The December 2012 Digital Edition of Clinical Oncology News

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Independent News on Advances in Hematology/Oncology

SOLID TUMORS Cost concerns of ziv-aflibercept continue . . . . . . . . . . . . . . . . . .......... 22 NSCLC: Maintenance gemcitabine and erlotinib . . . . . . . . . . . . . . . . . . ......... 30

HEMATOLOGIC DISEASE p53 as a B-cell lymphoma biomarker ....... 16 Bosutinib for chronic myeloid leukemia . . . ......... 29

CURRENT PRACTICE Maurie Markman, MD: Quality of life in determining care . . . . ............ 7 Clinical Oncology News essay contest runner-up . . . . . . . . . . . . . . . .......... 20 Clinical Conundrums: Focus on NEJM, M JCO and Blood . . . . . . .......... 28

Advances in Stent Technology for Esophageal Cancer . ........... 17

Testing Trastuzumab Duration

Research Misconduct On the Rise

Early data show altering length has little effect; Longer follow-up needed

Outright fraud rare, but selective analyses and reporting ‘highly prevalent’

Vienna—Two studies that tested changing the duration of adjuvant trastuzumab (Herceptin, Genentech) in patients with early breast cancer—shortening it to six months and extending it two years—have failed to overturn the standard of care, one year of treatment.

Researchers say, however, that further data is needed to definitively conclude that six months of trastuzumab is inferior. The two trials were presented at the recent annual meeting of the European Society for Medical Oncology (ESMO).

I

see DURATION, N page 15

Debating NextGeneration Deep Sequencing At ESMO, experts assess the clinical use of genome sequencing Vienna—Should oncologists begin using deep genome sequencing in their clinical practice? Next-generation sequencing (NGS) technologies have come a long way since 1977 when Frederick Sanger developed chaintermination sequencing, but are they ready for prime time? At the annual meeting of the European Society for Medical Oncology, two key opinion leaders battled it out over this topic in a debate. see SEQUENCING, G page 26

n late 2006, researchers at Duke University announced a remarkable discovery. The investigators, led by Anil Potti, MD, and Joseph Nevins, PhD, had figured out how to use microarray data to predict whether or not patients would be likely to respond to common chemotherapy regimens. The research, published in Nature Medicine (2006;12:1294-1300, PMID: 17057710), marked a leap forward in cancer treatment and personalized medicine.

“Part of the hope of some personalized medicine approaches is that we can pick up a pattern that may involve tens or evens hundreds of genes, something whose complexity makes it difficult to see, but that drives outcomes to therapies and allows us to make predictions or treat patients,” said Keith Baggerly, PhD, a biostatistician at the Year of retraction University of Texas MD Anderson Cancer Center in Houston. “This is certainly a tempting story, but it turns out that if you’re going to look at complex genetic signatures, you have to be really careful.”

A lesson Dr. Baggerly understands well. He and his colleague Kevin Coombes, PhD, spent years trying to replicate the Duke researchers’ original findings, but as they delved further, Drs. Baggerly and Coombes uncovered error after error in the data collection and analysis, finding, for instance, that genes labeled in Excel had been mistakenly shifted over by one data cell, and “sensitive” and “resistant” labels were switched, which meant if the data were applied to treatment, patients would get the worst drug for them, not the best.

Drs. Baggerly and Coombes voiced their concerns in several letters that spanned three years and involved subsequent publications by Drs. Potti and Nevins that contained the

Number of articles

INSIDE

see MISCONDUCT, T page 25

EXPERT COMMENTARIES FROM THE US ONCOLOGY NETWORK

The Molecular Portrait of Breast Cancer . . . . . . . . . . . . . . . . . ..... 8

Debra Patt, MD

Brain Metastases in Breast Cancer Tracked ................... 15

Stephen Jones, MD

Source: PLoS One. One 2012;7:e44118.

2012;7:e44118

CLINICALONCOLOGY.COM • December 2012 • Vol. 7, No. 12

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® 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

DOXIL Is Now Available. ®

We Are COMMITTED long-term to ensuring a reliable supply of DOXIL®.

Prescribe With CONFIDENCE.

– 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, 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 • Because of the potential for serious adverse reactions in nursing infants, discontinue nursing during treatment with DOXIL®.

• Recall reaction has occurred with DOXIL® administration after radiotherapy • DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl

Janssen Products, LP Distributed by: Janssen Products, LP, Horsham, Pennsylvania 19044-3607 © Janssen Products, LP 2012 10/12 KO8D121011C

• 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 VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information on the following pages.

K08D121023

The brand you’ve long relied on remains an important therapeutic option for you and your patients.

DOXIL®

DOXIL® (doxorubicin HCl liposome injection)

(doxorubicin HCl liposome injection) for intravenous infusion BRIEF SUMMARY. Please see Full Prescribing Information.

WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION 1. The use of DOXIL (doxorubicin HCl liposome injection) 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. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500-550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see Warnings and Precautions]. 2. 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 resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported.

Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXIL should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings and Precautions].] 3. Severe myelosuppression may occur [see Warnings and Precautions].]

4. Dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information].]

5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis [see Full Prescribing Information].]

INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. Multiple Myeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see Warnings and Precautions].]

WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should be carefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below.

Table 1: Number of Patients With Advanced Breast Cancer Patients who Developed Cardiotoxicity (LVEF Defined) Cardiotoxicity (With Signs & Symptoms of CHF) Cardiotoxicity (no Signs & Symptoms of CHF) Patients With Signs and Symptoms of CHF Only

DOXIL (n=250) 10 0 10 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated.

In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDSrelated Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Full Prescribing Information].]

Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions].] In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information].] For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions].] Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions].]

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described in Dosage and Administration section [see Full Prescribing Information].] Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Full Prescribing Information].] The reaction can be severe and debilitating in some patients and may require discontinuation of treatment.

Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy.

Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman.

There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Full Prescribing Information].]

Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies.

Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [see Warnings and Precautions].]

ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [see Warnings and Precautions] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma.

Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma.

Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.

Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Patients Topotecan Patients (n = 239) (n = 235) Neutropenia 3 19 (7.9%) 33 (14.0%) 500 - <1000/mm <500/mm3 10 (4.2%) 146 (62.1%) Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) <6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 10,000 - <50,000/mm3 3 (1.3%) 40 (17.0%) <10,000/mm3 0 (0.0%) 40 (17.0%) Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.

Table 3: Ovarian Cancer Randomized Studyy Non-Hematologic Adverse Reaction 10% or Greater

Body as a Whole Asthenia Fever Mucous Membrane Disorder Back Pain Infection Headache

DOXIL (%) treated (n = 239) All Grades grades 3-4

Topotecan (%) treated (n =235) All Grades grades 3-4

40.2 21.3 14.2

7.1 0.8 3.8

51.5 30.6 3.4

8.1 5.5 0

11.7 11.7 10.5

1.7 2.1 0.8

10.2 6.4 14.9

0.9 0.9 0

Digestive Nausea Stomatitis Vomiting Diarrhea Anorexia Dyspepsia

46.0 41.4 32.6 20.9 20.1 12.1

5.4 8.3 7.9 2.5 2.5 0.8

63.0 15.3 43.8 34.9 21.7 14.0

8.1 0.4 9.8 4.2 1.3 0

Nervous Dizziness

4.2

0

10.2

0

Respiratory Pharyngitis Dyspnea Cough increased

15.9 15.1 9.6

0 4.1 0

17.9 23.4 11.5

0.4 4.3 0

Skin and Appendages Hand-foot syndrome Rash Alopecia

50.6 28.5 19.2

23.8 4.2 N/A

0.9 12.3 52.3

0 0.4 N/A

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.

DOXIL® (doxorubicin HCl liposome injection) 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 4 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma.

Table 4: 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 Reaction DOXIL + bortezomib Bortezomib (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 Infections and infestations Herpes zoster 11 2 0 9 2 0 Herpes simplex 10 0 0 6 1 0 Investigations Weight decreased 12 0 0 4 0 0 Metabolism and Nutritional disorders Anorexia 19 2 0 14 <1 0 Nervous system disorders Peripheral Neuropathy* 42 7 <1 45 10 1 Neuralgia 17 3 0 20 4 1 Paresthesia/dysesthesia 13 <1 0 10 0 0 Respiratory, thoracic and mediastinal disorders Cough 18 0 0 12 0 0 Skin and subcutaneous tissue disorders Rash** 22 1 0 18 1 0 Hand-foot syndrome 19 6 0 <1 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, Stevens-Johnson 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: Pregnancy: Pregnancy Category D [see Warnings and Precautions].: DOXIL is embryotoxic at doses of 1 mg/kg/day in rats and is embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about one-eighth the 50 mg/m2 human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DOXIL, discontinue nursing during treatment with DOXIL. Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

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.

Hepatic Impairment: The pharmacokinetics of DOXIL has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Thus, DOXIL dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information].]

Prior to DOXIL administration, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as SGOT, SGPT, alkaline phosphatase, and bilirubin [see Full Prescribing Information].]

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.

Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Manufactured for: Janssen Products, LP Horsham, PA 19044 © Janssen Products, LP 2010 Revised September 2012 TM

An ALZA STEALTH® Technology Product

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

K08D121020

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

CURRENT PRACTICE

Letters to the Editor Readers respond to October CTCA case report To the Editor:

I

read through the October issue of Clinical Oncology News and found several very interesting articles. I was, however, concerned about the case report on page 8 that is to be a regular feature from the Cancer Treatment Centers of America (“Case Reports: Hematuria With Lymph Node Activity and Pulmonary Nodules”). I was confused as to whether this was meant to be an educational article or an advertisement for this network of cancer hospitals.

The case report is an unusual one and I question what the educational point is. The author indicates that although the “local doctors did a CT [computed tomographic] scan,” they began by doing “a medical history from the beginning and doing a fresh workup.” At that point in the evaluation was there a true indication for a PET [positron emission tomography]/CT? The patient received “naturopathic recommendations” to help manage the side effects but there is no discussion of the scientific background to make this an appropriate treatment. Where is the discussion and data regarding the beneficial use of coenzyme Q10? It is presented de facto as if this is a helpful addition to the patient’s care plan.

We can all agree that a team approach is essential in the care of patients with cancer, but complementary approaches still require scientific overview and justification especially if being espoused as important components of treatment.

Patients with advanced cancer have many complex issues and can benefit from second opinions, but we do need to be cognizant of the cost of care. Tests should not be repeated unless there is a specific indication and patients should be offered “realistic” but not “false” hope. With our intent to extend the lives of our patients and convert their illness to a chronic illness, lives should be normalized by developing a care plan in conjunction with their local oncologist to allow for as much care as close to home as possible.

We are all happy for the patient’s good outcome. I commend the physicians for being diligent in making a diagnosis in the face of data that did not completely add up, and perhaps this is the take-home point.

I would ask, however, “What is the intent of such a column?” If it is to be

educational, I would then ask the authors to include references and evidence-based data. I would also suggest that such a column not be that of one-upmanship.

Sincerely Yours, Philip L. Brooks, MD Medical Oncologist CancerCare of Maine

Editor’s Note: Dr. Brooks’ letter was not the only response that Clinical Oncology News received regarding the Case Reports column in the October issue; however, I am grateful that he was willing to have it published in the magazine.

This particular column was the result of conversations with Maurie Markman, MD, senior vice president of clinical affairs and national director of medical oncology for Cancer Treatment Centers of America (CTCA) and myself during spring and summer 2012. As managing editor of Clinical Oncology News, one of my most important priorities throughout the development of the column was making sure that it did not endorse or advertise CTCA management of this individual patient nor CTCA’s model for clinical care more broadly. Because every cancer patient is unique, my goal was to provide readers with a perspective on individual patient management outside of our more traditional coverage of clinical trials from major meetings, which naturally focus on more homogeneous treatment groups rather than the unique complexity that individual patients present.

It has always been my hope to feature multiple centers in our Case Reports series and I encourage readers who would like to contribute case reports featuring their center to contact me directly at gmiller@mcmahonmed.com. The focus of this series is on complex or unique patients, innovative treatments, and the interaction between oncologists and other members of the clinical care team.

Dr. Brooks’ point that treatments advanced in case reports should be referenced and more scientifically rigorous is one that is well taken and will be immediately implemented in future columns in this series.

Sincerely, Gabriel Miller Managing Editor Clinical Oncology News gmiller@mcmahonmed.com

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6

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Prostate Cancer Michael A. Carducci, MD AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Hematologic Malignancies

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Maura N. Dickler, MD

Harry Erba, MD, PhD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

University of Alabama Birmingham, AL

Gastrointestinal Cancer Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma

Sara S. Kim, PharmD

University of California, San Diego, CA

The Mount Sinai Medical Center New York, NY

Infection Control

Bioethics

Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY

Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

Oncology Nursing Betty Ferrell, RN, PhD City of Hope National Medical Center Duarte, CA

Michele Neskey, MMSc, PA-C University of Texas, MD Anderson Cancer Center Houston, TX

Shaji Kumar, MD Mayo Clinic Rochester, MN

Paul J. Ford, PhD Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Pharmacy Cindy O’Bryant, PharmD Richard Stone, MD

University of Colorado Cancer Center Denver, CO

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

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

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

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

Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Charles F. von Gunten, MD

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

Mission Statement

T

he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

Genitourinary y Cancer Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Steven Vogl, MD Medical Oncologist New York, NY

Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Lung, g, and Head and Neck Cancers Edward S. Kim, MD University of Texas, MD Anderson Cancer Center Houston, TX

Lung g Cancer,, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

Editorial Philosophy The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published.

Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

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

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

The Relevance of Quality-of-Life Studies in Cancer I

n recent years, the oncology clinical research community has focused increasingly on examining the effects of antineoplastic therapy on patients’ quality of life. It is reasonable to suggest that these are most relevant in settings where treatment is designed to extend survival and improve or prevent cancer-related symptoms, but not cure the disease.

Quality-of-life research may be particularly useful for examining the relative benefits of two competing management strategies in a unique clinical setting. In the absence of overwhelming evidence supporting one approach over another (e.g., improved overall survival), understanding the effect of each strategy on patients’ quality of life may help clinicians and patients decide which approach is optimal.

For example, consider the clinical utility of combination versus sequential drug delivery in the palliative management of patients with potentially platinum-sensitive, recurrent epithelial ovarian cancer. Several Phase III randomized trials have confirmed the superiority (either progression-free survival alone or both progression-free and overall survival) of combining a second agent with a platinum drug compared with the administration of a platinum drug alone.1,2

Comments or feedback on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor Gabriel Miller at

gmiller@mcmahonmed.com

®

McMahon Publishing is a 40-year-old, family-owned medical publishing and medical education company.

McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp.

Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2012 McMahon Publishing, New York, NY. All rights reserved.

POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

Unfortunately, depending on the choice of the second agent, there is a potential for considerable additional toxicity—neuropathy or bone marrow suppression, for example—with this approach.

So, the question to be tested: What is the relative effect on a patient’s quality of life resulting from a combination chemotherapy regimen versus planned sequential delivery of the same drugs in the setting of recurrent platinum-sensitive ovarian cancer? The result might be included in clinical practice guidelines, and perhaps most importantly, employed routinely in discussions with patients considering these specific treatment options.

An interesting, but unfortunately somewhat controversial, examination of this highly clinically relevant question was provided by a randomized Phase II trial comparing the combination of carboplatin and docetaxel with a sequential regimen of docetaxel followed by carboplatin in recurrent platinum-sensitive ovarian cancer.3 As anticipated based on the results of previous studies, the investigators found a statistically significant longer time to disease progression with the combination regimen compared with the sequential strategy. (Unfortunately, a serious flaw in this study’s design made interpretation of the primary study end point problematic: The investigators elected to administer docetaxel prior to carboplatin in the sequential regimen when existing data strongly indicate that the platinum agents are the single most active drugs. Therefore, comparing the response rate and time to initial disease progression in the combination regimen with single-agent docetaxel may exaggerate artificially the initial benefits of

the two-drug strategy.)

Despite the improvement in time to disease progression observed in the combination arm, overall survival did not differ between treatments.

However, using the Functional Assessment of Cancer Therapy-Ovarian instrument, the study demonstrated an impressive and statistically significant ((P=0.033) superior quality-of-life outcome with the sequential drug delivery strategy.4 Using well-validated quality-of-life survey instruments focuses our attention on the “real-world” impact of our treatments on the lives of individuals undergoing cancer therapy. Further, they can add powerful meaning to the impact of specific side effects experienced by patients (e.g., anemia, neutropenia, stomatitis and peripheral neuropathy) rather than the simple “numerical score” reflected in a toxicity grade.

For example, what is the real effect on a cancer patient’s life from the development of “grade 3 neutropenia” or “grade 2 mucositis,” or the combination of these two side effects?

It may be argued that quality-of-life scores represent a subjective interpretation of the impact of side effects on patients, but we should ask: Is there actually any other perspective that is more important than that of the patient?

It is critical to acknowledge that there is nothing in this discussion that suggests that “combination” antineoplastic drug therapy is either inherently inferior or superior to sequential drug delivery in its influence on the quality of life of cancer patients receiving these treatments, only that this is a highly clinically relevant question that should be directly addressed in both

EDITORIAL STAFF

SALES STAFF

Kevin Horty, Group Publication Editor khorty@mcmahonmed.com

Julianna Dawson, Publication Director jdawson@mcmahonmed.com

Gabriel Miller, Managing Editor gmiller@mcmahonmed.com

Marlena McMahon, Associate Publication Director marlena@mcmahonmed.com

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

ART AND PRODUCTION STAFF

James Prudden, Group Editorial Director

Michele McMahon Velle, Creative Director, MAX Graphics

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

well-designed trials and discussions with patients who are considering their therapeutic options in the noninvestigative setting.

References 1. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: The ICON4/AGOOVAR-2.2 trial. Lancet. 2003;361:2099-2106, PMID: 12826431.

2. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: An intergroup trial of the AGO-OVAR, the NCIG CTG, and the EORTC GCG. J Clin Oncol.

2006;24:4699-4707, PMID: 16966687.

3. Second AA, Berchuck A, Higgins RV, et al.

A multicentre, randomized, phase II study evaluating the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer. Cancer.

2012;118:3283-3293, PMID: 22072307.

4. Pokrzywinski R, Alvarez Secord A, Havrilesky LJ, et al. Health-related quality of life outcomes of docetaxel/carboplatin combination therapy vs. sequential therapy with docetaxel then carboplatin in patients with relapsed, platinum-sensitive ovarian cancer: Results from a randomized clinical trial. Gynecol Oncol. 2011;123:505-510, PMID: 21945310.

Brandy Wilson, Circulation Coordinator Mark Neufeld, Associate Director, Project Management

MCMAHON PUBLISHING Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner

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Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

Textt and T d iimage providede id d b

by The Th US Oncology O l Network N t k

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About The US Oncology Network

T

he US Oncology Network is one of the nation’s largest networks of community-based oncology physicians dedicated to advancing cancer care in America.

Approximately 1,000 like-minded physicians are united through The Network around a common vision of expanding patient access to high-quality, integrated cancer care in communities throughout the nation. Leveraging health care information technology, shared best practices, refined evidence-based medicine guidelines, and quality measurements, physicians affiliated with The US Oncology Network are committed to advancing the

quality, safety and science of cancer care to improve patient outcomes.

The US Oncology Network is supported by McKesson Specialty Health, a division of McKesson Corporation focused on empowering a vibrant and sustainable community patient care delivery system to advance the science, technology and quality of care.

Many physicians affiliated with The US Oncology Network also affiliate with US Oncology Research, which draws from a network of experienced investigators and dedicated clinical staff who specialize in Phase I through Phase IV oncology clinical trials.

Physicians affiliated with US Oncology Research have enrolled more than 53,000 patients in over 1,200 trials since inception in 1992 and have contributed to the development of 43 cancer therapies approved by the FDA.

Comprehensive Molecular Portrait of Breast Cancer Presented From Nature

A

n integrated molecular analysis of breast carcinomas has revealed that diverse genetic and epigenetic alterations converge phenotypically into four main breast cancer classes—luminal A, luminal B, basal-like and HER2enriched. The findings were announced by an international collective of researchers, The Cancer Genome Atlas (TCGA) Research Network, in an article published in the Oct. 4 issue of the journal Nature (2012;490:61-70, PMID: 23000897). The authors believe their work provides a “comprehensive catalogue of likely genomic drivers of the most common breast cancer subtypes.”

In the past, molecular studies of breast cancer have focused on mRNA expression profiling, DNA copy number analysis, and massively parallel sequencing. Although these studies have yielded important results, researchers from the TCGA Research Network believe newer assays that assess DNA methylation, microRNA (miRNA) expression and protein expression now allow for a more complete characterization of the molecular architecture of breast cancer.

To test this hypothesis, the team analyzed primary breast cancers in more than 800 patients from multiple centers using genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing

EXPERT INSIGHT Debra Patt, MD, MPH Medical Oncologist and Hematologist Texas Oncology Medical Director, Pathways Task Force Medical Director, Healthcare Informatics The US Oncology Network

T

he recent article from the TCGA Research Network characterizing comprehensive molecular portraits of breast cancer describes common features of the four classified subtypes of breast cancer by analyzing and comparing their molecular characteristics using six platforms for molecular analysis in hopes of providing a map for breast cancer.

The TCGA Research Network evaluated cancers from 825 patients across some of five different molecular analysis platforms: genomic DNA copy

number arrays, methylation, complete exome sequencing, mRNA arrays and microRNA sequencing (plus some on reverse-phase protein arrays), and then compared the results of each analysis with the others to aggregate commonalities and gain understanding about the behavior of various types of breast cancer. This analysis demonstrated that somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at a greater than 10% incidence across all breast cancers. Molecular commonalities within the different subtypes suggest

and reverse-phase protein arrays, with all patients assayed on at least one platform. In all, 466 samples (463 patients) were assayed on five of six platforms (excluding reverse-phase protein arrays) and 348 patients were assayed on six of six platforms.

The researchers identified many subtype-specific mutations and copy number changes that identify “therapeutically tractable genomic aberrations” potentially driving breast tumor biology.

In addition to identifying nearly all genes previously implicated in breast cancer, the researchers also isolated several new significantly mutated genes—TBX3, RUNX1, CBFB, AFF2, PIK3R1, PTPN22, PTPRD, NF1, SF3B1 and CCND3. However, only three genes—TP53, PIK3CA and

GATA3—had a greater than 10% incidence of somatic mutations across all breast cancers, they noted.

The team identified two novel protein expression–defined subgroups, which they believe may be produced by “stromal/microenvironmental elements.” Their work also identified “specific signaling pathways” dominant in each molecular subtype— including a “HER2/phosphorylated HER2/EGFR [epidermal growth factor receptor]/phosphorylated EGFR signature” within the HER2-enriched expression subtype. Finally, comparison of basal-like breast tumors with high-grade serous ovarian tumors showed “many molecular commonalities,” indicating a related etiology.

that tumor heterogeneity occurs within these four very different subtypes of breast cancer, and that variance occurs differently between each subtype. Basallike cancers share many molecular signatures with high-grade serous ovarian tumors, raising the suggestion of common therapeutic opportunities.

Although this study is sophisticated and unique in its incorporation of the various platforms of analysis and its ability to compare them, we are left with many questions. What insight does this study give us in understanding the etiology of each of these tumors? As many of these signal transduction or regulatory mediators are but one actor in a larger pathway, and thus alterations in expression can be complex and highly correlated, which alterations exactly are the important drivers of tumor growth, mutation and metastasis? Are there commonalities that will allow us to plan appropriate clinical trial

evaluation to test druggable targets in a way that we will evaluate the drug in an appropriate population so as not to miss an effect due to poor selection across this complex disease? Will we be able to use this information to gain insight into prognosis, or choose or predict response to therapeutic intervention? How will this information be used as tools to take care of patients?

The TCGA Research Network has provided a vast amount of scientific insight into the atlas of breast cancer and provides greater insight than any of the maps before it. It is a remarkable feat of scientific discovery, and it sheds light on the new worlds of neoplasia that are as of yet uncharted. It is an exciting time to be an explorer.

Dr. Patt reported no financial disclosures relevant to this study. Dr. Patt is chair of the Texas Medical Association’s Cancer Committee.

Consider starting your new patients on ZOMETA today, as they may be able to continue on generic zoledronic acid after the ZOMETA patent expires in March 2013

Indication ZOMETA® (zoledronic acid) 4 mg/5 mL Injection is indicated for the treatment of hypercalcemia of malignancy (HCM) and patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Safe and efficacious use of ZOMETA has not been established for use in hyperparathyroidism or non-tumor-related hypercalcemia.

Highlights from the Important Safety Information • There have been reports of renal toxicity with ZOMETA. Renal toxicity may be greater in patients with renal impairment. Treatment in patients with severe renal impairment is not recommended. Do not use doses greater than 4 mg and monitor serum creatinine before each dose • Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient • Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including ZOMETA. Patients may experience hip, thigh, or groin pain before presenting with a completed femoral fracture. Causality with bisphosphonates has not been established Please see additional Important Safety Information and brief summary of full Prescribing Information on adjacent pages.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2012 Novartis

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ZOM-1052241

Indication • ZOMETA (zoledronic acid) 4 mg/5 mL Injection is indicated for the treatment of hypercalcemia of malignancy (HCM) and patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Safe and effi ficacious use of ZOMETA has not been established for use in hyperparathyroidism or non-tumorrelated hypercalcemia. ®

Important Safety Information • ZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported. Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient.

• Patients with HCM must be adequately rehydrated prior to use of ZOMETA and loop diuretics (if applicable). Loop diuretics should be used with caution in combination with ZOMETA to avoid hypocalcemia. ZOMETA should be used with caution with other nephrotoxic drugs. Carefully monitor serum calcium, phosphate, magnesium, and serum creatinine following initiation of ZOMETA. Short-term supplemental therapy may be necessary.

• In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. Consider individual patient risk/benefit fi profi file before starting ZOMETA therapy in HCM patients with severe renal impairment. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment.

Preexisting renal insufficiency fi and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose.

• Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fi fitting dentures). Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible, as recovery may be prolonged. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefi fit/risk assessment.

• ZOMETA should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant or plans to breastfeed while taking this drug, the patient should be apprised of the potential harm to the fetus or baby.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

• In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including ZOMETA. Discontinue use if severe symptoms develop, as a subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. There have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates.

• Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including ZOMETA. These fractures may occur with minimal or no trauma. A number of case reports noted that patients were also receiving treatment with glucocorticoids at time of fracture.

Causality with bisphosphonates has not been established. Any patient with a history of bisphosphonate exposure who presents with hip, thigh, or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated.

Drug discontinuation in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit/risk fi assessment.

• Insufficient fi data exist on how to safely use ZOMETA in HCM patients with hepatic impairment.

• Acute-phase reaction symptoms can occur in HCM patients, with fever most commonly reported (44% with ZOMETA vs. 33% with pamidronate). Patients may occasionally experience fl flu-like syndrome (fever, chills, flushing, bone pain and/or arthralgias and myalgias). The most common adverse events (≥10%) in HCM clinical trials, regardless of causality, with ZOMETA 4 mg (n=86) were as follows: fever (44%), nausea (29%), constipation (27%), anemia (22%), dyspnea (22%), diarrhea (17%), abdominal pain (16%), progression of cancer (16%), insomnia (15%), vomiting (14%), anxiety (14%), urinary tract infection (14%), hypophosphatemia (13%), confusion (13%), agitation (13%), moniliasis (12%), hypokalemia (12%), coughing (12%), skeletal pain (12%), hypotension (11%), and hypomagnesemia (11%). In controlled HCM clinical trials, adverse events (5-10% frequency) occurring in greater incidence with ZOMETA than pamidronate include: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, non-specific fi infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Injection site reactions (redness, swelling) have been infrequently reported.

• The most common adverse events (≥15%) in bone metastases clinical trials, regardless of causality, with ZOMETA 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lower-limb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%), and paresthesia (15%). Patients should also be made aware of the potential for abdominal pain.

• Ocular adverse events may occur with bisphosphonates, including ZOMETA. Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation fl including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

• Caution is advised when bisphosphonates, including ZOMETA, are administered with aminoglycosides, loop diuretics, and potentially nephrotoxic drugs.

• Patients with multiple myeloma and bone metastases due to solid tumors should be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.

Please see brief summary of full Prescribing Information on adjacent pages.

© 2012 Novartis

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ZOM-1052241

Zometa® (zoledronic acid) Injection Ready-to-Use Solution for Intravenous Infusion (For Single Use) Concentrate for Intravenous Infusion Initial U.S. Approval: 2001 BRIEF SUMMARY: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin (g/dL)).

1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established.

4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2))].

5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient or in the Same Drug Class Zometa contains the same active ingredient as found in Reclast® (zoledronic acid).

Patients being treated with Zometa should not be treated with Reclast or other bisphosphonates.

5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs.

Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary.

5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1))]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa.

Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible.

Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine greater than 400 μmol/L or greater than 4.5 mg/dL were excluded.

Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine greater than 265 μmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information].

5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis.

Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment

reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2))].

5.5 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2))].

5.6 Atypical subtrochanteric and diaphyseal femoral fractures Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Zometa. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma.

Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of Zometa therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.

5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates.

5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients.

5.9 Use in Pregnancy Bisphosphonates, such as Zometa, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy.

Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1))].

6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypercalcemia yp of Malignancy g y The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.

Renal Toxicityy Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information].

The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 4).

Table 4 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials.

Adverse events are listed regardless of presumed causality to study drug.

Table 4: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

Patients Studied Total No. of Patients Studied Total No. of Patients with any AE Body as a Whole Fever Progression of Cancer Cardiovascular Hypotension Digestive Nausea Constipation Diarrhea Abdominal Pain Vomiting Anorexia Hemic and Lymphatic System Anemia Infections Moniliasis Laboratory Abnormalities Hypophosphatemia Hypokalemia Hypomagnesemia Musculoskeletal Skeletal Pain Nervous Insomnia Anxiety Confusion Agitation Respiratory Dyspnea Coughing Urogenital Urinary Tract Infection

Grade 4 Laboratory Parameter

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

86 (100) 81 (94)

103 (100) 95 (92)

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

0/86 0/86 1/70 0/71

— — (1%) —

1/100 0/100 4/81 1/84

(1%) — (5%) (1%)

1Grade

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

38 14

(44) (16)

34 21

(33) (20)

9

(11)

2

(2)

25 23 15 14 12 8

(29) (27) (17) (16) (14) (9)

28 13 17 13 17 14

(27) (13) (17) (13) (17) (14)

19

(22)

18

(18)

10

(12)

4

(4)

11 10 9

(13) (12) (11)

2 16 5

(2) (16) (5)

10

(12)

10

(10)

13 12 11 11

(15) (14) (13) (13)

10 8 13 8

(10) (8) (13) (8)

19 10

(22) (12)

20 12

(19) (12)

Table 7: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System

12

(14)

15

(15)

Zometa 4 mg n (%)

The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence.

Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa.

Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias.

Mineral and Electrolyte y Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use.

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 5 and 6.

Table 5: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Table 6: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

2/86 1/86 36/70 0/71

(2%) (1%) (51%) —

3/100 2/100 27/81 0/84

(3%) (2%) (33%) —

Injection j Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.

Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2))].

Multiple p Myeloma y and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors.

Table 7 describes adverse events that were reported by 10% or more of patients.

Adverse events are listed regardless of presumed causality to study drug.

Patients Studied Total No. of Patients 1031 (100) Total No. of Patients with any AE 1015 (98) Blood and Lymphatic Anemia 344 (33) Neutropenia 124 (12) Thrombocytopenia 102 (10) Gastrointestinal Nausea 476 (46) Vomiting 333 (32) Constipation 320 (31) Diarrhea 249 (24) Abdominal Pain 143 (14) Dyspepsia 105 (10) Stomatitis 86 (8) Sore Throat 82 (8) General Disorders and Administration Site Fatigue 398 (39) Pyrexia 328 (32) Weakness 252 (24) Edema Lower Limb 215 (21) Rigors 112 (11) Infections Urinary Tract Infection 124 (12) Upper Respiratory Tract Infection 101 (10) Metabolism Anorexia 231 (22) Weight Decreased 164 (16) Dehydration 145 (14) Appetite Decreased 130 (13)

Pamidronate 90 mg n (%)

Placebo

556 (100) 548 (99)

455 (100) 445 (98)

175 83 53

(32) (15) (10)

128 35 20

(28) (8) (4)

266 183 162 162 81 74 65 61

(48) (33) (29) (29) (15) (13) (12) (11)

171 122 174 83 48 31 14 17

(38) (27) (38) (18) (11) (7) (3) (4)

240 172 108 126 62

(43) (31) (19) (23) (11)

130 89 114 84 28

(29) (20) (25) (19) (6)

50 82

(9) (15)

41 30

(9) (7)

81 50 60 48

(15) (9) (11) (9)

n (%)

105 (23) 61 (13) 59 (13) 45 (10) (continued)

Table 7: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%) Musculoskeletal Bone Pain Myalgia Arthralgia Back Pain Pain in Limb Neoplasms Malignant Neoplasm Aggravated Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia Psychiatric Depression Anxiety Confusion Respiratory Dyspnea Cough Skin Alopecia Dermatitis

Pamidronate 90 mg n (%)

Placebo n (%)

569 239 216 156 143

(55) (23) (21) (15) (14)

316 143 131 106 84

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

284 74 73 40 52

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

205

(20)

97

(17)

89

(20)

191 180 166 149 127

(19) (18) (16) (15) (12)

149 91 111 85 65

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

50 58 73 35 43

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

146 112 74

(14) (11) (7)

95 73 39

(17) (13) (7)

49 37 47

(11) (8) (10)

282 224

(27) (22)

155 129

(28) (23)

107 65

(24) (14)

125 114

(12) (11)

80 74

(14) (13)

36 38

(8) (8)

Table 8: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Zometa 4 mg n/N

(%)

7/529 (1%) 6/973 (<1%) 115/973 (12%) 19/971 (2%) 1/971 (<1%)

Pamidronate 90 mg n/N

(%)

4/268 (2%) 4/536 (<1%) 38/537 (7%) 2/535 (<1%) 0/535 —

Placebo n/N

(%)

4/241 (2%) 0/415 — 14/415 (3%) 8/415 (2%) 1/415 (<1%)

1Grade

3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) 5Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L) Table 9: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 4 Laboratory Parameter

Creatinine1*

Serum Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5 1Grade

Renal Toxicityy In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (less than 1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (greater than or equal to 1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 10).

Table 10: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer Normal Abnormal Total

Zometa 4 mg

Pamidronate 90 mg

Normal Abnormal Total Prostate Cancer Normal Abnormal Total

Grade 3

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear.

Solid Tumors

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 8 and 9.

Laboratory Parameter

Among the less frequently occurring adverse events (less than 15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group.

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

2/529 7/973 5/973 0/971 2/971

(<1%) (<1%) (<1%) — (<1%)

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

(<1%) (<1%) — — (<1%)

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

— (<1%) (<1%) (<1%) —

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

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

27/246 2/26 29/272

(11%) (8%) (11%)

23/246 2/22 25/268

(9%) (9%) (9%)

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

17/154 1/11 18/165

(11%) (9%) (11%)

10/143 1/20 11/163

(7%) (5%) (7%)

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

12/82 4/10 16/92

(15%) (40%) (17%)

8/68 2/10 10/78

(12%) (20%) (13%)

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes.

The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate.

In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose.

6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa.

Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5))].

Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5))].

Atypical yp subtrochanteric and diaphyseal p y femoral fractures Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including Zometa [see Warnings and Precautions (5.6))].

Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Hypersensitivity yp y Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported.

Additional adverse reactions reported in postmarketing use include: CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: Increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia.

7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug.

7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials.

7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia.

7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs.

7.4 Thalidomide No dose adjustment for Zometa 4 mg is needed when co-administered with thalidomide.

In a pharmacokinetic study of 24 patients with multiple myeloma, Zometa 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of thalidomide with Zometa did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precaution (5.9)] There are no adequate and well-controlled studies of Zometa in pregnant women.

Zometa may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as Zometa, are incorporated into the bone matrix and are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. If this drug is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus.

In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect.

In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study.

In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were

observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.

8.3 Nursing Mothers It is not known whether zoledronic acid is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zometa, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Zoledronic acid binds to bone long term and may be released over weeks to years.

8.4 Pediatric Use Zometa is not indicated for use in children.

The safety and effectiveness of zoledronic acid was studied in a one-year activecontrolled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7).

At one year, increases in BMD were observed in the zoledronic acid treatment group.

However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk.

Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC((0-last)) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose.

8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.

10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose.

A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known.

In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information].

16 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Manufactured by Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2012-66 March 2012

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

Incidences of Brain Metastases in Breast Cancer Tracked by subtype.

The Boston-based authors of this study, first published online in Breast Cancer Research and Treatment (2012;136:153-160, PMID: 22968656), sought to better define the risks for BM following BCT and adjuvant systemic therapy in patients with earlystage breast cancer. The researchers, led by Nils D. Arvold, MD, of the DanaFarber Cancer Institute in Boston, believed earlier detection of BM might increase patient eligibility for noninvasive treatments such as stereotactic radiosurgery.

The authors assessed 1,434 consecutive patients with invasive breast cancer (stage I or II) who received BCT (i.e., lumpectomy and 45 to 50 Gy of external-beam radiation therapy to the whole

From Breast Cancer Research and Treatment

I

n patients with early-stage breast cancer, the use of adjuvant systemic therapy with chemotherapy, hormone therapy, targeted agents, radiation therapy or any combination thereof has increased significantly since the early 1990s, and has had a marked effect on outcomes. However, over the same period, several studies have identified a concomitant increase in central nervous system metastases within this patient population, perhaps due to poor penetration of these therapies across the blood–brain barrier. The present study confirms that the risk for brain metastases (BM) following breast-conserving therapy (BCT) varies significantly

EXPERT INSIGHT Stephen E. Jones, MD Medical Director of US Oncology Research McKesson Specialty Health The Woodlands, Texas

B

rain metastases (BM) in breast cancer remains a troublesome problem for many patients. We have learned over the years that certain groups of patients are more likely to suffer this complication of their cancer: those with known metastatic disease, HER2positive breast cancer and triple-negative breast cancer. In some instances, patients develop BM as their sole site of metastatic disease. Treatment of

DURATION continued from page 1

The trials are important, said Martine Piccart-Gebhart, MD, PhD, the director of medicine at the Jules Bordet Institute in Brussels, Belgium, because the optimal duration of trastuzumab is unknown. The one-year duration currently used by clinicians was chosen “in a total arbitrary fashion,” Dr. Piccart-Gebhart said.

The PHARE (Protocol for Herceptin as Adjuvant therapy with Reduced Exposure; abstract LBA5) trial was launched to compare six versus 12 months of adjuvant trastuzumab in early breast cancer. It was inspired by a study that showed that nine weeks of trastuzumab provided a similar magnitude of benefit as a oneyear course of therapy (N ( Engl J Med

BM has improved somewhat, but most patients still die of this complication.

Arvold et al have provided a new data set with some interesting, previously unknown facts about BM. Their group at Dana-Farber helped to pioneer the use of BCT with radiation therapy, and it is that population with long-term follow-up that provided this new information. Most of the 1,434 patients treated with BCT between 1997 and 2006

2006;354:809-820, PMID: 1649539).

The PHARE investigators enrolled 3,380 patients with HER2-positive early breast cancer who had received at least four cycles of neoadjuvant chemotherapy and were receiving adjuvant trastuzumab. The researchers then randomized the patients in a 1:1 fashion to either stop trastuzumab at six months or complete 12 months of treatment.

At 42.5 months of follow-up, diseasefree survival, which was the primary end point, was 87.8% in the 12-month group compared with 84.9% in the six-month group, a statistically insignificant difference (hazard ratio, 1.28; P=0.29). Overall survival data was not mature.

As expected, fewer cardiac events were reported in the six-month arm (1.9%) than in the 12-month arm (5.7%; P<0.0001).

“Because the confidence interval crosses the boundary of noninferiority,

breast; most of the patients also underwent surgical lymph node evaluation).

Among these patients, 91% received adjuvant systemic therapy (87% of the node-positive patients and 32% of the node-negative patients); additionally, 90% of the hormone receptor–positive patients received hormone therapy.

Within the study population, overall five-year cumulative incidence of BM was 1.7% (median number at diagnosis was 2); however, this number was 7.4% for patients with triple-negative breast cancer. Those with triple-negative disease also had the highest median tumor size: 27 mm. Younger patients and those with node-positive, hormone receptor–negative, and HER2-positive breast cancer were at increased risk for developing BM, the authors found.

Additionally, 34% of the patients in the study population who developed distant metastases ultimately also developed BM (median time from distant to BM was 12.8 months, although this varied by subtype). Finally, 81% of the patients who developed BM presented with neurologic symptoms, the most common being headache, cranial neuropathy, mental status change, ataxia, dizziness and vision changes.

The authors postulated that women developing distant metastases who have the subtypes with higher incidences of BM represent “an ideal population” in which to evaluate magnetic resonance imaging (MRI) screening, in the hope that earlier detection might increase eligibility for stereotactic radiosurgery.

also received systemic adjuvant therapy—either hormone therapy, chemotherapy or both—as is standard practice.

Although it is not common practice to routinely test breast cancer for genomic subtypes, they have inferred subtype status from the commonly used biomarkers of estrogen and progesterone receptors and HER2 status. These inferred genomic subtypes were used to provide information about the overall cumulative incidence of BM by subtype in a large, well-characterized population of patients treated by BCT. Whether this would be different in a mastectomytreated group is unclear.

Presumed luminal A breast cancer has a very low incidence of BM, despite its long natural history and propensity for ongoing late relapse. HER2 and triple-negative types have higher rates of

BM, which occurs earlier in these subtypes. Luminal B subtype had higher rates than luminal A. We have known for some time that patients with metastatic BC have a much greater risk for BM, with roughly one-third of these patients developing BM and one-fourth having leptomeningeal disease as well. Patients present with neurologic symptoms most of the time, and the size and number of BM varies by subtype as well.

BM remain a real therapeutic challenge, with a median overall survival in this series of seven months. The authors suggest the use of MRI screening in some groups to aid earlier detection. However, this series confirms that better treatment is still required.

six months was not proven to be noninferior to 12 months,” said Xavier Pivot, MD, an oncologist from the University Hospital of Besancon in Besancon, France, who presented the study. “The hazard ratio of 1.28 suggests a tendency favoring the 12-month duration.

Twelve months, at this time, should remain the standard treatment in this population.”

Dr. Pivot said further follow-up would be forthcoming and a more definitive answer would be available after other trials testing shorter durations of trastuzumab report their findings. The PERSEPHONE trial, testing six months of trastuzumab, as well two trials testing nine weeks of trastuzumab—ShortHER and SOLD (Synergism Or Long Duration)—are expected to report in the next few years. see DURATION, N page 16

Dr. Jones reported no financial disclosures relevant to this study.

AT A GLANCE Trastuzumab Duration Shortening trastuzumab duration to six months or lengthening it to two years had no effect on disease-free survival Overall survival data in the sixmonth trial is not mature One-year duration should remain standard Several ongoing trials are testing shorter durations with the goal of improving cardiotoxicity

15

16

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

p53 Is Biomarker in Patients With DLBCL on R-CHOP From Blood

M

utations of the p53 protein are a “valuable prognostic biomarker” in patients with diffuse large B-cell lymphoma (DLBCL) who have been treated with the chemotherapeutic regimen known as R-CHOP, and treatment approaches targeting the p53 pathway may enhance clinical outcomes in these patients, a new study has confirmed.

The study, published online by the journal Blood (2012 Sep 5. [Epub ahead of print], PMID: 22955915), looked at 506 de novo DLBCL patients diagnosed according to the World

Health Organization criteria who were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy in 29 participating medical centers.

Patients with primary mediastinal large B-cell lymphoma, cutaneous or central nervous system diffuse large B-cell lymphoma, HIV infection or a history of low-grade B-cell lymphoma with transformation to DLBCL were excluded from the study.

The role of p53 mutations as a marker of poor prognosis in DLBCL patients treated with CHOP therapy has been well studied; however, its role following the advent of immunochemotherapy with rituximab (Rituxan,

Genentech)—R-CHOP—had not been well defined until the present study.

In the Blood d study, led by Zijun XuMonette, PhD, of the University of Texas MD Anderson Cancer Center in Houston, gene sequencing revealed 133 p53 protein mutations in 112 of the patients included in the analysis (a prevalence of 21.9%). The remaining patients were considered to have wild-type p53. Most of these were missense mutations, which, the study’s authors noted, highlights the importance of maintaining p53 structure in tumor suppression. In all, DLBCL patients with wild-type p53 treated with R-CHOP had significantly better overall survival (median 94.49 vs.

52.90 months) and progression-free survival (PFS; median 93.14 vs. 51.95 months) than those with p53 mutations ( =0.0005 and P=0.0004, respectively).

(P Five-year PFS was 63.5% for patients with wild-type p53 compared with 46.3% for those with p53 mutations.

The researchers found that p53 protein mutations had a similar predictive value for R-CHOP patients with the germinal center B-cell (GCB)and activated B-cell subtypes of DLBCL, which was not the case in earlier studies of patients treated with CHOP alone. Additionally, the study also revealed that p53 protein deletion and loss of heterozygosity “did not confer worse survival.”

determines cell fate in response to a variety of cellular stresses by regulating transcription of important proteins resulting in cell cycle arrest or activation of pro-apoptotic machinery. Loss of p53 activity is therefore a common mechanism by which cancer cells avoid cell death in response to chemotherapy.

The article by Xu-Monette et al highlights the importance and complexity of p53 analysis in patients with DLBCL. Despite histopathologic similarities, patients with DLBCL can be clustered into distinct subgroups based on gene expression profiling. Beyond RNA expression differences, DNA mutational analysis adds further insight

into the prognosis of these patients.

This study evaluates a large multiinstitutional cohort of patients with de novo DLBCL (excluding patients with transformed disease), treated in uniform manner according to p53 status, using a variety of molecular techniques including sequencing, expression profiling, fluorescence in situ hybridization and immunohistochemistry. p53 mutation is shown to be an adverse molecular finding in the 21.9% of patients with abnormalities. Overall survival in patients with wild-type p53 was nearly twice as great as it was for those patients with mutated p53, with similar effect on PFS. This effect was independent of germinal center (GC) or activated B-cell subtype, which differs from the prior analysis of DLBCL patients treated with CHOP alone (pre-rituximab) where the effect was limited to patients with GC subtype DLBCL. This highlights the importance of re-evaluation of prognostic markers as standards of care change.

One concern is the incredible complexity of p53 alterations. This study

highlights the multitude of ways p53 can be altered in gene sequencing.

Although there are hotspots for recurring abnormalities, not all mutations are created equally. Some mutations may not affect amino acid sequence, whereas others cause an amino acid substitution or premature termination of the coding sequence.

It is tempting to consider p53 changes in a binary “yes/no” manner but that probably oversimplifies the biology. As personalized diagnostics emerge, the interpretation of such abnormalities may be as important as the detection of the change in the first place.

Identification of a high-risk cohort may enable therapeutic intensification, but such trials are difficult to design and execute. As the molecular taxonomy of cancer advances more quickly than our ability to know what to do with the data, clinical research remains a vital link in advancing the care of these patients.

will never learn which patients might do just as well with six months of therapy and avoid excess cardiotoxicity,” emphasized Dr. Gelber.

Dr. Gelber presented the results of the HERA (Herceptin Adjuvant; abstract LBA6) trial, the only trial testing a trastuzumab duration longer than one year. This trial, which began in 2001, involved 5,102 women with HER2-positive invasive, early breast cancer who were randomized in a 1:1:1 fashion to one year of trastuzumab, two years of trastuzumab or observation. Baseline characteristics and additional therapies were well balanced between the

arms. At eight years of median followup, the disease-free survival rate in the two trastuzumab arms was comparable, with a hazard ratio of 0.99 ((P=0.86).

The one-year arm continues to show a robust and statistically significant decrease in the risk for death compared with the observation arm, despite the fact that half of the women in the observation arm received trastuzumab once the efficacy of trastuzumab was disclosed in 2005.

“There was no statistically significant difference between two years of trastuzumab and one year,” said Dr. Gelber. He pointed out that at 3.5 years of

EXPERT INSIGHT Jeff Sharman, MD Medical Oncologist Willamette Valley Cancer Institute and Research Center Member, Hematologic Malignancies Research Committee The US Oncology Network

P

ersonalized medicine is the goal of detecting unique characteristics of an individual’s cancer and appropriately modifying therapeutic interventions to maximize efficacy and minimize side effects. A growing number of molecular diagnostics offer multiplex analysis of many oncologic targets bundled within one commercial assay. With the explosive progress in genome sequencing technology, a thorough understanding of molecular biomarkers is imperative if the goal of personalized medicine is to be reached. p53 is one of the most important molecular markers in cancer. Known as the “guardian of the genome,” p53

DURATION continued from page 15

Richard Gelber, PhD, a biostatistician at the Dana-Farber Cancer Institute in Boston, who was not involved with the PHARE trial, agreed. “Further update of PHARE is absolutely required, for I would say at least another year, before any conclusion that six months is inferior goes out to the public,” said Dr. Gelber. He said that if the message was miscommunicated, PERSEPHONE, Short-HER and SOLD may be stopped.

“If those ongoing trials are stopped, we

Dr. Sharman reported no financial disclosures relevant to this study.

follow-up, there was a trend favoring the two-year arm, but this disappeared over time. Dr. Gelber suggested that this was another reason longer follow-up of the PHARE trial was needed.

—Kate O’Rourke Dr. Pivot disclosed honoraria from and consultancy for GlaxoSmithKline and Roche.

Dr. Gelber disclosed that a portion of his academic salary was supported by the Breast International Group, which received funds from Roche to conduct the HERA trial. Dr. Piccart-Gebhart is a consultant for and received honoraria from Roche.

Supported by

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Advances in Stent Technology for Esophageal Cancer Rafael S. Andrade, MD Associate Professor Section of Thoracic and Foregut Surgery University of Minnesota Medical Center, Fairview Minneapolis, Minnesota

Introduction Esophageal stricture and tracheoesophageal fistula in the setting of advanced esophageal cancer can have a devastating effect on quality of life due to severe dysphagia, aspiration pneumonia, and the inability to sustain nutrition or enjoy meals.1 Management of dysphagia is indicated for palliative purposes in patients with unresectable esophageal cancer1 and in order to optimize nutrition prior to surgery in the neoadjuvant setting.2,3 Historically, management of malignant dysphagia consisted of radiation therapy with or without systemic chemotherapy, endoscopic tumor ablation, stricture dilation or enteral feeding.4,5 Although radiation therapy provides excellent palliation, its effect is delayed by weeks.6,7

Esophageal Stenting Endoscopically placed stents are being used for immediate palliation of dysphagia as well as tracheoesophageal fistulae.1,3 The SIREC (Stent or Intraluminal Radiotherapy for Inoperable Esophageal Cancer) study found that newer stents produced more immediate relief of dysphagia than radiation therapy,8 although the latter offers a more durable result for patients with more than 3 months’ life expectancy.8 Thus, the paradigm of esophageal stenting for immediate relief followed by radiation therapy may be the most effective way to palliate dysphagia in patients with malignant dysphagia and a life expectancy of at least 3 months.

The WallFlex® (Boston Scientific) fully or partially covered esophageal stent, constructed of multiple braided radiopaque nitinol wires, is indicated for the maintenance of esophageal luminal patency in malignant esophageal strictures or for the occlusion of concurrent esophageal fistulae.9

A prospective study10 assessed the clinical efficacy and safety of the esophageal WallFlex® stent for dysphagia palliation in 37 patients with esophageal cancer.10 Stent placement was successful in 36 of 37 patients, who experienced significant palliation.10 Major complications occurred in 3 patients (pneumonia in 1, severe pain in 2); 8 patients developed recurrent dysphagia because of stent migration, food impaction, or tissue ingrowth or overgrowth.10

Our Experience Multidisciplinary tumor board conferences present the perfect time to discuss our patients and select the most appropriate form of dysphagia palliation in esophageal cancer patients. The typical WallFlex® stent candidate at our institution presents with a T3 tumor and dysphagia; the stent is placed either for palliative purposes or to maintain nutrition and quality of life before neoadjuvant therapy and surgical management (Figure). Radiation therapists at our institution have no difficulty simulating and delivering treatment in the presence of an esophageal stent.11 For those patients who require nutritional support, I favor stenting in lieu of the placement of a jejunostomy feeding tube (J-tube). Placing a J-tube may require a 5-day hospital stay because bolus feeding needs to be gradually instituted. The stent is easier to place and quicker to re-establish enteral nutrition.

Stent placement at our hospital is done under general anesthesia and fluoroscopic guidance, and is frequently performed at the time of endoscopic ultrasound staging. We do not predilate except when the

stricture is so tight that we cannot pass the deployment system. We usually select the 18-mm diameter stent to relieve solid-food dysphagia. In instances when the stricture is not as tight, we will place a 23-mm diameter stent. We tend to put in longer stents if we have to stent across the gastroesophageal junction due to tumor involvement since we believe they help address higher migration rates in these instances. We admit the patient for overnight observation and obtain a chest x-ray the following morning to confirm proper stent position.

Patients receiving the esophageal stent are initiated on a clear liquid diet with a stepwise progression to a soft solid diet. The patient’s ultimate diet can be determined by trial and error. Patients who are stented across the gastroesophageal junction are instructed to follow aspiration precautions and prescribed twice-daily proton pump inhibitors. Patients are seen in the outpatient clinic 1 week after stent placement for symptom assessment and repeat chest x-ray to evaluate stent position and to assess clinical response. The majority of patients experience immediate dysphagia palliation, but patients often have variable amounts of retrosternal pain, which tends to resolve within 3 to 5 days with the use of oral narcotic pain medication. Reflux symptoms and stent migration remain concerns during follow-up of patients receiving esophageal stents. Stent migration very rarely requires emergent intervention or hospitalization. We usually perform endoscopy within 2 to 4 days.

My advice for learning how to place the WallFlex® stent is to approach someone with significant experience and observe the procedure. Ask them how they select patients

for this procedure, under which conditions they use general anesthesia and fluoroscopy, and how they ensure proper positioning, and make note of technical pearls.

References 1.

Sharma P, Kozarek R; Practice Parameters Committee of American College of Gastroenterology. Role of esophageal stents in benign and malignant diseases. Am J Gastroenterol. 2010;105(2):258-273.

2.

Pellen MG, Sabri S, Razack A, Gilani SQ, Jain PK. Safety and efficacy of self-expanding removable metal esophageal stents during neoadjuvant chemotherapy for resectable esophageal cancer. Dis Esophagus.

2012;25(1):48-53.

3.

D’Cunha J, Rueth NM, Groth SS, Maddaus MA, Andrade RS. Esophageal stents for anastomotic leaks and perforations. J Thorac Cardiovasc Surg. 2011;142(1):39-46.

4.

Gasper WJ, Jamshidi R, Theodore PR. Palliation of thoracic malignancies. Surg Oncol.

2007;16(4):259-265.

5.

Arends J, Bodoky G, Bozzetti F, et al. ESPEN guidelines on enteral nutrition: non-surgical oncology. Clin Nutr. 2006;25(2):245-259.

6.

Bown SG. Palliation of malignant dysphagia: Surgery, radiotherapy, laser, intubation alone or in combination? Gut. 1991;32(8):841-844.

7.

Siersema PD, Dees J, Van Blankenstein M. Palliation of malignant dysphagia from oesophageal cancer. Rotterdam Oesophageal Tumour Study Group. Scand J Gastroenterol Suppl. 1998;225:75-84.

8.

Homs MY, Steyerberg EW, Eijkenboom WM, et al. Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial. Lancet.

2004;364(9444):1497-1504.

9.

van Boeckel PG, Siersema PD, Sturgess R, et al. A new partially covered metal stent for palliation of malignant dysphagia: a prospective follow-up study. Gastrointest Endosc. 2010;72(6):1269-1273.

10.

Boston Scientific, Inc. WallFlex® Fully and Partially Covered Esophageal Stents. http://www.bostonscientific.com/Device. bsci?page=HCP_Overview&navRelId=100 0.1003&method=DevDetailHCP&id=10115 032&pageDisclaimer=Disclaimer. Accessed October 31, 2012.

11.

Rueth N, Shaw D, D’Cunha J, Cho C, Maddaus M, Andrade R. Esophageal stenting and radiation therapy: a multimodality approach for the palliation of symptomatic malignant dysphagia. Ann Surg Oncol.

2012;10.1245/s10434-012-2459-3.

Figure. Esophageal tumor before and after placement of the WallFlex® stent.

BB1168

Faculty

www.bostonscientific.com/endo-resources ENDO-114415-AA Nov2012

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

17

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

Essay Contest Winners Editor’s Note:

T

his summer, Clinical Oncology News launched the magazine’s inaugural writer’s contest, asking readers to submit essays on the theme of change in oncology/hematology. The first-place winning essay, by Paulette Mehta, MD, MPH, a professor of internal medicine and

pediatrics at the University of Arkansas for Medical Sciences, in Little Rock, Ark., ran in our November issue.

This month features an essay by the runner-up, Atis Barzdins, MD, a hematologist/oncologist at the Seattle Cancer Treatment and Wellness Center in Renton, Wash.

Dr. Barzdins’ essay was chosen because it attempts to assess,

frankly and openly, many fundamental problems facing oncologists today, from the difficulty of failing to cure patients to the growing ‘malignant crisis of data’ physicians must grapple with in their professional lives.

Clinical Oncology News thanks all of the readers who submitted essays as part of the inaugural writer’s contest.

The second annual contest will open in summer 2013.

Is ‘Happy Oncologist’ a Misnomer?

Optimism, cost and the ‘malignant crisis of information’ in oncologists’ pursuit of happiness

By Atis Barzdins, MD

W

ork with a fatal illness reminds us repeatedly how unforgivingly limited our abilities are. An oncologist has to live with this truth in a society that is currently distressed financially and grappling over Atis Barzdins, MD its priorities. Compared with the vast suffering that cancer produces, oncologists’ personal happiness seldom comes up for discussion.

It would probably be hard to sell our profession to a teenager trying to decide which path in life would bring them the most fun and glamour, and bring it fast. Unless they plan to find the magic “cure for cancer” in medical school, generally our path to success is lengthy and painstaking.

We might do better in the eyes of this hypothetical teenager if career stablity were the goal. Then again, changing reimbursement and practice restructuring in recent years has been a bumpy ride, leading to lesser autonomy and making our claim to stability less convincing.

How about the satisfaction that comes from helping people in great need? It’s undoubtedly there. This translates into support and admiration from a grateful society, right? Yes, the support is still there, although 40 years after President Nixon declared “War on Cancer,” our clinical choices and our achievements are being questioned by a society that is concerned about cost and disappointed with the modest improvements in our treatments. The current practice of oncology is associated not only with escalating costs but also with the unresolved misery our patients still experience. A cancer diagnosis remains frightening and it is not just the mythical symbolism of the term, like leprosy or plague. Real-life encounters with this deadly group of diseases leaves many patients and families scarred and traumatized.

Understandably, being an oncologist

can be frustrating. Our treatments fail.

We find out how deeply illness has devastated patients and families. We realize we don’t have the necessary expertise to serve our patient in the best manner. We may find ourselves in practice situations where we don’t get rewarded for doing what’s best for the patient. We realize that our path to success is taking much longer than anticipated. We spend our lives overworked with no time to invest in reaching our full potential. We feel bullied by insensitive bureaucrats and organizers. Perhaps even more painful— and an increasing reality for many of us— is that we may be losing what has already been achieved.

Many of us feel lonely and scared. We often are confused and sad.

Sometimes strain from the never-ending turnover of lives passing through our offices collides with loss in our personal lives. Nevertheless, we have to make decisions affecting hundreds of lives. No matter how hard it may be, we are expected to make sense out of tragic circumstances and turn devastation into determination.

We are in a difficult position. It can be considered extreme.

Defining the Problem Humans always look for manageable order among the chaos they encounter.

We need to know what we have to do when we get up in the morning, where to focus our attention. When we are unsure about how to deal with the never-ending challenges and uncertainty in life, we get overwhelmed. However, we need to make a rational decision about how to address them or how to proceed if a solution won’t be available.

Most challenges that we encounter have well-known solutions. We just need to find the time and motivation to apply them.

But then there are problems for which we have no clear solutions. How we deal with this latter category of problems— the important questions we don’t have immediate answers to—often defines our success or failure in life. We can get paralyzed by uncertainty and panic and

scramble chaotically. We may restore some sense of normalcy and avoid mental overload through denial, with the hope of at least preserving our ability to solve more mundane problems.

Or, recognizing our unresolved problems, we may proceed with confidence and seek solutions in the most rational manner.

Many solutions to problems become obvious as we keep going. Sometimes it is simply enough to remember the problem and when a potential solution crosses our way, we know, “That’s it!” The discovery of penicillin is one of the most striking examples of this ingenious ability to “connect the dots.”

As many of us know, penicillin was discovered by chance in 1928 when Alexander Fleming accidentally left a dish of staphylococcus bacteria uncovered for a few days. He returned to find the dish dotted with bacterial growth, apart from one area where a patch of mold ((Penicillin notatum) was growing. The rest is history. This “failure” required the openminded ability to recognize the phenomenal potential of the occurrence, and then the perseverance and faith to use it as a practical solution to a completely different problem.

You may ask at this point: Where exactly am I going with this philosophical exercise in categorizing problems and their solutions?

Am I talking about the problems encountered by patients or oncologists?

The answer: Both!

Our patterns of dealing with problems are virtually identical regardless of where we stand in terms of education, responsibilities and privilege. Variations tend to be much more distinct based on personality type, prior experience and personal expectations. I think this concept is important to understand, especially when we are in the business of solving other people’s problems.

Information Chaos We are bombarded daily with massive amounts of words, images and ideas. This inflow of information can be

overwhelming, unless we know how to organize, channel and address it properly.

As oncologists, we know there is a hidden needle in this haystack of information, yet we are often in total disbelief that we might find it, perhaps because we’ve been told how impossible it is many times before, or because we don’t think we’ll get credit for removing all the hay without ever finding the needle. Yet clearly we all benefit when patient outcomes improve. If only we could make individual contributions more noticeable, I bet our collective enthusiasm to participate would rise dramatically.

No other specialty in medicine evolves as rapidly as oncology. Because uncontrolled cancer produces serious consequences and death, and because many patients are incurable and treatments are toxic, we are always in quest of better solutions.

Integrating the latest research into practice is part of our job description.

Carefully conducted studies, often taking years and thousands of appropriately selected, consenting patients following an intended treatment plan, have given us answers to a multitude of “yes or no” questions. Not surprisingly, oncology was at the forefront of “personalized medicine” before the term was invented. We have embraced biomarkers. And each year, new factors have to be considered. Cancer genetics has introduced a plethora of new variables.

Without a better approach to managing this new information, progress in oncology will be stalled by a malignant crisis of data. We don’t have the time, resources or patients to answer the escalating number of questions using traditional clinical trials.

And I am not talking only about cuttingedge new treatments and evolving biomarkers. Aren’t we all surprised to find out that treatments we have been using for decades can be used better, or used for new indications? If decades were needed to find out how to use the old tools, are we going to wait for centuries to find out the potential our new treatments hold?

We can make real progress only if we

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

find new research platforms to generate and test hypotheses. And it seems stunning how little we keep track of what actually happens in the battlefield of our day-to-day practices—a testing ground that has been profoundly underutilized and underappreciated.

The Onco-Universe Let’s imagine for a second that we could solve the logistics of tracking every cancer patient’s baseline characteristics, treatments and outcomes. We could accumulate a massive database and using data mining technologies, recognize patterns that may answer unresolved questions.

Let me call this unified database an “Onco-Universe.” Here, every patient and everything that matters to them would count, and would be coupled with the invaluable information that we have already acquired about them. The OncoUniverse would be a place for oncologists to find outcomes that have been observed using certain interventions in a group of patients, and intelligently incorporate this information into their decision making.

Without a better approach to managing new information, progress in oncology will be stalled by a malignant crisis of data.

Naturally, a lot of red tape would need to fall and existing interfaces simplified.

In fact, removing barriers of mistrust and profit protection would probably be by far the most difficult task. However, much of this information already has been acquired in differing formats: medical records, reimbursement bills that record treatment quantities and timing, and baseline and follow-up data in laboratory and radiology databases. With the Internet already connecting all of us in one informational universe, it’s hard to imagine that there are all that many technical problems that haven’t been encountered already and resolved for this complex system to operate while protecting patient privacy with encrypted formats.

Currently, “human” tasks like intuition and pattern recognition, and even hypothesis generation itself, are within the reaches of computer science. These “human dimensions” of data mining could change the lives of oncologists.

Simple cross-sectional, multidimensional analyses could allow us to test the endless number of ideas that cross our minds daily. Being on the front lines in the “War on Cancer,” we observe phenomena that are intriguing and make us wonder, so much like Fleming’s petri dish. Yet we are too busy to overcome the many obstacles to testing and so we let the ideas go. This not only robs us of

potential solutions, but also creates frustration and a feeling of uselessness that harms our ability to observe and wonder.

Imagine that after a long day in the clinic, we could actually find relaxation by playing a game of generating and testing hypotheses in the comfort of our homes.

Make it as interactive, communicable and exciting as possible! A medium where posting our findings is as easy as adding a few intriguing snapshots from the ocean of endless data to support our argument.

Advancing the ship of knowledge would no longer be the privilege of the few.

Although real-life observational studies clearly have the limitation of unaccounted-for variables, by exponentially increasing the number of patients included in any analysis we really might overcome this limitation. Even if statistical significance would not be reached by standard criteria, highly suspicious findings could provide interim improvements in the accuracy of our guesses where we have no “gold standard” answers at all.

We might test whether a panel of experienced oncologists, equipped with a pool of raw data, actually could predict results of certain types of studies. Of course, well-designed clinical trials still will be needed to answer the most critical questions. They also would allow us to calibrate and improve temporary tools in our quest for more effective solutions.

Through the Onco-Universe, we also could empower our patients to channel their angst into searching for solutions to their problems—a resource I think we all too often overlook. Patients and their caregivers also could provide data about their experiences throughout their cancer journey, providing a better understanding of how our interventions actually affect them and where we need to focus more attention in alleviating the multifaceted suffering associated with cancer. It also could guide patients to physicians who more closely match their outcome philosophy. Once they are “plugged in,” patients would also likely provide input describing their doctors, motivating us to deliver the care that is most desired by patients.

Because Money Matters It is obvious that we need a better model for oncologists to be financially

successful. Currently, to stay afloat, we see more patients in lesser amounts of time. Incentives are biased toward overtreatment. A practicing physician is a business enterprise, and right now, quantity generates profit.

This is a sharp contradiction to what the rest of society wants from us. I don’t think anybody seriously wants to save money at the expense of oncologists or others involved in cancer care. People still admire us for what we do and would be willing to invest even more in us if it could optimize our performance. Yet money needs to be saved, and until we all participate with a shared sense of priorities, we as oncologists will only experience further restrictions by payers and regulators.

Onco-Universe could facilitate solutions to the age-old problems of comparing the quality of different providers and connecting incentives to desired outcomes. Patient outcomes, rather than treatments, are rightfully a reorganizing force in health care, but this effort can only be successful if there are tools to measure and understand the changing demands of oncology practice in real time.

Humanization Is Key Even with further progress, we’ll still be dealing with suffering patients who are coping with loss of function and life for quite some time. It really doesn’t matter to a patient what improvements we might be making in our oncology kitchen unless it resolves their problem today.

We need to have a much better plan for those whose problems cannot be fully resolved. We have to understand the main sources of distress to our cancer patients much more clearly and address them directly. It may very well be that those added months of survival have been spent in total misery, both mentally and physically, not only creating horrific torture for the patient, but also traumatizing and often financially devastating their families. We have to be much better equipped to follow and assist patients in their emotional journey. If we cannot bring our patients to a comfortable place again, we may be creating a lot of misery by extending their survival. That said, most patients can find their comfort zone, especially if they receive support at certain crucial

moments and feel reassured that their comfort will always be a priority.

The disconnect between patients’ priorities and the focus of our attention and resources is a major source of discomfort.

It only adds to patients’ sense of helplessness when they have to fight their way through a system of logistical and informational barriers simply to call attention to their most bothersome issue. We need better interfaces for communicating with patients, including the settings in which communication occurs.

We need to recognize, track and eradicate misery better. The Misery Index already exists in economics: the sum of the unemployment rate and inflation. It turns out that this seemingly trivial index very strongly correlates with crime rates a year or so later. I think it would be naive to think that unremedied misery in other spheres of life, like medicine, doesn’t have the same poisonous effect on the rest of society. If it remains unaddressed, misery penetrates society as well as sends a message of hopelessness and failure, in turn inhibiting optimism and triggering compensatory mechanisms that paralyze society. Ultimately, nobody escapes the ripple effect that misery creates.

In Pursuit of Happiness We need to understand better what brings people joy. We need to remember that only through a culture of encouragement can we grow and flourish and find solutions to our most difficult problems.

Optimism keeps our minds open for the invisible solutions that are knocking on our doors every day. When we are unhappy, we brush them off as another failed dream that we don’t want to face.

We need to have faith in ourselves that we are capable of addressing our most complex challenges without always needing to be censored, controlled and supervised. We need to strive to create an environment where the tools of increasing transparency use our competitive nature in ways that are more stimulating and less intimidating.

As oncologists we need to cultivate a culture of joy, pride and happiness in ourselves, our patients and the rest of society. We know—arguably better than anybody under the sun—the incredible strength and utter fragility of human nature. We stand in a very unique place.

By learning how to better navigate through the whirlpool of endless energy and angst, we may very well be in a position to trigger a new quantum leap in the development of humanity.

Comments or feedback Please write to Clinical Oncology News managing editor Gabriel Miller at

gmiller@mcmahonmed.com

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CLINICAL ONCOLOGY NEWS • DECEMBER 2012

Ziv-Aflibercept Helps Patients With mCRC, But at What Cost?

From Journal of Clinical Oncology

A

Phase III randomized clinical trial has concluded that the novel antiangiogenic agent ziv-aflibercept (ZALTRAP, Sanofi Oncology/Regeneron) in combination with infusional FOLFIRI (fluorouracil, leucovorin and irinotecan) produces a “statistically significant survival benefit” over FOLFIRI with placebo in patients with metastatic colorectal cancer (mCRC) previously treated with oxaliplatin (Eloxatin, Sanofi-Aventis). The results of the study were published in the Oct. 1 issue of the Journal of Clinical Oncology (2012;30:3499-3506, PMID: 22949147).

Patients in the trial were randomized to receive ziv-aflibercept (4 mg/ kg IV; n=612) or placebo (n=614) every two weeks in combination with FOLFIRI until disease progression or unacceptable toxicity. The trial’s primary end point was overall survival (OS). Historically, treatment of mCRC has involved FOLFIRI in combination with bevacizumab (Avastin, Genentech) or an epidermal growth factor receptor monoclonal antibody. FOLFIRI with placebo was selected as comparator—over an active comparator—due to the lack of available data demonstrating a survival benefit with FOLFIRI combined with targeted antiangiogenic therapy in patients previously treated for metastatic disease at the time of study design.

EXPERT INSIGHT Thomas H. Cartwright, MD Medical Oncologist and Hematologist Ocala Oncology The US Oncology Network

P

rogress in the treatment of advanced colon cancer has slowed during the past several years. In fact, until recently the most recent drug approval by the FDA for colon cancer was in 2006.

In August 2012, ziv-aflibercept was approved by the FDA for the treatment of second-line colorectal cancer added to FOLFIRI. A large randomized Phase III trial, published in the Journal of Clinical Oncology, showed that adding ziv-aflibercept to FOLFIRI significantly improved OS, PFS and response rate; however, the survival benefit was small. The absolute survival benefit was 1.4 months and improvement in PFS was a little more than two months.

This past year at the American Society of Clinical Oncology meeting, the results of the TML study were presented, which looked at bevacizumab beyond progression.1 This randomized Phase III trial compared FOLFIRI to FOLFIRI plus bevacizumab. The trial was positive and showed improvements in OS as well as PFS. However, the improvements in PFS and OS were small at 1.6 and 1.4 months, respectively.

With the approval of ziv-aflibercept, the question is where this new therapy fits in, especially with the long clinical experience with bevacizumab and its well-known toxicity profile. Although

it is difficult to do cross-trial comparisons, the magnitude of the benefit with ziv-aflibercept appears similar to what is seen with bevacizumab beyond progression in the TML study. The toxicity profile also appears similar with bevacizumab and ziv-aflibercept.

Although ziv-aflibercept is a novel antiangiogenesis drug (it is also known as VEGF-Trap), it is a recombinant infusion protein containing vascular endothelial growth factor (VEGF)-binding proteins from the extracellular domains, VEGF receptor 1 and 2 and the Fc proportion of immunoglobulin G1. Ziv-aflibercept blocks activity of VEGF-A, VEGF-B and placental growth factor. Exactly how these effects are important at this time is unknown.

In the past few years there has been increasing concern about the high cost of cancer care. Dr. Sandra Swain, president of ASCO, wrote a letter to the editor of The New York Times (published Oct. 19, 2012)2 about a recent article entitled “In Cancer Care, Cost Matters.” She stated that after reviewing the ziv-aflibercept data, the Memorial Sloan-Kettering Cancer Center physicians’ “decision to forgo an expensive new cancer drug reflects a much-needed willingness to address … unsustainable costs in cancer care.” She also

According to the researchers, adding ziv-aflibercept to FOLFIRI significantly improved OS relative to placebo plus FOLFIRI ((P=0.0032). Median OS was 13.50 months with FOLFIRI plus ziv-aflibercept compared with 12.06 months with FOLFIRI plus placebo. Additionally, they reported that progression-free survival (PFS) with FOLFIRI plus ziv-aflibercept was 6.90 months compared with 4.67 months with FOLFIRI plus placebo (P ( <0.0001).

Response rate was 19.8% among patients treated with FOLFIRI plus ziv-aflibercept compared with 11.1% among patients who received FOLFIRI plus placebo ((P=0.0001).

Adverse effects reported with zivaflibercept combined with FOLFIRI

noted that, as physicians, “we have a responsibility to provide high-quality, high-value care according to the best available evidence.”

Ziv-aflibercept is priced approximately double that of bevacizumab when bevacizumab is given at 5 mg/kg every two weeks. With the high cost of ziv-aflibercept and the uncertain additional benefits, it is unclear at this point where the drug will be used or how it will fit in, although it does have a novel mechanism of action and may benefit patients who overexpress VEGFB or placental growth factors. Data with these markers at this time are unavailable.

I agree with the physicians at Memorial Sloan-Kettering and Dr. Swain. At present, the use of ziv-aflibercept, a novel but expensive new option for treatment of colon cancer with no clear benefit over existing therapies, is uncertain and likely requires further studies before widespread adoption.

References 1. Arnold D, Andre T, Bennouna J, et al.

Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study).

2012 ASCO Annual Meeting. J Clin Oncol.

2012;30(suppl; abstr CRA3503).

2. Swain S. The high cost of a cancer drug: an oncologist’s view. Letter to the editor, Oct. 19, 2012. The New York Times. Online at http://www.nytimes.com/2012/10/20/ opinion/the-high-cost-of-a-cancer-drugan-oncologists-view.html?_r=0.

Dr. Cartwright is on advisory boards at Sanofi and Genentech, and is on the speakers’ bureau for Genentech.

included the usual antivascular endothelial growth factor effects—hypertension, mucosal bleeding and proteinuria. There also was an increased incidence of some chemotherapyrelated toxicities such as grade 3 and 4 diarrhea, asthenic conditions, stomatitis and ulceration, infections and palmar-plantar erythrodysesthesia. Additionally, grade 3/4 neutropenia, grade 3/4 complicated neutropenia and thrombocytopenia also were more common in the FOLFIRI plus ziv-aflibercept group. Overall, adverse events led to permanent treatment discontinuation in 26.8% of the patients in the FOLFIRI plus ziv-aflibercept group compared with 12.1% in FOLFIRI plus placebo group.

By the NUMBERS Ziv-aflibercept for mCRC Cost per month of zivaflibercept when it came to market in August: $11,000 Median time that secondline ziv-aflibercept prolongs patients’ lives when added to standard chemotherapy: 1.4 months Cost per month of bevacizumab for colorectal cancer: $5,000 Time that second-line bevacizumab prolongs life when added to standard chemotherapy: 1.4 months Percentage discount on zivaflibercept Sanofi offered to hospitals after Memorial Sloan-Kettering Cancer Center doctors published a New York Times editorial announcing their refusal to offer it: 50 Bach PB, Saltz LB, Wittes RE. “In Cancer Care, Cost Matters.” New York Times.

October 14, 2012:A25.

Goldberg B. “Zaltrap price cut in half effective immediately.” The Cancer Letter.

2012;38:1-4.

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MISCONDUCT continued from page 1

same types of errors. The Duke researchers had also started clinical trials to test their theory and launched a company to commercialize their idea. During this time, the biostatisticians encountered resistance from journal editors, Duke University, and Drs. Potti and Nevins themselves to acknowledge the mounting evidence of problems. It took a story in the Cancer Letterr published in July 2010, revealing that Dr. Potti had lied about being a Rhodes Scholar, to garner public interest and set a widespread investigation in motion.

At this point, it became clear that issues of misconduct, not just mistakes, were involved. To date, investigation into Dr. Potti’s work has resulted in 11 retracted articles, seven corrections and one partial retraction. And with lawsuits against Duke University and Drs. Potti and Nevins under way, the saga will surely continue.

Beyond the Duke Misconduct The Duke case does not represent an isolated instance of scientific misconduct.

In the first meta-analysis of its kind, Daniele Fanelli, PhD, of the Institute for the Study of Science, Technology & Innovation at the University of Edinburgh, U.K., found that, on average, 2% of surveyed scientists admitted to fabricating or falsifying data, and as many as 33% said they had altered an experiment, which included “dropping data points based on a gut feeling,” and “changing the design, methodology or results of a study in response to pressures from a funding source” (PLoS ( ONE 2009;4:e5738, PMID: 19478950).

Although many respondents did not consider “improving” data to be misconduct, Dr. Fanelli pointed out in her paper that “the fuzzy boundary between removing noise from results and biasing them toward a desired outcome might be unknowingly crossed by many researchers.”

John Ioannidis, MD, chief of the Stanford Prevention Research Center and a professor of health research and policy epidemiology at Stanford University, in Stanford, Calif., agrees: “Fraud is very rare, but distortion in the sense of selective analyses and selective reporting seems to be highly prevalent.”

Dr. Fanelli also found that, on average, survey participants were more willing to admit to a colleague’s wrongdoing than their own: More than 14% of respondents reported knowledge of others who had fabricated, falsified or modified data and as many as 72% noted colleagues had engaged in questionable research practices. She noted, however, that self-reports tended to underestimate the true prevalence of misconduct, whereas observed instances of

The reach of a retracted paper On average, 2% of scientists surveyed admitted to fabricating or falsifying data. As many as 33% said they had altered an experiment.

Retractions have increased by at least 10-fold over the past decade, comprising 0.02% of the current medical literature. Only one in five retractions is due to error.

571 secondary citations

82 primary citations

1 retracted paper

research misconduct overestimate it.

“Knowing how common [research misconduct] is has been defined as the million-dollar question,” said Dr. Fanelli in an email to Clinical Oncology News.

“No one knows, although evidence suggests that the numbers are higher than most people think.”

Despite the barriers to estimating misconduct, it is clear that the number of retractions in scientific papers is on the rise. Retractions have increased by at least 10-fold over the past decade, comprising 0.02% of the current medical literature ((J Med Ethics 2011;37:249-253, PMID: 21186208; PLoS ONE 2012;7:e44118, PMID: 23115617; J Med Ethics 2011;37:567570, PMID: 21486985).

fraud or suspected fraud, 14.2% to duplicate publication and 9.8% to plagiarism—and only 21.3% to error (PNAS ( 2012;109:17028-17033, PMID: 23027971).

Error was previously considered the most common reason for retractions of scientific papers, but after careful analysis, the authors found that previous estimates of error were high because of “incomplete, uninformative or misleading retraction announcements.”

Another recent study, published Oct. 24 ((PLoS ONE 2012;7:e44118, PMID: 23115617), confirms this high rate of misconduct. The authors reported retractions due to alleged publishing misconduct (i.e., plagiarism, duplicate publication, authorship disputes) at 47%,

‘This is a “winner-takes-all” system that gives disproportionate rewards to those who get there first and may encourage cheating in a small proportion of scientists.’

—Arturo Casadevall, MD, PhD And importantly, misconduct is the leading cause of these retractions. In a study published online Oct. 1, Arturo Casadevall, MD, PhD, the Leo and Julia Forchheimer Chair of Microbiology and Immunology at Albert Einstein College of Medicine in New York City, reviewed 2,047 biomedical and life science retracted research articles in PubMed as of May 3, 2012, and found that 67.4% could be attributed to misconduct—43.4% to

retractions due to alleged research misconduct at 20% and those due to questionable data or interpretations at 42% (some retraction notices provided several reasons for the retraction, which is why the total is more than 100%).

Misconduct in Cancer Research In the PNAS analysis, Dr. Casadevall as well as Ferric Fang, MD, a professor of laboratory medicine and microbiology at

CURRENT PRACTICE

the University of Washington and editorin-chief of Infection and Immunity, and R. Grant Steen, PhD, the president of MediCC (Medical Communications Consultants) in Chapel Hill, N.C., compiled a list of 17 investigators who had amassed 10 or more retracted articles, “some of the most notorious cases in the history of research ethics,” they wrote. Five of the 17—including Dr. Potti—were cancer researchers.

The investigator who tops the list is Naoki Mori, MD, PhD, who has had 36 retractions to date. Dr. Mori, a Japanese virologist who previously worked at the University of the Ryukyus in Nishihara, Okinawa, Japan, was investigating novel therapies to target and suppress human T-cell leukemia virus type 1, known to cause leukemia and lymphoma. However, according to the blog Retraction Watch, while considering a new manuscript Dr. Mori had submitted for publication in 2010, a reviewer found he had tampered with figures. Suspicious, the reviewer and his graduate students examined many papers published by Dr. Mori and found widespread manipulation and duplication of images.

Another notable case of research fraud in cancer is that of Jon Sudbø, MD, DDS, PhD, a dentist and cancer researcher at the Radium Hospital in Oslo, who faked an entire study. Dr. Sudbø showed that nonsteroidal anti-inflammatory drugs could lower the risk for oral cancer, even in smokers—research that was so compelling The Lancett fast-tracked its publication (2005;366:1359-1366, PMID: 16226613). What soon emerged was that Dr. Sudbø had invented his entire study population, which included 454 patients with oral cancer and 454 controls. Camilla Stoltenberg, MD, PhD, the deputy director general of the Norwegian Institute of Public Health, uncovered the fraud when she noticed that the patient data had come from a cancer patient database that “didn’t even exist for the time period when data collection supposedly took place,” she told the Journal of the National Cancer Institute (2006;98:374376, PMID: 16537825). So far, Dr. Sudbø has had 14 articles retracted ((PLoS ONE 2012;7:e44118, PMID: 23115617).

Other transgressors on the list include Friedhelm Hermann, MD, PhD, a German cancer researcher, who fabricated data in 94 papers ((BMJ J 2000;321:71, PMCID: PMC1127761), 21 of which were retracted, and Suresh Radhakrishnan, PhD, a researcher in the lab of Larry Pease, PhD, at Mayo Clinic in Rochester, Minn., with 14 retractions ((PNAS 2012;109:17028-17033, PMID: 23027971).

When asked whether misconduct is a particular problem in cancer research, Dr. Casadevall, who is also editor-inchief of mBio, wrote in an email, “I agree that large numbers of retractions are associated with some fields, but at this time, we would rather not make that see MISCONDUCT, T page 26

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MISCONDUCT continued from page 25

conclusion [regarding cancer research] given the available data.”

Still, misconduct affects the integrity of cancer research and often has implications that extend beyond the researchers and institutions immediately involved.

“Misconduct cases always set us back,” said Alex Adjei, PhD, the senior vice president of clinical research and the Katherine Anne Gioia Chair in Cancer Medicine at Roswell Park Cancer Institute in Buffalo, N.Y. “[Misconduct] increases skepticism, taints results from studies in the particular field and sometimes kills promising collaborative projects, which are above board and not problematic.”

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

subjects were enrolled, with 70,501 treated, in 851 secondary studies that cited a retracted paper (J ( Med Ethics 2011;37:688-692, PMID: 21586404).

“Retractions are a measurable sign of the health of the scientific enterprise, but they are only the tip of the iceberg,” Dr. Fang told Clinical Oncology News in an email. “Exploring the underlying causes of fraud, bias and error as well as measures that might be taken to improve the integrity and reliability of science are far more important than the retractions themselves.”

Why Commit Misconduct?

The impetus for researchers to commit research fraud is incredibly complex.

“Scientific misconduct is a bit like doping: It is about gaining an unfair advantage in a competition,” Dr. Fanelli said. “Factors

‘Knowing how common [research misconduct] is has been defined as the million-dollar question. No one knows, although evidence suggests that the numbers are higher than most people think.’

—Daniele Fanelli, PhD Dr. Fanelli agreed: “All evidence suggests that the costs of misconduct are high, not only to the research and authors directly involved, but even to closely related fields, which suffer a damage in credibility.”

For instance, one study found that more than 28,000 subjects were enrolled and 9,189 treated in 180 retracted primary studies, and more than 400,000

SEQUENCING continued from page 1

The Argument for Deep Genome Sequencing Arguing the pro p o s i t i o n , Fa b r i c e A n d r e , M D, P h D, of the Institut Gustave Roussy in Villejuif, France, said that embracing deep sequencing in daily clinical practice is not Fabrice Andre, MD, PhD only the right thing to do, it is a necessity. The number of genetic biomarkers known to influence patient outcomes and care has risen dramatically in recent years and is only expected to grow, he said.

“The current system is not sustainable for hospitals and academic centers,” said Dr. Andre. “It’s not possible for [them] to run more than 10 bioassays per patient. We need to move to

that become critical in the competition become potential motivators for cheating.” For instance, scientists are increasingly being judged by performance parameters such as “the length of one’s publication list or the ranking of journals one has published in,” she noted.

When asked what factors may motivate certain researchers to commit fraud or distort data, Dr. Casadevall said

that there are probably many motivations, but believes the basic problem is “the reward system of science. … This is a ‘winner-takes-all’ system that gives disproportionate rewards to those who get there first and may encourage cheating in a small proportion of scientists,” he said. Other contributing factors, he added, are “the scarcity of funds and the increased competition among scientists for the limited resources available.”

Poor mentoring relationships also might play a role. One study found that, of 33 cases where a trainee was found guilty of scientific misconduct, 90% involved fabrication, falsification or both. In 73% of the cases, research mentors did not look at the raw data prior to publication and 62% did not set standards for recording data ((Sci Eng Ethics 2008;14:323-336, PMID: 18615274).

Ultimately, one incentive to commit fraud may come down to human nature: People want the positive story to be true. “It’s a rush to have an idea that can potentially change how people are treated and medicine is done,” Dr. Baggerly said.

Elizabeth Wager, the chair of the Committee on Publication Ethics, an international council of journal editors, agreed, noting, “I think that some scientists start to believe their own theories so much that, if the data doesn’t fit the theory, they change the data.”

The path can start off with a minor transgression, but as these compound and are rationalized by the perpetrator, “this makes the next transgression seem not only easier, but even morally correct,” wrote Jennifer Crocker,

PhD, a professor of social psychology at Ohio State University, in an editorial addressing scientific fraud ((Nature 2011;479:151, PMID: 22071724).

Once it has occurred, misconduct can be difficult to spot. “One thing that caused problems in our context is that in addition to having some difficulty in understanding the raw data, there was lack of clarity about the methods used,” Dr. Baggerly said. “This [lack of clarity] helps people get away with misconduct.”

Additionally, because the data is complex, errors become harder to detect.

“If you’ve got a data matrix of 22,000 genes by five samples, it’s much harder to spot problems than if the matrix is 10 by five,” he added. “This is a nontrivial amount of effort, and if I’m reviewing a paper, that is an amount of effort I probably won’t go through.”

Experts are now looking at ways to reform the system to prevent scientific misconduct. Validating potentially important findings should be a priority, Dr. Adjei said. “New, exciting data need to be replicated before we push them out into press releases.”

Dr. Casadevall pointed to a range of reforms that could help address some of these issues. “I think we are going to need a multilayered system to reduce fraud in the scientific literature,” including “more attention to ethics, more vigilance in laboratories, whistleblower protection rules, more awareness of the potential of fraud among reviewers and editors, and a change in the culture, [which is] the hardest thing to do.”

—Victoria Stern

‘In the context of prospective cohorts, but not clinical trials, I think we need to deliver NGS [next-generation sequencing] in order to detect a high number of rare, relevant genomic alterations and then treatment can be done in the context of Phase I trials or drug access programs.’

—Fabrice Andre, MD, PHD multiplex technology.”

For breast cancer, he said, clinicians can run tests for ER/HER2, TOP2A, FGR1, IGFR1R, EGFR, PAK1, BRCA1, CYP2D6, PTEN N and PI3KCA among others. With whole genome sequencing, “you can assess all the genes that you want,” said Dr. Andre. “When you do one test for each biomarker, each biomarker has a cost. Keep in mind that three FISH [fluorescence in situ hybridization] is equal to the same cost of one whole genome CGH [comparative genomic hybridization] array.”

Whole genome sequencing also offers a number of other potential advantages.

High throughput approaches can identify a large number of rare targetable

gene alterations. This is increasingly important as researchers find genetic alterations that exist in 1% or 2% of patients. The technology also can capture minority clones that may be hard to identify when there is a low percentage of tumor cells in a sample. The nextgeneration sequencers have been proven to be accurate and they do not need large samples of tissue. Dr. Andre pointed out that some protein-based assays, which are used because they are less expensive than FISH, are not reliable.

One study found that the immunohistochemistry test for the HER2 protein was accurate only 81.6% of the time ((J Clin Oncol 2006;24:3032-3038, PMID: 16809727).

The “robust” deep sequencing technology is already being used for patient care at academic centers. One such example is the MOSCATO trial, which began in fall 2011. This trial enrolled 120 patients with difficult-to-treat cancers and is using whole genome sequencing to identify potential therapeutic targets. Once a target has been identified, patients receive targeted therapy in a clinical trial if one is available.

The turnover time for sequencing is 15 days and the total cost is 1,500 euros, or roughly $2,000 per patient.

The cost of technology is expected to decrease dramatically in the next few years. By the end of 2012, Oxford Nanopore Technology is expected to

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CLINICAL ONCOLOGY NEWS • DECEMBER 2012

launch a technology that is the size of a USB drive and will offer whole genome sequencing in 15 minutes for less than $1,000. Dr. Andre argued that deep sequencing will be less expensive than a multiplicity of tests.

He pointed to a case study recently described in the Journal of Thoracic Oncology as an example of a success story (2012;7:e14-e16). In the case report, a 43-year-old never smoker with lung cancer had tested negative for EML4ALK on the approved companion genetic test for crizotinib (Xalkori, Pfizer). Sensing that an oncogenic genetic driver was spurring the patient’s cancer, clinicians ordered deep sequencing and identified a novel ALK fusion.

The patient was treated with crizotinib and was recently reported to have had a complete response.

“In the context of prospective cohorts, but not clinical trials, I think we need to deliver NGS in order to detect a high number of rare, relevant genomic alterations and then treatment can be done in the context of Phase I trials or drug access programs,” said Dr. Andre.

The Argument Againstt Deep Genome Sequencing According to Kenneth O’Byrne, MD, a consultant medical oncologist at St. James Hospital and Trinity College Dublin, Ireland, Dr. Andre is jumping the gun.

“He makes the fundaKenneth O’Byrne, MD mental error that all people who are enthusiastic about new technologies always make and that is the non-application of evidence-based medicine,” Dr. O’Byrne said. “Deep sequencing is a fantastic tool, but it is a research toy and an expensive toy at the moment.

For day-to-day practical medicine, we have to go by evidence base.”

Dr. O’Byrne cast doubt on Dr. Andre’s success story example. “They treated the patient with crizotinib and made the false conclusion that the ALK rearrangement they detected was responsible for

the response. Do we know w if that patient expressed MET? Is theree any other reason [he] may have respo onded to crizotinib?” Dr. O’Byrne said.

He agreed that thee cost of the sequencing technology w was decreasing, but argued that analysiss would remain expensive. He argued th hat the clinical benefit of identifying genetic drivers is still uncertain.

“I would argue that in lung cancer, and indeed in aalmost every other tumor, th here are only a few proveen genetic alterations thaat can be identified thaat actually affect the way w we treat our patients in cliinic,” Dr. O’Byrne said. “EGFR R [epidermal growth factor receptor] mutations and ALK rearrangements arre the only validated predictive biomarrkers in NSCLC

‘[Dr. Andre] makes akes the fundamental error that all people eople who are enthusiastic about bout new technologies always make and nd that is the non-application of evidence-based sed medicine. Deep sequencing is a fantastic tool, ool, but it is a research toy and an expensive toy at the moment. For day-to-day practical medicine, cine, we have to go by evidence base.’

—Kenneth O’Byrne, MD [non-small cell lung cancer].” He pointed out that these affect only 15% of lung cancer patients, and although there are targeted agents available, the jury is still out on whether the drugs that target these mutations improve survival.

As an example of this, he pointed out that an interim analysis of the PROFILE 007 trial presented at the ESMO meeting (abstract LBA1) showed that although crizotinib increased progression-free survival by 4.7 months compared with chemotherapy, there was

no difference in overall survival. “If you look at all of the EGFR TKI [tyrosine kinase inhibitor] randomized controlled trials versus cytotoxic chemotherapy in EGFR mutation–positive disease, there has yet to be a proven [overall] survival benefit, despite obvious clinical benefits,” Dr. O’Byrne said. Researchers say the lack of overall survival advantage in many of these trials can be blamed on the large numbers of patients who cross over to the experimental therapy. “The argument is crossover, but we don’t know

Chasing the $1,000 Genome

A

re we on the cusp of achieving the $1,000 human genome? Oxford Nanopore Technologies has claimed it will offer technology in 2013 that will achieve this feat. Life Technologies and Illumina have said their technologies too will soon be able to achieve the $1,000 genome. Whether they can deliver on their promises remains to be seen.

Over the years, a number of companies, including Life Technologies, 454 Life Sciences, Illumina and Pacific BioSciences have toiled away at increasing sequencing speed and pushing down cost.

Companies have been successful in reducing the time needed to sequence a genome to a few weeks or months and the price to $5,000 or slightly less. Instruments have cost between $500,000 and $750,000. Life Technologies’ latest machine, the benchtop Ion Proton Sequencer, plus the server that accompanies it, has a price tag of $224,000.

The $1,000 genome has been heralded as a magic number in DNA sequencing, the number that health care providers would consider cost-effective to use in the clinic.

that yet,” he said.

Dr. O’Byrne urged cautiion, as several years ago, it was though ht that tumor angiogenesis inhibitors w would be the salvation of lung cancer patients and that did not happen. Theere was clear evidence that new blood d tumor vessels were associated witth poor outcome, but when reseaarchers tested a slew of antiangiogeenic TKIs in patients with lung canccer, none of them worked. These in ncluded apatinib, axitinib, cedariniib, motesanib, pazopanib, sorafenib, ssunitinib and vandetanib. “There is stilll some promise that some of these might break through,” Dr. O’Byrne said, pointiing to Boehringerr Ingelheim’s BIBF1120. “But “ to date, we’ve sspent billions of euros proving that many of these are of no valuee.

“In my m view, and I feeel this quite stron ngly, predictivve biomarker testss must undergo validation and quallity assurance beefore they are u s e d ro u tinely in clinical p r a c t i c e,” Dr. O’Byrne said. “Deep DNA sequencing holds huge promise … but it is a research tool, and I do genuinely believe that a lot of clinically irrelevant data is generated that actually confuses the clinician and the patient.”

—Kate O’Rourke

Dr. Andre disclosed being a consultant for or advisor to and receiving honoraria from Novartis. Dr. O’Byrne disclosed serving as an advisor or consultant for Roche, Boehringer Ingelheim, Eli Lilly and Merck Serono. He has received grants for clinical research from Merck Serono.

27

28

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Clinical Hematologic Review: NEJM, JCO and Blood

QUESTIONS

1.

True or False. A study published in The New England Journal of Medicine on behalf of the Blood and Marrow Transplant Clinical Trials Network clearly demonstrated better overall survival using peripheral blood stem cells compared with bone marrow grafts in patients undergoing matched unrelated donor (MUD) hematopoietic transplantation.

2. True or False. Immunohistochem-

ical (IHC) analysis of MYC and BCL2 protein expression expanded the proportion of patients with de novo diffuse large B-cell lymphoma (DLBCL) with double-hit biology with poor outcome in patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone).

3.

True or False. In the Phase III BELA (Bosutinib Efficacy and safety in chronic myeloid LeukemiA) trial, the complete cytogenetic response (CCyR) and major molecular response (MMR)

ANSWERS

1.

False. The Phase III, multicenter, randomized trial (clinicaltrials.gov identifier: NCT00075816) of transplantation with peripheral blood stem cells versus bone marrow from unrelated donors compared two-year survival probabilities with an intention-to-treat analysis.

It concluded that the rates of survival, relapse and acute graft-versus-host disease (GVHD) are similar with peripheral blood stem cell and bone marrow grafts from unrelated donors, but engraftment is better with peripheral blood progenitor cells and the rate of chronic GVHD is lower with bone marrow graft.

Anasetti C, Logan BR, Lee SJ et al. Peripheralblood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367:1487-1496, PMID: 23075175.

2. True. Fluorescence in situ hybrid-

ization technology is generally not designed to detect genetic deregulation that affects gene expression on the transcriptional and translational levels. IHC detection of MYC and BCL2 represents a more accurate identification of this aggressive subtype of DLBCL. Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

J Clin Oncol. 2012;30:3460-3467, PMID: 22665537.

rates at 12 months were higher with bosutinib (Bosulif, Tasigna) than with imatinib (Gleevec, Novartis).

new model with prognostic effects that requires 10 molecular markers and no additional cytogenetic testing at diagnosis for adults with de novo acute myeloid leukemia (AML).

4. True or False. Evi-

dence generated over the past 20 years has unequivocally shown that the p53 tumor suppressor is the most frequently altered gene in human tumors.

7. True or False. Bene-

dicte Hivert, of the Hopital Huriez in Lille, France, demonstrated that lower levels of von Willebrand factor (VWF) antigen in patients with WaldenPrimum non nocere. ström macroglobulinemia True or False. (First, do no harm.)

Sören Lehmann, MD, (WM) were associated PhD, of Karolinska University Hospi- with inferior survival independent of the tal in Stockholm, reported the first in- International Scoring System for WM. human study with APR-246 (PRIMA1MET), a novel drug that restores tranTrue or False. Despite advances scriptional activity of unfolded wild- in the treatment of classic Hodgkin lymtype or mutant p53. phoma (CHL), current therapies fail to cure 30% of patients with this disease.

True or False. Vera Grossmann, MSc, of the MLL Munich Leukemia LabTrue or False. A prospective, oratory in Munich, Germany, proposed a multicenter, Phase III trial comparing

5.

8.

6.

Ventura RA, Martin-Subero JI, Jones M, et al: FISH analysis for the detection of lymphoma-associated chromosomal abnormalities in routine paraffin-embedded tissue. J Mol Diagn. 2006;8:141151, PMID: 16645199.

3. False. The CCyR rate at 12 months

was not different for bosutinib versus imatinib. The MMR rate at 12 months was higher with bosutinib than with imatinib, 41% versus 27%, respectively. Time to CCyR and MMR was faster with bosutinib than with imatinib. Additionally, patients on bosutinib had a lower rate of disease progression or lack of efficacy than patients receiving imatinib (3% vs. 10%), including a trend toward fewer progressions to advanced disease.

Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30:3486-3492, PMID: 22949154.

9.

hematologic malignancies and prostate cancer. J Clin Oncol. 2012;30:3633-3639, PMID: 22965953.

5. True. This was the first-in-human

trial of the first-in-class p53-activating drug APR-246, which aimed to establish maximum tolerated dose (MTD), assess pharmacokinetics and evaluate safety. The MTD for APR-246 was defined as 60 mg/kg when given as a two-hour IV infusion for four days, and adverse effects were mainly reversible central nervous system–related, including fatigue, dizziness, sensory disturbances and confusion occurring during or shortly after infusion. Clinical protocols with extended exposures to the drug, as well as protocols with combination therapies, are currently in development.

Lehmann S, Bykov VJ, Ali D, Andrén O, et al.

Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012;30:3633-3639, PMID: 22965953.

4. True. Inactivation of the p53 path- 6. True. This new comprehensive way is essential for the formation of the majority of human tumors, making p53 an attractive target for both basic and applied research.

Lehmann BD, Pietenpol JA. Targeting mutant p53 in human tumors. J Clin Oncol. 2012;30:36483650, PMID: 22965952.

Lehmann S, Bykov VJ, Ali D, Andrén O, et al.

Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory

molecular characterization at diagnosis appears to be more robust prognostically. According to the investigators, such a comprehensive molecular characterization at diagnosis provides a molecular marker in the majority of cases (73.5%) and has a more precise prognostic algorithm than current and other proposed prognostic models. It is important to

Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

frontline ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) with Stanford V (doxorubicin, vinblastine, bleomycin, vincristine, mechloroethamine, etoposide and prednisone) chemotherapy (E2496 Intergroup trial) confirmed that inferior outcomes were associated with tumor-associated macrophages (TAMs) in locally extensive and advanced-stage CHL.

10. True or False. Schnitzler syndrome should alert one to the possibility of AA amyloidosis.

11. True or False. You are informed

of a positive Congo red stain on a 54-year-old woman. The next best step is to discuss the treatment options with your patient.

acknowledge multiple clinical variables, including administered therapies, when considering the proposed prognostic markers or models.

Grossmann V, Schnittger S, Kohlmann A, et al.

A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood.

2012;120:2963-2972, PMID: 22915647.

7. False. In 59% of patients, VWF lev-

els were actually increased (>110 U/ dL). The investigators proposed that an underlying chronic endothelial activation in WM could explain the high levels of VWF and that bone marrow microvessel density was higher in patients with more elevated VWF, indicating an association between VWF levels and angiogenesis in the bone marrow infiltration. This is the first time that a mediator directly or indirectly associated with angiogenesis and endothelial function has prognostic significance in WM. In the commentary accompanying this study, Efstathios Kastritis, MD, and Meletios A. Dimopoulos, MD, of the University of Athens, noted that these results generate more questions than answers. Do elevated levels of VWF have prognostic significance in other plasma cell dyscrasias or lymphomas? Does this imply that a “targeted” antiangiogenic therapy may have activity in patients with elevated VWF? Hivert B, Caron C, Petit S, et al. Clinical and prognostic implications of low or high level of von

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

Bosutinib a New Option for Chronic Myeloid Leukemia Oct. 1 issue of the Journal of Clinical Oncology (2012;30:3486-3492, PMID: 22949154).

This international, multicenter trial randomized 502 patients to receive either bosutinib (n=250; 500 mg per day) or imatinib (n=252; 400 mg per day); median duration of treatment for both study arms was 13.8 months.

During the study, nine patients receiving bosutinib and 30 patients receiving imatinib had their dose escalated to 600 mg per day because of lack

From Journal of Clinical Oncology

A

Phase III clinical trial comparing the novel oral Src/Abl tyrosine kinase inhibitor (TKI) bosutinib (Bosulif, Pfizer) with imatinib (Gleevec, Novartis) in the treatment of newly diagnosed chronicphase chronic myeloid leukemia (CML) failed to reach its primary end point—complete cytogenetic response (CCyR), the authors reported in the

EXPERT INSIGHT Kathryn Kolibaba, MD Medical Oncologist and Hematologist Compass Oncology The US Oncology Network

C

ML is caused by the BCR-ABL1 oncoprotein, an activated tyrosine kinase that occurs as a result of the reciprocal translocation between chromosomes 9 and 22 in the leukemic clone. The TKI imatinib was approved in 2001 for the treatment of CML, and quickly became the standard of care.

The second-generation TKIs dasatinib and nilotinib have both demonstrated efficacy in patients with CML that is resistant or intolerant to imatinib. Unfortunately, some patients also develop resistance or intolerance to dasatinib or nilotinib treatment, and additional options are needed.

Bosutinib is an oral Src/Abl TKI with more potent in vitro activity against BCR-ABL than imatinib. The present Phase III study, BELA (Bosutinib Efficacy and safety in newly diagnosed chronic myeloid LeukemiA), compared bosutinib with imatinib in untreated

Willebrand factor in patients with Waldenström macroglobulinemia. Blood. 2012;120:3214-3221, PMID: 22896002.

8.

False. Despite advances in the treatment of CHL, current therapies fail to cure 10% to 15% of patients, and a similar proportion of patients may be overtreated, resulting in both short- and longterm treatment-related complications.

Tan KL, Scott DW, Hong F, et al. Tumorassociated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial. Blood.

2012;120:3280-3287, PMID: 22948049.

chronic-phase CML patients. This trial failed to meet its primary objective of CCyR at 12 months. The CCyR rate of 70% for bosutinib was no different than the 68% CCyR rate reported for imatinib-treated patients. However, the major molecular response (MMR) rate at 12 months was higher with bosutinib (41%) than imatinib (27%). Time to CCyR and MMR was faster with bosutinib than with imatinib. Progression to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib.

There were three CML-related deaths in the bosutinib arm compared with eight in the imatinib arm. Nineteen percent of patients discontinued bosutinib as a result of an adverse event, including 15 of 48 patients who discontinued before their first post-baseline assessment. Early discontinuation in the bosutinib arm due to toxicity contributed to

9. True. It is important to note that

the investigators of this study used Aperio Technologies’ computer image analysis to assess CD68 and CD163 IHC and not manual visual scoring techniques.

Evaluation of TAMs should be considered in prospective clinical trials, and patients with increased TAMs may benefit from more intensive chemotherapy or novel agents designed to disrupt the crosstalk between Hodgkin and ReedSternberg cells and benign macrophages.

Tan KL, Scott DW, Hong F, et al. Tumor-associated macrophages predict inferior outcomes

of efficacy. To be eligible, patients had to be newly diagnosed (within six months) adults with Philadelphia chromosome–positive disease who were either treatment-naive or who had received no more than six months of treatment with anagrelide or hydroxyurea.

Most notably, given the study design, the CCyR rate at 12 months was virtually identical between the two groups (70% for bosutinib vs. 68% for imatinib; P=0.601), although the time to

CCyR was much faster with the study drug (12.9 vs. 24.6 weeks). The authors believe that the lower CCyR rate associated with bosutinib may be the result of early treatment discontinuations due to drug toxicities. They noted that “an unexpectedly high number of patients” in the bosutinib group (n=48) discontinued treatment because of an adverse event, including 15 who discontinued treatment prior to their first post-baseline assessment, an issue they feel warrants further study.

the lower rate of CCyR in the intentto-treat analysis, as these patients were analyzed as nonresponders. Continued follow-up will allow for long-term evaluation of efficacy in this population.

Bosutinib was associated with higher rates of diarrhea, nausea and aminotransferase elevations. Diarrhea was frequently reported in the first month of treatment but decreased over time, and frequently self-limited to the first two to three months of therapy. Imatinib was associated with neutropenia, musculoskeletal pain and edema.

Bosutinib was approved by the FDA in September 2012 for the treatment of CML with resistance or intolerance to prior therapy. The approval was based on a single-arm, open-label, multicenter trial that enrolled 546 patients with previously treated CML.1 All of the patients enrolled in this study had received prior imatinib; 73% were imatinib-resistant and 27% imatinib-intolerant. Of the evaluable 374 chronicphase CML patients, 206 received prior treatment with imatinib alone. Of these patients, 34% achieved a major cytogenetic response (MCyR) at week 24, with a cumulative MCyR rate of 53%.

Of the patients with a MCyR, 53% had that response last at least 18 months. Of chronic-phase CML patients, 108 had

received therapy with imatinib followed by either dasatinib and/or nilotinib. Of these patients, 27% achieved a MCyR at week 24, with a cumulative MCyR rate of 32%. Of these responding patients, 51% had a response that was durable for at least nine months. Responses were seen across various BCR-ABL mutations, although not T315I. Bosutinib now has a place among the options for CML therapy. We do not have molecular signatures or other diagnostics to identify TKI therapy that will produce the optimal cost-effective outcome for each patient’s disease.

Effective treatment for T315I-mutated BCR-ABL remains an unmet need, with promising data for ponatinib. Price will have an even greater influence on treatment choices when imatinib becomes generic. For now, side-effect profiles will continue to guide treatment decisions.

in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial. Blood.

2012;120:3280-3287, PMID: 22948049.

10. True. Schnitzler syndrome is

characterized by IgM monoclonal gammopathy, urticarial rash, arthralgia, bone pain and lymphadenopathy.

Lipsker D. The Schnitzler syndrome. Orphanet J Rare Dis. 2010;5:38, PMID: 21143856.

Leung N, Nasr SH, Sethi S. How I treat amyloidosis: the importance of accurate diagnosis and amyloid typing. Blood. 2012;120:3206-3213, PMID: 22948045.

Reference 1. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119:3403-3412, PMID: 22371878.

Dr. Kolibaba reported no financial disclosures relevant to this study.

11.

False. Once amyloids—“positive Congo red” staining—have been identified, further characterization and typing must be performed to choose accurate therapy.

Leung N, Nasr SH, Sethi S. How I treat amyloidosis: the importance of accurate diagnosis and amyloid typing. Blood. 2012;120:3206-3213, PMID: 22948045.

Dr. Mohammed Aziz assisted in preparing this column.

29

30

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • DECEMBER 2012

NSCLC: Gemcitabine and Erlotinib for Maintenance From Journal of Clinical Oncology

B

oth continuation maintenance with gemcitabine (Gemzar, Lilly) and switch maintenance with erlotinib (Tarceva, Genentech) significantly reduced disease progression in patients with advanced non-small cell lung cancer (NSCLC) who received cisplatin-gemcitabine as first-line therapy.

Results from this randomized, multicenter, Phase III clinical trial were published in the Oct. 1 issue of the Journal of Clinical Oncologyy (2012;30:3516-3524, PMID: 22949150).

EXPERT INSIGHT David Smith, MD Hematologist and Medical Oncologist and Research Medical Director Compass Oncology The US Oncology Network

T

he optimal duration and sequencing of chemotherapeutic agents in the first-line treatment of NSCLC has yet to be defined. Platinum-based doublets have been the backbone of therapy, but prolonged administration of the doublet is associated with decreasing quality of life. Docetaxel, pemetrexed and erlotinib all have demonstrated benefit at the time of disease progression, but many patients do not receive secondline therapy due to rapid progression of disease and deterioration of performance status. Integrating these active agents earlier into treatment regimens may improve survival.

Switch maintenance—the integration of a different antineoplastic agent after induction therapy—has been of interest for some time. Fidias et al randomized patients achieving stable disease or better with four cycles of gemcitabine and carboplatin to docetaxel immediately after induction or at disease progression (delayed).1 The median PFS for immediate docetaxel was significantly prolonged compared with delayed, but a trend toward improved OS did not reach statistical significance. In a double-blind, placebo-controlled trial of switch maintenance with pemetrexed following four cycles of non–pemetrexed-containing platinum doublet therapy, Ciuleanu et al reported a significant increase in both PFS and OS.2 In a prespecified subgroup analysis, this benefit was only seen in

The team of French researchers initially enrolled 834 patients with stage IIIb or IV NSCLC in the trial. These patients received induction chemotherapy with cisplatin-gemcitabine (cisplatin 80 mg/ m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8 of a three-week cycle). The 464 patients who responded to treatment (no tumor progression after four cycles) were then randomized to observation or to receive maintenance therapy with gemcitabine (1,250 mg/m2 days 1 and 8 of a three-week cycle) or daily erlotinib (150 mg per day). Patients in all three arms with demonstrated disease progression received pemetrexed (Alimta, Lilly; 500

mg/m2 once every 21 days) as secondline therapy. The trial’s primary end point was progression-free survival (PFS).

After a median follow-up period of 25.6 months for all patients, both gemcitabine and erlotinib significantly prolonged PFS (3.8 and 2.9 months, respectively) compared with observation (1.9 months; P<0.001 and P=0.003, respectively). The authors reported that both maintenance therapies were well tolerated, but that treatmentrelated grade 3/4 adverse events were approximately half as frequent with erlotinib as with gemcitabine.

However, they also noted that the PFS

nonsquamous histology. Cappuzzo et al also reported prolonged PFS and OS with erlotinib maintenance following platinum doublet chemotherapy in a double-blind, placebo-controlled trial.3 The benefit was seen across all histologic subtypes and in epidermal growth factor receptor wild-type NSCLC. In all three of these trials, the number of patients receiving additional therapy ranged from 60% to 75%.

Benefit from continuation maintenance also has been reported. The addition of bevacizumab in ECOG (Eastern Cooperative Oncology Group) 4599 to a backbone of carboplatin and paclitaxel demonstrated an increase in survival.

In that study, single-agent bevacizumab was continued after no more than six cycles of chemotherapy. There was no comparison arm, so it remains unclear how much benefit is derived from continuation maintenance of bevacizumab. The PARAMOUNT trial, reported

by Paz-Ares et al, was a placebo-controlled trial of cisplatin and pemetrexed followed by continuation maintenance of pemetrexed, which showed a significant improvement in PFS.4 As above, only 60% of patients went on to additional treatment. A subsequent update at American Society of Clinical Oncology (ASCO) 2012 reported a significant improvement in OS as well.5 This sets the stage for the present study, by Perol et al, which is the first study of NSCLC to explore continuation and switch maintenance in the same trial. There were 834 participants enrolled in this trial at multiple centers throughout France. All received induction with four cycles of cisplatin and gemcitabine and were eligible for randomization to maintenance therapy after achieving stable disease or better. Patients were then randomized to continuation maintenance with gemcitabine, switch

maintenance with elotinib or observation. There was a predefined secondline regimen of pemetrexed for all three arms. This was a well-designed trial powered to detect an improvement in the primary end point of PFS. Similar to the previously noted trials, there was a significant increase in PFS for both treatment arms compared with observation. Unlike the previous trials, a little over 90% of patients in the observation arm received second-line pemetrexed, whereas 72% and 79% of those randomized to the gemcitabine and erlotinib arms received pemetrexed. Although there was a trend toward improved OS, it did not reach statistical significance.

As the primary end point was PFS, the study was not powered for OS differences. The overall higher rate of second-line pemetrexed compared with the other studies, as well as the relative higher rate of use in the observation arm, also may have affected OS. The study also was not powered to detect a difference between the two maintenance arms. The authors conclude that either continuation maintenance with gemcitabine and switch maintenance with erlotinib significantly reduces disease progression.

How do we integrate this study into the body of literature on maintenance chemotherapy so far accumulated? It confirms the ability of both switch and continuation maintenance to improve PFS compared with observation, but does not shed light on the best approach as the study was underpowered to detect a superior maintenance strategy between the two arms. Although this study had a commendable rate of second-line therapy administration, the trial was designed and conducted prior to the labeling restriction for pemetrexed to nonsquamous cell carcinoma, which may confound survival analyses as well. Previous trials report a rate of

benefit did not translate into a statistically significant improvement in overall survival (OS) versus observation alone. An exploratory analysis revealed that patients with a performance status of 0 following first-line chemotherapy who had an objective response to firstline therapy might receive an OS benefit from continuation maintenance with gemcitabine but that those with stable disease did not seem to benefit from continuation maintenance. The same exploratory subgroup analysis found that patients who received the “entire therapeutic sequence” (ie, first- and second-line therapies in the control arm, first-line maintenance and second-line therapies in the erlotinib arm) seemed to benefit most from erlotinib maintenance.

treatment beyond first-line more in line with the reality of community practice (about two-thirds) and were associated with a survival advantage for maintenance therapy.

There are still many unanswered questions. What is the role and benefit of maintenance bevacizumab? How do we integrate maintenance strategies into bevacizumab-containing regimens? The addition of erlotinib to bevacizumab maintenance in the ATLAS trial showed a significant improvement in PFS but a nonsignificant improvement in OS (reported at ASCO 2010).6 The addition of bevacizumab to pemetrexed maintenance after induction with carboplatin, pemetrexed and bevacizumab was not superior to the control arm of carboplatin, paclitaxel and bevacizumab in terms of OS (as reported at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology). The role of maintenance chemotherapy at this point would seem to be restricted to non–bevacizumab-containing regimens. Meanwhile, we will await the results of ECOG 5508: a randomized study of maintenance pemetrexed versus maintenance bevacizumab versus the combination.

References 1. Fidias PM, et al. J Clin Oncol. 2009;27:591598, PMID: 19075278.

2. Ciuleanu T, et al. Lancet. 2009;374:14321440, PMID: 19767093.

3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521529, PMID: 20493771.

4. Paz-Ares L, et al. Lancet Oncol. 2012;13:247255, PMID: 22341744.

5. Paz-Ares L, et al. J Clin Oncol. 2012;30 (suppl; abstr LBA7507).

6. Kabbinavar FF, et al. J Clin Oncol.

2010;28:15s(suppl; abstr 7526).

Dr. Smith is on a speakers’ bureau for Lilly.

Cases and Conversations: Individualizing Therapy in Metastatic Breast Cancer

To participate in these new, FREE CME activities, log on to www.CMEZone.com

Perspectives in Non-Hodgkin’s Lymphoma: Evolving Treatment Paradigms MM111 Release Date: August 22, 2012 Expiration Date: August 22, 2013 The goal of this activity is to provide hematologists-oncologists, medical oncologists, specialty nurses, and other relevant health care professionals with up-to-date, clinically useful information on the management of non-Hodgkin’s lymphoma.

FACULTY • Julie M. Vose, MD, MBA, Nebraska Medical Center • John P. Leonard, MD, Weill Medical College of Cornell University • Jonathan W. Friedberg, MD, University of Rochester Medical Center

MM112 Release Date: October 22, 2012 Expiration Date: October 22, 2013 The goal of this activity is to educate community oncologists on recent evidence in the individualized management of metastatic breast cancer.

FACULTY • Linda T. Vahdat, MD, Weill Cornell Medical Center • Adam Brufsky, MD, PhD, University of Pittsburgh Cancer Institute • William J. Gradishar, MD, Northwestern University

Perspectives on Breast and Ovarian Cancers: Integrating Data, Improving Outcomes MN122 Release Date: October 31, 2012 Expiration Date: October 31, 2013 The goal of this activity is to provide general oncologists with a concise summary of the most clinically important findings in breast and ovarian cancer research in the previous year.

FACULTY • Stefan Glück, MD, PhD, FRCPS, University of Miami • Ruth O’Regan, MD, Emory University • Robert A. Burger, MD, Fox Chase Cancer Center •

Samer I. Schuman, MD, FACS, FACOG, University of Miami

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Atlas of Clinical Nuclear Medicine, Third Edition Susan Clarke; Gary Cook; Gopinath Gnanasegaran

March 29, 2013

Cancer: Principles and Practice of Oncology Primer of the Molecular Biology of Cancer Vincent Devita

April 1, 2011

Doctor’s Eyes Only: Exclusive Financial Strategies for Today’s Doctors and Dentists Thomas Martin; Paul Larson; Jeffrey Larson

March 13, 2012

MD Anderson Manual of Medical Oncology, Second Edition Hagop M. Kantarjian; Robert A. Wolff; Charles A. Koller

April 22, 2011

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Rare Cancers, An Issue of Hematology/Oncology Clinics of North America Guy D. Eslick

January 11, 2013

Surviving Triple Negative Breast Cancer: Hope, Treatment, and Recovery Patricia Prijatel; Carol Scott-Conner

November 1, 2012

The Medical Directory 2013 Brenda Wren

November 16, 2012

Year Book of Oncology 2012 Robert J. Arceci

November 9, 2012