Clinical Oncology News - November 2009 - Digital Exclusive Edition

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Advances in Cancer Care CLINICALONCOLOGY.COM • NOVEMBER 2009

POLICY & MANAGEMENT

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GPOs save hospitals billions annually. FDA NEWS

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Pazopanib approved for patients with advanced renal cell carcinoma. SOLID TUMORS

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Study bolsters use of panitumumab in second-line therapy for metastatic CRC. Vandetanib validated as second-line therapy for NSCLC. Prostate cancer trial yields puzzling results. PRN

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Court Battle Waged Over BRCA1/2 Patent

Berlin—First-line maintenance therapy with erlotinib (Tarceva, OSI/Genentech) significantly prolongs both progression-free survival (PFS) and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC), according to results of the SATURN trial presented at a late-breaking session during the recent joint meeting of the European CanCer Organisation and the European Society for Medical Oncology (ECCO-ESMO) (abstract 5229). The benefit was particularly robust in patients with nonsquamous histology and those with EGFR mutation–positive subgroup. “Erlotinib is approved for second- and third-line therapy of advanced NSCLC, but in clinical practice, approximately 50% of patients receive only first-

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see EGFR, page 6

Nanotechnology set to revolutionize medicine. S PE C I AL O FF ERS

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SATURN Encourages First-line Erlotinib Maintenance in NSCLC

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Denosumab Trumps Zoledronic Acid for Bone Metastases

how to act upon that information,� Dr. Chung said. Because Myriad owns the patents, no other test is available to patients. At press time, the lawsuit was winding its way through the courts. Some say the success of the lawsuit see LAWSUIT, page 10

POLICY & MANAGEMENT

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wo studies support the first-line use of denosumab (Prolia, Amgen) rather than zoledronic acid (Zometa, Novartis) for cancer patients with bone metastases. The studies were presented at the recent joint meeting of the European CanCer Organisation and the European Society for Medical Oncology (ECCO-ESMO). Amgen says it is currently evaluating when to apply for FDA approval for denosumab. “I don’t see any downside of using [denosumab] first-line whatsoever. It’s more efficacious, has less toxicity, has no renal monitoring and is more convenient,� said Alison Stopeck, see DENOSUMAB, page 9

oes a patent on a gene restrict the practice of medicine and science research? A lawsuit brought against Myriad, the maker of the BRCA gene test, and the United States Patent and Trademark Office, claims that it does. The lawsuit, organized by the American Civil Liberties Union (ACLU), seeks to strike down the patents on BRCA1 and BRCA2. Wendy Chung, MD, PhD, director of clinical genetics at Columbia University in New York City, is one of the 20 plaintiffs in the case. When patients ask Dr. Chung if they’ll face the breast or ovarian cancer that killed their mothers, she offers Myriad’s BRACAnalysis test that analyzes BRCA1 and BRCA2. The test might answer the question, but cannot always guarantee a clear result. “In some cases, patients are left with ambiguous interpretations, not knowing

MD Group Deters Frivolous Lawsuits

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n the late 1990s, Jeffrey Segal, MD, a neurosurgeon with a clinical practice in Indiana and a member of various medical review boards and panels, was participating in that state’s efforts to reduce medical malpractice premiums and cap total payouts. He observed that the financial and emotional toll caused by the filing of frivolous malpractice lawsuits, in which lawyers employed unscrupulous doctors as “hired gun� expert witnesses, was not addressed. He began work on a system for “countersuits.� What if, Dr. Segal thought, patients signed an agreement before treatment

commenced to not file frivolous lawsuits, and if they did have a legitimate gripe to only use expert witnesses who were board-certified in the same disciplines and were members of the same professional societies as their doctors? After being hit with a frivolous lawsuit and “viscerally� experiencing the malpractice system firsthand, Dr. Segal developed his idea into a system using a combination of patient–physician contracts, databases of member physicians and medical defense experts, and a system of progressively aggressive counterattacks. In 2001, he was issued a patent on a “method see LAWSUITS, page 3

McMahonMedicalBooks.com Atlas of Cancer Maurie Markman For more information, see page 13.

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • NOVEMBER 2009

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Policy and Management

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Community Oncology Michael J. Fisch, MD, MPH John W. Finnie, MD

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Oncology Nursing Betty Ferrell, RN, PhD

Russell K. Portenoy, MD Charles F. von Gunten, MD

Genitourinary Cancer Ronald M. Bukowski, MD

EDITORIAL STAFF

Gynecologic Cancer Maurie Markman, MD

Mary Lou Bowers, MBA Barbara Constable, RN, MBA Rhonda M. Gold, RN, MSN

Bioethics

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD

Solid Tumors

Lung, and Head and Neck Cancers Edward S. Kim, MD

Bone Metastases Allan Lipton, MD

Lung Cancer, Emesis Richard J. Gralla, MD

Breast Cancer Andrew Seidman, MD Maura N. Dickler, MD Gastrointestinal Cancer Edward Chu, MD Cathy Eng, MD Leonard Saltz, MD

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Guide to Cancer Therapeutic Regimens 2009 Pocket Guide The use of cancer therapeutic agents in combination is well established. The knowledge of cell kinetics and the pharmacology of antitumor agents have allowed the clinician to use combination therapy to maximize tumor cell kill with minimal or acceptable toxicity to the patient.

Guide to Cancer Therapeutic Regimens 2009 Wall Chart—Part 1 Part 1: Solid Tumor Cancers This wall chart lists common combination regimens and doses used in solid cancers.

Guide to Cancer Therapeutic Regimens 2009 Wall Chart—Part 2 Part 2: Hematologic Cancers This wall chart lists common combination regimens and doses used in hematologic cancers.

Oral Mucositis: Causative Regimens and Pathways for Treatment Mucositis can be best described as a distinct and complex pathobiologic entity resulting in mucosal barrier injuries that is a consequence and frequent complication of chemotherapy and radiation therapy in patients with cancer.

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Cancer Support 2009 This guide outlines characteristics of hazardous drugs, detrimental effects of occupational exposure, methods of determining exposure and common routes of exposure. It also highlights the technologies available to reduce risks and national guidelines for ensuring safe compounding, transport, delivery, administration and disposal of hazardous drugs by using personal protective equipment.

Guide for the Administration and Use of Targeted Cancer Agents 2009 The National Cancer Institute defines targeted therapy as “a type of treatment that uses drugs or other substances, such as monoclonal antibodies, to identify and attack specific cancer cells without harming normal cells.� Although other variations of the definition exist, collectively they define a change in the drug development process.

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POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • NOVEMBER 2009

Medical/Legal

LAWSUITS continued from page 1

‘Doctors for too long have been like fish in a barrel, with lawyers taking potshots [at] them.’

—S. Larry Schlesinger, MD

and apparatus for deterring frivolous professional liability claims� (U.S. patent 6,272,471). Although the malpractice suit against him was later dropped, the experience helped to give Dr. Segal the impetus, in 2002, to launch Medical Justice Corp. “Medical malpractice insurance doesn’t do anything to prevent a lawsuit and doesn’t do anything when the case is over to allow the physician to experience a sense of justice,� Dr. Segal said. “We fill a void because for most doctors, when they win, they don’t feel they’ve won. They just feel that they’ve lost less.� Medical Justice, based in Greensboro, N.C., has signed up more than 2,200 doctors as members and is available in all 50 states. Annual fees range from $625 to $1,995, depending on the specialty and location of the physician. Protection from defamation on the Internet—which the company calls a “vaccine against libel�—is included with full membership or available separately for $495. With it, patients agree to not post anything online about their experiences without the doctor’s prior approval.

Intimidation Factor? Since it started six years ago, Medical Justice has been involved in more than 1,000 cases, Dr. Segal said. The testimonies of 30 to 40 expert witnesses have been scrutinized by member physicians and various national medical specialty societies, state licensing boards and hospital credentialing committees, with actions having been taken against “the majority of them,� Dr. Segal said. In addition to filing and pursuing complaints against unqualified expert witnesses, Medical Justice may allocate up to $100,000 in attorney’s fees and expenses to pursue counterclaims against a patient—if given authorization to do so by the physician and after the case has been dismissed or won. (Medical Justice retains any money it wins in the counterclaim.) “Doctors for too long have been like fish in a barrel, with lawyers taking potshots at them,� said S. Larry Schlesinger, MD, a plastic surgeon in Kahului, Hawaii. “Along comes Medical Justice and arms every single fish with an Uzi, so when the lawyers come along, the fish can fire back.� Frivolous lawsuits will occur and they will cost money, time and emotional distress, Dr. Schlesinger said. “But if you have the sense that someone has given you an Uzi to fight back with, it makes all the difference in the world. When you get a little bit of control through Medical Justice, even the impression of control, you’ll be able to deal with the situation infinitely better.� Medical Justice is not without its critics, however. Some doctors worry that it might be intimidating to threaten patients with a lawsuit as part of a mandatory contract. After Dr. Segal gave a presentation to the American Society of Interventional Pain Physicians earlier this year, Andrea M. Trescot, MD, its past president, observed that there had been “some discussion about concerns regarding intimidation� among those in attendance. But several doctors had also said that they were considering joining, she added. “If I go back into private practice, I would strongly consider [ joining],� Dr. Trescot said. Dr. Segal prefers to call his approach “proportional� rather than intimidating. “We won’t bring out a sledgehammer until an atomic weapon has been launched in the doctor’s direction,� Dr. Segal said. But he acknowledged that “perhaps

‘Medical Justice connects you with other doctors who have been through something similar, so you have someone to talk to. They give you very valuable tools to help you keep your sanity.’ —Ronald V. Miller Jr.

there is a perception of aggression with it when nothing else will work.�

Avoid Seeking Retribution Howard Citron, a medical malpractice defense attorney in Fort Lauderdale, Fla., said that doctors too often get caught up in seeking retribution against colleagues who have said that he or she did something wrong; instead, the doctor should focus on the merits of the case. “Most of the time, there isn’t a valid claim that can be made against an expert witness,� Mr. Citron said. “Medicine isn’t an exact science and there are often judgment calls in which reasonable minds can differ,� he said. However, in cases that are frivolous or borderline frivolous in which an expert opinion is “so far off the wall, then yes, something like this could be meaningful,� Mr. Citron said. But, he suggested waiting until after litigation because such an approach not only takes the doctor’s focus off the case but could also hurt the matter before a jury. Afterward, there is nothing to stop a doctor from complaining about an expert witness to state licensing and medical certification boards on his or her own, Mr. Citron added. Looking from the other side of the courtroom, Medical Justice “provides an illusory security blanket for doctors,� said Ronald V. Miller Jr., a personal injury lawyer in Glen Burnie, Md. “I appreciate the fact that doctors are looking for some kind of a safety net, but

they are not going to find any use for this program other than the feeling of being united. Maybe that itself is the reward,� Mr. Miller said. “But practical benefits? There are none.� But the psychological benefits can be meaningful, according to Dr. Schlesinger, because the majority of doctors sued for malpractice have never been through it before and do not know what to expect. “Medical Justice connects you with other doctors who have been through something similar, so you have someone to talk to. They give you very valuable tools to help you keep your sanity,� he said. Dr. Schlesinger described a complaint filed by a patient whom he had treated for a superficial skin infection. The patient overheard him tell his nurse that she might have had a staph infection, but she apparently thought he had said “staff infection.� The patient’s lawyer now claims that Dr. Schlesinger’s staff infected her. “But wait, it gets better,� Dr. Schlesinger said. “I’m a board-certified plastic surgeon. She signed a contract saying she will only bring board-certified plastic surgeons against me as expert witnesses. She has a physician who is not board-certified in plastic surgery as her only witness. I can’t wait to get my chance to deal with her non–plastic surgeon and her lawyer over my ‘staff ’ infection,� he said. “Because of Medical Justice, I’m a little smarter and I worry a lot less about it.� —Ted Agres

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CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • NOVEMBER 2009

Cost Savings

Survey: GPOs Save U.S. Hospitals Billions Annually Group purchasing organizations save U.S. hospitals $36 billion each year in supply costs, plus another $2 billion or so in reduced staffing required for purchasing activities, a new survey has found. Of the nation’s estimated 5,000 hospitals, 429 participated in the survey, which was conducted by the consulting company Health Care Sector Advances, Inc., and funded by the Health Industry Group Purchasing Association (HIGPA), which represents 16 group purchasing organizations (GPOs). GPOs have been around for decades yet remain invisible to the public, said Eugene S. Schneller, PhD, a professor at Arizona State University in Phoenix, and owner of Health Care Sector Advances, in an April teleconference. “GPOs are key players in health care reform. They literally save the country tens of billions of dollars annually through the power of aggregated purchasing volume and negotiated discounts with manufacturers, distributors and vendors.� The average U.S. hospital would need to employ a minimum of nine additional people in order to provide the services that a GPO provides, Dr. Schneller added.

Supply and Labor Cost Savings The survey was sent to purchasing directors at 28 hospital systems—ranging from groups of two to 100 hospitals— located throughout the United States. On average, the hospitals had 380 beds and more than 20,000 admissions per year. The analysis did not look at capital equipment, but rather focused on key products used by hospitals and regularly purchased through GPOs: inpatient pharmaceuticals, general medical items, orthopedic implants, cardiology implants and other clinical products. Nonlabor costs for U.S. hospitals

are estimated at $310 billion per year, according to 2007 data from the Centers for Medicare & Medicaid Services. The survey respondents purchased 72.8% of their goods through GPOs, saving an average of 18.7%. That suggests an annual national savings of $42.2 billion. However, because 20% of nonlabor hospital products typically are not offered by GPOs, said Dr. Schneller, the report estimates that using GPOs results in a national cost savings of $36 billion, broken down as follows: • $8.5 billion on general medical products, such as bandages, gauze, physiotherapy supplies, needles, syringes and paper for electrocardiogram machines; • $6.8 billion on inpatient pharmaceuticals, IV solutions and contrast media; • $1.9 billion on cardiology implants, including pacemakers, stents and valves; • $840 million on orthopedic implants; and • $17.96 billion on other clinical products, such as anesthesiology, radiology and laboratory supplies; housekeeping products; and office materials. The report also highlighted that GPO prices are an important benchmark for negotiating prices for expensive physician-preference items such as cardiology and orthopedic implants, Dr. Schneller said. Todd Ebert, president and chief executive officer of Amerinet, Inc., a St. Louisbased GPO with customers in all 50 states, said the survey results confirm the added value of group purchasing. “In the current economic conditions,

there is not a health care provider that is not looking for ways to reduce costs and improve quality of patient care,� he said. “The bottom line is, GPOs are an important way to keep prices down, allowing our customers to provide more of the best quality care.�

The average U.S. hospital would need to employ a minimum of nine additional people in order to provide the services that a GPO provides.

spending volumes. “Lastly, and this is really a new area for many GPOs, there is now an increased focus on patient safety initiatives,� such as using unique patient identifiers for all implantable products. Curtis Rooney, president of HIGPA, added that the report highlights the added value that GPOs bring. “By saving hospitals and other providers money on nearly everything they buy—from surgical supplies and medical equipment and pharmaceuticals to food—GPOs enable hospitals to buy more equipment and hire more doctors and nurses.� Todd Nelson, MBA, technical director of the Healthcare Financial Management Association, agreed that GPOs provide access to lower prices and more favorable contract terms with suppliers based on economies of scale. However, Mr. Nelson said, when a hospital joins a GPO, its choice of suppliers for some items may be limited, or it may be forced to switch to a new supplier or renegotiate an existing supplier agreement. A hospital might also choose to contact a regional supplier directly when its GPO does not have an agreement with that supplier.

Senators Seek Transparency

Alan Yordy, president and chief executive officer of PeaceHealth, a health care system of seven hospitals serving Washington, Oregon and Alaska, added that his health care system obtains three main benefits from GPOs. “First, as a small system, there is simply no amount of staffing we could provide to do the work of contracting or data gathering that a GPO provides,� Mr. Yordy said. “Second, the GPO helps us connect with other health care providers across the country,� to benefit from lower prices for combined higher

Those supplier–purchaser relationships are far too secretive and might hide business practices that actually inflate health care costs, according to a group of U.S. senators. In mid-August, the legislators sent letters to the seven largest GPOs asking for more details on their contracting and negotiating polices. The effort was made because the U.S. government foots the bill for a large portion of GPO purchases, through Medicare payments. With health care reform efforts heating up, GPOs may be asked to play a role in paring more costs from the system. —Marlene Busko

Insurance

Uninsured Status Among Low-Income Workers Jumps in a Decade The poor grew poorer, at least in terms of employer-provided health insurance coverage, over a recent 10-year span, according to new data from the Agency for Healthcare Research and Quality (AHRQ). Results from the Medical Expenditure Panel Survey show that 34.5% of lowincome workers (average household income, $40,888) reported having no health insurance in 2006, up from 26% in 1996. The survey information is part

of the AHRQ’s News and Numbers summary, “Full-Time Poor and Low Income Workers: Demographic Characteristics and Trends in Health Insurance Coverage, 1996–97 to 2005–06� (www. meps.ahrq.gov/mepsweb/data_files/

publications/cb18/cb18.pdf ). The AHRQ also found that the number of younger workers without health insurance in this income bracket increased from 30% in 1996 to 38% 10 years later, while among those aged 35 to 49, the uninsured rate jumped from 22% to 32% during that time period. As might be expected, individuals employed by smaller firms fared worse than those at larger businesses, with 50% of workers at companies with less than 25 employees reporting a lack of

health insurance, increased from 39%. At companies with 25 to 99 employees, the uninsured rate increased from 22% to 31%, while companies employing more than 100 individuals saw the uninsured rate jump to 25.4%, up from 11%. Categorization by race revealed that low-income non-Hispanic black workers and white workers reported roughly the same uninsured rate, with jumps from 18% to 27% and 22% to 28%, respectively.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • NOVEMBER 2009

Colon

Study Bolsters Use of Panitumumab in Second-line Therapy Patients With KRAS Mutations Should Not Receive Panitumumab Berlin—A recent study reveals that adding panitumumab (Vectibix, Amgen) to FOLFIRI (5-fluorouracil [5-FU], folinic acid and irinotecan) prolongs progression-free survival (PFS) by an average of two months compared with FOLFIRI alone when used as second-line therapy for metastatic colorectal cancer (CRC) in patients with wild-type KRAS. As expected, panitumumab provided no benefit in patients with KRAS mutations. These results, from the so-called 181 study, were presented at the recent joint meeting of the European CanCer Organisation and Congress of the European Society for Medical Oncology (ECCO-ESMO; abstract LBA14). The difference of two months was deemed clinically meaningful by lead investigator Marc Peeters, MD, professor of digestive oncology at the University Hospital in Ghent, Belgium. “Panitumumab provides incremental benefit above chemotherapy alone as second-line therapy,� Dr. Peeters said. “About 40% of patients with metastatic colorectal cancer have KRAS mutations. This group should not be treated with panitumumab.� He pointed out that great strides have been made in the treatment of patients with colon cancer over the years. “In the 5-FU era, median overall survival was six to eight months, but with more modern drugs, it is now up to 24 and even 30 months,� he said. The study was singled out as one of the meeting highlights with respect to CRC, by Cornelius J.A. Punt, MD, an oncologist in the Department of Medical Oncology at the University Medical Centre, St. Radboud, Nijmegen, The Netherlands. In addition to providing information on panitumumab, he noted that the study provides further support for KRAS testing to select therapy for CRC. “ECCO-ESMO has been a good meeting, with important new data on colorectal cancer after we had a disappointing ASCO [American Society of Clinical Oncology meeting] in this regard,� Dr. Punt said. The global, multicenter, randomized Phase III study enrolled 1,186 patients with metastatic CRC treated at least six months previously with one prior 5-FU–based

Patients with wild-type KRAS receiving FOLFIRI

Progression-free Survival, mo

Patients with wild-type KRAS receiving FOLFIRI plus panitumumab

5.9

6 5 4

3.9

3 2 1 0

Figure. Comparison of progression-free survival. FOLFIRI, 5-fluorouracil (5-FU), folinic acid and irinotecan

chemotherapy for metastatic disease. Investigators obtained paraffin-embedded tumor tissue from patients’ primary tumors or metastasis sites for central analysis of KRAS mutations. Tumor KRAS status was ascertained in 91% of patients, after the study was amended to incorporate KRAS testing into the primary objective and before completion of the study. Patients were randomized 1:1 to receive FOLFIRI once every two weeks, with or without panitumumab 6 mg/kg every two weeks.

‘About 40% of patients with metastatic colorectal cancer have KRAS mutations. This group should not be treated with panitumumab.’ —Marc Peeters, MD

was not involved with the study. “Based on this study, it would now appear that panitumumab may now be moved from the disease-refractory setting where it is currently being used as monotherapy to the secondline setting where it can be combined with FOLFIRI chemotherapy.� Adverse events were comparable between the two study arms, except for known toxicities associated with anti-epidermal growth factor receptor (antiEGFR) agents. The incidence of several grade 3 and 4 adverse events was higher in patients receiving panitumumab, including rash (37% vs. 2%), diarrhea (14% vs. 9%) and stomatitis (8% vs. 3%). Infusion-related reactions were reported in less than 1% of patients receiving panitumumab. The investigators pointed out that adding panitumumab to chemotherapy in patients with KRAS mutations neither improved results nor caused harm. Panitumumab monotherapy is indicated in the United States as a single agent for the treatment of EGFR-expressing metastatic colon cancer that has progressed following fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. —Alice Goodman

The Oncology Business Institute

T

KRAS testing identified wild-type KRAS in 56% of the group randomized to panitumumab plus FOLFIRI (n=303) and 54% of those randomized to FOLFIRI alone (n=294). Patients with wild-type KRAS who were treated with panitumumab plus FOLFIRI had significantly improved PFS: a median of 5.9 months compared with 3.9 months (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.59-0.90; P=0.004; Figure). Subgroup analysis revealed a favorable benefit for all subgroups, including presence or absence of liver metastases, number of metastases, Eastern Cooperative Oncology Group Performance Status 0-1, age, gender and prior treatment with bevacizumab (Avastin, Genentech) or oxaliplatin (Eloxatin, Sanofi-Aventis). Median overall survival in the wild-type patients was numerically superior in those who were treated with panitumumab: 14.5 months compared with 12.5 months (HR, 0.85; 95% CI, 0.70-1.04), but this difference was not statistically significant. Response rate was improved with the addition of panitumumab from 10% with FOLFIRI alone to 35%. “This response rate is among the highest to be reported in the second-line metastatic setting,� Dr. Peeters said. Ed Chu, MD, is chief of the Section of Medical Oncology and deputy director of clinical research at the Yale Cancer Center, Yale University School of Medicine, New Haven, Conn. “The addition of the anti-EGFR antibody panitumumab to FOLFIRI chemotherapy provides clinical benefit when used in the second-line metastatic disease setting. Moreover, the level of benefit is similar to what was observed when cetuximab was combined with irinotecan-based chemotherapy to the same group of CRC patients,� said Dr. Chu, who

he Oncology Business Institute (TOBI) is open for membership. TOBI, a collaboration of the Pennsylvania-based Oncology Management Consulting (OMC) Group and Oncology Metrics, located in Texas, is a resource for productivity, staffing and financial benchmarks, education and professional networking for hospital cancer centers. TOBI brings to the table OMC Group’s decades of national experience in developing, running and advising successful hospital cancer centers and Oncology Metrics’ expertise in data. TOBI supports hospital cancer centers in making sound operational, financial and strategic decisions to become true centers of excellence. Through the institute, hospital cancer centers have access to resources designed specifically to answer challenging questions about their financial and operational performance. TOBI is dedicated to providing administrators of hospital outpatient cancer centers with the information they need to ensure maximum performance through comparative benchmarking, networking and education. TOBI benchmarks include staffing for infusion, radiation, registry and clinical trials; resources for cancer center departments; productivity metrics; financial benchmarks; and educational offerings based on the members’ requests and driven by their data. Professional networking is greatly enhanced because all TOBI members’ performance has been measured in precisely the same way.

For more information, call (215) 766-2065 or e-mail resources@TOBImember.com.

5

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CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • NOVEMBER 2009

Lung

Table. Benefits of Erlotinib in Lung Cancer by Patient Group

EGFR continued from page 1

line chemotherapy, probably because of their worsening condition. In this trial, all subgroups benefited from maintenance erlotinib, against a background of high use of subsequent post-study therapies,� said Federico Cappuzzo, MD, Istituto Clinico Humanitas, Rozzano, Milan, Italy. He noted that erlotinib could be given safely and that they did not see any deterioration in study subjects’ quality of life. The moderator of the session, Robert Pirker, MD, Medical University of Vienna, Austria, asked Dr. Cappuzzo which drug he would recommend as maintenance therapy in this setting—erlotinib or pemetrexed. Dr. Capuzzo said he did not prefer one drug over the other. “You need to discuss the option of maintenance therapy with patients who have advanced NSCLC,� he said. “Not all patients in this deteriorating condition want to take another drug.� Dr. Cappuzzo also noted the benefit of first-line erlotinib maintenance therapy in squamous cell patients seen in the trial is important and said that the greatest benefit was observed in the patients with stable disease. “Maintenance is an important point [in] both the SATURN study and the pemetrexed study. Maintenance therapy has proven that we can continually treat a patient with safe and effective drugs while helping maintain disease control with tolerable side effects,� said Ed Kim, MD. “It has changed the approach in which clinicians treat lung cancer patients.� Dr. Kim is an assistant professor of medicine in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas M.D. Anderson Cancer Center, Houston. The randomized, placebo-controlled Phase III study enrolled 889 patients with advanced NSCLC

Group

n

HR for OS

All patients

889

0.81

Adenocarcinoma

403

0.77

Squamous cell carcinoma

360

0.86

EGFR mutation–positive

49

0.83

EGFR wild-type

388

0.77

HR, hazard ratio; OS, overall survival

whose disease had not progressed after four cycles of platinum-based doublet therapy. Patients were randomized to receive erlotinib 150 mg per day or placebo until disease progression or unacceptable toxicity. Baseline characteristics were well balanced between the two arms. The median age of patients was 60 years, and 40% had squamous histology. Tumor specimens were collected for biomarker analysis of EGFR mutations, EGFR gene copy number and KRAS mutations. More than 70% of patients in both arms of the study had post-study therapies. Patients in the placebo arm received subsequent tyrosine kinase inhibitor treatment more often than those randomized to erlotinib: 21% and 11%, respectively. The study met its co-primary end points for PFS (hazard ratio [HR], 0.71 for all groups and 0.69 for those with EGFR protein expression; P<0.0001 for both groups). “PFS improved in all biomarker subgroups, even those with KRAS mutations,� Dr. Cappuzzo emphasized. “As expected, we saw a huge benefit in patients with mutated EGFR, with a hazard ratio of 0.10, and P<0.001.� In an intent-to-treat analysis of all patients entered in the trial, a significant OS benefit was observed for

erlotinib (HR, 0.81; P=0.0088); a greater benefit in survival was observed in the adenocarcinoma subgroup (HR, 0.77; Table). For both PFS and OS, erlotinib improved outcomes in patients with EGFR mutations and those with wildtype EGFR (HR, 0.83 and 0.77, respectively). Dr. Cappuzzo said that a survival benefit for erlotinib was observed in all subgroups, even those with squamous cell carcinoma. He said that the OS data for EGFRpositive patients is not yet mature. No unexpected toxicities were seen in the trial. Skin rash and diarrhea were the main side effects of erlotinib. “We were especially encouraged by the benefit we saw in wild-type EGFR patients, because those are the most fragile patients. Patients with EGFR mutations generally have a better prognosis, and the risk for losing these patients is lower than for those with wildtype EGFR,� Dr. Cappuzzo commented. Richard Gralla, MD, president of the New York Lung Cancer Alliance, said the question of maintenance therapy is “an interesting one,� not just with erlotinib, but with other agents such as pemetrexed—data from the pemetrexed study were presented at the annual meeting of the American Society of Clinical Oncology. He pointed out that the studies raise questions. “Is four cycles really sufficient? The studies of the number of cycles to give are not well conducted and do not look simply at patients without progression after four cycles, as SATURN did. If instead of getting placebo, if the control arm had continued with their same chemo, would the results have been different? One hundred percent of patients on erlotinib got treatment ... but not on the control arm. Would EGFR mutation–positive patients have done just as well to wait for progression and mutation patients done as well or better on chemo ... thus actually personalizing treatment?� —Alice Goodman and Kate O’Rourke

FDA NEWS

Votrient Approved for Advanced Kidney Cancer

T

he FDA has approved pazopanib (Votrient, GlaxoSmithKline) for patients with advanced renal cell carcinoma. It is the sixth drug to be approved for kidney cancer since 2005. The new drug is an oral medication that interferes with angiogenesis. The safety and effectiveness of pazopanib was evaluated in a 435-patient study that examined a patient’s progression-free survival (PFS); PFS averaged 9.2 months for patients receiving pazopanib compared with 4.2 months for patients who did not receive the drug. Treatment-naïve patients who received the drug experienced 11.1 months of median PFS versus 2.8 months with placebo. Additionally, patients who had previously received cytokine-based treatment achieved 7.4 months of median PFS with the drug compared with 4.2 months with placebo. The most common adverse events occurring in 20% or more of subjects

treated with pazopanib included diarrhea, hypertension, hair color changes, nausea, anorexia and vomiting. Grade 3/4 adverse events among these toxicities that differed by 2% or more included abnormal liver function, hypertension, diarrhea, asthenia and abdominal pain. Laboratory abnormalities occurring in more than 10% of patients and more commonly (>5%) in the pazopanib arm included increased transaminases, hyperglycemia, leukopenia, hyperbilirubinemia, neutropenia, hypophosphatemia, thrombocytopenia, lymphocytopenia, hyponatremia, hypomagnesemia and hypoglycemia. Drug-related deaths were observed in 1.4% of 290 patients and included hepatic failure (n=2), stroke (n=1) and perforation (n=1). Hepatic dysfunction is included as a boxed warning on the product label. Other warnings and precautions in the label relate to QT prolongation and torsades de pointes, hemorrhagic events, arterial thrombotic events, gastrointestinal perforation and fistula, hypertension, impaired wound healing, hypothyroidism, proteinuria and pregnancy.

FDA Clears Test for Ovarian Cancer

T

he FDA has cleared OVA1 (Vermillion), a test that can help detect ovarian cancer in a pelvic mass that is already known to require surgery. The test will help guide decisions about what type of surgery should be performed. In 2002, the American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncologists published recommendations for the role of generalist OB/GYNs in the early detection of ovarian cancer, which included a recommendation of patient referral to a gynecologic oncologist when specific indicators of malignancy are present. These recommendations and later reports indicate that patients with ovarian cancer have improved survival when the surgery is performed by gynecologic oncologists as opposed to general gynecologists or surgeons. OVA1 identifies women who will benefit from referral to a gynecologic oncologist for surgery, despite negative results from other clinical and radiographic tests for ovarian cancer. If other test results suggest cancer, referral to an oncologist is appropriate even with a negative OVA1 result. The new test

should be used by primary care physicians or gynecologists as an adjunctive test to complement, not replace, other diagnostic and clinical procedures. OVA1 uses a blood sample to test for levels of five proteins that change as a result of ovarian cancer. The test combines the five separate results into a single numerical score between 0 and 10 to indicate the likelihood that the pelvic mass is benign or malignant. OVA1 is intended only for women aged 18 years and older, who are already selected for surgery because of their pelvic mass. It is not intended for ovarian cancer screening or for a definitive diagnosis of ovarian cancer. Interpreting the test result requires knowledge of whether the woman is pre- or postmenopausal. The FDA reviewed a study of 516 patients, including 269 evaluated by nongynecologic oncologists, which compared OVA1 results with biopsy results. When combined with presurgical information, such as radiography and other laboratory tests, results from the OVA1 tests identified additional patients who might benefit from oncology referral who were not identified using presurgical information alone. continued on page 9

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CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • NOVEMBER 2009

Lung

Vandetanib Validated as Second-line Therapy for NSCLC

The objective benefits, including a significant extension of progression-free survival (PFS), were accompanied by significant protection from the symptoms of lung cancer, perhaps the key finding in this study for confirming a viable clinical advantage. “While patients were seeing their tumors progress more slowly, they also were having a prolongation to the time to worsening of their lung cancer–specific symptoms,� said Roy S. Herbst, MD, PhD. “Vandetanib is the first oral targeted therapy or perhaps the first therapy of any kind in a Phase III study to show a significant clinical benefit when added to standard chemotherapy in previously treated non-small cell lung cancer.� Dr. Herbst, chief of the Section of Thoracic Medical Oncology at the University of Texas M.D. Anderson Cancer Center, Houston, presented the data at the recent annual meeting of the American Society of Clinical Oncology (ASCO; abstract 8003). He emphasized that the “safety and tolerability of the vandetanib-docetaxel combination supports its use.�

ZODIAC Details In the multinational, Phase III study called ZODIAC, 1,391 patients were randomized to receive 100 mg of oral vandetanib plus docetaxel (in a standard dose of 75 mg/m2 every 21 days) or the same dose of docetaxel (Taxotere, Sanofi-Aventis) plus an oral placebo. The maximum number of cycles was six. Vandetanib is considered a dual-targeting inhibitor because it has been shown to block both vascular endothelial growth factor receptor and endothelial growth factor receptor in the experimental setting. The primary end point of the study was PFS, and secondary end points included objective response rates (ORR), overall survival (OS), safety and tolerability, and quality of life (QoL). To enter the trial, patients were required to have a performance status of 1 or 2. Although 60% of the population had adenomatous NSCLC, squamous cell cancers were also permitted and accounted for 25% of the primary tumors. Approximately 10% of the study population had brain metastases. Exposure to bevacizumab

(Avastin, Genentech) was not an exclusion criterion, but only 3% of the population had received this agent prior to randomization. The trial was conducted between May 2006 and April 2008, yielding a median follow-up of 12.8 months, at which point 84% of the participants had disease progression. Overall survival will be calculated later in the year when fewer than 20% of patients are expected to still be alive. The advantage in PFS from adding vandetanib relative to docetaxel was just short of one month (4.0 vs. 3.2 months; hazard ratio [HR], 0.79; 97.5% confidence interval [CI], 0.7-0.9; P<0.001; Figure). The ORR, favoring the addition of vandetanib, were 17% for the combination compared with 10% for docetaxel alone (P<0.001). The difference in the rates of disease control, defined as disease stabilization for at least six weeks, approached significance (60% vs. 55%; P=0.06). OS rates showed a positive trend for vandetanib that was not statistically significant (HR, 0.91; 97.52% CI, 0.78-1.07; P=0.196), but follow-up is incomplete. Although these benefits were modest, Dr. Herbst indicated that they are clinically meaningful based on QoL data collected with the Functional Assessment of Cancer Therapy-Lung (FACT-L) survey. The hazard ratio for the time to worsening of lung cancer–specific symptoms on the FACT-L was reduced 23% (HR, 0.77; P<0.001) in the patients receiving vandetanib versus those who did not. The safety and tolerability analyses also generally supported the viability of the combination. Although those randomized to vandetanib and docetaxel had greater rates of rash, diarrhea, neutropenia and hypertension, they had lower rates of nausea, vomiting and anemia. Rates of adverse events reaching grade 3 or higher severity were generally low in both groups, with the greatest difference confined to rash (9% on the combination vs. 1% for docetaxel alone).

ZEAL Trial Adds Support The relative safety of vandetanib in combination with chemotherapy for second-line therapy of NSCLC was supported by a second Phase III study called ZEAL (Zactima Efficacy with Alimta in Lung cancer) that was also presented at the recent ASCO meeting (abstract 8010). However, this study, combining vandetanib with pemetrexed (Alimta, Eli Lilly), did not meet its primary PFS end point. In this multinational study of 534 patients, the hazard ratio for PFS in the group receiving vandetanib (100 mg/d) plus

Docetaxel plus vandetanib

Progression-free Survival, mo

Orlando, Fla.—A Phase III study provides evidence validating the use of vandetanib (Zactima, AstraZeneca) as second-line therapy in patients with non-small cell lung cancer (NSCLC).

Docetaxel plus placebo

5 4.0 4

3.2 3 2 1 0

Figure. Comparison of progression-free survival. pemetrexed (500 mg/m2 every 21 days for a maximum of six cycles) relative to pemetrexed alone was 0.86 (97.5% CI, 0.65-1.13; P=0.108). However, the addition of vandetanib did again yield an advantage for the ORR (19.1% vs. 7.9%; P<0.001) and for time to deterioration of cancer symptoms (HR, 0.61; P<0.004). At the ASCO meeting, Martin J. Edelman, MD, director, Medical Thoracic Oncology, University of Maryland School of Medicine, Baltimore, served as the discussant for these results. He praised the use of a QoL component to the ZODIAC trial. Despite the modest benefits, he indicated that Dr. Herbst made a compelling case for “the potential use of vandetanib in combination with docetaxel after prior two-drug platinum-containing chemotherapy.� However, he also expressed some general concerns, including the fact that the small number of patients who received bevacizumab limits the ability of the study to reflect common practice. Other concerns were the still unclear role of angiogenic markers to further stratify patients who will benefit from vandetanib and whether tyrosine kinase inhibitors used after vandetanib have a potential to prolong response. “How applicable are the ZODIAC results?� asked Dr. Edelman. “According to the forest plots, most subgroups appeared to benefit, but we do not yet know who benefits most.�

Come see us at Booth #321 Be sure to pick up one of our Special Projects and Publications At the Chemotherapy Foundation meeting, we’re giving away free copies of a wide variety of medical education, covering such topics as idiopathic thrombocytopenia purpura, and updates on key cancer therapeutic regimens, chemotherapy-related medication errors and more.

—Ted Bosworth

7

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CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • NOVEMBER 2009

Prostate

Trial for Prostate Cancer Yields Puzzling Results Orlando, Fla.—Two recent randomized trials suggest that immunotherapy can improve overall survival in patients with metastatic, castration-resistant prostate cancer.

Patients receiving Provenge Patients receiving placebo

30 26

PROSTVAC-VF In the double-blind, placebo-controlled study presented at the ASCO meeting, 125 patients with

asymptomatic or minimally symptomatic metastatic prostate cancer were randomized in a 2:1 ratio to the PROSTVAC-VF vaccine plus granulocyte-macrophage colony-stimulating factor (GM-CSF) or matching placebos. Eligible patients had a Gleason score of 7 or less and a rising level of prostate-specific antigen (PSA) despite castration testosterone levels. The vaccine was administered by subcutaneous injection on days 0, 14, 28, 56, 84, 112 and 140. Despite comparable PFS at the initial analysis, the survival advantage after more than three years of follow-up has been substantial with 30% of those randomized to the vaccine still alive compared with 17% of those randomized to placebo. The median survival was 24.5 and 16 months, respectively, producing a hazard ratio (HR) of 0.60 (95% confidence interval [CI], 0.4-0.9; P=0.016) for survival favoring the vaccine (Figure 1). This relative advantage persisted despite the fact that only 25% of patients received all seven of the scheduled vaccinations due to disease progression and that half of the placebo patients crossed over to vaccine at the time of progression.

Despite comparable PFS at the initial analysis, the survival advantage after more than three years of follow-up has been substantial with 30% of those randomized to the vaccine still alive compared with 17% of those randomized to placebo.

Patients receiving PROSTVAC-VF Patients receiving placebo

25

24.5

20 16 15

10

5

0

Figure 1. Comparison of median survival with PROSTVAC-VF.

The PROSTVAC-VF vaccine is the newest generation of a series of related vaccine constructs encoding transgenes for PSA with additional elements to stimulate immunogenicity. The first of the series contained the Vaccinia recombinant viral vectors. Several generations later, the vaccines were produced with a second recombinant viral vector, Fowlpox. Costimulatory molecules, such as B7.1, were then added. The newest vaccine had three costimulatory molecules, adding ICAM-1 and LFA3 in addition to B7.1 (called a TRICOM). Clinicians provided a low dose of GMCSF simultaneously with the vaccine to boost patients’ immune response.

Provenge Provenge, an autologous active cellular immunotherapy, was tested in the IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1 and BRCA2 mutation carriers and controls) study. The results of IMPACT were presented at the most recent annual meeting

25

Median Survival, mo

Although the results are positive, they also are perplexing. The therapies appear to improve survival but had no effect on progression-free survival (PFS) or objective response. “These two studies raise the question of how survival can be prolonged in the absence of a difference in objective responses or change in progression rates,� conceded the senior author of the most recent study, Philip W. Kantoff, MD. Dr. Kantoff is director of the Lank Center for Genitourinary Oncology at DanaFarber Cancer Institute, and a professor in the Department of Medicine at Harvard Medical School, both in Boston. In presenting results of a study that tested the PROSTVAC-VF vaccine (Therion) at the most recent meeting of the American Society of Clinical Oncology (ASCO; abstract 5013), Dr. Kantoff acknowledged that the observed survival benefit, a secondary end point, can be considered “hypothesis-generating only.� The primary end point of PFS, which did not associate the vaccine with an advantage, was presented several years ago. The parallels between this study’s results and a second study of Provenge (Dendreon), a cell-based vaccine that was also recently associated with a survival benefit without generating many early signs of activity, has generated interest in understanding the mechanism of how the vaccines work. One theory is that immunogenic effect develops very slowly and not in time to alter initial response, but soon enough to allow patients to live longer. It is also possible, however, that the findings of the two studies are unrelated being that they are from very different trials.

Median Survival, mo

8

22 20 15 10 5 0

Figure 2. Comparison of median survival with Provenge. of the American Urological Association in Chicago. The study with 512 patients recruited a similar population of patients with castration-resistant metastatic prostate cancer. At three years, 31% of patients randomized to the vaccine were still alive compared with 23% of the patients who received placebo. The median survival was 26 months in patients receiving the vaccine and 22 months in patients receiving the placebo, generating an HR of 0.735 (P=0.001) for survival in favor of the vaccine (Figure 2). The manufacturer of Provenge has already announced plans to conduct a Phase III registration trial to confirm the survival advantage and to move toward marketing the vaccine. The PROSTVAC-VF vaccine also may be moved forward, even though the initial sponsoring company dissolved immediately after completion of the trial’s treatment phase. The same team of academic investigators, however, has remained involved in the follow-up after a change in sponsorship. An invited discussant at ASCO, Mario A. Eisenberger, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, suggested that the concept of a vaccine remains attractive, but he believes these results are mostly confusing. Regarding the most recent study, he expressed concern about controlling for the effect of GM-CSF independent of the vaccine, and he wondered whether it might make sense to have an active control for future studies, such as docetaxel (Taxotere, Sanofi-Aventis), which is the only approved therapy in this setting. Even if a survival benefit is confirmed, he suggested that more information is needed to determine what it means for the patient. “What do you do with a therapy that does not shrink cancer, does not make your feel any better, does not make the cancer progress slower?� Dr. Eisenberger asked. Although he noted that prostate cancer is rich in immunogenic peptides, such as PSA, that make it a good candidate for immunotherapy, it may still be early in the process to speculate about what these results portend clinically. —Ted Bosworth

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SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • NOVEMBER 2009

Bone Metastases

DENOSUMAB ‘The results of these Phase III studies suggest that future studies will be needed to define the optimal use [of] osteoclast inhibitors. We do not yet know if subsets of patients may benefit more from one drug over another and we haven’t yet got data on the use of combination or sequential therapy.’

continued from page 1

MD, associate professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson. She presented results from a study comparing the use of the two drugs in patients with breast cancer. Dr. Stopeck noted that up to 80% of patients with stage IV breast cancer develop bone metastases at some point during the course of their disease. “In breast cancer, unlike some of the other solid tumors, patients live years with metastatic disease, so treating or palliating bone metastases is actually a very important part of what I do,� Dr. Stopeck said. In the international trial (abstract LBA2), investigators enrolled 2,046 patients with advanced breast cancer and bone metastases and randomized them to 120 mg subcutaneous denosumab and an IV infusion of placebo or 4 mg IV zoledronic acid plus a subcutaneous injection of placebo. Patients who had prior IV bisphosphonate administration for bone metastases were excluded from the study; however, patients were eligible if they had received bisphosphonates for osteopenia or osteoporosis. Patients taking zoledronic acid had their renal function monitored and their drug dose reduced if creatinine levels indicated a need per the prescribing information for zoledronic acid. The investigators found that denosumab was 18% better than zoledronic acid in delaying the time to first on-study skeletalrelated events (SREs)—fracture, radiation to bone, surgery to bone, or spinal cord compression—or hypercalcemia (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.95; P=0.01). Denosumab was 23% better than zoledronic acid at delaying the time to first and subsequent onstudy SRE (HR, 0.77; 95% CI, 0.66-0.89; P=0.001). “On average, patients were in the study 26.5 months when they were in the Zometa arm before they developed a skeletal-related event and on denosumab, it hadn’t been reached,� Dr. Stopeck said. “Not even 50% of the patients in the denosumab arm had had a skeletalrelated event.� Rates of adverse events and infectious serious events were similar, but patients

—Catherine Van Poznak, MD

taking denosumab had a lower incidence of renal toxicity (4.9% vs. 8.5%). In a prespecified exploratory analysis, patients receiving denosumab reported worsening of pain later than those on zoledronic acid (88 vs. 64 days, respectively; HR, 0.87; 95% CI, 0.79-0.97; P=0.009). Osteonecrosis of the jaw was infrequent in both treatment groups (20 patients receiving denosumab [2%] compared with 14 patients [1.4%] receiving zoledronic acid), but this difference was not statistically significant. Overall survival (HR, 0.95; 95% CI, 0.81-1.11; P=0.50) and time to cancer progression (HR, 0.99; 95% CI, 0.89-1.11; P=0.90) were balanced between treatment arms. In a second randomized, doubleblind trial presented at ECCO-ESMO (abstract 5187), investigators enrolled 1,776 cancer patients with solid tumors or multiple myeloma who had bone metastases and were naĂŻve to IV bisphosphonates; the study excluded patients with breast or prostate cancer. Patients were randomized to receive subcutaneous denosumab 120 mg and an IV placebo or 4 mg IV zoledronic acid and a subcutaneous placebo. Patients were encouraged to take daily supplemental calcium and vitamin D. Treatment groups were well balanced.

Investigators found that denosumab delayed the time to first on-study SRE (pathologic fracture, radiation therapy or surgery to bone, or spinal cord compression) and was noninferior to zoledronic acid (HR, 0.84; 95% CI, 0.71-0.98; P=0.0007). The median time to first onstudy SRE was 20.6 months for patients taking denosumab and 16.3 months for those taking zoledronic acid. Although numerically greater, the delay in time to first on-study SRE with denosumab was not superior to zoledronic acid based on statistical analysis. “At 0.06, it was very close to being superior, but did not reach statistical significance,â€? said David Henry, MD, clinical professor of medicine at Pennsylvania Hospital, Philadelphia. Time to first and subsequent SRE was also numerically greater for denosumab, but not statistically significant (HR, 0.90; 95% CI, 0.77-1.04; P=0.14). Both drugs were equivalent at decreasing pain over time, but denosumab was superior when it came to how long it took for patients’ pain to get worse (57 days with denosumab vs. 36 days with Zometa), however, this did not quite reach statistical significance. Adverse events, progression-free survival and overall survival were equivalent in the two groups. “Denosumab met the primary end point of this trial. It was not inferior to Zometa when looking to prevent or delay first on-study SRE. ‌ Pain improvement was a little better in the denosumab arm. There was no difference in overall survival, disease progression, or adverse-event rates. There was a little more renal toxicity and acute phase reactions in the Zometa arm and there was a little more hypocalcemia in

the denosumab arm that was not clinically significant. ONJ [osteonecrosis of the jaw] is an infrequent event and not different between the two arms,� Dr. Henry said. “I think the most important [message], when I take this home and play it out in the clinic to patients, is that you can give denosumab monthly subcutaneously, much [easier] than having to have an IV started,� said Dr. Henry. “While superiority was statistically not met, to me the convenience of the drug and lack of renal monitoring is such a winner for patients that it moves in my mind to first position.� Catherine Van Poznak, MD, an assistant professor of internal medicine specializing in breast oncology at the University of Michigan Medical School, Ann Arbor, said the studies show progress is being made. “The results of these Phase III studies suggest that future studies will be needed to define the optimal use [of ] osteoclast inhibitors. We do not yet know if subsets of patients may benefit more from one drug over another and we haven’t yet got data on the use of combination or sequential therapy,� Dr. Van Poznak said. “Our ability to decrease SREs is improved with the inhibition of osteoclast activity. For example, in the placebo arm of the earlier bisphosphonate studies, patients may have experienced an SRE three to four times within a year. The median time to first SRE in the study of metastatic breast cancer, NCT00321464, was over two years. Clearly, the field is making progress.� Both studies were supported by Amgen. —Kate O’Rourke

the tissue of origin comprising a metastatic tumor. The test identifies 25 different tumor types—e.g., brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, testis—and measures the expression level of 48 microRNA biomarkers. ProOnc TumorSourceDx uses a proprietary classifier to assign a primary site to the cancer sample based on the microRNA expression

in the tumor and may become a critical tool in the detection of cancer of unknown primary. ProOnc SquamousDx classifies non–small-cell lung carcinoma tumors into two histological groups—cancers of squamous histology and nonsquamous cancers. The test measures the expression level of a squamous microRNA biomarker to differentiate patients that have

squamous cell carcinoma of the lung from patients that have nonsquamous non–small-cell lung cancer. ProOnc MesotheliomaDx is a cutting-edge molecular diagnostic test that uses microRNA to differentiate malignant pleural mesothelioma from peripheral adenocarcinoma of the lung and metastatic carcinomas involving the lung and pleura.

Fluorodeoxyglucose positron emission tomography image depicting bone metastases in a patient with inflammatory breast cancer.

FDA NEWS continued from page 6

Diagnostic Tests Launched

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rometheus Laboratories Inc. has launched three new cancer diagnostic products: ProOnc TumorSourceDx, ProOnc SquamousDx and ProOnc MesotheliomaDx. Each of the tests is based on highly sensitive microRNA technology. ProOnc TumorSourceDx identifies

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CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • NOVEMBER 2009

Patents

LAWSUIT continued from page 1

could stimulate slowed research, but others fear a win by the ACLU would eliminate the capital that drives innovation. Christopher A. Hansen, the ACLU’s lead attorney in the case, said, “At the most basic level, the notion that the government can give exclusive control over human genes is inherently troubling.� He said it also runs against a foundation of patent law. “Patenting of human genes is a patenting of a product of nature, that there was no inventiveness, no human discovery. They simply identified what nature is already doing,� he said. The ACLU case has attracted wide support from the medical community. In addition to groups like the Association for Molecular Pathology and the American College of Medical Genetics, which joined the case as plaintiffs, groups including the American Medical Association, the March of Dimes and the Council for Responsible Genetics have filed amicus briefs supporting the ACLU’s position in the case. Dr. Chung said the case presents a few of the issues physicians face in using the Myriad diagnostic test. Some patients cannot afford the $3,000 cost of the test and some insurance companies simply will not cover it, but there is another issue that is as important, she said. “With some patients, the test comes across a genetic variation for which they don’t have enough experience to either classify it as completely normal or pathogenic and disease-associated,� Dr. Chung said. “That is [the] worst of all scenarios.� Dr. Chung said these situations are complicated because they often involve patients from ethnic groups that make up a smaller proportion of the Myriad variation database, meaning that it is unclear if the variations are in fact normal in these groups. Patients tend to think that variations mean they will develop cancer, Dr. Chung said. While there are now researchers

‘At the most basic level, the notion that the government can give exclusive control over human genes is inherently troubling.’ —Christopher A. Hansen

outside of Myriad looking into these variations, she said, they do not have access to all the information available through Myriad’s proprietary database. “If a therapy is developed for BRCA1/BRCA2 mutation carriers, it’s possible that Myriad could have some reach-through ability to have part of the patent on that therapy,� Dr. Chung said. Fergus J. Couch, PhD, a professor in the Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minn., one of the researchers looking into gene variations, declined comment for this story.

Lawsuit Misguided Stacy L. Taylor, a partner at DLA Piper in San Diego, who secures, manages and enforces intellectual property rights for biomedical companies, said the focus of the case is misguided. The patenting of genes is needed, she said, for the same reasons it is needed in all biotechnical fields. “There is a compelling rationale,

from a capitalistic standpoint, for issuing patents for medical treatments, drugs and diagnostics in general because of the amount of investment that has to go into their identification and development, and the time frame it takes to test and bring those products to market,� she said. As a patent case, Ms. Taylor said, the challenge has already been answered by the courts. “The question discussed in the context of the ACLU case is ‘should we be granting patents for products derived from nature?’ The U.S. Supreme Court has consistently answered yes, starting in a 1911 case involving adrenaline developed by Parke-Davis to a case last year involving a diagnostic test like this one,� she said. Ms. Taylor believes the case is not a patent case at all, but a First Amendment case that seeks to show that physicians and patients are having their free speech limited by Myriad charging for the test. “There are all kinds of products that people would like to have that they can’t afford, and I don’t mean to minimize the plight of breast cancer patients,� she said. “The BRCA1 and BRCA2 test doesn’t deny them treatment, it is just a piece of information about their cancer that is useful to have. The test isn’t perfect. The test frequently may not give you the answer you want, or be as useful as you have hoped, but that gets to the quality of the test, not the patent.� Ms. Taylor noted that research aimed at improving patented products for FDA approval is usually exempt from patent infringement claims. She fears that an ACLU win could inhibit investment in product development. “If they were to win, anything derived from nature would be susceptible to no longer being patented, including drugs used to treat conditions like breast cancer,� she said. Robert W. Sweet, U.S. District Judge, Southern District of New York, heard a motion to dismiss the case on Sept. 30. The ACLU has filed a motion for summary judgment that could be heard later this year. —David Jakubiak

CME

CME Struggles T he industry that supplies continuing medical education (CME) to physicians and other medical personnel is under stress, under investigation and underwhelmed by declining opportunities. But the CME picture is not all bad; in fact, it appears increasingly likely that CME programs of the future will offer enhanced educational approaches and innovation, due in part to the industry’s recent difficulties. Today, CME is placing a sharper emphasis on ensuring complete independence of content development, creating thorough “needs assessments� that accurately analyze competency gaps that may exist in clinical knowledge, using verified adult learning methodologies and obtaining outcomes measurements to gauge how much clinicians’ performance has improved following the completion of the CME program.

The changes have come about because of scrutiny leveled against the industry following past abuses, in which aggressive marketers manipulated accredited medical education as a way to disseminate off-label drug information. The investigations led to fines levied against pharmaceutical companies and, eventually, new accreditation criteria for education providers, but CME has borne the brunt of criticism against industry-supported medical education. As a result, funding from pharmaceutical companies dramatically declined over the past two years, and many CME providers have either gone out of business or moved to the promotional side of the medical education and communications business. Nevertheless, CME remains a vital element for maintaining the quality of the U.S. health care system, and the industry that works to create unbiased, informative educational programs is slowly

emerging from this difficult period, having become more careful but also more creative. “We are seeing some of the best accredited medical education ever produced as a result of all the changes that have taken place over the past five years,� said Darren M. Casonhua, JD, the founder and principal of ONECONSORTIUM, a collaboration of CME industry partners whose ultimate goal is the improvement of patient outcomes. “Today, there is a tremendous focus on the impact these educational activities are having on improving professional performance and, more importantly, patient outcomes.� ONECONSORTIUM is one example of the more innovative approaches being taken by the CME industry today. “This collaboration has selected members and partners who are well-qualified providers of medical education,� said Mr. Casonhua, “with each adding a unique set of strengths. By pooling our collective

expertise and channeling those efforts toward meeting the educational needs of health care professionals in oncology, rheumatology and pain management, we are in a great position.� ONECONSORTIUM also limits its activities to those that are supported by more than one funding source, thereby minimizing the perception of bias or undue influence. The CME industry’s biggest challenge likely is the need to capture outcomes data to assess the impact of their educational activities, both on health care professionals and on the quality of health care received by patients. “Ultimately,� Mr. Casonhua said, “outcomes measurements will play a beneficial role in medical relicensure by helping to determine the educational needs of health care professionals and providing timely feedback about practice performance and competence.� —James Prudden

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Technology

Nanobots Go Where No Robot Has Gone Before Medicine is set to go small—very small. As in instruments smaller than red blood cells. Drug delivery systems that are dwarfed by a single human hair. professor at the Massachusetts Institute of Technology (MIT), in Cambridge. “Nanotechnology has huge implications,� said Debabrata Mukhopadhyay, PhD, a professor of biochemistry and nanomedicine specialist at Mayo Clinic College of Medicine in Rochester, Minn. “I could go on for hours talking about the possibilities. In a nutshell, the impact will be huge.�

Credit: Roger Harris/Photo Researchers, Inc.

It sounds like something out of The Jetsons but this is the cutting edge of medicine today. Nanomedicine—therapeutic and diagnostic techniques that are based on tiny particles one-billionth the size of regular molecules—has moved from the realm of science fiction into the American health care system. “Nanotechnology is the next revolution in health care,� wrote Bhuvaneashwar Subramanian, a senior research analyst in health care in an August 2008 report for the Frost & Sullivan market research group. Nanotechnology is the science of systems in which the key component or the whole system itself measures one to 100 nanometers. Put into perspective, a sheet of paper is about 100,000 nanometers thick; a human hair is about 80,000 nanometers wide. About 130 nanotech-based drugs and delivery systems and 125 devices or diagnostic tests have entered preclinical, clinical or commercial development since 2005, according to a 2007 FDA report. Around the world, laboratories are hard at work on developing smart nanosized medical devices and applications. Hundreds of different medical uses for nanotechnology are being explored. The list includes things like catheters coated with antimicrobial nanoparticles, detection systems that can pick up cancer biomarkers at extremely low levels in blood serum and nanomaterials that can regenerate bone and cartilage growth.

Nanotechnology Top to Bottom Scientists create “nanodevices� in one of two ways: They often use a “topdown� method in which they take existing devices and refine them to make them smaller and smaller. For example, in November 2008, the Dutch group Philips announced it had developed an “intelligent pill� that contains a microprocessor, battery, wireless radio, pump and a drug reservoir to release medication to a specific area of the body. The team behind this futuristic capsule essentially shrank all these technologies into the size of a single pill. One aspect of top—down nanotechnology derives from microelectromechanical systems (MEMS), the technology used to make tiny accelerometers, which are used as air bag deployment sensors in cars and in force and tilt sensing in Nintendo Wii game consoles. MEMS is based on three ‘Ms,’ said Shuvo Roy, PhD, an expert in MEMS and nanotechnology in medicine, who was previously with the Department of Biomedical Engineering, Cleveland Clinic. “Make

Computer artwork of a medical nanorobot injecting a drug into a tumor.

‘Nanotechnology is out there as a technology that is still waiting for an application for a human use.’ —Suresh Chari, MD melting point lowers, ultimately dropping to well under 50% of the bulk melting point. Gold nanoparticles have a large surface area and strong bonding properties, which allow researchers to load anti-cancer drugs onto them as well as

Nanotechnology researchers say they expect to see nanomedicine in hospitals within the next five to 10 years. In some labs, researchers are experimenting with the stuff of pure sci-fi fantasy—microbots small enough to be injected into the body through a syringe that would head for a specific area of the body and do “surgery.� Every area of medicine could be changed by nanotechnology, industry watchers say. “This is a very exciting time in which surgery and medicine are merging with biotechnology in ways that are going to change medicine,� said nanotechnology expert Robert Langer, ScD, an Institute

things tiny, make things smart by putting electronics next to them, make them low cost by making many of them.� The opposite approach is the “bottomup� method. Scientists start with a nanoparticle and build up, particle by particle until they have a more complex structure.What makes the bottom-up method so fascinating are the unusual properties of nanoparticles. Chemical elements act very differently at the nanoparticle level than at the cellular level. For example, gold typically melts at 1,064 C. But when chopped into nanoparticles, gold’s

The iPill from Philips contains a microprocessor, battery, wireless radio, pump and a drug reservoir to release medication to specific areas of the body.

agents that target drug delivery to a specific disease site. Gold’s bonding properties also help the drugs stay where they are supposed to rather than go off into the bloodstream. All of this opens up new uses for gold in medicine, said Priyabrata Mukherjee, PhD, the key nanotechnologist on the Mayo team. He is testing gold

nanoparticles to treat pancreatic cancer, using the nanoparticles as a delivery vehicle for gemcitabine. “This system has huge promise to seek out and reduce cancer and toxicity,� he said. Laboratory studies indicate the gold nanoparticle delivery system works, inhibiting pancreatic tumor cell proliferation (Cancer Res 2008;68:19701978). Gold nanoparticles also show promise for treating leukemia, multiple myeloma and ovarian cancer, Dr. Mukherjee added. Modern nanotechnology has grown in fits and starts from the 1950s when Western society began an infatuation with electronics, particularly miniaturized electronics. The field—a mixture of atomic physics, chemistry and electronics—got its name in the 1980s when MIT physicist K. Eric Drexler popularized the term “nanotechnology.� In the late 1990s, nanotechnology development kicked into high gear when improved microscopes made it easier to visualize and move tiny particles to the point where scientists could control matter at the atomic nanoscale.

Clinically Relevant? Type nanotechnology into PubMed see NANOBOTS, page 12

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Technology

NANOBOTS continued from page 11

today and more than 15,500 citations pop up. Scientists have published on everything from diamond coatings for knee and hip prostheses to an alternative pregnancy test using gold nanoparticles. The topics range from the abstruse—for example, “the Interaction of Fe(III) tetrakis(4-N-methylpyridinium)porphyrin with sodium dodecyl sulfate at submicellar concentrations�—to the bizarre: a spidey suit made of “nanohoops� that could enable the wearer to remain attached to a ceiling (Small 2008;4:1044-1045). “The list goes on and on,� said Dr. Mukherjee. Nanotechnology researchers say they expect to see nanomedicine in hospitals within the next five to 10 years. Dr. Mukherjee and his colleagues hope to begin testing their nanotech system of drug delivery in human patients with pancreatic cancer within the next five years. Several cancer-drug delivery systems will likely become available before 2015, said Dr. Roy. “A number of groups are working in this area and these systems are possibly only five or 10 years down the road,� he said. An Australian team has developed a nanobot that they hope to test in human patients in 2010. The field of nanotechnology is “ripe to move forward,� said Dr. Roy. The engineering fundamentals have been established. Testing facilities exist throughout the United States, backed by a $2.5 billion grant from the federal government. And medical professionals are quicker today to adopt cutting-edge technologies than in the past and are collaborating more with bioengineers than ever before. Cancer specialists, in

A gold nanoparticle delivery system has shown potential to inhibit pancreatic tumor cell proliferation. particular, are leading the way, he said. “As we have more comfort from the medical community who can use nanotechnologies and adapt them and make an impact, I think we’ll see more nanotechnology in real life.�

Hold On Just a Nanosecond ... Some experts, however, stress that nanomedicine today is about possibilities—none of them proven in humans. Nanotechnology is a science, they say, that’s yet to find a single medical application that is proven to be safe and effective outside of a laboratory. The possibilities are “breathtaking and exciting, yes, but are just that—possibilities right now,â€? cautioned Bolanle Asiyanbola, MD, an assistant professor of surgery at The Johns Hopkins University School of Medicine in Baltimore. Dr. Asiyanbola spent several years researching nanomedical oncology with Princeton engineer Winston Soboyejo, PhD. The pair was looking for ways to use nanotechnology to detect pancreatic cancer. “The technology isn’t really there ‌ yet,â€? she said in an interview. “As things currently stand, there is still a long way to go.â€? In a 2008 article (J Surg Educ 2008;65:155-161) in which she analyzed nanotechnology from a surgical perspective, Dr. Asiyanbola concluded: “This is a science that is still in its infancy.â€? Much more research is needed to understand and prevent the potential for harm, she noted. Experts and anti-nanotechnology activists argue that the emerging field brings new safety risks that could take decades to be fully understood.

Scientists cannot say with certainty what the long-term effects of nanoparticles are once they are injected or implanted into the body. Some nanoengineered structures may cause cytotoxicity. Some nanoparticles may “translocate� from the site of deposition to other organs in the body. The broader community, too, could be at risk from environmental concerns associated with the production of nanoparticles (Environ Health Perspect 2007;115:1654-1659). No one understands what happens when the particles are dispersed into the environment. Nor do they know the dangers associated with workforce exposure. Scientists in Europe and America have said they are concerned about possible toxic qualities of nanoparticles of materials that are harmless at their full size. In July 2007, a Nanotechnology Task Force organized by the FDA called for the agency to “consider developing guidance and taking other steps to address the benefits and risks of drugs and medical devices using nanotechnology.� The agency has not yet issued clear regulations regarding the manufacturing and monitoring of nanotechnology. Doctors who spoke with Clinical Oncology News said that, other than the few who are doing research in the field, physicians know very little about nanomedicine. However, the doctors and surgeons who are involved in nanomedicine research tend to be more hesitant than engineers and biochemists about how this technology is going to change clinical practice. It may change practice, they say, but it is unlikely to do so

Credit: Kenneth Eward/Photo Researchers, Inc.

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Quantum dot nanoparticle probes used to target and image tumors. In this image, several quantum dots are attaching to a tumor on the wall of a blood vessel.

in the near future. “Nanotechnology is out there as a technology that is still waiting for an application for a human use,� said Suresh Chari, MD, a Mayo Clinic gastroenterologist and specialist in pancreatic cancer who works with a nanotechnology research team. “Doctors don’t know too much about it. Technologies come and go. For example, gene therapy came out many years ago as a very promising technology to treat cancer and it never made it to the clinical arena, at least in pancreatic cancer. Clinicians will wait for it to be translated to human disease before they get excited about it. “This technology has potential, tremendous potential both in diagnosis and treatment. The question is ‘will it fulfill its potential?’ Hopefully, yes.� —Christina Frangou

PEOPLE AND PLACES

Around the Water Cooler

T

he ASCO Cancer Foundation (TACF) presented merit awards to 26 breast cancer scientists from around the globe at the recent 2009 Breast Cancer Symposium. The awards are designed to promote clinical research by oncology fellows and provide them the opportunity to present their research and interact with other clinical investigators at the meeting. The recipients were selected based on the scientific merit of their abstracts and received funding to assist with their travel expenses to attend the symposium. The awards are supported through restricted educational grants from Novartis Oncology, Aptium Oncology, GE Healthcare and OSI Oncology. The 2009 Breast Cancer Symposium Merit Awards recipients are as follows: • Tarek M. Abdel-Fatah, University of Nottingham • Mariana Chavez-MacGregor, MD, MSc, University of

Texas M.D. Anderson Cancer Center • Todd A. Swanson, MD, PhD, William Beaumont Hospital • Heather L. McArthur, MD, MPH, Memorial SloanKettering Cancer Center • Iwa Kong, MD, FRCPC, Odette Cancer Centre • Partha S. Ray, MD, John Wayne Cancer Institute • Larissa J. Lee, MD, Harvard Radiation Oncology Program • Amit Goyal, Cardiff University • Candace R. Correa, MD, University of Michigan Medical Center • Aditya Bardia, MD, MPH, Johns Hopkins University • Bedanta P. Baruah, MBBS, University Hospital of Wales • Conleth Murphy, Memorial Sloan-Kettering Cancer Center • Sekwon Jang, MD, University of Minnesota • Swati Kulkarni, MD, FRCPC, Cancer Centre of SE Ontario, Queen’s University

• Nathaniel P. Reuter, MD, MPH, University of Louisville • Rajni Sethi, MD, New York University Langone Medical Center • Shari B. Goldfarb, MD, Memorial Sloan-Kettering Cancer Center • Mark Jesus Magbanua, PhD, University of California, San Francisco • Saira Nasim, MRCP, Odette Cancer Centre • Frederik Marme, MD, University Hospital Heidelberg • Laura S. Dominici, MD, University of Texas M.D. Anderson Cancer Center • Charles B. Simone, MD, National Cancer Institute • Samer I. Schuman, MD, University of Miami— Jackson Memorial Hospital • Nabil Wasif, MD, John Wayne Cancer Institute • Simone Schrading, MD, Department of Radiology, University of Bonn • Luke J. Peppone, PhD, University of Rochester

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Razelle Kurzrock; Maurie Markman

The treatment of cancer is increasingly being individualized, based on an understanding of underlying biologic mechanisms. Poised to change the landscape in oncology, Targeted Cancer Therapy provides a state-of-the-art overview. Targeted Cancer Therapy is valuable to practicing and academic physicians, fellows, residents and students, as well as to basic scientists interested in the cancer field.

Christopher R. Jarvis, MBA; David B. Mandell, JD, MBA; Celia R. Clark, JD, LLM; Glenn M. Terrones, Esq.

This book teaches doctors how to protect their personal and practice assets from lawsuits, taxes, bad investments, bankruptcy and divorce by combining the expertise of a financial planner, asset protection attorney and estate planning attorney. This comprehensive guide explains domestic and offshore asset protection, tax-saving vehicles, captive insurance companies and more. CO1109

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