Clinical Oncology News - Jul/Aug 2009 - Vol. 4, No. 3

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Advances in Cancer Care CLINICALONCOLOGY.COM â&#x20AC;˘ JULY/AUGUST 2009 â&#x20AC;˘ Vol. 4, No. 3

HEMATOLOGIC DISEASE

4

Richard Stone, MD, and Jennifer Brown, MD, PhD, highlight ASCO meeting news.

SOLID TUMORS

7

Maurie Markman, MD, discusses practice-changing ovarian cancer news.

10

Bevacizumab, pazopanib ripe for approval in RCC, says expert.

FDA NEWS

14

Pemetrexed gets fourth indication. Opioid gets green light.

PARP-1 Inhibitors Touted as Next Big Breakthrough

Maintenance Therapy in NSCLC:

Paradigm Shift in Care?

Orlando, Fla.â&#x20AC;&#x201D;PARP-1 inhibitors have shown strong potential to treat challenging forms of cancer, according to three studies presented at the annual meeting of the American Society of Clinical Oncology (ASCO). In a Phase II study, PARP inhibitors increased overall survival by roughly 50% in patients with metastatic, triple-negative breast cancer. In another Phase II study of patients with BRCA-deficient advanced breast cancer, PARP-1 inhibitors resulted in a progression-free survival duration of 5.7 months, a PFS not usually seen in a population with very limited treatment options. And in a third study, PARP inhibitors showed promise for the treatment of relapsed ovarian cancer. â&#x20AC;&#x153;[PARP inhibition] is an area that will explode in the next year or two,â&#x20AC;? see PARP, page 9

SUPPORTIVE CARE

22

Is VKORC1 test needed in all patients receiving warfarin?

22

Interventional pain techniques effective in children

EDUCATIONAL REVIEWS

Treatment Options for Platinum-Sensitive Recurrent Ovarian Cancer After page 6.

Guide to the Prevention Of Chemotherapy Medication Errors: Part 1 After page 14.

WWW.CMEZONE.COM

Orlando, Fla.â&#x20AC;&#x201D;Results from three Phase III trials have shown that maintenance therapy provided after firstline chemotherapy, but before disease progression, can improve progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC). In the one trial that had a sufficient number of events to analyze overall survival (OS), this was increased, too. In July, the results of this third trial sparked the FDA to approve pemetrexed (Alimta, Eli Lilly) as maintenance therapy for locally advanced or metastatic NSCLC,

specifically for patients with a nonsquamous histology whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. The drug is not approved for the treatment of patients with squamous cell NSCLC. Each of the studies, presented at the annual meeting of the American Society of Clinical Oncology (ASCO), met its primary end point, leading at least one of the lead authors to characterize the results as a potential paradigm shift in care of advanced NSCLC. Although the discussant, see MAINTENANCE, page 6

ADVISORY BOARD EDITORIAL

The Impact of LBA4 On Clinical Trials And Patient Care

POLICY & MANAGEMENT

O

ne of the most anticipated presentations at the annual meeting of the American Society of Clinical Oncology (ASCO) was the long-awaited results of NSABP C-08 (abstract LBA4), which tested the efficacy of bevacizumab (Avastin, Genentech) as adjuvant therapy in stages II and III colon cancer patients. In this Phase III trial, 2,710 patients were randomized to a standard arm of six months of adjuvant oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (modified FOLFOX6) with or without bevacizumab (5 mg/kg), with see IMPACT, page 12

Oncology Practices Struggle To Weather Financial Storm National Harbor, Md.â&#x20AC;&#x201D;A few months ago, Cliff Goodman, PhD, senior vice president of the Lewin Group, was stressed out. He serves on the board of directors at a mid-size oncology practice in the Midwest and the practice was in â&#x20AC;&#x153;serious financial trouble.â&#x20AC;? â&#x20AC;&#x153;We are having trouble securing enough reimbursement to cover costs. I have lost some of my workforce. The competition recently acquired some of this big-ticket technology and is marketing in the community. And my accountant is telling me that I canâ&#x20AC;&#x2122;t afford to buy that CT scanner our staff

McMahonMedicalBooks.com Targeted Cancer Therapy Razelle Kurzrock; Maurie Markman For more information, see page 13.

is demanding,â&#x20AC;? Dr. Goodman said.

His oncology practice is not aloneâ&#x20AC;&#x201D;practices around the country are struggling.

Economic Woes One big challenge is the purchase of big-ticket items when cash flow is a problem. This is particularly problematic for oncology centers that have radiation oncology departments. â&#x20AC;&#x153;I think physicians started out saying, â&#x20AC;&#x2DC;we are going to add this service.â&#x20AC;&#x2122; [They] struggled with the cost of a startup and, like a rat on the see FINANCIAL STORM, page 3

NEW PRODUCT INDICATION Alimta from Eli Lilly approved for maintenance therapy in NSCLC. See page 14.

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POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Finance

FINANCIAL STORM continued from page 1

wheel, they have to replace their equipment because the guy down the street replaced his equipment and is now advertising that he has better equipment,â&#x20AC;? said Ed Braud, MD, a medical oncologist at ACT Medical Group in Rockford, Ill. Other oncologists agree. â&#x20AC;&#x153;When a radiation oncologist comes and asks you for $50,000, that is chump change to themâ&#x20AC;&#x201D;that is not chump change to any other department in the hospital,â&#x20AC;? said Richard Reiling, MD, medical director of the Cancer Center at Presbyterian Hospital, Novant Health, in Charlotte, N.C.

Staffing Shortages Another problem exacerbated by the current recession is staffing shortages, a problem many might find odd given the growing unemployment crisis. In many cases, however, a cancer center staff member quits because his or her spouse has been laid off and the couple must relocate because of a dearth of jobs in the area. Oncology practices are left hangingâ&#x20AC;&#x201D;they cannot easily find replacements for credentialed staff, such as nurses and physiatrists. This is particularly true in oncology practices in the more remote areas of the United States, where skilled individuals with the degrees necessary to do the work are not available. â&#x20AC;&#x153;In terms of the workforce, particularly in Richmond, Virginia, over the last several months, we have been hit very hard,â&#x20AC;? said Tom Gallo, executive director of the Virginia Cancer Institute, the largest medical oncology practice in Virginia. He said that Richmondarea companies, such as Circuit City, Land America Financial Group and Chesapeake Paper, are just a few of the casualties of the economic downturn. â&#x20AC;&#x153;Our unemployment rate has swung very dramatically,â&#x20AC;? Mr. Gallo said. Virginia Cancer Institute has experienced

TM

a shortage of oncologists, nurses and other trained oncology staff. â&#x20AC;&#x153;Nurse practitioners have certainly been a tremendous complement to the practice, but finding those professionals who are trained in oncology is also difficult. One of the indirect things we have seen [from the recession] is losing staff because many of our employees are from two-earner families and their spouses have lost their job (forcing a relocation),â&#x20AC;? said Mr. Gallo.

Many oncologists echo this sentiment. â&#x20AC;&#x153;Radiation therapy technicians are hard to get,â&#x20AC;? said Dr. Reiling. â&#x20AC;&#x153;Physicists are hard to get.â&#x20AC;? At a presentation at the annual meeting of the American Association of Community Cancer Centers (ACCC) held in March, Dr. Braud asked the audience how many were looking for help in their office. Roughly 50% of the audience members raised their hands.

Solutions So, how do cancer centers adjust to the changing economy? â&#x20AC;&#x153;That is a loaded question because the economy is a floating boat in a stormy sea and itâ&#x20AC;&#x2122;s going up and down,â&#x20AC;? said Dr. Reiling, speaking at the ACCC meeting. â&#x20AC;&#x153;I donâ&#x20AC;&#x2122;t think there is anyone in this group who has not cut off all travel and all capital expenditures.â&#x20AC;?

This will have serious implications for the future, especially in light of the fact that the cancer burden is only expected to increase. A recent study in the Journal of Clinical Oncology revealed that over the next 20 years, the number of new cancer cases diagnosed annually in the United States will increase by 45% (2009; Epub ahead of print, PMID: 19403886). â&#x20AC;&#x153;We are not going to be able to handle this load when we

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD

Genitourinary Cancer

ADVISORY BOARD

Ronald M. Bukowski, MD

Bioethics

Gynecologic Cancer

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

Maurie Markman, MD

Community Oncology

Lung, and Head and Neck Cancers

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

Edward S. Kim, MD

Hematologic Malignancies

Lung Cancer, Emesis

get all 40 billion people into the system and all the baby boomers are coming in and testing for cancer,â&#x20AC;? Dr. Reiling said.

Mr. Gallo said his practice has responded to the economy and workforce shortage problem by pooling resources and relying on mid-level practitioners. â&#x20AC;&#x153;One thing we have done is outsourced our lab service,â&#x20AC;? said Mr. Gallo. â&#x20AC;&#x153;I am strictly a medical oncology practice with four offices and we ran a lab internally for years.

From a financial point of view, it was a marginal or break-even [venture]. Eighteen months ago, we decided to contract with an outside provider to rent space in our office and provide for lab services. Itâ&#x20AC;&#x2122;s a national program. They have training programs and access to a much wider pool of talent than we had individually.â&#x20AC;?

The second way his office has responded is by adding mid-level practitioners. â&#x20AC;&#x153;Over the last seven years, we have added mid-level practitioners. In 2001, we were probably a 12-doctor practice with no mid-levels and now we have 15 full-time doctors and six mid-level practitioners in order to supplement the increased volume,â&#x20AC;? said Mr. Gallo.

Dr. Goodman said that, in these tough economic times, pooling resources and drawing on the capacity of larger organizations should provide practices with more flexibility and depth. Struggling clinics need to explore these and other alternatives to stay afloat and competitive right now.

To weigh in and discuss how your practice is reacting to the economic crisis, visit www.clinicaloncology.com and enter your thoughts in the comment section next to this story online.

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Multiple Cancers

Experts Highlight Hematology News From ASCO Refining Prognostics In AML and Related Disorders

Richard Stone, MD, highlights news on acute leukemias, chronic myelogenous leukemia and myelofibrosis. Dr. Stone is director of the Adult Leukemia Program, Dana-Farber Cancer Institute, and a professor of medicine, Harvard Medical School, both in Boston.

A

randomized trial of anthracycline dose intensification during induction of younger patients with acute myeloid leukemia has revealed that tweaking the dose can increase survival by 8 months (abstract 7003). The study was conducted by the Eastern Cooperative Oncology Group (ECOG; study E1900).

Cytarabine (100 mg/m2/d) + daunorubicin (90 mg/m2/d) Cytarabine (100 mg/m2/d) + daunorubicin (45 mg/m2/d)

25

23.7

20

15.7 15 10 5 0

Figure 1. Comparison of induction therapies in patients with acute myeloid leukemia.

Disappointingly, induction therapy for patients with acute myeloid leukemia (AML) has changed little in three decades. Adults of all ages with AML who are deemed treatment candidates are generally given an anthracycline for three days plus seven days of continuous infusional cytarabine. A Phase I study performed by the CALGB dedicated to devising an induction therapy (including etoposide) that could be given with or without a drug resistance modulator showed that doses of daunorubicin over 90 mg/m2 for three days were well tolerated.

The ECOG thus sought to determine whether high-dose daunorubicin might actually lead to a superior outcome compared with standard-dose daunorubicin. Adult patients with previously untreated AML were randomized to receive either daunorubicin at the standard dose (45 mg/m2 per day) or a high dose (90 mg/m2 per day), each for three days combined with standard-dose cytarabine (100 mg/m2 per day) for seven days by continuous

intravenous infusion. A second course of induction therapy was given (using standard-dose daunorubin in either arm) if leukemia persisted mid-cycle.

Those achieving a complete remission were allocated to allogeneic stem cell transplantation or high-dose cytarabine prior to high-dose chemotherapy with peripheral blood stem cell rescue.

This study is one of the few trials to show a survival benefit based on a change in induction therapy. Those randomized to high-dose daunorubicin had a significantly higher complete remission rate (70.6% vs. 57.3%) and median overall survival (23.7 vs.

15.7 months; P=0.003) (Figure 1).

This is a most striking result suggesting that the higher dose of daunorubicin was probably leading to a lower leukemia burden at the time of remission and, therefore, a lower incidence of relapse. Fortunately, the benefit was not achieved at a higher costâ&#x20AC;&#x201D;induction death rates were similar in the two groups (about 5% in each arm).

Subgroup analysis revealed that the patients who benefited from the higher-dose daunorubicin were those with favorable or intermediate cytogenetics, those without FLT3 internal tandem duplication (ITD) mutations and those who were younger than age 55 years.

This is an important study that suggests that 45 mg/m2 per day of daunorubicin is an insufficient dose for induction therapy in patients under the age of 60 years. However, it is not clear whether 90 mg/m2 is better than 60 mg/m2 per day, which is now probably the most commonly used dose (based on the CALGB trial) in induction therapy for patients between the ages of 18 and 60 years. Another criticism of this trial is that the control group fared particularly poorly compared with what might have been expected. Nonetheless, this trial answers a clinically important question only possibly asked by a cooperative group.

Wheat Grass: An Effective Iron Chelator in MDS?

A

small study presented at the ASCO meeting (abstract 7012) suggests that wheat grass may be an

S effective iron chelator in patients with myelodysplastic syndromes (MDS). The juice is rich in oxalic and malic acids that could prevent intestinal dietary iron absorption as well as active ingredients that can chelate iron.

One of the major controversies in the management of patients with MDS is the optimal role of iron chelation therapy. Many patients with lower risk (International Prognostic Scoring System low-risk or intermediate-1) are expected to survive at least five years and may require many red cell transfusions to maintain their hematocrit.

These patients typically have high serum iron and ferritin levels. Whether or not patients with MDS generally have complications of iron overload is unclear. Nonetheless, it has been the practice to provide chelation therapy for a selected group of patients with MDS. Historically, the available chelation therapy in this country, deferoxamine, which must be administered subcutaneously for about 12 to 16 hours daily, is cumbersome and disliked by patients.

The recent approval of deferasirox (Exjade, Novartis), an oral iron chelation agent, has made it more feasible to treat a larger number of patients with MDS in an attempt to decrease iron stores. At the ASCO meeting, investigators from India reported on 20 patients with transfusion-dependent MDS who used five- to sevenday-old wheat grass (including stems) to make juice, of which 30 mL was given daily to each patient for six months. The mean serum ferritin level of the patients was 2,250 mcg/L before wheat grass treatment and 950 mcg/L after treatment.

Although side effects of this therapy were not listed in the abstract, it appears that this natural remedy might be an effective iron chelator.

How wheat grass compares to deferasirox in terms of iron chelation ability is not clear. This study does not deal with the most important question: Is iron chelation therapy â&#x20AC;&#x153;worth itâ&#x20AC;? in MDS? On the other hand, if a side effectâ&#x20AC;&#x201C;free, inexpensive and easy-toadminister regimen could reduce iron stores, it would certainly be easier to conduct a study that could answer the question.

everal abstracts presented at the ASCO meeting dealt with new ways to provide prognostic information for patients with acute myeloid leukemia and related disorders.

Two of the abstracts involved highrisk myeloid malignancies. Investigators from the Cleveland Clinic (abstract 7016) showed that single nucleotide polymorphism (SNP) arrays could identify gross chromosomal abnormalities with more resolution than standard karyotyping and could detect copy-neutral loss of heterozygosity, a defect not detected by routine cytogenetics. They found more chromosomal defects compared with standard cytogenetics (71% vs. 47%) and showed that those with such SNP lesions had a worse median overall survival (41% vs.

Patients with NPM1 mutations

Overall Survival at Three Years

Tweaking Induction Therapy for AML Increases Survival

Median Overall Survival, mo

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Patients without NPM1 mutations

35

34

30 25 20 15 10

7

5 0

Figure 2. Comparison of survival in patients with acute myeloid leukemia. not reached) than those without lesions.

The prognostic significance of individual SNP abnormalities and how one should actually incorporate SNP abnormalities into our current prognostic scoring systems for MDS is also unclear.

Marcucci and colleagues from Ohio State University (abstract 7000) showed that older adults with AML, known to fare poorly with available therapy, do somewhat better if they have normal cytogenetics and an NPM1 (nucleophosmin gene) mutation.

Patients with an NPM1 mutation had a higher complete response (CR) rate (85% vs. 45%) and a better overall survival (34% vs. 7% at three years) than similar patients without this genetic abnormality (Figure 2). Although these mutations predict a better outcome in this subgroup of adults with AML, the results are still inferior to what would be expected in a similar cytogenetics/genetic class of younger patients.

Younger adults with cytogenetically normal AML have been the focus of intense attempts to define prognostic subgroups. It is already recognized

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Multiple Cancers

longer disease-free survival and better overall survival.

Finally, Marcucci and colleagues (abstract 7002) derived a prognostic classification system for younger patients with de novo cytogenetically normal AML which takes into account the FLT3 ITD, NMP1, CEBPÎą and WT1 mutational status, as well as ERG and BAALC expression.

A Bridge to Transplant Or a Bridge to Nowhere?

T

he study described in abstract 7032 analyzed the impact of azacitidine induction chemotherapy on post-transplant outcomes in patients with MDS. Patients with MDS have no option for cure other than allogeneic stem cell transplantation. However, a major

controversy has been whether or not patients with excess marrow blasts would be better served by having some degree of cytoreductive therapy prior to transplant. Historically, there has been an aversion to giving aggressive induction chemotherapy to the largely older cohort of patients with demonstrated limited bone marrow reserve.

The advent of DNA-hypomethylating agents such as azacitidine has made it possible to more safely treat patients with MDS in an attempt to reduce the blasts and, therefore, make transplant outcomes better.

It has been known for quite some time that patients who have a minimal disease burden fare better at the time of transplant. On the other hand, it is not known whether response to pretransplant chemotherapy is a biological marker for better outcome after transplant or whether the pre-transplant chemotherapy actually â&#x20AC;&#x153;worksâ&#x20AC;? by lowering the disease burden. Cogle

Median Event-Free Survival, mo

that patients with an FLT3 gene internal tandem duplication (ITD) mutation (with or without an NMP1 mutation) have an inferior prognosis. This, however, was contradicted by a small study by M.D. Anderson Cancer Center investigators led by Santos (abstract 7015). Their study (481 patients) suggested that having an FLT3 mutation did not have prognostic importance in AML in those with either good- or poor-risk cytogenetics.

Marcucci and colleagues also showed (abstract 7001) that microRNA181a expression is associated with a good prognosis, including longer diseasefree interval and overall survival, compared with those without microRNA181a expression. MIR181a expression was useful prognostically in the otherwise higher-risk group of cytogenetically normal patients, those with FLT3 ITD or NPM1 wild-type disease. In this subgroup, those with higher MIR181a expression had a high rate of CR,

Jennifer R. Brown, MD, PhD, highlights news regarding chronic lymphocytic leukemia (CLL), Hodgkinâ&#x20AC;&#x2122;s disease, non-Hodgkinâ&#x20AC;&#x2122;s lymphoma (NHL) and multiple myeloma (MM).

Dr. Brown is an attending physician with the CLL & Lymphoma Program, Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, both in Boston.

Idiotype Vaccination Beneficial in Follicular Lymphoma

A

Phase III trial has revealed that an idiotype vaccine can extend remission duration in certain patients with follicular lymphoma (FL; abstract 2). This is the third Phase III double-blind, randomized trial of an autologous tumorderived patient-specific vaccine in FL. The study enrolled previously untreated advanced-stage FL patients and treated them with PACE chemotherapy (prednisone, doxorubicin,

Median Time to Relapse, mo

Patients receiving placebo Patients receiving idiotype vaccination 50

44

40

31 30 20 10 0

Figure 1. Comparison of median time to relapse in patients with follicular lymphoma.

cyclophosphamide, and etoposide).

Those patients who achieved a complete response/complete response unconfirmed (CR/CRu), 76% of the starting population, were randomized. Of those 177 randomized, only 117 maintained their CR/CRu for six months as required to receive vaccine or placebo. Of the remaining 117 treated with vaccine or placebo, at a median follow-up of 57 months, the median time to relapse for the idiotype vaccine group was 44 months, compared with 31 months for the control group (P=0.045; Figure 1). Thus, idiotype vaccination extended remission duration in the subgroup of FL patients, about half the starting group, who were able to achieve a CR/CRu that persisted at least six months after chemotherapy.

The other two previously reported studies of idiotype vaccination failed to show a benefit, which may have been due to more relaxed criteria for the response required to move on to the vaccine phase, a shorter waiting time to vaccination or differences in the vaccine. The most important problem with the study, however, is the absence of rituximab (Rituxan, Genentech/Biogen Idec), which is now a standard therapy for FL and which may alter responsiveness to or benefit from vaccine. Future studies will be required to address this question.

Patients not receiving consolidation therapy Patients receiving consolidation therapy with rituximab

24

50 40 30

13

20 10 0

Figure 2. Comparison of event-free survival in patients with follicular lymphoma.

Long-term Follow-up Of FL Patients Receiving Rituximab

I

n the SAKK study (abstract 8512), FL patients received four weekly doses of rituximab and then were randomized to no further treatment or to four additional doses of rituximab at twomonth intervals.

At a median follow-up of nine years and a minimum follow-up of five years in all patients, the median eventfree survival (EFS) increased from 13 months in the observation arm to 24 months in the consolidation arm (Figure 2). Furthermore, those patients receiving consolidation therapy had a 25% and 18% chance of remaining in remission at five and eight years, respectively, suggesting remarkable sensitivity to rituximab in a subset of FL patients. The authors, however, were unable to identify a predictor of prolonged remission.

R-ICE Versus R-DHAP

I

et al tried to answer this question by analyzing post-transplant outcomes in 43 MDS patients, nine of whom received azacitidine before transplant and 34 who did not. It is important to point out that this was a retrospective, nonrandomized study and that it is possible that 5-azacitidine patients were either better or worse candidates than their counterparts who did not receive this drug.

The group that received azacitidine before the transplant demonstrated better overall survival; however, the rates of acute and chronic graft-versus-host disease and median overall survival did not differ. There was a trend toward a higher relapse rate in the azacitidine group, suggesting that this was a population with a higher original disease burden. Certainly, a randomized controlled trial would be necessary to prove or disprove the need to give hypomethylating agents prior to transplant.

n the CORAL study (abstract 8509), patients with diffuse large B-cell

lymphoma who were refractory to initial therapy or in first relapse were randomized to salvage therapy with R-ICE (rituximab, ifosfamide, etoposide and carboplatin) or R-DHAP (rituximab, dexamethasone, aracytine and cisplatinum). The overall response rate was 63%, with 38% complete remissions. No difference was observed between the arms in response rate or in three-year EFS or overall survival.

Utilization of Radiation Therapy in Early-Stage Hodgkinâ&#x20AC;&#x2122;s Disease

I

n recent years, the efficiacy of chemotherapy in Hodgkinâ&#x20AC;&#x2122;s disease, as well as increasing awareness of the longterm complications of radiation therapy, have led to increased interest in treating early stage Hodgkinâ&#x20AC;&#x2122;s disease with chemotherapy alone. In the study described in abstract 8511, researchers set out to assess the use of RT. Investigators used the Surveillance, Epidemiology and End Results program registry to analyze patients diagnosed with early-stage Hodgkinâ&#x20AC;&#x2122;s disease between 1990 and 2004, to look at the effect of RT on survival (abstract 8511). Subgroup analyses were performed by era of treatment, sex and patient age. Receiving RT was associated with a significant improvement in overall survival and cause-specific survival (HR, 0.537 and 0.437, respectively) in all subgroups. These results are intriguing and suggest that we should perhaps be circumspect in the current trend toward chemotherapy-only regimens, although the risks for long-term complications related to RT do need to be considered.

5

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Lung

continued from page 1

Nasser H. Hanna, MD, invited to critique the three studies at the meeting remained circumspect about their relevance to routine care in all patients because of a lack of reported quality-of-life (QoL) data, others saw the results as highly meaningful to extending the benefit of first-line chemotherapy. Dr. Hanna is an associate professor of medicine in the Department of Medicine and Division of Hematology/Oncology at the Simon Cancer Center, Indiana University, Indianapolis.

Pemetrexed Proves Potent In a trial (abstract CRA8000) presented by Chandra P. Belani, MD, deputy director of Penn State Cancer Institute, Hershey, Pa., 663 patients with stage IIIb/IVa NSCLC who had not progressed after four cycles of platinum-based chemotherapy were randomized to 500 mg/m2 pemetrexed plus best supportive care (BSC) or BSC plus placebo. Overall, the PFS was increased by almost two months (4.3 vs.

2.6 months; P<0.0001); OS was increased by almost three months (13.4 vs. 10.6 months; P=0.012). However, the relative benefits of pemetrexed maintenance were even greater in nonsquamous cell histologies. Although there was no OS advantage in the squamous cell tumors (9.9 vs. 10.8 months; P=0.678), the survival advantage exceeded five months (15.5 vs. 10.3; P=0.007) when the squamous cell cancers were removed from the analysis. This translated into a highly significant reduction in the hazard ratio for death (hazard ratio [HR], 0.47; P<0.0001).

The survival advantage, however, was not without side effects. These included fatigue and neutropenia, and overall, 16% of patients on pemetrexed versus 4% on BSC alone (P<0.001) experienced a grade 3 adverse event (AE). According to Dr. Belani, however, AEs can be considered relatively modest in the context of one of the largest survival benefits yet observed in advanced NSCLC. He believes that these results are meaningful to routine patient care. Although he did not report QoL data, he said that such data were

Pemetrexed plus best supportive care (BSC) BSC plus placebo

5 4.3

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Figure 1. Comparison of overall survival with two different maintenance therapies.

Erlotinib plus bevacizumab

collected and will be made available with the published manuscript.

Bevacizumab plus placebo

ATLAS A second study reported at the ASCO meeting was called ATLAS (abstract LBA8002). The largest of the three studies, ATLAS was stopped early by the Data and Safety Monitoring Committee because the primary end point of PFS was met in a second planned interim analysis. In this study, 768 patients with stage IIIb/ IV NSCLC who had achieved an objective response or stable disease on a combination of bevacizumab (Avastin, Genentech) and a platinum-containing doublet chemotherapy were randomized to 150 mg of erlotinib plus 15 mg/kg of bevacizumab administered every three weeks or bevacizumab plus placebo in the same schedule. At the time the study was stopped, the PFS advantage on the combination of erlotinib plus bevacizumab was a month greater than on bevacizumab alone (4.8 vs.

3.7 months). The difference was highly significant (HR, 0.72; 95% confidence interval [CI], 0.59-0.81; P=0.0012). â&#x20AC;&#x153;The improvement in PFS was seen across multiple subgroups, including those defined on gender, histology, age and smoking status,â&#x20AC;? said the first author, Vincent A. Miller, MD, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York City. He

5

Progression-free Survival, mo

MAINTENANCE

Overall Survival, mo

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Figure 2. Comparison of overall survival with two different maintenance therapies.

â&#x20AC;&#x2DC;Most patientsâ&#x20AC;&#x2122; life expectancy is very short and you really do not know whether exposing them to even the mild toxicities of longerduration therapy is really benefiting them.â&#x20AC;&#x2122;

â&#x20AC;&#x201D;Nasser H. Hanna, MD

reported that the safety profile was consistent with previous studies of the combination and indicated an acceptable level of tolerability. Survival data are not yet mature but are being collected.

SATURN In a third study, called SATURN, 489 patients with stage IIIb (25%) or stage IV (75%) stable NSCLC who achieved stable disease or an objective response after a first-line, platinum-based chemotherapy were randomized to 150 mg erlotinib once daily or placebo (abstract 8001). At 24 weeks, the proportion of patients in PFS was 32% versus 18%, favoring erlotinib (HR, 0.71; 95% CI, 0.62-0.82; P<0.0001), according to senior author Federico Cappuzzo, MD, Department of Medical Oncology, Instituto Clinico Humanitas, Milan, Italy.

The PFS was greater in the 45% of patients with adenocarcinoma (HR, 0.60; 95% CI, 0.48-0.75; P<0.0001) than in those with squamous cell histology (HR, 0.76; 95% CI, 0.60-0.95; P=0.0148). â&#x20AC;&#x153;Erlotinib met the primary end point of PFS with a high degree of statistical significance, and significant improvement was seen in the secondary end points of response and disease control,â&#x20AC;? Dr. Cappuzzo said. He added that AEs were consistent with those previously associated with erlotinib. Most importantly, â&#x20AC;&#x153;there was no deterioration in quality of life for erlotinib versus placebo.â&#x20AC;? Again, survival data are not yet available, but are being collected.

Putting It in Perspective Asked to discuss these three papers together, Dr. Hanna focused on the absence of QoL data. He was not sure if the gains in PFS for ATLAS and SATURN and

even the gain in OS with the pemetrexed study warranted a switch to this strategy in all patients. â&#x20AC;&#x153;The questions I think patients are most interested in are: does the earlier initiation of these agents in my care result in me living longer and/or living better?â&#x20AC;? suggested Dr. Nasser. Although he conceded that some patients may benefit from maintenance therapy, such as those who gain symptom control from maintenance therapy and have a good QoL before their disease progresses, he recommended that this approach must be used selectively. â&#x20AC;&#x153;It is clear from these strategies that maintenance therapy improves progression-free survival, but in my opinion, improvement in progression-free survival alone is less meaningful unless it also results in patients experiencing fewer cancer symptoms, fewer complications of their cancer or somehow measuring an improved quality of life, and none of that has been demonstrated by any of these trials,â&#x20AC;? Dr. Hanna said. Although maintenance therapy â&#x20AC;&#x153;does have great valueâ&#x20AC;? in the right patient, he noted that â&#x20AC;&#x153;most patientsâ&#x20AC;&#x2122; life expectancy is very short and you really do not know whether exposing them to even the mild toxicities of longer-duration therapy is really benefiting them.â&#x20AC;?

This view was not well accepted by Dr. Belani, who stressed that the improvements in OS in his study were not only highly statistically significant, but clinically significant for a therapy that was reasonably well tolerated. He believes that the data validate the concept of maintenance therapy in advanced NSCLC, and he expects this concept to be widely embraced. â&#x20AC;&#x201D;Ted Bosworth

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Ovarian

Ovarian Cancer News at ASCO To Impact Practice Two abstracts presented at the annual meeting of the American Society of Clinical Oncology can be deemed to be practice-changing news for patients with gynecologic malignancies. Both impact clinicians treating patients with ovarian cancer.

In the plenary session, Gordon J. Rustin, MD, et al. reported the long-awaited results of the randomized Phase III trial that examined the impact on survival associated with a CA-125 monitoring strategy in women with advanced ovarian cancer who had achieved a clinically defined complete response

While routine monitoring of asymptomatic women on an every-three-month schedule resulted in a median five-month earlier initiation of therapy for recurrent disease, there was no effect of this somewhat earlier treatment on overall survival.

to primary platinum-based chemotherapy (abstract 1). The study found that while routine monitoring of asymptomatic women on an every-three-month schedule resulted in a median fivemonth earlier initiation of therapy for recurrent disease, there was no effect of this somewhat earlier treatment on overall survival. When ultimately published in the peer-reviewed literature, it will be important for these study results to be discussed by clinicians with their patients, as they may influence an individual ovarian cancer patientâ&#x20AC;&#x2122;s desire to undergo intensive routine CA-125 surveillance following completion of the primary treatment regimen.

Eric Pujade-Lauraine, MD, PhD,

Whatâ&#x20AC;&#x2122;s Your View? =?6;A

@5.?2

?20<::2;1

2 :.69

0<::2;A

How will the results from the Rustin et al study impact how you care for patients? How have your patients responded to the news?

Send replies to

korourke@mcmahonmed.com

presented the results of a second practice-changing abstract, the results of the CALYPSO trial (LBA5509). This trial directly compared a regimen of carboplatin plus pegylated liposomal doxorubicin to carboplatin plus paclitaxel when used for treatment of recurrent (potentially platinum-sensitive) ovarian cancer. The study revealed an improvement in progression-free survival in favor of the pegylated liposomal

doxorubicin-containing regimen (median, 11.3 vs. 9.4 months; hazard ratio, 0.82; P=0.005).

Another interesting finding was the lower risk for carboplatin-associated hypersensitivity reactions associated with the pegylated liposomal doxorubicin program (grade >2; 18% vs. 5%).

This factor may have influenced the amount of carboplatin that could be delivered to a substantial number of

GEMZARĺ§&#x17E; (GEMCITABINE HCl) FOR INJECTION BRIEF SUMMARY (OVARIAN). For complete safety please consult the package insert for complete prescribing information.

INDICATION AND USAGE: THERAPEUTIC INDICATIONâ&#x20AC;&#x201D;Ovarian Cancerâ&#x20AC;&#x201D;Gemzar in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

CLINICAL STUDIES: Ovarian Cancerâ&#x20AC;&#x201D;Gemzar was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy.

Patients were randomized to receive either Gemzar 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS).

The addition of Gemzar to carboplatin resulted in statistically significant improvement in PFS and overall response rate. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received Gemzar after progression. There was not a significant difference in overall survival between arms.

CONTRAINDICATION: Gemzar is contraindicated in those patients with a known hypersensitivity to the drug (see Allergic under ADVERSE REACTIONS).

WARNINGS: Cautionâ&#x20AC;&#x201D;Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity (see CLINICAL STUDIES in the full Prescribing Information).

Hematologyâ&#x20AC;&#x201D;Gemzar y can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia (see ADVERSE REACTIONS), and myelosuppression is usually the dose-limiting toxicity.

Patients should be monitored for myelosuppression during therapy. See DOSAGE AND ADMINISTRATION in the full Prescribing Information for recommended dose adjustments.

Pulmonaryâ&#x20AC;&#x201D;Pulmonary toxicity has been reported with the use of Gemzar. In cases of severe lung toxicity, Gemzar therapy should be discontinued immediately and appropriate supportive care measures instituted (see Pulmonary under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information).

Renalâ&#x20AC;&#x201D;Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS (see Renal under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information).

Hepaticâ&#x20AC;&#x201D;Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs (see Hepatic under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information).

Pregnancyâ&#x20AC;&#x201D;Pregnancy y Category D. Gemzar can cause fetal harm when administered to a pregnant woman.

Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. There are no studies of Gemzar in pregnant women. If Gemzar is used during pregnancy, or if the patient becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to the fetus.

PRECAUTIONS: Generalâ&#x20AC;&#x201D;Patients receiving therapy with Gemzar should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. There was a greater tendency in women, especially older women, not to proceed to the next cycle.

Laboratory Testsâ&#x20AC;&#x201D;Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected (see DOSAGE AND ADMINISTRATION in the full Prescribing Information).

Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter (see WARNINGS).

Carcinogenesis, Mutagenesis, Impairment of Fertilityâ&#x20AC;&#x201D;Long-term animal studies to evaluate the carcinogenic potential of Gemzar have not been conducted. Gemcitabine induced forward mutations in vitro in a mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay.

Gemcitabine was negative when tested using the Ames, in vivo sister chromatid exchange, and in vitro chromosomal aberration assays, and did not cause unscheduled DNA synthesis in vitroo. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day IV (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day IV (about 1/1300 the human dose on a mg/m2 basis).

Pregnancyâ&#x20AC;&#x201D;Category D. See WARNINGS. Nursing Mothersâ&#x20AC;&#x201D;It is not known whether Gemzar or its metabolites are excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Gemzar in nursing infants, the mother should be warned and 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 and the potential risk to the infant.

Elderly Patientsâ&#x20AC;&#x201D;Gemzar clearance is affected by age (see CLINICAL PHARMACOLOGY in the full Prescribing Information). There is no evidence, however, that unusual dose adjustments (i.e., other than those already recommended in DOSAGE AND ADMINISTRATION section in the full Prescribing Information) are necessary in patients over 65, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65. Grade 3/4 thrombocytopenia was more common in the elderly.

Genderâ&#x20AC;&#x201D;Gemzar clearance is affected by gender (see CLINICAL PHARMACOLOGY in the full Prescribing Information). In the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments (i.e., other than those already recommended in DOSAGE AND ADMINISTRATION section in the full Prescribing Information) are necessary in women. In general, in single-agent studies of Gemzar, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia.

Pediatric Patientsâ&#x20AC;&#x201D;The effectiveness of Gemzar in pediatric patients has not been demonstrated. Gemzar was evaluated in a Phase 1 trial in pediatric patients with refractory leukemia and determined that the maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Gemzar was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) using 10 mg/m2/min for 360 minutes three times weekly followed by a one week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial.

Patients with Renal or Hepatic Impairmentâ&#x20AC;&#x201D;Gemzar should be used with caution in patients with preexisting renal impairment or hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemzar in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency.

GEMZARĺ§&#x17E; (GEMCITABINE HCl) FOR INJECTION

PV 4067 AMP

ADVISORY BOARD EDITORIAL Maurie Markman, MD Vice President for Clinical Research University of Texas M.D. Anderson Cancer Center, Houston, Texas

patients, subsequently affecting the time of disease progression. â&#x20AC;&#x201D;Maurie Markman, MD

Drug Interactionsâ&#x20AC;&#x201D;No specific drug interaction studies have been conducted. For information on the pharmacokinetics of Gemzar and cisplatin in combination, see Drug Interactions under CLINICAL PHARMACOLOGY. Radiation Therapyâ&#x20AC;&#x201D;A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of Gemzar.

Non-concurrent (given >7 days apart)â&#x20AC;&#x201D;Analysis of the data does not indicate enhanced toxicity when Gemzar is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that Gemzar can be started after the acute effects of radiation have resolved or at least one week after radiation.

Concurrent (given together or â&#x2030;¤7 days apart)â&#x20AC;&#x201D;Preclinical and clinical studies have shown that Gemzar has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of Gemzar, frequency of Gemzar administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where Gemzar at a dose of 1000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm3]. Subsequent studies have been reported and suggest that Gemzar administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of Gemzar with therapeutic doses of radiation has not yet been determined in all tumor types.

ADVERSE REACTIONS: Combination Use in Ovarian Cancerâ&#x20AC;&#x201D;In the Gemzar plus carboplatin versus carboplatin study, dose reductions occurred with 10.4% of Gemzar injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of Gemzar doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse events between arms (10.9% versus 9.8%, respectively).

Table 1 presents the adverse events (all grades) occurring in â&#x2030;Ľ10% of patients in the ovarian cancer study.

Table 1: Adverse Events From Comparative Trial of Gemzar Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancera CTC Grades (% incidence) Gemzar plus Carboplatin (N=175) Carboplatin (N=174) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 b Laboratory Hematologic Neutropenia 90 42 29 58 11 1 Anemia 86 22 6 75 9 2 Leukopenia 86 48 5 70 6 <1 Thrombocytopenia 78 30 5 57 10 1 38 15 RBC Transfusions c Platelet Transfusions c 9 3 Non-laboratory b Nausea 69 6 0 61 3 0 Alopecia 49 0 0 17 0 0 Vomiting 46 6 0 36 2 <1 Constipation 42 6 1 37 3 0 Fatigue 40 3 <1 32 5 0 Neuropathy-sensory 29 1 0 27 2 0 Diarrhea 25 3 0 14 <1 0 Stomatitis/pharyngitis 22 <1 0 13 0 0 Anorexia 16 1 0 13 0 0 a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades â&#x2030;Ľ10%). b Regardless of causality. c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.

In addition to blood product transfusions as listed in Table 1, myelosuppression was also managed with hematopoetic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoetic agents: 7.3% and 3.9%, respectively).

The following are the clinically relevant adverse events, regardless of causality, that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse events (Gemzar plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65.

Post-marketing experienceâ&#x20AC;&#x201D;The following adverse events have been identified during post-approval use of Gemzar. These events have occurred after Gemzar single-agent use and Gemzar in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to Gemzar.

Cardiovascularâ&#x20AC;&#x201D;Congestive heart failure and myocardial infarction have been reported very rarely with the use of Gemzar. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely.

Vascular Disordersâ&#x20AC;&#x201D;Clinical signs of peripheral vasculitis and gangrene have been reported very rarely.

Skinâ&#x20AC;&#x201D;Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely.

Hepaticâ&#x20AC;&#x201D;Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs.

Pulmonaryâ&#x20AC;&#x201D;Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of Gemzar administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last Gemzar dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy.

Renalâ&#x20AC;&#x201D;Hemolytic-Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS. Injury, Poisoning, and Procedural Complications â&#x20AC;&#x201D; Radiation recall reactions have been reported (see Radiation Therapy under PRECAUTIONS).

Dosage and administration: Gemzar is for intravenous use only. Please consult full prescribing information for complete dosage and administration guidelines.

Literature revised May 7, 2007 PV 4067 AMP

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Eli Lilly and Company Indianapolis, IN 46285, USA Copyright Š 1996, 2007, Eli Lilly and Company. All rights reserved.

GEMZARĺ§&#x17E; (GEMCITABINE HCl) FOR INJECTION

PV 4067 AMP

7

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PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Treatment Options for

Platinum-Sensitive Recurrent Ovarian Cancer BRADLEY J. MONK, MD Associate Professor Division of Gynecologic Oncology Department of Obstetrics and Gynecology Chao Family Comprehensive Cancer Center University of California, Irvine Orange, California

F

or almost 2 decades, the traditional management of women with recurrent epithelial

ovarian cancer has dichotomized therapeutic recommendations based on the platinum-free interval (PFI) and the probability of response to platinum retreatment.

These recommendations have defined much of the current clinical â&#x20AC;&#x153;standard of careâ&#x20AC;? for these patients. It also has formed the basis for a research agenda, which, until recently, has explored nonplatinum agents in women considered at low probability for response to platinum retreatment, and platinum-based therapy in those with a higher probability of response. This paradigm is now in question as Phase III trials investigate newer agents and unique combinations. This monograph reviews the historical development of these contemporary practice patterns and suggests alternative strategies that may further improve efficacy among women with â&#x20AC;&#x153;platinumsensitiveâ&#x20AC;? relapsed ovarian cancer.

The Concept of â&#x20AC;&#x153;Platinum Sensitivityâ&#x20AC;?

In the late 1980s and early 1990s, Blackledge,1 Gore,2 and Markman3 reported on the increasing success of retreating recurrent epithelial ovarian cancer with platinum compounds based on the length of the PFI; the response rate (RR) to platinum retreatment approached 60% as the PFI reached 2 years and beyond (Table 1).

These findings became the foundation for the current

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

paradigm of treating relapsed ovarian cancer with a second platinum-based regimen if the PFI was longer than 6 months. This was largely reinforced by the Gynecologic Oncology Group (GOG), which evaluated serial nonplatinum agents in successive clinical studies of women with recurrent measurable disease who had recurred in 6 months or less.4 Blackledge, Gore, and Markman made their observations before active nonplatinum drugs had been identified or well studied (circa 1990). In 1992, the FDA approved paclitaxel as a new chemical entity for patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy. Data from 5 noncontrolled Phase I and II studies led to the regular approval of this compound based on durable RRs between 20% and 30% in both platinum-resistant (PFI <6 months) and platinum-sensitive (PFI >6 months) patients.5,6 It is now well appreciated that PFI is prognostic to the expected RR and duration of response (Figure 1).7 This effect appears to be somewhat linear, and it may be independent of specific chemotherapeutic agents, including platinum compounds. It is important to compare agents in formal Phase III trials rather than making

C L I N I C A L O N C O L O G Y N E W S â&#x20AC;˘ J U LY/A U G U S T 2 0 0 9

1

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Table 1. Effect of Platinum-free Interval on Second-Line Response

Inclusion criteria:

Response Rate in Trials, %

â&#x20AC;˘ Fallopian tube cancer

Platinumfree Interval, mo

Platinum Therapy

0-6

10

7-12

29

13-18

63

19-24

94

1989

1a

>24

b

Non-platinum Therapy 3

10

â&#x20AC;˘ Peritoneal cancer 11

1990

1991

1997

2001

17

â&#x20AC;&#x201D;

10-16.7

12

27b

12.5-20

28

27

33

20-28.8

57

59

â&#x20AC;˘ Measurable disease â&#x20AC;˘ 1 prior front-line platinum-based regimen

a

Premedication with dexamethasone is required.

Based on reference 14.

Platinum-free interval 5 to 12 months

small sample size, Phase II design, and nearly 50% â&#x20AC;&#x153;dropoutâ&#x20AC;? at crossover, this trial has been cited as support that platinum should be considered first in women with platinum-sensitive recurrent cancer.9

Platinum-Sensitive 1.0

800

0.8

600

0.6

Days

1000

400

0.4

200

0.2

0

0

0-3 mo Progression

0-3 mo NonPD

3-12 mo

12-18 mo

18+ mo

PFS, d

90

176

174

275

339

OS, d

217

375

393

657

957

RR, %

0.09

0.24

0.35

0.52

0.62

Figure 1. Line and bar graphs showing the linear relationship between PFS, OS and RR, and PFI. OS, overall survival; PD, progressive disease; PFI, platinum-free interval; PFS, progression-free survival; RR, response rate Based on reference 6.

inferences from cross-trial assessments.

One randomized trial has assessed the impact of platinum versus nonplatinum treatment in women with recurrent ovarian cancer.8 This Phase II crossover trial between single-agent paclitaxel and the platinum triplet, cyclophosphamide, doxorubicin, and cisplatin (CAP), demonstrated that RRs were higher in those receiving CAP than in those receiving paclitaxel. All patients were platinumsensitive using a PFI greater than 12 months. Although the generalizability of these results is limited by the studyâ&#x20AC;&#x2122;s

2

PLD 30 mg/m2 90-min infusion followed by trabectedina 1.1 mg/m2 3-h infusion every 3 wk

PLD, pegylated liposomal doxorubicin

First-line therapy included platinum agents and other agents in Phase II investigation

Platinum-Resistant

PLD 50 mg/m2 90-min infusion every 4 wk

Figure 2. OVA-301: study schema.

Percent

a

2

â&#x20AC;˘ Ovarian cancer

R A N D O M I Z A T I O N

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

The New Era of Novel Agents Beginning in the mid-1990s, the development of new compounds provided alternative mechanisms of action to the platinum and taxane portfolio. Positive results in 2 trials in recurrent ovarian cancer and 3 positive trials in platinum-sensitive recurrent ovarian cancer led to adjustment of the traditional treatment algorithm. The first was a challenge to single-agent platinum or paclitaxel in patients (â&#x20AC;&#x153;resistantâ&#x20AC;? and â&#x20AC;&#x153;sensitiveâ&#x20AC;?) failing one regimen. ten Bokkel Huinink et al compared paclitaxel to topotecan (Hycamtin, GlaxoSmithKline) in relapsed disease and suggested that topotecan had efficacy at least equivalent to that of paclitaxel, as manifested by a higher RR and significantly longer time to progression.10 Not only did this trial include patients with platinum-resistant disease, but it also used a nonplatinum drug to treat women with a PFI greater than 6 months; in this study, topotecan resulted in an increase in RR with longer PFIs that was similar to the increase Blackledge,1 Gore,2 and Markman3 observed when they retreated with platinum compounds (Table 1). This study was not persuasive enough to convince most clinicians to use nonplatinum compounds in platinum-sensitive patients, but it did lead to the 1996 regulatory approval of topotecan in the United States.

Gordon et al reported a second positive Phase III trial comparing topotecan with pegylated liposomal doxorubicin (PLD; Doxil, Ortho Biotech), which led to the accelerated FDA approval of PLD in 1999 and full FDA approval in 2005.11 This trial also was performed in a mixed population of both platinum-sensitive and platinum-resistant patients and, like the ten Bokkel Huinink trial, showed a greater RR as the PFI increased (Table 1).

The FDA recognized this by not restricting the label

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Table 2. Platinum-Sensitive Recurrent OC: Positive Trials in Perspective Study

Treatment

N

Prior Taxane

% PFI >12 Mo

Measurable Disease Required

RR,a %

PFS, mo

OS, mo

Gordon11

PLD

123

NS

NS

Measurable

28

6.6

24.7

Parmar12

Carboplatin + paclitaxel

392

43

77

Italy (not MRC CTU or AGO)

66

12b

29

Pfisterer13

Carboplatin + gemcitabine

178

70

60

SWOG (measurable or assessable)

47

8.8b

18

Monk14

PLD + trabectedin

218

80

44

RECIST

47

9.2b

20.5 (not mature)

PujadeLauraine16

Carboplatin + PLD

466

99

65

RECIST or CA125

NA

11.3b

(not mature)

AGO, Arbeitsgemeinschaft Gynaekologische Onkologie; CA125, cancer antigen 125; MRC CTU, Medical Research Council Clinical Trials Unit; OC, ovarian cancer; OS, overall survival; PFI, platinum-free interval; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; RECIST, Response Evaluation Criteria In Solid Tumors; RR, response rate; SWOG, Southwestern Oncology Group a

By independent radiologist; b By investigator

to use in platinum-resistant patients, but few clinicians use PLD over a platinum compound if the PFI is greater than 6 months. Perhaps this is because of the emerging evidence that doublets are superior to single agents in treating platinum-sensitive patients.

ICON 4 (International Collaborative Ovarian Neoplasm 4) was the first trial to definitively show that platinum doublets (in this case with paclitaxel) were more effective than single-agent platinum compounds when the PFI was longer than 6 months.12 This observation that doublets are superior to single agents was confirmed by an intergroup trial of the Arbeitsgemeinschaft Gynaekologische Onkologie-OVAR, the National Cancer Institute of Canada Clinical Trials Group, and the European Organisation for Research and Treatment of Cancer Gynecologic Cancer Group, leading to the FDA approval of gemcitabine (Gemzar, Eli Lilly) plus carboplatin in platinum-sensitive second-line ovarian cancer in 2006.13 However, the â&#x20AC;&#x153;addictionâ&#x20AC;? to platinum in this setting has been called into question based on the most recent positive Phase III trial in recurrent ovarian cancer, which compared PLD with PLD plus trabectedin (Yondelis, Centocor Ortho Biotech; Figure 2).14 This is the first randomized Phase III trial in relapsed ovarian cancer to include a nonplatinum doublet. It is not surprising that this study, like the Gordon and the ten Bokkel Huinink studies, showed increasing activity with increasing PFI (Table 2).

[Editorâ&#x20AC;&#x2122;s Note: On July 15, the FDAâ&#x20AC;&#x2122;s Oncology Drugs Advisory Committee (ODAC) recommended that the combination of trabectedin administered with doxorubicin HCI liposome injection not be approved because it did not provide a sufficient benefitrisk profile for the treatment of relapsed ovarian cancer. However, the FDA is not bound by the ODACâ&#x20AC;&#x2122;s recommendation. Centocor Ortho Biotech has stated that they are continuing trials with the drug and are working to address the concerns that were raised.

Look for in-depth coverage of the ODAC meeting in an upcoming issue and at clinicaloncology.com.]

Perhaps more acceptable alternatives to paclitaxel plus carboplatin in treating platinum-sensitive relapsed ovarian cancer are gemcitabine plus carboplatin and PLD plus carboplatin because only paclitaxel is replaced in these regimens. Gemcitabine plus carboplatin is being studied in the Phase III OCEANS (Ovarian Cancer Evaluation of Avastin and Safety) trial.15 The date for final data collection for the primary outcome measure of progression-free survival is June 2010. PLD plus carboplatin is being studied in the CALYPSO (CAELYX in Platinum Sensitive Ovarian Patients) study (Figure 3).16 Preliminary results of this trial, the largest in relapsed ovarian cancer, showed superiority of the PLD-carboplatin combination in terms of progression-free survival (median after 824 events, 11.3 vs 9.4 months; hazard ratio, 0.821; 95% confidence interval, 0.72-0.94; P=0.005) (Table 2). Compared with paclitaxel-carboplatin, PLD-carboplatin was well tolerated, with lower rates of severe and long-lasting (neuropathy) toxicities, but thrombocytopenia and skin reactions occurred at higher rates in the PLD group.

Replacing Paclitaxel, Carboplatin, or Both The question of whether nonplatinum doublets can be used in preference to the commonly used platinum doublets of carboplatin plus paclitaxel or carboplatin plus gemcitabine remains unanswered because Phase III trials comparing PLD plus trabectedin or other active nonplatinum doublets versus platinum doublets are lacking.

However, the level of activity of the PLD plus trabectedin doublet suggests that it is an acceptable alternative in treating platinum-sensitive ovarian cancer (Table 2). This combination is especially appealing because, like gemcitabine-carboplatin,13 it is not associated with adverse effects of paclitaxel (bone pain, neuropathy, and alopecia) or carboplatin (risk for allergy).14 However, PLD plus trabectedin is associated with more bone marrow suppression and gastrointestinal toxicity compared with PLD

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

3

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Inclusion criteria: â&#x20AC;˘ Ovarian cancer in late relapse (>6 mo) after first- or secondline platinumbased therapy (previous taxane required) Stratification: â&#x20AC;˘ Therapy-free interval (6-12 mo vs >12 mo)

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is the most appropriate characterization for patients who experience a relapse after 6 months.

R A N D O M I Z A T I O N

Experimental arm: CD PLD 30 mg/m2 IV day 1 and carboplatin AUC 5 day 1, every 28 d for 6 coursesa

Control arm: CP Paclitaxel 175 mg/m2 day 1 and carboplatin AUC 5 day 1, for 21 d for 6 coursesa

References 1.

Blackledge G, Lawton F, Redman C, Kelly K. Response of patients in phase II studies of chemotherapy in ovarian cancer: implications for patient treatment and the design of phase II trials. Br J Cancer.

1989;59(4):650-653, PMID: 2713253.

2. Gore ME, Fryatt I, Wiltshaw E, Dawson T. Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol. 1990;36(2):207-211, PMID: 2404837.

3. Markman M, Rothman R, Hakes T, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9(3):389-393, PMID: 1999708.

4. Bookman MA. Developmental chemotherapy and management of recurrent ovarian cancer. J. Clin Oncol. 2003;21(10 suppl):149s-167s, PMID: 17633784.

â&#x20AC;˘ Measurable disease (yes vs no) â&#x20AC;˘ Treating center

5. Trimble EL, Adams JD, Vena D, et al. Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103. J Clin Oncol. 1993;11(12):2405-2410, PMID: 7902426.

â&#x20AC;˘ Randomization

Figure 3. CALYPSO: study schema.

6. Ozols RF. USA update on paclitaxel in ovarian cancer. Ann Med. 1995;27(1):127-130, PMID: 7741991.

AUC, area under the curve; CALYPSO, CAELYX in Platinum Sensitive Ovarian Patients; CD, carboplatin plus PLD; CP, carboplatin and paclitaxel; PLD, pegylated liposomal doxorubicin

7. Pujade-Lauraine E, Paraiso D, Cure H, et al. Predicting the effectiveness of chemotherapy (Cx) in patients with recurrent ovarian cancer (ROC): a GINECO study. J Clin Oncol. 2002;21: abstract 829.

a

or on progression

Based on reference 16.

8. CantĂš MG, Buda A, Parma G, et al. Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol. 2002;20(5):12321237, PMID: 11870165.

alone,11,14 similar to how carboplatin plus gemcitabine is associated with more toxicity than single-agent carboplatin.13 On the other hand, the dose of PLD (30 mg/m2 every 3 weeks) used with trabectedin is less intensive than the single-agent dose of PLD (50 mg/m2 every 4 weeks) and is associated with less skin toxicity (stomatitis and handâ&#x20AC;&#x201C;foot syndrome).14 The preferential use of PLDcarboplatin over paclitaxel-carboplatin is easier to evaluate given the recently reported CALYPSO study above.

However, PLD-carboplatin has not been compared with gemcitabine-carboplatin.

9. Cannistra SA. Is there a â&#x20AC;&#x153;bestâ&#x20AC;? choice of second-line agent in the treatment of recurrent, potentially platinum-sensitive ovarian cancer?

J Clin Oncol. 2002;20(5):1158-1160, PMID: 11870154.

Future Developments

13. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24(29):4699-4707, PMID: 16966687.

The future will likely involve the addition of bevacizumab (Avastin, Genentech)15,17 and/or other targeted agents 18 to chemotherapy, including nonplatinum doublets, in this setting. As the use of maintenance and consolidation chemotherapy increases, the incidence of clinically evident recurrent disease will likely increase, making the term platinum-free interval preferable to treatment-free interval because the activity of retreatment with platinum or even a nonplatinum agent most likely will depend on when the patient completed front-line platinum-based therapy. Additionally, because some front-line Phase III trials are employing nonâ&#x20AC;&#x201C;taxane-based platinum doublets, it is likely that future trials also may need to consider taxane naĂŻvete when making treatment decisions.19 Furthermore, because other agents, such as topotecan, bevacizumab, PLD, and trabectedin have shown clear activity in women with platinum-sensitive disease, it may be that the term chemotherapy-sensitive disease

4

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

10. ten Bokkel Huinink W, Gore M, Carmichael J, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer.

J Clin Oncol. 1997;15(6):2183-2193, PMID: 9196130.

11. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol.

2001;19(14):3312-3322, PMID: 11454878.

12. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/ AGO-OVAR-2.2 trial. Lancet. 2003;361(9375):2099-2106, PMID: 12826431.

14. Monk BJ, Herzog T, Kaye S, et al. A randomized phase III study of trabectedin with pegylated liposomal doxorubicin versus PLD in relapsed, recurrent ovarian cancer. In: Proceedings of the 33rd annual meeting of the European Society of Medical Oncology, Stockholm, Sweden, 2008; abstract LBA3.

15. Ovarian Cancer Evaluation of Avastin and Safety: ClinicalTrials.gov Identifier: NCT00434642.

16. Pujade-Lauraine E, Mahner S, Kaern J, et al. A randomized, phase III study of carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in relapsed platinum-sensitive ovarian cancer (OC): CALYPSO study of the Gynecologic Cancer Intergroup (GCIG).

J Clin Oncol. 2009;27(18 suppl); abstract LBA5509.

17. Fallopian Tube Cancer. Gynecologic Oncology Group Protocol 213: ClinicalTrials.gov Identifier: NCT00565851.

18. ICON6. ClinicalTrials.gov Identifier: NCT00544973.

19. Pignata G, Scambia A, Savarese R, et al. Carboplatin plus paclitaxel (CP) versus carboplatin plus stealth liposomal doxorubicin (CLD) in patients with advanced ovarian cancer (AOC): activity and safety results of the MITO-2 randomized multicenter trial. J Clin Oncol.

2009;27(15 suppl); abstract LBA5508.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Breast

PARP continued from page 1

predicted Merrill J. Egorin, MD, professor of medicine and pharmacology, University of Pittsburgh Cancer Institute, in Pittsburgh. He was not involved in any of the studies.

As a member of the PARP (poly [ADP-ribose] polymerase) family, which includes at least 17 proteins, PARP-1 is particularly promising as a target because

â&#x20AC;&#x2DC;[PARP inhibition] is an area that will explode in the next year or two.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Merrill J. Egorin, MD

15

Progression-free Survival, mo

Gemcitabine + Carboplatin (GC) GC + PARP-1 inhibitor BSI-201

12 9.2

9

5.7

6

3

0

Figure 1. Comparison of treatments for metastatic triple-negative breast cancers.

100 mg olaparib (PARP-1 inhibitor)

Objective Response Rate, %

50

400 mg olaparib (PARP-1 inhibitor)

41

40

30 22

20

10

0

Figure 2. PARP-1 inhibitors for BRCA-deficient advanced breast cancer.

of its role in DNA repair. The hypothesis, now substantiated by results from clinical trials, is that inhibition of PARP-1 can greatly potentiate the activity of conventional cytotoxic agents in malignancies where inhibiting DNA repair is likely to be important. The considerable interest in PARP-1 inhibition, despite the fact that support so far is limited to Phase II data, is driven by the level of activity.

Success in Triple-Negative Breast Cancer In the larger of the two studies in patients with metastatic triple-negative breast cancer, the survival advantage of adding the PARP-1 inhibitor BSI-201 (BiPar Sciences) to a combination of gemcitabine (Gemzar, Eli Lilly) and carboplatin versus the cytotoxic agents alone was 9.2 months compared with 5.7 months (hazard ratio [HR], 0.348; 95% confidence interval [CI], 0.19-0.65; P=0.0005). Joyce Oâ&#x20AC;&#x2122;Shaughnessy, MD, director of the Breast Cancer Prevention Program at Baylor-Charles A. Sammons Cancer Center in Dallas, presented these data on behalf of the U.S. Oncology Group at the ASCO annual meeting (abstract 3).

In the initial analysis of 116 randomized patients, other outcomes measured also showed improvement with the addition of the PARP drug, including objective response rate (ORR; 48% vs. 16%), progression-free survival (PFS; 6.9 vs. 3.3 months; HR, 0.342; P<0.0001) and clinical benefit rate (ORR plus stable disease; 62% vs. 21%; P=0.0002). Also encouraging, Dr. Oâ&#x20AC;&#x2122;Shaughnessy reported that there were no significant differences between the study arms for either hematologic or nonhematologic adverse events. The addition of BSI-201 did not lead to any dose reductions in chemotherapy.

The final data from this study are expected at the end of 2009. At that time, information will be made available on patients who were initially randomized to the chemotherapies alone but crossed over to chemotherapy plus BSI-201 at the time of progression.

In the treatment protocols, all patients received gemcitabine (1,000 mg/m2) and carboplatin (area under the curve = 2) on days 1 and 8 of a 21-day cycle. For patients who received the PARP-1 inhibitor, the dose was 5.6 mg/kg on days 1, 4, 8 and 11. The median age of the study population was about 55 years. Approximately 60% of the patients received the PARP-1 inhibitor as first-line therapy, while the remaining were treated as second- or third-line.

BRCA-Linked Breast Cancer and Ovarian Cancer Similar promise was demonstrated in a much smaller study of 54 patients with BRCA-deficient advanced breast cancer treated with the oral PARP-1 inhibitor, olaparib (AstraZeneca) (ASCO abstract CRA501).

Two doses, 400 and 100 mg, both given twice daily, were evaluated without a control arm. All patients were treatment-experienced. The median number of previous regimens was three. Most patients had received a taxane or an anthracycline or both, and

Poly (ADP-ribose) polymerase family, member 1

about 30% had been previously exposed to a platinum-containing agent. Although almost 70% demonstrated BRCA1 deficiency, a substantial minority had a BRCA2 deficiency, and one patient had both.

Despite advanced disease and substantial exposure to previous regimens, 41% of those on the higher dose and 22% on the lower dose had an objective response.

In the higher-dose arm, 4% of these were complete responses. The PFS in the higher-dose arm was 5.7 months (3.8 months for the lower dose), which is highly encouraging for a population with very limited treatment options. â&#x20AC;&#x153;This is the first report of a Phase II study employing a PARP-1 inhibitor to target BRCA1- and BRCA2deficient advanced breast cancer. It provides a proof of concept of the activity and tolerability for PARP-1 as a target of treatment,â&#x20AC;? said senior author Andrew Tutt, MD, Breakthrough Breast Cancer Research Unit, Kings College, London School of Medicine. He noted that the results were consistent with a second, similar multicenter study in BRCA-deficient, chemotherapy-refractory ovarian cancer that was conducted by many of the same investigators. In that series of 57 patients, the ORR was 33%.

The activity in these Phase II studies, which is consistent with the promise of PARP-1 inhibition in experimental studies, may just be the beginning success stories in a very promising path of clinical research. For example, it is conceivable that PARP-1 inhibition might prevent cancer in patients with inherited BRCA1 or BRCA2 mutations. It may also be possible to inhibit other PARPs important to cell survival.

Dr. Egorin said that the activity seen in these studies is particularly promising at a stage when several key variables that might affect activity, particularly the optimal timing of PARP-1 inhibition in relation to cytotoxic effects, remains incompletely understood.

A greater understanding of this area may lead to even more efficacious use of drugs that act on this target. â&#x20AC;&#x201D;Ted Bosworth

9

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A

PEOPLE AND PLACES

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009 â&#x20AC;˘ DIGITAL EDITION

Around the Water Cooler This new section will bring you news about people and places in the field of oncology. If you have news to share (a new job, an award, a cancer center closure or expansion, etc), please send information to korourke@mcmahonmed.com.

The National Cancer Coalition (NCC) recently announced its Angel Grant recipients. The NCC implemented the Angel Grant program to provide seed funding to innovative projects that benefit and further cancer research, education and programs. Grants also are awarded to act as a catalyst for scientists to secure additional funding from U.S. government agencies and other sources.

Steven S. Brem, MD, is the director of neurosurgery and the division chief of the Neuro-Oncology Department at H. Lee Moffitt Cancer Center in Tampa. He will use the Angel Grant to pursue the development of new anti-angiogenic therapies for pediatric brain tumors. Dr. Brem is a member of the Scientific Advisory Board of the American Brain Tumor Association and the Florida Brain Tumor Association and is vice president of the U.S. Central Brain Tumor Registry. He has served on

several national committees and National Institutes of Health (NIH) review panels. He is chairman of the National Comprehensive Cancer Centers NeuroOncology Guideline Committee.

Julie Blatt, MD, is chief of pediatric hematology/oncology at the University of North Carolina (UNC) at Chapel Hill. Her award furthered UNCâ&#x20AC;&#x2122;s study demonstrating no overall link between autism and cancer in children, as well as a teaching program for childhood cancer survivors and health care providers.

Dr. Blatt is a consultant to the Childhood Cancer Survivor Study, a multicenter NIH-funded study that is examining late effects in more than 20,000 survivors of childhood cancer. She also is a past member of the Strategy Group of the Surveillance and End Results Committee of the Childrenâ&#x20AC;&#x2122;s Oncology Group, which generates late effects study components of therapeutic trials.

J e f f r e y W. Ta u b , M D, i s the director of t h e He m a t o l o gy/Oncology Fellowship program at the Childrenâ&#x20AC;&#x2122;s Hospital of Michigan, Detroit. Dr. Taub plans to use the grant to provide a new visible wavelength microplate reader, which is integral to his innovative research and treatment of acute leukemias. Dr. Taubâ&#x20AC;&#x2122;s primary research focus, funded by the National Cancer Institute and the Leukemia and Lymphoma Society, is the mechanism of chemotherapy sensitivity in children with Down syndrome who have acute myeloid leukemia (AML), drug resistance in childhood acute lymphoblastic leukemia and AML, and the molecular epidemiology of childhood leukemia.

Dr. Taub has won numerous awards including Scholar in Clinical Research (2002-2007) from the Leukemia and Lymphoma Society and the 1994 Young

Investigator Award from the American Society of Clinical Oncology.

Eric C. Beyer, MD, PhD, is the chief of pediatric hematology/oncology at the University of Chicagoâ&#x20AC;&#x2122;s Comer Childrenâ&#x20AC;&#x2122;s Hospital. The Angel Grant will be used to further his investigations of the biology of pediatric glioblastoma multiforme brain tumors and their treatment. Dr. Beyer heads an internationally recognized molecular and cellular biology laboratory funded through grants awarded by the NIH and other government and private agencies. He and his colleagues are investigating the process of intercellular communication, specifically the direct exchange of ions and small molecules between cells through channels formed of proteins called connexins. Their studies of this process may lead to new pharmacologic or molecular approaches to cancer therapy by manipulating exchange of drugs and drug metabolites between cells and the growth and viability of blood vessels.

These studies also have major implications for other clinical areas, including cardiac arrhythmias and cataracts.

Nearly Half of Hospitals Flunk Reporting Rule for Problem Docs Thousands of hospitals in the United States may be shirking their responsibility to report cases of wrongdoing by physicians to a national data bank, a new report has found.

Nearly half of U.S. hospitals have reported no instances of disciplinary action against their physicians, despite a 17-year-old law requiring them to make disclosures, according to the report by the advocacy group Public Citizen.

Public Citizen claims that hospitals use loopholes to evade the spirit of the reporting law, which mandates that the name of any doctor who has had his or her admitting privileges revoked or restricted for at least 30 days must be entered into the National Practitioner Data Bank.

The group said hospitals are plagued by â&#x20AC;&#x153;lax peer review, including a culture among doctors of not wanting to â&#x20AC;&#x2DC;snitchâ&#x20AC;&#x2122;â&#x20AC;? on colleagues. Hospital administrators also impose light penalties on transgressors, keeping sanctions under the threshold that would trigger a report or offering leaves of absence instead of suspensions, Public Citizen said.

Before launching the database, federal health officials projected that hospitals would submit 5,000 reports of privilege actions each year. â&#x20AC;&#x153;However, the average number of hospital reports per year has been 650,â&#x20AC;? Public Citizen said in a

to hundreds of thousands of doctors, have not reported a single discipline case in 17 years,â&#x20AC;? said Sidney Wolfe, MD, acting president of Public Citizen, in a statement. â&#x20AC;&#x153;Our report shows there is an urgent need for the Obama administration to step in and hold hospital administrators accountable, as well as ensure that hospital medical staffs hold their own physicians accountable for patient safety.â&#x20AC;?

â&#x20AC;&#x2DC;It is impossible to justify the fact that thousands of hospitals, which collectively have granted admitting privileges to hundreds of thousands of doctors, have not reported a single discipline case in 17 years.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Sidney Wolfe, MD

letter to Kathleen Sebelius, secretary of the Department of Health and Human Services. â&#x20AC;&#x153;As of December 2007, there was a total of only 11,221 such reports.â&#x20AC;? â&#x20AC;&#x153;It is impossible to justify the fact that thousands of hospitals, which collectively have granted admitting privileges

Failure to report disciplinary action against physicians prevents state medical boards from learning about such cases, creating the potential for harm to patients, the group said.

Public Citizen has called for changes to the Health Care Quality Improvement

Act of 1986, including imposing fines on hospitals that fail to report disciplinary actions against doctors. The group also would like the government to make compliance with the reporting law a component of hospital accreditation, as well as of participation in the Medicare program.

Elizabeth Lietz, a spokesperson for the American Hospital Association, dismissed the Public Citizen report. â&#x20AC;&#x153;Hospitals, physicians and caregivers all work together to provide patients the right care in the right place at the right time and take seriously their responsibility for patient care,â&#x20AC;? Ms. Lietz said. â&#x20AC;&#x153;The premise that the number of reports received by the National Practitioner Data Bank correlates to jeopardized patient care is inaccurate.â&#x20AC;?

Reporting to the practitioner data bank is one of several disciplinary actions hospitals can take against physicians, Ms. Lietz added. Others include requiring counseling and reporting offenders to state medical boards. â&#x20AC;&#x201D;Adam Marcus

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Genetics

Genetic Predisposition to Cancer Presents Difficult Choices A family in Charlotte, N.C. been getting a lot of press lately: Since September 2008, three of the family members have undergone prophylactic gastrectomies to avoid developing the gastric cancer that took the lives of two first-degree relatives.

The youngest family member to take this preemptive step is 26.

Although most people cannot conceive of life without a stomach, those in the know understand that life and nourishment are in fact manageable without that major organ. The lifestyle changes may be inconvenient, but the alternative for people with the germline CDH1 (E-cadherin) gene mutation is a very high risk for a very deadly cancer.

Prophylactic gastrectomy is â&#x20AC;&#x153;pretty much the standard recommendation for patients who have CDH1, if theyâ&#x20AC;&#x2122;re healthy,â&#x20AC;? said Sam Yoon, MD, Division of Surgical Oncology, Massachusetts General Hospital and assistant professor of surgery, Harvard Medical School, Boston.

Dr. Yoon performed the gastrectomies on the North Carolina family members.

The CDH1 mutation, which is thought to affect about 100 families worldwide,

was originally described among some Maori families in New Zealand. In people with CDH1, the risk for developing gastric cancer by the age of 80 is about 83% in women and about 67% in men.

Women with CDH1 also have a high risk for lobular breast cancer.

Screening has proven fairly ineffective at identifying hereditary diffuse gastric cancer early enough to effectively treat the patient. â&#x20AC;&#x153;This diffuse-type gastric cancer often does not form a solid massâ&#x20AC;&#x201D; itâ&#x20AC;&#x2122;s kind of an infiltrative tumor,â&#x20AC;? Dr. Yoon said. â&#x20AC;&#x153;The lesions start just underneath the visible mucosa. By the time screening picks it up, itâ&#x20AC;&#x2122;s often lethal.â&#x20AC;?

The whole field of prophylactic surgery after genetic identification of hereditary cancer risk is on the rise, said Daniel Coit, MD, attending surgeon at

Memorial Sloan-Kettering Cancer Center (MSKCC), New York City, citing in particular thyroidectomy in patients with the RET mutation, which is a sure indicator the patient will develop medullary thyroid cancer. â&#x20AC;&#x153;If you do a thyroidectomy in a child [with the RET gene mutation], youâ&#x20AC;&#x2122;ll find early signs of it. The BRCA1 gene is not as penetrant. Not 100% of people with a BRCA1 gene get breast cancer or ovarian cancer,â&#x20AC;? Dr. Coit said. â&#x20AC;&#x153;We believe that in CDH1-mutated patients, close to 90% will develop cancer if it is left untreated.â&#x20AC;?

It is unlikely, however, that awareness of CDH1 from publicity around the North Carolina family will result in a rush of concerned patients demanding prophylactic gastrectomies. Genetic counselors use fairly rigorous criteria to determine who is at inherent risk for this hereditary syndrome, Dr. Yoon explained. â&#x20AC;&#x153;Youâ&#x20AC;&#x2122;d have to have two or more cases of diffuse hereditary cancer in first- or second-degree relatives, with one case under age 50; or three family members of any age with diffuse gastric cancer,â&#x20AC;?

Dr. Yoon said. Family members who meet

those criteria have a 30% to 50% chance of carrying the mutation.

Even if patients have genetic information about their cancer risk, the decision to undergo any type of prophylactic surgery is difficult, to say the least. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s extremely gratifying to prevent cancer before it becomes incurable, but these are tough decisions for patientsâ&#x20AC;&#x201D;whether to have it and when to get it,â&#x20AC;? Dr. Coit said. He listed the extensive team of medical professionals any CDH1 patient will see at MSKCC for guidance in reaching a decision. â&#x20AC;&#x153;I donâ&#x20AC;&#x2122;t want to belittle the loss of a thyroid or the loss of a breast, but there are reconstructive options that work toward restoration of quality of life after breast surgery; after thyroidectomy, replacement of the thyroid hormone is a pill that you take every day for the rest of your life,â&#x20AC;? Dr. Coit said. â&#x20AC;&#x153;But in gastrectomy patients, not only is there a risk for dying from the operation itself and from acute complications of it, there are also the long-term sequelae of it that patients need to adjust to, and thatâ&#x20AC;&#x2122;s a big issue.â&#x20AC;? â&#x20AC;&#x201D;Monica J. Smith

POLICY & MANAGEMENT Staffing

Addressing Oncology Workforce Shortage

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he American Society of Clinical Oncology (ASCO) has commissioned a new study to investigate how nonphysician practitioners, such as nurse practitioners (NPs) and physician assistants (PAs), can be used to address projected future oncology workforce shortages.

According to a 2007 ASCO workforce study, demands for oncology visits will increase 48% by 2020 and there will be a shortage of 4,000 oncologists. A recent study in the Journal of Clinical Oncology revealed that over the next 20 years, the number of new cancer cases diagnosed

annually in the United States will increase by 45% (2009; Epub ahead of print, PMID: 19403886). Cancer specialists are expected to face a difficult challenge in dealing with this patient load. â&#x20AC;&#x153;ASCO and the Workforce Advisory Group continue to explore a variety of solutions to the anticipated oncology workforce shortage,â&#x20AC;? said Douglas W. Blayney, MD, ASCO president, in a press statement. â&#x20AC;&#x153;We believe collaborative practice models will help cancer care professionals cope with the realities of having too many patients and not

enough doctors.â&#x20AC;?

Oncology Metrics will conduct the comprehensive analysis of how oncologists, NPs and PAs collaborate to provide patient care. Up to 40 private and hospital-based oncology practices will be involved, and researchers will specifically examine the satisfaction, efficiency and productivity of each collaborative care team in order to establish â&#x20AC;&#x153;best practices.â&#x20AC;? Researchers will survey practices that vary in size, patient population and location. Results are expected in early 2011.

According to ASCOâ&#x20AC;&#x2122;s 2007 workforce

study, 56% of oncologists work with NPs or PAs, and providers who use these professionals have higher visit rates than those who do not. NPs and PAs provide services such as ordering and administering routine chemotherapy, as well as patient education and counseling.

The study is part of a collaboration between the ASCO Cancer Foundation, ASCO and Susan G. Komen for the Cure, in which Komen is providing $10 million in support of projects and programs designed to improve the quality of cancer care in the United States.

Cancer Therapeutic Agents Guide Now Available

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he â&#x20AC;&#x153;Guide to the Administration and Use of Cancer Therapeutic Agents 2009â&#x20AC;? is available.

Brought to you by Clinical Oncology News, the guide is authored by Val R. Adams, PharmD, associate professor at the University of Kentucky College of Pharmacy in Lexington, and Susanne E. Liewer, PharmD, clinical pharmacy specialist, Stem Cell Transplant, Childrenâ&#x20AC;&#x2122;s Mercy Hospital in Kansas City, Mo. The drug information in this review is based on the most recent product literature at the time of printing; see the package insert for each product for complete prescribing information.

To request a hard copy of this pocket guide, please visit www.clinicaloncology.com/copyorderform.asp.

All pocket guides are free to MDs in oncology and hematology/oncology, oncology nurses and oncology pharmacists, plus shipping and handling of $5.99 for the first copy and $1.00 for each additional copy.

For bulk orders of up to 10 copies, pay only $15.99 and $1.00 for each additional copy shipping and handling (U.S. orders only).

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Ethics

Revised Code of Ethics Seeks To Balance Physicianâ&#x20AC;&#x201C;Industry Ties The relationship between industry and the physicians who use their products is always a delicate balancing act, and both perceived and real conflicts of interest must be carefully monitored.

Now, significant revisions to the Advanced Medical Technology Association (AdvaMed) Code of Ethics aim to restrict some practices that may have led to abuses in the past. â&#x20AC;&#x153;The goal is always to make sure that every time a doctor makes a decision, it is in the best interest of the patient, and not because of a relationship with a device company,â&#x20AC;? said Andrew Van Haute, AdvaMedâ&#x20AC;&#x2122;s deputy general counsel. According to its Web site, AdvaMedâ&#x20AC;&#x2122;s member companies produce nearly 90% of the medical technology purchased in the United States.

The revised code of ethics (www. advamed.org/MemberPortal/About/code) includes a number of changes to how industry representatives can interact with health care professionals. There now is an explicit prohibition from providing entertainment to physicians, and the provision of meals is allowed only under specific circumstances.

There also are changes to the guidelines regarding consulting and other relationships between industry and physicians. AdvaMed specifies that the need for a consultant must be legitimate, and selection of the consultant should be based on his or her qualifications and expertise to meet that predefined need. Furthermore, the code states that the compensation in such an agreement needs to be consistent with fair market value, and should not in any way be dependent on the volume of the consultantâ&#x20AC;&#x2122;s potential business with the company. â&#x20AC;&#x153;I think the revised guidelines are an improvement,â&#x20AC;? said Jaimie Henderson, MD, professor of neurosurgery at Stanford University Medical Center, in Stanford, Calif., and president of the North American Neuromodulation Society. â&#x20AC;&#x153;I think it is very important for industry and physiciansâ&#x20AC;&#x201D;especially in the area of neuromodulationâ&#x20AC;&#x201D;to have a very well-defined relationship, and that needs to follow very clear-cut ethical principles.â&#x20AC;?

inform some of the decisions that we made on the revisions,â&#x20AC;? Mr. Van Haute said. AdvaMed first wrote its code of ethics in 1991, and undertook a first major revision in 2003 that went into effect in 2004. The new revisions officially took effect on July 1, 2009.

Under the new rules, companies will not be permitted to provide gifts of any type to physicians, regardless of value, including the perennial favorite, the free pen.

Backlash to Major Abuses Dr. Henderson said that some recent high-profile cases involving inappropriate relationships between medical device companies and doctors have increased scrutiny of the field. One notable case involved five major orthopedic device companies (Zimmer, DePuy Orthopaedics, Stryker, Biomet and Smith & Nephew) and an investigation into whether consulting agreements with physicians violated the federal antikickback statute. The case was settled with the U.S. Department of Justice in September 2007, with the companies agreeing to pay more than $300 million in penalties. â&#x20AC;&#x153;Those situations arenâ&#x20AC;&#x2122;t necessarily what made us decide to revise the code, but they did in a way

Some think that the reaction to such public and costly issues is leading to practices that may hinder the development of new technologies and efforts to better treat patients. â&#x20AC;&#x153;Before, maybe there was too little scrutiny of relationships between physicians and industry, but now thereâ&#x20AC;&#x2122;s too much,â&#x20AC;? said David Schultz, MD, medical director of Medical Advanced Pain Specialists medical pain clinics in Minneapolis and president of the American Society of Interventional Pain Physicians. â&#x20AC;&#x153;I think that was a minority of cases; I donâ&#x20AC;&#x2122;t think that it is a common, epidemic problem. There is a kind of overreaction now, to the point where almost

any relationship between a physician and industry is suspect, which I think is very unfortunate. I certainly believe in transparency and compensation that is commensurate for actual work performed. But if physicians are stigmatized for collaborating with industry, then medical progress will be hindered and patients will suffer.â&#x20AC;?

The End of the Free Pen? The changes to AdvaMedâ&#x20AC;&#x2122;s code go beyond consulting and other financial relationships. Under the new rules, companies also will not be permitted to provide gifts of any type to health care professionals, regardless of value.

This includes â&#x20AC;&#x153;noneducationalâ&#x20AC;? branded promotional items such as pens, notebooks or mugs.

Some believe that such prohibitions go beyond making sure that the patientâ&#x20AC;&#x2122;s wellbeing is the first priority, but Dr. Henderson said eliminating any possibility of unconscious bias is important. â&#x20AC;&#x153;Everybody says that they wonâ&#x20AC;&#x2122;t be influenced by industry gifts and that they take conscious steps to distance themselves from any individual company even if they do provide something of value,â&#x20AC;? he said. â&#x20AC;&#x153;But I think the supposition that we can eliminate our own biases is a false one. I think we need to have strict guidelines, like the AdvaMed guidelines, in order to help us with that.â&#x20AC;?

Dr. Schultz disagreed, saying that the effect of the high-profile settlements and abuses causes unnecessary changes to standard practice. â&#x20AC;&#x153;I think physicians can realize that and actively prevent [bias] from entering into their decision-making process,â&#x20AC;? he said. â&#x20AC;&#x153;I think weâ&#x20AC;&#x2122;re sophisticated professionals, and I donâ&#x20AC;&#x2122;t think that weâ&#x20AC;&#x2122;re going to be influenced by that type of thing to actually take an action. I donâ&#x20AC;&#x2122;t buy that subconsciously Iâ&#x20AC;&#x2122;m going to be prescribing things because of some lunch that somebody gave me. I find it insulting, actually.â&#x20AC;?

Whether or not a pen or a lunch would influence a physician into using a device or prescribing a drug is not explicitly addressed in the revised code of ethics, but Mr. Van Haute said the perception of impropriety is important to avoid. Branded promotional items, he said, are â&#x20AC;&#x153;rightly or wrongly seen as putting a cloud over the physicianâ&#x20AC;&#x2122;s decision making. And we thought it best to just eliminate that entirely.â&#x20AC;?

Although Dr. Henderson said the revisions are a step forward in improving the relationship between industry and health care professionals, it will require some new thinking on how to continue some of the collaborative efforts that help to push technology in the right direction. â&#x20AC;&#x153;The evolution is toward ever-stricter rather than looser guidelines,â&#x20AC;? he said. â&#x20AC;&#x153;I think that, overall, these guidelines are proper, theyâ&#x20AC;&#x2122;re good and theyâ&#x20AC;&#x2122;re helpful, but there are some areas where they may in fact impact patient care negatively.â&#x20AC;? â&#x20AC;&#x201D;Dave Levitan

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Breast

â&#x20AC;&#x153;Top 10â&#x20AC;? Breast Cancer Studies Reviewed at Meeting Expert Discusses Potential Practice-Changing Research In what has become one of the most popular presentations at the annual meeting of the American Society of Breast Surgeons (ASBS), Helen Pass, MD, assistant professor of clinical surgery at Columbia University in New York City, and attending surgeon at NewYorkPresbyterian/Columbia University Medical Center and Lawrence Hospital in Bronxville, N.Y., discusses what she considers the top 10 breast cancer papers of the year.

Dr. Pass selects the papers based on a variety of issues. â&#x20AC;&#x153;When you PubMed â&#x20AC;&#x2DC;breast cancer 2008,â&#x20AC;&#x2122; there are almost 8,000 papers,â&#x20AC;? she said. â&#x20AC;&#x153;So I try to limit it to any landmark studies, studies that when you go home might change what you are going to do, or [topics] that [were] highlighted in the news that patients seem to ask about.â&#x20AC;?

Dr. Pass came up with the idea of a Top 10 presentation in 2003, when she was program chair of the ASBS meeting. â&#x20AC;&#x153;Trying to keep up with the wealth of literature out there is all-consuming,â&#x20AC;? she said. â&#x20AC;&#x153;I always wanted somebody to tell me, â&#x20AC;&#x2DC;here, read this.â&#x20AC;&#x2122; â&#x20AC;? At that time, she was also the editor of a review journal, for which reading all of the breast research papers was a requirement. â&#x20AC;&#x153;It was a natural marriage. That journal has ceased to exist, but I still do this paper every year.â&#x20AC;?

The Top 10 Breast Cancer Papers of 2008 1. Azimm A, Constantini-Ferrando M, Oktay K. Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study. J Clin Oncol. 2008;26:2630-2635, PMID: 18509175.

Fertility issues are becoming more important as more breast cancer patients are being diagnosed at younger ages. Recent American Society of Clinical Oncology guidelines now encourage the assessment of desire for fertility preservation and emphasize the need for appropriate referral, and patients are increasingly aware of this issue.

Fertility preservation makes surgeons apprehensive, however, due to the hormonal component of breast cancer and the fact that the supraphysiologic levels of estradiol that occur with conventional ovarian stimulation may increase the risk for recurrence. The purpose of this trial was to determine if letrozole plus standard fertility medication affected the disease-free survival of women undergoing treatment.

In this nonrandomized trial, 215 women were prospectively evaluated for in vitro fertilization (IVF); 79 patients underwent IVF with letrozole and standard agents, and 136 did not receive IVF.

At post-chemotherapy follow-up (median, 23.4 months for the letrozole group and 33.1 months for the control group), there were no differences in disease-free status or overall survival rate between the two groups. Conclusion: IVF with letrozole and standard agents does not seem to increase the risk for recurrence in women with breast cancer who undergo fertility treatment.

The short follow-up gave Dr. Pass some concern. Although a large percentage of cancers will recur within two years, cancer may recur later in life. â&#x20AC;&#x153;But IVF stimulation with letrozole did work and was effective,â&#x20AC;? she said.

Application for practice: Women of childbearing age should be offered referral for counseling about fertility preservation. â&#x20AC;&#x153;I hate to tell you this, but as the surgeon this is now one more obligation,â&#x20AC;? along with referral or counseling for the genetic component of the disease, considering the patientâ&#x20AC;&#x2122;s molecular profile and having a meaningful discussion about breast reconstruction before they see the plastic surgeon, Dr. Pass said. â&#x20AC;&#x153;We are the first line of education for our patients. If they are interested in fertility preservation, you need to be the one to start this conversation.â&#x20AC;? She recommended that surgeons identify nearby fertility clinics with the expertise to deal with women with breast cancer so that this information is readily available. â&#x20AC;&#x153;I do think this challenge is falling on us and the best way to [face] it is to be prepared.â&#x20AC;?

2. Thompson M et al. Intraoperative radioisotope injection for sentinel lymph node biopsy. Ann Surg Oncol. 2008;15:3216-3221, PMID: 18777194.

Preoperative injection of technetium sulfur colloid (Tc-99) is painful for patients and can cause problems with scheduling and operating room (OR) delays. This study was conducted to determine if intraoperative injection of Tc-99 is feasible.

This was an IRB-approved, prospective study of patients with operable breast cancer who were candidates for sentinel lymph node (SNL) biopsy. The patients underwent subareolar injection of 1 mCi Tc-99 after general anesthesia. The

236 patients underwent 252 SNL biopsies; time from injection to incision was 25.5Âą16.2 minutes; identification rate was 96%; average number of SNLs was 1.6Âą0.8; 20% of patients had a positive SNL; radiation exposure to surgical staff was well below established acceptable limits; and cost savings were $1,325 per patient. Conclusion: Intraoperative subareolar injection of Tc-99 is pain-free for patients, simplifies surgical scheduling, avoids surgical delays and is less costly.

Application for practice: â&#x20AC;&#x153;This paper caught my eye because itâ&#x20AC;&#x2122;s a dream of mine,â&#x20AC;? Dr. Pass said. This study provides evidence that there is no magical time window for Tc-99, and that the injection can be given in a pain-sparing way. â&#x20AC;&#x153;I know my nuclear medicine colleagues cringe because they donâ&#x20AC;&#x2122;t like inflicting pain,â&#x20AC;? Dr. Pass said. She recommended surgeons discuss the study with their nuclear medicine colleagues, and ask them to consider coming to the OR to provide the service or, if regulatory issues can be resolved, turning the performance of that service over to the surgeons themselves.

3. Arora S et al. Atypical ductal hyperplasia at the margin of breast biopsyâ&#x20AC;&#x201D;is re-excision indicated?

Ann Surg Oncol. 2008;15:843-847, PMID: 17987337.

Atypical ductal hyperplasia (ADH) warrants surgical excision when it is found on a core biopsy. It is not so clear, however, what to do when ADH is found at the border of a lumpectomy. Dr. Pass herself questions the biologic relevance when there is not a frank malignancy, but her pathologistâ&#x20AC;&#x2122;s concernsâ&#x20AC;&#x201D;â&#x20AC;&#x153; â&#x20AC;&#x2DC;this one is bad, that one is OKâ&#x20AC;&#x2122; â&#x20AC;?â&#x20AC;&#x201D;have made her wonder. â&#x20AC;&#x153;I think itâ&#x20AC;&#x2122;s the extent of volume in all of the margin, but I want the pathologist to come up with the clinical relevance to these problems.â&#x20AC;?

This study was a retrospective review of the pathology database of Mount Sinai Medical Center, New York City, over five-and-a-half years. Of 44 lumpectomy specimens with ADH involving the surgical margin, 24 patients (55%) underwent re-excision at the surgeonâ&#x20AC;&#x2122;s discretion. The re-excisions revealed no additional disease in nine and ADH in two, and more ductal carcinoma in situ (DCIS) or invasive ductal carcinoma

(IDC) in four patients. Of the 15 patients originally diagnosed with ADH, four (27%) were upstaged, and of the eight with a known diagnosis of malignancy, four (50%) had additional cancer at reexcision even when there was no cancer present at the margin. Conclusion: ADH at the margin of a lumpectomy is associated with a high rate of residual ADH and cancer; re-excision of all patients with ADH is recommended. â&#x20AC;&#x153;I wish medicine were that simple,â&#x20AC;?

Dr. Pass said, noting the study consisted of a highly selected, small retrospective cohort with modest long-term follow-up. Critical examination of the data reveals that in patients with a diagnosis of ADH alone, upgrading was most likely if there was a residual mammographic abnormality indicating a mass or calcifications, which would imply that the original lesion wasnâ&#x20AC;&#x2122;t adequately sampled with surgical excision, she explained.

Application for practice: â&#x20AC;&#x153;If I have ADH on a core and I remove the area and find ADH at the margin but remove the vast majority of the mammographic abnormality, those patients donâ&#x20AC;&#x2122;t necessarily have to go on for re-excision,â&#x20AC;?

Dr. Pass said. â&#x20AC;&#x153;They need to be treated as high-risk patients and have a discussion about chemoprevention.â&#x20AC;?

In patients with a cancer diagnosis, however, the extent and amount of ADH should be considered. â&#x20AC;&#x153;One duct with ADH at the margins is very different than a ton of ADH at multiple margins,â&#x20AC;? Dr. Pass said. â&#x20AC;&#x153;Maybe we need to be thinking more critically [whether] we could re-excise those patients much like we do for DCIS at the margin, especially if they still have a [cosmetically] acceptable outcome.â&#x20AC;?

4. Ciocca R, Li T, Freedman G, Morrow M. Presence of lobular carcinoma in situ does not increase local recurrence in patients treated with breast-conserving therapy.

Ann Surg Oncol. 2008;15:2263-2271, PMID: 18506537.

Surgeons usually perform an excision when lobular carcinoma in situ (LCIS) is found on core biopsy. This study was conducted to determine the need for re-excision if LCIS is present in the lumpectomy specimen, especially at the margin.

The study was a retrospective database review of 894 early-stage (0-II) cancer patients treated at a single institution over 27 years. Of 290 patients with LCIS, 84 had LCIS at the final margin; 2,604 patients without LCIS served as controls. Median follow-up duration was 5.2 years. see TOP 10, page E

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doing multiple frozen sections.â&#x20AC;?

TOP 10 continued from page D

In patients with LCIS at the margin, the local recurrence rate at five to 10 years was 6%. When LCIS was present in the specimen but not in the margin, the local recurrence rate was 1% and 15% at five and 10 years, respectively. In the absence of LCIS, the local recurrence rate was 2% and 6% at five and 10 years, respectively. Conclusion: The presence of LCIS in the margin of breast-conserving therapy specimens does not affect local recurrence and does not mandate re-excision.

Application for practice: â&#x20AC;&#x153;Not all highrisk lesions are equalâ&#x20AC;&#x201D;what you do for ADH may not extrapolate to LCIS, and we have no information on ALH [atypical lobular hyperplasia],â&#x20AC;? Dr. Pass said. â&#x20AC;&#x153;But we know that the presence of DCIS at the margin is an indication for re-excision, so even all in situs are not the same.

This is an evolving field and one to stay tuned to and to begin to monitor in your own practice.â&#x20AC;?

5. Julian T et al. Novel intraoperative molecular test for sentinel lymph node metastases in patients with early-stage breast cancer. J Clin Oncol. 2008;26:3338-3345, PMID: 18612150.

For intraoperative SNL evaluation, most surgeons currently use frozen section and touch prep cytology. The authors of this study conducted a beta trial and a validation trial to validate use of the intraoperative molecular sentinel node test (aka, the breast lymph node [BLN] assay).

The beta trial consisted of 304 patients to determine the threshold of mammaglobin and cytokeratin 19, which correlate with metastases within the sentinel node greater than 0.2 mm. The validation trial of 416 patients was done to corroborate this threshold. The BLN assay required 36 to 46 minutes to complete. Conclusion: The BLN assay allows rapid evaluation of the sentinel node that is more accurate than conventional techniques.

Compared with frozen section analysis, the BLN assay â&#x20AC;&#x153;had a superior sensitivity and negative predictive value,â&#x20AC;? Dr. Pass said. â&#x20AC;&#x153;The negative predictive value is important because none of us wants to do a completion axillary lymph node dissection [and find out] the sentinel node really wasnâ&#x20AC;&#x2122;t positive.â&#x20AC;?

Application for practice: The technology is yet not widely available, but â&#x20AC;&#x153;if itâ&#x20AC;&#x2122;s something your pathology department is interested in pursuing, the fact that it is molecularly based instead of pathologically based should not give you pause for concern,â&#x20AC;? Dr. Pass said. â&#x20AC;&#x153;In very busy centers, since this is a [technologistâ&#x20AC;&#x201C;dependent] rather than a pathologist-dependent assay, this may allow for ease and greater simplicity in cases where theyâ&#x20AC;&#x2122;re

6. Martelli G et al. Elderly breast cancer patients treated by conservative surgery alone plus adjuvant tamoxifen. Cancer. 2008;112:481-488, PMID: 1809826.

Elderly patients with breast cancer often do not receive treatment in compliance with national guidelines.

Many surgeons individualize care of the elderly because of their comorbidities, their reduced life expectancy, the presumed favorable biologic behavior of their tumors and the effectiveness of adjuvant hormonal therapy. This study evaluated the need for SNL biopsy and radiation therapy in elderly patients with breast cancer.

The prospective study followed 354 women older than 70 years with operable breast cancer for a median of 15 years. The patients had margin-negative breast-conserving therapy and no axillary procedures or radiation, and all received adjuvant tamoxifen. The crude cumulative index of axillary disease was 4.2%, in-breast recurrence was 8% and distant metastasis was just under 8.8%. Overall mortality was 76%, with 17% from breast cancerâ&#x20AC;&#x201C;specific causes. Conclusion: Elderly patients with clinically node-negative disease can be treated with conservative surgery and hormone therapy, without an axillary procedure or radiation.

Application for practice: Surgeons often face an unsettling conundrum when deciding how much treatment to subject their elderly patients to. â&#x20AC;&#x153;You always feel guilty if you withhold one form of treatment or another,â&#x20AC;? Dr. Pass said. â&#x20AC;&#x153;This study justifies the art of medicine that we practice every day and [supports] this approach in a selected patient population.â&#x20AC;?

If the surgeon and patient decide to forgo radiation, obtaining negative margins is critical and the delivery of adjuvant hormonal treatment is important to increase local control. Surgeons should keep in mind the original National Surgical Adjuvant Breast and Bowel Project studies showing that if patients have an axillary relapse, surgery performed at a later date is still effective. Also, elderly patients vary greatly in fitness; chronologic age should not be the main factor determining treatment.

7. Hooning M et al. Roles of radiotherapy and chemotherapy in the development of contralateral breast cancer. J Clin Oncol.

2008;26:5561-5568, PMID: 1885457.

Women who have breast cancer have a threefold to fourfold increase in the risk for developing contralateral breast cancer. This study examined the role of modern radiation and chemotherapyâ&#x20AC;&#x201D;which are constantly evolvingâ&#x20AC;&#x201D;in the risk for contralateral breast cancer

development.

In this Dutch registry review of 7,425 patients with a follow-up rate of 95%, the risk for contralateral breast cancer increased in women under 35 years of age receiving radiation (hazard ratio [HR], 1.78); in women over 45, HR approached 1; there was little comment on women aged 35 to 45. Conclusion: Women under 45 irradiated with tangential fields have an increased risk for contralateral breast cancer, especially if they have a positive family history. Chemotherapy in the first five years may mitigate this risk (thereafter, it makes no difference).

Application for practice: â&#x20AC;&#x153;We have to counsel these women regarding the risk of contralateral breast cancer and discuss surgical options,â&#x20AC;?

Dr. Pass said. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s very difficult to tell a woman who has a lumpectomy option that she might want to consider mastectomy or bilateral mastectomy, but women need to be apprised of their risk of contralateral disease.â&#x20AC;?

This also calls into question postoperative surveillance. â&#x20AC;&#x153;We tend to take for granted that once these women are five years out, theyâ&#x20AC;&#x2122;ll be followed by their primary care providers; but maybe as their breast surgeon, we need to be more aware of their risk for contralateral breast disease,â&#x20AC;? Dr. Pass said.

8. Mortimer J et al. Tamoxifen, hot flashes, and recurrences in breast cancer. Breast Cancer Res Treat.

2008;108:421-426, PMID: 17541741.

In this study, 864 women on tamoxifen, diagnosed between 1995 and 2005, filled out an extensive questionnaire on a variety of topics, including their experience of hot flashes. The women were staged I-IIIa breast cancer. Those who reported hot flashes had a recurrence rate of 12.9%, while those who did not report hot flashes had a recurrence rate of 21%. Conclusion: Hot flashes are a stronger predictor of recurrence than age, hormone receptor status or whether the patient is stage I or II. Application for practice: â&#x20AC;&#x153;In our practice, compliance with hormonal therapy is variableâ&#x20AC;&#x201D;many women get discouraged and want to stop,â&#x20AC;? Dr. Pass said, noting that she herself has always been nervous when patients breeze through chemotherapy. â&#x20AC;&#x153;In the back of my mind, I wonder if anything is really being biologically affected. This study is evidence for surgeons to share with patients who complain bitterly about hot flashes. That means the drug is really working and they [will have] a better outcome.â&#x20AC;?

9. Goss P et al. Late extended adjuvant treatment with letrozole

improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol.

2008;26:1948-1955, PMID: 18332475.

The Oxford overview of hormonal therapy for early-stage breast cancer indicates that more than half of all breast cancer recurrences or deaths happen after five years of adjuvant tamoxifen; longer duration of tamoxifen use has not been shown to be beneficial. â&#x20AC;&#x153;What happens to women who have been off tamoxifen for a substantial period of time?â&#x20AC;? Dr. Pass asked. â&#x20AC;&#x153;Many women who took tamoxifen for five years were told that it was time to stop it and sent on their way.

Should they now initiate a separate round of treatment?â&#x20AC;?

In the National Cancer Institute of Canada Clinical Trials Group MA.17 trial, patients were initially randomized to receive placebo versus letrozole after five years of tamoxifen. The trial reached stopping criteria after 2.5 years, and treatment was unblinded. There was a significant improvement in women who were on letrozole, and women on placebo were offered the option of switching to letrozole. Consequently, 1,579 patients switched and 804 patients remained on placebo.

The median follow-up was 5.3 years.

In the letrozole group, disease-free survival improved impressively (HR, 0.37), as did distant diseaseâ&#x20AC;&#x201C;free survival (HR, 0.39). Conclusion: Letrozole improves disease-free survival and distant diseaseâ&#x20AC;&#x201C;free survival even if substantial time has passed since the discontinuation of tamoxifen.

Application for practice: â&#x20AC;&#x153;Not only do you have to do more pre-diagnosis in these women, but Iâ&#x20AC;&#x2122;m asking you to do more post-diagnosis as well,â&#x20AC;? Dr. Pass said. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s important that we disseminate this information to our primary care providers,â&#x20AC;? and alert them that the algorithm has changed. â&#x20AC;&#x153;After five years of tamoxifen, women need to be either started on another agent or referred back to their medical oncologist, breast surgeon or another provider for consideration of additional treatment.â&#x20AC;?

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10. Cady B, Nathan R, Michelson J. Matched pair analyses of stage IV breast cancer with or without resection of primary breast site.

Ann Surg Oncol. 2008;15:3384-3395, PMID: 18726129. â&#x20AC;&#x153;Weâ&#x20AC;&#x2122;ve heard a lot about women with stage IV breast cancer who have a survival benefit when the primary tumor is resected, but this is still debated,â&#x20AC;?

Dr. Pass said. The authors of this study sought to determine if selection bias accounts for the improved survival of women with stage IV breast cancer who undergo resection of the primary tumor.

The study analyzed patients with stage IV breast cancer, matching cases on age, date of diagnosis, location of metastatic disease, estrogen receptor (ER) status and use of adjuvant and systemic therapy.

Of 622 patients, 388 (62%) had no primary site surgery, 234 (38%) underwent surgery of their site. Survival was significantly improved in patients who underwent surgery (P=0.0001).

Survival, however, was better in patients who received chemotherapy before surgery; there was no benefit for those who received chemotherapy and surgery without a time delay. Conclusion: The case

selection bias of stage IV patients who undergo surgery explains most of the apparent survival benefit seen with this approach. There is no biologic explanation for the improved outcome.

Application for practice: Resecting primary patients with stage IV disease is still not a standard of care, but it is no longer taboo. â&#x20AC;&#x153;We used to be told, if you operate on these patients youâ&#x20AC;&#x2122;re breaking some sort of rule,â&#x20AC;? Dr. Pass said. But â&#x20AC;&#x153;on a case-by-case basis, there are probably several selected patients who will benefit from what we used to term the â&#x20AC;&#x2DC;effort effect.â&#x20AC;&#x2122; â&#x20AC;? The patients most likely to

benefit from this resection of the primary tumor are those who have â&#x20AC;&#x153;a dramatic response to chemotherapy, have oligometastases, have a good performance status and are highly motivated.â&#x20AC;?

Keeping up with the literature is a Sisyphusian task for most. â&#x20AC;&#x153;Given the vast quantity of published material, staying current is a challenge for the practicing physician, which is why I review articles such as these,â&#x20AC;? Dr. Pass said. â&#x20AC;&#x153;Attendance at meetings can [also] help highlight important advances and keep the practitioner up to date.â&#x20AC;? â&#x20AC;&#x201D;Monica Smith

cancer patient referrals, because of the hospitalâ&#x20AC;&#x2122;s aggressive hiring of doctors and specialists and the hospital intentionally diverting referrals away from him to generate profit.

According to a spokesman for OMC, the lawsuit is without merit and the business practices of the hospital are legal and ethical.

nutrition throughout treatment.

Nutritional support for cancer outpatients is often limited to minimal advice from their oncologists and some specific cookbooks that are on the market. â&#x20AC;&#x153;Studies have shown that customized nutritional modifications to complement a patientâ&#x20AC;&#x2122;s course of treatment can be very beneficial before, during and after treatment,â&#x20AC;? said James Hermann, president and CEO of TherapEase Cuisine. â&#x20AC;&#x153;Thatâ&#x20AC;&#x2122;s why weâ&#x20AC;&#x2122;ve developed a program for cancer patients that they can individually sign up for or that health care systems can purchase and offer to their patients.â&#x20AC;?

Program participants receive individualized and detailed food recommendations, as well as direct support via e-mail or phone from staff dietitians. The program features expert advice customized to each patientâ&#x20AC;&#x2122;s diagnosis, treatment and criteria; regular reassessment and modifications based on symptoms and side effects as they materialize; and a library of educational information including updates for new studies and developments in the field of oncology dietetics. The companyâ&#x20AC;&#x2122;s headquarters is in Greenfield, Wis.

PEOPLE & PLACES

Around the Water Cooler O. Carl Simonton, MD, Dies O. Carl Simonton, MD, a radiation oncologist who advocated treating the emotional and psychological needs of cancer patients, has died. He was 66. Dr. Simonton popularized the mindâ&#x20AC;&#x201C;body connection in fighting cancer and helped push this notion into mainstream medicine. He advocated for treating patients through techniques such as meditation and image-guided therapy.

In the early 1970s, he founded the Cancer Counseling and Research Center in Fort Worth, Texas. In 1978, he co-wrote the book â&#x20AC;&#x153;Getting Well Again.â&#x20AC;? In 1984, he moved his practice to California, where he founded the Simonton Cancer Counseling Center, currently located in Malibu. He died suddenly, choking during a meal at his home in Agoura Hills, Calif.

Oncologist Files Lawsuit

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ccording to an article in the Peninsula Daily News, a regional paper in Washington state, cancer specialist

Robert Witham, MD, has filed a federal lawsuit against Olympic Medical Center (OMC), in Port Angeles, arguing that the hospital is a monopoly and violates the federal Sherman Antitrust Act. The suit resurrects accusations of unfair competition that he first made in 2004.

In his suit, Dr. Witham alleges that the medical center and its public hospital is illegally driving him out of business and violating the law by directly employing doctors to unfairly compete with private physicians. He claims that the hospitalâ&#x20AC;&#x2122;s intention to hire a second medical oncologist will virtually drive him out of business. â&#x20AC;&#x153;OMC has now obtained monopoly power over the delivery of most professional medical services in Clallam County,â&#x20AC;? the lawsuit states.

According to the Peninsula Daily News, Dr. Witham claims the hospitalâ&#x20AC;&#x2122;s actions including disparaging his reputation have cost him hundreds of thousands of dollars in losses. He has also experienced a precipitous decline in new

Cancer Survivors Launch Company

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ancer survivors in Wisconsin have launched a company to offer an online nutritional service and meal-planning program for cancer patients. The company, called TherapEase Cuisine, Inc., can be accessed at www.therapeasecuisine.com. According to the companyâ&#x20AC;&#x2122;s Web site, their program is based on accepted oncology-dietetic practice and was developed by registered dietitians. It is available to cancer patients and health care systems treating cancer patients to assist in maintaining

CME Opportunity Available: Cutaneous T-Cell Lymphoma Are you in need of continuing medical education (CME) credits?

The CME activity, â&#x20AC;&#x153;Cutaneous T-Cell Lymphoma: Early Diagnosis and Optimal Management Strategies,â&#x20AC;? is available at www.clinicaloncology.com.

The review covers categorization and clinical-histologic features of CTCL, diagnosis and staging, and optimal medical management. The activity is valid for CME credits for physicians, pharmacists and nurses until Aug. 1, 2010.

F

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Bevacizumab, Pazopanib Ripe for Approval in RCC Ronald Bukowski, MD, Highlights What You Need To Know From the ASCO Meeting Orlando, Fla.â&#x20AC;&#x201D;At the 2009 annual meeting of the American Society of Clinical Oncology (ASCO), significant new information and data on renal cell carcinoma (RCC) was presented.

Physicians and scientists submitted more than 100 abstracts, of which 49 were chosen for either oral or poster presentation. Several of these were notable for the information provided and their potential influence on patient care. These abstracts can be divided into three categories: clinical trial updates, novel agent development for therapy of metastatic RCC (mRCC) and toxicity management.

Bevacizumab News During the ASCO 2008 meeting, the final overall survival (OS) update for the Phase III trial comparing sunitinib (Sutent, Pfizer) to interferon (IFN)-Îą in patients with treatment-naĂŻve mRCC was presented (J Clin Oncol 2008;26: abstract 5024). A clinically significant improvement in median OS for patients receiving the tyrosine kinase inhibitor (TKI) sunitinib was noted (26.4 vs. 21.8 months; hazard ratio [HR], 0.818; stratified log rank P=0.0491).

This year, two large Phase III studies comparing bevacizumab (10 mg/kg IV every two weeks) plus subcutaneous IFN-Îą (9 mU three times per week) or the same dose of IFN-Îą monotherapy in untreated patients were updated, and final survival analyses discussed. Previously reported results from both trials had revealed a significant improvement in progression-free survival (PFS) and overall response rate (ORR) for patients receiving bevacizumab plus IFN-Îą. At ASCO, Rini and colleagues presented results from the Cancer and Leukemia Group B (CALGB) trial in which 732 patients were randomized in open-label fashion to either treatment (J Clin Oncol 2009;27: LBA5019); 369 patients received the combination and 363 received IFN-Îą. The median OS for the cohort receiving combination therapy was 18.3 months (95% confidence interval [CI], 16.5-22.5) compared with 17.4 months for IFN-Îą treated patients (HR, 0.86; 95% CI, 14.4-20.0; stratified log rank P=0.068) (Figure 1). The data for MSKCC prognostic subgroups were also presented. The median OS in the favorable-risk group receiving bevacizumab plus IFN-Îą versus IFN-Îą was 32.5 versus 33.5 months (P=0.524); in the intermediate-risk group, 17.7 versus 16.1 months (P=0.174); and in poor-risk patients, 6.6 versus 5.7 months (P=0.245). It was noted that 53% of patients had received secondary therapy following disease progression.

The AVOREN trial, updated by Escudier and colleagues, also compared bevacizumab plus IFN-Îą with IFN-Îą alone (J Clin Oncol 2009;27: abstract 5020). In this double-blind, placebo-controlled study, 648 patients were randomized to either bevacizumab plus IFN-Îą (n=327) or placebo plus IFN-Îą (n=322). The final median OS for patients receiving bevacizumab was 23.3 months, compared with 21.3 months (HR, 0.86; stratified log rank P=0.1291) for patients treated with IFN-Îą and placebo. Secondary therapy including TKIs, mTOR inhibitors, cytokines and chemotherapy was administered to 180 patients (55%) in the bevacizumab plus IFN-Îą arm and 202 patients (63%) in the placebo plus IFN-Îą arm. A subset analysis of patients receiving subsequent

Overall Response Rate, %

10

30

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ADVISORY BOARD EDITORIAL Ronald M. Bukowski, MD Director of Experimental Therapeutics Program Taussig Cancer Center Cleveland Clinic Foundation Cleveland, Ohio

Pazopanib Placebo

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findings from the CALGB trial provide additional evidence for this effect.

Novel TKIs 10 3 0

Figure 2. Comparison of response rate in RCC patients.

This series of Phase II trials reported the activity of these multi-kinase inhibitors, and a noted investigator assessed ORR between 19.6% (ABT-869) and 27.2% (AVI-951).

TKIs (96 and 81 patients, respectively) demonstrated a median OS of 38.6 months for those initially treated with bevacizumab plus IFN-Îą versus 33.2 months for the placebo plus IFN-Îą group (HR, 0.77; P=0.1948).

Survival data for the various MSKCC subsets was not presented.

These two very important trials were different in design and eligibility criteria, but represent the current data set for patients receiving bevacizumab plus IFN-Îą. The previously reported improvements in PFS and ORR have been maintained; however, no significant differences in survival were identified. It is possible that secondary therapy with agents such as sunitinib, sorafenib or temsirolimus confounded these analyses, but the subset data presented could not demonstrate this effect. A second interesting finding in the CALGB study was the lack of OS difference in the favorable MSKCC subgroup, something that was also noted in the sunitinib versus IFN-Îą trial (J Clin Oncol 2009;27:1-7). It may well be that this group of patients with few symptoms and limited disease experiences major effects with secondary treatments, or patients with indolent disease experience different clinical outcomes. Further analyses of these studies hopefully will clarify some of these issues.

Finally, based on the available information, it seems likely that the FDA will approve the combination of bevacizumab and IFN-Îą for treatment of patients with advanced RCC. The significant improvement in PFS associated with bevacizumab and IFN administration supports this approval, and the supportive

A second set of presented abstracts described a series of TKIs with significant antitumor effects in metastatic clear cell RCC. Sternberg and colleagues presented an initial report of a blinded, placebocontrolled Phase III trial in which patients with mRCC were randomized (2:1) to either the multikinase inhibitor pazopanib (GlaxoSmithKline) at 800 mg daily (n=290) or a placebo (n=145) (J Clin Oncol 2009;27: abstract 5021). Therapy was continuous, and at progression, patients receiving placebo were permitted to cross over to pazopanib. The study included both untreated (n=233) and cytokinerefractory patients (n=202).

Investigators found that PFS was significantly prolonged by pazopanib compared with placebo (9.2 vs. 4.2 months; HR, 0.46; P<0.0000001). A similar effect was seen in both the treatment-naĂŻve (11.1 vs. 2.8 months; HR, 0.40; P<0.0000001) or cytokinerefractory groups (7.4 vs. 4.2 months; HR, 0.54; P<0.001). The ORR with pazopanib was 30% compared with 3% in the placebo arm (Figure 2). The median response duration was 58.7 weeks. Adverse events were described as mild; however, 12% of pazopanib-treated patients experienced grade 3 or greater hepatic toxicity.

These data clearly demonstrate the effectiveness of pazopanib in mRCC, and suggest regulatory approval of another novel agent for mRCC therapy is likely in the near future. An ongoing Phase III study comparing pazopanib with sunitinib in first-line mRCC patients will provide additional clinical information on this agent.

Three additional presentations highlighted preliminary data with the novel TKIs AVI-951 (J Clin Oncol 2009; 27: abstract 5032), BAY 73-4506 (J Clin Oncol 2009; 27: abstract 5033), and ABT-869 (J Clin Oncol 2009;27: abstract 5036). This series of Phase II trials reported the activity of these multi-kinase inhibitors, and a noted investigator assessed ORR between 19.6% (ABT-869) and 27.2% (AVI-951). These studies highlight the sensitivity of clear cell RCC to vascular endothelial growth factor (VEGF) receptor TKIs, and suggest a variety of other agents with different toxicity and efficacy patterns will be tested in clinical trials in the near future.

Sunitinib Toxicity The final area of interest for RCC at the ASCO annual meeting included two presentations that focused on pharmacogenetic factors influencing sunitinib toxicity in patients with mRCC. The two studies used analysis of patientsâ&#x20AC;&#x2122; single nucleotide polymorphisms (SNPs) and correlated this

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Micrograph of papillary renal cell carcinoma, showing vascular papillae with foam cells.

information with toxicity.

A presentation by Kim et al reported a group of 62 patients with mRCC who were treated with sunitinib, in whom the frequency of VEGF SNPs (â&#x20AC;&#x201C;634 C/C and â&#x20AC;&#x201C;1478 T/T) were then correlated with the development of hypertension (J Clin Oncol 2009;27: abstract 5005). The data demonstrated a significant association of VEGF SNPâ&#x20AC;&#x201C;634 G/G with sunitinib-induced hypertension, but no asso-

These two presentations require confirmation, but suggest that genetic determinants can influence the development of sunitinib toxicity.

ciation with ORR or PFS. A presentation by van Erp et al highlighted a multicenter study in which 31 SNPs in 12 candidate genes were assessed in 219 patients

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receiving sunitinib (J Clin Oncol 2009;27: abstract 5006). A variety of SNPs from genes encoding metabolizing enzymes (CYP1A1), efflux transporters (ABCB1) and drug targets (VEGFR-2) appeared to predispose patients to developing toxicities such as leukopenia, handâ&#x20AC;&#x201C;foot syndrome, mucosal inflammation, and in a nonspecific fashion any toxicity greater than grade 2.

These two presentations require

These data clearly demonstrate the effectiveness of pazopanib in mRCC, and suggest regulatory approval of another novel agent for mRCC therapy is likely in the near future.

confirmation, but suggest that genetic determinants can influence the development of sunitinib toxicity. This approach may be used in the future to optimize therapy and decrease toxicity for individual patients.

In summary, the ASCO 2009 meeting continued the recent trend for a large number of significant new

presentations dealing with mRCC. Data from the Phase III trials may ultimately influence the treatment of this patient group. Finally, the possibility that pharmacogenomic analyses will assist in optimizing therapy with a TKI such as sunitinib seems reasonable. â&#x20AC;&#x201D;Ronald M. Bukowski, MD

CHEMOTHERAPY FOUNDATION SYMPOSIUM XXVII INNOVATIVE CANCER THERAPY FOR TOMORROW November 11-13, 2009 New York City The Greenspan Meeting WEDNESDAY, NOVEMBER 11 Hematology: Therapeutic Advances in Myeloproliferative & Myelodysplastic Syndromes, AML, CML, CLL, NHL, MM, JAK2, AML in the Elderly, HDAC Inhibitors, Anti-Myeloma Agents, Acute Leukemia, Mayo Risk StratiďŹ cation MM. Lymphomas, Proteasome Inhibitors GI Cancers: Colorectal, Gastric Cancer, Pancreatic Cancer, Biliary Tract, Appendiceal, New Agents, TOGA, SPARC, AVANT Trials, VEGF Inhibitor, Recurrence Risk Prediction, Screening Advances, Hedgehog Pathway, mTOR Inhibition, C-Met Inibitors, Neuroendocrine Tumors THURSDAY, NOVEMBER 12 GYN Cancers: PARP, Recurrent Ovarian, Current Trials, Novel Treatments, Relapse Therapy, BRCA and Outcomes, Targeted Therapy, Melanoma: Biomarker Links, Analysis of Brain Metastases, Prognostic Indicator Head & Neck Cancer: Targeted Therapy Sarcoma: Monotherapy and Chemotherapy in Tumor Hypoxia Breast Cancer: Gene Expression ProďŹ le, Triple Negative Breast Cancer, PARP, Novel Target, Mechanisms of Resistance to HER2, Novel HER2 Therapy Update, HER3 Measurement & Outcomes, Targeted Therapies in HER2 Negative Cancer, Anti-estrogen Therapy Thyroid: Treatment in Advanced Disease

If you didnâ&#x20AC;&#x2122;t, you missed the following articles. â&#x20AC;˘ Study Says Off-Label Resources Are Outdated, Flawed â&#x20AC;˘ Standard of Care Established For Inoperable Biliary Cancer â&#x20AC;˘ Immunotherapy Increases Cure Rate in Neuroblastoma â&#x20AC;˘ Will Second-Gen TKIs Move to FirstLine Therapy for CML?

FRIDAY, NOVEMBER 13 Immunotherapy: Vaccines, Blockage in Myeloma Therapy GU Prostate: Combination Therapy, Vaccine Therapy in PC, Phase II Clinical Trials, Neoadjuvant Therapy in High Risk PC Renal: Sarcomatoid Features, Novel AKT Inhibitor Lung Cancer: Novel Agents, PARP, Combination Chemotherapy, KRAS Mutatations and Targeted Therapy in NSCLC, EGFR Resistance, Biomarkers, Personalized Chemotherapy, Mesotheoloma Diverse Presentations: Unknown Primary, New Agents in Solid Tumors, Neuroendocrine Tumors, Recurrent Glioma, Dendritic Cells, CTEP Clinical Trials, Practice Patterns, EHRS

â&#x20AC;˘ Sorafenib Dosing Poses Problem for Asian Patients â&#x20AC;˘ High Risk For Parainfluenza Virus Infection Identified In Leukemia and HSCT Patients To read these and other stories, visit www.clinicaloncology.com and click on the appropriate department heading. To register for the Digital Edition of Clinical Oncology News, click on the banner at the top of the page.

Register on line at chemotherapyfoundationsymposium.org Contact: Jaclyn.silverman@mssm.edu CME Accredited by the Mount Sinai School of Medicine

11

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12

SOLID TUMORS

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Colon Cancer ADVISORY BOARD EDITORIAL

IMPACT

Cathy Eng, MD continued from page 1

single-agent bevacizumab continued for an additional six months in the investigational arm. At the meeting, the investigators provided details of how the trial failed to meet its primary end point of three-year disease-free survival (DFS). What remains to be seen is what this study means for ongoing clinical trials and the drugâ&#x20AC;&#x2122;s future in patient care.

Associate Professor Department of Gastrointestinal Medical Oncology University of Texas M.D. Anderson Cancer Center Houston, Texas

Micrograph of a tubular adenoma, a type of colonic polyp and a precursor of colorectal cancer.

High Hopes Bevacizumab, an anti-VEGF (vascular endothelial growth factor) antibody, is the first FDA-approved anti-angiogenic agent in the treatment of metastatic colorectal cancer following a significant improvement in overall survival noted in the pivotal trial of irinotecan, bolus 5-FU, and leucovorin (IFL), with or without bevacizumab. To date, the majority of bevacizumab trials in metastatic colorectal cancer have demonstrated an improved response rate, progression-free survival and overall survival. The drug has since been approved for the treatment of metastatic breast and lung cancers, as well as for glioblastoma.

Bevacizumab is the most commonly used biologic agent in metastatic colorectal cancer patients without contraindications to anti-angiogenic therapy.

Investigators have not identified any markers that predict patient resistance to anti-VEGF therapy, and data regarding resistance to therapy are scarce. Given its well-documented efficacy in advanced colorectal cancer in conjunction with chemotherapy and preclinical data suggesting an impact of anti-VEGF therapy on preventing the development of metastatic disease in animal models, bevacizumab appeared to be an appropriate biologic agent for investigation in the adjuvant setting. Reported safety data suggest that prolonged use of bevacizumab is not associated with significant toxicity.

The negative DFS results were discussed in detail one month later at the ASCO plenary session on May 31, 2009. After a median follow up of 35.6 months, no difference in DFS was noted (hazard ratio [HR], 0.89) regardless of substratification by stage. Yet, the senior author of the trial suggested that the benefit of bevacizumab was present at the first year and implied that bevacizumab may need to be provided for a longer interval for optimal outcome (HR, 0.60; DFS first year only). What remained unanswered, however, was the potential impact on future patient care and how the results of the trial will affect ongoing adjuvant trials not only in colon cancer but also other malignancies.

Criticisms of Trial Design One of the greatest criticisms of NSABP C-08 may lie in its clinical trial design. As a clinical investigator, when considering clinical trial design for an investigational agent, the objective is to establish superiority of the agent versus the standard of care with the ultimate goal of changing the existing treatment paradigm. Yet, NSABP C-08 required patients to receive an additional six months of bevacizumab when previous studies failed to demonstrate any benefit with single-agent bevacizumab in metastatic colorectal cancer.

versus oxaliplatin and capecitabine (CapeOX) plus bevacizumab in high-risk stage II and stage III patients with a primary end point of DFS. Because AVANT completed accrual (N=3,451) in June 2007, the impact of NSABP C-08 is less in question. It is of note, however, that AVANT mandated routine CT scans and CEA levels for both treatment arms.

The impact on ECOG 5202, however, is uncertain.

It continues to accrue patients (1,889/3,610 patients as of May 16, 2009), and is the first prospective trial of its kind being conducted solely in stage II colon cancer patients with treatment stratification based on molecular prognostic markers. The trial hopes to address the ongoing dilemma for many treating physicians in deciding treatment for the heterogenous stage II patient. Results of the Phase III INT-0035 and IMPACT B2 trials noted no additional benefit for adjuvant 5-FU in patients with stage II colon cancer.

The recent QUASAR trial noted a minor benefit in five-year overall survival of 2.9% with adjuvant 5-FU. Yet, results from the adjuvant MOSAIC trial noted an improvement in DFS (HR, 0.74) for high-risk stage II patients who received six months of FOLFOX compared with 5-FU/LV (leucovorin) alone. The complexity of the decision of whether or not to treat the stage II patient population is reflected by ASCOâ&#x20AC;&#x2122;s nondirectional recommendation that adjuvant chemotherapy may be considered and can be discussed with the stage II patient. As a result, definitive treatment for the stage II patient is currently at the dis-

Failure To Meet End Point When Genentech announced in a press release that NSABP C-08 had failed to meet its primary end point in April, many oncologists were in disbelief. Given the success of bevacizumab in previous metastatic colon cancer trials, it did not seem possible that bevacizumab would not have a role in the adjuvant setting, and some oncologists held out hope that the drug could benefit a subset of patients given a statement

by Roche/Genentech. â&#x20AC;&#x153;Our initial review of the data leads us to continue to believe Avastin may be active in patients with early-stage colon cancer and look forward to NSABPâ&#x20AC;&#x2122;s presentation at ASCO,â&#x20AC;? said Hal Barron, MD, senior vice president of development and chief medical officer at Genentech. â&#x20AC;&#x153;We remain fully committed to the ongoing Avastin adjuvant programs in early-stage colon, breast and lung cancers.â&#x20AC;?

The announcement caused many investigators to express concerns about ongoing trials in which bevacizumab was being utilized in the adjuvant colon cancer setting, notably AVANT (Roche) which had completed patient accrual and ECOG 5202 which continued to accrue patients. Clinicians are keenly aware that to change the treatment paradigm in the adjuvant setting, thousands of patients must be accrued and followed extensively to identify any minute improvement in median disease-free or overall survival.

Appropriately enough, the press release resulted in the immediate temporary closure of ECOG 5202 for an amendment in its consent form informing patients of the preliminary negative results of NSABP C-08.

The results of NSABP C-08 have significant implications for patient care, since they highlight that experimental therapies should not be used outside of a clinical trial setting.

Of greater interest is that stringent surveillance for tumor recurrence, computed tomography (CT) scans and carcinoembryonic antigen (CEA) levels at predefined intervals were not mandated in NSABP C-08. Given the primary end point of DFS, how were patients to be captured for recurrence of disease if only at the discretion of the treating physician? This point is of particular importance given the different duration of bevacizumab therapy in both arms of the trial, six months in the control arm versus 12 months in the experimental arm. Temporal imbalances in the timing of CT scans, and thus detection of recurrent disease, could have greatly influenced the reported results. This obvious oversight in trial design is surprising, because the study was considered a potential registration trial for bevacizumab in the adjuvant setting and would have been scrutinized by the National Cancer Institute and the Cancer Therapy Evaluation Program (CTEP) as well as the FDA.

Impact on Clinical Trials So, how will the results of NSABP C-08 impact clinical trials? AVANT is a three-arm, randomized Phase III trial of FOLFOX versus FOLFOX plus bevacizumab

cretion of the treating physician.

Unlike other clinical trials that define a high-risk stage II patient as one with poorly differentiated histology, T4 disease, lymphovascular invasion or suboptimal lymph node dissection (<10 lymph nodes), ECOG 5202 is a unique trial comprised only of stage II colon cancer patients who are treated based on low risk (MSIH or no 18q loss of heterozygosity [LOH], surveillance arm) or high-risk molecular markers (MSI-S or MSIL, plus 18q LOH), and are treated with six months of FOLFOX with or without bevacizumab for 12 months, which is analogous to the design of NSABP C-08 with the primary end point of DFS. ECOG 5202 is 88% powered to detect a 37% difference in median DFS (absolute difference of 5% in three years).

So, should the negative results of NSABP C-08 cause the closure of ECOG 5202 or should we believe that bevacizumab can benefit patients if it is continued for a longer duration? If the latter, should bevacizumab be continued for more than three years to achieve a difference in three-year DFS? What refinements in the number of patients accrued would be needed to demonstrate a statistical difference in median DFS, given see IMPACT, page 15

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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 into one practical, clinically focused, easy-to-use volume. It incorporates basic science, pathology, diagnosis, management, outcomes, rehabilitation and preventionâ&#x20AC;&#x201D;all in one convenient resourceâ&#x20AC;&#x201D;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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The Molecular Basis of Cancer With Expert Consult

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Textbook of Lung Cancer, 2nd Edition, published in association with the European Society of Medical Oncology, is a comprehensive and multidisciplinary text, which examines all aspects of this disease, with contributions from a multinational team of authors on etiology, epidemiology, molecular biology, pathology, smoking, detection and management, clinical features, staging and prognostic factors, surgery, radiotherapy, and chemotherapy.

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Successfully fighting cancer starts with understanding how it begins. This thoroughly revised third edition explores the scientific basis for our current understanding of malignant transformation, and the pathogenesis and treatment of cancer. A team of leading experts thoroughly explains the molecular biologic principles that underlie the diagnostic tests and therapeutic interventions now being used in clinical trials and practice.

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This book presents the latest, most authoritative cancer management recommendations in the famous fast-access Washington Manual ÂŽ outline format. This edition has been reorganized into three major sections: principles of oncology, site-specific diseases and supportive therapy.

Philip Rubin; John T. Hansen

The TNM Staging Atlas presents cancer staging in a highly visual, rapid-reference format, with clear full-color diagrams and TNM stages by organ site. The illustrationsâ&#x20AC;&#x201D; some original and some derived from Grant's Atlas of Anatomyâ&#x20AC;&#x201D;are three-dimensional, three-planar, cross-sectional presentations of primary anatomy and regional nodal anatomy. They show the anatomic features identifiable on physical and/or radiologic examination and the anatomic extent of cancer spread which is the basis for staging.

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FDA NEWS

Pemetrexed Approved for Fourth Indication

T

he FDA has approved pemetrexed for injection (Alimta, Eli Lilly) as maintenance therapy for locally advanced or metastatic non-small cell lung cancer (NSCLC), specifically for patients with a nonsquamous histology whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

The drug is not indicated for treatment of patients with squamous cell NSCLC. This is the fourth approval for the drug.

The drug was approved based on results from a multicenter, double-blind Phase III trial that compared efficacy with regard to overall survival of pemetrexed plus best supportive care (BSC) versus placebo plus BSC in 663 patients with stage IIIB/IV NSCLC, whose disease had not progressed after four cycles of platinum-based induction chemotherapy. The trial supported previous studies looking at the use of histopathology to tailor treatment for patients with advanced nonsquamous NSCLC. Patients in the trial were treated with pemetrexed (500 mg/m2 on day 1 of each 21-day cycle) or placebo, plus BSC. All patients were supplemented with vitamin B12, folic acid and dexamethasone.

Overall, pemetrexed increased progression-free survival by almost two months (4.3 vs. 2.6 months; P<0.0001) and overall survival (OS) by almost three months (13.4 vs. 10.6 months; P=0.012).

However, the relative benefits of pemetrexed maintenance were even greater in nonsquamous cell histologies.

Although there was no OS advantage in the squamous cell tumors (9.9 vs. 10.8 months; P=0.678), the survival advantage exceeded five months (15.5 vs. 10.3; P=0.007; hazard ratio, 0.47; P<0.0001) when the squamous cell cancers were removed from the analysis.

Opioid Pain Reliever Approved

T

he FDA has approved fentanyl buccal soluble film (Onsolis, Aveva Drug Delivery Systems) to help manage breakthrough pain in certain cancer patients. Onsolis is in a class of drugs that deliver the potent opioid fentanyl through the mouthâ&#x20AC;&#x2122;s mucous membranes. Onsolis delivers fentanyl via an absorbable film that adheres to the inside of the cheek.

The drug is indicated for the management of breakthrough pain in patients with cancer, aged 18 and older, who already use opioid pain medication around the clock and who need and are able to safely use high doses of an additional opioid medicine. Such patients are considered opioid-tolerant because of their current opioid medication use.

Because fentanyl is subject to abuse and misuse, this new drug was approved with a Risk Evaluation and Mitigation

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Strategy, or REMS, which is a required plan for managing risks associated with a drug or biological product. The Food and Drug Administration Amendments Act of 2007 gave the FDA the authority to require that drugs and biological products have a REMS to ensure that the benefits of a drug or biological product outweigh its risks.

As part of the REMS, Onsolis will only be available through a restricted distribution program called the FOCUS program. Under this program, only those prescribers, patients and pharmacies registered with the program will be able to prescribe, dispense and receive Onsolis.

The FOCUS program will provide training

and educational materials to prescribers and pharmacy personnel, and a counseling call will be placed to patients before dispensing to ensure they have been adequately educated about the appropriate use of the drug. Prescription orders will be filled only by participating pharmacies

that will send the medication directly to the patientsâ&#x20AC;&#x2122; homes.

Onsolis was approved with a boxed warning, which states that the medication should not be used for the management of migraines, dental pain, or postoperative pain or by patients who use opioids intermittently, or on an as-needed basis. It also warns that the drug should be kept out of the reach of children and should not be substituted for other fentanyl products.

Onsolis is manufactured by Aveva Drug Delivery Systems, and marketed under license from BioDelivery Sciences International Inc., by Meda Pharmaceuticals Inc.

ABRAXANE delivers ÂŽ

nab deďŹ ned: nab technology exploits the natural properties of albumin, facilitating the delivery of water-insoluble compounds to the tumor. ÂŽ

ÂŽ

ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

WARNING: ABRAXANE for Injectable Suspension (paclitaxel proteinbound particles for injectable suspension) (albumin-bound) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drugâ&#x20AC;&#x2122;s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.

IMPORTANT SAFETY INFORMATION The use of ABRAXANE has not been studied in patients with hepatic or renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. ABRAXANE can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Men should be advised to not father a child while receiving treatment with ABRAXANE. It is recommended that nursing be discontinued when receiving ABRAXANE therapy.

ABRAXANE contains albumin (human), a derivative of human blood.

Caution should be exercised when administering ABRAXANE concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4.

ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. It is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE.

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Colon

IMPACT continued from page 12

that the trial has thus far accrued more than 50% of its patients? Once open for accrual, will participating sites be willing to continue to enroll patients or will physicians defer enrollment altogether due to the negative results of the trial presented at the ASCO meeting? Will an investigator be able to explain this complex trial to patients in such a way as to enhance enrollment while incorporating the recent data from NSABP C-08, or will it be too difficult to explain

these issues so that it actually dissuades patient enrollment?

Although duplicity in a trial is not ideal, the advantage to the AVANT trial is that it may firmly establish whether there is any role for adjuvant bevacizumab in highrisk stage II or stage III patients. As mentioned before, strict radiographic surveillance is required in this trial. The results of AVANT will not be available until late 2010 or early 2011, but unless AVANT fails to meet its primary end point, it is likely ECOG 5202 will remain open given its unique trial design. Unfortunately, for any large cooperative group trial such as ECOG 5202, any revisions will

require significant delays by the cooperative group of origin, CTEP, followed by each institutionâ&#x20AC;&#x2122;s institutional review board. This will only further delay patient accrual and our ability to answer whether prognostic markers have a role in determining a plan of care for the stage II patient population and whether there is a role for bevacizumab in the high-risk stage II patient population.

Conclusion NSABP C-08 demonstrated that we can successfully and rapidly accrue patients to a Phase III adjuvant trial. The results have significant implications for patient

efficacy* to make more possible In a pivotal phase III trial in metastatic breast cancer patients,

ABRAXANEÂŽ delivered nearly double the overall response rate* vs solvent-based paclitaxel1

21.5% vs 11.1%

15.5% vs 8.4%

(P=.003) for all study patients.1 95% Cl, 16.2% to 26.7% for ABRAXANE 95% Cl, 6.9% to 15.1% for solvent-based paclitaxel

(P=NS) for study patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy.1 95% Cl, 9.3% to 21.8% for ABRAXANE 95% Cl, 3.9% to 12.9% for solvent-based paclitaxel

BOUND AND DETERMINED Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.

In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses is recommended.

Sensory neuropathy occurs frequently with ABRAXANE. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary embolism, and hypertension.

In the randomized metastatic breast cancer study, the most important adverse events included alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), anemia (all 33%; severe 1%), infections (24%), nausea (any 30%; severe 3%), vomiting (any 18%; severe 4%), diarrhea (any

27%; severe <1%), and mucositis (any 7%; severe <1%).

Other adverse reactions have included ocular/visual disturbances (any 13%; severe 1%), ďŹ&#x201A;uid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%, alkaline phosphatase 36%, AST [SGOT] 39%), renal dysfunction (any 11%; severe 1%), thrombocytopenia (any 2%; severe <1%), hypersensitivity reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), and injection site reactions (<1%). During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. Reference: 1. ABRAXANE [prescribing information]. Los Angeles, Calif: Abraxis Oncology, a division of Abraxis BioScience, Inc; August 2007.

Please see the Brief Summary of the ABRAXANE full prescribing information on the next page.

ABRAXANE, Abraxis, Abraxis Oncology, nab, and ARC of Support are registered trademarks, and Abraxis Oncology Resource Center is a service mark, of Abraxis BioScience, LLC. Abraxis OncologyŽ is a division of Abraxis BioScience, LLC. Š2009 Abraxis BioScience, LLC. All Rights Reserved.

AO 1305 06/09 Printed in USA ÂŽ SM

care, since they highlight that experimental therapies should not be used outside of a clinical trial setting. The contrasting negative data for bevacizumab in the adjuvant (micrometastatic) setting in comparison to its well-documented efficacy in (macro)metastatic disease may eventually help us better understand the role and actual mechanism of action of anti-VEGF therapy in malignant tumors.

This may open the door for future clinical trial design based on a better understanding of the biologic implications of anti-angiogeneic therapy. â&#x20AC;&#x201D;Cathy Eng, MD

15

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16

SOLID TUMORS Rectal

Longer Time Between Neoadjuvant Therapy, Surgery Recommended For Rectal Cancer Hollywood, Fla.â&#x20AC;&#x201D;Surgeons should wait at least eight weeks after neoadjuvant therapy before resecting rectal cancers, according to a new study.

In the study, waiting more than eight weeks after neoadjuvant therapy resulted in higher pathologic complete response (CR) rates and lower rates of recurrence, without any increase in postoperative complications, investigators found.

The study results were presented at the American Society of Colon and Rectal Surgeons annual meeting (abstract S1).

In the analysis, 177 patients with stage II and III rectal cancer undergoing neoadjuvant chemoradiation and surgery were identified from a prospectively maintained database of patients with colorectal cancer. Adjuvant chemotherapy was 5-FU-based and median radiotherapy dose was 5,040 cGy (range 4,0006,100 cGy). The operations included both abdominoperineal resections (29%) and low anterior resections (71%).

Patients were retrospectively divided into two groups based on time to surgery (median, eight weeks); 86 patients underwent surgery at four to seven weeks and 91 patients at eight to 14 weeks. The investigatorsâ&#x20AC;&#x2122; primary outcomes were complete pathologic response, disease recurrence and survival rates, and short-term surgical outcomes.

None of the surgical outcomes were statistically different between the groups; in particular, rates of blood loss, anastomotic leaks and wound infections all were similar regardless of the time of surgery. Oncologic outcomes, however, were significantly better in several measures among the patients who underwent resection at more than eight weeks.

In particular, both pathologic CR (17% vs.

31%; P=0.03) and three-year local recurrence rates (11% vs. 1%; P=0.04) were better. Five-year disease-free and overall survival rates were better in the group that had surgery later as well, but neither was statistically significant. â&#x20AC;&#x153;An interval of greater than eight weeks resulted in higher pathologic complete response rate, lower local recurrence, regardless of the tumor response, with no changes in perioperative complications,â&#x20AC;? said Luiz F. Campos-Lobato, a surgeon in the Division of Colorectal Surgery at Cleveland Clinic in Ohio, and lead author of the study. â&#x20AC;&#x153;We recommend an interval between neoadjuvant [therapy] and surgery of at least eight weeks due to its safety and oncological benefits.â&#x20AC;? â&#x20AC;&#x201D;Gabriel Miller

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PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Part 1 of a 2-Part Series

Guide to the Prevention of

Chemotherapy Medication Errors Causes of Chemotherapy Errors DWIGHT D. KLOTH, PHARMD, FCCP, BCOP Director of Pharmacy Fox Chase Cancer Center Philadelphia, Pennsylvania

M

edication error prevention is a critical goal for pharmacists, nurses,

and physicians in all treatment settingsâ&#x20AC;&#x201D;especially in oncology.

Antineoplastic agents have a lower therapeutic index and safety margin than do other drug classes. Additionally, in cancer chemotherapy, the dose, dosing interval, and even the route of administration may vary as a function of the tumor type and the stage of disease. Chemotherapyrelated medication errors, such as the administration of a 10-fold higher dose as a result of a transcription error, or the intrathecal administration of drugs that only should be administered by IV infusion, are potentially fatal.1-4 In 2006, the Institute of Medicine (IOM) released the landmark report Preventing Medication Errors,5 which stated that â&#x20AC;&#x153;medication errors harm at least 1.5 million patients every year in hospitals, long-term facilities, and outpatient clinics, resulting in billions of dollars in additional medical costs.â&#x20AC;? To help prevent medication errors, the committee recommended that all organizations

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implement an electronic prescribing and dispensing system by 2010. Additionally, the report contained several other important recommendations pertinent to facilities that treat patients with cancer: â&#x20AC;˘ monitor medication safety literature; â&#x20AC;˘ develop and implement a structured error-avoidance plan; â&#x20AC;˘ establish a routine procedure for double-checking filled prescriptions; â&#x20AC;˘ designate a practice-wide medication safety officer with widespread authority and responsibility to improve care; â&#x20AC;˘ create a safer work environment by looking at lighting and noise levels, minimizing distractions, and improving drug storage areas by separating lookalike and sound-alike medications;

C L I N I C A L O N C O L O G Y N E W S â&#x20AC;˘ J U LY/A U G U S T 2 0 0 9

1

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â&#x20AC;˘ continuously evaluate technology and automation to reduce medication errors; â&#x20AC;˘ be assertive in requesting resources to promote accurate medication prescribing, processing, dispensing, and administration; and â&#x20AC;˘ involve patients in an aggressive education and reconciliation program.

This 2-part educational review is intended to help clinicians develop practical strategies to recognize and prevent chemotherapy medication errors. Part 1 includes information on selected publicized chemotherapy errors and their outcomes as well as examples of potential causes of errors, such as look-alike/ sound-alike drug names and the use of handwritten orders. Part 2, which will be published in an upcoming issue, discusses how health care professionals can assess the risk for medication errors at their institutions and practice sites and offers strategies to help prevent such errors. Because nearly all authorities recommend implementation of an electronic order entry system, this guide discusses the use of technology and computerization (eg, computerized prescriber order entry [CPOE] and bar coding) in medication error prevention, including the advantages of and caveats to these technologies.

Causes of Chemotherapy Errors The consequences of antineoplastic drug errors can be devastating because these agents have one of the lowest therapeutic indices and safety margins of any drug class.

Combination chemotherapy regimens are very complex and intensive. Doses can vary tremendously for different diseases. For example, a â&#x20AC;&#x153;normalâ&#x20AC;? dose of methotrexate can range from 10 to 20,000 mg, and appropriate total doses and infusion durations of regimens for 5-fluorouracil (5-FU) for colorectal cancer can vary widely, even for the same tumor type and stage of disease. Similarly, targeted agents such as bevacizumab (Avastin, Genentech) now include FDA-approved labeling at substantially different dose intensities, even within the colorectal cancer arenaâ&#x20AC;&#x201D;that is, 5 mg/kg every 14 days if given with FOLFIRI (a chemotherapy regimen for colon cancer comprising irinotecan [Camptosar, Pfizer Oncology], 5-FU, and leucovorin)6,7 and 10 mg/kg every 14 days if given in conjunction with FOLFOX (a chemotherapy regimen for colon cancer combining oxaliplatin [Eloxatin, Sanofi-Aventis], 5-FU, and leucovorin).8 This 100% dose variation is yet another potential opportunity for errors, although the clinical risks for such errors are not as clearly defined as with conventional cytotoxic anticancer therapies.

Several publicized accounts of chemotherapy medication errors have appeared in the scientific and lay press within the past decade9-26 (Table 1), reflecting the small to nonexistent margin of error that health professionals have when ordering, dispensing, and administering cytotoxic agents. Medication safety was recently evaluated in the ambulatory chemotherapy setting, where most antineoplastic drug doses are administered. Gandhi and colleagues24 reviewed

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10,112 medication orders in 1,606 patients (15% pediatric) and found an error rate of 3%, including 2% of orders with the potential to cause harm. Pharmacists and nurses intercepted 45% of potential adverse drug events before they reached the patient.

Errors occur not only at private practice oncology offices and smaller, nonspecialty hospitals but also at renowned teaching and research centers. Although some errors involve only one practitioner, in clinical experience most errors occur when several staff members are involved. These incidents often are the result of a lack of critical information or the presence of inaccurate data.25 Significant potential causes of chemotherapy errors are highlighted in Table 2.6,8,27

LOOK-ALIKE/SOUND-ALIKE DRUG NAMES One of the most common causes of medication errors is the similar-sounding names of drugs used in oncology practice.28 For example, fatal errors have occurred when the dose for one drug was mistaken for the dose of another (eg, when vincristine was dispensed instead of vinblastine, when docetaxel [Taxotere, Sanofi-Aventis] was administered instead of paclitaxel, and when cisplatin was administered instead of carboplatin).11,12,26 A theoretical risk is the potential for confusion between conventional paclitaxel (eg, Taxol, Bristol-Myers Squibb) and the new albumin-bound paclitaxel, Abraxane (Abraxis Oncology), because the doses for these 2 versions of paclitaxel are not identical. One could argue that the risk for confusion between the albumin-bound paclitaxel and conventional paclitaxel is even greater than the risk for confusing cisplatin with carboplatin or vincristine with vinblastine. Additionally, concerns have been raised because the official generic name for Abraxane, paclitaxel protein-bound particles for injectable suspension (albumin bound), is neither intuitive or manageable for paper-based systems nor feasible for computer database entries. Thus, this medication, like liposomal doxorubicin (Doxil, Tibotec Therapeutics), is an example of an instance where the trade name may be the most practical and feasible drug name to use to maximize safety in everyday practice. Oncology treatment centers (hospitals and practices) recognize that doxorubicin dosing and liposomal doxorubicin dosing are not the same and should not be substituted for each other. The same concern exists for conventional paclitaxel and albumin-bound paclitaxel and the same level of precautions should be taken. In fact, the package insert for Abraxane carries the following warning29: Note: An albumin form of paclitaxel may substantially affect a drugâ&#x20AC;&#x2122;s functional properties relative to those of drug solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. One method practitioners can use to differentiate chemotherapeutic drugs with similar-sounding names is to use TALL MAN lettering on labels and electronic records: CISplatin versus CARBOplatin; vinBLASTine versus vinCRISTine or vinORELbine; DOXOrubicin versus

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Table 1. Selected Publicized Chemotherapy Medication Errors And Outcomesa Drug

Error and Outcome

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Table 2. Examples of Potential Causes Of Chemotherapy Medication Errors Miscommunicated verbal orders Total course (or cycle) dose given every day

Amphotericin B Conventional amphotericin B and liposomal administered at liposomal amphotamphotericin9 ericin doses: multiple patient deaths

Lack of pertinent patient health care information (eg, lab data and patient demographics such as age, height, and weight)

Carboplatin10

Overdose administered to 2 children: possible deafness in 1 child

Use of incorrect patient information/lab data or the information/lab data for a different patient

Carboplatin and cisplatin11

Confusion of proper dose ranges; cisplatin administered at dose intensity appropriate for carboplatin: consistently fatal outcome (numerous examples prior to labeling changes in 1996)

Docetaxel and conventional paclitaxel12

An incorrect dose of 260 mg docetaxel (Taxotere, Sanofi-Aventis) was administered instead of 260 mg conventional paclitaxel (Taxol, Bristol-Myers Squibb): patient died 5 days later, although the error may not have caused the death

Doxorubicin hydrochloride and liposomal doxorubicin13,14

Liposomal doxorubicin administered instead of doxorubicin hydrochloride: increased morbidity and possible cause of patient death

Lomustine13,15

Serious errors have occurred when this oral agent was administered daily rather than every 6 weeks: patient harm, prolonged hospitalization, and death

Methotrexate16-18 Multiple cases of accidental daily administration of oral methotrexate when weekly dosing was intended: at least 25 fatalities and an equal number of incidents of serious patient harm Vincristine19-25

Vincristine and vinblastine26

Accidental intrathecal administration: multiple patient deaths over many years (universally fatal when this error occurs): patient harm Vincristine accidentally given at dose appropriate for vinblastine; patient death

a

Not all-inclusive; selected examples are given here to illustrate the nature of the error. Some examples have occurred numerous times in the literature.

LIPOSOMAL DOXOrubicin; DOCEtaxel versus PACLItaxel; and mitoMYCIN versus mitoXANTRONE. However, as stated above, in some cases the trade name actually may be the best choice available.

At Fox Chase Cancer Center (FCCC), in Philadelphia, the pharmacy computer system allows use of both TALL MAN lettering and scalable fonts for chemotherapy IV bag or syringe labels, enabling further differentiation

Excessive interruptions during order processing or dose preparation Substantial distance between the pharmacy and the patient treatment area, which inhibits communication between pharmacy, nursing, and medical staff Poor packaging and labeling by manufacturers Use of abbreviations of drug names Similar-sounding drug names within the therapeutic class Lack of a proper copy of the physician order or use of a fax copy, which might be illegible Use of trade names, which may vary even for generically available agents, rather than generic names Lack of procedures (eg, using larger volumes for vincristine doses) and warning stickers/labels to prevent inadvertent intrathecal administration of drugs such as vincristine, doxorubicin, and daunorubicin Failure to round drug doses to the nearest whole integer, potentially leading to a 10-fold overdose if the decimal point is not seen Widely differing dosing regimens for the same drug even for the same tumor type and stage (eg, various regimens of 5-fluorouracil and bevacizumab in colorectal cancer) Use of outdated lab data (eg, outdated serum creatinine or liver function tests) Adapted from references 6, 8, and 27.

of drug names. Additionally, use of supplemental labels or stickers in different bright colors highlights and distinguishes between various agents of a particular drug class (eg, a neon green DOCETAXEL sticker sharply distinguishes a docetaxel dose from a paclitaxel dose with a neon purple PACLITAXEL sticker)â&#x20AC;&#x201D;an important distinction when these drugs sound alike, are used for the same tumor types, and may be given to patients seated next to each other in a busy infusion center, but have significantly different dosing regimens and toxicity profiles.

HANDWRITTEN PRESCRIPTION DRUG ORDERS Some consider a CPOE system to be the best prevention for medication errors; however, most oncologists still handwrite orders, often because commercially available

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3

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AVOIDâ&#x20AC;Ś (Error-Prone Transcription)

USEâ&#x20AC;Ś (Strongly Recommended Transcription)

qd or QD

daily

qn, qhs, hs, BT (bedtime)

at bedtime

q 6pm

6 p.m. nightly

qod or QOD

every other

Ă&#x2014;3d

Ă&#x2014; 3 days

abbreviations, symbols, and dose designations that can be used as a benchmark to improve patient safety (Table 3).30 Table 4 lists antineoplastic ordering terms and shows some potentially problematic names and abbreviations. In the absence of a CPOE system, strict enforceable rules for medication orders should be in place (eg, write â&#x20AC;&#x153;dailyâ&#x20AC;? instead of â&#x20AC;&#x153;qdâ&#x20AC;? and â&#x20AC;&#x153;unitsâ&#x20AC;? instead of â&#x20AC;&#x153;Uâ&#x20AC;?). â&#x20AC;&#x153;If in doubt, write it outâ&#x20AC;? is a mantra adopted by many leading health systems. The Joint Commission also recognizes the risks associated with various error-prone abbreviations and mandates that hospitals and health systems create and periodically review and update a list of error-prone abbreviations that are not permitted in any component of the medical record.31

tiw or TIW

3 times weekly

CLARIFYING TERMS

Îźg or Ug

mcg (for micrograms)

U, IU, u

units

cc

mL

SS

sliding scale

per os (misread as â&#x20AC;&#x153;left eyeâ&#x20AC;?)

PO, by mouth, or orally

SC, subQ, SQ

subcutaneous

od

right eye

Another problem is a â&#x20AC;&#x153;disconnectâ&#x20AC;? in the communication system, in which prescribers think of antineoplastic drug therapy as a â&#x20AC;&#x153;courseâ&#x20AC;? or a â&#x20AC;&#x153;cycle,â&#x20AC;? which is usually several doses, whereas pharmacists and nurses evaluate, prepare, and administer a single dose. Additionally, a decimal point can be missed if the prescriber fails to round doses of more than 5 or 10 mg to the nearest whole number, which can potentially cause a 10-fold overdose.30 Similarly, the unwise use of a â&#x20AC;&#x153;trailing zeroâ&#x20AC;? or â&#x20AC;&#x153;leading decimalâ&#x20AC;? also has the potential to cause a 10-fold dosage error.30

os

left eye

AU

both ears

terminal zeros for doses expressed in whole numbers (eg, AVOID 1.0 mg â&#x20AC;Ś)

instead USE 1 mg

failure to use a zero before a decimal point when the dose is less than a whole unit (eg, AVOID .1 mg â&#x20AC;Ś)

instead USE 0.1 mg

lack of a space between the drug name, dose, and unit of measure (eg, AVOID vinblastine10mg â&#x20AC;Ś)

instead USE vinblastine 10 mg

Table 3. Error-Prone Medical Transcription

Adapted from reference 30.

software simply is not available; when it is available it often is poorly written, incompatible with other existing computer systems, or otherwise unreliable. As a result, other safety steps remain vital.

In one such example, FCCC banned chemotherapy drug name abbreviations (eg, CPT-11, which might indicate irinotecan or cisplatin) from all chemotherapy order forms in 1995. Trade names are still permitted and in some cases encouraged (eg, Doxil to indicate liposomal doxorubicin) in response to such recommendations by the Institute for Safe Medication Practices (ISMP; www.ismp. org). The ISMP has a comprehensive list of error-prone

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DEADLY DRUG ADMINISTRATION ERRORS The inadvertent intrathecal administration of drugs such as vincristine, doxorubicin, and daunorubicin continues to occur and almost always is fatal. From an order-entry standpoint, these errors could be avoided if all pharmacy computer systems had an automatic â&#x20AC;&#x153;dead stopâ&#x20AC;? whenever a pharmacist tried to enter one of these drugs to be administered intrathecally. All manufacturers of vincristine include auxiliary warning labels that state: â&#x20AC;&#x153;Fatal if given intrathecally, for IV use only. Do not remove covering until moment of injection.â&#x20AC;?32 Tragic deaths ensue because some practitioners choose not to use this United States Pharmacopeia-required label; and in some cases, the labels have been used by the pharmacy department but with no protective effect at the patient bedside.21,33,34 For example, in 2003, a patient at a university hospital in New Jersey died after mistakenly being injected intrathecally with vincristineâ&#x20AC;&#x201D;by a board-certified radiologistâ&#x20AC;&#x201D;despite the warning label that the drug is fatal if administered this way.21 Because pharmacists are not routinely at the bedside when lumbar puncture procedures are performed, pharmacy CPOE warnings and/or syringe labeling cannot ensure the prevention of this error. Some researchers have suggested routinely diluting all vincristine doses in 50-mL IV piggyback (IVPB) bags to prevent recurrences of this type of error.35,36 Before employing this approach, one is encouraged to consider the possible morbidities associated with increased extravasation risk. This presents a struggle for balance between the prevention of fatal errors versus the prevention of more frequent

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F\b N_R ]_R_RTV`aR_RQ a\ _RPRVcR

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Table 4. Antineoplastic Ordering Terms and Routes of Administration Ideal Generic Drug Names

Not Ideal Branda/ Generic Drug Names and Abbreviations

Most Common Administration Route(s)

Albumin-bound paclitaxel

Abraxane

Intravenous

Aldesleukin

Proleukin, interleukin-2 (IL-2)

Intravenous, subcutaneous

Alemtuzumab

Campath, monoclonal antilymphocyte antibody

Intravenous

Altretamine

Hexalen, hexamethylmelamine (HMM)

Oral

Amifostine

Ethyol, Ethiofos, Gammaphos, WR2721

Intravenous

Aminoglutethimide

Cytadren, Elipten

Oral

Anastrozole

Arimidex

Oral

Arsenic trioxide

Trisenox

intravenous

Asparaginase

Elspar, Colaspace, ASN-ase

Intramuscular, intravenous

Azathioprine

Imuran

Intravenous, oral

Bendamustine

Treanda

Intravenous

Bexarotene

Targretin

Oral

Bicalutamide

Casodex

Oral

Bleomycin

Blenoxane, Bleo

Intravenous, intramuscular, subcutaneous

Busulfan

Myleran, Busulfex

Oral

Capecitabine

Xeloda, Ro 09-1978

Oral

Carboplatin

Paraplatin, CBDCA

Intravenous

Carmustine

BiCNU, bischloronitrosourea (BiCNU)

Intravenous

Chlorambucil

Leukeran

Oral

Cisplatin

Platinol, cis-diaminedichloro-platinum (CDDP)

Intravenous, intraperitoneal

Cladribine

Leustatin, 2-chlorodeoxyadenosine (2-CdA), CDA

Intravenous, subcutaneous

Clofarabine

Clolar

Intravenous

Cyclophosphamide

Cytoxan, Neosar, CTX, CPM, CYT

Intravenous, oral

Cytarabine

Cytosar-U, Tarabine, aytosine, cytosine arabinoside (Ara-C)

Intravenous, intrathecal

Dacarbazine

DTIC-Dome, DIC, imidazole carboxamide

Intravenous

Dactinomycin

Cosmegen, Actinomycin-D (ACT-D)

Intravenous

Dasatinib

Sprycel

Oral

Daunorubicin

Cerubidine, Daunomycin, Rubidomycin, DNR

Intravenous

Denileukin diftitox

Ontak, LY-335348

Intravenous

Dexrazoxane

Zinecard, ICRF-187, ADR-529

Intravenous

Docetaxel

Taxotere, RP-56976

Intravenous

Doxorubicin

Adriamycin, Rubex, Adria

Intravenous, intraperitoneal

Doxorubicin liposome

Doxil

Intravenous

Epirubicin

Ellence, 4'-epidoxorubicin (EPI)

Intravenous

Erlotinib

Tarceva

Oral

Estramustine

Emcyt

Oral

Etoposide

Etopophos, VePesid, VP-16, EPEG

Intravenous, oral, intrapleural

(continued on next page)

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F\b N_R ]_R_RTV`aR_RQ a\ _RPRVcR

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Table 4. Antineoplastic Ordering Terms and Routes of Administration

(continued)

Ideal Generic Drug Names

Not Ideal Branda/ Generic Drug Names and Abbreviations

Most Common Administration Route(s)

Everolimus

Afinitor

Oral

Exemestane

Aromasin, Nikidess

Oral

Floxuridine

Fluorodeoxyuridine (FUDR)

Intravenous

Fludarabine

Fludara, FAMP

Intravenous

Fluorouracil

Adrucil, Efudex, 5-FU

Intravenous, topical

Flutamide

Eulexin, Niftolid

Oral

Gemcitabine

Gemzar, LY-18801

Intravenous

Goserelin

Zoladex, ICI-118630

Subcutaneous

Hydroxyurea

Hydrea, Droxia, Mylocel, hydroxycarbamide

Oral

Idarubicin

Idamycin, 4-demethoxydaunorubicin, IDR, IDA

Intravenous

Ifosfamide

Ifex, IFX

Intravenous

Imatinib

Gleevec, STI-571

Oral

Interferon alfa

Roferon-A, Intron A, IFN

Intramuscular, subcutaneous

Irinotecan

Camptosar, CPT-11

Intravenous

Isotretinoin

Accutane, 13-cis-retinoic acid (13-CRA)

Oral

Ixabepilone

Ixempra

Intravenous

Lapatinib

Tykerb

Oral

Lenalidomide

Revlimid

Oral

Letrozole

Femara

Oral

Leucovorin

Wellcovorin, citrovorum factor, folinic acid (FA), LV

Intravenous, oral

Leuprolide

Lupron, Lupron Depot, leuprorelin

Intramuscular, subcutaneous

Levamisole

Ergamisol, l-tetramisole, ICI-59623

Oral

LEVO-leucovorin

Fusilev, leucovorin, L-leucovorin

Intravenous

Lomustine

CeeNU, CCNU, bis-chloro-nitrosourea

Oral

Mechlorethamine

Mustargen, Chlorethazine, HN2, nitrogen mustard

Intravenous, topical

Medroxyprogesterone

Provera, Depo-Provera

Oral, intramuscular

Megestrol

Megace

Oral

Melphalan

Alkeran, phenylalanine mustard, L-PAM

Oral, intravenous

Mercaptopurine

Purinethol, 6-MP

Oral

Mesna

Mesnex, sodium 2-mercaptoethane sulfonate

Intravenous, oral

Methotrexate

Amethopterin, MTX, Folex

Intravenous, oral, intrathecal

Mitomycin

Mutamycin, mitomycin-c

Intravenous

Mitotane

Lysodren, o,p'-DDD

Oral

Mitoxantrone

Novantrone, DHAD, DHAQ

Intravenous, intraperitoneal

Nelarabine

Arranon

Intravenous

Nilotinib

Tasigna

Oral

This information is based on the prescribing information for each drug. a

Brand names are listed in bold.

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Table 4. Antineoplastic Ordering Terms and Routes of Administration Ideal Generic Drug Names

Not Ideal Branda/ Generic Drug Names and Abbreviations

Most Common Administration Route(s)

Octreotide

Sandostatin, 1-cysteinamide, SMS

Subcutaneous

Oprelvekin

Neumega, interleukin-11 (IL-11), rIL-11

Subcutaneous

Oxaliplatin

Eloxatin, diaminocyclohexane platinum

Intravenous

Paclitaxel

Taxol, TX, PCL, PCT, TX

Intravenous

Pegaspargase

Oncaspar, polyethylene glycol L-asparaginase

Intramuscular

Pemetrexed

Alimta

Intravenous

Pentostatin

Nipent, co-vidarabine, 2-deoxycoformycin (DCF)

Intravenous

Plicamycin

Mithramycin, Mithracin, aureolic acid

Intravenous

Prednisone

Deltasone

Oral

Procarbazine

Matulane, Natulana, N-methylhydrazine

Oral

Rituximab

Rituxan, IDEC-C2B8

Intravenous

Sorafenib

Nexavar

Oral

Streptozocin

Zanosar

Intravenous

Sunitib

Sutent

Oral

Tamoxifen

Nolvadex

Oral

Temozolomide

Temodar

Oral

Temsirolimus

Torisel

Intravenous

Thalidomide

Thalomid

Oral

Thioguanine

Tabloid, 6-thioguanine (6-TG), TG, WR-1141

Oral

Thiotepa

TESPA, Thioplex, WR-45312

Intravenous, intravesical

Topotecan

Hycamtin, SKF-104864

Intravenous

Toremifene

Fareston, EC-11570

Oral

Trastuzumab

Herceptin, anti-HER2 antibody

Intravenous

Tretinoin

Vesanoid, all trans-retinoic acid (ATRA)

Oral

Trimetrexate

NeuTrexin, TMQ, TMTX

Intravenous

Vinblastine

Velban

Intravenous

Vincristine

Oncovin, Vincasar

Intravenous

Vinorelbine

Navelbine

Intravenous

This information is based on the prescribing information for each drug. a

Brand names are listed in bold.

nonâ&#x20AC;&#x201C;life-threatening, albeit severe, adverse events (eg, vesicant drug extravasation when a drug is administered from an IVPB minibag into a peripheral IV line). In cases when a 50-mL IVPB vincristine, vinblastine, or vinorelbine dose might present excessive risk for extravasation, some centers use 20- or 30-mL fixed-volume syringes for all vinca alkaloid medication doses, with warning stickers and label text, to achieve the same purposeâ&#x20AC;&#x201D; namely, making the drug volume too large to be accidentally administered intrathecally.

Prevention of vincristine administration errors was

reviewed in a 2005 Sentinel Event Alert issued by the Joint Commission.37 The alert was distributed to all health care organizations in the United States. More recently, the ISMP has recommended revised wording for supplemental stickers applied to vinca medication doses.

Specifically, the ISMP no longer recommends â&#x20AC;&#x153;NOT for Intrathecal Useâ&#x20AC;? based on the concern that the presence of the word â&#x20AC;&#x153;intrathecalâ&#x20AC;? may contribute to confusion if the sticker is not read completely or becomes damaged.38 The ISMP now recommends supplemental warning stickers that include the following text: â&#x20AC;&#x153;For IV Use

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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Only: Fatal if given by other routes.â&#x20AC;?38 Recommendations for preparing, dispensing, and administering IV vincristine and other vinca alkaloids (in addition to diluting vincristine and affixing the required warning labels) include conducting a â&#x20AC;&#x153;time outâ&#x20AC;? with at least 2 licensed, qualified health care professionals to independently review the drug, dose, and route at the time of pharmacy preparation, as well as separating the dispensing of vincristine from other antineoplastics that may be given by the intrathecal route as part of the treatment regimen. In Australia, pharmacists are lobbying the national governmental organization to abolish the syringe as a vehicle to administer vincristine.39 As this discussion illustrates, significant differences of opinion remain regarding the best (and safest) manner to avoid fatal accidental intrathecal administration of vincristine and other vinca alkaloids in light of the significant risk for severe local tissue injury if an IVPB dose of a vinca extravasates during a peripheral line administration.39

References 1.

Beckwith MC, Tyler LS. Preventing medication errors with antineoplastic agents, part 1. Hosp Pharm. 2000;35(5):511-525.

2. Womer RB, Tracy E, Soo-Hoo W, Bickert B, DiTaranto S, Barnsteiner JH. Multidisciplinary systems approach to chemotherapy safety: rebuilding processes and holding the gains. J Clin Oncol.

2002;20(24):4705-4712, PMID: 12488417.

3. MĂźller T. Typical medication errors in oncology: analysis and prevention strategies. Onkologie. 2003;26(6):539-544, PMID: 14704927.

4. Schulmeister L. Preventing chemotherapy errors. Oncologist.

2006;11(5):463-468, PMID: 16720846.

5. Aspden P, Wolcott J, Bootman JL, Cronenwett LR, eds, for the Committee on Identifying and Preventing Medication Errors. Preventing Medication Errors: Quality Chasm Series. Washington, DC: National Academy Press; 2006.

6. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342, PMID: 15175435.

7. Avastin [prescribing information] South San Francisco, CA: Genetech; May 2009.

8. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol. 2007;25(12):1539-1544, PMID: 17442997.

9. Institute for Safe Medication Practices. Urgent Drug Safety Message.

Medication errors with certain lipid-based products. http://www. ismp.org/newsletters/acutecare/articles/19980818.asp. Accessed July 16, 2009.

10. Chemotherapy overdoses for 2 Children at Johns Hopkins.

The New York Times. August 2, 2002. http://www.nytimes. com/2002/08/02/us/national-briefing-health-and-science-chemotherapy-overdoses-for-2-children.html?n=Top/Reference/ Times%20Topics/Organizations/J/Johns%20Hopkins%20University. Accessed April 15, 2009.

11. Fritsch J. Syracuse hospital admits causing death of patient.

The New York Times. May 13, 1992. http://www.nytimes. com/1992/05/13/nyregion/syracuse-hospital-admits-causingdeath-of-patient.html. Accessed July 16, 2009.

12. ISMP Medication Safety Alert 2/7/01. FDA Advise-ERR: Medication errors associated with taxotere and taxol. http://www.ismp.org/ newsletters/acutecare/articles/20010207.asp. Accessed July 16, 2009.

13. ISMP Medication Safety Alert 10/21/04. http://www.ismp.org/ MSAarticles/A4Q04Action.htm. Accessed July 16, 2009.

14. Hazard Medication Alert. 8/18/98. MSA Acute Care Edition

8

F\b dVYY NY`\ OR Nba\ZNaVPNYYf R[aR_RQ V[a\ N Q_NdV[T a\ dV[ N[ V=\Q a\bPU

Newsletter. http://www.ismp.org/hazardalerts/lipid.asp. Accessed July 16, 2009.

15. Institute for Safe Medication Practices. Medication Safety Alert 7/15/04. Lowdown on lomustine: weâ&#x20AC;&#x2122;d hate CEENU make this mistake. http://www.ismp.org/newsletters/acutecare/articles/20040715.asp. Accessed July 16, 2009.

16. Moore TJ, Walsh CS, Cohen MR. Reported medication errors associated with methotrexate. Am J Health Syst Pharm.

2004;61(13):1380-1384, PMID: 15287234.

17. National Patient Safety Agency. Reducing the harm caused by oral methotrexate. http://www.nacc.org.uk/downloads/factsheets/ npsaMethotrexateAlert.pdf. Accessed July 16, 2009.

18. Institute for Safe Medication Practices. Medication Safety Alert 12/3/02. http://www.ismp.org/hazardalerts/ha.pdf. Accessed July 16, 2009.

19. Institute for Safe Medication Practices. Medication Safety Alert 4/5/00. Pain, paralysis, and knowledge of impending death marks intrathecal vincristine. http://www.ismp.org/ newsletters/acutecare/articles/20000405.asp. Accessed July 16, 2009.

20. Berwick DM. Not again! Preventing errors lies in redesignâ&#x20AC;&#x201D;not exhortation. BMJ. 2001;322(7281):247-248, PMID: 11157508.

21. Narayanan A. Family tells of tragedy following fatal injection. The Home News Tribune. April 17, 2003. http://www.thnt.com/thnt/ story10,21282,723614,00.html. Accessed April 15, 2009.

22. Bennett C. Is jail the answer for fatal negligence? Guardian (UK).

September 25, 2003. http://www.guardian.co.uk/uk/2003/sep25/ ukcrime.comment. Accessed April 15, 2009.

23. Cohen MR. Vincristine therapy: days â&#x20AC;&#x153;4-11â&#x20AC;? misunderstood as days 4 through 11. Hosp Pharm. 2006;41(9):811-815.

24. Gandhi TK, Bartel SB, Shulman LN, et al. Medication safety in the ambulatory chemotherapy setting. Cancer. 2005:104(11):2477-2483, PMID: 16245353.

25. Alcaraz A, Rey C, Concha A, Medina A. Intrathecal vincristine: fatal myeloencephalopathy despite cerebrospinal fluid perfusion. J Toxicol Clin Toxicol. 2002;40(5):557-561, PMID: 12215050.

26. Twedt S. Deadly hospital mistakes are doomed to be repeated.

Pittsburgh Post-Gazette. October 24, 1993;section A,1.

27. Kloth DD. Prevention of chemotherapy medication errors. J Pharm Pract. 2002;15(1):17-31.

28. Joint Commission. Sentinel Event Alert. Look-alike, sound-alike names. 2001. http://www.jointcommission.org/SentinelEvents/SentinelEventAlert/sea_19.htm. Accessed July 16, 2009.

29. Abraxane [prescribing information]. Los Angeles, CA: Abraxis Oncology; August 2007.

30. Institute for Safe Medication Practices. ISMPâ&#x20AC;&#x2122;s List of Error-Prone Abbreviations, Symbols, and Dose Designations. http://www.ismp. org/Tools/errorproneabbreviations.pdf. Accessed April 15, 2009.

31. The Joint Commission. Official â&#x20AC;&#x153;Do Not Useâ&#x20AC;? list. http://www. jointcommission.org/NR/rdonlyres/2329F8F5-6EC5-4E21-B93254B2B7D53F00/0/dnu_list.pdf. Accessed July 16, 2009.

32. Vincristine [product label]. http://patient.cancerconsultants.com/ druginserts/vincristine.pdf. Accessed July 20, 2009.

33. Dyer C. Junior doctor charged with manslaughter after medical error [news item]. BMJ. 2002;325(7365):616, PMID: 12269306.

34. Dyer C. Doctor sentenced for manslaughter of leukaemia patient [news item]. BMJ. 2003;327(7417):697, PMID: 14512453.

35. Davis NM. The preparation of vincristine in minibags will prevent deadly medication errors. Hosp Pharm. 2001;36(7):707.

36. Trissel LA, Zhang Y, Cohen MR. The stability of diluted vincristine sulfate used as a deterrent to inadvertent intrathecal injection.

Hosp Pharm. 2001;36(7):740-745.

37. Joint Commission. Sentinel Event Alert. Preventing vincristine administration errors. http://www.jointcommission.org/sentinelEvents/SentinelEventAlert/sea_34.htm. Accessed July 16, 2009.

38. Institute for Safe Medication Practices. Medication Safety Alert Nurse Advise-ERR. 2008;6(10).

39. Gilbar PJ, Carrington CV. The incidence of extravasation of vinca alkaloids supplied in syringes or mini-bags. J Oncol Pharm Pract.

2006;12(2):113-118, PMID: 16984750.

For a pocket guide version of The Guide to the Prevention of Chemotherapy Medication Errors, visit www.CLINICALONCOLOGY.COM

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AT A GLANCE Address 545 W. 45th Street, 8th Floor New York, NY 10036 Phone: (212) 957-5300 Fax: (212) 957-7230 www.mcmahonmed.com www.clinicaloncology.com www.cmezone.com

Products Medical newsmagazines, custom medical publications, educational reviews, educational and instructional pocket guides, special editions.

Publisher, CEO and Managing Partner Raymond E. McMahon

President, Partner Van Velle

Clinical Oncology News Staff Vice President, Medical Education; Group Publication Director Thomas Ciriacks Associate Publication Director Julianna Dawson Executive Manager, Classifieds Nancy Parker Managing Editor Kate Oâ&#x20AC;&#x2122;Rourke Senior Editor Sarah Tilyou Art Director Frank Tagarello

McMahon Publishing McMahon Publishing was founded in 1972 by Raymond E. McMahon. McMahon Publishing has grown to become one of the nationâ&#x20AC;&#x2122;s largest family-owned medical publishers, with a projected 2009 annual revenue of roughly $23 million across all product categories.

Today, McMahon publishes a broad array of medical newsmagazines in various specialties, including oncology, anesthesiology, gastroenterology, general surgery, hospital pharmacy, infectious diseases, and pain medicine. McMahon publications are at or near the top of their markets in independent readership scores. The combined circulation of McMahon Publishing publications approaches 330,000 doctors and pharmacists.

Clinical Oncology News was launched in September 2006 and has become a rising star among oncology publications. The mission of the publication is threefold: to improve the quality of oncology care, to increase its cost-effectiveness and to facilitate the job of the oncologist. To achieve these goals, the editorial staff of Clinical Oncology News follows developments in the field, both in the academic and private-practice settings. The majority of the news coverage comes from major oncology meetings, roughly 10 to 15, including the annual meetings of the American Society of Clinical Oncology, American Society of Hematology, European Society for Medical Oncology and American Society of Pediatric Hematology/Oncology. Each month, Clinical Oncology News also provides in-depth educational reviews.

McMahon Publishing also produces a wide variety of Special Editions, compendia of educational reviews written by thought leaders in various specialties. These

include oncology, anesthesiology, gastroenterology and endoscopy, hospital pharmacy, general surgery, infectious disease, and pain medicine. The Special Projects division of McMahon Publishing produces educational reviews, wall charts and custom pocket guides and Special Reports and Literature Reviews. The educational reviews, written by authorities in a given treatment area, are comprehensive summaries of state-of-the-art thinking on a specific disease state.

These often are published as wall charts and pocket guides that serve as on-the-spot educational tools for health care providers. Special Reports are individual, custom-written monographs that are bound inside Clinical Oncology News or other McMahon publications. Special Reports can be based on symposium coverage, interviews with experts, the medical literature and any combination of these. Special Reports can be CME/CE accredited.

Literature Reviews also are individual, custom-written monographs that are bound inside Clinical Oncology News or other McMahon publications and distributed to the newsmagazineâ&#x20AC;&#x2122;s full readership. We conduct a literature search for all peer-reviewed, published studies on a given subject and compile a detailed, scientifically sound review of these articles. Literature Reviews also can be CME/CE accredited.

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Abraxis BioScience AT A GLANCE Address 11755 Wilshire Blvd., 20th Floor Los Angeles, CA 90025 Phone: (310) 883-1300 Fax: (310) 998-8553 www.abraxisbio.com

Executive Committee Lonnie Moulder Patrick Soon-Shiong, MD Mary Lynne Hedley, PhD

Abraxis BioScience is a fully integrated global biotechnology company dedicated to the discovery, development and delivery of next-generation therapeutics and core technologies that offer patients safer and more effective treatments for cancer and other critical illnesses.

The companyâ&#x20AC;&#x2122;s portfolio includes the worldâ&#x20AC;&#x2122;s first and only protein-bound nanoparticle chemotherapeutic compound (ABRAXANE), which is based on the companyâ&#x20AC;&#x2122;s proprietary tumor targeting technology known as the nabÂŽ platform. The first FDA-approved product to use this nab platform, ABRAXANE was launched in 2005 for the treatment of metastatic breast cancer and is now approved in 36 countries. The company continues to expand the nab platform through a robust clinical program and deep product pipeline. Abraxis trades on the NASDAQ Global Market under the symbol ABII. For more information about the company and its products, please visit www. abraxisbio.com.

Rick Rodgers Bruce Wendel

Board of Directors Patrick Soon-Shiong, MD Lonnie Moulder Kirk K. Calhoun David S. Chen, PhD Stephen D. Nimer, MD Leonard Shapiro

18

Corporate Profile 2009

Special Advertising Section Clinical Oncology News

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Amgen:

Pioneering Science Delivers Vital Medicines

Scientists at Amgen pursue fundamental cellular signaling pathways. Following these uncharted molecular trials can lead to important discoveries about the root causes of grievous illnesses, as well as to new targets for drug development.

Amgen researchers have found pathways that play a role in various types of cancer, bone loss and immune system and inflammatory disorders.

The result is a robust pipeline that currently contains more than 50 molecules from late discovery research through Phase III clinical trials.

The Principled Pursuit of Innovation Amgenâ&#x20AC;&#x2122;s research and development teams follow four guiding principles:

1. Focus on grievous illnesses Patients suffering from the greatest unmet needs are Amgenâ&#x20AC;&#x2122;s first priority. The majority of new molecules that Amgen is bringing into the clinical target pathways have never previously been addressed in humans. Many of these are aimed at cancer, an area in which Amgen is conducting clinical trials in more than a dozen tumor types.

Growth Regulation: Identifying and blocking the pathways that regulate the ability of cancer cells to proliferate, migrate, invade and survive.

Angiogenesis: Preventing tumors from stimulating the formation of new blood vessels to feed them.

Apoptosis: Enabling programmed cell death, or â&#x20AC;&#x153;cancer cell suicide.â&#x20AC;?

Bone Metabolism and Metastases: Controlling the signals that trigger bone buildup and breakdown, in an effort to treat and prevent the spread of cancer to the bones.

Amgen: Bringing the Promise of Biotechnology to Life

AT A GLANCE Address One Amgen Center Drive Thousand Oaks, CA 91320-1799 Phone: (805) 447-1000 Fax: (805) 447-1010 www.amgen.com For information about Amgen medicines, including important safety information, visit www.amgen.com/medpro/ products.html

Amgen uses innovative research to improve the health of patients. As pioneers in biotechnology, Amgen applies its expertise to discover, create and deliver vital medicines that so far have helped more than 15 million people in their fight against cancer, kidney disease, rheumatoid arthritis and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen is working to continue to bring the promise of biotechnology to lifeâ&#x20AC;&#x201D;to help many more.

2. Be modality-independent In other words, choose the right tool for the task. Amgen scientists look first at the disease process, then seek to determine the most advantageous therapeutic approach, be it large-molecule biologic, antibody, peptibody or small-molecule (oral) therapy.

3. Study disease in people

Amgen explores several oncology research areas including tumor angiogenesis, the abnormal process of new blood vessel formation.

Studying disease in people is the best way to develop medicines for people. Experimental models often have little predictive value, and promising preclinical studies too often lead to highcost clinical failures. Amgen seeks to identify safe and effective disease intervention methods as early as possible in the developmental process, using biomarkers and other tools.

4. Seamless integration Amgen is structured to incorporate perspectives from health economics, regulatory and government affairs, clinical development and basic research into all development programs. Being rigorous in its prioritization, clear in its focus and attentive to all aspects of therapeutic intervention enables Amgen to develop medicines that address important unmet medical needs while also presenting a compelling value proposition for society.

Pathways in Cancer Research Amgen oncology researchers are fighting cancer on multiple fronts, including:

Special Advertising Section Clinical Oncology News

In the United States, one out of every two women over age 50 will suffer an osteoporotic fracture. Bone biology is an important area of exploration where Amgen scientists work to address unmet needs.

Corporate Profile 2009

19

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Dako AT A GLANCE Address 6392 Via Real Carpinteria, CA 93013 Phone: (805) 566-6655 Fax: (805) 566-6688 www.dako.com

Products HercepTest HER2 FISH pharmDx EGFR pharmDx ER/PR pharmDx c-Kit pharmDx

Dako is a global leader in tissue-based cancer diagnostics. Hospital and research laboratories worldwide use Dakoâ&#x20AC;&#x2122;s know-how, reagents, instruments and software to make precise diagnoses and determine the most effective treatment for patients with cancer.

With more than 1,000 employees and operations in more than 70 countries, Dako covers essentially all of the global anatomic pathology markets. Headquartered in Denmark, Dakoâ&#x20AC;&#x2122;s focus is to become first choice for pathologists around the globe.

Drug-Diagnostic Codevelopment In an effort to improve patient care, the FDA encourages the use of companion diagnostics to enable identification of patients who are eligible for a particular cancer therapy.1 Through the pharmDxâ&#x201E;˘ program, Dako offers partnership opportunities to pharmaceutical and biotechnology companies that wish to codevelop their drug with a companion diagnostic test. Dakoâ&#x20AC;&#x2122;s approach is uniquely suited to complement the entire pharmaceutical value chain, from preclinical research through clinical trials, regulatory approval and commercialization.

About the Dako pharmDxâ&#x201E;˘ Program

Dako subsidiary in North America.

and has numerous new pharmDxâ&#x201E;˘ products in the pipeline.

Dakoâ&#x20AC;&#x2122;s pharmDxâ&#x201E;˘ Capabilities Dakoâ&#x20AC;&#x2122;s exceptional track record demonstrates the companyâ&#x20AC;&#x2122;s unique ability to collaborate with pharmaceutical companies to develop, manufacture and commercialize predictive tests for anatomic pathologists worldwide. Dakoâ&#x20AC;&#x2122;s unique pharmDxâ&#x201E;˘ capabilities include the following: â&#x20AC;˘ Basic research and pharmDxâ&#x201E;˘ assay development capabilities for both immunohistochemistry and in situ hybridization assays in manual and automated formats; â&#x20AC;˘ Development of image-analysis algorithms to enable more uniform interpretation; â&#x20AC;˘ FDA- and ISO-certified manufacturing facilities; â&#x20AC;˘ Regulatory filing and approval in the United States, Europe and Japan; and â&#x20AC;˘ Access to global markets through worldwide sales, marketing and distribution channels.

Dakoâ&#x20AC;&#x2122;s pharmDxâ&#x201E;˘ products are predictive tests that enable targeted therapeutics by providing tools to accomplish the following: Partnership Opportunities â&#x20AC;˘ Identify potential responders to a specific drug; Dako is strongly committed to developing â&#x20AC;˘ Aid in differential diagnosis or identificaand maintaining successful partnerships for tion of patient subsets; the long term. Dako is actively seeking new â&#x20AC;˘ Permit data mining and re-evaluation of partners for drug-diagnostic codevelopment previously studied drugs; and Identify opportunities. As a partner, Dako will leverage patients at risk for adverse events its industry-leading diagnostic and pharmDxâ&#x201E;˘ Lars Holmkvist, President and CEO In 1998, Dako pioneered this field with the expertise to facilitate successful discovery, introduction of HercepTest as a companion development and commercialization of new diagnostic for HerceptinÂŽ. Since then, Dako has commercialized targeted therapies and companion diagnostics. the following companion diagnostics: HER2 FISH pharmDxâ&#x201E;˘ for For press releases and further information, HerceptinÂŽ treatment, EGFR pharmDxâ&#x201E;˘ for Erbitux treatment, please see www.dako.com.

ER/PR pharmDxâ&#x201E;˘ for antihormonal or aromatase inhibitor therapies and c-Kit pharmDxâ&#x201E;˘ for diagnosis of gastrointestinal stromal tumors and treatment with Gleevec/Glivecâ&#x201E;˘. Currently, Dako is work1. â&#x20AC;&#x153;Drug-Diagnostic Co-Development Concept Paper (Draft)â&#x20AC;? published by the ing with several pharmaceutical and biotechnology companies, FDAâ&#x20AC;&#x2122;s Department of Health and Human Services (HHS), April 2005.

20

Corporate Profile 2009

Special Advertising Section Clinical Oncology News

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Every door opened could be a discovery made.

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Making science personal.

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© 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Thromboembolism

Case for Genetic Screen Debated

Is VKORC1 Test Needed in All Warfarin Patients?

Miamiâ&#x20AC;&#x201D;Genetic testing to determine an individual patientâ&#x20AC;&#x2122;s sensitivity to warfarin would make dosing of the agent more efficient and reduce the risk for bleeding or clotting events.

But whether such testing should become routine is still a matter for debate.

At the 2009 annual conference of the Hematology/Oncology Pharmacy Association (HOPA), Rowena N. Schwartz, PharmD, director of oncology pharmacy at The Johns Hopkins Hospital, Baltimore, argued that pharmacogenomic testing for vitamin K epoxide reductase (VKORC1), the gene that codes for the enzyme that is the site of action where warfarin exerts its effect, should be done in all patients receiving warfarin.

Kelly Nystrom, PharmD, assistant professor of pharmacy practice at Creighton University, Omaha, Neb., took the opposite view, telling HOPA delegates

that testing for VKORC1 should not be done in all patients because it is still not known whether the information from the test will actually affect clinical outcomes.

The Evidence for VKORC1 Testing There is a single nucleotide polymorphism (SNP) in the VKORC1 gene that influences the pharmacodynamics of warfarin. The pharmacokinetics of warfarin are influenced by an SNP in the cytochrome P450 C29 (CYP2C9) gene.

Together, these genetic factors account for 30% to 35% of the variability in warfarin dosing. However, it is very difficult to determine which individuals have these variants, Dr. Schwartz said.

â&#x20AC;&#x153;A study by Limbi [Pharmacotherapy 2008;28:1084-1097] found that the frequency of the VKORC1 allele 1173C/T was 10.6% among African Americans, 36.5% in Euro-Americans and 87% in

international normalized ratio (INR) than individuals with homozygous wild-type alleles, according to a study

by Stehle and colleagues (Clin Pharmacokinet 2008;47:565-594).

â&#x20AC;&#x2DC;We know that VKORC1 affects the dosing of warfarin that we are going to use, but what we donâ&#x20AC;&#x2122;t know is how that affects clinical outcomes. I donâ&#x20AC;&#x2122;t think that we have adequate information yet to tell us this.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Kelly Nystrom, PharmD

Hong Kong Chinese. But you can no longer say for certain which patient will have the variation. So even though this data is really helpful, it doesnâ&#x20AC;&#x2122;t help us make the adjustment in individual patients,â&#x20AC;? she said.

Adding to the case for testing is the abundant evidence that the 1173C/T allele affects the variability of the dose requirement in patients who are receiving warfarin. Carriers of this allele need a longer time to reach a stable

Dr. Schwartz said that to date, the most convincing data for the benefit of VKORC1 testing comes from the International Warfarin Pharmacogenetics Consortium, which pooled data from 21 research groups from nine different countries (N Engl J Med 2009;360:753-764). The consortium used data from 4,043 patients to create a dose algorithm based on clinical variables alone, or on genetic information plus clinical variables. Consortium researchers concluded that the algorithm

Pain

Interventional Pain Techniques Effective in Children Interventional pain management can reduce pain scores in pediatric cancer patients, a new study reveals.

Phillip C. Phan, MD, director of interventional pain management at The University of Texas M.D. Anderson Cancer Center, in Houston, said interventional pain management strategies can reduce pain without increasing the use of oral analgesics that cause side effects in pediatric patients. â&#x20AC;&#x153;There are two problems with using pain medicine in children. They are very susceptible to side effects, so they get sleepy, drowsy and nauseated. Tolerance also develops much more rapidly with children,â&#x20AC;? said Dr. Phan, a coauthor of the study.

Interventional strategies, such as blocking a nerve plexus, can disrupt the transmission of pain, said Dr. Phan, who presented the findings at the 2009 annual meeting of the American Academy of Pain Medicine, in Honolulu (abstract 153). â&#x20AC;&#x153;With cancer, the location of the cancer is the source of the pain. So we can dampen it by local blocking, or we can put a catheter into that area and infuse medicine to block the pain signal.â&#x20AC;?

In the retrospective review of 58

children treated at the center between 2006 and 2008 for a range of cancer diagnoses, the most commonly used procedures were neural blockade, neurolytic blockade, intrathecal therapy, neurostimulation and vertebral augmentation. The techniques reduced pain scores by 68.7% and opioid consumption by 65.0%. Dr. Phan stressed that these therapies augment traditional pain control methods.

definitive cancer treatment.

Christina Ullrich, MD, MPH, a specialist in pediatric oncology and pediatric palliative care at the Dana-Farber Cancer Institute, in Boston, said the study adds to a growing body of literature showing interventional pain management strategies to be effective, â&#x20AC;&#x153;particularly when dealing with refractory pain and medications that are causing side effects, and in the setting of

Dr. Ullrich said.

Arthur D. Zepeda, MD, director of pain management at the University of California at Irvine College of Medicine, noted that neuroaxial opioids have long been used for postoperative pain in pediatric patients and that treating pediatric cancer patients with similar procedures is a next step. â&#x20AC;&#x153;They can be at least as beneficial as they have been in adults,â&#x20AC;? he said. Concerns about

â&#x20AC;&#x2DC;If a patient is going to be discharged with an implanted pump or port, it can be challenging to find a home care agency that is able to support that technology in the outpatient setting.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Christina Ullrich, MD, MPH

â&#x20AC;&#x153;You may have a patient with an osteosarcoma of the lower leg who is on adequate pain medication, but once in a while the kid moves the leg and causes a pain flare-up,â&#x20AC;? he said. â&#x20AC;&#x153;In that case, the medication would not help, so we would go in and do a temporary nerve block, injecting a local anesthetic and a steroid. That would give the patient relief for 24 to 48 hours.â&#x20AC;? Thus, interventional pain therapy can optimize pain control while pediatric patients are receiving

advanced illness.â&#x20AC;? She was particularly encouraged by the results in pediatric patientsâ&#x20AC;&#x201D;few pain control studies are conducted in children. She added, however, that the availability of home care must be considered up front for patients undergoing such procedures. â&#x20AC;&#x153;If a patient is going to be discharged with an implanted pump or port, it can be challenging to find a home care agency that is able to support that technology in the outpatient setting,â&#x20AC;?

device management, however, need to be addressed during patient selection. â&#x20AC;&#x153;Even with adults, we have to make sure the patients have the resources and psychosocial capability to handle the postoperative and maintenance part of this therapy,â&#x20AC;? Dr. Zepeda said.

Complications reported in the study included postdural puncture headaches in two patients who received intrathecal therapy. â&#x20AC;&#x201D;David Jakubiak

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY/AUGUST 2009

Thromboembolism

WARFARIN continued from page 22

that contained the genetic information provided a significantly better prediction of the appropriate dose of warfarin than the algorithm containing just clinical variables. The pharmacogenetic algorithm was also better than a fixed-dose approach based on 35 mg per week of warfarin.

The consortium also found that 1,711 (33.9%) of the total cohort of patients in their review required a low doseâ&#x20AC;&#x201D;less than 21 mg per week of warfarin, and that the pharmacogenetic algorithm provided better prediction, with fewer overestimations of dose. Similarly, for 625 (12.4%) individuals requiring high doses (>49 mg per week of warfarin), the pharmacogenetic algorithm provided better prediction, with fewer underestimations. â&#x20AC;&#x153;The data from the consortium shows that if you use a fixed dose, you are not right often. You can make up for this if you have very close monitoring. But frequent monitoring and patient visits and the time it takes to evaluate those measures is not cheap either,â&#x20AC;? Dr. Schwartz said.

She concluded, â&#x20AC;&#x153;There is clear evidence that there is a difference in response to warfarin in patients with different genetic variants. If we can know those and make more knowledgeable decisions about what the dosing should be, especially the initiation dosing, I think that we save people time and problems.â&#x20AC;?

Jury Still Out Dr. Nystrom disagreed that evidence justifies VKORC1 testing in all patients receiving warfarin. â&#x20AC;&#x153;We know that VKORC1 affects the dosing of warfarin that we are going to use, but what we donâ&#x20AC;&#x2122;t know is how that affects clinical outcomes. I donâ&#x20AC;&#x2122;t think that we have adequate information yet to tell us this.â&#x20AC;?

She cited a study by Schwartz et al.

(N Engl J Med 2008;358:999-1008) that showed the risk for bleeding complications in 297 patients was the same regardless of VKORC1 genotype. â&#x20AC;&#x153;Their take-home message was that the patients with the VKORC1 *A/*A variant had a higher INR than patients with the VKORC1 *non-A/*non-A variants, even with empiric dose adjustments, but that serious bleeding effects were not significantly affected by the VKORC1 haplotype or CYP2C9 status.â&#x20AC;?

Whatâ&#x20AC;&#x2122;s Your View? =?6;A

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Should VKORC1 testing be done in all patients receiving warfarin therapy?

Send replies to

korourke@mcmahonmed.com

In addition to genetic testing, Dr. Nystrom said other factors to consider when it comes to dosing warfarin include smoking, alcohol use, comorbidities, weight, height, vitamin K intake, age, gender, medications and amount of exercise.

Cost-effectiveness is another factor that needs to be examined when recommending universal VKORC1 testing, Dr. Nystrom said. A study by Eckman and colleagues (Ann Intern Med 2009;150:7383) studied the cost-effectiveness of pharmacogenetic-guided warfarin dosing and found that, in comparison with standard warfarin dosing, the strategy cost $144,000 per quality-adjusted life

year. The researchers concluded that there is a small group of patients who might benefit, and that the cost-effectiveness may improve as the cost of peforming the test decreases. â&#x20AC;&#x153;Still, it is not cheap,â&#x20AC;? Dr. Nystrom said.

Finally, the Centers for Medicare & Medicaid Services (CMS) released a statement in May announcing that it would not reimburse warfarin genetic testing, noting a lack of evidence that such testing improves health outcomes in Medicare beneficiaries.

The CMS also released statements from major medical groups, including the American College of Chest

Physicians, the American College of Medical Genetics, the Association for Molecular Pathology and the American Society of Hematology, calling for more randomized data from clinical trials before they could support routine VKORC1 testing. â&#x20AC;&#x153;Once we have this information, we can make a better judgment on whether this is something that should be offered to all patients, but currently, I donâ&#x20AC;&#x2122;t think there is enough information available to offer testing to all patients who are receiving warfarin,â&#x20AC;? Dr. Nystrom concluded. â&#x20AC;&#x201D;Fran Lowry

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Based on independent review of disease progression, a statistically significant prolongation in PFS was observed in patients receiving VectibixÂŽ plus BSC vs those patients receiving BSC alone1,2 100% 90%

Kaplan-Meier Plot of PFS Time as Determined by the Independent Review Committee1,2

80%

Proportion Event Free

The first fully human* anti-EGFR monoclonal antibody

70%

Treatment Group VectibixÂŽ + BSC (n=231) BSC Alone (n=232)

P < 0.0001

60% 50% 40% 30% 20% 10% 0% 0

Safety data are available from 15 clinical trials in which 1467 patients received VectibixÂŽ; of these, 1293 received VectibixÂŽ monotherapy and 174 received VectibixÂŽ in combination with chemotherapy.

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 VectibixÂŽ monotherapy. Withhold VectibixÂŽ for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to â&#x2030;¤ grade 2 within 1 month, permanently discontinue VectibixÂŽ. 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.

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension. Although not reported with VectibixÂŽ, fatal infusion reactions 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 VectibixÂŽ.

VectibixÂŽ 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 VectibixÂŽ 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.

In a single-arm study of 19 patients receiving VectibixÂŽ in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving VectibixÂŽ plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

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1

1

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1

0

Infusion reactions

Important Safety Information including Boxed WARNINGS:

6

232 209 175 149 75 41 31 20 17 11

Q2W dosing

INDICATION: VectibixÂŽ 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 VectibixÂŽ as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival.

Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with VectibixÂŽ.

4

231 217 209 197 118 85 76 65 49 41 40 40 31 22 19 19 13 8

Prolonged PFS

*Correlation with safety and efficacy is unknown

2

7

7

7

4

4

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Weeks Subjects at risk: VectibixÂŽ + BSC BSC Alone

Statistically significant prolongation in PFS time vs BSC alone1,2 The recommended dose of VectibixÂŽ is 6 mg/kg administered over 60 minutes (for doses over 1000 mg infuse over 90 minutes) as an intravenous infusion every 14 days1 The use of premedication was not standardized in clinical trials (the utility of premedication in preventing infusional toxicity is unknown)1 ~1% incidence of severe infusion reactions reported1 - See Important Safety Information including Boxed WARNINGS for infusion reactions

Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of VectibixÂŽ. 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 such patients is uncertain. Permanently discontinue VectibixÂŽ therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the VectibixÂŽ arm. Additionally, hypomagnesemia (NCI-CTC grade 3 or 4) requiring electrolyte repletion occurred in 2% of patients 6 weeks or longer after the initiation of VectibixÂŽ. In some patients, both hypomagnesemia and hypocalcemia occurred. Patientsâ&#x20AC;&#x2122; electrolytes should be periodically monitored during and for 8 weeks after the completion of VectibixÂŽ therapy, and appropriate treatment instituted, as needed.

Exposure to sunlight can exacerbate dermatologic toxicity. It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving VectibixÂŽ.

Dermatologic, mucosal, and ocular toxicities were also reported.

Adequate contraception in both males and females must be used while receiving VectibixÂŽ and for 6 months after the last dose of VectibixÂŽ therapy.

The most common adverse events of VectibixÂŽ 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 VectibixÂŽ are pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Please see brief summary of Prescribing Information on next page.

References: 1. VectibixÂŽ (panitumumab) prescribing information, Amgen.

2. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol.

2007;13:1658-1664.

Š2009 Amgen. All rights reserved.

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