Clinical Oncology News - January 2011 - Digital Edition

McMahon Publishing

Advances in Cancer Care clinicaloncology.com • January 2011 • Vol. 6, No. 1

SOLID TUMORS

2 6

Drug shortage puts cancer centers in crisis.

FDA will remove Avastin’s breast cancer indication—a look at the impact.

7 8

Extended first-line chemo improves overall survival in MBC. Study examines treatment patterns at the end of life for patients with solid tumors, hematologic malignancies.

13

New HER2 -targeted agent pertuzumab is effective for breast cancer and has few side effects.

PRN

13

Justice Department files brief arguing against gene patents.

POLICY & MANAGEMENT

16

Improper use of EMRs can create errors.

HematOlogic DISEASE

2 22

Drug shortage impacts hematologic cancer patients.

In advaced-stage Hodgkin’s Lymphoma, Stanford V Regimen Fails to Beat ABVD.

WWW.CMEZONE.COM

Brentuximab On Horizon For Relapsed Hodgkin’s Lymphoma Orlando, Fla.—A new drug, brentuximab vedotin, may soon provide an option for patients with Hodgkin’s lymphoma who have relapsed after autologous stem cell transplant (ASCT).

The drug produced a 75% overall response rate (ORR) and was well tolerated in this patient population, according to Phase II trial results reported at the American Society of Hematology’s (ASH) annual meeting (abstract 283).

“This is very active for single-agent therapy in the relapsed Hodgkin’s lymphoma setting,” said Robert Chen, MD, assistant professor at the City of Hope National Medical Center, Duarte, Calif., who presented the study. “Patients in this study had very high-risk disease; 71% had primary refractory disease, see brentuxiMAB, page 22 

Neoadj Dual HER2 Blockade: The Future Of Breast Cancer Rx? San Antonio—Evidence is accumulating that neoadjuvant dual HER2 blockade may improve outcomes in patients with breast cancer. Some oncologists are predicting that, although costly, the dual therapy may be the future of breast cancer care, but they emphasize that it should not be used outside of a clinical trial at this point.

Two Phase III trials presented at the recent San Antonio Breast Cancer Symposium (SABCS) explored HER2 blockade as part of neoadjuvant therapy for early HER2-positive (HER2+) breast cancer. The Neo ALTTO study revealed that the see HER2, page 12 

Controversy Swirls Around Zoledronic Acid Use

San Antonio—Interim results from the Phase III AZURE trial designed to test whether zoledronic acid (Zometa, Novartis) can improve disease-free survival (DFS) in breast cancer patients has revealed that it does not. A subanalysis, however, showed improved DFS in specific patients, and evidence from other studies continues to feed the controversy over whether clinicians should use this drug as an anticancer agent.

The results of AZURE, presented at the San Antonio Breast Cancer Symposium (SABCS), have been eagerly awaited, since a 48-month analysis of the ABCSG-12 trial showed that adding zoledronic acid to endocrine therapy in premenopausal women with see ZOLEDRONIC, page 14 

POLICY & MANAGEMENT

New Year, New Rules: Is Your Practice Up to Speed?

T

he Centers for Medicare & Medicaid Services (CMS) has released its final rules for Medicare payments for both hospital outpatient programs and physician practices in 2011. The changes ensure compliance with legislation that recently has been passed. Following are highlights of the changes that will impact oncologists.

Doctors Avoid Burdensome Identity Theft Protection Law Due to legislation signed during the lame duck session, doctors will not have

to abide by the Red Flags Rule, an identity theft protection law. Under this rule, creditors, including small professional services businesses, would need to have written plans in place to prevent, identify and see NEW RULES, page 16 

McMahonMedicalBooks.com Principles and Practice of Pediatric Oncology Philip A. Pizzo; David G. Poplack

For more information, see page 19

2

MULTIPLE CANCERS

Clinical Oncology News • January 2011

Drug Shortage Puts Cancer Centers in Crisis Physicians cite treatment delays that could compromise patient safety An unprecedented nationwide shortage of chemotherapy drugs has left many cancer centers scrambling to prioritize their patient loads, snarled some clinical trials and delayed treatment for at least some patients.

As of the first of December, 199 new drug shortages had been identified for 2010, according to Erin Fox, PharmD, who coordinates the Drug Information Service at the University of Utah Healthcare Hospitals and Clinics, in Salt Lake City. By comparison, “we only had 166 new shortages for all of 2009, and 149 for 2008,” she said.

Chemotherapy drugs make up an alarmingly high percentage of the medications in short supply—a potentially dangerous subplot to the general shortages

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reported earlier this year by the Institute for Safe Medication Practices (ISMP).

“To date, we’ve had 20 shortages of chemotherapy drugs,” Dr. Fox said. “It’s never been nearly that high before; in past years, we would have perhaps 10 or 12 chemotherapy drug shortages. This year, it’s just exploded.”

The past year has seen almost a perfect storm of supply chain issues for all

Gastrointestinal Cancer

James Prudden, Group Editorial Director

Edward Chu, MD

David Bronstein, Editorial Director, Hospital Group

Cathy Eng, MD

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

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

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

Oncology Nursing Betty Ferrell, RN, PhD

Pharmacy

drugs—one that has hit oncology particularly hard. “Many chemotherapy drugs are generic, and we don’t have many generic suppliers,” Dr. Fox explained. “If one company has a manufacturing problem, that almost guarantees that there’s going to be some kind of a shortage. And this year two of our very largest manufacturers of generics, Teva Injectables and Hospira, both had manufacturing problems at the same time.”

The shortages are not all that surprising. “The manufacturing capacity at these firms is limited,” noted Capt.

Valerie Jensen, RPh, associate director of the Center for Drug Evaluation and Research’s Drug Shortage Program at the FDA. “These older sterile injectables get discontinued by firms, often in favor of newer, more profitable products.

“Sterile injectables have a long manufacturing lead time and a complex process,” Ms. Jensen added. “When one of the few firms making these products experiences a problem, a shortage almost always occurs since it is extremely difficult for the remaining firms to keep up with demand.”

Dr. Fox compared the situation to the federal government’s financial bailout of

Leonard Saltz, MD

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD

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Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 W 45th Street, New York, NY 10036. Copyright 2011 McMahon Publishing, New York, NY. All rights reserved. Application for Periodicals Postage rate is pending at New York, NY, and additional mailing offices.

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Solid Tumors

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Genitourinary Cancer Gynecologic Cancer

the insurance giant AIG. “You’ve heard about banks that are too big to fail? Well, we almost have generic companies that are too big to fail, but we don’t have anyone stepping in” to help fix the company’s manufacturing issues, she said.

Compounding the problem is the fact that while manufacturers are encouraged to alert the FDA if they are anticipating a supply chain issue with one of their drugs, they’re not required to do so. “If a manufacturer is having trouble with raw materials, the FDA can smooth the pathway there. They can approve new generics in line if a company’s going to have problems,” Dr. Fox said. “They can suggest to competitors to ramp up production of a product. But it takes time to do those things, and if manufacturers don’t alert the FDA, they can’t take action.”

The following oncology-related drugs have been in particularly acute short supply this year, according to recent reports: • Bleomycin • Cisplatin • Doxorubicin • Etoposide • Leucovorin • Nitrogen mustard

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

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For your patients receiving or about to start treatment with DOXIL® for recurrent ovarian cancer or relapsed/refractory multiple myeloma…

DOXIL® C.A.R.E.S. Provides Help and Support DOXIL® C.A.R.E.S. Complements the Efforts of the Healthcare Team With: ◗ Treatment follow-up — Regularly scheduled telephone calls from oncology nurses to review lifestyle tips to help manage potential side effects of DOXIL® therapy such as hand-foot syndrome and stomatitis ◗ Patient education materials Invite your patients to enroll in DOXIL® C.A.R.E.S.: 1-877-CARES-49 (1-877-227-3749) Monday to Friday, 9:30 AM to 10:00 PM (ET). To learn more, visit www.doxil.com.

INDICATIONS

◗ DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy ◗ DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATION

BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution ◗ The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 — Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose — Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy ◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate — Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use — The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions ◗ Severe myelosuppression may occur ◗ DOXIL® dosage should be reduced in patients with impaired hepatic function ◗ Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS ◗ Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ◗ Nursing mothers

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored

— Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury — In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defined as absolute decrease 15% over baseline or a 5% decrease below institutional lower limit of normal)

◗ Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® — In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL® — In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE — Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage — Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death ◗ DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow ◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL® — Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required — HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy ◗ DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation ◗ DOXIL® can cause fetal harm when used during pregnancy ◗ Recall reaction has occurred with DOXIL® administration after radiotherapy ◗ DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl ◗ In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%) — In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%) ◗ In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL® plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/ stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) — In addition, 19% vs <1% reported HFS Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages.

VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2010 9/10 08D10019A

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks.

Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m 2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.

Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 74) Neutropenia <1000/mm3 <500/mm3 Anemia <10 g/dL <8 g/dL Thrombocytopenia <150,000/mm3 <25,000/mm3

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 720)

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

(60.9%) (4.2%)

Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in With AIDS-Related Kaposi’s Sarcoma Adverse Reactions

Nausea Asthenia Fever Alopecia Alkaline Phosphatase Increase Vomiting Diarrhea Stomatitis Oral Moniliasis

Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 77) 14 5 6 7 1 6 4 4 1

(18.2%) (6.5%) (7.8%) (9.1%) (1.3%) (7.8%) (5.2%) (5.2%) (1.3%)

Infections and infestations Herpes zoster Herpes simplex Investigations Weight decreased Metabolism and Nutritional disorders Anorexia Nervous system disorders Peripheral Neuropathy* Neuralgia Paresthesia/dysesthesia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash** Hand-foot syndrome

11 10

2 0

0 0

9 6

2 1

0 0

12

0

0

4

0

0

19

2

0

14

<1

0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

18

0

0

12

0

0

22 19

1 6

0 0

18 <1

1 0

0 0

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.

Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis have been reported.

DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

5% of Patients

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 705) 119 70 64 63 55 55 55 48 39

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. (continued) Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4

(16.9%) (9.9%) (9.1%) (8.9%) (7.8%) (7.8%) (7.8%) (6.8%) (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills.

Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.

Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma.

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology.

Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

0016716-5B Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670

TM

An ALZA STEALTH® Technology Product

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.

6

SOLID TUMORS

Clinical Oncology News • January 2011

Breast

FDA Rules on Avastin for MBC: What’s Next?

Rockville, Md.—The FDA has started the process of removing the breast cancer indication for bevacizumab (Avastin, Genentech), saying the drug is too toxic and confers no survival benefit for women with HER2-negative metastatic breast cancer (MBC). The drug has been shown to improve progression-free survival (PFS).

The FDA’s decision was based on four clinical trials: E2100, AVADO, and RIBBON-1, which studied bevacizumab in the first-line treatment of MBC, and AVF 2119g, which studied it as secondline treatment in this setting. “Today’s announcement is the first step in a process and will not have immediate impact on use of Avastin to treat breast cancer or the drug’s availability,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press briefing. “For patients, this means no disruption in treatment. Their access to Avastin will not be affected.”

She added that oncologists currently treating patients with bevacizumab should use their judgment in deciding whether to continue with the drug. Genentech has indicated that it will request a hearing with the FDA to appeal its decision.

Dr. Woodcock emphasized that the FDA’s decision did not take into account the cost of bevacizumab, which is estimated at about $100,000 per year per patient. “Reimbursement is a decision that is made by insurance providers that often use different criteria from those used by the FDA when we determine that a drug is safe and effective for marketing,” she said. “At this time, the CMS [Centers Medicare & Medicaid Services] will not be making any changes to its reimbursement policy for Avastin and is waiting until the resolution of this process before deciding whether to make any changes.”

Meanwhile, as the FDA was announcing its decision, the European Medicines Agency (EMA) declared that bevacizumab in combination with paclitaxel remained a valuable treatment option for women with MBC, claiming that the benefits of the combination outweighed the risks. Although the EMA’s Committee for Medicinal Products for Human Use came out against the use of bevacizumab with docetaxel or capecitabine, stating that these combinations are of questionable benefit and are associated with high toxicity, it concluded that the available data about bevacizumab and paclitaxel “have convincingly shown [the combination] to prolong progression-free survival of breast cancer patients without a negative effect on the overall survival.”

‘I Will Miss the Drug’ “I think this is actually a good drug,” commented Steven Vogl, MD, an oncologist in private practice in White Plains and Bronx, New York. “I don’t know

why it doesn’t prolong survival and it bothers me that it doesn’t prolong survival, but at least in my limited experience, I’ve had some extraordinarily long remissions in some patients I have treated with Avastin and weekly paclitaxel.”

Dr. Vogl recalled that the first patient he treated with weekly paclitaxel and bevacizumab had a two-year remission, and the next several patients had remissions that lasted more than a year.

“I think these are wonderful results,” Dr. Vogl said. “Most of my patients tolerate bevacizumab ok. Their biggest problem is actually headache. We’re talking about metastatic breast cancer. These are ladies with relatively limited life expectancy and if you can control their cancers for an extra six months, that’s a lot, even if they don’t live longer. If those six months are better, that’s a lot. So, I will miss the drug and my patients will miss the drug because I think they’ll have shorter remissions.”

Dr. Vogl added that the FDA’s action will probably cause insurance companies to stop paying for the drug. “This is a pity.

In my view, most treatment for metastatic cancer is to relieve symptoms because most of the time, the longevity benefits are very limited. The lung cancer doctors get all excited about extending life eight weeks. I do not. Especially if those are eight miserable weeks,” he said. “I explain this to my patients and they all agree with me. A cure is worth a lot of suffering, but if you’re not going to cure somebody, then you worry about their quality of life. If I have a symptomatic patient who is short of breath from lung metastases or pleural effusion, or her bones hurt, or she is yellow from liver metastases, and you make that better with Avastin, then some mild degree of headache from the drug is justified to relieve her symptoms, especially if you relieve them for a long time and she is functional. In this regard, Avastin is not a bad drug at all.”

Dr. Vogl predicted that bevacizumab will continue to be used in patients with MBC. “Of course, good doctors will use it off-label. We always do, provided someone will pay for the drug. The FDA was never mandated, nor is it equipped, to dictate or determine best medical practice. Its narrow job is to regulate marketing and determine safety,” he said.

Whether insurance companies will continue to cover bevacizumab depends on two things, Dr. Vogl added. “One is the quality of the computer programs of

payers and prescription plans,” he said.

“Some are quite poor and fail to distinguish unlabeled indications—thank goodness! The other is whether some of the compendia and the National Comprehensive Cancer Network [NCCN] guidelines continue to support the use of bevacizumab against breast cancer.”

As of Jan. 4, the NCCN had made no changes to its level 2A recommendation for the use of bevacizumab in advanced breast cancer. “That is our recommendation from a scientific, clinical basis, as of today,” said Bill McGivney, PhD, the NCCN’s CEO. Whether this will change is not known, he said. “The panel and the panel chair are certainly aware of events and they are closely monitoring the literature and the FDA actions.”

Payors basically follow the NCCN drugs and biologics compendium with regard to cancer care, according to Dr. McGivney.

“Our recommendation is a category 2A, based on low-level evidence and uniform agreement, but most payers, for example United [Healthcare] and Aetna, have stated publicly that they will cover drugs for specific indications if NCCN has a recommendation that is 2B or above. Obviously, there is variation across payers but generally, in cancer care, the NCCN’s drugs and biologics compendium is the basic reference or basis for coverage policy for drugs and biologics in cancer care.”

Decision Will Discourage Use Sara K. Butler, PharmD, BCOP, clinical pharmacist for medical oncology at Barnes Jewish Hospital, St. Louis, gave a somewhat wry view of the drug approval process. “It’s interesting to see how drugs get rapid FDA approval up front, with fast-track approval, but then, when additional trials come out, to look at what the differences are between the early and later trials,” she said.

As a pharmacist involved in the care of inpatients, Dr. Butler agreed bevacizumab has important toxicities. “The hypertension is real, the effect on thrombosis and bleeding is real, so these are definitely things to keep in mind and make sure that patients are educated about them.”

She believes the FDA ruling will discourage doctors from starting new patients on bevacizumab. “I think that some physicians will still use bevacizumab off-label, but some will not prescribe it at all. For patients who are already on bevacizumab and responding, I can see where the oncologist and patient may want to try to continue therapy.” The danger is that the drug may not be paid for, she added. “I think the most important thing is for the oncologist and pharmacy to check with the insurance company prior to giving bevacizumab to make sure that it is covered.”

Dr. Butler suggested bevacizumab may benefit a particular subgroup of patients.

“Is there a subset of patients that we could predict who will have a benefit?” Dr. Butler noted. “That might be a future avenue for the company to explore.”

Thumbs Up, Thumbs Down Bevacizumab originally was granted accelerated approval in 2008 on the basis of the E2100 trial results. In that trial, the addition of bevacizumab to paclitaxel resulted in a 5.5-month increase in median PFS but no statistically significant improvement in overall survival. The tumor response rate also was higher with bevacizumab plus paclitaxel as compared with paclitaxel alone (48.9% vs. 22.2%), but there was a 20.2% increase in grade 3 to 5 toxicity in the bevacizumab arm. The major toxicities included hypertension, thromboembolic events, left ventricular dysfunction, myocardial infarction, gastrointestinal and nasal perforations and proteinuria. Additionally, the death rate attributed to bevacizumab was 1.7% (six of 363 patients).

Oncologists have been warily awaiting the FDA decision since the Oncology Drugs Advisory Committee (ODAC) voted 12 to 1 to recommend removing its MBC indication in July 2010. Richard Pazdur, MD, director of the FDA’s Office of Oncology Drug Products, who led the accelerated approval process for bevacizumab in 2008, admitted that the FDA’s recommendation is a disappointment for patients and the FDA. “I oversaw the initial approval of Avastin for breast cancer in 2008 and hoped that the magnitude of improvement in progression-free survival observed in the E2100 trial would be confirmed in additional clinical studies,” he said. “However, we concluded that the benefit of Avastin in delaying progression of disease has not been shown to translate into prolonged survival of patients and the additional trials identified to confirm the initial magnitude of improvement in PFS have also failed to accomplish this objective.”

—Fran Lowry

7

SOLID TUMORS

Clinical Oncology News • January 2011

Breast

Extended First-line Chemo Improves Overall Survival in MBC Milan—Prolonging chemotherapy until disease progression improves not only progression-free survival (PFS), but also overall survival (OS), in patients with metastatic breast cancer (MBC).

That’s the conclusion of a new metaanalysis from Italian scientists presented at the recent European Society for Medical Oncology’s (ESMO) annual Congress (abstract 2760). The researchers, led by Alessandra Gennari, MD, PhD, of the National Cancer Institute in Genoa, Italy, pooled data from 11 randomized clinical trials of first-line chemotherapy in MBC, involving 2,269 patients. Along with a 34% (P<0.0001) improvement in PFS—a finding that has been previously published— they found that extending chemotherapy until disease progression was associated with a 9% improvement in OS (P<0.04).

The effect was similar across groups of trials, in terms of PFS and OS, suggesting the effect was independent of time of randomization, study design, number of cycles in the control arm and endocrine therapy.

According to Steven Vogl, MD, a

community oncologist in Bronx, N.Y., who attended ESMO, the study provides evidence that he can share with his patients on the effect of continuing therapy on outcomes. In the United States, and indeed in North America generally, the current standard of care for firstline chemotherapy for MBC is to treat until disease progression, unless intolerable toxicities develop. But in Europe and other countries, women with MBC generally receive their first-line chemotherapy for a set amount of doses—often

six—and then only resume chemotherapy once the disease progresses again. “The issues in Europe are more complex than in the U.S.,” Dr. Buzdar said. “There are often restrictive local policies that do not allow physicians the same freedom we have in the U.S. Hopefully, this finding will change those policies; I find it quite compelling.”

Andrew Seidman, MD, an attending physician in the Breast Cancer Medicine Service at Memorial-Sloan see SURVIVAL, page 11 

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CilENgitide in combination with Temozolomide and Radiotherapy In newly diagnosed glioblastoma phase III randomized Clinical trial A randomized multicenter, open-label, controlled phase III study to evaluate cilengitide in combination with standard treatment (TMZ with concomitant RT, followed by TMZ maintenance therapy) versus standard therapy alone in newly diagnosed glioblastoma patients with methylated MGMT gene promoter status.

A breast cancer campaign truck parked in front of the Duomo in Milan, the city that hosted the European Society for Medical Oncology Congress.

‘The pooled numbers show that there is quite strong suggestive evidence that if you continue therapy until disease progression, there is a positive impact on overall survival.’

—Aman Buzdar, MD

“The individual studies were small,” said Aman Buzdar, MD, professor of medicine in the Department of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston. “But the pooled numbers show that there is quite strong suggestive evidence that if you continue therapy until disease progression, there is a positive impact on overall survival. I think that finding is real. In the individual studies, the hint was in the same direction.”

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Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized multicenter, open-label phase II study, investigating two cilengitide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy).

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8

Multiple Cancers

Clinical Oncology News • January 2011

Knocking on Death’s Door Study Unearths Troubling Data About End-of-Life Care Whether older Americans with advanced cancers die in the hospital or while receiving hospice care varies tremendously depending on where they live and receive care, according to a new study by the Dartmouth Atlas Project.

More than one-third of Medicare patients with poor-prognosis cancers spent their last days in hospitals and intensive care units (ICUs), according to the project that produces reports based on analyses of Medicare data. A significant proportion of these patients received advanced life support interventions such as endotracheal intubation, feeding tubes and cardiopulmonary resuscitation.

Additionally, researchers found a wide variance in the use of hospice care. In at least 50 academic medical centers, less than half of patients with poor-prognosis cancers received hospice services. In some hospitals, referral to hospice occurred so close to the day of death that it was unlikely to have provided much comfort at all to patients.

Variations in care occurred by region, across academic medical centers and in care directed toward cure at the end of life. Overall, the report found no consistent pattern of care or evidence that treatment patterns followed patient preferences, and the authors concluded that many physicians treat patients too aggressively at the expense of improving the quality of their last weeks and months.

Improvements Needed “My recommendation is that oncology services need to periodically re-examine the care provided and their communication with patients,” said lead author David C. Goodman, MD, director of the Center for Health Policy Research at the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, N.H. “I think we would all agree that clinicians are very well intentioned, but the care patients get with advanced cancer is not often aligned with their preferences, and there needs to be continual improvement.”

For the study, Dr. Goodman and colleagues reviewed the records of 235,821 Medicare patients aged 66 and older who died between 2003 and 2007. A number of the other findings are striking. About 6% of these patients received chemotherapy in the last two weeks of life, although the rate exceeded 10% in some regions and academic medical centers. Cancer patients were most likely to die in a hospital in the New York City hospital referral region. About 47% died in a hospital in Manhattan; the rates also were high in surrounding regions.

These rates were six times higher than

in Mason City, Iowa, where only 7% of cancer patients died in the hospital. Cincinnati (18%) and Fort Lauderdale, Fla. (20%) had moderate rates of inpatient cancer deaths. Cancer patients also were more likely to receive aggressive treatment in the last weeks of life in Manhattan, where 18% experienced a procedure like an endotracheal intubation.

Approximately 61% of all cancer patients were hospitalized at least once during their last month of life. Cancer patients spent an average of 5.1 days in the hospital during their last month of life, and about 24% were admitted to the ICU at least once during their last month of life. The percentage of cancer patients dying in a hospital varied threefold among patients at academic medical centers, from about 19% in Evanston, Ill., to 57% in Valhalla, N.Y. Generally, the hospital where a patient received care determined their level of care intensity, and the greater the number of hospital inpatient days experienced by patients during the last month of life, the more likely they were to receive advanced life support measures.

Differences in hospital culture contribute to the findings, Dr. Goodman said, with some medical centers investing relatively little in palliative care or not integrating such care with traditional treatments. In some cases, these hospitals also are the ones investing in ICU beds.

Also, many oncologists may not initiate conversations about palliative and end-oflife care early enough, and opportunities for comfort often are missed, according to Dr. Goodman. “It’s not a conversation about dying, but a conversation about quality of life. Patients want to live long, but they also want to live well,” he said.

Since 1998, the American Society of Clinical Oncology has recommended frank, open discussions between doctors and patients with metastatic disease, but has no set policies on when to refer patients to hospice, according to George W. Sledge Jr., MD, the organization’s president. The variations in care suggest that “a lot of education lies in front of us,” Dr. Sledge said. “For the average patient, it strikes me as a tragedy to die intubated, in the hospital or receiving chemotherapy. …

If you have a relationship with a patient, it’s very hard to tell that person you’re out of options, but it’s part of the honesty in the process and it’s humane and decent.

We need to make the end of life as pleasant and comfortable as possible.”

Hospice Days Per Cancer Patient, Last Month of Life ‘There are lots of complexities to the story but it’s all rooted in communication. There needs to be more attention to communication … but it’s not on the radar of most health care organizations.’

—Michael J. Fisch, MD, MPH

Percentage of Cancer Patients Dying in Hospital Maps courtesy of the Dartmouth Atlas Project

The variations indicate that many cancer patients are not receiving good end-oflife care, said Charles F. von Gunten, MD, PhD, provost of the Institute for Palliative Medicine at San Diego Hospice, and clinical professor of medicine at the University of California, San Diego. “We know how to care for patients at end of life better now than at any time in history,” Dr. von Gunten said, and good hospice care at the end of life represents the gold standard of care. In his region, 70% of cancer patients are cared for by hospice.

The study’s finding of a low percentage of patients enrolled in hospice could reflect that patients didn’t know about that option, or that hospice programs

were too rigid or couldn’t care for some cancer patients, he said. He encouraged oncologists to discuss palliative care early on. “Relief of suffering is an important part of cancer care,” said Dr. von Gunten.

“It begins with diagnosis and should be incorporated with anti-cancer care.”

A Complex Issue Other oncologists said the issue is more complicated than it appears on paper, stemming from a variety of factors.

Michael J. Fisch, MD, MPH, associate professor of general oncology at The University of Texas M.D. Anderson Cancer Center in Houston, said changes in the see DEATH’S DOOR, page 11 

Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

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

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Metabolized principally by CYP3A4 CYP2D6 does not play a signicant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical prole Efcacy comparable to tamoxifen in head to head trials Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON is contraindicated in patients with known hypersensitivity to the drug. FARESTON has been shown to prolong the QTc interval in a dose and concentration dependent manner. FARESTON should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice and others) increases the steady-state concentration in serum and should be avoided. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively.

References: FARESTON® Prescribing Information, 2004. Data on file, GTx, Inc.

Please see full prescribing information on the following page.

For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

© 2010 GTx, Inc., Memphis, TN 38103. All rights reserved. FAR-071R0 June 2010

FARESTON® (toremifene citrate) tablets DESCRIPTION FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene.

FARESTON is a nonsteroidal antiestrogen. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro-1,2diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: OCH2CH2N

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

C

COOH

CH2COOH

and the molecular formula is C26H28 H O . The molecular weight of toremifene citrate is 598.10.

6 8 7 The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL. FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch.

CLINICAL PHARMACOLOGY Mechanism of Action: Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mam-mary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, ie, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor.

Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Pharmacokinetics: The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (deaminohydroxy) toremifene were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5L/h.

Absorption and Distribution: Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady-state concentrations were reached in about 4-6 weeks. Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly to albumin.

Metabolism and Excretion: Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state.

Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Special Populations: Renal insufficiency: The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

Hepatic insufficiency: The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients: The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. Race: The pharmacokinetics of toremifene in patients of different races has not been studied.

Drug-drug interactions: No formal drug-drug interaction studies with toremifene have been performed.

CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table).

Clinical Studies Study North American Eastern European Nordic Treatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 No. Patients 221 215 157 149 214 201 Responses 1 2 14+33 11+30 7+25 3+28 19+48 19+56 CR + PR 21.3 19.1 20.4 20.8 31.3 37.3 RR3 (CR + PR)% Difference in RR 2.2 -0.4 -6.0 95% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1 Time to Progression (TTP) Median TTP (mo.)

5.6 5.8 4.9 5.0 7.3 10.2 Hazard Ratio (TAM/FAR) 1.01 1.02 0.80 95% CI4 for Hazard Ratio (%) 0.81 to 1.26 0.79 to 1.31 0.64 to 1.00 Survival (S) Median S (mo.)

33.6 34.0 25.4 23.4 33.0 38.7 Hazard Ratio (TAM/FAR) 0.94 0.96 0.94 95% CI4 for Hazard Ratio (%) 0.74 to 1.24 0.72 to 1.28 0.73 to 1.22 1 CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of

22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months).

significant age-related differences in FARESTON effectiveness or safety were noted.

Race: Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted.

INDICATION AND USAGE FARESTON is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

ADVERSE REACTIONS Adverse drug reactions are principally due to the antiestrogenic hormonal actions of FARESTON and typically occur at the beginning of treatment.

The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

North American Study FAR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4%

CONTRAINDICATIONS FARESTON is contraindicated in patients with known hypersensitivity to the drug.

WARNINGS Hypercalcemia and Tumor Flare: As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, FARESTON treatment should be discontinued.

Tumorigenicity: Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (about 1/4 and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m2 basis).

Pregnancy: FARESTON may cause fetal harm when administered to pregnant women. Studies in rats at doses ≥1.0 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that toremifene is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies; including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Fetal anomalies may have been a consequence of maternal toxicity. Toremifene has been shown to cross the placenta and accumulate in the rodent fetus.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known.

Embryotoxicity and fetotoxicity were observed in rabbits at doses ≥1.25 mg/kg/day and 2.5 mg/kg/ day, respectively (about 1/3 and 2/3 the daily maximum recommended human dose on a mg/mt basis); fetal anomalies included incomplete ossification and anencephaly.

There are no studies in pregnant women. If FARESTON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

PRECAUTIONS General: Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment (see Warnings). Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.

Information for Patients: Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs.

Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.

Laboratory Tests: Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

Drug-drug Interactions: Drugs that decrease renal calcium excretion, eg, thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. There is a known interaction between antiestrogenic compounds of the triphenylethylene derivative class and coumarin-type anticoagulants (eg, warfarin), leading to an increased prothrombin time. When concomitant use of anticoagulants with FARESTON is necessary, careful monitoring of the prothrombin time is recommended.

Cytochrome P450 3A4 enzyme inducers, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the steady-state concentration in serum.

Metabolism of toremifene may be inhibited by drugs known to inhibit the CYP3A4-6 enzymes. Examples of such drugs are ketoconazole and similar antimycotics as well as erythromycin and similar macrolides.

This interaction has not been studied and its clinical relevance is uncertain.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (about 1/100 to 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (about 1/15 to 2 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors, and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human antiestrogenic agents that have primarily estrogenic activity in mice.

Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests).

Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). No significant adduct formation could be detected using 32P post-labeling in liver DNA from rats administered toremifene when compared to tamoxifen at similar doses. A study in cultured human lymphocytes indicated that adducting activity of toremifene, detected by 32P post-labeling, was about 1/6 that of tamoxifen at approximately equipotent concentrations. In addition, the DNA adducting activity of toremifene in salmon sperm, using 32P post-labeling, was 1/6 and 1/4 that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively.

However, toremifene exposure is fourfold the exposure of tamoxifen based on human AUC in serum at recommended clinical doses.

Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (about 3.5 times and 1/50 the daily maximum recommended human dose on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (about 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) for 52 weeks.

Pregnancy: Pregnancy Category D: (see WARNINGS).

Nursing mothers: Toremifene has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. (See WARNINGS and PRECAUTIONS).

Pediatric use: There is no indication for use of FARESTON in pediatric patients.

Geriatric use: The median ages in the three controlled studies ranged from 60 to 66 years. No

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse events occurring in patients receiving FARESTON in the three major trials are listed in the table below.

Adverse Events North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) Cardiac Cardiac Failure 2 (1) 1 (<1) 1 (<1) 2 (1) 3 (1.5) Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) 1 (<1) Arrhythmia 3 (1.5) 1 (<1) Angina Pectoris 1 (<1) 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) 5 (3) Dry Eyes 20 (9) 16 (7.5) Abnormal Visual Fields 8 (4) 10 (5) 1 (<1) Corneal Keratopathy 4 (2) 2 (1) Glaucoma 3 (1.5) 2 (1) 1 (<1) 1 (<1) Abnormal Vision/Diplopia 3 (1.5) Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) 1 (<1) Thrombophlebitis 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis 1 (<1) 1 (<1) 3 (1.5) 4 (2) CVA/TIA 1 (<1) 1 (<1) 4 (2) 4 (2) Elevated Liver Tests** SGOT 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17) Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15) Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5) Hypercalcemia 6 (3) 6 (3) 1 (<1) * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher.

Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms.

Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/ dilatation leading to interference with digestion and adrenal enlargement.

Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.

Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

HOW SUPPLIED FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white.

FARESTON Tablets are identified with TO 60 embossed on one side.

FARESTON Tablets are available as: NDC 11399-005-30 bottles of 30 NDC 11399-005-01 bottles of 100 Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Protect from heat and light.

Distributed by GTx, Inc. Memphis, TN 38163, USA Product covered by Orion Product Patents and related patent numbers. © 2004 GTx, Inc. All rights reserved.

1E Rev. 12/2004

Multiple Cancers

Clinical Oncology News • January 2011

DEATH’S DOOR continued from page 8 

financial climate contribute, with rapidly increasing demand for skillful palliative care professionals but no infrastructure to support that. There may not be enough capacity in a local hospice program to accommodate the needs of the growing numbers and complexities of cancer patients. Also, the quality and scope of hospice services can vary widely. Some patients may be interested in hospice, but find the service doesn’t go to their neighborhood. Others may be referred to hospice, but it doesn’t work out.

“Hospice care is only as good as the person or team who comes to your house,” Dr. Fisch commented.

Another source of variation in care is the provider “wild card,” he added, like a

local oncologist who may have different ideas about treatment than physicians in an academic medical center to which a patient has traveled.

According to James L. Wade III, MD, a founder of Cancer Care Specialists of Central Illinois in Decatur, hospice services are becoming more difficult to deliver. Medicare has made the admission criteria for outpatient hospice care more stringent because of concerns about fraud or abuse. In many areas, Medicare will no longer cover transfusions or radiation to reduce pain once patients elect hospice care.

Patient preferences also contribute.

Many older, poor patients who live alone tend to prefer to die in a hospital, said Dr. Wade, who is also associate professor of clinical medicine at Northwestern University in Chicago. Those with dysfunctional families look to

‘For the average patient, it strikes me as a tragedy to die intubated, in the hospital or receiving chemotherapy.’

—George W. Sledge Jr., MD

Garden of Death by Hugo Simberg

hospitals for support, and some patients “just want everything done in spite of a poor prognosis, and this kind of patient will more commonly go to an academic medical center,” Dr. Wade said. “Patients and families are continuously exposed to the latest ‘medical breakthroughs,’ and have an underlying belief that cancer specialists are not keeping up with the latest, or that a better outcome is just one new medical center away down the road.”

Taking Action To Improve End-of-Life Care

T

he recent Dartmouth Atlas Project study found significant shortcomings in end-of-life care. So, what can hospitals do to improve this care?

Hospitals need to embrace patient- and family-centered care for all patients, especially those with poor-prognosis cancers, according to Joan M. Teno, MD, professor of community health and medicine at Brown University in Providence, R.I., and associate medical director of Home and Hospice Care of Rhode Island.

She contributed to the recent Dartmouth study.

Hospitals should examine their rates of intensive care utilization, hospice referral and other measures and ask if the patterns identified reflect that they are educating patients and forming care plans that respect patients’ choices, she told Clinical Oncology News. If they are, then revisit every year or two to ensure staying on track. If not, hospitals should form a continuous quality improvement team and try to partner with the palliative care consult service and/or local hospice, or start a palliative care consult service if necessary, to better design care that meets the needs of patients and their family members.

In focus groups, the No. 1 complaint is from family members saying they had to fight to get what they wanted, Dr. Teno said. Hospitals can employ a patient navigator dedicated to helping patients and their family members make choices.

Michael J. Fisch, MD, MPH, associate professor of general oncology at The University of Texas M.D. Anderson Cancer Center in Houston, advises open communication with patients. Oncologists should discuss early on the goals of care, what patients should expect and develop a trusting and open relationship.

He said financial constraints have led to fewer opportunities to educate physicians on how to communicate with patients and families, and hospitals are using more mid-level practitioners to discuss high-stakes topics.

In an era in which hospitals are trying to increase activity and decrease costs, he said, “It’s hard to be optimistic that communication will improve unless institutional leaders recognize the value of investing in communication skills training for both physicians and mid-level providers.”

—Karen Blum

“There are lots of complexities to the story but it’s all rooted in communication,” Dr. Fisch said. “There needs to be more attention to communication … but it’s not on the radar of most health care organizations.”

J. Donald Schumacher, PsyD, president and CEO of the National Hospice and Palliative Care Organization, still encourages oncologists and their patients to discuss end-of-life care

before patients are in clinical or emotional distress. He said most communities have more than one hospice service.

To find a good outfit, check if the group is a member of his organization, and how they advertise quality measures, he recommended.

A full copy of the Dartmouth study is available online at www.dartmouth atlas.org.

—Karen Blum

SOLID TUMORS

SURVIVAL continued from page 7 

Kettering Cancer Center, in New York City, agreed. “In general, this information should make oncologists steer away from an arbitrary predetermined number of cycles in metastatic breast cancer,” he said. “That never made sense to me. When patients walk into my office and ask, ‘Dr. Seidman, how long am I going to be on this therapy?’ I don’t give them a specific duration. The natural history of metastatic breast cancer is to progress and cause death. If you’ve altered that natural history with your first-line chemotherapy, provided that the treatment is not excessively toxic, leave it alone.”

But Dr. Seidman notes that the heterogeneity of breast cancer argues for a much more individualized approach in

the real world. “One shoe doesn’t really fit all feet. Even though this metaanalysis suggests an overall approach that is to treat for as long as possible in first-line metastatic breast cancer, unless you have to stop for progression or toxicity, what we do in real life is consider that in the context of the individual patient. This is the unique place where the science and the art of oncology come together.”

Dr. Seidman also pointed out that the trials pooled in the meta-analysis only allowed oncologists to reduce doses of drugs to a certain degree. In clinical practice, physicians often are willing to continue therapy even at much more reduced doses than clinical trials will permit. “In some of these studies, the patients might have had to come off of therapy because of side effects, whereas in the real world, we might dial down the dose or frequency of their treatment, if

it’s working, in order to continue it with less toxicity,” he said. “That’s another place where data from these trials doesn’t faithfully reflect practice.”

Harold Burstein, MD, PhD, associate professor of medicine at Harvard Medical School and a medical oncologist in the Breast Oncology Center at DanaFarber Cancer Institute, both in Boston, does not expect the meta-analysis to change practice significantly. “While we often do run continuous treatment in practice, we tell people that if they need to take a break from chemotherapy for a period of time—for a family event or some other life circumstance—it won’t jeopardize their survival, and there is evidence to support that.”

He also noted that most of the studies in the meta-analysis date back to the 1990s, when breast oncologists had far fewer options available to treat women with MBC. “Now we have many more

chemotherapy drugs, multiple generations of taxane-based treatments, ixabepilone, and just recently, eribulin, which was approved by the FDA on Nov. 16. It’s not clear that treating to progression with your first-line drug would still make a difference in this setting, since we have so many more drugs to offer.”

Like Dr. Seidman, Dr. Burstein considers chemotherapy for MBC “much more of an art than almost anything we do in breast cancer medicine. You are constantly balancing the apparent benefits of chemotherapy with side effects and the patient’s own preferences and individual needs. Neither posture—treating everyone to progression, or sticking to a prescribed six doses with your first-line drug—is an appropriate approach to individual patients.” Therapy, he said, needs to be tailored to a specific patient.

—Gina Shaw

11

SOLID TUMORS

Clinical Oncology News • January 2011

Breast

HER2 continued from page 1 

combination of lapatinib (Tykerb, GlaxoSmithKline) and trastuzumab (Herceptin, Genentech) plus paclitaxel chemotherapy improved pathologic complete remission (pCR) rate prior to surgery compared with either drug alone plus paclitaxel (abstract S3-3). The GeparQuinto study (GBG 44) demonstrated that neoadjuvant lapatinib combined with chemotherapy was inferior to neoadjuvant trastuzumab combined with the same chemotherapy in attaining pCR prior to surgery (S3-1).

Trastuzumab’s side-effect profile is more favorable than that of lapatinib.

Lapatinib causes severe diarrhea, which may limit its usefulness in this setting as newer and better-tolerated HER2directed therapies become available.

According to Luca Gianni, MD, director of medical oncology at the National Cancer Institute in Milan, one investigational HER2-blocking therapy that has an excellent side-effect profile is pertuzumab (Genentech). Preliminary studies suggest it can be combined safely and effectively with trastuzumab plus chemotherapy. (See story, page 13.) Dr. Gianni is on the advisory board of Genentech.

Michael Untch, MD, head of the multidisciplinary breast cancer department at Helios Clinic in Berlin, who led the GeparQuinto study, admitted that the combination therapies would be expensive, but he said that cost savings may be achievable if patients could then forgo other therapies. He said he had no relevant financial ties to the companies involved. “If within 12 weeks of very effective treatment with chemotherapy and targeted therapy, we achieve a 50% or more complete remission, the eradication of tumor cells, do we really need to treat these patients for an additional 12 months?” Dr. Untch said. “That is going to save some costs.” He said that the next generation of clinical trials may be able to answer that question.

Neo ALTTO Study The Neo ALTTO study enrolled 450 patients with invasive, operable, HER2+ breast cancer, with tumor size greater than 2 cm and adequate cardiac function (left ventricular ejection fraction ≥50%). Patients were randomized to one of three arms: lapatinib 1,500 mg per day, trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly, or lapatinib 1,000 mg per day plus the same dose of trastuzumab for six weeks.

Paclitaxel was added to all three arms at week 6 for an additional 12 weeks of neoadjuvant therapy. Following surgery, patients in the lapatinib arm received 34 weeks of lapatinib; individuals in the trastuzumab arm received trastuzumab

Pathologic Complete Remission Rate, %

100

‘If within 12 weeks of very effective therapy, we achieve a 50% or more complete remission [and] the eradication of tumor cells, do we really need to treat these patients for an additional 12 months? That is going to save some costs.’

80 60

51.3

40

29.5

—Michael Untch, MD

24.7

20 0

Trastuzumab Trastuzumab + lapatinib

The benefit of the combined lapatinib and trastuzumab arm was more robust in hormone receptor-negative patients at 61.3% (P=0.005) than in the receptor-positive patients at 41.6% (P=0.03), compared with the trastuzumab-alone arm.

Grade 3 adverse events were more frequent in the arms that included lapatinib (Figure 2). Over time, grade 3 diarrhea with lapatinib increased from 11% to 22% at the end of neoadjuvant therapy.

Dr. Baselga characterized the increased toxicity in the lapatinib arms as “manageable,” but one-third of the patients were unable to complete treatment as planned in these arms. There was no evidence of cardiac dysfunction.

Lapatinib

Figure 1. Pathologic complete remission rates in the Neo ALTTO study. for 34 weeks; and patients in the triple combination arm received both lapatinib and trastuzumab for 34 weeks.

Tumor sample collection was mandatory, and the investigators collected more than 11,000 samples, which they plan to examine to identify predictive markers for response and resistance to these drugs.

“These first results from the neoadjuvant trial show that dual anti-HER2 blockade [with lapatinib plus trastuzumab] is valuable in this group of patients with breast cancer,” said lead author José Baselga, MD, associate director of the Massachusetts General Hospital Cancer Center, in Boston, who had no relevant financial disclosures.

The primary end point of Neo ALTTO was pCR, defined as the absence of invasive cells in the breast at surgery or only non-invasive in situ cancer in the breast.

The pCR rate was 51.3% in the combination arm, 29.5% in the trastuzumab arm and 24.7% in the lapatinib arm, which was significant for the difference between the combination arm and the trastuzumab arm (P=0.0001). The difference between the lapatinib and trastuzumab arms was not statistically significant (Figure 1).

The rate of pCR in the breast and lymph nodes was 46.9% in the combination arm and 27.6% in the trastuzumab arm, a significant difference (P=0.001).

The corresponding rate was 20% in the lapatinib arm, which was not significantly different from the trastuzumab arm.

GeparQuinto Study The Phase III GeparQuinto trial enrolled 620 patients with untreated primary invasive HER2+ breast cancer. Patients were randomized to receive four cycles of epirubucin-cyclophosphamide every three weeks followed by four cycles of docetaxel given in combination with either trastuzumab 6 mg/ kg every three weeks (loading dose 8) or lapatinib 1,000 to 1,250 mg throughout all cycles until surgery. After surgery, patients in the lapatinib arm received 12 months of adjuvant trastuzumab, while patients in the trastuzumab arm received six months of trastuzumab.

Treatment discontinuation was more common in the lapatinib arm at 23% than with trastuzumab at 13%. Midway through the trial, patients were given loperamide for diarrhea, and Dr. Untch said that this decreased the frequency of grade 3 diarrhea. He said that loperamide should be given to all patients receiving lapatinib.

The median age of the patients was about 49 years. Approximately 17% had locally advanced disease, 28% had multifocal disease, 69% were clinically node-

50 Trastuzumab

40

Patients, %

12

Lapatinib + trastuzumab Lapatinib

30 23

20

21 16

3

2

0

13 9

10 Diarrhea

Neutropenia

9 1

Hepatic abnormalities

7

7

3

Skin disorders

Figure 2. Grade ≥ 3 adverse events in Neo ALTTO.

positive at baseline, 47% had high-grade aggressive tumors, and 42% were both estrogen receptor (ER)- and progesterone receptor-negative. The median tumor size was 4 cm.

The pCR rate, according to more stringent criteria than used in the Neo ALTTO study (i.e., no invasive cells in the breast and nodes, and no ductal carcinoma in situ), was 31% in the trastuzumab arm and 21.7% in the lapatinib arm (P<0.05) prior to surgery. Using other definitions of pCR, the rate was still higher in the trastuzumab arm.

“This study confirms a pCR rate of 50% with trastuzumab plus chemotherapy in HER2-positive patients. pCR with chemotherapy plus lapatinib was significantly lower at 35%. Compliance with lapatinib plus chemotherapy was also lower than with trastuzumab plus chemotherapy,” Dr. Untch said. “We learned a lesson and gave loperamide for diarrhea.”

Putting It Into Perspective The formal discussant of these trials, Eric Winer, MD, director of the Breast Cancer Center at Dana-Farber Cancer Institute, in Boston, pointed out that in both trials trastuzumab outperformed lapatinib. “It is not clear to what extent this is due to the patients who were not able to complete lapatinib treatment as planned,” Dr. Winer told the audience.

Neo ALTTO supports the concept of dual HER2 blockade, he continued.

“There are abundant data to suggest that the combination of trastuzumab plus lapatinib is better than either drug alone.” Each drug attacks different HER2 targets, he said.

Dr. Winer emphasized that ER-negative patients are more likely to achieve pCR, regardless of which pCR definition is used. It is possible that failure to achieve pCR in ER-positive patients may not compromise eventual disease-free survival (DFS), he noted, but follow-up for a longer period is needed. “pCR is variable and associated with hormone receptor subtype. We need further data on anti-HER2 therapies [before we use pCR as a surrogate for DFS],” Dr. Winer told symposium attendees. “The combination of lapatinib and trastuzumab plus docetaxel will be studied in the adjuvant setting. It should not be used as neoadjuvant therapy outside the setting of a clinical trial.”

Dr. Winer said he had no relevant company relationships to disclose.

—Bonnie Gillis

SOLID TUMORS

Clinical Oncology News • January 2011

Breast

New HER2-Targeted Agent Shows Its Mettle San Antonio—The addition of the investigational monoclonal antibody (mAb) pertuzumab to a trastuzumab-docetaxel regimen resulted in superior tumor eradication compared with the standard regimen of trastuzumab-docetaxel only in patients with HER2-positive breast cancer, according to a Phase II trial.

Additive HER2 blockade with pertuzumab significantly improved the rate of pathologic complete response (pCR) from 29% with standard therapy to 46% with the combination (P=0.014), according to the NEOSPHERE (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) trial. The study was presented at the recent annual San Antonio Breast Cancer Symposium (SABCS; abstract S3-2).

Recognizing that the mAbs pertuzumab, in development by Genentech, and trastuzumab (Herceptin, Genentech) attack different targets on the HER2 receptor, the NEOSPHERE investigators conducted the trial to determine whether the two mAbs would be potent when used in combination. According to lead investigator Luca Gianni, MD, they found that “the addition of pertuzumab to a regimen of trastuzumab and chemotherapy has at least additive efficacy and should be tested in Phase III trials in early breast cancer.” Presenting the results during the SABCS, Dr. Gianni, director of medical oncology at the National Cancer Institute in Milan, further noted that “the very favorable therapeutic ratio of the combination of pertuzumab and trastuzumab justifies continuing its use as adjuvant therapy after the end of chemotherapy.” He disclosed that he is on the advisory board of Genentech.

The NEOSPHERE adjuvant therapy trial enrolled 417 patients with centrally confirmed, operable or locally advanced breast cancer, including a small proportion with inflammatory breast cancer. Patients were randomly assigned to one of four treatment arms: docetaxel plus trastuzumab (standard therapy, n=107), docetaxel plus pertuzumab (n=96), trastuzumab plus pertuzumab (n=107) or docetaxel plus trastuzumab

and pertuzumab (n=107). Neoadjuvant treatment was given every three weeks for four cycles, followed by surgery.

After surgery, the three docetaxel-containing arms received FEC (fluorouracil, epirubicin and cyclophosphamide) plus trastuzumab as adjuvant therapy, while the trastuzumab plus pertuzumab arm received adjuvant therapy with docetaxel plus trastuzumab, considered standard therapy.

The combination of chemotherapy, trastuzumab and pertuzumab resulted in significantly higher rates of pCR: 45.8% versus 29% with standard docetaxel plus trastuzumab (P=0.014) and 24% with docetaxel plus pertuzumab (P=0.0003).

Patients in the trastuzumab-pertuzumab arm had a pCR rate of 16.8% (P=0.0198), which Dr. Gianni said was excellent for two mAbs alone. The NEOSPHERE investigators plan to study more tumor tissue samples obtained from trial participants to identify which patients with HER2-positive early breast cancer would respond well to the two mAbs alone. “Five years ago,” Dr. Gianni said, “a complete eradication of tumor in 16% of HER2-positive patients would have

Justice Department Weighs in on Gene Patenting Lawsuit

Myriad and the U.S. Patent and Trademark Office that sought to strike down the patents on BRCA1 and BRCA2. The American Civil Liberties Union and the Public Patent Foundation organized the lawsuit. The plaintiffs argued that isolating a gene does not alter the structure of the DNA itself, and so what has been patented is a product of nature and therefore not patentable.

In March 2010, the New York court agreed and ruled that the BRCA patents were not valid.

Myriad has appealed this decision, and the case is now winding its way through

T

he U.S. Department of Justice has weighed in on the ongoing lawsuit against Myriad Genetics in the U.S. Court of Appeals with an amicus brief arguing that it should be illegal to patent a gene. Myriad makes the BRCA gene detection test.

In 2009, a group of organizations and individuals filed a lawsuit against

60

Patients, %

50

57

been considered outstanding for neoadjuvant therapy. And there was much less toxicity with this regimen than with chemotherapy. We need to figure out which patients respond to this combination so then we could avoid chemotherapy in that subgroup.”

HER2-positive patients who were estrogen receptor (ER)- and progesterone receptor (PR)-negative achieved superior pCR rates compared with their ER- and PR-positive counterparts, with the combination of docetaxel, trastuzumab and pertuzumab having the highest rate (63.2%) versus 36.8% with standard docetaxel plus trastuzumab, and about 29% each for trastuzumab-pertuzumab and for docetaxel-pertuzumab.

The addition of pertuzumab did not lead to increased cardiac risk during four short cycles of neoadjuvant therapy.

Grade 3 or higher adverse events (AEs) were similar in the docetaxel-containing arms and were as expected with this drug; neutropenia, febrile neutropenia and leukopenia were the most common AEs in those arms. The trastuzumab plus pertuzumab arm had the least toxicity.

In an interview with Clinical Oncology

News, Dr. Gianni explained that the NEOSPHERE trial was designed to rank therapies in terms of pCR before surgery. “It is possible that higher pCR rates would be achieved with longer treatment,” he suggested.

Commenting on the findings during the SABCS, Eric Winer, MD, director of the Breast Oncology Center at Dana-Farber Cancer Institute in Boston, said that the combination of trastuzumab plus chemotherapy can achieve good diseasefree survival, with rates of 86% and higher. “Where we are headed,” he said, “is to improve upon trastuzumab and chemotherapy, to identify patients unlikely to be cured by chemotherapy and trastuzumab and to identify candidates for less-intensive therapy.”

Preclinical evidence had suggested that pertuzumab was more effective than trastuzumab and was active even after resistance to trastuzumab developed (Cancer Res 2009;69:9330-9336, PMID: 19934333. “In NEOSPHERE, the combination arm was the winner,” said Dr. Winer. However, he urged clinicians not to “ignore the biological combination regimen alone.” Although it was more effective with chemotherapy, he stressed that the pertuzumab-trastuzumab combination resulted in a complete disappearance of tumor cells in more than 16% of patients, even when given without chemotherapy.

—Bonnie Gillis

55.3 Trastuzumab plus docetaxel 44.9

Trastuzumab, docetaxel, and pertuzumab Docetaxel plus pertuzumab

40

Trastuzumab plus pertuzumab

30 20 7.5

10 0.9

0

Neutropenia

12.1

8.4

7.4 0

Febrile neutropenia

7.4

4.7

3.7

0

Leukopenia

5.6

4.3 0

Diarrhea

2.8

0

0

1.1

ALT increase

Figure. Selected grade ≥3 adverse events.

the U.S. Court of Appeals. The brief is the latest development in the case. Specifically, the brief states that “genomic DNA that has merely been isolated from the human body, without further alteration or manipulation, is not eligible to be patented.” If the New York decision is upheld, the impact will be far-reaching—researchers estimate that roughly 20% of the human genome has been patented.

Many medical associations, such as the Association for Molecular Pathology, American College of Medical Genetics, American Medical Association and Council for Responsible Genetics have argued

against the patenting of genes. Some indviduals argue that patenting genes restricts research in this field by outside institutions and drug companies.

According to Peter Meldrum, president and CEO of Myriad, the final outcome of the litigation will not have a material impact on the BRCA test “due to the patent protection afforded Myriad by its remaining patents.”

—Kate O’Rourke

13

14

SOLID TUMORS

Clinical Oncology News • January 2011

Breast

ZOLEDRONIC

‘AZURE will not be the final word on this. I think there will be a lot of controversy and differences of opinion on how to interpret this data.’

continued from page 1 

breast cancer improved DFS. Since these results were reported, some oncologists have been prescribing the bone-targeted therapy off-label to treat breast cancer. Many oncologists say AZURE should change this practice.

“Zoledronic acid used in this schedule does not have broad applicability to the adjuvant treatment of early breast cancer,” said Robert Coleman, MD, professor of medical oncology at the University of Sheffield in England, who led AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) (SABCS abstract S4-5).

Not all clinicians, however, are convinced.

At SABCS, investigators from the ABCSG-12 trial (Austrian Breast and Colorectal Cancer Study Group) reported that at 62 months, the improvement in DFS from zoledronic acid was maintained in patients over age 40 years (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.40-0.83; P=0.003).

A trend toward improved overall survival also was identified, but it just missed statistical significance (HR, 0.57; 95% CI, 0.32-1.02; P=0.057). “Combining zoledronic acid with adjuvant endocrine therapy should be considered for premenopausal women with early stage endocrine-responsive breast cancer,” said Michael Gnant, MD, professor of surgery from the Medical University of Vienna. He presented the study update (poster P5-11-02).

The topic likely is to remain controversial for some time and at the symposium, oncologists argued that differences in patient characteristics might account for the vastly different results.

The international AZURE trial included 3,360 patients with stage II/III breast cancer from 174 participating centers.

Patients were given standard therapy of a physician’s choice or standard therapy

—Sharon Giordano, MD, MPH

with zoledronic acid treatment for five years.

Patients received 4 mg of zoledronic acid in six doses every three or four weeks for six months, then eight doses every three months for the next two years, and five doses every six months for the next 30 months (Figure).

Patients were included if they were nodepositive and T3/T4 or confirmed N+ neoadjuvant patients. They also had to have no evidence of metastases, a complete primary tumor resection and a Karnfosky performance status of at least 80. Patients were excluded if they had other malignancies, prior treatment with bisphosphonates in the last year or bone disease including osteoporosis.

With a median follow-up of roughly 59 months, no difference was identified in DFS (HR, 0.98; 95% CI, 0.85-1.13; P=0.79) or invasive DFS (HR, 0.98; 95% CI, 0.851.12; P=0.73) (Table 1). “It is highly unlikely that this conclusion will change with further follow-up,” Dr. Coleman said.

“Only 8.7% of patients in the control arm ever saw bisphosphonates before recurrence, so we don’t have this result because of extensive use of bisphosphonates for other reasons such as osteoporosis.”

A subgroup analysis of women with established menopausal status, however, told another story. In women more than five years postmenopause or women over age 60, zoledronic acid provided

ABCSG-12

AZURE

3,360 stage II/III breast cancer patients

a 29% reduction in the risk for death from their disease (P=0.001). The investigators called the P value “remarkable.” “This is rarely seen in subgroup analyses,” Dr. Coleman said.

“Please note that this is not a small subgroup.

This is about 1,100 patients with 200 events.” He hypothesized that adjuvant bisphosphonate efficacy is dependent on a low estrogen environment, which could explain the positive results seen in the ABCSG-12. Although the AZURE trial included both pre- and postmenopausal patients, ABCSG-12 only included premenopausal patients, but all patients were treated with goserelin.

According to Rowan Chlebowski, MD, a medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, data from the Women’s Health Initiative (WHI) support the hypothesis that a hormonemediated therapy could require a lowestrogen environment to have a benefit.

Data from the WHI showed that estrogen alone had no effect on breast cancer incidence in women who were less than five years postmenopause, but had a positive effect on breast cancer incidence in women who were in menopause for longer than five years.

Sharon Giordano, MD, MPH, an internist at the Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, pointed

R A N D O M I Z E D

Standard therapy + zoledronic acid 4 mg 6 doses q3-4wk Months

8 doses q3mo 6

5 doses q6mo 30

Zoledronic acid duration 5 y

Figure. Comparison of trial design.

60

DFS

IDFS

Chest wall recurrence

√

√

Ipsilateral breast recurrence

x

√

Regional recurrence

√

√

Distant recurrence

√

√

Death without recurrence

√

√

Contralateral breast cancer

x

√

New primary cancer

x

√

DCIS/LCIS

x

x

DCIS, ductal carcinoma in situ; DFS, diseasefree survival; IDFS, invasive disease-free survival; LCIS, lobular carcinoma in situ

out other differences in the two trial designs. Patients in the AZURE trial had stage II/III cancer compared with patients in the ABCSG-12 study who had stage I/II disease. The duration of therapy was longer in the AZURE trial, five years with a total of 19 total treatments compared with three years and six total treatments. The AZURE trial also had more patients receiving chemotherapy (95% vs. 5%) and fewer hormone receptor-positive patients (78% vs. 97%). “Although we can speculate the benefit could be dependent on a low-estrogen environment, this very interesting idea does remain a hypothesis,” Dr. Giordano said. “Based on these data, I believe that routine adjuvant use of zoledronic [acid] to prevent recurrence is not indicated.”

Two camps of thought have definitely formed. “I would conclude that perfect suppression or natural lack of estrogen in

Tamoxifen 20 mg/d

Standard therapy 1,803 stage I/II breast cancer patients— surgery (+ radiation)

Table 1. AZURE Study End Points

Goserelin 3.6 mg q28d

R A N D O M I Z E D

Tamoxifen 20 mg/d + zoledronic acid 4 mg q6mo for 3 y

Anastrozole 1 mg/d Anastrozole 1 mg/d + zoledronic acid 4 mg q6mo for 3 y

SOLID TUMORS

Clinical Oncology News • January 2011

Breast

Table 2. Key Trials Showing Contradictory Results for Impact of Bisphosphonates on DFS in Patients With Breast Cancer J Clin Oncol 2002;20(15): 3219-3224, PMID: 12149294 Concluded that clodronate may reduce the occurrence of bone metastases, but only during the medication period, and the drug reduces mortality.

combination with zoledronic acid leads to significant disease-free and overall survival benefits,” Dr. Gnant said. “What has changed for me today? I kept being asked what I would do [as an oncologist], and I would say if my wife was diagnosed with breast cancer and she is age 42, I would say yes, let’s go get the drug. If my mother had asked, she is 83, I would say wait for AZURE,” Dr. Gnant said. “Now, I would say my mother should also receive zoledronic acid.”

A number of previous studies also have shown contradictory results for the ability of bisphosphonates to prevent breast cancer recurrence (Table 2),

and the debate likely is to continue. Dr. Giardano said results from bisphosphonate trials in progress would hopefully provide more insight. These include the NSABP-34 (National Surgical Adjuvant Breast and Bowel Project) trial of daily clodronate compared with placebo; the GAIN (German Adjuvant Intergroup Node-positive) trial comparing ibandronate daily with observation for two years; the NATAN trial of zoledronic acid treatment for residual disease after preoperative chemotherapy; and a Southwest Oncology Group trial comparing clodronate, zoledronic acid and ibandronate.

N Engl J Med 1998;339(6): 357-363, PMID: 9691101 Reported a lower rate of metastases and improved survival with clodronate use.

J Clin Oncol 2001;19(1):10-17, PMID: 11134190.

Adjuvant clodronate had a negative effect on DFS by increasing the development of nonskeletal metastases.

Ann Oncol 2010(11):2188-2194, PMID: 20444845 ZO-FAST (Zometa-Femara Adjuvant Synergy Trial) showed immediate zoledronic acid use improved DFS compared with delayed zoledronic acid use.

Clin Breast Cancer 2009;9(2): 77-85, PMID: 19433387 ZFAST (Zoledronic Acid–Letrozole Adjuvant Synergy Trial) showed no difference on DFS with immediate versus delayed zoledronic acid use AZURE, SABCS 2010, abstract S4-5 Zoledronic acid use does not increase DFS overall, but does increase DFS in women who have been in menopause for more than 5 years.

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“AZURE will not be the final word on this. I think there will be a lot of controversy and differences of opinion on how to interpret this data,” Dr. Giordano said. “The ABCSG is a different patient population than I would tend to see in my clinic. I don’t routinely use ovarian ablation in my patients and we use a lot more frequent chemotherapy than the patients in that study. I personally will not be giving bisphosphonates to my patients, but I respect that there will likely be others who will interpret the data differently.”

—Kate O’Rourke

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POLICY & MANAGEMENT

Clinical Oncology News • January 2011

Regulations

NEW RULES continued from page 1 

mitigate identity theft. In May 2010, the American Medical Association (AMA) filed a federal lawsuit to prevent the Federal Trade Commission from extending the Red Flags Rule to physicians. In a statement, Cecil B. Wilson, MD, AMA president-elect, stated, “This unjustified federal regulation of medicine treats physician practices like banks, credit card companies and mortgage lenders.

The extensive bureaucratic burden of complying with the Red Flags Rule outweighs any benefit to the public.”

On Dec. 18, the Red Flag Program Clarification Act of 2010 was signed into law. The Act clarifies the term “creditor” and effectively exempts physicians from the rule.

Changes Impact Clinical Trial Patients, Those Receiving Preventive Services This year, Medicare will pay for all patients enrolled in approved clinical trials, even those enrolled in Medicare Advantage (MA) programs. MA providers will be responsible for paying the patient portion of deductibles and coinsurance for its patients.

There will be no copayments or deductibles attached to several preventive services that may be performed by oncologists. These include annual wellness visits, initial preventive physician examination; pneumovax, influenza, hepatitis B vaccinations; and PAPs/pelvic examinations. It also includes prostate cancer screening; colorectal cancer screening, even if it includes removal of polyps; bone mass assessments; and smoking screening and cessation for asymptomatic patients.

Important Changes to CPT and J Codes Oncologists should be aware that there are a number of new Current

Procedural Terminology (CPT) codes and several are notable for oncology services. Subsequent Observation Care now has new CPT codes in three levels: 99224, 99225 and 99226. The peritoneal cavity chemotherapy administration code changes from 96445 to 96446.

Influenza vaccines have five new CPT codes changing from 90658 to Q2035 for Afluria, Q2036 for Flulaval, Q2037 for Fluvirin, Q2038 for Fluzone and Q9039 for an otherwise nonspecified vaccine.

The Healthcare Common Procedure Coding System J codes have significant changes for 2011. Check the listing for additions, deletions and changes that will affect billing for existing drugs as well as new drugs. There are 22 new drugs, 39 deletions and one change.

Physician Fee Schedule News In terms of sustainable growth rate, Congress passed legislation in December that eliminates the planned reduction for Medicare in 2011. This means that the planned 23% decrease that was proposed because of rising costs of Medicare will not be implemented during the next year. This is great news for physicians.

The Medicare economic index is always on the minds of oncologists, and in 2011, CMS implements the second year of a four-year transition to new practice expense using the physician practice survey and oncology cost data. Last September, CMS determined to rebase and revise the payments. The result is that medical oncology has a 0% impact in 2011. Radiation should expect a 1% decrease.

The new rules also impact biosimilars.

A product approved under an abbreviated application because it relies on the similarity to an existing licensed product will be paid by analyzing the payment of all average sale prices (ASPs) of similar products plus 6%.

This year’s changes include a primary care bonus. For primary care physicians who bill 60% of their total charges

for evaluation and management codes (99201-99215 and 99304-99350), Medicare will provide an additional payment of 10%. The bonus will be made quarterly. Even though oncologists are not eligible, physician extenders may be.

New Requirements for CTs, PETs and MRIs For practices that provide computed tomography (CT) scans, positron emission tomography (PET) or magnetic resonance imaging (MRI), new requirements must be met for disclosing information about ownership and competitors to patients at the time referral is made for the diagnostic imaging service.

The requirements can be found on the CMS site by clicking on Medicare, then Physician Self-Referral (under Fraud and Abuse), and then on Self-Referral Disclosure Policy.

Payments for CT, PET and MRI procedures will be reduced due to the increased use required in cost calculation.

Increasing Your Money For drugs, the final rules continue payment at ASP plus 6%. ASP reporting requirements for pharmaceutical manufacturers have been increased with the addition of a carryover clause for late quarterly reporting. Note that CMS has clearly updated regulations to define “overfill” and the fact that it is ineligible for payment.

The Physician Quality Reporting Initiative continues with 1% payment for successful reporting. There are two reporting periods, Jan. 1 through June 30 or July 1 through Dec. 31 for claimsbased reporting. For those using a registry to report, reporting will be for 12 months. CMS has included an interim feedback for providers in June.

For e-prescribers, CMS will issue an additional 1% payment to billed and allowed services in 2011, unless these prescribers participate in the electronic records incentive (American Recovery and Reinvestment Act Electronic

Health Records/Health Information Technology). Practices that are not taking advantage of this may want to reconsider in 2011.

Hospital Outpatients Impacted Several changes impact the hospital outpatient setting. Pass-through drugs will be paid at ASP plus 5% beginning in January. This is an increase of 1% over 2010. The new threshold for bundled drugs is $70. All drugs that are less than $70 per dose will be bundled into administrative payments, rather than being paid separately.

The Hospital Outpatient Prospective Payment System payment includes a 2.35% increase. Legislators originally voted for a 2.6% increase, but this was reduced by 0.25%. Hospitals must meet quality measure standards to receive full payment. There are additional quality measures, so oncologists should ensure that they are aware of the complete list of standards for 2011.

CMS has modified the requirements for supervision. It is important for oncology to note that chemotherapy, radiation and blood transfusions are not services thought to qualify for generalized supervision. Direct supervision requires immediate availability of a physician. There is no geographic limitation on what constitutes “immediate” availability.

It’s time to prepare for the changes you must make to meet the new requirements. It’s a new year with new rules!

—Mary Lou Bowers, MBA President & CEO of The Pritchard Group, LLC, Rockville, Md. www.thepritchardgroup.net

Electronic Medical Records

Improper Use of EMRs Can Introduce New Types of Errors San Diego—Punching a prescription into a computer may keep a doctor’s sloppy penmanship from misleading the dispensing pharmacist, but a new study suggests that it also can lead to its own dangerous mishaps.

“There’s a big conversion to electronic prescribing going on today,” said David W. Bates, MD, professor of medicine at Harvard Medical School, in Boston. “But there is a downside to the technology, as we found: Nearly any electronic prescribing application

can create new errors as well as prevent them.”

Dr. Bates and his colleagues decided it would be useful to catalogue these new errors in an effort to minimize them in future computerized prescriber order entry (CPOE) applications. The team

reviewed and classified 3,898 electronic prescriptions received by commercial outpatient pharmacy chains across Florida, Arizona and Massachusetts during fall 2008. Of those, 452 (11.6%) contained errors, with rates ranging from 5% to 17.4%, depending on the prescribing system used, the investigators reported at the 2010 annual meeting of the American Society of Anesthesiologists (abstract 183).

The most common error was missing information (60.8%), typically an omitted duration, dose or frequency. A lack

of clarity (15.9%), conflicting information (15.7%) or an incorrect prescription (7.6%) comprised the remaining errors.

More than one out of every three errors, a total of 163, were deemed dangerous enough to classify as a potential adverse drug event. Of those, 95 (58.3%) were deemed significant, and 68 (41.7%) were considered serious, the investigators reported.

“We were a bit surprised to see [error] rates this high,” Dr. Bates said, “although rates are still considerably

POLICY & MANAGEMENT

Clinical Oncology News • January 2011

Electronic Medical Records

More Data on CPOE Versus Prescription Pad

A

lthough CPOE systems are not foolproof, there is still a large body of evidence showing that the technology is far superior to handwritten prescriptions.

Much of that evidence has been documented in the inpatient setting. But outpatient data are slowly trickling in. A study conducted earlier this year, for example, underscored CPOE’s effectiveness in community-based, outpatient health care clinics. In the study (J Am Med Inform Assoc 2010;17:78-84), investigators examined the accuracy of more than 10,000 drug orders that were processed before and after CPOE system implementation. They found that the frequency of errors declined from 18.2% to 8.2%—a reduction in adjusted odds of 70% (odds ratio [OR], 0.30; 95% confidence interval, 0.23-0.40). The largest reductions in errors were those attributed to illegible handwriting (97%), use of inappropriate abbreviations (94%) and missing information (85%), the researchers noted.

On the inpatient side, even more data favor CPOE—but with some of the studies echoing the pluses and minuses of the findings seen in the Bates et al study. British researchers, for example, compared CPOE with handwritten drug orders in an ICU. The rate of medication errors with CPOE was significantly lower (117 errors from 2,429 prescriptions, 4.8%) than with handwritten drug orders (69 errors from 1,036 prescriptions, 6.7%; P<0.04).

However, two of the errors with CPOE led to patient harm, requiring an increase in hospital length of stay. Additionally, three computerized prescription errors that were caught before they reached patients could have led to permanent harm or death, the investigators reported (Crit Care 2005;9:R516-R521).

—L.P.

higher in nonelectronic systems.” (See sidebar.)

Older Is Not Better Depending on the type of drug being prescribed, handwritten drug orders “can really be a problem,” said Matthew Grissinger, RPh, director of error reporting programs at the Institute for Safe Medication Practices in Horsham, Pa. For example, “some drug names out there look the same only when hand-written. An electronic

system can prevent those kinds of [potential errors],” Mr. Grissinger said. “On the flip side, new errors are often introduced.”

As for why CPOE systems are prone to their own errors, Mr. Grissinger cited several potential causes. For one, doctors usually are unaccustomed to entering orders into a computer system

and it may be easy for them to pick the wrong drug or dose. “How would a pharmacist know if a patient is supposed to get a drug at 10 mg, but the doctor picked 20 mg? The pharmacist wouldn’t even know if the right drug was picked off the list [on the CPOE screen] or not,” he said.

The new CPOE systems also contain comment fields where doctors have been known to enter contradictory notes or “correct” a previous error they made in the data entry form. “Pharmacists are not used to having to look at this comment field and recognize that it could be contradictory,” he pointed out.

“There’s a lot going on here,” Mr. Grissinger added. “There’s the design of the system, but also the training of physicians and pharmacists.”

Dr. Bates, too, pointed to the importance of internal consistency checks, including the setting of default doses.

“If a patient is going to be given one tablet daily for seven days, then the amount dispensed should be seven,” he said. “Unfortunately, many applications don’t do that.”

Although dosing can be particularly dangerous, such as with antibiotics, perhaps the most important consistency see EMRS, page 18

Physician in Chief for Cancer Clinical Affairs

17

HEMATOLOGIC DISEASE

Clinical Oncology News • January 2011

Lymphoma

In Advanced-Stage Hodgkin’s Lymphoma

Stanford V Regimen Fails To Beat ABVD 30

Orlando, Fla.—The Phase III study designed to provide an objective demonstration that the Stanford V regimen is superior to the ABVD regimen with or without radiation in locally extensive and advanced-stage Hodgkin’s lymphoma has failed to do so.

The trial instead found that outcomes with a median follow-up of just over five years were almost exactly the same.

Although investigators maintained that the Stanford V regimen still may be a reasonable alternative in selected patients, they concluded that the ABVD regimen remains the standard of care in the United States.

The study was characterized as the largest Phase III trial of Hodgkin’s lymphoma ever conducted in North America. “[There was] no significant difference in response rate, failure-free survival (FFS), overall survival (OS) or five-year toxicity when ABVD was compared with Stanford V,” said Leo I. Gordon, MD, director of the Lymphoma Program at Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, in Chicago. Presenting the results at the recent annual meeting of the American Society of Hematology (ASH; abstract 415), Dr. Gordon noted that a one-third reduction in the hazard ratio for FFS had been projected when the study was designed.

In the study, 854 patients with early locally extensive (Ann Arbor stage I or II with bulky mediastinal disease [BMD]) or advanced (stage III or IV) Hodgkin’s lymphoma were randomized to a conventional six to eight cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or to Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide and prednisone). Stanford V is given over a 12–week period or about half of the time as ABVD. Another major difference between the

Stanford V

Patients, %

18

ABVD

20

P<0.0001

10

10

regimens is that the cumulative doses of both adriamycin and bleomycin in Stanford V are less than half of that used in ABVD. Both regimens were augmented with radiotherapy for patients with BMD and, in the case of Stanford V, in patients with macroscopic splenic disease or nodes greater than 5 cm.

The response rates and outcomes at the most recent follow-up were very similar. The complete response (CR) rates (including clinical CRs) were about 70% on either regimen. About half of the remaining patients achieved either partial response or stable disease.

The FFS rates at the median follow-up for the ABVD and Stanford V regimens were 73% and 71% (P=0.29), respectively. The OS rates were 88% and 87% (P=0.87), respectively.

Although the toxicity of these two regimens was characterized as similar in regard to most cytopenias and patient complaints, more grade 3 or 4 sensory neuropathy (10% vs. 3%; P<0.0001) was observed on Stanford V relative to ABVD. The most common side effect was grade 3 or 4 neutropenia, which occurred in about 75% of both arms. A second primary cancer developed in roughly 3% of each study arm over the course of the trial, and the rate was not significantly different.

In a subgroup analysis of stage I and II patients who received radiotherapy for BMD, which represented about onethird of patients included in the study, the results also were similar. Again, both the FFS (85% vs. 77%; P=0.13) and the OS (95% vs. 92%; P=0.31) at the median follow-up of 5.47 years was slightly higher

in the ABVD group on a numerical, but not a statistical, basis. In presenting the subanalysis results at ASH (abstract 416), Ranjana Advani, MD, associate professor of medicine/oncology at Stanford University Medical Center, Stanford, Calif., cautioned that more follow-up is needed to compare the late effects of radiation in combination with these two chemotherapy regimens. However, she also concluded that ABVD for six to eight cycles with radiation is now reasonably characterized as the standard of care for stage I and II lymphoma with BMD in North America on the basis of the new study’s results.

“The focus now should be on evaluating how to identify the 15% to 20% of patients who are destined to relapse on ABVD plus radiation and in whom we might consider intensification strategies,” Dr. Advani suggested. Conversely, she said, it also makes sense to consider whether “we can reduce or eliminate radiation in at least some of the 80% to 85% of patients who are being cured on this standard.”

The investigators were careful to conclude that the trial results establish ABVD as the standard over the Stanford V regimen in North America rather than worldwide, because some centers in Europe, particularly in Germany, consider an escalated regimen of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) as the current standard. BEACOPP has been used primarily in patients younger than age 60 years because of toxicity. Although one study found a modest

freedom from treatment failure and a survival advantage at 10 years with escalated BEACOPP relative to alternating cycles ABVD and COPP (cyclophosphamide, vincristine, procarbazine and prednisone), it rendered most males infertile and produced early menopause in a substantial proportion of women (J Clin Oncol 2009;27:4548-4554, PMID: 19704068).

“Failure to embrace the escalated BEACOPP regimen outside of Germany is a result of physicians choosing to expose fewer numbers of patients to sterilizing and potentially leukemogenic therapy,” said Nancy L. Bartlett, MD, Siteman Cancer Center, Washington University, St. Louis. The author of an overview on the challenges of lymphoma therapy for the 2010 Education Program Book distributed at the ASH meeting, Dr. Bartlett agreed that although there are unresolved issues about the optimal first choice in advanced Hodgkin’s lymphoma, ABVD “remains the standard of care.”

—Ted Bosworth

restrict them from moving forward with a contraindicated prescription.

A recent study published in the Archives of Internal Medicine (2010; 170:1578-1583) comparing both types of CPOE alerts noted that gains in patient safety had been modest, largely due to frequently overridden soft alerts. In the study, only 13.5% of pharmacist-based (i.e., soft) alerting succeeded in prompting prescribers not to reorder concomitant warfarin and trimetho­prim-sulfamethoxazole, versus 57.2% of the harder alerts issued.

But the stricter alerts also postponed

care for some patients who urgently needed the potentially risky combination.

In fact, the study was stopped early due to these dangerous delays.

“It’s not just about getting rid of handwritten prescriptions. Electronic prescribing should be about guiding you to make [the] right decisions, so people aren’t having to call you to make changes and the patient isn’t harmed,” said Mr. Grissinger. “We’ve got a fragmented health care system out there. All of these systems, including those from labs and pharmacies, need to work together

to provide information. We need to have higher expectations.”

About 20% of drug prescribers in the United States are currently using computer-generated prescribing applications, with complete conversion anticipated within the next five years.

There are approximately 200 CPOE applications on the market, Dr. Bates said. “Each has its own strengths and weaknesses—an important factor to keep in mind when planning a CPOE rollout.”

—Lynne Peeples

3

0

Grade 3 or 4 Sensory Neuropathy

Figure. Comparison of grade 3/4 sensory neuropathy.

ABVD, doxorubicin, bleomycin, vinblastine and dacarbazine; Stanford V, doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide and prednisone

POLICY & MANAGEMENT Electronic Medical Records

EMRs continued from page 17 

checks relate to kidney issues, added Dr. Bates, noting a number of medications that should have doses modified for patients with renal insufficiency.

Stop alerts for physicians are one potentially powerful safeguard offered by electronic systems. A soft stop alert will pop up on the computer screen to warn a doctor about possible drug–drug interactions, whereas a hard stop alert is intended to

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MULTIPLE CANCERS

SHORTAGES continued from page 2 

• Vinblastine • Vincristine The impact on patients, treatment centers and clinical trials has been enormous, say oncologists across the country.

“I’m in a very big practice; we have 45 doctors in 20 offices in three states. So far, we have not failed to give a patient curative therapy because of these shortages, but it’s easy to see how that could happen, and that raises the whole level of anxiety,” said Michael Neuss, MD, past chair of the American Society of Clinical Oncology’s (ASCO) Clinical Practice Committee. “Last year, with the leucovorin shortage, you could find it if you really needed it. Now, one day we have leucovorin and one day we don’t. And we really are out of doxorubicin, just plain out of it.”

Clinical Oncology News • January 2011

[N Engl J Med 2003;348:694-701] demonstrating a 15% improvement in the cure rate when added with ifosfamide to the three-drug standard which, incidentally, included doxorubicin. Since etoposide was the specific drug studied in that setting, we cannot extrapolate these results to another, alternative drug.”

Dealing With Doxorubicin Shortages At Georgia Cancer Specialists, an Atlanta-based community hematology and oncology practice, some 220 patients usually receive regimens containing doxorubicin. “We’ve had to switch about one-third of them to epirubicin,” said Cheryl Jones, MD, a breast specialist with the practice. “The shortage hit suddenly and unexpectedly for us, around the end of November. We no longer stockpile or maintain a large inventory, since typically you can get what you need very rapidly.”

‘I know my stocking up [on drugs in short supply] may impact other practices, but my goal is to not interrupt therapy and never have the availability of a drug determine the regimen that a patient receives.’

—Melissa Dinolfo, PharmD, BCOP

In some cases, there is an acceptable substitute for a drug on the shortage list.

For example, for breast cancer, epirubicin can be substituted for doxorubicin.

“But it’s not 100% clear exactly what conversion factor to use when switching from doxorubicin to epirubicin,” Dr. Neuss pointed out. “There are different versions of what dose you can use, and as a generic, there’s no one to call to ask.”

And although it may be acceptable clinically, substituting epirubicin for doxorubicin in a clinical trial may well violate that trial’s protocol and put its results in jeopardy, he added. (A number of clinical trials have been slowed or stopped because of the shortages.)

In other cases, a substitute for the missing drug does not exist. “For lymphoma, doxorubicin is curative and there is no substitute,” Dr. Neuss said. “Vincristine in childhood tumors—there’s no substitute. Leucovorin as a rescue agent in childhood tumors—there may or may not be a substitute.”

ASCO president-elect John Link, MD, further highlighted the critical nature of many of these drugs in an ASCO Action Alert interview held on Nov. 23. “Vincristine simply has no substitute in diseases such as acute lymphocytic leukemia, Hodgkin and non-Hodgkin lymphoma and Wilms’ tumor. Not only does it improve outcomes, it has relatively low toxicity,” he said. “Likewise, doxorubicin is critical in the treatment of lymphomas, osteosarcoma and Ewing sarcoma.

Etoposide also has shown clear activity in Ewing sarcoma, with one study

Since Georgia Cancer Specialists has a robust electronic medical records system, they were able to quickly identify all patients currently receiving doxorubicin-containing regimens. “As a core team of physicians, we prioritized patients who are receiving adjuvant and curative therapy first, compared with those patients getting metastatic or palliative regimens,” Dr. Jones said. “Then we identified other alternative, published regimens that might give us similar results for patients who would not receive doxorubicin.”

Similarly, when the etoposide shortage hit, they limited that drug to patients with limited-stage small cell lung cancer and testicular germ cell carcinoma, because those were curative regimens.

“With leucovorin, every adjuvant or curative patient got a full dose, and every palliative patient got a reduced dose,” Dr. Jones said. “We used the guidelines for standard dose reductions, supported by the literature, but it was a significant reduction.”

Transplants Delayed “We’ve had to delay patients starting chemotherapy until we were able to get an emergency supply of a drug in,” said Ali McBride, PharmD, MS, BCPS, a clinical pharmacy specialist at the Alvin J. Siteman Cancer Center at BarnesJewish Hospital, in St. Louis. In some cases, autologous transplants also have been delayed, he said. “With the etoposide shortage, one thing physicians have been doing for lung cancer patients is

switching from an IV to a PO formulation. But there is a risk of dosage errors, because patients usually have to double up on PO medication.”

A Sept. 23 report from the ISMP documented a number of dosage errors that have indeed occurred with chemotherapy drugs as a result of the need for substitutions. So far, none of the “at least six” deaths attributable to the drug shortage has involved an oncology drug, according to ISMP President Michael Cohen, RPh, MS, ScD. But there have been a number of errors and adverse events, he noted, including: • A dosing error made when a vinBLAStine shortage led to replacement with vinCRIStine for a patient with a hematologic disease • An error in converting IV etoposide to oral dosing, which needs to be double the IV dose • An incorrect dose prescribed when levoleucovorin was substituted for leucovorin.

[The ISMP report, based on a nationwide survey of health care practitioners, documented severe shortages of a wide range of medications, including propofol, neuromuscular blocking agents, morphine, epinephrine, heparin, fosphenytoin and certain antibiotics. In some cases, survey respondents noted, patients died as a result of not getting the best available drug in a timely manner. The full report can be accessed at www.ismp.org.]

‘A Horrible Position To Be In’ Like the Georgia practice, Dr. McBride says Barnes-Jewish also has had to prioritize patients who are on curative regimens. “It’s a horrible position to be in,” she said.

that experience to watch trends. I don’t like running out of things,” she said. “If I see that a drug is manufactured by three different people, and one of the houses is back-ordered—I hate to do this, but I start buying. I feel badly, because my peers in other places may not have the opportunity to watch as closely as I do, and I know my stocking up may impact other practices, but my goal is to not interrupt therapy and never have the availability of a drug determine the regimen that a patient receives.”

Because she saw the doxorubicin shortage coming, Dr. Dinolfo has a 600-mg supply. She also set aside 13 vials of cisplatin. “I was, however, impacted by a shortage of etoposide the practice was using to treat a young man with testicular cancer. There’s nothing we can substitute, so we had to go to the brandname drug, which costs $135 more per vial,” she related. “I said I don’t care, we’re buying it, and laid aside as much of the expensive stuff as I could get my hands on so I wouldn’t have to interrupt this kid’s care.”

Parents ‘Distraught’ Over Treatment Delays Dr. Dinolfo said she spoke to doctors elsewhere in the country who are having similar problems. “I talked to a colleague in a pediatric practice in San Francisco, who is switching patients to different regimens five to eight times a week, and has therapy being delayed two

‘As a core team of physicians, we prioritized patients who are receiving adjuvant and curative therapy first, compared with those patients getting metastatic or palliative regimens.’

—Cheryl Jones, MD

“That’s a difficult discussion to have with patients,” agreed Dr. Jones. “They’re comfortable and they know that you’ve planned the best regimen for them. Then you come back and say there’s a shortage: manufacturing problems, regulatory delays, downsizing in the pharmaceutical industry. But economics don’t mean much to patients who are in a very personal fight for their individual life.”

Melissa Dinolfo, PharmD, BCOP, director of pharmacy and clinical operations at Premiere Oncology in Santa Monica, Calif., confesses that she has stockpiled drugs as she’s seen shortages coming.

“The first six years I was here, there were probably two to four shortages overall that were impactful, and I learned from

to five times a week,” she said. “Parents are distraught about their child’s regimen; they’re angry, frustrated and anxious about outcomes as regimens change and therapy is delayed.”

It’s not just antineoplastic agents that are running short. Limited access to hundreds of other supportive drugs has impacted oncology practices. “I couldn’t get injectable Lasix, which is part of our chemotherapy regimen, for months.

So I had to give oral, which is not as rapid-acting,” Dr. Dinolfo said. “We were short for many months on injectable Ativan.”

A few months ago, she switched several of her patients with head and neck cancer, who were so nauseated

MULTIPLE CANCERS

Clinical Oncology News • January 2011

‘We really are out of doxorubicin, just plain out of it. ...

For lymphoma, doxorubicin is curative—there’s no substitute.’

—Michael Neuss, MD

that they couldn’t take anything orally, to Sancuso (Prostrakan), a sevenday release transdermal patch version of Roche’s anti-nausea medication Kytril (granisetron). “I had one young man gain seven pounds in a month,” she said. “It makes all the difference. I have four people now on the patch who are doing so much better—but now I can’t get the patches. So they have to go back to being miserable for a few weeks, at least.”

No one expects the shortage to improve anytime soon. “This is a serious and widespread problem; it didn’t evolve overnight and won’t be fixed overnight,” said Bona E. Benjamin, BS Pharm, director of medication use quality improvement with ASHP, which hosted a drug shortage summit in early November jointly with ASCO, ISMP and the American Society of Anesthesiologists. “We are very concerned that things will get worse before they get better.”

Ms. Benjamin urges anyone who becomes aware of a looming drug shortage to immediately report it to ASHP

using its drug shortages site (http://www. ashp.org/shortages). “Not just pharmacists—anyone in the health care community, including patients—can report a shortage to our Web site if they know or suspect that [a shortage] is pending,” she said. “Our site simultaneously notifies the FDA, and we’ve heard that sometimes these reports are their first notification of a shortage. The sooner the agency knows, the more latitude they have to activate their management plans and work with other firms to encourage ramping up production. On our part, we work with our partners to get information and shortage management resources posted on our Web site as soon as possible.”

“I know Hospira is working very hard on improving quality,” said Dr. Fox. “They had manufacturing problems and stepped up their quality improvement activities. They are an incredibly large manufacturing company, but it’s going to take time, and their deadlines keep getting pushed back.”

As for Teva, “we don’t know if [the company is] back in production yet.

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Some [generic chemotherapy drugs are] trickling out, but we can’t tell if that’s because it’s so medically necessary that the FDA is allowing it to go out, or if they have started back into production.

Teva won’t say, and the FDA can’t say.”

For its part, Bedford Laboratories, now the sole manufacturer of leucovorin (although the FDA has reported that Teva plans to return to the market in April 2011), and one of three manufacturers of doxorubicin and cisplatin issued a statement to Clinical Oncology News.

“Bedford Laboratories is committed to providing pharmaceutical products that improve the health and quality of life of patients. In April 2010, Bedford moved from 40% to 100% market share for leucovorin when the only other available supplier exited the market, making Bedford the sole provider of this critical-care product,” the statement reads. “Due in part to this fact, we are currently facing manufacturing constraints that are resulting in back orders. We are working diligently to expedite manufacturing for all current orders and to anticipate future demands so that the patients and physicians who depend on this product as part of treatment have access to it.”

Meanwhile, a response from Hospira notes that the company hopes to resume

manufacture of bleomycin late in the first quarter of 2011, and that it is doing what it can to meet the demand for vincristine with tight supplies after another manufacturer left the market.

‘Economics don’t mean much to patients who are in a very personal fight for their life.’

—Cheryl Jones, MD

“The situation highlights how fragile our supply chain is,” Dr. Fox said. “Of course, it’s good business practice to have a lean inventory and just-in-time manufacturing and no redundancies. But then, when one glitch happens it impacts patients all over the country. And it’s not like there’s not enough peanut butter on the shelves— people can die as a result of this.”

A broader public health response to the growing drug shortage crisis is needed, Dr. Neuss says. “Somebody needs to step in and say that these drugs are a vital interest to society. We, as a society, have to decide how we’re going to be sure that the people who stand to benefit most from a drug are going to get it.”

—Gina Shaw

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21

HEMATOLOGIC DISEASE

Clinical Oncology News • January 2011

Hodgkin’s Lymphoma

brentuXIMAB

25

continued from page 1 

20 6%

Patients, %

which means they never achieved a remission with up-front chemotherapy. Patients in this study had failed a median of 3.5 prior regimens.” Dr. Chen said the impressive results have spurred Seattle Genetics, which is developing the drug and funded the study, to seek FDA approval for the agent based on the Phase II data.

According to Robert Hromas, MD, program co-chair of the ASH meeting, the trial was one of the most exciting studies presented at this year’s meeting. “Brentuximab vedotin is effective for the treatment of relapsed Hodgkin’s lymphoma,” said Dr. Hromas, chief of the Division of Hematology/Oncology at the University of New Mexico School of Medicine and Health Sciences Center, Albuquerque. “These patients had already failed autologous stem cell transplant, and it would therefore be expected to be very difficult to obtain responses in them. It is possible that adding brentuximab vedotin up-front in high-risk Hodgkin’s lymphoma patients also might prove highly beneficial.”

Approximately 50% of patients with Hodgkin’s lymphoma who undergo ASCT will relapse and these patients fare poorly, with a median overall survival of 2.4 years. Chemotherapy options post-ASCT cause substantial morbidity and no approved treatments exist. “For many of them, palliative care or hospice is the only option since there is no FDA-approved treatment,” Dr. Chen said. “The median age of patients [in this study] was 31 years old. There are many young patients who need better treatment options.”

The Phase II trial involved 26 centers in the United States, Canada, France and Italy. Brentuximab vedotin, an anti-

15

Grade 4 Grade 3

10

CD30 monoclonal antibody, is a potent antitubulin agent and a protease-cleavable linker. In the trial, 102 patients received brentuximab vedotin 1.8 mg/kg IV, administered via a 30-minute infusion on an outpatient basis, every 21 days (maximum 16 cycles for stable disease or better). Restaging was done at cycles 2, 4, 7, 10, 13 and 16. Follow-up was conducted every 12 weeks. An independent review of the data found that the ORR, the study’s primary end point, was 75% with a median duration of 29 weeks. The complete response rate was 34%, with the median duration not yet reached, and 40% of patients achieved a partial remission. Ninety-four percent of patients receiving brentuximab vedotin achieved tumor reduction and roughly 88% of patients were alive at 12 months. The median progression-free survival was 25.1 weeks and the median overall survival had not been reached.

Patients who were 12 years or older were eligible for the study if they had relapsed or refractory CD30+ Hodgkin’s lymphoma, measurable disease of at least 1.5 cm, an Eastern Cooperative Oncology Group status of 0 or 1, and prior ASCT. The median number of prior chemotherapy regimens was

8%

6%

5%

Neutropenia

Peripheral sensory neuropathy

Thrombocytopenia

Anemia

0

Figure 2. Grade 3/4 adverse events of any relationship occurring in ≥5% of patients.

‘These patients had already failed autologous stem cell transplant, and it would therefore be expected to be very difficult to obtain responses in them.’

—Robert Hromas, MD

3.5, 42% of patients were refractory to their most recent treatment, and 66% of patients had prior radiation. The time from ASCT to first post-transplant relapse was 6.7 months.

The drug had manageable side effects and although it caused peripheral neuropathy, this was largely reversible (Figures 1 and 2). The median time to onset of grade 2 peripheral neuropathy was 27.3 weeks and the median time to improvement or resolution was 6.9 weeks. Some improvement or

60 46

40

42

37

36 29 22

22

21

Neutropenia

Vomiting

Cough

20 0

Peripheral sensory neuropathy

Fatigue

1%

14%

80

47

2%

5

100

Patients, %

22

Nausea

Upper respiratory tract infection

Diarrhea

Pyrexia

Figure 1. Treatment-emergent adverse events of any relationship occurring in ≥20% of patients.

resolution of peripheral neuropathy was seen in 68% of patients.

“This agent has very manageable side effects when compared with combination chemotherapy regimens,” Dr. Chen said. “This is because brentuximab vedotin is an antibody drug conjugate and a truly targeted therapy. The antibody component of the drug allows for selective delivery of the chemotherapeutic agent directly into Hodgkin’s lymphoma cells. This results in a high response rate and a low toxicity profile.”

He said two ongoing trials are testing brentuximab vedotin in early-stage Hodgkin’s lymphoma. A Phase I study is testing ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) with brentuximab vedotin in the up-front setting, and a randomized Phase III trial is testing brentuximab vedotin as maintenance immediately post-ASCT to prevent relapse.

—Kate O’Rourke

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