Clinical Oncology News - March/April 2009 - Vol. 4, No. 2

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Advances in Cancer Care clinicaloncology.com • MARCH/APRIL 2009 • Vol. 3, No. 2

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K-ras testing could save $604 million.

Sunitinib improves progression-free survival in pancreatic cancer.

HematOlogic DISEASE

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Some patients with CML may be able to take an imatinib holiday.

CLINICAL TRIALS

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A list of Phase II and III trials initiated within the past 30 days.

SUPPORTIVE CARE

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Are blood transfusions a safe alternative to ESAs?

In Prostate Cancer Patients ...

Trials Reveal Benefits Of Postoperative Radiotherapy Orlando, Fla.—Adjuvant radiotherapy (RT) may significantly reduce biochemical failure, according to the latest data from three randomized controlled trials. In addition, one trial has found that distant metastasis and mortality may be reduced significantly with adjuvant postoperative RT. Although these latest findings are rather convincing, they still do not address the issue of whether an approach consisting of active surveillance (watchful waiting) followed by salvage RT is a better choice, according to researchers see RADIOTHERAPY, page 6

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EDUCATIONAL REVIEW

Safe Handling of Hazardous Drugs: Reviewing Standards for Worker Protection See page 9.

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FDA Mandates Opioid Risk Management Program

Improving Resectability of CRC Liver Metastases Searching for the Best Neoadjuvant Regimen San Francisco—Survival for most patients with stage IV colorectal cancer depends on the ability to resect liver metastases, but what neoadjuvant regimen improves outcome? At the 2009 Gastrointestinal Cancers Symposium, several presentations shed light on the topic.

FOLFOX and Bevacizumab In a Phase II study that garnered the meeting’s “Merit Award,” investigators showed that extended preoperative chemotherapy (≥ nine cycles) did not improve pathologic response, but did increase the incidence of hepatotoxicity after hepatic

Program May Increase Workload

s a i d Da r i a Zorzi, MD, an oncology fellow at M.D. Anderson Cancer Center in Houston, noting that pathologic complete and major response have been shown to see LIVER METASTASES, page 3

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POLICY & MANAGEMENT

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n an effort to blunt the growing problem of prescription painkiller abuse, the FDA has announced that it will require the makers of two dozen opioid formulations to create elaborate risk management plans for their products. Oncologists will most likely be saddled with additional work because of the program.

The mandate will not take effect until the FDA develops a final Risk Evaluation and Mitigation Strategy (REMS) for opioids, which may take up to a year, officials said. The agency has released see RISK MANAGEMENT, page 22

resection for colorectal liver metastases.

“We found that the type of chemotherapy has more impact on path­ologic response than the duration of the chemotherapy,”

Credit: Annie Cavanagh, Wellcome Images

SOLID TUMORS

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Medicare Expands Coverage of Off-Label Cancer Drugs

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n a move that expanded coverage of offlabel cancer drugs, in 2008, the Centers for Medicare & Medicaid Services (CMS) added three new compendia it references to determine coverage for off-label cancer treatments. Many doctors, however, are unaware that two of the compendia exist.

The addition of the documents satisfies the requirements of a 1993 federal statute that requires accepted compendia to be used as resources in making coverage decisions.

The agency made the change because two of the three compendia in the original

statute are no longer published, and many in the cancer community were also calling on CMS to name new resources to keep up with new cancer drugs. Four compendia now serve as a reference for making offlabel treatment decisions.

“Medicare was left with one compendium, and I think, in general, the compendium tended to be somewhat out of date,” said William T. McGivney, PhD, chief executive officer of the National Comprehensive Cancer Network (NCCN). “The see COVERAGE, page 20

McMahonMedicalBooks.com Atlas of Cancer Maurie Markman For more information, see page 17.

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SOLID TUMORS

Clinical Oncology News • MARCH/APRIL 2009

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Colon

continued from page 1 

significantly improve survival over minor response.

Specifically, the combination of FOLFOX (leucovorin, fluorouracil and oxaliplatin) and bevacizumab (Avastin, Genentech) was associated with greater complete and major pathologic response than FOLFOX alone, independent of treatment duration.

The study included 219 patients with resectable or borderline resectable liver metastases who underwent hepatic resection following chemotherapy with FOLFOX, with or without bevacizumab given as a short course (one to eight cycles; n=157) or long course (≥ nine cycles; n=62).

Outcomes were not significantly different according to duration of chemotherapy. Complete response was observed in 7% after a short course and 11% after a long course; major response was seen in 50% and 44%, respectively; and less than 50% residual tumor (complete with or without major response) was found in 57% and 55%, respectively, Dr. Zorzi said.

The regimen, however, did make a significant difference: For patients receiving FOLFOX plus bevacizumab, 70% had less than 50% residual tumor, compared with 45% receiving FOLFOX alone (Figure).

Prolonged cycles were also more toxic, she added.

Patients receiving at least nine cycles of chemotherapy were significantly more likely to have sinusoidal injury (42%) than patients receiving a shorter course (26%), and to have postoperative liver insufficiency (11% vs.

4%). In a multivariate analysis, prolonged chemotherapy was the only independent predictor of liver insufficiency, and it increased the risk fourfold, she said.

“Interestingly, the pathophysiology of liver insufficiency after FOLFOX appears to be independent of sinusoidal injury because, although bevacizumab significantly reduced the incidence of sinusoidal injury, the rate of hepatic insufficiency was similar whether a long or a short course was given,” she added.

Cetuximab Combinations In a second presentation at the meeting, Gunnar Folprecht, MD, of the University Hospital Carl Gustav Carus, Dresden, discussed a randomized multicenter trial from Germany that revealed the effectiveness of combinations with cetuximab (Erbitux, Bristol-Myers Squibb).

Pathologic Response, %

100

Major response

Complete response P=0.011

80 P=0.007

60 40 20 0

1-8 Cycles

≥9 Cycles

FOLFOX

1-8 Cycles

≥9 Cycles

FOLFOX + Bevacizumab

FOLFOX, leucovorin, fluorouracil and oxaliplatin

Figure. Comparison of adverse events.

A regimen of FOLFOX6 plus cetuximab or FOLFIRI (leucovorin, fluorouracil and irinotecan) plus cetuximab resulted in confirmed responses in 70% of initially unresectable patients with wild-type Kras status (and 43% among patients with mutated Kras). Responses (regardless of Kras status) were seen in 68% of the FOLFOX arm and 57% of the FOLFIRI arm, for an overall rate of 62%, with stable disease achieved in 29%.

The study included 111 patients randomized to receive eight cycles of one of these two regimens.

Patients whose metastases remained unresectable received an additional four cycles of chemotherapy.

R0 resections were achieved in 34% of all patients, and 46% achieved R0 resection or R1 resection followed in some cases by radiofrequency ablation, according to Dr. Folprecht.

The R0 resection rate was 40% among patients with at least five metastatic sites, 33% among Kras wildtype patients and 28% among those initially considered technically unresectable.

Preoperative toxicity was predictable, based on historical controls. Thrombopenia, nausea/vomiting grade ≥ 3 and neuropathy ≥ grade 2 were more common in the FOLFIRI/cetuximab arm, while infections ≥ grade 3 and alopecia ≥ grade 2 were seen more often with FOLFIRI/ cetuximab. There were two perioperative deaths.

“To confirm that resectability could really be improved by preoperative chemotherapy, we performed a blinded surgical review at baseline and at 16 weeks and considered the patient resectable if there was a consensus among at least half the surgeons,” he said.

Surgical review of 75 of the patients showed that 32% went from unresectable to resectable, 61% were unchanged and 6% went from resectable to unresectable.

“The net effect was that 19 of 75 patients (25%) were converted from unresectable to resectable status,” he said.

Putting It in Perspective David P. Ryan, MD, clinical director of the Tucker Gosnell Center for Gastrointestinal Cancer at Massachusetts General Hospital, in Boston, discussed these two presentations at the meeting.

As background, he noted that unresectable patients who are converted to resectable have similar five-year survival as initially resectable patients, that perioperative FOLFOX may improve progression-free survival according to EORTC 40983, that pathologic complete response may be a good surrogate for overall survival and that chemotherapy can cause liver injury (steatohepatitis).

“The current studies add to what is known,” he said.

Dr. Zorzi’s study showed that longer duration of chemotherapy does not improve outcome but does increase liver injury, and that bevacizumab may alter the liver injury pattern. Bevacizumab also increased pathologic responses, but this needs further study, he suggested.

“The experience of these investigators and others provides enough rationale for moving forward with bevacizumab in large Phase III studies,” Dr. Ryan said.

According to him, the German investigators showed cetuximab to be safe and associated with very high response and R0 resection rates. “Whether the high R0 resection rate actually matters will be determined by the overall survival data, which we await,” he added. “While it is high, we need to take into account the ‘moving target’ of unresectability in the surgical community.”

He praised the study’s use of blinded surgical review, which used consensus rather than a definition of resectability. “This gives us an idea of the conversion rate by a committee of surgeons, and has familiarity,” he said. But

‘The net effect was that 19 of 75 patients (25%) were converted from unresectable to resectable status.’

—Gunnar Folprecht, MD

Colour-enhanced image of human colon cancer cells in culture.

it could be subject to regional differences and surgical bias and it is not applicable to large clinical trials, which still require definitions of resectability, he noted.

What is needed in the future, Dr. Ryan suggested, is consensus regarding the staging of patients with isolated liver metastases (i.e., “clearly resectable,” “technically unresectable” and “high risk”) and consensus on the definition of “technically unresectable,” he said. There is also a need for Phase III studies to evaluate perioperative versus postoperative multi-agent chemotherapy in clearly resectable patients, and for studies to discern the relative role of cetuximab or panitumumab versus bevacizumab, particularly in high-risk patients.

—Carolyn Helwick

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ow is the recession impacting your oncology practice? Clinical Oncology News would like to hear from you and is currently accepting articles on how the economic crisis is affecting oncologists. Send submissions to korourke@mcmahonmed.com. The best entry will receive $500 and will be published.

Web-Exclusive Articles Available

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o read the following articles and other Web exclusives, visit www.clinicaloncology.com and click on “Web exclusives” underneath “Departments” on the left-hand navigation bar. Web-exclusive articles are posted on Monday, Wednesday and Friday.

✪ Anesthesia method used during breast cancer surgery impacts outcomes.

✪ Doctors are not adequately informing women about treatment options for early-stage breast cancer.

✪ Methadone treats neuropathic cancer pain. ✪ Investigators shine further light on ADT hazards.

Credit: Annie Cavanagh, Wellcome Images

LIVER METASTASES

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CLINICAL ONCOLOGY NEWS

Clinical Oncology News • MARCH/APRIL 2009

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Pharmacy Polly E. Kintzel, PharmD Melvin E. Liter, MS, PharmD

Advisory Board

Policy and Management

Bioethics Joseph P. DeMarco, PhD Paul J. Ford, PhD

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

Community Oncology

Solid Tumors

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

Betty Ferrell, RN, PhD

Editorial Staff Kate O’Rourke, Editor korourke@mcmahonmed.com Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com James Prudden, Group Editorial Director

Lung Cancer, Emesis Richard J. Gralla, MD

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Gastrointestinal Cancer Edward Chu, MD Cathy Eng, MD Leonard Saltz, MD

Oncology Nursing

Genitourinary Cancer Ronald M. Bukowski, MD

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

Breast Cancer Andrew Seidman, MD

Jennifer R. Brown, MD, PhD Agnes Y.Y. Lee, MSc, MD Richard Stone, MD

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

Gynecologic Cancer Maurie Markman, MD

Bone Metastases Allan Lipton, MD

Hematologic Malignancies

Gastrointestinal Cancer and Sarcoma Ephraim Casper, 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.

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.

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Current Strategies for the Treatment of Acute Promyelocytic Leukemia 2007 Acute promyelocytic leukemia (APL) was first described as a distinct clinical entity in 1957. Since the introduction of all-trans retinoic acid (ATRA [Vesanoid, Roche]) in the early 1990s and its administration with anthracycline-based chemotherapy, APL has become curable in the majority of patients.

Guide for the Administration and Use of Targeted Cancer Agents 2007/2008 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.

Therapeutic Strategies for Patients With Chronic Lymphocytic Leukemia In the past 10 years, progress in the understanding of the biologic basis of chronic lymphocytic leukemia, the introduction of novel prognostic factors to complement the clinical staging systems, the use of monoclonal antibodies and the development of better measures of response assessment have led to a revised approach to this most common of the adult leukemias.

The Medical Treatment of Metastatic Breast Cancer Breast cancer is a global health burden with more than 1 million new cases diagnosed worldwide and more than 250,000 new cases diagnosed in the United States each year. The rationales for several common management strategies are reviewed.

Treating the Patient With Metastatic Non–Small-Cell Lung Cancer Lung cancer is a major health problem worldwide. In recent years, new chemotherapeutic compounds and biologic agents have been developed and approved by the FDA for the treatment of metastatic non–small–cell lung cancer.

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SOLID TUMORS

Clinical Oncology News • MARCH/APRIL 2009

5

Colon SPOTLIGHT ON TARGETED THERAPIES AND DIAGNOSTICS

K-ras Testing Could Save $604 Million San Francisco—If patients with metastatic colorectal cancer (mCRC) were routinely tested for K-ras gene status before receiving an epidermal growth factor receptor (EGFR) inhibitor, the U.S. health care system could be spared $604 million per year in treatment costs, according to a recent analysis.

“Our findings show that K-ras testing is not only good medicine, it is good economics,” said principal author Veena Shankaran, MD, a postdoctoral oncology fellow at Northwestern University, Chicago and the VA Center for the Management of Complex and Chronic Care in Hines, Ill. She presented the analysis at the 2009 Gastrointestinal Cancers Symposium.

Several key studies, including the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial, have revealed that response to cetuximab (Erbitux, Bristol-Myers Squibb) and panitumumab (Vectibix, Amgen) is observed only in patients with normal (wild-type) K-ras gene status, whereas patients with K-ras mutations virtually never respond. K-ras testing, however, has not been universally adopted.

Dr. Shankaran and her colleagues developed an economic model to determine the net savings when K-ras status was allowed to guide treatment decisions for a theoretical population of patients receiving first-line cetuximab-containing treatment for mCRC. Based on publicly available data on laboratory and drug costs, U.S. cancer incidence according to the American Cancer Society and clinical outcomes from the CRYSTAL trial, investigators estimated the net dollars saved when cetuximab was limited to patients with normal K-ras.

They estimated 28,724 cases of mCRC per year, a cost of $452 per K-ras test (totaling $13 million), and a wholesale price of $3,986 per loading dose and $2,491 per weekly dose of cetuximab.

They multiplied this cost by 24 infusions per patient and determined that the total cost for treating one patient was $61,279 (excluding costs associated with appointments, toxicity management and infusions).

When they excluded the estimated 35.6% of patients with K-ras mutations, and treated only those with normal K-ras, the savings was $617 million, minus $13 million for testing, resulting in a net savings of $604 million.

“This is a timely study, considering that the cost of cancer care is growing by 15% per year, nearly three times the rate of increase in overall health care costs in 2007,” said Jennifer Obel, MD, a gastrointestinal cancer specialist at NorthShore Health Systems, Chicago.

The findings support the American

Society of Clinical Oncology’s (ASCO) recent provisional clinical opinion that recommends the use of routine K-ras gene testing to guide the use of EGFR inhibitors in metastatic disease. The

recommendation supports the emerging trend of “personalized medicine,” according to Richard L. Shilsky, MD, ASCO president and professor of medicine at the University of Chicago. “This

is an example of where cancer care is heading.”

—Caroline Helwick

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HEMATOLOGIC DISEASE

Clinical Oncology News • MARCH/APRIL 2009

Chronic Myeloid Leukemia

Can Patients Take an Imatinib Holiday?

San Francisco—Some patients with chronic myeloid leukemia (CML) may be able to take an imatinib holiday, after a prolonged complete molecular remission (CMR), according to initial results from the multicenter STIM (Stop Imatinib) study.

The observation is considered preliminary because only 49 patients have a follow-up greater than six months, and only 22 of these remained in remission for up to 14 months after discontinuing imatinib. Investigators, however, are still excited because all patients who did relapse were sensitive to imatinib (Gleevec, Novartis) rechallenge. “We need more patients and longer follow-up to identify which factors affect the persistence of a CMR after imatinib discontinuation, but this is the first study to evaluate this concept using strict criteria,” said Francois-Xavier Mahon, MD, Division of Hematology, Victor Segalen Institution, Centre Hospitalier Universitaire (CHU), in Bordeaux, France.

Dr. Mahon said that the greatest likelihood of sustained remission after discontinuing imatinib was pretreatment with interferon, but two individuals in the group of patients with longest remission received imatinib alone. Dr. Mahon presented the study at the most recent annual meeting of the American Society of Hematology (abstract 187).

Study Details The STIM study was initiated in July 2007 at 18 participating centers after a pilot study of 15 patients with CML indicated that sustained CMRs were possible after imatinib discontinuation (Blood 2007;109:5860, PMID: 16973963). Of the 15 patients, eight remain in CMR, defined as BCR-ABL/ABL levels below the threshold of detection, after more than two years off therapy. The eight patients had received interferon, with or without additional therapies such as cytarabine (ARA-C), for at least 29 months. Five of those who relapsed also received interferon for sustained periods, but two did not.

For entry into STIM, CML patients were required to be in CMR for at least two years on imatinib therapy.

They were not permitted to have previous treatment with corticosteroids, chemotherapy, radiotherapy or

other treatments with the potential to complicate the evaluation. Of the 69 patients enrolled, 31 had received previous interferon and 29 had received imatinib alone. The median age of the study population was 62 years, and approximately two-thirds were females.

The median follow-up was only five months and nine patients had not completed a full month of follow-up at the time results were presented.

One month after therapy was discontinued, eight (14%) of the 60 patients relapsed, and at the end of the third month, an additional 17 patients relapsed. After this, however, the relapse rate appeared to slow substantially. Of the 28 patients who were still being followed and had not relapsed by month 3, only three additional relapses were reported in subsequent follow-up. Two of these occurred in month 4 and one occurred in month 7.

Although the number of patients with follow-up exceeding eight months diminished rapidly (16 in month 9, seven in month 14 and one in month 16), the absence of any additional relapses was highly encouraging.

“At month 9, the probability of being in CMR was 46%. However, when we stratified patients by previous interferon therapy, the increased likelihood of remaining in CMR among those receiving interferon approached statistical significance,” Dr. Mahon said.

Specifically, the rates were 53% for those who had previously received interferon compared with 39% for those who had not received interferon (P=0.054).

According to Richard Stone, MD, clinical director of the Adult Leukemia Program, Dana-Farber Cancer Institute, “although the prior use of interferon could have provided an ‘immunologic milieu’ making it less likely for disease relapse after imatinib therapy was halted, it is possible that other factors might have been more important.” He thinks a future clinical trial should test stopping imatinib in all patients and then randomizing them to interferon or observation. According to Dr. Stone, although some patients with very low CML disease burden levels were able to stop imatinib for a few months, discontinuing imatinib cannot be considered standard of care in any subset of patients at this time.

Benefits of a Holiday In patients who relapsed during the STIM study, imatinib was restarted and all returned to CMR status. This has important implications for imatinib holidays, even if longer follow-up is unable to confirm the indefinite remissions that may indicate possible cure. The ongoing STIM study will attempt to evaluate the economic impact of discontinuing imatinib, a step that depends on the ability to restart treatment without compromising long-term outcome.

Even in the absence of cure, evidence that patients

‘The data are definitely encouraging, and bring good news not only to the CML patients but also to the treatment-funding institutions.’

—Junia V. Melo, MD, PhD

can remain off imatinib therapy for sustained periods without relapse and without compromising long-term outcome may provide an opportunity to improve the quality of life of patients. Insight into the biological mechanisms of a sustained remission also may help further identify disease-control strategies. Investigators await longer follow-up with great anticipation because of the large clinical advantages expected to accrue if formal guidelines can be developed for treatment discontinuation.

According to Junia V. Melo, MD, PhD, who was not involved with the study, the results of the STIM study are not only important, but also supported by at least one other ongoing study. Dr. Melo, professor of hematology, Institute of Medical and Veterinary Science, Adelaide, Australia, noted that colleagues from her institution, Professor Tim Hughes and David M. Ross, MD, presented data on 22 patients in a multicenter Phase II study of imatinib withdrawal, conducted by the Australasian Leukaemia & Lymphoma Group. In that study, 14 patients achieved CMR on imatinib after prior interferon treatment. With an average follow-up of 12 months after stopping imatinib, the probability of sustained CMR in this group was 57%. Four out of eight patients who received imatinib alone also remain in CMR off therapy, but the follow-up in this group is short, with three patients off treatment for less than six months.

“The data are definitely encouraging, and bring good news not only to the CML patients but also to the treatment-funding institutions,” reported Dr. Melo, responding to an inquiry about what these data signify. She expects this to be an area of intense scrutiny as a growing number of patients whose CML is in CMR continue to show undetectable BCR-ABL on several years of imatinib.

—Ted Bosworth

SOLID TUMORS Chronic Myeloid Leukemia

RADIOTHERAPY continued from page 1 

at the University of Miami.

“It is a complicated issue,” said Alan Pollack, MD, PhD, professor and chairman of the Sylvester Comprehensive Cancer Center, University of Miami

Leonard M. Miller School of Medicine, Miami. “There are some results that suggest that patients don’t do as well long term with salvage radiotherapy, but we need a trial that directly compares the two, and we don’t have that kind of data yet. A Medical Research Council study led by investigators in the United Kingdom will address this issue. ”

For several years, a debate has been raging as to whether post-prostatectomy RT should be administered adjuvantly to patients with high-risk pathologic features or in the form of salvage therapy when the prostate-specific antigen (PSA) levels rise and recurrence is detected. Now, results have been published from three Phase III trials

suggesting that clinicians may want to reconsider how they counsel men facing this conundrum.

Dr. Pollack, who presented an overview of the findings from the three trials at the 2009 Genitourinary Cancers Symposium, said approximately 40% to 50% of men with prostate cancer who undergo a definitive prostatectomy will have continued on page 7

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SOLID TUMORS

Clinical Oncology News • MARCH/APRIL 2009

high-risk pathologic features and undetectable PSA levels. These men, however, may now have a better idea of what the potential benefits are if they opt for adjuvant RT rather than watchful waiting.

Retrospective studies indicate that adjuvant RT is associated with a significantly reduced risk for biochemical failure in comparison with salvage therapy.

There is, however, a caveat. These studies have significant limitations, and no data are yet available from head-to-head comparisons. What researchers can say now is that there may be a 20% to 30% gain at five years in freedom from biochemical failure after prostatectomy plus adjuvant RT. Dr. Pollack said the EORTC (European Organization for Research and Treatment of Cancer) 22911 trial and ARO (German Cancer Society) trial looked at biochemical failure as the primary end point. The SWOG (Southwest Oncology Group) 8794 trial used distant metastasis as the primary end point.

Dr. Pollack said the initial report of SWOG 8794 did not identify a difference between rates of distant metastasis in men who had prostatectomy with watchful waiting and rates in men who had prostatectomy with adjuvant RT. The most recent update from this trial, however, suggests that at 12.5 years of follow-up, metastasis or death occurred in 54% of the men in the trial who had not received adjuvant RT, compared with 43% of the men who received adjuvant RT. He said that at 10 years after prostatectomy, 61% of the patients who received adjuvant RT had metastatic cancer, compared with 71% of the patients who had not received adjuvant RT. Furthermore, overall mortality was found to be significantly reduced by adjuvant RT; at 12.5 years, the overall survival rate was 52% among the men who received adjuvant RT, compared with 41% among those who did not receive adjuvant RT. The overall survival rate at 10 years was 66% without adjuvant RT versus 74% with adjuvant RT. “I think for patients with high-risk features, these patients need to be educated on the existing randomized studies. The studies show a proven benefit with adjuvant radiotherapy. If they wish to wait, then those patients should be monitored closely. When the PSA rises, even if it rises just slightly, they should be treated then, and there should be no waiting for the PSA to get over 0.5 [ng/mL],” said Dr. Pollack. “We know from a number of studies that the higher the PSA in the salvage setting, the less chance we have of eradicating the disease with radiation alone. So, early intervention in the salvage setting is a reasonable alternative today, but we have more data to support adjuvant.”

Dr. Pollack said that in all three of the randomized trials, adjuvant RT significantly reduced biochemical failure, and in the SWOG 8794 trial, adjuvant RT significantly decreased distant metastasis

‘Radiation therapy has side effects, and it has economic and human costs. … If we were to adopt a recommendation that all men with positive margins receive radiation therapy, many patients would be treated unnecessarily.’

—Gerald Andriole, MD

and mortality. However, he cautioned that these findings still do not definitively answer the question of whether active surveillance is a better or worse approach.

Gerald Andriole, MD, professor and chairman of the department of urology at Washington University School of Medicine, St. Louis, said he agrees with Dr. Pollack. Dr. Andriole said that if a man has an adverse pathologic finding

after undergoing a radical prostatectomy, then there are nomograms that will predict the risk for failure over a period of five to 10 years. He said that each man will take that probability from the nomogram and evaluate it differently.

“Some men may think, ‘I have a 30% chance for recurrence,’ and so they may opt for radiotherapy. Other men will say, ‘That means I have a 70% chance it won’t

Prostate

return,’ and so they opt for active surveillance. This is a dilemma most urologists and the patients face,” said Dr. Andriole.

“Radiation therapy has side effects, and it has economic and human costs. In a purely adjuvant therapy setting, some patients would get it unnecessarily. More than half of patients could receive radiation they don’t need, and it is a therapy that affects bladder function, erectile function and GI function. If we were to adopt a recommendation that all men with positive margins receive radiation therapy, many patients would be treated unnecessarily.”

—John Schieszer

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research

Unique Cutting-Edge ONCOLOGY Opportunities The Office of Oncology Drug Products is recruiting BC/BE (or equivalent) Medical Oncologists, Hematologists and Pediatric Hematologists/Oncologists to serve as Clinical Reviewers at our beautiful new campus in Silver Spring, MD. Our work involves cutting-edge biotechnology-based therapies for malignant disease including: Signal Transduction Inhibitors

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Opportunities for scientific conferences, professional meetings and career advancement. Up to one day per week for academic clinical activities or research possible. Flexible and/or home-based working schedules available.

Salary & Benefits: An excellent benefits package (health insurance, life insurance, thrift savings plan, retirement) · Civil Service Salary at the GS-14 level of $83,445 plus an additional very generous supplemental allowance determined by relevant experience and medical specialty. · Recruitment Bonuses and Student Loan Repayments · Flexible and/or Home-based work schedules available · Opportunities to continue Professional Development GENERAL INFORMATION: Positions being filled as civil service or U.S. Commissioned Corps require U.S. citizenship. Permanent U.S. residents may apply for Staff Fellowship appointments in physician and scientist positions. Graduates of foreign colleges/universities must provide proof of U.S. education equivalency certification.

PHYSICIANS: (Oncology, Hematology, or Pediatric Hematology/Oncology): Basic Requirements: Degree: Doctor of Medicine or Doctor of Osteopathy from a school in the United States or Canada approved by a recognized accrediting body in the year of the applicant’s graduation. [A Doctor of Medicine or equivalent degree from a foreign medical school that provided education and medical knowledge substantially equivalent to accredited schools in the United States may be demonstrated by permanent certification by the Educational Commission for Foreign Medical Graduates (ECFMG) (or a fifth pathway certificate for Americans who completed premedical education in the United States and graduate education in a foreign country).] Board Certified or Board Eligible in Oncology, Hematology, or Pediatric Hematology/Oncology.

FOR CONSIDERATION: Submit electronic curriculum vitae with a cover letter to Recruitment Team via e-mail at: OND-Employment@fda.hhs.gov mailto: JACOBSA@CDER.FDA.GOV. Please indicate that you are applying to source code #09-027.

For more information, please contact Joseph E. Gootenberg, M.D. at joseph.gootenberg@fda.hhs.gov or at 301-796-1362.

FDA IS AN EQUAL OPPORTUNITY EMPLOYER AND HAS A SMOKE FREE ENVIRONMENT. MINORITIES, WOMEN, INDIVIDUALS WITH DISABILITIES AND VETERANS ARE ENCOURAGED TO APPLY.

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Safe Handling Of Hazardous Drugs: Reviewing Standards for Worker Protection Luci A. Power, MS, RPh

Martha Polovich, MN, RN, AOCN

Senior Pharmacy Consultant Power Enterprises San Francisco, California

Associate Director Clinical Practice Duke Oncology Network Durham, North Carolina

A

s a new generation of health care workers joins those a­lready e­ngaged in patient care, it is es­sential that they

understand the occupational risks associated

with the handling of hazardous drugs and the need for training in proper techniques for all handling activities to reduce occupational exposure to hazardous drugs.

These drugs, which include antineoplastic agents, antiviral agents, biological modifiers, hormones, and others, provide therapeutic benefit to patients but may result in adverse health effects for healthy workers.1-4 Potential health risks for workers who compound and administer these drugs include adverse reproductive outcomes and the development of cancer.5 This article emphasizes new information about this well-recognized issue. It focuses on activities of the National Institute for Occupational Safety and Health (NIOSH) and the 2008 revision of United States Pharmacopeia Chapter <797> that mandates compliance with environmental, engineering, and training standards for worker protection.

Routes of Occupational Exposure Many studies have documented both surface and worker contamination with hazardous drugs.6-13 Standard work

practices for handling injectable drugs generate powder and liquid aerosols from vials and syringes. This drug residue may contaminate the air and surfaces in the work area.6-8,14,15 It has been shown that many hazardous drug vials are delivered from the manufacturer with drug residue on the outside of the vials, creating yet another opportunity for contamination.16 Certain hazardous drugs have been shown to vaporize at room temperature, resulting in drug contamination in the air.17-19 Workers may breathe contaminated air or touch contaminated surfaces and, subsequently, absorb hazardous drugs. Drug uptake may also occur through the ingestion of contaminated food or drink that is improperly located in or near drug-handling areas. Additionally, the transfer of contamination from hands to mouth may result in the ingestion of drugs.

Needlesticks with drug-contaminated needles or cuts

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g CL I N I CAL O NC O L O GY N E W S • M A R CH /AP R I L 2 0 0 9

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from glass fragments of vials or ampules may also trigger exposure by injection.

Guidelines for the Safe Handling Of Hazardous Drugs Guidelines for the safe handling of hazardous drugs have been issued by numerous groups since 1980. The Occupational Safety and Health Administration (OSHA) issued guidelines in 1986,20 updated them in 1995,21 and made them available online in 1999.22 The American Society of Health-System Pharmacists (ASHP) published guidelines on the safe handling of cytotoxic agents as Technical Assistance Bulletins in 1985 and 1990, and new guidelines on hazardous drugs in 2006.23-25 The Oncology Nursing Society (ONS), in an attempt to influence nursing practice and protect its members from exposure, published guidelines for safe handling and also developed an extensive educational program based on “Chemotherapy and Biotherapy Guidelines and Recommendations for Practice.”26-28

Continuing Exposure Adverse health effects and chances for exposure have been demonstrated among health care workers for more than 2 decades. Studies of surface and worker contamination conducted in the late 1990s and the early years of this decade continued to document exposure.6-8,10,14,15 Some possible reasons for the problem include new workers’ lack of awareness of the issue, a lack of vigilance in work practices, poor adherence to the use of personal protective equipment (PPE),29-33 and other potential sources of contamination that have yet to be discovered.30 In 2000, NIOSH convened a working group of interested individuals to examine the issue of occupational exposure of health care workers to hazardous drugs.

The Hazardous Drug Safe Handling Working Group was composed of representatives from government (OSHA, NIOSH, and FDA), industry, pharmaceutical manufacturers, academia, membership organizations (eg, American Nurses Association [ANA], ASHP, and ONS), and union leaders whose members handle hazardous drugs.

The Working Group assessed existing information and formulated a plan to increase affected workers’ awareness of the risks and to reduce those risks. In 2004, as a result of the efforts of the Working Group, NIOSH issued “Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings.”34 This NIOSH Alert is similar to the OSHA documents in that it is a guidance document without enforcement authority. However, the recommendations in the NIOSH Alert and the OSHA Technical Manuals may be enforced

by OSHA under the general duty clause of the Occupational Safety and Health (OSH) Act, which sets safety and health standards for US workers. Employers subject to the OSH Act have a general duty to provide work and a workplace free from recognized, serious hazards.35 NIOSH actively continues to increase awareness of this issue by maintaining 2 Safety and Health Topic

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pages online: “Hazardous Drug Exposures in Health Care”36 and “Occupational Exposure to Antineoplastic Agents.”37 These pages provide links to extensive background information, the latest studies, updates on related activities, and NIOSH publications.

In 2007, the US Pharmacopeia (USP) released Chapter <797>, “Pharmaceutical Compounding—Sterile Preparations,” which became effective in 2008.38 This revision of the 2004 standard includes a section specific to the compounding of hazardous drugs, and this document is coordinated with much of the 2004 NIOSH Alert. More importantly, the USP Chapter <797> is an enforceable standard and establishes many of the NIOSH recommendations as requirements. The standards set by USP Chapter <797> are applicable in all settings in which sterile doses of hazardous drugs are compounded, not just hospitals and clinics.

Defining Hazardous Drugs A number of drug types that are potent and toxic in patients have the potential to cause adverse effects in persons exposed to them occupationally. In 1990, ASHP attempted to categorize these drugs in its “Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs,”24 for the first time using the term “hazardous drug” in reference to drugs that involve risks from occupational exposure. The terminology was selected to be inclusive of the types of drugs with safety concerns and to be compatible with the then–newly developed OSHA Hazard Communication Standard (HCS).39,40 The HCS is intended to ensure that employers and workers who are at risk for exposure to hazardous chemicals in the workplace are informed of the specific hazardous chemicals, their associated health and safety hazards, and the appropriate protective measures to be taken.

The HCS defines a “hazardous chemical” as any chemical that poses a physical hazard or a health hazard. It further defines a “health hazard” as any chemical for which statistically significant evidence from at least one study conducted in accordance with established scientific principles is available to indicate that it may cause acute or chronic health effects in exposed employees. The HCS further notes that the term “health hazard” includes chemicals that are carcinogens, toxic or highly toxic agents, reproductive toxins, irritants, corrosives, sensitizers, and agents that produce target organ effects.

ASHP has used similar criteria to define hazardous drugs.23,24 Data on the side effects of a drug are collected during both the premarket investigational phase of the drug and clinical use. These data may reasonably be used to infer “health hazards” in workers occupationally exposed to the drug. As such, ASHP proposed the following criteria to define hazardous drugs24: • genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems); • carcinogenicity in animal models, in the patient population, or both, as reported by the International Agency for Research on Cancer (IARC); • teratogenicity or fertility impairment in animal

Table 1. Comparison of 2004 NIOSH and 1990 ASHP Definitions NIOSH

ASHP

Carcinogenicity

Carcinogenicity in animal models, in the patient population, or both as reported by the International Agency for Research on Cancer

Teratogenicity or developmental toxicity

Teratogenicity in animal studies or in treated patients

Reproductive toxicity

Fertility impairment in animal studies or in treated patients

Organ toxicity at low doses

Evidence of serious organ or other toxicity at low doses in animal models or treated patients

Genotoxicity

Genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems)

Structure and toxicity profile of new drugs that mimic existing drugs determined hazardous by the above criteria ASHP, American Society of Health-System Pharmacists; NIOSH, National Institute for Occupational Safety and Health Originally published in reference 23 © 2006, American Society of Health-System Pharmacists, Inc. All rights reserved.

Reprinted with permission. (RO908)

studies or in treated patients; and • evidence of serious organ or other toxicity at low doses in animal models or treated patients.

ASHP’s criteria for hazardous drugs were revised by NIOSH for the 2004 Hazardous Drug Alert.

USP Chapter <797> has adopted the following definition of hazardous drugs, which supports both the HCS and the NIOSH Alert definitions: Drugs are classified as hazardous if studies in animals or humans indicate that exposures to them have a potential to cause cancer, developmental or reproductive toxicity, or harm to organs.38 NIOSH has adopted a mechanism both to review its hazardous drug criteria and to judge newly FDAapproved drugs against these criteria on a regular basis.

In 2007, a group of experts met to review the drugs that have been approved by the FDA since 2004 to evaluate which should be considered hazardous. Sixty-two drugs from many different therapeutic categories met at least 1 criterion of the hazardous definition in the preliminary analysis by NIOSH.41 The final list will be published when it is approved by the Office of Management and Budget (OMB) [Connor T. Personal communication, July 10, 2008.] Once published, the complete list will include nearly 200 pharmacologic agents available in the United States that are deemed hazardous to health care workers. The current NIOSH list of drugs that should be considered hazardous can be found in Appendix A of the NIOSH Alert.42 Table 1 compares the 2004 NIOSH and 1990 ASHP definitions of hazardous drugs.

Recommendations Recommendations for the safe handling of hazardous drugs have been available since the early 1980s. As more

research has been conducted and more groups have been involved, the recommendations have been coordinated in an attempt to provide uniformity. Each group, however, has a somewhat different focus. The NIOSH Alert and OSHA Technical Manuals are broad guidelines; the ONS “Chemotherapy and Biotherapy Guidelines” focus on administration and patient safety information; ASHP addresses pharmacists’ concerns; and USP Chapter <797> deals exclusively with sterile compounding.

All guidelines agree that to reduce exposure to hazardous drugs in the occupational setting, a comprehensive safety program must be developed that deals with all aspects of drug handling—from selection and receipt of the product to storage, compounding, administration, spill control, and waste management. Key components of such a program are administrative controls, environmental and engineering controls, work practice controls, and PPE. These components are based on principles of industrial hygiene that have been successfully used to mitigate other risks of occupational exposure.43

Administrative Controls Administrative controls include policies, procedures, staff education and training, validation of competency, and medical surveillance. All aspects of hazardous drug handling must be identified, staff performance expectations clearly defined, methods for validating staff competency determined, and processes for the ongoing monitoring of adherence to policies judiciously established.

USP Chapter <797> emphasizes administrative controls for the safe compounding of hazardous drugs by mandating conditions that protect health care workers and other personnel in preparation and storage areas.

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Further requirements include extensive training of all personnel who handle hazardous drugs in the storage, handling, and disposal of such drugs. USP Chapter <797> reinforces the OSHA and NIOSH recommendations by requiring training before the preparation or handling of hazardous compounded sterile preparations, and by mandating that the effectiveness of training be verified by testing specific hazardous drug preparation techniques. Ongoing training must be documented at least annually. The components of the training program are specified to include didactic overview of hazardous drugs and their mutagenic, teratogenic, and carcinogenic properties. The training program must address each new hazardous drug that enters the marketplace.

Training in work practices must also include the following: aseptic manipulation; negative-pressure technique; correct use of safety equipment; containment, cleanup, and disposal procedures for breakages and spills; and treatment of personnel for contact and inhalation exposure.

OSHA and NIOSH include medical surveillance in their safety program recommendations. Medical surveillance involves collecting and interpreting data to detect changes in the health status of working populations potentially exposed to hazardous substances. In 2007, NIOSH released â&#x20AC;&#x153;Workplace Solution: Medical Surveillance for Health Care Workers Exposed to Hazardous Drugs,â&#x20AC;? which provides direction for establishing such a program and the elements that should be included.44 USP Chapter <797> requires that all compounding personnel with reproductive capability confirm in writing that they understand the risks of handling hazardous drugs. Although USP Chapter <797> mandates this only for personnel responsible for compounding, prudent practice dictates that the requirement should extend to all personnel who handle hazardous drugs.

Environmental

and

Engineering Controls

The recent revision to USP Chapter <797> contains extensive mandates to improve the environment in which sterile doses of hazardous drugs are compounded. These directives are designed to increase safety for patients by reducing the potential for the microbial contamination of sterile dosage forms, and to improve worker safety by addressing design concerns in traditional, positive-pressure compounding environments.

Table 2 compares the NIOSH, ASHP, and USP Chapter <797> recommendations for the environment in which hazardous drugs are compounded.

Hazardous drugs must be stored separately from other inventory in a manner to prevent contamination and exposure of personnel. Because of the concerns of volatilization at room temperature, storage is preferably within a containment area such as a negative-pressure room with sufficient exhaust ventilation and at least 12 air changes per hour (ACPH) to dilute and remove airborne contaminants.

An International Organization for Standardization

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(ISO) class 5 primary engineering control (PEC) is required for hazardous drug compounding that both protects sterile preparations from microbial contamination and protects workers and the environment by preventing the escape of hazardous drug aerosols or residue. Appropriate PECs for compounding sterile hazardous drug preparations include class II biological safety cabinets (BSCs) and compounding aseptic containment isolators (CACIs) meeting or exceeding the standards set forth in USP Chapter <797>.

Isolators are recommended as a PEC in both the NIOSH Alert and the ASHP hazardous drug guidelines.

The USP Chapter <797> revision sets performance standards for isolators used to compound sterile preparations, for compounding aseptic isolators (CAIs), and for isolators used to compound sterile hazardous drug preparations (CACIs). To meet the criteria of USP Chapter <797>, an isolator must provide isolation from the room and maintain ISO class 5 air quality within the cabinet during dynamic operating conditions. CAI and CACI air quality must be documented by particle counts during compounding operations and during material transfer in and out of the isolator. Recovery time to ISO class 5 air in the main chamber must be documented after material is transferred in and out of the main chamber. Work practices must be developed to reduce disruption of the air quality in the isolator and to minimize recovery time.

A CACI meeting all of these conditions, as detailed in USP Chapter <797>, is exempt from the requirement of placing the CACI in an ISO class 7 buffer area. For hazardous drug compounding, however, the compounding area must maintain negative pressure and have a minimum of 12 ACPH. A class II BSC has an open front and depends on an air barrier to prevent hazardous drug contamination from escaping the cabinet.45 This air barrier can be compromised by worker technique, allowing escape of the contaminated air.46 The design of this type of cabinet is questionable for product protection because the air barrier is composed of air coming from the buffer area around the BSC. As air is pulled into the BSC, poor air quality in the buffer area may compromise the ISO class 5 compounding environment within the class II BSC. A class II BSC or CACI not meeting the conditions listed in USP Chapter <797> must be placed in an area that is physically separated from other compounding areas and has air quality of ISO class 7. Optimally, this area should be at negative pressure relative to adjacent positive-pressure ISO class 7 or better ante-areas, thus providing inward airflow to contain airborne drug. Optimally, a PEC used for compounding sterile hazardous drug preparations should be 100% vented to the outside air through high-efficiency particulate air (HEPA) filtration.

All environments where sterile preparations are compounded must be provided with HEPA-filtered air from outside the environment. The PEC may not be the sole source of HEPA-filtered air and it may not provide more

Table 2. Comparison of the NIOSH, ASHP, and USP Chapter <797> Recommendations for the Hazardous Drugâ&#x20AC;&#x201C;Compounding Environment NIOSH

ASHP

USP Chapter <797>

Storage environment

Store hazardous drugs separately from other drugs in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.

Segregate hazardous drug inventory and store in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.

Hazardous drugs shall be stored separately from other inventory, preferably within a containment area such as a negative-pressure room.

Compounding

Prepare hazardous drugs in an area that is devoted to that purpose alone and is restricted to authorized personnel.

Hazardous drugs should be compounded in a controlled area where access is limited to authorized personnel trained in handling requirements.

Hazardous drugs shall be prepared in a PEC, which shall be placed in an ISO class 7 area that is physically separated from other preparation areas.

Ventilation

Where feasible, exhaust 100% of the filtered air to the outside.

Because of the hazardous nature of these preparations, a contained environment where air pressure is negative relative to that of the surrounding areas or that is protected by an air lock or anteroom is preferred.

Storage: area should have exhaust ventilation of at least 12 air changes per hour.

Compounding: optimally at negative pressure relative to adjacent positive-pressure ISO class 7 or better ante-areas.

ASHP, American Society of Health-System Pharmacists; ISO, International Organization for Standardization; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; USP, United States Pharmacopeia Based on references 23, 34, and 38.

than 50% of the ACPH in that environment. The ISO class 7 buffer area and ante-area must be supplied with HEPA-filtered air providing a total of at least 30 ACPH. Table 3 compares the NIOSH, ASHP, and USP Chapter <797> recommendations for hazardous drug PECs.

Work Practice Controls Work practices must be designed to minimize the generation of hazardous drug contamination and maximize the containment of inadvertent contamination that occurs during routine handling or in the event of a spill.

The compounding techniques described by Wilson and Solimando continue to be the standard for any procedure in which needles and syringes are used to manipulate sterile dosage forms of hazardous drugs.47 These techniques, when performed accurately, minimize the escape of drug from vials and ampules.

Many adjunct devices have been developed to reduce the generation of contamination during the compounding process. Vented needles with 0.2-micron hydrophobic filters were designed to reduce the powder and liquid drug residue that escapes from vials through standard vented needles. Dispensing pins with small spikes and hydrophobic filters were introduced to make the compounding process more efficient. One study documents

the effectiveness of one of these devices, but the investigators used only a visual inspection process because no sensitive drug assays were available at the time of the study.48 Since then, sensitive, drug-specific assays have been developed that provide a means to validate work practice controls at different work sites. The persistent presence of contamination in hospitals and pharmacies generated interest in an adjunct device, generically named by NIOSH in the 2004 Alert as a â&#x20AC;&#x153;closed-system drug-transfer deviceâ&#x20AC;? (CSTD). NIOSH defines a CSTD as a drug-transfer device that mechanically prevents the transfer of environmental contaminants into the system and the escape of hazardous concentrations of drug or vapor from the system.34 These systems provide some of the benefits of the earlier devices, but with the added protection that they can be locked into place on the drug vial. CSTD components also provide protection during the administration of I.V. push and I.V. infusion doses, which was previously unavailable.

Numerous studies using hazardous drug marker drugs have demonstrated the effectiveness of a CSTD in reducing hazardous drug contamination in the workplace.6,14,15 At clinical practice sites representing inpatient and outpatient compounding and

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Table 3. Comparison of NIOSH, ASHP, and USP Chapter <797> Recommendations for Primary Engineering Controls NIOSH

ASHP

USP Chapter <797>

Primary engineering controls

•A septic containment ventilation control class II BSC-type B2 is preferred.

• Class III BSC or CACI

•C lass II BSC-type B2 with outside exhaust is preferred.

• Total exhaust is required if the hazardous drug is known to be volatile.

• Class III BSC or CACI

•B SC or CACI that meets or exceeds the standards for CACI in USP Chapter <797>

Ventilation

•D o not use a ventilated cabinet that recirculates air inside the cabinet or exhausts air back into the room environment if a drug is volatile.

•W ithout special design considerations, class II BSCs are not recommended in traditional, positive-pressure clean rooms.

•B SCs and CACIs optimally should be 100% vented to the outside air through HEPA filtration.

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; HEPA, high-efficiency particulate air; NIOSH, National Institute for Occupational Safety and Health; USP, United States Pharmacopeia Based on references 23, 34, and 38.

administration, the implementation of a CSTD reduced surface contamination significantly compared with standard practice.6,14,15,49 USP Chapter <797> similarly defines CSTDs as “vialtransfer systems that allow no venting or exposure of hazardous substance to the environment.” USP Chapter <797> further states that CSTDs must be used within the ISO class 5 environment of a BSC or CACI. In facilities that prepare a low volume of hazardous drugs, the use of 2 tiers of containment (eg, a CSTD within a BSC or a CACI that is located in a non–negative-pressure room) is acceptable. The NIOSH Alert specifies that CSTDs should be used only within a ventilated cabinet.

Neither USP Chapter <797> nor NIOSH has developed performance standards for any device marketed as a CSTD. Because the configurations of available CSTDs vary from that of the tested device, it is unclear how effective these devices are in reducing environmental contamination resulting from the compounding and administration of hazardous drugs. Any device marketed as a CSTD should be clinically tested.

for Testing and Materials has developed a standard for testing chemotherapy gloves.50 There is no standard for chemotherapy gowns, but recommendations have been made based on several studies.51-53 See Table 4 for a comparison of PPE recommendations.

During sterile compounding, barrier garments must be worn to prevent the shedding of human skin and hair cells and the deposition of mucus or respiratory residue into the compounding area. USP Chapter <797> specifies that compounding garb must include the following: dedicated shoes or shoe covers, face masks, head and facial hair covers (eg, beard covers in addition to face masks), a nonshedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck, and sterile powder-free gloves.

Appropriate PPE must be worn when the sterile compounding of hazardous drugs is performed in a BSC or CACI and when CSTDs are used. PPE includes coated gowns, masks or respirators, eye protection, hair covers, shoe covers, and double gloving with sterile hazardous drug–tested gloves.

Personal Protective Equipment

New Technologies

In addition to environmental and engineering controls, PPE is required to provide a barrier between the health care worker and the hazardous drug during episodes of potential contact. This is especially important during administration, spill control, handling of drug waste, and handling of patient waste because no PECs are in place for these activities. All PPE should be selected for effectiveness. Glove and gown materials should be able to withstand permeation by a selection of hazardous drugs. Several hazardous drugs require nonaqueous diluents for patient use, which may permeate PPE more readily than others. The American Society

Technologic advances include robotic automation that can compound sterile doses of hazardous and nonhazardous drugs. By replacing the human compounder, these robots reduce the occupational exposure of health care workers during the compounding process. Robotic units provide contained ISO class 5 environments and use techniques to reduce the generation of hazardous drug residue during compounding. Robots operate with sophisticated mechanics and software and provide a degree of accuracy and patient safety not available with manual compounding. CytoCare from Health Robotics, IntelliFill Chemo from ForHealth Technologies, Inc, and

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Table 4. Comparison of NIOSH, OSHA, ASHP, And USP Chapter <797> Recommendations for PPE

General handling

NIOSH/OSHA

ASHP

USP Chapter <797>

•U se double gloving for all activities involving hazardous drugs.

•W ear double gloves for all activities involving hazardous drugs.

• Guidelines for the safe handling of hazardous drugs recommend the use of gowns for compounding in the BSC, administration, spill control, and waste management to protect the worker from contamination by fugitive drug generated during the handling process.

Hazardous drugs shall be handled with caution at all times with the use of appropriate chemotherapy gloves during receiving, distributing, stocking, taking inventory, preparing for administration, and disposal.

OSHA: • Protective equipment, including PPE for eyes, face, head, and extremities, protective clothing, respiratory devices, and protective shields and barriers shall be provided, used, and maintained in a sanitary and reliable condition wherever it is necessary by reason of hazards of processes or environment, chemical hazards, radiologic hazards, or mechanical irritants encountered in a manner capable of causing injury or impairment in the function of any part of the body through absorption, inhalation, or physical contact.

Receiving and storage

•W ear chemotherapy gloves, protective clothing, and eye protection when opening containers to unpack hazardous drugs.

• Gloves must be worn at all times when drug packaging, cartons, and vials are handled, including during the performance of inventory control procedures and the gathering of hazardous drugs.

Compounding

•W ear PPE (including double gloves and protective gowns) while reconstituting and admixing drugs.

• Make sure that gloves are labeled as chemotherapy gloves.

• Use disposable gowns made of polyethylene-coated polypropylene material (which is nonlinting and nonabsorbent).

•S elect disposable gowns of material tested to be protective against the hazardous drugs to be used.

• Coated gowns must be worn for no longer than 3 hours during compounding and changed immediately when damaged or contaminated.

• Gowns worn as barrier protection in the compounding of hazardous drugs must never be worn outside the immediate preparation area.

•W ear PPE (including double gloves, goggles, and protective gowns) for all activities associated with drug administration.

•G owns worn during administration should be changed when the patient care area is left and immediately if contaminated.

Administration

Sterile compounding: Shoe covers, head and facial hair covers (eg, beard covers in addition to face masks), and face masks; a nonshedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck; sterile powder-free gloves.

Hazardous drug compounding: • Appropriate PPE shall be worn during compounding in a BSC or CACI and during the use of CSTDs. PPE should include gowns, face masks, eye protection, hair covers, shoe covers or dedicated shoes, double gloving with sterile chemotherapy-type gloves, and compliance with manufacturers’ recommendations when a CACI is used.

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; CSTD, closed-system drug-transfer device; OSHA, Occupational Safety and Health Administration; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; PPE, personal protective equipment; USP, United States Pharmacopeia Based on references 22, 23, 34, and 38.

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g

15

RIVA (Robotic IV Administration) from Intelligent Hospital Systems all provide robotic solutions to the compounding of sterile preparations of hazardous drugs.

Like most technology, these robots are not perfect.

They require human staff to load and clean them. Hazardous drug contamination may be generated in the compounding environment and transferred to the final product. Cleaning of the compounding environments requires both disinfection and the decontamination of hazardous drug residue. No particular cleaner has been shown to effectively deactivate all known hazardous drugs,11 so routine cleaning and spill control are still challenges to the health care personnel working with these robots. The robots help only with the compounding process, leaving the workers administering hazardous drugs without protection. Spill control and waste handling also remain issues for human workers to address.

Conclusion Despite almost 3 decades of data on the adverse health effects of occupational exposure to hazardous drugs, skepticism about the risks continues, as evidenced by the failure to implement programmatic controls for reducing exposure. NIOSH has renewed its dedication to this health risk by continuing to promote worker awareness of safety. USP Chapter <797>

has elevated many of the NIOSH recommendations to a standard, ensuring both awareness and compliance with at least the compounding segment of safety program controls.

Each new generation of health care workers needs to be educated about the risks of handling hazardous drugs and the importance of training in the proper techniques to reduce their exposure. Employers and employees must implement all aspects of hazardous drug safety programs to reduce occupational exposure and its potential adverse effects.

Suggested Readings American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm.

2006;63(12):1172-1191.

National Institute for Occupational Safety and Health. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. DHHS (NIOSH) Publication No. 2004-165. Washington, DC: NIOSH; 2004. http://www.cdc.gov/niosh/docs/2004-165/.

Accessed March 5, 2009.

Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (OSHA Instruction CPL 2-2.20B CH-4). Washington, DC: Directorate of Technical Support, Occupational Safety and Health Administration; 1995:chap 21.

Polovich M, Whitford JM, Olsen M, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice.

3rd ed. Pittsburgh, PA: Oncology Nursing Press; 2009.

For full reference list, go to clinicaloncology.com

16

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g

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Martin D. Abeloff; James O. Armitage; John E. Niederhuber; Michael B. Kastan; W. Gillies McKenna

Carrying on the tradition established by its founding editor, the late Martin Abeloff, MD, the fourth edition of this respected reference synthesizes all of the latest oncology knowledge in one clinically focused, easy-to-use volume. It incorporates basic science, pathology, diagnosis, management, outcomes, rehabilitation and prevention—all in one convenient resource—equipping you to overcome your toughest clinical challenges. What's more, you can access the complete contents of this Expert Consult title online and tap into its unparalleled guidance wherever and whenever you need it most!

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Angiogenesis William D. Figg; Judah Folkman

In a 1971 issue of The New England Journal of Medicine, Judah Folkman, MD, proposed the theory that tumor growth is angiogenesis-dependent. This premise was the basis of this field of research and has become the focus of scientists worldwide.

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Atlas of Cancer

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The second edition of the Atlas of Cancer highlights the major features of current cancer management and clearly presents fundamental facts regarding our understanding of the etiology and pathophysiology of malignant disease.

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Acclaimed by the worldwide medical community as “the ultimate authority on cancer” (JAMA), Cancer: Principles and Practice of Oncology is now in its seventh edition. This completely revised, updated classic reflects the latest breakthroughs in molecular biology, cancer prevention and multimodality treatment of every cancer type.

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This book provides general guidelines for clinicians and practice administrators for approaching cost containment issues within a medical practice. Identifies key areas where costs are more likely to become unmanageable and offers solutions that have been successful in some practices.

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CO0309

CLINICAL TRIALS

Clinical Oncology News • MARCH/APRIL 2009

New Phase II and III Clinical Trials

Solid Tumors

Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to March 12, 2009. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Hematologic Malignancies

18

Protocol Type

Age

Protocol ID

Trial Sites

PET Imaging With [F-18] FLT & [F-18] FDG in Lung and Head and Neck Cancer Patients, Phase II/III

18 and over

FLT101

TX

Study to Compare CyberKnife Stereotactic Radiotherapy With Surgical Resection in Stage I NSCLC, Phase III

18 and over

Accuray STARS

FL

An Open-Label Study of QD Oral Administration of AV-951 in Subjects With NSCLC, Phase I/II

18 and over

AV-951-08-105

DC, NY

Study of Stereotactic Body Radiation Therapy Using Tomotherapy for Tumors of the Lung, Phase II

18 and over

INST 0810

NM

Study of Cetuximab With Platinum-Based Chemo as First-Line Treatment of Recurrent or Advanced NSCLC, Phase II

18 and over

AC01L08

TN

Dose-Escalating Study of the Safety and Efficacy of Patupilone in Patients With NSCLC, Phase II

18 and over

CEPO906A2209

KY, MO

Study of Stereotactic Body Radiotherapy in Patients With Node-Negative, Peripheral Stage I or II NSCLC, Phase II

18 and over

RPCI-I-124407

NY

Study of Trastuzumab, Cyclophosphamide, and Allogeneic Sargramostim (GM-CSF)-Secreting Breast Cancer Vaccine in Patients With High-Risk or Metastatic HER2/neu-Overexpressing Breast Cancer, Phase II

18 and over

JHOC-NA_00021048

MD

Study of Neoadjuvant Everolimus in Women With Resectable Breast Cancer, Phase II

18 and over

UMN-2005LS029

MN

Trastuzumab-MCC-DM1 vs. Capecitabine + Lapatinib in HER2-Positive Locally Advanced Cancer or MBC, Phase III

18 and over

TDM4370g

FL, IL, OH, TX

ThermoDox With Microwave Hyperthermia in Treatment of Breast Cancer Recurrence at the Chest Wall, Phase I/II

18 and over

105-08-201

FL

6 Week Treatment of Locally Advanced Breast Cancer With BIBW 2992 or Lapatinib or Trastuzumab, Phase II

18 and over

1200.44

TX

Study of Acolbifene Hydrochloride in Premenopausal Women at High Risk for Breast Cancer, Phase II

30 to 55

WCCC-UW-CO0610

KS, WI

Open-Label, Dose-Escalation Study of JI-101 in Patients With Advanced Solid Tumors, Phase I/II

18 and over

JI-101-001

AZ

A Study Evaluating the Efficacy and Safety of GDC-0449 in Patients With Advanced Basal Cell Carcinoma, Phase II

18 and over

SHH4476g

CA, FL, TN

Neoadjuvant Gemcitabine, Docetaxel and Capecitabine With Stereotactic Radiosurgery [pancreatic cancer], Phase II

18 and over

MCC-15587

FL

Intensity-Modulated Radiotherapy for the Pelvis Post-Hysterectomy, Phase I/II

NA

ID03-0047

TX

Continuing Access to AG-013736 (A406) for Patients Previously Receiving AG 013736 in Clinical Trials, Phase II

NA

A4061008

CA, IL, MI, WI

Neoadjuvant Weekly Ixabepilone for High-Risk, Clinically Localized Prostate Cancer, Phase II

Over 18

BrUOG-Pros-221

RI

Study of Gleevec and Paclitaxel in Recurrent Patients of Ovarian and Other Cancers of Mullerian Origin, Phase II

18 and over

06-226

NY

Efficacy and Safety and Pharmacokinetic Study of Avastin and Doxil in Ovarian Cancer, Phase II

18 and over

06-948

NM, NY

Sentinel Lymph Node Biopsy for Sebaceous Gland Carcinoma of Eyelid, Phase II

18 and over

2008-0266

TX

Medical Treatment of High-Risk Neurofibromas, Phase II

2 to 30

2008-260

MI

A Study of R1507 in Patients With Recurrent or Refractory Sarcoma, Phase II

2 and over

NO21157

MA, NE, UT

Gemcitabine, Oxaliplatin w/Erlotinib in Hepatocellular Cancer, Phase II

Over 18

INST OX-05-024

NM

Study of Epstein-Barr Virus-Specific Immunotherapy for Nasopharyngeal Carcinoma, Phase II

18 and over

08-292

MA

Sorafenib and Dacarbazine in Soft Tissue Sarcoma, Phase II

18 and over

08-068

NY

Study of Sunitinib Malate and Irradiated Allogeneic Lymphocytes in Patients With Metastatic Clear Cell RCC, Phase II

18 to 75

CINJ-080708

NJ MN

Endoscopic Therapy of Early Cancer in Barrett’s Esophagus, Phase II

18 and over

1399-05

Study of the MUC1 Peptide-Poly-ICLC Adjuvant Vaccine in Individuals With Advanced Colorectal Adenoma, Phase II

40 to 70

PRO07030214

PA

Study of 7-Day Erlotinib Before Surgery Followed by After-Surgery Erlotinib-Gemcitabine in Pancreatic Ca, Phase II

19 to 80

F080718006

AL

A Study Using Two Oral Chemotherapy Agents for Chronic Lymphocytic Leukemia (CLL), Phase I/II

18 and over

SCLL084993

CA

Study of Alemtuzumab and Rituximab in Patients With Previously Untreated B-Cell CLL, Phase II

Over 18

NU-04H6

IL

Open-Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of CC-4047 Alone or in Combination With Dexamethasone in Patients With Relapsed and Refractory Multiple Myeloma, Phase I/II

18 and over

CC-4047-MM-002

CL, MA, NJ

Combination of Revlimid, Melphalan and Dexamethasone as First-Line Treatment for Multiple Myeloma, Phase II

18 and over

07-919

NY

Pilot Study of Reduced-Intensity Conditioning Regimen Comprising Fludarabine Phosphate, Melphalan and Low-Dose Total-Body Irradiation Followed by Allogeneic Stem Cell Transplantation in Patients With Hematologic Malignancies or Bone Marrow Failure Disorders, Phase II

3 to 75

RPCI-I118807

NY

Temozolomide in Acute Myeloid Leukemia (AML) Patient Age ≥ 60 Years and Poor-Risk/Refractory Disease, Phase II

60 and over

SU-12142007-936

CA

Trial of MLN8237 in Adult Patients With AML and High-Grade Myelodysplastic Syndrome, Phase II

18 and over

C14005

NJ

Lenalidomide in Combination With Cyclosporine A in Patients With Myelodysplastic Syndromes, Phase II

18 and over

0810010063

NY

Bendamustine With Rituximab for Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Phase II

18 and over

PI-08904

SC

Temsirolimus for Relapsed/Refractory Hodgkin’s Lymphoma, Phase II

18 and over

201170

IL

Reduced Duration Standford V Chemotherapy With Low-Dose Tailored-Field Radiation for Favorable-Risk Pediatric Hodgkin Lymphoma, Phase II

21 and under

HOD08

TN

Lenalidomide and Rituximab in Patients With Relapsed or Refractory Follicular or Small Lymphocytic NHL Phase II

18 and over

UCD-197

CA

Study of Bortezomib, Pegylated Liposomal Doxorubicin Hydrochloride, and Rituximab in Patients With Relapsed or Refractory CD20-Positive Diffuse Large B-Cell Lymphoma, Phase II

18 and over

RPCI-I-136508

NY

Study to Evaluate Efficacy and Safety of P276-00 in Relapsed and/or Refractory Mantle Cell Lymphoma, Phase II

18 and over

P276-00/23/08

OH

Rituximab, Ifosfamide, Carboplatin and Etoposide Followed by Gallium Nitrate, Rituximab and Dexamethasone for Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Phase II

Over 18

200119

IL

Study of BL22 Immunotoxin in Patients With Relapsed or Refractory Hairy Cell Leukemia, Phase II

18 and over

NCI-09-C-0076

MD

CLINICAL TRIALS

Clinical Oncology News • MARCH/APRIL 2009

Protocol Type

Age

Supportive Care

Low-Dose Vs. Weight-Based IV Acyclovir Sodium as Herpes Simplex Virus Prophylaxis in Patients With Neutropenia, Phase III Adult

Protocol ID

Trial Sites

CCCWFU-98608

NC

Targeting Inattention in Childhood Cancer Survivors, Phase II

8 to 16

Pro00003249

NC

Pilot Study of Psilocybin in Patients With Clinically Significant Depression or Anxiety Secondary to Cancer, Phase II

21 to 70

JHOC-J0647

MD

Randomized Study of Lenalidomide With Versus Without Epoetin Alfa in Patients With Low- or Intermediate-1-Risk Myelodysplastic Syndromes and Symptomatic Anemia, Phase III

18 and over

ECOG-E2905

FL, IA, IL, ND, NJ, OH, PA, WI

Morphine Versus Methadone as First-Line Strong Opioid for Cancer Pain, Phase III

16 and over

2007-0477

TX

Randomized Pilot Study of Botulinum Toxin A in Patients With Painful Cutaneous Leiomyomas, Phase II

18 and over

NCI-09-C-0072

MD

Computerized Assessment for Patients With Cancer, Phase III

18 and over

08-284

MA, WA

A Study of Vascular Endothelial Growth Factor Inhibition in Patients With Unilateral Upper Extremity Lymphedema Following Treatment for Cancer, Phase II

18 and over

0811-15 / IUCRO-0248

IN

Sunitinib Trial Halted: Drug Improves PFS in Pancreatic Cancer

LOOKING FORWARD TO SEEING YOU AT

A

Phase III clinical trial of sunitinib malate (Sutent, Pfizer) has been stopped early after the drug demonstrated a significant benefit in patients with advanced pancreatic islet cell tumors, otherwise known as pancreatic neuroendocrine tumors.

SAVE THE DATE

HOPA June 17–20, 2009 Doral Marriott Hotel 4400 NW 87th Avenue Miami, Florida 33178

An independent Data Monitoring Committee (DMC) recommended halting the trial after concluding that the drug demonstrated greater progression-free survival than did placebo plus best supportive care in patients with pancreatic islet cell tumors.

Pfizer has notified clinical trial investigators involved in the trial and regulatory agencies of the DMC recommendations. Patients in the trial taking the placebo will be given the option to switch from placebo to sunitinib if they want. The full data set from this trial is being analyzed and more details will be presented at an upcoming scientific meeting.

This Phase III trial of sunitinib in patients with advanced pancreatic islet cell tumors was initiated based on the results of an earlier Phase II trial published in the Journal of Clinical Oncology (2008;26:3403-3410, PMID: 18612155) In contrast to exocrine pancreatic adenocarcinoma, pancreatic islet cell tumors are rare, indolent tumors of the endocrine pancreas with an annual incidence of five to 10 per million worldwide. Pancreatic islet cell tumors include insulinomas, glucagonomas and gastrinomas.

Current treatment options are limited.

Sunitinib is currently approved for advanced renal cell carcinoma and second-line gastrointestinal stromal tumor.

19

2009

Online registration available at www.hoparx.org. www.HopaRx.org | www.HopaU.org Jers erse ey y 08540 085 85 540 40 4 0 175 Wall Street, Princeton, New Jersey 877-467-2791

www.HopaUniversity.org

www.HopaU.org

HOPA UNIVERSITY

Educational Activities Now Available Seven educational programs are currently available on HOPA U at www.hopaU.org/activities.aspx.

Those who claimed credit for the live version of these programs are ineligible to claim credit for the online activity.

Original activity not based on a previous live program New Directions in Metastatic Renal Cell Carcinoma

Based on live programs at HOPA/ISOPP 2008 in Anaheim Integrating the Epothilones into Clinical Practice: Focus On Breast Cancer Optimizing Patient Adherence to Self-Administered Chemotherapy: Best Practices for Hematology/ Oncology Pharmacists

Targeted Drug Therapies for the Treatment of Non–SmallCell Lung Cancer Updates in Cancer Supportive Care: VTE, Tumor Lysis Syndrome, and Chemotherapy-Induced Nausea and Vomiting What’s New in the Management of Multiple Myeloma?

Based on a live program at HOPA 2007 in Denver Taking Aim at Multiple Targets: Oncology Pharmacist Perspectives on TKIs

20

POLICY & MANAGEMENT

Clinical Oncology News • MARCH/APRIL 2009

Healthcare Costs

COVERAGE continued from page 1 

most evident and acute need to have an updated compendium is in cancer care where you have a rapidly advancing field and life-threatening illnesses.”

Inclusion of the NCCN Compendium Dr. McGivney had long called for CMS to include a cancer-specific compendium as a reference. That happened when the NCCN Drugs and Biologics Compendium was accepted. Many oncologists hailed the move. Peter D. Eisenberg, MD, of California Cancer Care in Greenbrae, Calif., said the move was important because “the NCCN compendium and guidelines are easily accessible online.”

If a patient needs treatment, Dr. Eisenberg said, he or she can go online, check the NCCN standards and know if Medicare will cover it. “If I have read, or am acting

upon reliable information that suggests that, Avastin, for instance, has activity in glioblastomas, I want to be able to verify that easily and quickly.”

Leonard B. Saltz, MD, a gastrointestinal oncology specialist at Memorial Sloan-Kettering Cancer Center in New York City, and a member of the NCCN’s Colon, Rectal and Anal Cancers Panel, added that the NCCN compendium gives oncologists a say in the coveragedecision process.

“The people who are on this panel are taking that responsibility very seriously, and I’m sure that will continue to be the case. We need to be very aware that we can’t just say ‘well, there was an abstract showing a hint of activity and therefore we’ll put it in the guidelines because we want to be able to use it.’ We need to require compelling evidence that a drug or procedure works before adding it to the guidelines,” said Dr. Saltz. “But, if we continue to carefully and critically evaluate the evidence regarding usefulness of anticancer agents in particular indications, I think that will

Conflict of Interest in Creating Compendia

F

or publishers of the compendia that serve as references for physicians and guides for coverage by public and private insurers, potential for conflicts of interest abounds. But those behind the publications say they take the necessary steps to keep money from clouding their decision making.

“We have a long litany of processes to mitigate and decrease any bias in the development of NCCN [National Comprehensive Cancer Network] guidelines, and therefore in compendium recommendations,” said William T. McGivney, PhD, chief executive officer of the NCCN, which produces the NCCN Drugs & Biologics Compendium.

Several drug companies support the network’s Web site, and many members of the NCCN panels accept money from companies for their research as members of drug company speakers’ bureaus or as consultants. But, Dr. McGivney added, “We are also extremely open about who our clinicians work with, and that’s also on our Web site.”

Dr. McGivney said the compendium relies on input from dozens of members of dozens of panels and from member cancer centers, “so the ability for any one person to dominate the discussion is pretty small.”

Leonard B. Saltz, MD, a gastrointestinal oncology specialist at Memorial Sloan-Kettering Cancer Center in New York City and a member of the NCCN’s Colon, Rectal, and Anal Cancers Panel, said that organizing a panel of experts without ties to drug makers may be a disservice to patients.

“Anyone in private practice makes a portion of their living by prescribing these drugs, so they have an intrinsic conflict of interest. Most people in academia have industry-sponsored research, because that is who sponsors most research these days,” he said. “If we exclude all these people, who will have the expertise to evaluate which treatments are appropriate?”

Last year, the American Society of Health-System Pharmacists, publisher of the American Hospital Formulary Service Drug Information (AHFS DI), announced a partnership with the Foundation for Evidence-Based Medicine (FEBM) to expedite evaluation of off-label uses of drugs.

Under the plan, those seeking to have an off-label oncology use reviewed could submit an application to the FEBM with a $50,000 application fee. The AHFS would then review the evidence supporting the application, and its expert oncology committee would make a decision based on the risks and benefits of the drug. According to the rules of the AHFS, members of the expert committee are recused from an application if they have a potential for conflict of interest either with the drug under consideration or with a competitor product.

Gerry McEvoy, assistant vice president of drug information with the society, said the plan included “adequate firewalls to protect us from undue influence from the applicants.”

For example, he said, the FEBM received the applications, and “from the point of receipt of the application to the final determination, there was absolutely no communication between the applicant and AHFS staff or with our expert oncology committee.”

David Wilkins, public relations manager for the Healthcare business of Thomson Reuters, the publishers of Thomson Micromedex DRUGDEX, said that his company also makes transparency the focus of its efforts.

“To that end, we describe our off-label policy, editorial process, conflict-of-interest guidelines and external oncology review panel on our Web site.”

Yet Peter D. Eisenberg, MD, of California Cancer Care in Greenbrae, Calif., said ideally, all decisions would be evidence-based. “The real problem is that we haven’t done adequate studies to show if drugs are effective or not.”

Dr. Eisenberg stressed the importance of developing a national plan. “Wouldn’t it be nice if we could use the results from all the treatments we give folks as if they were clinical trials and actually learn whether the drugs had effectiveness or not? What we really need is a national system to measure clinical effectiveness.”

Dr. McGivney said the current system allows the experts to decide. “I would challenge anybody who has a diagnosis of cancer, or a loved one with a diagnosis of cancer, to tell me who better to make those decisions than world-leading thought leaders who have developed the literature and have dedicated their lives to improving therapeutics for patients,” he said.

—David Jakubiak

Four Compendia That Determine Reimbursement ❏ American Hospital Formulary Service Drug Information

❏ NCCN Drugs and Biologics Compendium ❏ Thomson Micromedex DRUGDEX ❏ Clinical Pharmacology

really help us make cancer care better.”

While the inclusion of the NCCN compendium has been big news, the other new compendia used to guide coverage decisions remain unknown to some clinicians. For example, Dr. Saltz said he learned of the others when asked about them by a reporter, and Dr. Eisenberg said, “I’m not so sure I’ve ever seen the other compendia.”

Compendia at Work Peter Ashkenaz, deputy director of media relations at CMS, said the four compendia are the American Hospital Formulary Service Drug Information (AHFS DI), which has been in use for years, and three new compendia: NCCN Drugs & Biologics Compendium, Thomson Micromedex DRUGDEX and Clinical Pharmacology. If any of the four compendia determine a “medically acceptable use for a drug or biologic,” it can be covered by CMS. Mr. Ashkenaz said this means that if a use appears in only one compendium, it can be covered, but added “if any has a ‘not recommended’ indication, it overrules any positive recommendation.”

While this seems straightforward, figuring out what is actually covered is not. For instance, the FDA has approved bevacizumab (Avastin, Genentech) for colorectal cancer, non-small cell lung cancer, and HER2negative breast cancer. If listing in a compendium allows coverage, CMS may now also cover the use of bevacizumab in specific tumor types, and as part of specific drug combinations for renal cell cancer, ovarian cancer and glioblastoma multiforme. Representatives at CMS, however, declined to confirm this change, saying that listing in a compendium does not guarantee that it will be covered, but only that an indication may be covered. In addition, CMS said they “do not have a list” of drugs they cover, because coverage decisions are made at the contractor level.

Dr. Saltz said this lack of clarity has caused confusion. “In theory, if it is in a compendia it is covered.

But we have been unable to get CMS to tell us what is covered,” he said.

Compendium Creation Every compendium used by CMS is developed in a unique way. The NCCN compendium is created based on the input of 44 panels, each with 20 to 30 members, and input from the network’s member institutions.

Clinical Pharmacology is published by the Tampa, Fla.–based Gold Standard company, which is owned

by Elsevier, a medical publisher based in Amsterdam, the Netherlands. Kathleen Vieson, vice president and director of clinical references at Gold Standard, said three people are primarily responsible for the publication’s oncology drug information: “the senior editor for oncology, a practicing clinical pharmacist who specializes in oncology and is a board-certified oncology pharmacist; the managing editor for clinical pharmacology, a clinical pharmacist who is a board-certified pharmacotherapy specialist; and the vice president and editor-in-chief for Gold Standard, a clinical pharmacist, who is the senior clinical drug informatics

POLICY & MANAGEMENT

Clinical Oncology News • MARCH/APRIL 2009

21

Healthcare Costs

content officer.”

Thomson Micromedex DRUGDEX is published by Thomson Reuters, a New York–based conglomerate that includes the Reuters news service and a wide range of financial and investment reports.

David Wilkins, public relations manager for the Healthcare business of Thomson Reuters, explained that an internal staff of clinicians who monitor developments of off-label treatments develops their compendium. According to the company’s Web site, they also consider external requests for review. According to Dr. Wilkins, the company has “an external review board made up of practicing clinicians who specialize in oncology,” and the publication is intended as an information resource to guide clinicians. “Its primary purpose is not for determining reimbursement under public or private health care insurance programs,” Dr. Wilkins said.

American Hospital Formulary Service Drug Information is the only remaining compendium named in the original federal legislation. In the past year, however, it launched a supplemental application process to address CMS’s request

that the compendium expedite off-label decisions.

To do this, it announced a partnership with the Foundation for Evidence-Based Medicine (FEBM). Under the plan, anyone seeking review of an off-label use can submit an application to the FEBM, along with a $50,000 application fee.

The American Hospital Formulary Service then reviews the evidence supporting the indication, consults an external panel of oncology experts and makes a determination of medical acceptance.

But, Gerry McEvoy, assistant vice president of drug information at the society, said that the agreement with the FEBM expired at the end of 2008.

“The landscape has changed since we first announced this new program, and we haven’t received any applications since the end of last year,” he said. “Of course, AHFS DI has a process in place, outside of this application process, to examine offlabel uses. We are re-examining the application process itself, and we haven’t made any determinations on how to best proceed with that.”

—David Jakubiak

Director of the Prostate Cancer Research Center (PCRC) Division of Hematology/Oncology Department of Medicine Cedars-Sinai is pleased to announce an outstanding Medical Oncology leadership opportunity in our Prostate Cancer Program. The successful candidate for the position will be an innovative leader with a background that spans a robust medical oncology clinical practice and an active laboratory. An outstanding group of peer program leaders add to the potential for a world class program. Focus of the position includes: 

Leading the development, coordination, and administration of the PCRC

 Maintaining an active research program in prostate cancer, creating new opportunities for basic and clinical prostate cancer research, publications in peer reviewed journals/publications; cancer research grant submittals to various federal and state granting agencies and pharmaceutical companies, and actively participating in philanthropic endeavors to enhance the Center.  Overseeing and maintaining quality control at the Center in order to provide the highest standard of care to both the inpatient and outpatient populations, and to attract physicians of exceptional ability to the Medical Center. 

Establishing training and procedural criteria and standards for performing prostate cancer clinical research.

 Responsible for the development and strengthening of an active teaching program in urologic malignancies within the Division, with activities that would include educational programs such as teaching rounds, formal rounds and lectures to medical students, house staff, fellows and other attending staff.  Works closely with the Directors of the Hematology/Oncology Fellowship Program and the Medicine Residency Program to optimize the knowledge and experience of students, house staff, and fellows in urologic malignancies, and is involved in the recruitment of research and clinical fellows Ideal candidates will demonstrate the following qualifications:        

Medical Degree from an accredited medical school Board Certification (or eligibility) in General Internal Medicine and in the subspecialty of Hematology/Oncology.

Eligible for an unrestricted California license as Physician Successful application for CSMC Medical Staff Membership Demonstrated evidence of focus in prostate cancer A published author of high value peer reviewed articles Demonstrated ability to serve as principal investigator for peer reviewed funding A track record of excellence in teaching, patient care and administration

Cedars-Sinai, a tertiary acute care academic medical center is proud to be on the list of “America’s Best Hospitals” as ranked by US News and World Report. If you are interested in this opportunity to join a flourishing clinical, teaching and research environment, please send your curriculum vitae to: Search Committee Chairman, Dr. Steven Piantadosi c/o Patricia Carson 8700 Beverly Boulevard, 5th Floor, South Tower, 5724 ~ Los Angeles, California 90048 Email: carsonp@cshs.org CEDARS-SINAI ENCOURAGES AND WELCOMES DIVERSITY IN THE WORKPLACE. AA/EOE

IN BRIEF

Blood Transfusions To Treat Anemia Increase Risk for Clots

W

hether their doctors use blood transfusions or erythropoiesis-stimulating agents (ESAs) to treat anemia, patients with cancer have a similarly increased risk for blood clots, according to a recent study. The findings, published in a recent issue of the Archives of Internal Medicine (2008;168:2377-2381), are not good news for doctors who want to treat anemia safely.

“The purpose of doing this study was to evaluate outcomes in cancer patients receiving transfusions, since transfusions are being proposed as an acceptable alternative to ESAs in treating cancer-induced anemia,” said Alok Khorana, MD. “Little is known about the influence of transfusions on outcomes, although studies from critically ill patients suggest that they may have an adverse influence. Our analysis, with several limitations, also suggests adverse outcomes for cancer patients getting transfusions.” Dr. Khorana, associate professor of medicine, James P. Wilmot Cancer Center and the University of Rochester School of Medicine and Dentistry, in New York, who is lead author of the study, says clinicians should be cautious in the use of transfusions and search for ways to reduce patients’ risk for blood clots.

In the retrospective cohort study, researchers used the discharge database of the University HealthSystem Consortium to investigate the associations between transfusions and venous thromboembolism, arterial thromboembolism and mortality in hospitalized patients with cancer. The database included information on more than 500,000 people hospitalized at 60 medical centers from 1995 to 2003.

Of these patients, 70,542 (14.1%) received at least one red blood cell (RBC) transfusion, and 15,237 (3.0%) received at least one platelet transfusion. Of the patients who received RBC transfusions, venous thromboembolism developed in 7.2% and arterial thromboembolism developed in 5.2%. These percentages are significantly greater than the rates of 3.8% and 3.1%, respectively, documented in hospitalized patients with cancer not receiving transfusions (P<0.001). The figures, however, are comparable with data for ESAs, Dr. Khorana noted.

In a multivariate analysis, RBC transfusion (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.53-1.67) and platelet transfusion (OR, 1.20; 95% CI, 1.11-1.29) were independently associated with an increased risk for venous thromboembolism. Both RBC transfusion (OR, 1.53; 95% CI, 1.46-1.61) and platelet transfusion (OR, 1.55; 95% CI, 1.40-1.71) were also associated with an increased risk for arterial thromboembolism (P<0.001 for each). Furthermore, transfusions were associated with an increased risk for in-hospital mortality (RBCs: OR, 1.34; 95% CI, 1.29-1.38; platelets: OR, 2.40; 95% CI, 2.27-2.52; P<0.001).

“We believe caution is necessary before substituting transfusions for ESAs,” said Dr. Khorana. “In terms of clot prevention, several studies are evaluating primary prophylaxis with anticoagulants, but this is still not standard of care. Both physicians and providers should be aware of the risk for clots and the warning signs/symptoms thereof.”

—Kate O’Rourke

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22

SUPPORTIVE CARE

Clinical Oncology News • MARCH/APRIL 2009

Pain Management

RISK MANAGEMENT

Table. Opioids Required To Have Risk Evaluation and Mitigation Strategies (REMS) Brand Name Products

continued from page 1 

few details about the sweeping program, which affects many of the most widely used branded and generic opioids: oxycodone, oxymorphone, hydromorphone, fentanyl tablets and transdermal patches, morphine and methadone. Officials said the products on the list were largely extended-release formulations of opioids, which are more likely to cause serious adverse reactions and death in patients who misuse them than immediate-release formulations.

“There are concerns about physicians prescribing these drugs to patients who are inappropriate,” said John Jenkins, MD, director of the Office of New Drugs in the FDA Center for Drug Evaluation and Research.

“We are focusing on extended-release formulations because they generally contain higher doses.”

Trade Name

Applicant/Sponsors

Fentanyl

Duragesic Extended Release Transdermal System

Ortho-McNeil-Janssen

Hydromorphone

Palladone Extended Release Capsulesa

Purdue Pharma

Methadone

Dolophine Tablets

Roxane Laboratories

Morphine

Avinza Extended Release Capsules

King Pharmaceuticals

Morphine

Kadian Extended Release Capsules

Actavis

Morphine

MS Contin Extended Release Tablets

Purdue Pharma

Morphine

Oramorph SR Sustained Release Tablets

Xanodyne Pharmaceuticals

Oxycodone

OxyContin Extended Release Tablets

Purdue Pharma

Oxymorphone

Opana ER Extended Release Tablets

Endo Pharmaceuticals

Generic Products

Impact on Oncologists Dr. Jenkins said the risk management initiative will focus on educating patients as well as prescribers of opioids about the hazards of misuse. One component of the plan will be additional “training” of physicians who write orders for opioids, although the nature of such training is unclear.

One aspect of existing FDA risk management programs—called Risk Minimization Action Plans (RiskMAPs)—is the use of restricted distribution systems. These systems limit access to drugs for target populations and often include mandatory registries of patients, prescribers and pharmacists, in addition to patient monitoring. “It is likely [that] legitimate patients will see new procedures” as part of the new program, Dr. Jenkins said.

“The problems with opioid prescribing are not arising from the treatment of cancer pain, but this [REMS] is highly relevant to oncologists for two reasons,” commented Michael Fisch, MD, associate professor of general oncology at The University of Texas M.D. Anderson Cancer Center, Houston. “One, the hassle factor associated with these new opioid-prescribing programs will certainly affect oncology practice, and two, cancer survivors with chronic pain can be problematic when it comes to deciding how appropriate it is to prescribe strong opioids, how long those drugs should be prescribed and who are the most appropriate providers for ongoing assessment of such patients.”

According to John Dombrowski, MD, director of the Washington Pain Center, in Washington, D.C., practicing sensible medicine with opioids is not difficult. What’s required is the discipline to closely track a patient’s use of the drugs—counting pills, checking urine for signs of abuse and ordering smaller numbers of high-dose pills at a time to deter the sale or diversion of the medication.

Generic Name

a

Generic Name

Drug Name

Applicant/Sponsors

Fentanyl

Fentanyl Extended Release Transdermal System

Actavis

Fentanyl

Fentanyl Extended Release Transdermal System

Lavipharm Labs

Fentanyl

Fentanyl Extended Release Transdermal System

Mylan Technologies

Fentanyl

Fentanyl Extended Release Transdermal System

Teva Pharmaceuticals

Fentanyl

Fentanyl Extended Release Transdermal System

Watson Pharmaceuticals

Methadone

Methadose Tablets

Mallinckrodt

Methadone

Methadone HCl Tablets

Mallinckrodt

Methadone

Methadone HCl Tablets

Sandoz

Morphine

Morphine Sulfate Extended Release Tablets

Endo Pharmaceuticals

Morphine

Morphine Sulfate Extended Release Tablets

KV Pharmaceuticals

Morphine

Morphine Sulfate Extended Release Tablets

Mallinckrodt

Morphine

Morphine Sulfate Extended Release Tablets

Watson Labs

Oxycodone

Oxycodone Extended Release Tablets

Mallinckrodt

Oxycodone

Oxycodone Extended Release Tabletsb

Impax Labs

Oxycodone

Oxycodone Extended Release Tabletsb

Teva Pharmaceuticals

No longer being marketed, but is still approved.

b

Discontinued products.

Source: http://www.fda.gov/cder/drug/infopage/opioids/Opioid_Products_chart.htm

Also important are frank conversations with patients before and after opioids have been prescribed for them.

“If you talk to your patients, you can pretty much get an idea very quickly how they use the medication,” said Dr. Dombrowski. “If they say they don’t notice much of a difference in what they can do even though they’re taking this very powerful drug, why give it?”

Largest Risk Plan Ever The REMS plan, announced in February, is the largest of its kind to date, covering 24 drugs from 16 manufacturers that in 2007 accounted for 21 million prescriptions involving 3.7 million unique patients, the FDA said. The plan dwarfs similar programs for isotretinoin, thalidomide (Thalomid, Celgene), alvimopan (Entereg, Adolor) and other drugs, officials said.

According to the FDA Office of Surveillance and Epidemiology, as of February 2007 some type of risk management program was in place for 30 drugs, and at least nine of these were opioids. Officials, however, have said the existing risk management programs

“have not met the criteria we would like to see.”

Drug makers have been working for some time to create REMS for opioids under development, so the FDA mandate was expected. The agency’s policy, however, also applies to products already on the market, which officials said would require relabeling of approved drugs. Products with risk management plans are required to carry clear statements to patients about specific risks of the medications.

Meanwhile, companies have been approaching the abuse issue from a pharmacologic angle, developing products they hope to market as having features that deter abuse and prevent tampering. This strategy, however, has been met with skepticism from the FDA, which has rejected every one of the applications—from King, Abbott and Purdue—it has reviewed so far.

To fill out the details of the new opioid risk management program, the FDA will hold several meetings of “stakeholders”—physicians, industry and patient groups—starting in early March, Dr. Jenkins said.

—Adam Marcus and Gabriel Miller

PRN Eye on the Community Oncologist

Community Oncologist James Radford, MD, Honored

T

he Association of Community Cancer Centers (ACCC) has honored James E. Radford Jr., MD, with the David King Community Clinical Scientist Award.

Dr. Radford leads the Cancer Research Program at the Margaret R. Pardee Memorial Hospital in Hendersonville, N.C. He also is a medical oncologist in private practice with Hendersonville Hematology and Oncology, PLLC. Dr. Radford received the award for

spearheading efforts at the Margaret R. Pardee Memorial Hospital Cancer Research Program to recruit older patients to clinical trials. Under Dr. Radford’s leadership, Pardee’s cancer research program has achieved an exceptional record of cancer clinical trial participation.

In 2008, a record 64 new patients were enrolled in 17 different studies.

These patients represent 11% of the

number of new cancer patients (582) diagnosed and treated at Pardee Hospital. At present, 50 separate national (and, in some cases, international) clinical trials are open locally to patients with 14 different types of cancer.

The David King Community Clinical Scientist Award, presented at the ACCC’s recent annual meeting, recognizes active community clinical research leaders. Award winners have demonstrated

leadership in the development, participation and evaluation of clinical studies and/or are active in the development of new screening, James E. risk assessment, treat- Radford Jr., MD ment or supportive care programs for cancer patients.

The award is given annually.

Vectibix® (panitumumab) Injection for Intravenous Use Brief Summary of Prescribing Information.

For complete prescribing information consult official package insert.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. [see Warnings and Precautions and Adverse Reactions]. Although not reported with Vectibix®, fatal infusion reactions have occurred with other monoclonal antibody products. [see Dosage and Administration].

INDICATIONS AND USAGE Vectibix® is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Preparation and Administration].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions.

Dose Modifications for Infusion Reactions [see Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

• Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions.

Dose Modifications for Dermatologic Toxicity [see Adverse Reactions] • Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix®.

• If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix®, treatment may be resumed at 50% of the original dose.

– If toxicities recur, permanently discontinue Vectibix®.

– If toxicities do not recur, subsequent doses of Vectibix® may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached.

Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus.

Preparation Prepare the solution for infusion, using aseptic technique, as follows: • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Although Vectibix® should be colorless, the solution may contain a small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates (which will be removed by filtration; see below). Do not shake. Do not administer Vectibix® if discoloration is observed.

• Withdraw the necessary amount of Vectibix® for a dose of 6 mg/kg.

• Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL. • Mix diluted solution by gentle inversion. Do not shake.

Administration • Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter.

• Vectibix® must be administered via infusion pump.

– Flush line before and after Vectibix® administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Vectibix® with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab.

– Infuse over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. Doses higher than 1000 mg should be infused over 90 minutes.

Use the diluted infusion solution of Vectibix® within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Discard any unused portion remaining in the vial.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Dermatologic Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported. Withhold Vectibix® for severe or life-threatening dermatologic toxicity [see Boxed Warning, Adverse Reactions, and Dosage and Administration].

Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3–4).

Across all clinical studies, severe infusion reactions occurred with the administration of Vectibix® in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension [see Boxed Warning and Adverse Reactions]. Although fatal infusion reactions have not been reported with Vectibix®, fatalities have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix® [see Dosage and Administration].

Increased Toxicity With Combination Chemotherapy Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix®-treated patients included rash/dermatitis/acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs <1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 4%) and included fatal events in three (<1%) Vectibix®-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Pulmonary Fibrosis Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patients is uncertain.

One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix® in combination with chemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix®. The second case was characterized by cough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix® as monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix® in combination with chemotherapy. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

Electrolyte Depletion/Monitoring In Study 1, median magnesium levels decreased by 0.1 mmol/L in the panitumumab arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®.

In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed.

Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

EGF Receptor Testing Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix® therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage, and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit.

Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix® and for full instructions on assay performance.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning and Warnings and Precautions] • Infusion Reactions [see Boxed Warning and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix® were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis.

Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy [see Warnings and Precautions].

The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients with a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix® Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* Body System All Grades Grade 3–4 All Grades Grade 3–4 % % % % Body as a Whole Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Acneiform Dermatitis 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0.

Dermatologic, Mucosal, and Ocular Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to: conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced a NCI-CTC grade 3 event of mucosal inflammation.The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions].

Median time to the development of dermatologic, nail, or ocular toxicity was 14 days; the time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported.

Infusion Reactions Infusional toxicity was defined as any event described at any time during the clinical study as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration].

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity.The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%).

For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10 of the 613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies.

No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with Vectibix®.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring.

[See Reproductive and Developmental Toxicology]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers It is not known whether panitumumab is excreted into human milk; however human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients.

Geriatric Use Of 229 patients with mCRC who received Vectibix® in Study 1, 96 (42%) were ≥age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix® between these patients and younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17 -estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment.A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified.The effects of panitumumab on male fertility have not been studied. However, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight).

Animal Toxicology and/or Pharmacology Weekly administration of panitumumab to cynomolgus monkeys for 4 to 26 weeks resulted in dermatologic findings, including dermatitis, pustule formation and exfoliative rash, and deaths secondary to bacterial infection and sepsis at doses of 1.25 to 5-fold higher (based on body weight) than the recommended human dose.

Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20–50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).

PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning and Warnings and Precautions], • Persistent or recurrent coughing, wheezing, or dyspnea [see Warnings and Precautions], • Pregnancy or nursing [see Use in Specific Populations].

Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations].

This brief summary is based on the Vectibix® prescribing information v4, 6/2008.

Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, as well as other patents or patents pending. © 2006–2008 Amgen Inc.All rights reserved.

Important Safety Information Including Boxed WARNINGS: Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy.

WARNING:DERMATOLOGICTOXICITYandINFUSIONREACTIONS

The first fully human* anti-EGFR monoclonal antibody

DermatologicToxicity:Dermatologictoxicitiesoccurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤grade 2 within1month,permanentlydiscontinueVectibix®.The clinical manifestations included, but were not limited to, dermatitis acneiform,pruritus,erythema,rash,skin exfoliation, paronychia, dry skin, and skin fissures.

Subsequenttothedevelopmentofseveredermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported.

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm,andhypotension.Althoughnotreported with Vectibix®, fatal infusion reactions have occurred withothermonoclonalantibodyproducts.Stopinfusion if a severe infusion reaction occurs. Depending on the severityand/orpersistenceofthereaction,permanently discontinue Vectibix®.

* Correlation with safety andefficacyisunknown

Vectibix®isindicatedasasingleagentforthetreatmentofEGFR-expressing,metastaticcolorectalcarcinoma (mCRC)withdiseaseprogressiononorfollowingfluoropyrimidine-,oxaliplatin-,andirinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-freesurvival(PFS).Currently,nodatademonstrateanimprovementindisease-relatedsymptomsor increased survival with Vectibix®.

Basedonindependentreviewofdiseaseprogression, a statistically significant prolongation in PFS was observed with Vectibix®1 100%

Q2Wdosing,typicallyadministered over 60 minutes (doses >1000 mg administered over 90 minutes), with no loading dose required† 3 available vial sizes: 400 mg (20 mL), 200 mg (10 mL), 100 mg (5 mL)

Vectibix® + BSC‡ (n=231) (Mean PFS: 96 days)

80%

BSC‡ Alone (n=232) (Mean PFS: 60 days)

70% 60%

P < 0.0001

50%

†

40% 30% 20%

Dose modifications may be needed if toxicity occurs; appropriate medical resources for the treatment of severe infusion reactions should be available.

Reference: 1. Vectibix® (panitumumab) prescribing information. Amgen.

10% 0%

Convenient dosing1

Kaplan-Meier Estimate of PFS Time

90%

Proportion Event Free

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of Vectibix® to thecombinationofbevacizumabandchemotherapyresulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions.

In a single-arm study of 19 patients receiving Vectibix® in combinationwithIFL,theincidenceofNCI-CTCgrade3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Pulmonary fibrosis occurred in less than 1% (2/1467) of patientsenrolledinclinicalstudiesofVectibix®.Following the initial fatality, patients with a history of interstitial pneumonitis,pulmonaryfibrosis,evidenceofinterstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in such patients is uncertain.PermanentlydiscontinueVectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

In the randomized, controlled clinical trial, median magnesiumlevelsdecreasedby0.1mmol/LintheVectibix® arm.Additionally,hypomagnesemia(NCI-CTCgrade3or4) requiringelectrolyterepletionoccurredin2%ofpatients 6 weeks or longer after the initiation of Vectibix®. In some patients,bothhypomagnesemiaandhypocalcemiaoccurred.

Patients’electrolytesshouldbeperiodicallymonitoredduring andfor8weeksafterthecompletionofVectibix® therapy, and appropriate treatment instituted, as needed.

Exposuretosunlightcanexacerbatedermatologictoxicity.It isrecommendedthatpatientswearsunscreenandhatsand limit sun exposure while receiving Vectibix®.

Dermatologic, mucosal, and ocular toxicities were also reported.

Adequatecontraceptioninbothmalesandfemalesmustbe used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy.

ThemostcommonadverseeventsofVectibix®areskinrash withvariablepresentations,hypomagnesemia,paronychia, fatigue,abdominalpain,nausea,anddiarrhea,including diarrhea resulting in dehydration. The most serious adverseeventsofVectibix®arepulmonaryfibrosis,severe dermatologictoxicitycomplicatedbyinfectioussequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks

‡

best supportive care

Nodifferenceinoverallsurvivalobservedbetweenstudyarms ©2008 Amgen. All rights reserved.

41900-B

7- 0 8

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