators have searched in vain for a predictive bevacizumab marker

his past fall, when the FDA withdrew bevacizumab’s approval for metastatic breast cancer, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, urged the company’s manufacturer, Genentech, to identify a biomarker that predicts response to the drug. The advice was well taken: Genentech had already submitted a proposed Phase III trial to the FDA to test the suitability of vascular endothelial growth factor (VEGF)-A as see BEVACIZUMAB, page 11 

Contralateral Breast Cancer Risks in BRCA1/2 Carriers. A new DCIS test from the makers of Oncotype DX PRN

Apps for practicing clinicians.

McMahonMedicalBooks.com MedInfoNow Subscription See page 27.

Modifying Initial Breast Cancer Treatments Based on early response

e have seen mountains of data to the effect that failure to achieve pathologic complete remission (pCR) with chemotherapy given Vogl, before resection (neoad- Steven MD juvant chemotherapy) of a primary breast cancer predicts a relatively poor prognosis. We all assumed that women who do not achieve pCR need better therapy before surgery— when the failure to achieve pCR is discovered—or more effective therapy after residual cancer has been see RESPONSE, page 24 

In studies presented at ASH …

Nilotinib Continues To Produce Deep Response in Patients San Diego—Twice as many patients with chronic myeloid leukemia who switch to the secondgeneration tyrosine kinase inhibitor nilotinib (Tasigna, Novartis) achieve undetectable levels of Bcr-Abl within one year compared with patients who continue on imatinib (Gleevec, Novartis), according to a new study. About 40% of imatinibtreated patients with chronic phase chronic myeloid leukemia (CML-CP) who achieve durable complete molecular response (CMR) are able to discontinue therapy without recurrence. However, the remaining majority of patients with CML do not achieve CMR on imatinib even with longterm therapy of more than six years,

Nilotinib is a tyrosine kinase inhibitor that is 10-30 fold more potent than imatinib in inhibiting activity of the Bcr-Abl tyrosine kinase, according to studies.

see NILOTINIB, page 4 

AMA Delegates Balk at ICD-10 Too many codes; lack of EMR systems to support it New Orleans—At the 65th Interim Meeting of the American Medical Association (AMA) House of Delegates, delegates voted to “work vigorously to stop the implementation” of the International Classification of Diseases, Tenth Revision (ICD-10) and “to reduce its unnecessary and significant burdens on the practice of medicine.” Delegates were vocal in their disdain for the ICD-10 during the AMA Legislative Advocacy Committee meeting. They claimed the ICD-10 is overly

complex, burdensome to their practices, expensive to implement and worthless in terms of patient care. “The fact is, this will be an absolute disaster for the physicians in this country,” remarked orthopedic surgeon David Teuscher, MD, of the Texas delegation. “Already, our physicians can’t understand ICD-9. What will happen when we implement this version?” “The timing is just terrible,” said gastroenterologist Peter Kaufman, MD, see ICD-10, page 29 

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

FDA approves Subsys (fentanyl sublingual spray; Insys Therapeutics) for cancer pain.

See page 20.

CLINICAL ONCOLOGY NEWS

Clinical Oncology News • February 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

University of Colorado Cancer Center Denver, CO

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

Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

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

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

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

Steven Vogl, MD Medical Oncologist New York, NY

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

Steven D. Passik, PhD

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.

Vanderbilt University Medical Center Nashville, TN

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.

Joseph V. Pergolizzi Jr., MD

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

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

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

Cindy O’Bryant, PharmD

Shaji Kumar, MD Mayo Clinic Rochester, MN

Leonard Saltz, MD

Betty Ferrell, RN, PhD

Pharmacy

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

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

FDA NEWS

Clinical Oncology News • February 2012

Classwide TIRF REMS Approved T he FDA has approved a single shared risk evaluation and mitigation strategy (REMS) for transmucosal immediate-release fentanyl (TIRF) products. According to an FDA press release, the new shared REMS will replace the individual REMS for this class of medications, which includes Abstral (fentanyl sublingual tablets; ProStrakan), Actiq (oral transmucosal fentanyl citrate; Cephalon), Fentora (fentanyl buccal tablet, Cephalon), Lazanda (fentanyl nasal spray; Archimedes), Subsys (fentanyl sublingual spray, Insys) and Onsolis (fentanyl buccal soluble film, Meda). All are opioid analgesics indicated for breakthrough pain in cancer patients who are already receiving and who are tolerant to opioid therapy for underlying persistent cancer pain. Called the TIRF REMS

Einstein College of Medicine, New York City, said in an email. “The legislative mandate to have REMS programs will be much simpler to implement and more likely to lead to clinician practice change if it is created as a series of uniform take-home points that clinicians will see repeated each time they decide to prescribe a TIRF,” Dr. Portenoy said. “Of course, the details are critical, but we anticipate the mandatory education included in the classwide REMS for both the TIRF products and the long-acting opioids to be appropriate and necessary to advance safe prescribing.” According to the FDA, the goals of the TIRF REMS Access Program are to ensure patient access while mitigating risk by prescribing and dispensing TIRF medications only to appropriate patients; preventing inappropriate conversion between fentanyl formulations; preventing accidental exposure to those for whom TIRF drugs are not prescribed; and educating prescribers, pharmacists and patients on the potential for misuse, abuse, addiction and overdose. Until the TIRF REMS is launched, prescribers, pharmacies and patients should continue to enroll in the

individual REMS programs, according to the FDA. Prescribers and pharmacies already participating in an individual REMS program for at least one TIRF medication will automatically be transitioned to the new program. Clinicians who prescribe TIRF medications for use in an inpatient setting, and patients who receive them there, will not be required to enroll. The announcement of the TIRF REMS Access Program comes months after the September start of enrollment in the individual Actiq and Fentora REMS Program. Asked about the timing, Denise Bradley, vice president, Corporate Communications, Teva Pharmaceuticals, stated by email that even while the Actiq and Fentora REMS was being developed, “the FDA asked all sponsors of immediate-release fentanyl products to work together to develop a shared REMS.” —George Ochoa

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Access Program, the new shared system will begin in March. “This TIRF REMS will ensure safe use and access to these drugs for patients who need them,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, in the press release. “We have worked with the sponsors of both the innovator and generic drugs to develop this single, shared system that will streamline the process and decrease the burden of the REMS on the health care system.” The general concept of classwide REMS is one that clinicians should highly favor, Russell K. Portenoy, MD, chairman, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, and professor of neurology and anesthesiology, Albert

Correction Letter from the Editor:

n our January issue, the story “Pertuzumab: Practice-Changing for HER2+ Metastatic Breast Cancer” incorrectly referred to pertuzumab as having the trade name Omnitarg. According to Genentech, the company developing pertuzumab, at one time the compound did go by the trade name “Omnitarg,” but this name was discontinued by Genentech in 2007 because at the time, the compound was ultimately not approved by the FDA. No subsequent brand name has been assigned to date.

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Dr. Portenoy disclosed that in the past 12 months, he received an honorarium for speaking for Grupo Ferrer, which markets two TIRF products in Europe, and his department has received research grants from Archimedes Pharmaceuticals, Meda Pharmaceuticals and ProStrakan.

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Having trouble keeping up with all of the oncology and medical journals that cross your desk? 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. We hope you find this a useful tool.

HEMATOLOGIC DISEASE

Clinical Oncology News • February 2012

Leukemia

NILoTINIB continued from page 1 

said Timothy P. Hughes, MD, head of hematology at IMVS Pathology and consultant haematologist at the Royal Adelaide Hospital in Australia, during the 2011 American Society of Hematology (ASH) annual meeting. In ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients), significantly more patients treated with nilotinib achieved major molecular response (MMR) or deeper responses compared with patients treated with imatinib. Dr. Hughes led a study, called ENESTcmr, which is the first exploratory randomized trial to investigate the impact of switching adult CML patients with residual disease after a minimum of two years of treatment with imatinib to nilotinib to determine if a deeper level of response could be achieved. The study included 207 patients with CML who had been taking imatinib 400 or 600 mg for at least two years—with more than 80% taking imatinib for three years or more—and had achieved a complete cytogenetic response but were still Bcr-Abl positive. Half of the patients continued on imatinib and half switched to nilotinib 400 mg twice daily. At 12 months, 23% of patients on nilotinib achieved a CMR—defined as undetectable Bcr-Abl levels—compared with 11% of patients on imatinib. Similarly, more than twice as many patients on nilotinib achieved the primary end point of confirmed CMR (undetectable BcrAbl levels in two consecutive samples as patients on imatinib; nilotinib 15% vs. imatinib 6%), although this was not a statistically significant difference. Threefourths of patients in the nilotinib group had achieved MMR compared with 36% of patients in the imatinib group. Two patients had a confirmed loss of MMR, one in each treatment arm. “Patients remaining on imatinib had minimal evidence of improvement in molecular response, while patients who switched to nilotinib had a median 0.5log reduction in Bcr-Abl,” Dr. Hughes said. “Patients with no evidence of an improvement in molecular response after long-term exposure to imatinib can be induced to a more potent response by a more potent drug.” Eighty-four percent of nilotinib-treated patients and 96% of imatinib-treated patients remained on treatment at 12 months. Most discontinuations in the nilotinib arm were due to adverse events (AEs). The vast majority of AEs were grade 1 or 2 and included headache, pruritus, rash, nausea, fatigue and myalgia. “Patients experienced adverse events early on nilotinib after switching from long-term imatinib therapy. These changes were expected and consistent with the

safety profile of nilotinib observed in other studies,” Dr. Hughes said. The results suggest that a new group of patients may ultimately be able discontinue therapy. “For patients with ongoing Bcr-Abl positivity on imatinib, switching to nilotinib leads to faster, deeper molecular responses,” Dr. Hughes said. “Further followup over the next four years should help to determine if more patients can reach undetectable levels of CMR over time.” Dr. Hughes said that he has patients with CML who have discontinued therapy with tyrosine kinase inhibitors (TKIs).

“Some patients want to stop drug therapy, and once they get a taste of life without drugs, they want to stay off,” he said. But there may be long-term safety issues. “Is it safe to stop TKI therapy? Can we drive down the CMR rate and give patients an opportunity to discontinue?” he asked. “The data are promising that we have the ability to recruit more patients to CMR. The challenge is the group whose response has reached a plateau. We can now show that they can be induced to a deeper response. Can those patients successfully stop therapy? This is the critical question we will

address over the next few years.” Giuseppe Saglio, MD, of the University of Turin in Orbassano, Italy, agreed that nilotinib has opened the door for CML patients to potentially discontinue treatment. Dr. Saglio presented a 36-month update of the ENESTnd study, reporting that twice as many patients with CML achieved deeper levels of response with nilotinib as with imatinib. The ENESTnd study included 846 adult patients with newly diagnosed Philadelphia chromosome–positive CML-CP; they were randomized to nilotinib 300 mg twice daily (n=282), nilotinib

Indication ZOMETA 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, and 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. 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.

February 2011

ZOM-1010315

HEMATOLOGIC DISEASE

Clinical Oncology News • February 2012

Leukemia

‘For patients with ongoing Bcr-Abl positivity on imatinib, switching to nilotinib leads to faster, deeper molecular responses.’ —Timothy P. Hughes, MD 400 mg twice daily (n=281) or imatinib 400 mg once daily (n=283). Three-year data from the large Phase III clinical trial showed that 32% of newly diagnosed CML patients taking nilotinib reached the deepest levels of molecular response compared with 15% of those taking imatinib.

“After 36 months of follow-up, the update clearly shows persistent superiority of both dosages of nilotinib with respect to imatinib, with faster, deeper responses,” said Dr. Saglio. “Nilotinib is clearly cutting the rate of progression immediately after diagnosis. We found an

extremely high level of CMR with a low level of residual disease with nilotinib.” Both Drs. Saglio and Hughes believe that if 40% of patients can discontinue imatinib, then nilotinib treatments may increase discontinuation rates to 60% to 70%. “But will we see the same rate of success when we drag patients into CMR?” said Dr. Hughes, noting that TKI discontinuation for CML patients is only safe in the context of a clinical trial that includes sensitive, reliable and frequent polymerase chain reaction measurements. Both researchers say they

Proven efficacy across multiple malignancies1 Indicated across more advanced malignancies than any other approved bone-remodeling agent1-8

Bone metastases from solid tumors

*ZOMETA 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 • Spinal cord compression • Surgery to bone • Radiation to bone • Hypercalcemia of malignancy 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.

are planning long-term clinical trials to assess which patients with CML can discontinue TKI therapy. —Mark Fuerst Disclosures: The ENESTnd trial was supported by Novartis Pharmaceuticals. Timothy P. Hughes, MD, reports that he has financial or other commercial relationships with Novartis, Bristol-Myers Squibb and Ariad. Giuseppe Saglio, MD, reports that he has financial or other commercial relationships with Novartis, Bristol-Myers Squibb and Pfizer.

Zometa® (zoledronic acid) Injection 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 >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.

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 3). Table 3 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. Table 3: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

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 Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast. 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 >400 μmol/L or >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 >265 μmol/L or >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 >2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance <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 Pregnancy Zometa should not be used during pregnancy. Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure (an IV dose if 4 mg based on an AUC comparison) resulted in pre- and postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. 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)]. 5.6 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)]. 5.7 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. 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.

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)

(11)

(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)

(22)

(18)

(12)

(4)

11 10 9

(13) (12) (11)

2 16 5

(2) (16) (5)

(12)

(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)

(14)

(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 4 and 5. Table 4: 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

Serum Creatinine1 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%) —

Table 5: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 4 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4 1Grade

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%)

3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (<0.8 mEq/L); Grade 4 (<0.5 mEq/L) 2Grade

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 6 describes adverse events that were reported by ≥10% of patients. Adverse events are listed regardless of presumed causality to study drug. Table 6: 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) Musculoskeletal Bone Pain 569 (55) Myalgia 239 (23) Arthralgia 216 (21) Back Pain 156 (15) Pain in Limb 143 (14) Neoplasms Malignant Neoplasm Aggravated 205 (20) Nervous Headache 191 (19) Dizziness (excluding vertigo) 180 (18) Insomnia 166 (16) Paresthesia 149 (15) Hypoesthesia 127 (12) Psychiatric Depression 146 (14) Anxiety 112 (11) Confusion 74 (7) Respiratory Dyspnea 282 (27) Cough 224 (22) Skin Alopecia 125 (12) Dermatitis 114 (11)

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)

105 61 59 45

(23) (13) (13) (10)

316 143 131 106 84

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

284 74 73 40 52

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

(17)

(20)

149 91 111 85 65

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

50 58 73 35 43

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

95 73 39

(17) (13) (7)

49 37 47

(11) (8) (10)

155 129

(28) (23)

107 65

(24) (14)

80 74

(14) (13)

36 38

(8) (8)

n (%)

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 7 and 8. Table 7: 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

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg n/N (%) 7/529 6/973 115/973 19/971 1/971

(1%) (<1%) (12%) (2%) (<1%)

Pamidronate 90 mg n/N (%) 4/268 4/536 38/537 2/535 0/535

(2%) (<1%) (7%) (<1%) —

Placebo n/N 4/241 0/415 14/415 8/415 1/415

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

(%) (2%) — (3%) (2%) (<1%)

Table 8: 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

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg n/N (%) 2/529 7/973 5/973 0/971 2/971

Pamidronate 90 mg n/N (%)

(<1%) (<1%) (<1%) — (<1%)

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

Placebo

(<1%) (<1%) — — (<1%)

n/N

(%)

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

— (<1%) (<1%) (<1%) —

Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenzalike 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 (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥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 9). Table 9: 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)]. 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 Zometa should not be used during pregnancy. There are no studies in pregnant women using Zometa. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [see Warnings And Precautions (5.4)]. Pregnancy Category D Bisphosphonates are incorporated into the bone matrix, from where they 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. 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 Zometa is excreted in human milk. Because many drugs are excreted in human milk, and because Zometa binds to bone long term, Zometa should not be administered to a nursing woman.

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 active-controlled 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 T2011-01 ©Novartis

CLINICAL TRIALS

Clinical Oncology News • February 2012

Patient Care

Applying Clinical Trial Results to ‘Real-World’ Care It is widely accepted in cancer medicine that the results of Phase III randomized trials— when available and appropriately applied—are the “gold standard” in determining optimal patient management. (And for the record it should be noted that some investigators have claimed that meta-analyses of multiple Phase III trials represent an even higher “level of evidence” and should be considered the “gold standard.”) Unfortunately, while data from these trials clearly add to any discussion of a particular component of care with a cancer patient, the required homogeneity of the study population in these trials often leads to serious questions about the applicability of the conclusions in “realworld” medicine outside the confines of the often very narrowly defined trial population.1 Established areas of concern include the exclusion of patients with common comorbid conditions like heart disease and diabetes; the inclusion of few, if any, truly elderly patients over the age of 70 years, and the potential use of the strategy in settings not identical to those tested in the trial, for example, second-line rather than first-line treatment of metastatic disease. A far less frequently discussed aspect of transitioning trial results into routine care is the realistic potential that when the strategy in question is undertaken by individuals without the same level of clinical expertise, the actual outcome may not be as favorable as the one demonstrated in the investigative setting. Consider, for example, the recently reported results of the National Lung Screening Trial.2 This study revealed that screening for lung cancer in a highrisk patient population with low-dose helical computed tomography (CT) could reduce the relative risk for death from lung cancer by approximately 20%. The trial also documented that 96.4% of “positive screening results in the low-dose CT group” were false positives. However, by following the specific study-defined paradigm as outlined for clinicians who experienced “positive screening results,” a low rate of serious adverse events was found.2 The question to be asked here is whether it is appropriate to assume that the widespread, non-investigative

use of screening CT—with the very high false-positive rate documented in the research setting—will result in a similarly acceptable low risk for

complication—for a diagnostic procedure—required a blood transfusion. Because the potential of finding a curable lung cancer is significant, the risks

‘The required homogeneity of a Phase III study population often leads to serious questions about the applicability of the conclusions in “real-world” medicine.’

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

screening on the relative risk for death from lung cancer in a large population, it is vital that we also fully understand both the risks and the benefits of that strategy when it leaves the domain of clinical investigation and enters the realm of routine medical practice. Finally, it should be noted that the scenario presented is simply one of many that could have been provided as a word of caution in this important and complex discussion, that has relevance for both individual patients and society at large.

References 1. Elting LS, Cooksley C, Bekele BN, et al. Generalizability of clinical trials results: prognostic differences between participants and non participants. Cancer. 2006;106:2452-2458, PMID: 16639738.

serious adverse events, specifically those screening events that may lead to unnecessary biopsy procedures. The importance of this issue has been highlighted in a recent report, unaffiliated with the National Lung Screening Trial, in which investigators examined the risk for complications from transthoracic needle biopsy of pulmonary lesions.3 In several large databases involving more than 15,000 patients undergoing this procedure, complications were common. In fact, 15% of procedures resulted in a pneumothorax and almost 7% of all biopsies were revealed to cause a pneumothorax that required chest tube placement. In addition, 1% of transthoracic needle biopsies resulted in hemorrhage and 18% of the individuals experiencing this

of a transthoracic needle biopsy can theoretically be justified. But the realistic risk-to-benefit ratio has to be questioned in a setting where the likelihood of a positive finding is low and the potential for harm may be far greater than that suggested by a well-controlled and wellmonitored clinical trial undertaken by clinicians with specific expertise that may be superior to the community norm. It is essential to emphasize that I am not suggesting that any individual practitioner—in this case, a physician asked to perform a transthoracic needle biopsy—is less than fully qualified to undertake the procedure in question. However, in considering how to interpret the results of a clinical trial that demonstrates the statistically significant favorable impact of low-dose CT

2. The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409, PMID: 21714641. 3. Wiener RS, Schwartz LM, Woloshin S, et al. Population-based risk of complications after transthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records. Ann Intern Med. 2011;155:137-144, PMID: 21810706.

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Do you have thoughts on Dr. Markman’s commentary? Please send comments to gmiller@mcmahonmed.com

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Clinical Oncology News • February 2012

Breast

Opioid Gene Variants Tied To Cancer Survival in Women Mounting laboratory and epidemiologic data suggest a link between opioid exposure during cancer surgery and metastasis of, and eventual death from, the disease. Now, a major genetics study has turned up some of the most compelling evidence yet for a connection between the pain killers and malignancy—even beyond the operating room. T h e n e w wo r k , b y researchers at the University of North Carol i na a t C h ap e l H i l l , found that breast cancer patients with variants of the µ-opioid receptor that make their cells less responsive to the analgesic are as much as fourfold less likely to die of their tumors as those with the most widespread form of the receptor. The findings, presented at the 2011 annual meeting of the American Society of Anesthesiologists (ASA; abstract JS05), came as “pretty much of a surprise” to the investigators, said study leader Andrey Bortsov, MD, PhD, assistant professor of anesthesiology at UNC. “We think this is a very strong association.” Dr. Bortsov and colleagues analyzed the genetic makeup of 2,039 women diagnosed with breast cancer, who had participated in the Carolina Breast Cancer Study—a longitudinal population analysis of the disease that began in 1993.

Opioid Genetics The researchers wanted to see if variations in the G allele of the µ-opioid receptor gene, OPRM1 A118G, affected a woman’s risk for death from breast cancer. In particular, because the 118G form of the allele ratchets down the receptor’s responsiveness to opioids, the UNC team hypothesized that women with one or more of these variants would be more likely to survive their cancer. The results of the study supported that hypothesis. According to Dr. Bortsov’s group, women who had at least one variant copy of the allele were twice as likely to survive breast cancer by 2006 as those with the typical form. Women with two copies of the 118G variant were four times as likely to survive the disease (Table). Samuel McLean, MD, said OPRM1 is the best understood opioid gene. “We know that if you have a G allele, you respond less well” to the drugs. “If you have cancer, you will need more opioids over time if you have a G allele. If it takes more opioids, that’s bad for you for controlling your pain, but it may

30% of European Americans but only about 7% of African Americans. That difference might help explain why black women are significantly more likely to die of breast cancer than women from other racial and ethnic groups with the malignancy, the researchers suggested. Dr. McLean cautioned that although opioids appear to play an important role in the growth and spread of cancer, how they do so remains unclear. Indeed, it’s not even known if the opioids that patients take for cancer pain have an effect on cancer cells beyond that of the endogenous opioids that the body already produces. “We’re a long way from having any evidence that opioids patients take for cancer pain are harming them,” Dr. McLean said. “There is animal data that’s provocative, but obviously we can’t take humans and not give them opioids if they have cancer. That’s the last thing we want to do.”

Mouse Data Bolster Link

be good because of the other effect,” he said. Most Americans of European and

African ancestry have an A allele of the OPRM1 gene, Dr. McLean noted. The G allele is less common, appearing in about

New cellular evidence backs the UNC findings. In an unrelated study also presented at the ASA meeting (abstract JS08), researchers from the University of Chicago showed that cancer cells modified to overexpress the µ-opioid receptor are far more likely to grow and spread than those with normal levels of the protein. Using a line of human lung cancer cells that they transplanted into nude mice, the researchers found that overexpression of the opioid receptor see GENES, page 12 

‘We’re a long way from having any evidence that [the] opioids patients take for cancer pain are harming them. There is animal data that’s provocative, but obviously we can’t take humans and not give them opioids if they have cancer. That’s the last thing we want to do.’ —Samuel McLean, MD

Table. Double-A Genotype Strongly Associated With Cancer Deaths A118G Genotype

Number of Participants

Breast Cancer Deaths

Breast Cancer Deaths, %

P Value

A/A

1,682

296

17.6

0.0001

A/G

323

8.7

G/G

4.6

A/A

1,332

290

21.8

A/G

233

G/G

All cases

Invasive cases 0.0006

SOLID TUMORS

Clinical Oncology News • February 2012

Breast

BEVACIZUMAB continued from page 1 

a biomarker. Genentech’s effort, however, is only one of many. For roughly 10 years, researchers have been chasing down a biomarker for bevacizumab (Avastin) that has, so far, remained out of reach. “We began to put a lot of the negative [biomarker] data into the public domain in the past five years, but the effort has been under way for many, many years,” said Philippe Bishop, MD, Genentech’s vice president and head of clinical development for Avastin. “We just haven’t been able to identify, along the way, biomarkers that could be predictive.”

A Long, Frustrating Search Researchers have explored tumorbased markers, serum- and plasmabased markers such as cytokines and growth-factor expression, DNA-based markers, toxicity-based markers and radiographic predictors. They have looked not only at breast cancer patients, but also at those with colon, kidney, lung and brain cancers. The net has been cast widely but it has come up empty thus far. And throughout, expectations have been raised only to be quashed later. “There was hope that triple-negative patients might derive the most benefit as there has been some data that supports that suggestion; however, there has been other data that does not,” said Maura Dickler, MD, an associate attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York City. At the 2010 San Antonio Breast Cancer Symposium (SABCS), Gunter von Minckwitz, MD, PhD, the managing director of the German Breast Group in Neu-Isenburg, reported that a subset analysis of the GeparQuinto trial that tested neoadjuvant bevacizumab plus chemotherapy in early breast cancer showed the drug increased pathologic complete response in women with triple-negative breast cancer. A benefit in the triple-negative group, however, was not confirmed by results of the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-40 trial of neoadjuvant bevacizumab. “It’s been frustrating,” said Dr. Dickler. In 2008, researchers led by Bryan Schneider, MD, an associate professor of medical and molecular genetics and an oncologist at the Indiana University Melvin and Bren Simon Cancer Center in Indianapolis, reported a biomarker subanalysis of the E2100 trial in the Journal of Clinical Oncology (2008;26:46724678, PMID: 18824714). They identified two genotypes that were associated with improved survival with the use of bevacizumab and two that predicted hypertension, the drug’s most common toxicity. “There have been several other groups

that have looked a t similar genetic variations since then,” said Dr. Schneider. “Some groups have found findings similar to ours and some have not.” The trend has been typical—subanalyses of studies yield biomarkers that look promising and then confirmatory studies are negative or yield mixed results. Rakesh Jain, PhD, the A. Werk Cook Professor of Radiation Oncology for Tumor Biology at Massachusetts General Hos-

pital in Boston, has conducted studies that have suggested that vascular imaging can be used as a biomarker in recurrent glioblastoma. The findings need to be validated in Phase III trials however, and whether this could translate to breast cancer remains to be seen. “At the end of the day, although there has been interest in a myriad of biomarkers including VEGF genotypic polymorphisms, VEGF-A and VEGFR-2 in tumor tissue, circulating VEGF levels and the development of bevacizumab-induced hypertension, none of these biomarkers have met the level of evidence to incorporate them into clinical care at the pres-

Bevacizumab’s Y-like shape has two antigen binding sites that bond to vascular endothelial growth factor A (VEGF-A) proteins.

On a basic level, it is still somewhat unclear why bevacizumab works on some cancers and not on others because seemingly, all tumors need to be fed by blood vessels. interesting interaction between the host and the tumor,” said Dr. Schneider. The drug is designed to block tumor vasculature, but vasculature may be regulated by the host, by the tumor, or by both. “I think most other groups, at least prior to 2008, had really focused on variability within the tumors,” Dr. Schneider said. “I think that may be part of the difficulty.” Dr. Schneider said another problem in the biomarker search is that some correlative studies are lumping different

‘I strongly believe there is a subgroup of patients who probably gain substantial benefit and this is simply based on anecdotal observations from my clinic.’ –Bryan Schneider, MD

ent time,” said Dr. Dickler. “Although there has been some inkling of hope, it has been a tough nut to crack.” On a basic level, it is still somewhat unclear why bevacizumab works on some cancers and not on others because seemingly, all tumors need to be fed by blood vessels. “The VEGF pathway may not be equally important across solid tumors, and I think that is likely the best explanation,” said Dr. Dickler. Varying mechanisms of resistance or other driving mutations or pathways may be more important in one type of tumor than in another. “I think Avastin is a tricky drug in terms of finding the perfect biomarker and that may be a function of a few things, one of which is that there is an

anti-angiogenic drugs together. “I think many people have looked at a variety of the different anti-angiogenic drugs as a group, combining the data with small tyrosine kinase inhibitors like sunitinib [Sutent, Pfizer], sorafenib [Nexavar, Bayer Healthcare] or pazopanib [Votrient, GlaxoSmithKline], and I think you simply can’t do that,” Dr. Schneider said. “I think biomarkers are going to be different for these other drugs because they simply hit more targets.” Well-powered studies have been another stumbling block. Although there are hundreds of bevacizumab studies, there are few large prospective trials with a suitably powered biomarker component. Subanalyses are plentiful. A

recent JCO editorial by Dr. Schneider and George Sledge Jr., MD, also from the Melvin and Bren Simon Cancer Center, points out that all the attempts to identify the optimal subgroups for bevacizumab therapy thus far have been conducted retrospectively on prospectively collected clinical trial samples and many of them did not include a control arm (doi: 10.1200/JCO.2011.34.9266). Subgroup analyses are tricky for a number of reasons. Investigators need to take steps to ensure that the subgroups being tested mirror the parent study and take into account why samples are missing, so that selection bias can be avoided, the editorial argues. It also is difficult to get sufficient statistical power to determine differences in subgroup analyses. It may be that a biomarker has remained elusive because of “pitfalls in the testing system,” rather than the fact that researchers are testing the wrong markers. “These biomarker studies are being done in really small trials and that makes the power of finding something really difficult,” Dr. Schneider said. “The danger is [that] if you say ‘Well, nothing was positive here,’ one may interpret that as simply ‘There is just no association,’ when in reality, it had nothing to do with the biological association, but rather the fact that the trial wasn’t set up right to answer that question from a statistical standpoint.” In their editorial, Drs. Schneider and Sledge argue that retrospective analyses of “old prospective clinical trials will be destined to only cloud the picture,” regardless of how promising the biomarker in question may be. Prospective trials are what are needed.

Current Directions E5103, an ongoing prospective trial with which Dr. Schneider is involved, is looking at this question. This 5,000-patient trial is testing the addition of bevacizumab to a backbone of doxorubicin and cyclophosphamide followed by taxane-based chemotherapy in the adjuvant setting of breast cancer. “We have done a genome-wide association study, so we are looking at over 1 million SNPs [single nucleotide polymorphisms] within each of the first 2,200 patients. So, we hope that not only can we validate or refute what we found in the E2100 trial, but if there are other pathways or mechanisms, we can identify them with this approach,” said Dr. Schneider, referring to the hypertension and efficacy biomarkers previously identified. The trial that Genentech recently submitted to the FDA is another prospective see BEVACIZUMAB, page 12 

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Clinical Oncology News • February 2012

Breast

GENES continued from page 10 

caused the growth rate of the tumors to rise 2.5-fold. Metastasis of the tumors spiked by a factor of 20. Jonathan Moss, MD, PhD, professor of anesthesia and critical care at the University of Chicago, said the North Carolina work “confirms a growing body of in vitro and animal data from several laboratories, including our own, suggesting a role of the µ-opioid receptor in cancer progression.” However, Dr. Moss said, too many questions remain to consider altering clinical practice. “We don’t want to

BEVACIZUMAB continued from page 11 

Phase III trial built around biomarkers. “We have designed the study around it. We are specifically asking a question around the value of plasma VEGFA,” said Dr. Bishop, who added they would also be looking for other markers. He said that subanalyses of two trials, AVADO and AVEREL, provided evidence that VEGF-A is a good candidate for a predictive marker for bevacizumab benefit. The most recent subanalyses of

Although there are hundreds of bevacizumab studies, there are few large prospective trials with a suitably powered biomarker component. these two studies were presented at the 2011 SABCS. The double blind, randomized Phase III AVADO trial evaluated bevacizumab in combination with docetaxel as first-line therapy for HER2-negative, locally recurrent metastatic breast cancer. VEGF-A and VEGF-R2 were identified as potentially promising candidates for predicting progression-free survival (PFS) with bevacizumab, and VEGF-A levels at baseline did not correlate with known prognostic factors, thus indicating it could be predictive. In a cohort of patients who had received 15 mg/kg bevacizumab and had VEGF-A levels in the top quartile, the hazard ratio for PFS was 0.39 (95% confidence interval, 0.19–0.77) and the difference in median PFS was more pronounced than in the other groups. The randomized Phase III AVEREL trial evaluated bevacizumab in

“While I may personally believe there could be effects that would change practice ... there are no direct, prospective, randomized controlled [trial] data suggesting that opioids influence cancer progression in humans.” —Jonathan Moss, MD, PhD

combination with trastuzumab plus docetaxel in the first-line therapy of patients with HER2-positive, locally recurrent metastatic breast cancer. Patients were randomized to docetaxel plus trastuzumab alone or in combination with bevacizumab. The median PFS was improved in patients receiving bevacizumab (16.8) compared with those receiving docetaxel plus trastuzumab alone (13.9; P=0.0162). An exploratory analysis of plasma VEGF-A suggested a potentially predictive effect with a greater benefit with high VEGF-A levels (plasma VEGF-A equal to or less than median: hazard ratio [HR], 0.83; plasma VEGF-A greater than median: HR, 0.70). “VEGF-A happens to be a biomarker that is prognostic in breast cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer and renal cancer. In a lot of tumor types that we have tested, we have seen consistently across all of the tumor types that VEGF-A was indeed prognostic,” said Dr. Bishop. He said it wasn’t until recently, however, when a newgeneration assay became available that was able to identify a certain isoform of VEGF-A, that researchers began to see inklings that the marker could be predictive. If approved, the Phase III trial will try to confirm that patients who express higher levels of VEGF-A derive the greatest benefit from bevacizumab and those with lower levels derive a lesser benefit.

In the Trenches While the biomarker search continues, clinicians around the country are deciding whether or not to continue using the drug. Decisions are based on what doctors feel comfortable with given the FDA decision and whether they can get reimbursement. “We tend to use a paclitaxel-bevacizumab combination whenever a rapid response is needed; that means patients with metastatic breast cancer who are symptomatic or those who have

scare patients,” Dr. Moss said. “Our paper and theirs did not address giving opioids and may relate to endogenous opioids. While I may personally believe there could be effects that would change practice. ...there are no direct, prospective, randomized controlled [trial] data suggesting that opioids influence cancer progression in humans, but

several studies contribute to the debate.” Jeffrey L. Apfelbaum, MD, professor of anesthesia at the University of Chicago, who was not involved in the studies, agreed. “They need some prospective studies to clearly delineate what major practice changes might need to take place,” Dr. Apfelbaum said. “But they’re working on that.” —Adam Marcus

extensive visceral disease where there is little margin for error,” said Gabriel N. Hortobagyi, MD, chair of breast medical oncology at the University of Texas MD

being reimbursed. Coverage varies. A spokesperson for the Centers for Medicare & Medicaid Services said Medicare is still paying for it, but

‘We tend to use a paclitaxel-bevacizumab combination whenever a rapid response is needed; that means patients with metastatic breast cancer who are symptomatic or those who have extensive visceral disease where there is little margin for error.’ –Gabriel N. Hortobagyi, MD Anderson Cancer Center in Houston. “In a large institution like mine, we are a bit sheltered from reimbursement issues, so I cannot tell you who is reimbursing and who is not, except that I know Medicare is reimbursing routinely, and I have not received calls from pharmacy or administration indicating that we are not getting reimbursed.” Dr. Dickler said she provides bevacizumab to selected patients in combination with chemotherapy. “I give it to patients who have aggressive and/ or symptomatic disease for whom I opt for taxane-based chemotherapy in the first-line setting. Generally, these patients have either progressive disease on endocrine therapy or are not appropriate candidates for endocrine therapy,” said Dr. Dickler. John Finnie, MD, staff hematologist and medical oncologist at the David C. Pratt Cancer Center at St. John’s Mercy Medical Center in St. Louis, Mo., said he follows the guidelines of the National Comprehensive Cancer Network when deciding which patients with metastatic breast cancer get bevacizumab. “I think it is an appropriate drug for most patients,” he said. He added that he has not had any problem getting reimbursed, but that he has spoken to colleagues who were not using it because they were not

each Medicare contractor has the discretion of whether or not to pay. Representatives of United Healthcare, Harvard Pilgrim Health Care and Aetna said they are still covering the drug for metastatic breast cancer. Blue Shield of California is continuing to cover the drug for patients who were already using it in October, but coverage for new patients is now being determined on a case-by-case basis. Dr. Schneider said he is not prescribing bevacizumab for his patients with metastatic breast cancer based on the FDA’s recommendation and is hopeful that a biomarker can be identified. “I strongly believe there is a subgroup of patients who probably gain substantial benefit and this is simply based on anecdotal observations from my clinic,” said Dr. Schneider. “I truly believe the FDA and regulatory boards would be enthused about using this drug if they can simply find the group who gains good benefit similar to what we have seen with trastuzumab.” For now, the search continues. —Kate O’Rourke Drs. Dickler, Hortobagyi and Schneider have served as consultants for Genentech. Drs. Finnie, Sledge, and Jain have no relevant disclosures.

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Breast

Study Details Risks for Contralateral Cancer in BRCA1/2 San Antonio—A study has provided some hard statistics regarding the risk that women carrying a BRCA1/2 mutation will develop a contralateral breast cancer (CBC) and how factors, such as age and having a triple-negative diagnosis, affect that risk. The findings provide risk estimates that doctors can use to counsel patients when discussing treatment options. “Medical decision making weighs the risks and benefits of the situation at hand. For a woman with breast cancer to make a decision on the management of the nonaffected breast, it is important to quantify the risk for developing

contralateral breast cancer,” said Catherine Van Poznak, MD, medical oncologist at the University of Michigan, in Dearborn, who was not involved with the study. “The data generated in this study aids that risk assessment.”

For years, researchers have known that the risk that a woman will develop CBC is higher than an average woman’s risk for developing a first cancer and that this risk is even greater if the woman carries the BRCA1/2 mutation. Until this study, however, CBC risk

estimates for a large unselected population did not exist, said Alexandra van den Broek, doctoral candidate at the Netherlands Cancer Institute. She presented the new study at the recent San Antonio Breast Cancer Symposium (abstract S4-2).

‘The low-risk subgroup [3.5%] were the patients with a non–triplenegative first breast cancer diagnosed between the ages of 41 and 50, which had almost similar risk to the noncarriers.’ —Alexandra van den Broek

Treatment Strategies

Vitamin D Cuts Pain Associated With Breast Cancer Therapy Weekly high-dose oral vitamin D2 supplementation is significantly more effective than placebo in reducing musculoskeletal pain in breast cancer patients undergoing aromataseinhibitor therapy, according to findings from a randomized, double-blind, placebocontrolled trial of 60 patients (Breast Cancer Res Treat 2011;129:107-116). The results add to a growTable. Pain at Baseline and Two Months After Study ing body of evidence suggesting vitamin D should be part Outset of the clinician’s armamentarium in treating chronic pain, Vitamin D (mean) Placebo (mean) P-Value commented Allen W. Burton, BPI worst pain baseline 5.2 6.1 NS MD, co-director of Houston Pain Associates, in Texas. Dr. BPI worst pain 2 mo 3.6 5.1 0.041 Burton was not involved in BPI average pain baseline 4.2 4.6 NS the trial. “Vitamin D has many saluBP average pain 2 mo 2.7 3.7 0.0067 tary effects on overall health, BPI pain severity baseline 3.9 4.4 NS including in this population of breast cancer patients,” BPI pain severity 2 mo 2.7 3.5 0.04 said Dr. Burton. “Physicians treating patients with chronBPI interference baseline 2.7 3.0 NS ic pain need to be aware of BPI interference 2 mo 1.8 2.5 0.034 the growing significance of BPI, Brief Pain Inventory (including 10-point worst pain, average pain, pain severity, vitamin D deficiency, and and interference subscales); NS, not significant the positive symptom impact of vitamin D supplementation in these patients.” Primary investigator Antonella Ras- either one capsule of 50,000 interna- supplementation. However, the differtelli, MD, assistant professor, Division tional units (IU) vitamin D2 once week- ences between the treatment and plaof Oncology, Department of Medicine, ly for two months and then monthly for cebo groups were not significant at four Washington University School of Med- another four months or 50,000 IU vita- and six months, by which time most icine, St. Louis, and several of her col- min D2 once weekly for four months and patients had switched to monthly vitaleagues examined data from 60 breast then once monthly for the remaining min D2. When Dr. Rastelli and her team cancer patients with nonmetastatic dis- two months. The researchers also ran- separated the data according to extent ease who had received at least eight domly assigned 30 patients to receive of baseline vitamin D deficiency, they weeks of anastrozole adjuvant thera- placebo. Additionally, all participants discovered that vitamin D-deficient py and reported new or worsened mus- received 1,000 mg calcium carbonate patients—those whose course of weekly treatment was two months longer—had culoskeletal pain unrelated to prior and 400 mg vitamin D3 daily. Dr. Rastelli reported that treatment significantly lower average pain scores trauma. Patients also were vitamin D insufficient (20-29 ng/mL) or deficient recipients had significantly lower at all of the time points compared with scores on several pain measures, com- placebo controls. (<20 ng/mL). In light of the findings, Dr. RastelDr. Rastelli and her team randomly pared with those in the placebo group, assigned 30 of the patients to receive two months after starting vitamin D2 li believes a weekly dosing regimen is

most effective in reducing pain. Loss of the pain-reducing effects of high-dose supplementation after switching was most likely the result of the relatively short half-life of vitamin D2, Dr. Rastelli said. “The short half-life of vitamin D2 and its rapid metabolization make it a safe and attractive option for long-term treatment,” she said. “[Especially given that] breast cancer patients are bound to be treated with aromatase inhibitors for at least five years, if not longer.” —David Wild

Breast

Table. 10-year Risk for Contralateral Breast Cancer: Key Stats In the BOSOM (Breast Cancer Outcome Study of Mutation Carriers) study, a consecutive series of patients with invasive breast cancer were tested for BRCA mutations. The study included women who were diagnosed before the age of 50 between 1970 and 2003 in 10 different hospitals throughout the Netherlands. Of the 5,061 women in the study, roughly 4% were BRCA carriers; 3.04% had BRCA1 mutations and 1.13% had BRCA2 mutations. The cumulative 10-year CBC risk was 6% for noncarriers. This risk was lower compared with BRCA2 carriers who had a risk of 11.1% (P<0.05) and BRCA1 carriers who had a risk of 20.3% (P<0.01).

SOLID TUMORS

Clinical Oncology News • February 2012

BRCA status Noncarriers

BRCA2 carriers

11.1%

BRCA1 carriers

20.3%

Age at Diagnosis, BRCA Carriers 41-50 y

11.6%

<41 y

26%

Triple-Negative Status, BRCA Carriers Triple-negative

18.9%

Non–triple-negative

11.2%

‘The analysis performed in this large database of European women under the age of 50 suggests that risk for contralateral breast cancer within 10 years may be estimated based on age and BRCA1/2 status.’

in the study would help doctors counsel patients. “The analysis performed in this large database of European women under the age of 50 suggests that risks for contralateral breast cancer within 10 years may be estimated based on age and BRCA1/2 status,” she said. Ms. van den Broek said that if the results are confirmed in other studies, age criteria and receptor status of the first breast cancers might be included in guidelines for prophylactic measures and screening in the follow-up of BRCA1/2 mutations carriers. —Kate O’Rourke

Op en En For rol lme n

—Catherine Van Poznak, MD Age at diagnosis was a significant predictor of cumulative 10-year risk for CBC in BRCA carriers, with a risk for CBC of 26% in women diagnosed younger than age 41 and 11.6% in women diagnosed between the ages of 41 and 50. The cumulative 10-year CBC risk was 18.9% in patients with triple-negative status compared with 11.2% in patients who were not triple-negative, but this was not statistically significant. “Although this was not significant, the effect is most strong in the first five years. When looking only at the first five years, the effect is significant,” said Ms. van den Broek. The analysis allowed the researchers to define subgroups of BRCA1/2 carriers with decreased and increased 10-year risk for CBC. “The low-risk subgroup [3.5%] were the patients with a non–triple-negative first breast cancer diagnosed between the ages of 41 and 50, which had almost similar risk to the noncarriers,” said Ms. van den Broek. She defined two high-risk groups. The first group was women with triple-negative breast cancer who were first diagnosed between the ages of 41 and 50. They had a 15% risk. The second group was women with a first breast cancer diagnosed before the age of 41. This group had a 26% risk. Dr. Van Poznak said the information

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Clinical Oncology News • February 2012

Head & Neck

A Note on Commentaries From Cancer Centers

eaders may have noticed in recent months that Clinical Oncology News has featured several commentaries from NewYork-Presbyterian Hospital oncologists and hematologists/oncologists. These physicians were asked to comment on just-published clinical studies, an approach we hope is helpful to our readers who do not have the time to read all 40+ oncology journals! We hope this program will encourage readers to visit our pages to keep up with the most important research findings. The plan, which will continue in next month’s edition, is to have prestigious cancer centers around the nation provide commentary on a quarterly basis. And we are very pleased to announce that starting in March Johns Hopkins’ Sidney Kimmel Comprehensive Cancer Center will provide commentary for

the next three months. Please note that the cancer centers that comment in Clinical Oncology News are not paying us for the privilege, nor we them. These cancer centers are important centers of oncologic research and we believe the thoughts of these physician-researchers make valuable reading. If you are interested in arranging for your cancer center to be included in our commentaries program, I would be interested in hearing from you. James Prudden Group Editorial Director jprudden@mcmahonmed.com

Bevacizumab Plus Radiation Feasible for Nasopharyngeal Carcinoma From Lancet Oncology

he addition of bevacizumab (Avastin, Genentech/Roche) to standard chemoradiation treatment was shown to be safe in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). No grade 3 or 4 hemorrhages or grade 5 adverse events (AEs) were reported within the first year of treatment in 44 adult patients with stage IIB-IVB NPC. During year 1, these patients received three cycles of bevacizumab (15 mg/kg) in addition to standard chemoradiation therapy including cisplatin (Platinol) concurrent with intensity-modulated radiation therapy (IMRT), followed by

EXPERT INSIGHT Edward S. Kim, MD Associate Professor of Thoracic/Head and Neck Medical Oncology Chief of Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Treatment for patients with NPC has relied on radiotherapy. The majority of patients will present with locally

three cycles of bevacizumab (15 mg/kg) and standard adjuvant therapy with cisplatin and fluorouracil (5-FU). Patients were treated at 19 centers in North America and Hong Kong. The results of this Phase II clinical trial, which was funded by the National Cancer Institute, were published online in the journal Lancet Oncology (2011 Dec 15. [Epub ahead of print], PMID: 22178121). Interest in bevacizumab for the treatment of locoregionally advanced NPC stems from its role as a monoclonal antibody against vascular endothelial growth factor (VEGF). Standard chemoradiation for the disease includes cisplatin therapy concurrent with IMRT, followed by adjuvant chemotherapy with

cisplatin and 5-FU. Although the need for adjuvant chemotherapy has been debated, the use of cisplatin concurrent with IMRT has demonstrated improvement in patients’ overall survival (OS). However, the development of distant metastases remains a problem, occurring in approximately 30% of patients with locoregionally advanced NPC, according to recent data. Several studies have pinpointed a role for VEGF in the development of lymph node metastases in this patient population, and researchers are actively engaged in identifying a safe and effective therapeutic option that addresses this issue. Although serious AEs were rare in this trial, there were some safety issues in

adding bevacizumab to standard therapy. Within the study population, nine patients had a treatment-related grade 1 or 2 hemorrhage and nine patients had one or more grade 4 blood or bone marrow–related complications. Additionally, one patient had two grade 4 infections with grade 3/4 neutrophils, one patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis and two reported grade 4 pharyngolaryngeal pain. Still, with a median follow-up of 2.5 years, two-year progression-free survival was 74.7% and two-year OS was 90.9%. Most notably, given the focus of the study, the two-year distant metastasis–free interval within the study population was 90.8%.

advanced disease (approximately 60%) and the mainstay of treatment for years has been radiotherapy with cisplatin. This has been effective in local control, but 30% of patients will recur in a distant site. Better systemic therapy may help improve this. Epstein-Barr virus is a universal cause of NPC and has been an area of much study for prognosis and biomarkers. This Phase II study treated patients with NPC with IMRT and concurrent cisplatin and bevacizumab given every three weeks. The study consisting of 44 eligible patients found tolerability with mostly grade 1 and 2

bevacizumab-related AEs. Toxicities with bevacizumab tend to occur more often in patients with squamous histology but no additional significant AEs were observed in this study. The progressionfree survival of 75% is lower than prior studies performed with IMRT. However, OS was 91%, which is quite favorable when compared with prior studies. Only limited conclusions can be formulated based on this study. There is a desire to add biologic agents to standard therapy in order to improve efficacy. Because VEGF could have a role in disease recurrence and spread,

studying compounds such as bevacizumab, which inhibit the VEGF pathway, may be preferred. The attraction of using bevacizumab as opposed to some other angiogenesis compounds is its demonstrated efficacy, especially with chemotherapy in several solid tumors including lung and colorectal cancers. The study collected tumor and blood samples and additional correlative testing is planned. Although the study presented some promising data, more randomized studies are needed to further validate bevacizumab as an active agent in patients with NPC.

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SOLID TUMORS

Clinical Oncology News • February 2012

Supportive Care

Palliative Radiopharmaceuticals: Effective but Often Underused From Journal of Supportive Oncology

adiopharmaceuticals remain under used for pain palliation in patients with multifocal osteoblastic metastases, despite the fact that they may be easier to administer and are both less invasive and less expensive than some other, more commonly used modalities that target both pain and the underlying tumor, such as chemotherapy and external beam radiation. In addition, radiopharmaceuticals do not have the same dose-limiting side effects associated with nontumoricidal approaches, such as nonsteroidal anti-inflammatory drugs and opiates. Several clinical studies have demonstrated the safety and efficacy of radionuclide therapy in patients with

EXPERT INSIGHT Charles von Gunten, MD, PhD Clinical Professor of Medicine University of California, San Diego Provost The Institute for Palliative Medicine at San Diego Hospice San Diego, California

Fabio M. Paes, MD, and colleagues have written an excellent review of the role of commercially available radiopharmaceuticals to treat pain associated with osteoblastic metastases. If I were to summarize the “take-home”

osteoblastic bone metastases. A review published in the November/December issue of the Journal of Supportive Oncology (2011;9:197-2005, PMID: 22055888) aimed to address the apparent disconnect between published research and clinical practice concerning these important therapeutic options from the armamentarium of radiation oncologists. This assessment analyzed the existing data in order to develop a framework for appropriate patient selection and administration. The review—authored by radiation oncologists Fabio M. Paes, MD, and Aldo N. Serafini, MD, and hematologists/oncologists Vinicius Ernani, MD, and Peter Hosein, MD, all of whom are from the University of Miami/Jackson Memorial Medical Center Sylvester Comprehensive Cancer Center—focuses

specifically on samarium-153 lexidronam (Quadramet, EUSA Pharma) and strontium-89 chloride, two FDA-approved radiopharmaceuticals that are indicated for bone pain palliation. The authors attempt to summarize current data on indications, safety and efficacy. Samarium-153 and strontium-89, as well as rhenium-188 (also a radionuclide), each have demonstrated similar efficacy in clinical studies. As a result, the authors note, the “radiopharmaceutical of choice has not been established.” They emphasize that therapy must therefore be tailored to the individual patient, based on the physical characteristics of the radioisotope in relation to the extent of the disease and the patient’s bone marrow reserve.

For example, samarium-153 and rhenium-188 are the preferred options in patients with impaired renal function due to their lower physical half-lives. The JSO review points out that the onset of pain relief varies from patient to patient and its duration also may vary, depending on the extent of metastatic bone disease. The authors conclude that the use of systemic treatment of pain related to metastatic bone lesions using radiopharmaceuticals is a safe and effective option that “should always be considered in the earlier stages of osseous metastasis dissemination rather than as a last resort.” They conclude that the existing clinical data demonstrate that these agents decrease morbidity and improve the quality of life of these patients.

messages, they would be as follows: • Strontium-89 and samarium-153 improve pain relief in 50% to 90% of treated patients. • Prostate and breast cancers have been the diseases most studied. • Improvement means that the patient says he or she feels less pain and is taking less analgesic pain medication. • Myelotoxicity, meaning a decrease in platelet count, white blood cell count (WBC) and hemoglobin, is expected. • Many centers require patients to have stable platelet counts above 100,000/mm3; WBC counts above 2,400/mcL and a hemoglobin greater than 9 mg/dL before treatment. The total blood count will likely be lower after treatment than before.

Because myelotoxic chemotherapy should not be given for the one- to three-month period when the nadir from treatment is expected to occur, many oncologists may be unwilling to forgo such options. There are a few other issues that aren’t mentioned, but are important for the clinician in practice to know. Most important is prognosis. For all of the solid tumors receiving maximal medical therapy, the time from a significant change in performance status to death is on the order of four to six weeks. This can explain why radiopharmaceuticals are not used soon enough. In short, it all seems to go very fast near the end. Consequently, when physicians are thinking about the use of radiopharmaceuticals,

the patient may not have enough time left to benefit. Second in importance is cost. The cost of strontium or samarium is not just the acquisition cost of the drug; it’s the entire process of needing to give it in an appropriate environment. Although no one wants to reveal total charges, there is no question that it is thousands of dollars for a single dose. Therefore, I think clinicians should know these are effective drugs in highly selected patients. Only patients with longer life expectancy, no plans for treatment with myelotoxic chemotherapy, and challenges with conventional pain management, principally movement pain, should be considered.

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Clinical Oncology News • February 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

A quiz for the practicing hemocologist/oncologist QUESTIONS

A 40-year-old woman presents with recurrent medullary thyroid cancer (MTC). The patient is symptomatic with metastatic bone lesions. Laboratory data demonstrate rising calcitonin and carcinoembryonic antigen levels. She comes to you for a second opinion. You recommend the multikinase inhibitor vandetanib (Caprelsa, AstraZeneca). All of the following statements about this drug are true except: a. Baseline and periodic electrocardiograms are recommended. b. Vandetanib requires dose adjustment with creatinine clearance ≤50 cc per minute. c. Diarrhea is one of the most common side effects. d. Unlike bevacizumab (Avastin, Genentech/Roche), this drug has no effect on blood pressure.

marrow with fibrosis, 4% blasts and complex cytogenetics. The BCR/ABL tests using fluorescence in situ hybridization and polymerase chain reaction are negative. JAK2(V617F) mutation is present. All of the following risk factors are included in the International Prognostic Scoring System (IPSS) and the Dynamic IPSS (DIPSS) except: a. age older than 65 years b. massive splenomegaly c. constitutional symptoms d. circulating blasts ≥1% e. hemoglobin <10 g/dL f. platelet count <100,000/mm3

According to the DIPSS Plus model, what is the expected median survival of the patient presented in question 2? a. 185 months b. 16 months c. 78 months e. 35 months

True or false: In the ZETA (Zactima Efficacy in Thyroid Cancer Assessment) trial, patients with sporadic MTC and known RET (ret protooncogene) mutation status, the predominant mutation—M918T—was associated with improved progression-free survival when treated with vandetanib. a. True b. False

A 54-year-old man presents with a two-month history of fatigue, early satiety, dyspnea on exertion and increase in abdominal girth. Physical examination is notable for massive splenomegaly. Laboratory data demonstrate a white blood cell count of 26,000/mm3, hemoglobin concentration of 8.5 g/dL and a platelet count of 11,000/mm3. Uric acid and lactate dehydrogenase (LDH) levels are elevated. The peripheral blood demonstrates leukoerythoblastic smear without circulating blasts. You are unable to obtain bone marrow aspirate but the biopsy demonstrates replacement of the

Ruxolitinib (Jakafi, Incyte/Pharmaceuticals/Novartis) was approved by the FDA on Nov. 16, 2011, for intermediate- and high-risk myelofibrosis (MF), including PMF, post-polycythemia vera MF and post-essential thrombocythemia MF. The patient presented in question 2 is in the medical profession. He talks to you about the results of the COMFORTI (COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment) and COMFORT-II trials and expresses a desire to be started on this oral drug. Would you start him on ruxolitinib with an FDA-approved dosing schedule? a. Yes b. No

A 45-year-old woman is diagnosed with metastatic breast cancer. The scans were performed following positive left breast biopsy, which are consistent with metastatic disease in the liver only. The histology from the liver is similar to the breast biopsy and shows estrogen receptor/progesterone receptor–negative and HER2-positive tumor. The cardiac function is normal with a left ventricular ejection fraction (LVEF) of 65%. All of the following statements about hormone receptor–negative and HER2positive metastatic and locally advanced breast cancer are correct except: a. The dual anti-HER2 therapy combining pertuzumab and trastuzumab with docetaxel as first-line therapy prolonged progression-free survival by six months when compared

with a combination of trastuzumab and docetaxel. b. The dual anti-HER2 therapy combining pertuzumab and trastuzumab with docetaxel as first-line therapy resulted in increased cardiac toxicity. c. A Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab failed to demonstrate superiority of any drug in terms of efficacy, but the vinorelbine combination had significantly fewer adverse effects.

cancer cases. BRCA1/2 mutations are associated with 66% to 75% of these cases. Which of the following statements about BRCA1/2 mutations is true? a. The risk of ovarian cancer is higher in women with BRCA1 compared with BRCA2 mutations. b. Breast cancers associated with the BRCA1 mutation are usually of lower grade. c. The lifetime cumulative risk for contralateral breast cancer until age 70 in women with BRCA1/2 mutations is approximately 20% to 30%.

All of the following statements about trastuzumab are correct except: a. It acts against epithelial growth factor receptor-2 and is a humanized immunoglobulin G1 antibody. b. The Phase III HannaH (EnHANced treatment with NeoAdjuvant Herceptin) study demonstrated the comparable efficacy of a new, investigational subcutaneous formulation of trastuzumab with the standard IV infusion of trastuzumab in women with HER2-positive early breast cancer. c. If LVEF declines to 16% or lower from baseline or 10% from baseline to below the lower limit of normal, trastuzumab should be withheld for four weeks, at which time LVEF must be reassessed. d. In the neoadjuvant setting for stage II/III breast cancer, women who received chemotherapy in combination with lapatinib and trastuzumab had inferior pathologic clinical response (pCR) compared with treatment with either lapatinib or trastuzumab alone with chemotherapy.

Familial breast cancer accounts for approximately 10% of all breast

True or false: Deletion of the NFKBIA gene has an effect similar to EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival. a. True b. False

10.

One hundred patients are screened for cancer using a newly developed test with the following results: • truly positive, n=4 • falsely positive, n=2 • falsely negative, n=4 • truly negative, n=90 Which of the following formulas is used to determine the positive predictive value (PPV) of the test? a. 90 divided by (2 + 90) b. 4 divided by (90 + 2) c. 90 divided by (90 + 4) d. 4 divided by (4 + 2) CONUNDRUMS, continued on page 20 

SOLID TUMORS

Clinical Oncology News • February 2012

Breast Cancer

Less Surgery Is Better for Some Breast Cancer Patients San Antonio—Doctors now have additional evidence that axillary lymph node dissection (ALND) does not add benefit to sentinel lymph node resection in clinically node-negative breast cancer patients with minimal sentinel node involvement. These results come from an update of the Phase III International Breast Cancer Study Group (IBCSG) trial 23-01. The study was reported at the San Antonio Breast Cancer Symposium (SABCS; abstract S3-1). “Our findings are consistent with those of the ACOSOG Z-11 trial,” said Viviana Galimberti, MD, of the European Institute of Oncology in Milan, referring to the study conducted by the American College of Surgeons Oncology Group (ACOSOG). That randomized trial, first presented at the 2010 annual meeting of the American Society of Clinical Oncology, showed no benefit from ALND in clinically node-negative patients with one or two positive sentinel nodes. Since then, surgeons have gradually been adopting the more conservative approach to surgery. Dr. Galimberti said the two trials together should change clinical practice.

Patients eligible for the IBCSG 23-01 trial had clinically node-negative breast tumors that were 5 cm or smaller as well as minimal sentinel node (SN) involvement, defined as one or more micrometastatic (≤2 mm) SNs. Patients were not included if they had pure ductal carcinoma in situ, previous systemic therapy for breast cancer, chemoprevention within the past year, distant metastases, palpable axillary lymph nodes, and a previous or concomitant malignancy. Patients were randomized to receive ALND or no ALND. The arms were well balanced in terms of tumor size, tumor grade, tumor histology, estrogen and progesterone receptor status, and local and systemic treatment. At SABCS, the researchers discussed outcomes of 931 patients. With a median follow-up of 57 months, no difference was identified between the two arms in the primary end point of

We’re in a

position

‘I hope everyone will go home and stop doing axillary dissections on women with clinically negative nodes and a positive sentinel node.’ —Laura Esserman, MD

disease-free survival (88.4%, no ALND vs. 87.3%, ALND; hazard ratio, 0.87; 80% confidence interval, 0.67-1.12; below non-inferiority boundary of 1.25; P=0.48) and for the secondary end point of overall survival (98.0%, no ALND vs. 97.6%; P=0.35). As expected, adverse events were more frequent in patients in the ALND arm than in the non-ALND group, including sensory neuropathy (18% vs. 12%), lymphedema (13% vs. 4%) and motor neuropathy (8% vs. 3%). Both IBCSG 23-01 and ACOSOG Z-11 met less than half of their targeted accrual goals, reflecting the difficulties

in conducting a trial that challenges conventional practice; however, the results demonstrate the value of such trials. “I hope everyone will go home and stop doing axillary dissections on women with clinically negative nodes and a positive sentinel node,” said Laura Esserman, MD, professor in the Departments of Surgery and Radiology and affiliate faculty at the Institute for Health Policy Studies, and director of the Carol Franc Buck Breast Care Center, University of California, San Francisco. “More is not better—that is what the data show.” —Kate O’Rourke

Corporal Greg Caron McMahon Publishing, the publisher of this newspaper, is sponsoring a fundraiser for Cpl. Greg Caron. Cpl. Caron is an Ellington, Conn. Marine. He was injured in November in the line of duty after stepping on an IED in Afghanistan. He lost both of his legs and a finger, and also broke his collarbone. We are raising funds to help Greg and his family as they face a very long recovery.

to fill your

position

For classified advertising: contact Jessica Pichardo 212-957-5300 x308 jpichardo@mcmahonmed.com

If you would like to help, please visit www.gregcaronfoundation.com. If you would like to donate, please mail checks to: Greg Caron Foundation P.O. Box 262 Ellington, CT 06029 Checks can be made payable to: Greg Caron Family Fund Please indicate McMahon Publishing on the subject line of your check so the family knows where the donation came from. Please note, contributions to this fund are not tax-deductible.

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Clinical Oncology News • February 2012

Community Oncology

CONUNDRUMS continued from page 18

ANSWERS

Answer: d. Vandetanib is the first drug approved for MTC and the first tyrosine kinase inhibitor approved for any thyroid cancer indication. The FDA approved vandetanib for the treatment of symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease. Hypertension is a common side effect and may lead to ischemic cerebrovascular events. Other common side effects include rash, fatigue, headache and nausea. Baseline and periodic monitoring of cardiopulmonary, renal and hepatic systems are recommended. Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010;28:767-772, PMID: 20065189.

Answer: True. Vandetanib seems active in M918T-mutant sporadic MTCs, which is reassuring for the majority of patients with this disease. Several important questions are raised by the ZETA trial and will be the focus of future research. Some of these questions are: 1) How closely are phenotype, genotype and responses linked together with the availability of this novel agent? 2) Will patients with MTC and concurrent pheochromocytoma experience clinical benefit with vandetanib? and 3) Does vandetanib have a therapeutic role for patients with elevated MTC-related tumor markers but without any measurable disease? Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012; 30:134-141, PMID: 22025146. Houvras Y. Completing the arc: targeted inhibition of RET in medullary thyroid cancer. J Clin Oncol. 2012;30:200-202, PMID: 22162569.

Answer: f. The IPSS and DIPSS models use the following five adverse risk factors: age older than 65

years, hemoglobin lower than 10 g/dL, leukocyte count higher than 25×109/L, circulating blasts of 1% or greater and constitutional symptoms. There are multiple differences between the two prognostic models; the DIPSS model can be applied at any time during the disease course and assigns two adverse points for hemoglobin lower than 10 g/dL, whereas the IPSS model is applicable only at the time of diagnosis and assigns only one adverse point for hemoglobin lower than 10 g/dL. These differences have important clinical implications. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895, PMID: 18988864. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115:1703-1708, PMID 20008785.

Answer: b. A new prognostic model, DIPSS Plus, has been introduced into clinical practice, which effectively adds three additional factors to the DIPSS model—karyotype, platelet count and transfusion status—to predict overall survival in primary myelofibrosis (PMF). Based on DIPSS Plus, the patient has five points that allocate him into the high-risk category. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29:392-397, PMID: 21149668.

Answer: b. Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, demonstrated a significant reduction in spleen size and improvements in MF-related symptoms, however, in the COMFORT-I and COMFORT-II studies, the drug was avoided if baseline platelet counts were below 100,000/mm3.

Verstovsek S, Mesa RA, Gotlib J, et al. Consistent benefit of ruxolitinib over placebo in spleen volume reduction and symptom improvement across subgroups and overall survival advantage: results from COMFORT-I. ASH Annual Meeting Abstracts. 2011;118:278. Harrison CN, Kiladjian JJ, Gisslinger H, et al. Ruxolitinib provides reductions in splenomegaly across subgroups: an analysis of spleen response in the COMFORT-II study. ASH Annual Meeting Abstracts. 2011;118:279. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363:1117-1127, PMID: 20843246.

Answer: b. Pertuzumab, an antiHER2 monoclonal antibody that inhibits receptor dimerization, has shown synergistic activity when used with trastuzumab and has an acceptable safety profile. According to the safety data, the incidence of significant neutropenia and diarrhea was escalated but not cardiac toxicity in patients receiving pertuzumab.

Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119, PMID: 22149875. Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011;29:264-271, PMID: 21149659.

Answer: d. The Phase II CHERLOB (Preoperative AnthracyclineBased Chemotherapy Plus Lapatinib, Trastuzumab or Both in HER2 Positive Breast Cancer) trial demonstrated that women who received chemotherapy in combination with lapatinib and trastuzumab had a superior pCR, compared with treatment with either lapatinib or trastuzumab alone with chemotherapy. The study showed pCR rates of 28%, 32% and 48% in the trastuzumab-only, lapatinib-only and combination arms, respectively.

DeVita VT, Lawrence TS, Rosenberg SA. DePinho RA, Weinberg RA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of

Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2008. Ratner M. Roche plans for more convenientto-use Herceptin and Rituxan. Nat Biotechnol. 2010;28:298, PMID: 20379157. Guarneri V, Frassoldati A, Bottini A, et al. Final results of a phase II randomized trial of neoadjuvant anthracycline-taxane chemotherapy plus lapatinib, trastuzumab, or both in HER2-positive breast cancer (CHER-LOB trial) J Clin Oncol. 2011;29(suppl):abstract 507.

Answer: a. Breast cancers associated with BRCA1 are usually of higher grade and are hormone receptor–negative. The lifetime cumulative risk for contralateral breast cancer until age 70 in women with a BRCA1/2 mutation is approximately 50% to 65%. This has important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation.

Chen S, Iversen ES, Friebel T, et al. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol. 2006;24:863871, PMID: 16484695. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003;100:8418-8423, PMID: 12829800. Malone KE, Begg CB, Haile RW, et al. Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol. 2010;28:2404, PMID: 20368571.

Answer: True. Deletion and low expression of NFKBIA were associated with unfavorable outcomes despite therapy when compared with tumors having neither abnormality.

Bredel M, Scholtens DM, Yadav AK, et al. NFKBIA deletion in glioblastomas. N Engl J Med. 2011;364:627-637, PMID: 21175304.

10.

Answer: d. PPV is the proportion of people with a positive test who have the disease. DeVita VT, Lawrence TS, Rosenberg SA. DePinho RA, Weinberg RA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

S. Mustafa, MD, assisted in preparing this article.

FDA NEWS

FDA Approves Subsys Fentanyl Sublingual Spray T

he FDA has approved the cancer pain medication Subsys (fentanyl sublingual spray; Insys Therapeutics). Subsys is a sublingually administered formulation of fentanyl in a novel delivery device indicated for episodes of breakthrough cancer pain. Breakthrough cancer pain is

characterized by sudden, often unpredictable episodes of intense pain that can peak in severity at three to five minutes despite background pain medication. Subsys is approved in cancer patients aged 18 years and older who are already receiving, and who are tolerant to, opioid therapy for their

underlying persistent cancer pain. Breakthrough cancer pain episodes

can last anywhere from several seconds to hours, with the average episode lasting approximately 30 minutes. Breakthrough cancer pain is believed to occur in approximately one-third of patients being treated for cancer and up to 80% of patients with later-stage disease. —Based on a press release from Insys Therapeutics

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Clinical Oncology News • February 2012

Technology

Appetite for Health Care Apps Fuels Growth With the increasing popularity of tablets and smartphones, mobile medical applications or “apps” are on the rise. There are thousands of mobile apps available for download, some free and many at varying prices. In 2009, health care applications comprised about 1.5% of the total mobile application market, and by 2015, it’s estimated that there will be 500 million smartphone users with health care applications, according to the FDA. In September 2011, the agency held a public workshop to draft guidance on its oversight for certain mobile medical applications that may impact the performance or functionality of currently regulated medical devices. Public comments were accepted until mid-October. The apps are part of a natural progression of technology, explained Kevin Clauson, PharmD, director of the Center for Consumer Health Informatics Research at Nova Southeastern University in Fort Lauderdale, Fla. He gave a lecture on helpful apps in October at the Florida Society of Health-System Pharmacists meeting. Those interested in mobile technology used to use personal digital assistants like the Palm products, “but since cell phones are ubiquitous, there’s been a massive amount of interest and effort to make this available for smartphones,” he said. “We are still in the early days [of apps],

where we will see a lot more use.” Already there are a plethora of apps that could be helpful (box), including medication reference tools, medical calculators, medical journals and literature libraries and dictation tools.

A current trend is creating mobile versions of electronic health records that can be accessed via smartphones or iPads, Dr. Clauson said. Some hospitals already have rolled these out but the coming years should see a bigger spike in adoption, he noted. Although security/privacy issues are still being worked out at many facilities, there is an enterprise configuration of the iPhone that enables HIPAA-compliant FaceTime calls and secure transmission of

patient information. The surge of apps may also help physicians to engage with patients more. There are apps available to help patients manage their medication lists and set digital reminders to take their medicines. Other apps can help patients manage weight loss, diabetes and other chronic medical conditions. see APPS, page 22 

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More Apps on Tap Dr. Clauson recommends the following resources for more information:

Tabbed Navigation • iMedicalApps.com: Web site providing reviews and commentary on mobile medical technology and applications submitted by physicians and other members of the medical community.

• Happtique.com: Mobile application store allowing hospitals and other health care enterprises the ability to create individually branded substores supporting employee and patient mobile technology use. • itunes.com/healthcare professionalsiphone apps: Catalogue to purchase mobile apps.

Educational Reviews

ORDER POCKET GUIDES Guide to Cancer Therapeutic Regimens 2012 Guide to the Administration and Use of Cancer Therapeutic Agents 2011/2012

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Clinical Oncology News • February 2012

Breast

New Molecular Test Predicts Risk for DCIS Clinicians waiting for further validation San Antonio—Researchers say they have validated a tool for predicting breast cancer recurrence risk in patients with ductal carcinoma in situ (DCIS) who undergo surgical excision and have not had radiation. The new Oncotype DCIS score (Oncotype DX Breast Cancer Assay for DCIS, Genomic Health) can identify patients who do not need radiation after surgery for DCIS, according to investigators. The study was presented at the 2011 San Antonio Breast Cancer Symposium (SABCS; abstract S4-6). “This is important work as we try to better tailor therapies for individual patients,” said Jennifer Ligibel, MD, an assistant professor of medicine at Harvard Medical School in Boston, who was not involved with the study. She said that she is not yet planning to use the test in her practice however. “We are not planning to incorporate this tool in our practice until more validation is available from other studies,” she said. Although randomized clinical trials have shown that radiation and tamoxifen reduce the risk for recurrence after DCIS surgery, they have not been shown to increase survival. Until now, oncologists have not had a way to identify patients who can skip radiation because their recurrence risk is acceptably low. “Reliable methods to select treatment for surgery alone without adjuvant therapies have not been established using conventional clinical and pathologic factors in a reproducible fashion,” said

Several foci of ductal carcinoma in situ are seen. The arrow points to a focus of invasion.

Lawrence Solin, MD, the principal investigator of the study and chair of radiation oncology at Einstein Medical Center in Philadelphia. He said the new tool will help fill this need. The Oncotype DCIS score uses information from 12 of the 21 genes in the Oncotype DX test and an algorithm to

treated with surgical excision, optional tamoxifen and no radiation. The five- and seven-year rates of IBEs were published in the Journal of Clinical Oncology (2009;27:5319-5324, PMID: 19826126). At the SABCS, the researchers reported updated data with 10-year follow-up outcomes. They presented figures showing the DCIS score and 10-year IBE rates according to three prespecified risk groups and noted that they could “see a very nice differentiation” in patients in the low-, intermediate- and high-risk groups.

Table. Ten-year Outcomes With the New DCIS Score DCIS Score Risk Group

Number of Patients (%)

Low (<39)

246 (75%)

10-Year Kaplan-Meier Rate (95% CI) IBE (Invasive or DCIS)

Invasive IBE

12% (8.1%-17.6%)

5.1% (2.8%-9.5%)

Intermediate 45 (14%) (39-54)

24.5% (13.8%-41.1%)

8.9% (2.9%-25.8%)

High (≥55)

27.3% (15.2%-45.9%)

19.1% (9%-37.7%)

0.02

0.01

Log rank P value

36 (11%)

CI, confidence interval; DCIS, ductal carcinoma in situ; IBE, ipsilateral breast event

predict recurrence that was developed using data from several randomized trials. The score, which ranges from 0 to 100, predicts the risk for an ipsilateral breast event (IBE) after surgery for DCIS. In the study, IBE was defined as a local DCIS recurrence or an invasive carcinoma in the same breast. The risk score generated is independent of whether patients receive adjuvant tamoxifen. The validation study was designed to determine whether there was a significant association between the DCIS score and the risk for an IBE and whether the DCIS score provides value beyond standard clinical and pathologic factors. Researchers analyzed 327 DCIS tumor specimens from the Eastern Cooperative Oncology Group E5194 study. This prospective study, conducted from 1997 to 2,000, enrolled two cohorts of patients with DCIS using low-risk criteria based on clinical and pathologic information. Patients were

In the study, about 75% of patients had a low DCIS score. Their chance of having any IBE was 12% and their chance of having an invasive IBE was 5%. Patients with a high score had a 27% chance of any IBE and a 19% chance of developing an invasive IBE. Patients with an intermediate score had a 24.5% chance of developing any IBE and an 8.9% chance of developing an invasive IBE. Using multivariable models of risk, the researchers showed that the DCIS score improved risk assessment compared with standard clinical and pathologic factors of tumor size and postmenopausal status. “The DCIS score provides independent information beyond clinical and pathologic parameters,” Dr. Solin said. “We can use this DCIS score to quantify the individual patient’s 10-year risk for an ipsilateral breast event.” A few researchers, including Daniel Hayes, MD, clinical director of the

drug to meet their health needs and help them identify potentially harmful drug interactions. The app, available on Verizon Wireless Android handsets and BlackBerry devices, provides information about out-of-pocket costs for any prescription drug and lower-cost options specific to a patient’s prescription drug plan, and drug interaction alerts based

on the patient’s prescription history— even if the patient has been treated by several doctors or has filled prescriptions at multiple pharmacies. The app also allows patients to view their medications and set reminders for themselves or family members to take or refill medications. Nearly 40,000 Medco members have

breast oncology program at the University of Michigan Comprehensive Cancer Center in Ann Arbor, said further studies should be done to confirm that the DCIS score is accurate. According to Dr. Solin, the DCIS score should make “discussions more individualized and tailored between a physician and an individual patient.” Many oncologists, however, say it is not clear how to use the score beyond prognosis. That is, how exactly should it be used to impact treatment plans? “The implication is that there is a group of patients who have such a low risk that radiation is not needed and the issue is where that is. What is the recurrence score below which you don’t need to treat?” asked Dr. Hayes during a question-and-answer session after the SABCS presentation. “That is going to have to be a decision that patients and doctors make together,” Dr. Solin responded. “I think that many patients would take that [12%] as reasonable for no adjuvant treatment,” he said, referring to the patients with a low-risk score in the study. Dr. Hayes pointed out that there is a rate at which the risk for an IBE is the same as or lower than the risk for cancer in the contralateral breast and that this might be a good place to draw the line. After learning from Dr. Solin that the risk for contralateral breast cancer in the current study was 7%, Dr. Hayes mused to the audience that 12% might be setting the bar high. The price tag for the DCIS score is $4,175 per patient. According to a spokesperson at Genomic Health, the average cost for irradiating a DCIS patient is $22,000, so the test, when used correctly, could save health care costs overall. “I think in a broader sense, cost is the total care cost for the patient,” said Dr. Solin. “If we can use this test to spare other adjuvant therapies, then in fact, it becomes very cost-effective.” —Kate O’Rourke Drs. Ligibel and Solin have no relevant financial relationships to disclose. Dr. Hayes collaborates with Genomic Health.

PRN

APPS continued from page 21 

Verizon and Medco Partnership In April, Verizon Wireless and Medco Health Solutions, Inc., launched an app to help guide patients and their physicians to the lowest-cost prescription

downloaded the app, according to Amy Foley, chief Web officer for Medco. “The feedback from our clients and members has been positive, and members who are active mobile users are looking forward to additional enhancements coming by year end, including refills and pharmacy care alerts,” she said. —Karen Blum

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Clinical Oncology News • February 2012

Breast

RESPONSE continued from page 1 

discovered at surgery. It turns out that this assumption is totally wrong for those with low-grade hormone receptor (HR)–positive tumors, and also for those with human epidermal growth factor receptor (HER)2-positive tumors that are also HR-positive! To date there has been no progress, and to my knowledge, no ongoing trials, on the issue of additional chemotherapy after failure to achieve pCR. However, new 62-month follow-up data from the GeparTrio trial of neoadjuvant chemotherapy presented at the

population was typical of induction chemotherapy trials, including many women with larger tumors who, it was hoped, might be spared mastectomy if their tumors could be reduced in size by induction chemotherapy. Among the enrolled women, 61% had primary tumors greater than 4 cm in size, 13% had T4 primaries, 55% were clinically node-positive, 14% had lobular cancers, 38% had histologic grade 3 tumors; 35% of tumors were HR–negative, and 30% HER2–positive. Eighteen percent of women were aged 39 years or younger. No trastuzumab (Herceptin, Genentech) was given because it had not yet been shown to be beneficial when given before or after defini-

clinical response rate among the initial responders to two additional cycles of TAC, and a very low pCR rate among the initial nonresponders, regardless of whether therapy was switched or not (6% vs. 5.3%).2,3

EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, New York City

Latest Report: Big Benefit In Disease-Free and Overall Survival The current report presented at the SABCS by the German Breast Group turns these results upside down, with statistically significant improvements in both disease-free survival (DFS) and overall survival (OS) for the groups that had their chemotherapy programs altered based on six-week clinical response.

‘The division of HR-positive, HER2-negative tumors needs to be repeated with more sophisticated discriminators. In many studies, histologic grade has been poorly reproducible among pathologists.’

Table 1. pCR Rates and Benefits From pCR Achievement Number of Patients

pCR, % (#)

Hazard Ratio for DFS for pCR Compared with no pCR

6-Year Absolute DFS Benefit From pCR, %a

HR-positive, grade 1/2

572

5 (30)

0.99

HR-positive, grade 3

211

18 (39)

0.26

+23

HR-positive/HER2-positive

281

9.5 (27)

1.14

–5

HR-negative/HER2-positive

178

28 (50)

0.191

+25

HR-negative/HER2-negative

362

37 (133)

0.15

+42

DFS, disease-free survival; HER2, human epidermal growth factor receptor-2, HR, hormone receptor; pCR, pathologic complete response a

Based on visual estimates from Kaplan-Meier curves.

than the usual 80% clinical response rate reported at the end of a full course of induction chemotherapy. Women who achieved an early clinical partial response had a modestly better prognosis than those who did not, based on an analysis not presented by the German Breast Group, but that can be estimated from the DFS curves of the six-cycle TAC control groups in each of the two randomizations: 68% versus 62% at six years from enrollment. Thus, six-week clinical response is only weakly prognostic, but may be predictive of the benefit of changing chemotherapy. Had the presentation stopped here, the German Breast Group would have a clearly positive result, and many of us would have gone home and given neoadjuvant TAC to women who obviously needed adjuvant chemotherapy, and then changed therapy after six weeks based on initial response. Happily, von Minckwitz and his colleagues are aware of the heterogeneity of breast cancer, and did the best they could to look at their results in different groups of patients.

Subgroup Analysis of Benefit From pCR

‘Because of the efficacy of adjuvant trastuzumab regardless of HR status, we have all thought of these tumors as primarily HER2-positive—perhaps we need to rethink this in terms of their biology.’ most recent San Antonio Breast Cancer Symposium (SABCS) by Gunter von Minckwitz, MD, indicates that failure to achieve pCR is not necessarily bad for some groups of women. Additionally, change of therapy based on initial clinical response to chemotherapy improves long-term outcome in some groups without impact on pCR. The trial is very complicated, and the subgroup analysis even more so. Both are worthy of detailed review, since the results will probably change the way we all give adjuvant chemotherapy to women with HR-positive tumors who clearly need chemotherapy.

Details of the GeparTrio Trial In the GeparTrio trial, all of the approximately 2,000 women entered initially received two cycles of TAC chemotherapy (docetaxel [T] 75 mg/m2, doxorubicin [A] 50 mg/m2 and cyclophosphamide [C] 500 mg/m2, repeated every three weeks). The patient

tive surgery. Those achieving a clinical partial response based on ultrasound (>50% decrease in the product of two perpendicular diameters) after six weeks (two cycles of TAC) were randomized to either four or six additional cycles of the regimen, with the total of six being the “adjuvant standard” defined by Mackey in 2005.1 The trial randomized those achieving less than clinical partial response at six weeks to either four additional cycles of TAC (“standard therapy”) or four threeweek cycles of alternative chemotherapy with NX (vinorelbine [N] 25 mg/m2 days 1 and 8 and capecitabine [X] 1,000 mg/ m2 twice daily on days 1 to 14).

Initial Surrogate Outcome (pCR): No Benefit From Response-Guided Therapy The initial reports, based on the surrogate end point of pCR, were negative, with a trivial 2.5% increase in pCR

Response-guided therapy improved DFS by a relative 29% (P<0.001) and OS by 21% (P=0.048); estimated six-year absolute DFS improved about 10% and OS about 6% based on Kaplan-Meier plots. In a multivariate analysis of DFS, response-guided therapy was a statistically significant prognostic factor, along with HR status, primary tumor (T) stage and nodal positivity. Response-guided chemotherapy really has two components: extra TAC×2 for the responders and a switch to NX for the nonresponders. Among patients with clinical partial response after six weeks, eight total TAC cycles improved DFS by a relative 22% compared with six TAC cycles—approximately a 9% absolute benefit at six years. Among those with nonresponding tumors at six weeks, switching to NX for the last four cycles improved DFS by a relative 41%—an absolute benefit of approximately 12% at six years. The rate of clinical partial response at six weeks was 69%, just a little lower

The researchers divided patients according to a clinical scheme adopted by the St. Gallen consensus meeting according to HR status, histologic grade and HER2 status.4 The names given to the different groups in the GeparTrio report derive from an “intrinsic classification” scheme based on mRNA expression.5 I believe it is misleading to use these names when mRNA expression has not been measured, and so will describe each group according to the tests that defined it. Even with this fairly simple, indeed primitive, classification system, about 20% of the women entered could not be classified because of missing measurements. I assume the subgroup analysis was not planned because 20% of the patients would not have missing data if it were. At the time the study was conducted, measurement of HER2 was not standard because adjuvant trastuzumab had not yet been shown to be effective – indeed, this analysis was not planned before the study started. As is clear from Table 1, the pCR rate was very low for HR-positive, HER2negative grade 1/2 tumors. Achievement of pCR in this group is not favorably prognostic, as was reported at

SOLID TUMORS

Clinical Oncology News • February 2012

Breast

Table 2. Benefits From Response-Guided Therapy: Absolute DFS Benefit Hazard Ratio (Compared With TACx6)

Absolute DFS Benefit at 6 Yearsa, %

P Value (Responseguided Therapy vs. TACx6)

HR-positive, grade 1/2

0.55

0.003

HR-positive, grade 3

0.40

0.006

HR-positive/ HER2-positive

0.56

0.035

HR-negative/ HER2-positive

1.01

0.978

HR-negative/ HER2-negative

0.87

0.464

DFS, disease-free survival; HER2, human epidermal growth factor receptor-2; HR, hormone receptor a

Based on visual estimates from Kaplan-Meier curves.

‘It is crucial to understand whether the decision to change therapy should be based on pCR or early clinical partial response.’

the 2011 American Society of Clinical Oncology (ASCO) meeting in a combined analysis of seven German neoadjuvant chemotherapy trials.6 This was new information for me, and I suspect for most clinicians. Some argue that pCR is not prognostic for women with HR-positive lowgrade tumors because the effectiveness of later postoperative hormonal therapy overwhelms the chemotherapy effect, even if it produced a pCR. I doubt this, because the pCR patients in this group had a fairly high relapse rate compared with the pCR patients in the HR-negative groups. On the contrary, it seems that the high relapse rate among pCR patients in the low-grade HR-positive group reflects the relative lack of potency of neoadjuvant chemotherapy when treating micrometastatic disease, even if all detectable tumor was cleared in the breast. The issue is not one of effective later hormonal therapy, but a later lack of efficacy of chemotherapy that appeared very effective early. Rate of pCR was higher for

HR-positive/HER2-negative, grade 3 tumors, and DFS was substantially improved in this group by achievement of pCR. These tumors are apparently more sensitive to chemotherapy than the low-grade HR-positive tumors, and the benefit is long-lasting. HR-negative/HER2-negative tumors had the highest rate of pCR, and this achievement substantially improved their prognosis. The rate of pCR was nearly as high as in triple-negative tumors among women with HR-negative/HER2-positive tumors, and those achieving pCR benefited substantially in DFS with excellent outcomes even in the absence of trastuzumab. Surprisingly, in this study, those women with HER2-positive/HRpositive tumors had a much lower pCR rate and no benefit at all from achieving pCR. In a separate paper presented by Dr. Sybelle Loibl of the German Breast Group at SABCS that looked at the influence of pCR on prognosis for women given neoadjuvant chemotherapy for HER2-positive cancers across a large

number of trials, pCR was strongly and favorably prognostic, but the analysis did not look at subgroups according to HR and the achievement of pCR status.7 Obviously, rates of pCR rose after trastuzumab was introduced. The 77 HER2positive pCR patients from the GeparTrio trial made up about two-thirds of the 119 pCR HER2-positive women who did not receive neoadjuvant trastuzumab in Loibl’s meta-analysis. Therefore, we need to look elsewhere for independent confirmation that achievement of pCR in HR-positive/HER2-positive tumors fails to improve DFS or OS.

pCR Is Not Favorable for DFS In HR-positive/HER2-positive Tumors It turns out Dr. von Minckwitz did look at the influence of HR positivity and pCR in HER2-positive tumors at ASCO 2011.6 In a review of the results of all seven German neoadjuvant trials, pCR was not prognostic in the HRpositive/HER2-positive patients in the presence or absence of trastuzumab. In two trials with concurrent trastuzumab (the GeparQuattro and Techno trials), the 98 HR-negative pCR patients had almost no relapses, but the 79 HRpositive pCR patients had a relapse rate of about 38% at 50 months, identical to that of the women who did not achieve pCR in this subgroup. Once follow-up is available, studies like the Neo-ALLTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) and NEOSPHERE (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) trials should provide plenty of independent data with which to examine the prognostic value of pCR in HR-positive/HER2-positive patients. In the meantime, pCR is not a valid goal in the HR-positive/HER2-positive population, and failure to achieve pCR should not be considered a negative prognostic factor in these women.

Only HR-Positive Tumor Patients Benefit From Response-Guided Therapy Response-guided therapy, as conducted in the GeparTrio trial, seemed effective in all three HR-positive groups, however, not at all in the “triple-negative” and HER2-positive/HR-negative groups (Table 2). The question of how to handle a positive trial with no apparent benefit in some large subgroups is a real problem. Because the subgroups were not predefined and the number of potential subgroups was not restricted in the protocol, the analysis should be seen as “hypothesis-generating” only. On the other hand, because failure to achieve pCR was so strongly negatively prognostic in the same groups in which response-guided therapy was not apparently helpful (HER2-positive/HR-negative and HER2-negative/HR-negative),

‘Six-week clinical response is only weakly prognostic but may be predictive of the benefit of changing chemotherapy.’ failure to achieve pCR after all induction therapy—rather than clinical partial response at six weeks—should be used as the key eligibility characteristic for further study of response-guided therapy in these groups. Based on the GeparTrio subgroup analysis, I have no enthusiasm at all for studying either two more TAC cycles or four cycles of NX in women whose HR-negative tumors fail to achieve pCR after six cycles of TAC or something similar. I think we need to test better ideas. For women with HR-negative/HER2positive tumors failing to achieve pCR, dual HER2-targeting using trastuzumab plus either pertuzumab or lapatinib, as suggested by Dr. Loibl in San Antonio, alone or together with alternate chemotherapy, seems attractive for study. For similar women with triple-negative tumors, I find it much harder to come up with readily available candidate regimens for a Phase III trial. Alas, I am not the only one without great ideas for this population. On the other hand, I am enthusiastic about giving an extra six weeks of TAC induction chemotherapy to women with HR-positive/HER2-negative tumors who achieve partial response at six weeks. “Give more of what worked” seems an easy conclusion. One potential problem is the long-term cardiotoxicity from the extra 100 mg/m2 of doxorubicin; this could be easily avoided by using prolonged infusions over 72 to 96 hours, which halves the rate of cardiotoxicity at a given cumulative anthracycline dose, or perhaps adding desrazoxane, although this may reduce the anti-cancer effect of the doxorubicin. A second problem could be the enhanced neurotoxicity from two more taxane cycles. If further data confirm recent suggestions that those at highest see RESPONSE, page 26 

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Do you have thoughts on Dr. Vogl’s commentary? Please send comments to gmiller@mcmahonmed.com

SOLID TUMORS

Clinical Oncology News • February 2012

Breast

RESPONSE continued from page 25 

risk for taxane-induced neuropathy can be picked out by germline single nucleotide polymorphisms, then those at highest risk by such tests can be excluded from extended taxane chemotherapy, as can those who develop early neuropathy of significant severity.8 Similarly, I would have little trouble switching a woman whose HR-positive/ HER2-negative tumor did not achieve even a partial response at six weeks to four cycles of NX. Switching to NX did not decrease the chance of breast preservation in the GeparTrio trial (about 58% with either NX or four more TAC cycles).3 Because only 30% of the GeparTrio patients failed to achieve a clinical partial response at six weeks, the number of patients for subgroup analysis among the nonresponders was relatively small, and our confidence in the validity of the results should be smaller. Perhaps the next study should compare switching to NX versus some other regimen. Gabriel Hortobagyi, MD, chief of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, suggests altering the hormonal adjuvant regimen as a comparator, adding either everolimus or fulvestrant to an aromatase inhibitor.9 The anomalous behavior of women with HER2-positive/HR-positive tumors in GeparTrio—who showed no benefit from pCR but a big benefit from change of therapy based on clinical response at six weeks, the opposite of what happened to those whose tumors were HER2-positive/HR-negative—suggests to me that response-guided therapy for this subgroup should be looked at again with chemotherapy given with concurrent trastuzumab. I note that in Perou’s “intrinsic classification” based on mRNA, these tumors sort with the HER2-positives, not the HR-positives. I think the study needs to be repeated with concurrent trastuzumab. It is crucial to understand whether the decision to use more effective therapy should be based on pCR or early clinical partial response. Because of the efficacy of adjuvant trastuzumab regardless of HR status, we have all thought of these tumors as primarily HER2-positive—perhaps we need to rethink this in terms of their biology.

More Sophisticated Sorting of HR-positive Tumors Is Needed I feel strongly that the division of HRpositive/HER2-negative tumors needs to be repeated with more sophisticated discriminators. In many studies, histologic grade has been poorly reproducible among pathologists. The German group plans on measuring proliferation by immunohistochemistry for Ki-67 in all 2,000 women and reclassifying the

tumors, but this has not yet been done. At least in Dr. Mitchell Dowsett’s lab in London, adding Ki-67 immunohistochemistry to quantitative estimates of HRs based on immunohistochemistry gives an excellent prognostic model for HR-positive tumors equal to the Oncotype DX.10 Determining intrinsic subtype using tools like the PAM-50, which can be done on paraffin-embedded fixed tissue, or the MammaPrint, which requires

control groups that give nonresponding patients at six weeks the additional six cycles of TAC, for a total of eight, and responding patients four cycles of NX. The goal would be to prove that different folks do indeed need different strokes, rather than all folks just needing better strokes. Although this point is theoretically valid, I personally would be reluctant to conduct a large, long trial to address the issue. I prefer to design new

‘We are missing data to prove that the observed benefit from response-guided therapy is not just from the use of better regimens, regardless of the initial response.’ fresh tissue, would be even more sophisticated. All the women with HR-positive tumors in GeparTrio seemed to benefit from response-guided therapy—the difference seems to be in the incidence and importance of pCR. A more sophisticated division of the HR-positive/HER2-negative tumors may solve an anomaly created by this analysis. Most of us believe that a fraction of women with these tumors benefit little from adjuvant chemotherapy—Oncotype DX calls these low or intermediate risk—but benefit greatly from adjuvant hormonal therapy. That group was not identified in the GeparTrio analysis, because more chemotherapy, be it six more TACs as opposed to four, or four NX cycles instead of four more TACs, benefited both the early clinical responders and the nonresponders. Women entered into GeparTrio had more aggressive, larger tumors than the general breast cancer population. Therefore, these exquisitely hormone-sensitive and chemotherapy-resistant tumors may be underrepresented in the GeparTrio population compared with adjuvant studies of smaller tumors. It is also conceivable that women who did not benefit from CMF (cyclophosphamide, methotrexate and fluorouracil) in NSABP (National Surgical Adjuvant Breast and Bowel Project) B20, the basis of the Oncotype DX predictive algorithm, would have benefited from other chemotherapy like NX had their risk been high enough to detect the benefit. In thinking carefully about the GeparTrio conclusions, I believe we are missing data to prove that the observed benefit from response-guided therapy is not just from the use of better regimens, regardless of the initial response. It seems unlikely, but maybe even the early nonresponders would have benefited from two extra cycles of TAC, and maybe the responders would have benefited from four cycles of NX rather than four more TAC cycles. To be absolutely certain the conclusions are correct, we would need

trials to refine response-guided therapy. Along the same lines, we need to explore the utility of four cycles of NX after the eight cycles of TAC. The decision to limit the duration of adjuvant chemotherapy to four or six cycles was made arbitrarily in the late 1980s and may well have been deleterious for many of our higher-risk patients. Indeed, four cycles of TAC was inferior to eight cycles of AC (adriamycin and cyclophosphamide)-paclitaxel in the recent NSABP B30 study, but six cycles of TAC was equal to the same AC-paclitaxel in the International Breast Cancer Study Group trial—suggesting six cycles of TAC is superior to the four-cycle regimen, and that the number of cycles does indeed matter.11,12 The negative CALGB study presented at SABCS 2010 by Lawrence N. Shulman, MD, of the Dana-Farber Cancer Institute in Boston, on four versus six cycles of AC or paclitaxel was in a very low-risk population (93% node-negative, four-year DFS 91.7%, with the majority of events likely local recurrences and new primaries rather than metastases), many of whom probably would not have predicted benefit from any chemotherapy by Oncotype DX analysis.13 Therefore, I do not think Dr. Shulman’s negative trial contradicts the GeparTrio conclusion that more TAC is better, because the latter was done in a population in which there was a much higher rate of DFS events, especially distant metastases. We now need to acknowledge that— at least for early responding patients, though probably only those whose tumors are HR-positive—eight cycles of TAC is better than six. Identifying the patients who may benefit from more TAC chemotherapy (or more AC followed by taxane) or a switch to NX, may be a good reason to give chemotherapy before surgery, as opposed to after it, even for women whose tumors can be easily managed without mastectomy. This is a major change in systemic adjuvant therapy of breast cancer. We should thank the German Breast

Group for working this out for us and for our patients.

References 1. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005;352:2302-2313, PMID: 15930421. 2. von Minckwitz G, Kümmel S, Vogel P, et al. Intensified neoadjuvant chemotherapy in early-responding breast cancer: Phase III randomized GeparTrio study. J Natl Cancer Inst. 2008;100:552-562, PMID: 18398094. 3. von Minckwitz G, Kümmel S, Vogel P, et al. Neoadjuvant vinorelbine–capecitabine versus docetaxel–doxorubicin–cyclophosphamide in early nonresponsive breast cancer: Phase III randomized GeparTrio trial. J Natl Cancer Inst. 2008;100:542-551, PMID: 18398097. 4. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ; Panel members. Strategies for subtypes—dealing with the diversity of breast cancer: Highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22(8):17361747, PMID: 21709140. 5. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci. 2001;98:10869-10874, PMID: 11553815. 6. von Minckwitz G, Kaufmann M, Kümmel S, et al. Correlation of various pathologic complete response (pCR) definitions with long-term outcome and the prognostic value of pCR in various breast cancer subtypes: results from the German neoadjuvant meta-analysis. J Clin Oncol. 2011;29(suppl): abstract 1028. 7. Loibl S, von Minckwitz G, Blohmer J, et al. pCR as a surrogate in HER2-positive patients treated with trastuzumab. Presented at the CTRC-AACR San Antonio Breast Cancer Symposium, San Antonio, Texas, December 6-10, 2011; abstract S5-4. 8. Schneider BP, Wang M, Stearns V, et al. Relationship between taxane-induced neuropathy and clinical outcomes after adjuvant chemotherapy. J Clin Oncol. 2011;suppl 27; abstract 270. 9. Hortobagyi G. Personal communication. 10. Cuzick J, Dowsett M, Pineda S, et al. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health Recurrence Score in early breast cancer. J Clin Oncol. 2011;29:4273-4278, PMID: 21990413. 11. Swain SM, Jeong JH, Geyer CE Jr, et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010;362:2053-2065, PMID: 20519679. 12. Eiermann W, Pienkowski T, Crown J, et al. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011;29:3877-3884, PMID: 21911726. 13. Shulman LN, Cirrincione C, Berry DA, et al. Four vs 6 cycles of doxorubicin and cyclophosphamide (AC) or paclitaxel (T) as adjuvant therapy for breast cancer in women with 0-3 positive axillary nodes: CALGB 40101 – A 2x2 factorial Phase III trial: first results comparing 4 vs 6 cycles of therapy. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S6-3.

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Tariq Mughal Informa Healthcare, November 13, 2009 This guide presents all clinically relevant aspects of leukemias, lymphomas and myelomas. Using clear terminology, the book discusses salient features, diagnostic procedures, prognosis and treatments for these cancers. CO_HEM0212

SOLID TUMORS

Clinical Oncology News • February 2012

Patient Care

Chemo During Pregnancy Does Not Harm Child Development Stockholm—Prenatal exposure to chemotherapy does not appear to have a detrimental effect on a child’s cognitive and cardiac functions, according to a study conducted by a multicenter international team from Belgium, the Netherlands and Canada. Historically, many women have been advised to terminate their pregnancies before undergoing chemotherapy, because it was thought that the toxic effects of the treatment would do irreparable harm to the developing fetus. But more recent research has found that,

particularly when given after the first trimester of pregnancy, chemotherapy may not have any lingering effects on the baby. In this study, presented at the European Multidisciplinary Cancer Congress, investigators followed a cohort of 140 children who were prenatally

exposed to chemotherapy, beginning in 2005 (abstract LBA12). At predefined ages (first at 18 months, and again at ages 5-6, 8-9, 11-12, 15-16, and 18 years), the children were given a battery of tests, including a Bayley/IQ test, an electrocardiography/echocardiography exam and

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a questionnaire on general health and development. From the age of 5 years on, children received additional testing and assessment, including audiometry, an Auditory Verbal Learning Test, subtasks of the Children’s Memory Scale and Test of Everyday Attention for Children and the Child Behavior Checklist. Of the 140 children followed, half could be assessed for the study. (Some were still too young, whereas others left the study for a variety of reasons.) The neurocognitive and cardiac function results for the 70 children who were assessed were within normal ranges at a median follow-up period of 22.3 months (range, 16.8-211.6 months). “There appeared to be no effect of prenatal exposure to chemotherapy on cognitive or cardiac outcomes,” said Frederic Amant, MD, of University Hospitals Leuven, in Belgium, the lead investigator of the study. Although chemotherapy did not appear to have any damaging effects, prematurity did. The children in the study were born at a median gestational age of 35.7 weeks (range, 28.3-41 weeks); 47 of the 70 children who were assessed were considered premature (<37 weeks gestation), and those born at less than 34 weeks did appear more likely to have cognitive problems. “According to these results, if a child exposed to chemotherapy is delivered at term, it will develop normally,” said Dr. Amant. “There is a linear correlation between intelligence and prematurity; chemotherapy, according to our findings, does not really add to this outcome.” “This is very nice confirmatory data for mothers who are facing this tough issue: They can be treated for their cancer, they can have normal babies and things can be OK,” said Richard Theriault, DO, professor in the Division of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, and a leading authority on cancer during pregnancy. Decisions about what to do when cancer is diagnosed during pregnancy are still not necessarily easy, and some malignancies may pose more challenges than others. “Acute leukemias, for example, are more problematic because of the nature of the disease and the type of chemotherapy administered,” noted Dr. Theriault. “Some women may still make the personal choice to terminate, but generally speaking, a lot of studies—both retrospective and prospective—have shown that you can successfully treat cancer and have a healthy pregnancy.” —Gina Shaw Drs. Amant and Theriault report no relevant conflicts of interest.

POLICY & MANAGEMENT

Clinical Oncology News • February 2012

Technology

ICD-10 has value in the long run, “but are pushing back the standards for it’s putting the cart before the horse,” claims submissions systems that are needed for handling ICD-10, isn’t it he said. continued from page 1  “The timing is off; it should be EMR obvious they will have to push back the American Gastroenterological first, then ICD-10. Otherwise, there’s no the ICD-10 compliance requirement Association’s (AGA) delegate to the AMA. as well?” benefit.” But this would only lessen the inter“We are in the middle of implementMedical practices that are not yet ing electronic medical records [EMRs]. using EMR systems “will have to imple- val between ICD-10 and the next iterDealing with the new code at the same ment ICD-10 on their old systems, and ation, ICD-11—rumored to be a better time will take away resources and further then implement it again once they get system—which is rolling out in 2015. “Why put effort and money into getburden physicians financially.” their EMR up,” he said. Delegates bemoaned the expense of He further noted that the deadlines ting up to speed on ICD-10 when ICD11 is coming along anyway? It seems silimplementing the ICD-10, which is profor the two mandates are off-kilter. jected to be $83,000 for a “ICD-10 has an October 2013 dead- ly to spend all this effort and money three-physician office line, and this has not been pushed back. on training, electronic compliance and The penalty for not using an EMR was conversion for a couple of years of use,” extended and now it is past the ICD-10 Dr. Weinstein said. FILE SLUG The delegates presented a resolution deadline.” PROOF 1 12/10 Current file: single-CMEzone qtrpg.indd 1ST PROOF LAYOUT APPROVED FINAL OK ‘From our standpoint, as a 58-member, the everything “Our own practice may be OK,” Dr. that asked INITIALS AND DATE INITIALS AND DATEAMA to “do REV 1 12/17 Weinstein added. “We are a large possible to let the physicians of America REV 2 specialty gastroenterology group, the Full Name of project MAX sign-off group and are at the front end of know that the AMA is fighting to repeal REV 3 Senior Editor REV 4 ICD-10 is a major headache without any EMR implementation, and we proba- the onerous ICD-10 requirements on REV 5 with other Style chges fr. prev. Copy Editor bly have the resources to handle ICD- their behalf ” and to work recognizable benefit to be achieved in 10. But the average practice is lagging national and state medical REV 6 and inforRevision # R2 Sales REV 7 in EMR implementation and this puts matics associations to assess an approthe immediate future.’February 6, 2012 1:58 PM REV 8 Layout Date/Time Production them past the ICD-10 implementation priate replacement for ICD-9. REV 9 Editorial Date/Time Creative deadline.” —Arnold Levy, MD —Caroline Helwick COMMENTS: to see the Trim Size Half Vertical Dr. Weinstein hopes October 2013 deadline extended, such Color Specs 4C as recently occurred with the deadand $285,000 codes will increase the actual number of line for compliance with the New None of the sources interviewed for a 10-person group. codes they use?” asked Dr. Kaufman, the Health Care Electronic Transactions for this article disclosed any relevant conflicts of interest. Aside from the expense of AGA delegate, who practices at Capital Standards, Version 5010. “If they implementation, they are bracing Digestive Care with Dr. Levy and is also for collateral damage as well. chief medical officer of DrFirst, an elec“ICD-10 will be used by every insur- tronic prescribing software vendor. er in the country to deny payment “Most physicians will pick up the because with so many codes, it’s sim- simplest codes that match, as they are ple to say, ‘You coded this wrong,’ ” said already doing, and not use the added Michael Greene, MD, a Georgia dele- granularity unless forced to do so.” gate. “At best, it will significantly delay Dr. Levy acknowledged that the ICDpayment. There are many practices in 10 includes “good things that could my area that run month to month. You ultimately improve health care in the interrupt the cash flow, and the physi- United States.” cian is either taking out a loan or closBut, he added, “Once again, the probing his doors.” lem is in the timing of the scheduled Arnold Levy, MD, president and CEO implementation. From our standpoint, of Capital Digestive Care in Washington, as a 58-member, single-specialty gasD.C., also was concerned about the tim- troenterology group, the ICD-10 is a ing of reimbursements. major headache without any recogniz“If insurance companies have the able benefit to be achieved in the immeopportunity to delay the payment diate future.” process and hold onto money due to the providers, they will,” he said. Bad Timing Physicians emphasized that to ease “Implementation of ICD-10 at this time Pancreatic Exocrine Insufficiency: Diagnosis and Treatment will indeed make it easier for payers the implementation of ICD-10, medical MN112 in Chronic Pancreatitis and Pancreatic Cancer to initially decline coverage and delay practices should have a solid EMR sysExpires May 1, 2012 tem in place. But many medical pracpayment of claims.” tices have yet to fully integrate EMR Unnecessarily Complex systems. Tailoring Therapy in Metastatic Breast Cancer: The ICD-10 contains approximate“We will have five times the numly 68,000 codes; this compared with ber of codes in a setting where no one MN1113 Novel Clinical Approaches the ICD-9, which has just 14,000 codes. is ready,” Dr. Levy said. “The vendors Expires october 1, 2012 Implementation of the ICD-10 is slated are not up and ready. The physicians for October 2013. are having a hard time. Until EMR is Some delegates view the exhaustive in place, the only ones who could E-Journal Exchange: Current and Emerging number of codes as slightly ridiculous. potentially benefit are the insurance WE1113 Therapies in Chronic Pain “Who cares if your concussion is sec- companies.” Expires october 1, 2012 ondary to a lamp post or to the iron Michael Weinstein, MD, vice presithat your wife threw at you?” said urol- dent of Capital Digestive Care and chair ogist Jeff Terry, MD, a delegate from of the group’s information technoloMobile, Ala. gy committee, acknowledged that the

ICD-10

Dr. Greene agreed. “It doesn’t take an expert in coding to review this and ask, ‘Do we really need to know what kind of dog bit you to be able to code a dog bite?’ ” The ICD-10 is designed to be more “granular,” with the goal of capturing data that are useful for measuring quality and outcomes, tracking public health concerns, designing research projects and so forth. Some physicians agree that this level of complexity may have value in the long run, but offers no immediate benefit to patient care. “What is there to make physicians feel that going from 14,000 to 68,000

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PICKED UP APPLIED T

CLINICAL TRIALS

Clinical Oncology News • February 2012

New Phase II and III Clinical Trials

Hematologic Malignancies

Solid Tumors

The studies listed below are actively recruiting trials that were added to the National Cancer Institute’s list of U.S. clinical trials in the 30 days before January 30, 2012. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials/search, and enter the protocol ID.

Supportive Care

Protocol Type

Age

Protocol ID

Trial Sites

Fluorescence-guided Surgery for Low- and High-grade Gliomas, Phase III

Over 18

IRB#10BN132

Study of Veliparib, Radiotherapy, and Temozolomide in Children With Newly Diagnosed Diffuse Pontine Gliomas, 21 and under Phase I/II

PBTC-033

CA, DC, IL, MD, NC, PA, TN, TX

Randomized Efficacy Study of TPI 287 to Treat Primary Refractory or Early Relapsed Neuroblastoma, Phase I/II

12 to 21

NMTRC 005

FL, NC

Axitinib (AG-013736) in Elderly Glioblastoma Multiforme Patients, Phase II

Over 70

UCCR-2

Panitumumab and Bortezomib for Patients With Advanced Colorectal Cancer, Phase I/II

18 and over

2011-033

Safety Study of BEZ235 With Everolimus in Subjects With Advanced Solid Tumors, Phase I/II

18 and over

CBEZ235ZUS08T

Autophagy Inhibition to Augment mTOR Inhibition: Trial of RAD001 and Hydroxychloroquine in Patients With Previously Treated Renal Cell Carcinoma, Phase I/II

18 and over

UPCC 07811

Immune Response and Safety of HS110 Vaccine in Combination With Erlotinib in Patients With Non-Small Cell Lung Cancer (NSCLC), Phase II

18 and over

HS110-10-01

GRN1005 in NSCLC Patients With Brain Metastases (GRABM-L), Phase II

18 and over

CP10 05B017

FL, IL, MI, TN

Trial of pIL-12 Electroporation Malignant Melanoma, Phase II

18 and over

11854

Randomized Study of Selumetinib With Versus Without Akt Inhibitor MK2206 in Patients With BRAF V600E Mutant Stage III or IV Melanoma Who Failed Prior Therapy With Vemurafenib or Dabrafenib, Phase II

18 and over

MCC-VICCMEL1120

FL, GA, TN, VA

Hypofractionated Stereotactic Body Radiation Therapy as a Boost to the Prostate, Phase II

18 and over

H-29665

Randomized Study of Tivantinib in Patients With Asymptomatic or Minimally Symptomatic Metastatic Castrate-Resistant Prostate Cancer, Phase II

18 and over

OSU-11132

Intra-op Detection of Occult Ovarian Carcinoma Using a Folate-Alpha Receptor Specific Fluorescent Ligand, Phase II

18 and over

11-002980

Pharmacodynamic Study of Hydroxychloroquine in Combination With Gemcitabine/Abraxane to Inhibit Autophagy in Pancreatic Cancer, Phase I/II

18 and over

UPCC 19211

Study of LY2495655 in Participants With Pancreatic Cancer, Phase II

18 and over

12552

DC, MO, TX, WA, WI

Treatment of Endometrial Cancer, Phase II

18 and over

11-GYN-130MCC

Preliminary Efficacy and Safety of INNO-206 Compared to Doxorubicin in Advanced Soft Tissue Sarcoma, Phase II

15 to 80

INNO-206-P2STS-01

Study of Ofatumumab and Dinaciclib in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or B-Cell Prolymphocytic Leukemia, Phase I/II

18 and over

OSU-11120

Sorafenib for the Treatment of Chronic Lymphocytic Leukemia, Phase II

18 and over

110574

PCI-32765 for Special Cases of Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma, Phase II

18 and over

120035

Vorinostat, Lenalinomide and Dexamethasone in Multiple Myeloma Refractory to Previous Lenalidomide Containing Regimens, Phase I/II

18 and over

PRO-2580

Study to Learn if Two Doses of a Test Drug (Fostamatinib) Helps People With Large B-Cell Lymphoma, Phase II

18 and over

D4302C00001

Pooled Unrelated Donor Umbilical Cord Blood Transplant For Hematologic Malignancy Needing Allogeneic Stem Cell Transplant Without Related HLA-Match, Phase II

18 to 65

1127920

Brentuximab Vedotin (SGN-35) in Transplant Eligible Patients With Relapsed or Refractory Hodgkin Lymphoma, Phase II

12 to 72

11-142

A Study Comparing Siltuximab Plus Best Supportive Care to Placebo Plus Best Supportive Care in Anemic Patients With International Prognostic Scoring System Low- or Intermediate-1-Risk Myelodysplastic Syndrome, Phase II

18 and over

CR100752

Trial of Cladribine, Cytarabine, Mitoxantrone, Filgrastim (CLAG-M) in Relapsed Acute Lymphoblastic Leukemia, Phase II

Not specified

L-10,442

Therapeutic Interventions For Pain Induced By Vincristine Treatment For Childhood Acute Lymphoblastic Leukemia (ALL), Phase II

1 to 18

TINALL

Memory Training Intervention for Breast Cancer Survivors, Phase II/III

45 and over

64194

The Women In Steady Exercise Research (WISER) Survivor Trial, Phase III

Any age

U54-CA 155850

Evaluation of the Use of Trental and Vitamin E for Prophylaxis of Radiation Necrosis, Phase II

18 and over

BTC-W1

Respiratory Syncytial Virus - RSV Protocol, Phase II

18 and over

2011-0813

BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions]. INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side. CONTRAINDICATIONS Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug. QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia. WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology]. Hypercalcemia and Tumor Flare As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued. Tumorigenicity Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology]. General Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia. Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained. Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 n = 221

TAM20 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below. Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies]. Adverse Reactions Cardiac Cardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular* Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia Thromboembolic Pulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests** AST Alkaline Phosphatase Bilirubin Hypercalcemia

North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) 1 (<1) 3 (1.5) -

1 1

(10) (9) (4) (2) (1.5)

16 (7.5) 16 (7.5) 10 (5) 2 (1) 2 (1) -

1 -

(2)

2 (1) 2 (1) 1 (<1) -

1 1 1 -

(<1) (<1) (<1)

4 24 4 6

30 16 2 1

(19) (10) (1) (<1)

2 2 -

(1) (1)

22 20 8 4 3 4 1

(<1)

11 (5) 41 (19) 3 (1.5) 6 (3)

(2) (11) (2) (3)

(<1) (<1)

(<1)

1 (<1) 2 (1) -

2 (1) 3 (1.5) 1 (<1)

3 (1.5) 1 (<1) 1 (<1) 2 (1)

3 (1.5)

5 (3) 1 (<1) 1 (<1) -

(<1)

4 (2) 3 (1.5) 4 (2)

1 (<1) 3 (1.5) 4 (2) 4 (2)

22 (15) 13 (9) 1 (<1) -

32 (15) 18 (8) 2 (1) -

35 (17) 31 (15) 3 (1.5) -

1 1

(<1)

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated deﬁned as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. Post-marketing Experience The following adverse reactions were identified during post approval use of FARESTON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge. DRUG INTERACTIONS Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions]. Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum. Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions]. Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and -hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and -hydroxymidazolam Cmax and AUC were reduced by less than 20%. Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely. Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure). USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly. Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero. Nursing Mothers It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use There is no indication for use of FARESTON in pediatric patients. Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. Hepatic Impairment The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Race The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted. OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

CLINICALPHARMACOLOGY Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Pharmacodynamics Toremifene causes a decrease in the estradiol-induced vaginal corniﬁcation index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately ﬁve times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions]. Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions]. Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Toremifene 20 mg (N = 47) Toremifene 80 mg (N = 47) Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms 7 (0.9, 13.6) 26 (21.1, 31.2) 65 (60.1, 69.2)

ΔQTc > 60 ms (n, %) 0 2 (4.3%) 43 (89.6%)

QTc > 500 ms (n, %) 0 0 5 (10.4%)

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks. Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin. Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies. Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function. Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food. Race – The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks. PATIENT COUNSELING INFORMATION Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations]. Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions]. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology]. Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment. Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions]. Distributed by GTx, Inc. Memphis, TN 38103, USA Product covered by Orion Product Patents and related patent numbers. © 2011 GTx, Inc. All rights reserved. 2E Rev. 03/2011

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Fareston helps reduce the guess work FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

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Parent compound binds to and blocks estrogen receptors

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Important safety information: FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor ﬂare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively. References: FARESTON® Prescribing Information, 2011. Data on ﬁle, GTx, Inc.

Please see brief summary of prescribing information including boxed warning on the following page. For more information about Fareston call 1-877-362-7595 or visit www.fareston.com