June 2009 Vol. 2 No. 4

SAFE HANDLING National initiative highlights risks of occupational drug exposure

NEW IN THIS ISSUE In the Literature Concise reviews of studies relevant to cancer care

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fo gi r Y st ou er ww r F To w. re day co e CE ex m .co m

M u Sec lti ond p le a My nnu elo al m Con a page 6 ne sid ws era le t t i o te n s www.theoncologypharmacist.com rs i er n ie s .

page 30 JUNE 2009 • VOL. 2, NO. 4

er d a Le and e h T ews in N eeting e M erag Cov PHARMACY PRACTICE

PROSTATE CANCER

HOPA President Foresees Opportunities for Growth An Interview with Cindy O’Bryant, PharmD, BCOP

I

n addition to her responsibilities as associate professor in the Department of Clinical Pharmacy at the University of Colorado School of Pharmacy and director of the Oncology Pharmacy Practice Residency there, Cindy O’Bryant, PharmD, BCOP, has spent the past year as president of the Hematology/ Oncology Pharmacy Association (HOPA). Dr O’Bryant recently

spoke with The Oncology Pharmacist about achievements during the past year, plans for the future of the organization, and future directions for oncology pharmacy in general.

How did you get involved in oncology pharmacy and HOPA in particular?

When I was in pharmacy school at Mercer University Southern

School of Pharmacy in Atlanta, Georgia, I did an oncology rotation at Emory and saw the collaborative, multidisciplinary nature of oncology pharmacy and how oncology pharmacists were well integrated into the cancer care team. That was exactly what I wanted to do—to have a lot of direct patient contact and also to work collaboratively Continued on page 10

AUA Counters Mainstream Recommendations with New Position on Prostate Cancer Screening CHICAGO—The American Urological Association (AUA) is lowering the recommended age for PSA (prostate-specific antigen) testing by 10 years, from age 50 years to age 40 years. The AUA issued new clinical guidance, which directly contrasts with recent recommendations by other major groups, at its 104th Annual Scientific Meeting in April. The new recommendation by the AUA is that PSA testing should be offered to well-informed men aged 40 years or older who have a life expectancy of at least 10 years.

Continued on page 28

COMPLIMENTARY CE CREDIT

GASTROINTESTINAL CANCERS

BREAST CANCER

AT WWW.THEONCOLOGYPHARMACIST.COM

KRAS Testing Added to Colon and Rectal Cancers Guidelines

Genetic Counseling Added to Breast Cancer Guidelines

PROGRAM #C1K10107

H

OLLYWOOD, FL—New Kirsten rat sarcoma (KRAS) testing recommendations, survivorship protocols, and resectability criteria are the main highlights from the latest colon and rectal cancers guideline updates from the National Comprehensive Cancer Network (NCCN), as reported at the 14th Annual NCCN Conference: Clinical Practice Guidelines & Quality Cancer Care.

The guidelines were presented by Paul F. Engstrom,

I

n the annual update of its breast cancer guidelines, the National Comprehensive Cancer Network (NCCN) encourages oncologists and their staff to offer genetic counseling for patients with ductal carcinoma in situ (DCIS) and a strong family history to consider eliminating the “boost” after radiotherapy in older patients with early invasive breast cancer. The breast cancer panel lists surgical excision as an option for locally advanced or recurrent stage IV disease, and

Continued on page 22

Continued on page 22

Oral Biologic Therapy versus Chemotherapy for Pretreated Non–small-cell Lung Cancer

PAGE 23

YOU COULD BE HOLDING YOUR LAST ISSUE! Register online at www.theoncologypharmacist.com to ensure uninterrupted FREE delivery of The Oncology Pharmacist © 2009 Green Hill Healthcare Communications, LLC

For patients 55 years and older with acute myelogenous leukemia (AML) following induction chemotherapy…

Go Beyond Neutrophil Recovery With

LEUKINE is a multilineage colony-stimulating factor that stimulates the production and activity of monocytes/macrophages and dendritic cells, as well as neutrophils1 Significantly fewer deaths due to serious infections in patients treated with LEUKINE versus placebo*2 75% DECREASE

90% DECREASE

83% DECREASE

73% DECREASE

LEUKINE, 3/52 (5.8%) vs placebo, 11/47 (23.4%)

LEUKINE, 1/52 (1.9%) vs placebo, 9/47 (19.1%)

LEUKINE, 1/8 (12.5%) vs placebo, 9/12 (75%)

LEUKINE, 2/14 (14.3%) vs placebo, 7/13 (53.8%)

P=.019 Fatal infections during and within 30 days of study completion

P=.006 Death from fungal infections in all patients

P=.02 Fatal fungal infections in patients with grade 3/4 fungal infections

P=.046 Death from pneumonias in patients with pneumonia

*In a phase III, multicenter, randomized, double-blind, placebo-controlled trial of 99 newly diagnosed adult patients, 55 to 70 years of age, receiving induction chemotherapy with or without consolidation therapy.2

References: 1. LEUKINE® (sargramostim) [package insert]. Bayer HealthCare Pharmaceuticals Inc.; April 2008. 2. Rowe JM, Rubin A, Mazza JJ, et al. Incidence of infections in adult patients (> 55 years) with acute myeloid leukemia treated with yeast-derived GM-CSF (sargramostim): results of a double-blind prospective study by the Eastern Cooperative Oncology Group. In: Hiddemann W, et al, eds. Acute Leukemias V: Experimental Approaches and Management of Refractory Diseases.

Berlin, Germany: Springer-Verlag; 1996:178-184.

© 2009 Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ 07470 All rights reserved. 561-10-0001-09b Printed in USA May 2009

Drug Interactions Drugs that can increase white blood cells (WBCs), such as lithium and corticosteroids, should be used with caution while receiving LEUKINE. Also, LEUKINE should not be used 24 hours before through 24 hours after any chemotherapy or radiation therapy. Interactions between LEUKINE and other drugs have not been fully evaluated.

Important Safety Considerations LEUKINE is contraindicated in patients with excessive leukemic blasts in bone marrow or peripheral blood (≼10%); in patients with known hypersensitivity to GM-CSF, yeast-derived products, or any component of LEUKINE; and for concomitant use with chemotherapy and radiotherapy.

Serious allergic or anaphylactic reactions have been reported with LEUKINE. If any serious or anaphylactic reactions occur, LEUKINE therapy should immediately be discontinued and appropriate therapy initiated.

Liquid solutions containing benzyl alcohol (including liquid LEUKINE) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates.

LEUKINE should be used with caution and monitored in patients with preexisting fluid retention, pulmonary infiltrates, or CHF; respiratory symptoms or disease; cardiac symptoms or disease; and renal or hepatic dysfunction.

Edema, capillary leak syndrome, pleural and/or pericardial effusion, supraventricular tachycardia, sequestration of granulocytes in the pulmonary circulation, and dyspnea have been reported in patients after LEUKINE administration. LEUKINE has induced the elevation of serum creatinine or bilirubin and hepatic enzymes in some patients. Monitoring of renal and hepatic function in patients with preexisting renal or hepatic dysfunction is recommended at least every other week during LEUKINE administration.

Nearly all patients reported leukopenia, thrombocytopenia, and anemia. Adverse events occurring in >10% of AML patients receiving LEUKINE in controlled clinical trials and reported in a higher frequency than placebo were: fever, skin reactions, metabolic disturbances, nausea, vomiting, weight-loss, edema, and anorexia.

If ANC >20,000 cells/mm3 or if platelet counts >500,000/mm3, LEUKINE administration should be interrupted or the dose reduced by half. Twice weekly monitoring of CBC with differential should be performed.

LEUKINE therapy should be discontinued if disease progression is detected during treatment.

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

6701801BS (11981) Revision date 4/08 US License 1791

Rx only

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE LEUKINE is Use Following Induction Chemotherapy in Acute Myelogenous Leukemia indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of LEUKINE have not been assessed in patients with AML under 55 years of age.

The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification.

Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progenitor Cells LEUKINE is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of LEUKINE following peripheral blood progenitor cell transplantation.

Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation LEUKINE is indicated for acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin’s disease undergoing autologous bone marrow transplantation (BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin’s disease, LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential cell counts performed twice per week.

Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation LEUKINE is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization.

Use in Bone Marrow Transplantation Failure or Engraftment Delay LEUKINE is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. LEUKINE has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay, no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF) score ≤ two (see CLINICAL EXPERIENCE). Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential performed twice per week.

CONTRAINDICATIONS LEUKINE is contraindicated: 1) in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%); 2) in patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product; 3) for concomitant use with chemotherapy and radiotherapy.

Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received LEUKINE and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without LEUKINE. The patients randomized to LEUKINE had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.11 WARNINGS Pediatric Use Benzyl alcohol is a constituent of liquid LEUKINE and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Fluid Retention Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies using LEUKINE at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention (LEUKINE vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed LEUKINE, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINE may aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has been reversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.

Sequestration of granulocytes in the pulmonary circulation has been Respiratory Symptoms documented following LEUKINE infusion12 and dyspnea has been reported occasionally in patients treated with LEUKINE. Special attention should be given to respiratory symptoms during or immediately following LEUKINE infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during LEUKINE administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. LEUKINE should be administered with caution in patients with hypoxia.

Cardiovascular Symptoms Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of LEUKINE. LEUKINE should be used with caution in patients with preexisting cardiac disease.

Renal and Hepatic Dysfunction In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of LEUKINE administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between LEUKINE (250 mcg/m2/day by 2-hour IV infusion) and placebotreated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during LEUKINE administration.

PRECAUTIONS General Parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, LEUKINE therapy should immediately be discontinued and appropriate therapy initiated.

A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of LEUKINE in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment.

Stimulation of marrow precursors with LEUKINE may result in a rapid rise in white blood cell (WBC) count. If the ANC exceeds 20,000 cells/mm3 or if the platelet count exceeds 500,000/mm3, LEUKINE administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within three to seven days following cessation of LEUKINE therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts.

Growth Factor Potential LEUKINE is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that LEUKINE can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics.

Should disease progression be detected during LEUKINE treatment, LEUKINE therapy should be discontinued.

LEUKINE has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolled studies without evidence of increased relapse rates.13, 14, 15 Controlled studies have not been performed in patients with MDS.

Use in Patients Receiving Purged Bone Marrow LEUKINE is effective in accelerating myeloid recovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to LEUKINE. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 x 104/kg), a beneficial effect of LEUKINE on myeloid engraftment has been reported.16 Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy In patients who before autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of LEUKINE on myeloid reconstitution may be limited.

Use in Patients with Malignancy Undergoing LEUKINE-Mobilized PBPC Collection When using LEUKINE to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released and reinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied and the data are inconclusive.

Information for Patients LEUKINE should be used under the guidance and supervision of a health care professional. However, when the physician determines that LEUKINE may be used outside of the hospital or office setting, persons who will be administering LEUKINE should be instructed as to the proper dose, and the method of reconstituting and administering LEUKINE (see DOSAGE AND ADMINISTRATION). If home use is prescribed, patients should be instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, drug product, and diluent. A puncture resistant container should be used by the patient for the disposal of used needles.

Patients should be informed of the serious and most common adverse reactions associated with LEUKINE administration (see ADVERSE REACTIONS). Female patients of childbearing potential should be advised of the possible risks to the fetus of LEUKINE (see PRECAUTIONS, Pregnancy Category C).

Laboratory Monitoring LEUKINE can induce variable increases in WBC and/or platelet counts. In order to avoid potential complications of excessive leukocytosis (WBC >50,000 cells/mm3; ANC >20,000 cells/mm3), a CBC is recommended twice per week during LEUKINE therapy. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least biweekly during LEUKINE administration. Body weight and hydration status should be carefully monitored during LEUKINE administration.

Drug Interaction Interactions between LEUKINE and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of LEUKINE, such as lithium and corticosteroids, should be used with caution.

Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted with LEUKINE to evaluate the carcinogenic potential or the effect on fertility.

Pregnancy (Category C) Animal reproduction studies have not been conducted with LEUKINE. It is not known whether LEUKINE can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. LEUKINE should be given to a pregnant woman only if clearly needed.

Nursing Mothers It is not known whether LEUKINE is excreted in human milk. Because many drugs are excreted in human milk, LEUKINE should be administered to a nursing woman only if clearly needed.

Pediatric Use Safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that LEUKINE does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with LEUKINE in clinical trials at doses ranging from 60-1,000 mcg/m2/day intravenously and 4-1,500 mcg/m2/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see WARNINGS).

Geriatric Use In the clinical trials, experience in older patients (age ≥65 years), was limited to the acute myelogenous leukemia (AML) study. Of the 52 patients treated with LEUKINE in this randomized study, 22 patients were age 65-70 years and 30 patients were age 55-64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65-70 yrs) vs younger patients (55-64 yrs). Greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS Autologous and Allogeneic Bone Marrow Transplantation LEUKINE is generally well tolerated.

In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral blood progenitor cell transplantation, events reported in at least 10% of patients who received IV LEUKINE or placebo were as reported in Table 6.

No significant differences were observed between LEUKINE and placebo-treated patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS). In addition, there was no significant difference in relapse rate and 24 month survival between the LEUKINE and placebotreated patients.

In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients who received IV LEUKINE or placebo were as reported in Table 7.

There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the LEUKINE and placebo-treated patients.

Adverse events observed for the patients treated with LEUKINE in the historically-controlled BMT failure study were similar to those reported in the placebo-controlled studies. In addition, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with LEUKINE in the graft failure study.

In uncontrolled Phase I/II studies with LEUKINE in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, and rash.

Reports of events occurring with marketed LEUKINE include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities.

In patients with preexisting edema, capillary leak syndrome, pleural and/or pericardial effusion, administration of LEUKINE may aggravate fluid retention (see WARNINGS). Body weight and hydration status should be carefully monitored during LEUKINE administration.

Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients.

Acute Myelogenous Leukemia Adverse events reported in at least 10% of patients who received LEUKINE or placebo were as reported in Table 8.

Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between LEUKINE and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the LEUKINE group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the LEUKINE and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate.

In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the LEUKINE treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two LEUKINE treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when LEUKINE was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).15 Antibody Formation Serum samples collected before and after LEUKINE treatment from 214 patients with a variety of underlying diseases have been examined for immunogenicity based on the presence of antibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving LEUKINE by continuous IV infusion (three patients) or subcutaneous injection (SC)(two patients) for 28 to 84 days in multiple courses. All five patients had impaired hematopoiesis before the administration of LEUKINE and consequently the effect of the development of anti-GM-CSF antibodies on normal hematopoiesis could not be assessed. Antibody studies of 75 patients with Crohn’s disease receiving LEUKINE by subcutaneous injection with normal hematopoiesis and no other immunosuppressive drugs showed one patient (1.3%) with detectable neutralizing antibodies. The clinical relevance of the presence of these antibodies are unknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of the therapeutic effect of LEUKINE secondary to formation of neutralizing antibody remain a theoretical possibility.

Serious allergic and anaphylactoid reactions have been reported with LEUKINE but the rate of occurrence of antibodies in such patients has not been assessed.

Overdosage The maximum amount of LEUKINE that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of LEUKINE. In case of overdosage, LEUKINE therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.

Table 6

Percent of AuBMT Patients Reporting Events LEUKINE Placebo Events by Body System (n=79) (n=77) Body, General 95 96 Fever 78 Mucous membrane disorder 75 Asthenia 66 51 Malaise 57 51 Sepsis 11 14 Digestive System 90 96 Nausea Diarrhea 89 82 85 90 Vomiting 54 58 Anorexia GI disorder 37 47 GI hemorrhage 27 33 Stomatitis 24 29 Liver damage 13 14 Skin and Appendages Alopecia 73 74 44 38 Rash

LEUKINE Placebo Events by Body System (n=79) (n=77) Metabolic, Nutritional Disorder Edema 34 35 11 7 Peripheral edema Respiratory System Dyspnea 28 31 20 23 Lung disorder Hemic and Lymphatic System Blood dyscrasia 25 27 Cardiovascular System Hemorrhage 23 30 Urogenital System Urinary tract disorder 14 13 Kidney function abnormal 8 10 Nervous System CNS disorder 11 16

Table 7

Percent of Allogeneic BMT Patients Reporting Events LEUKINE Events by Body System (n=53) Body, General 77 Fever 38 Abdominal pain 36 Headache Chills 25 17 Pain Asthenia 17 Chest pain 15 9 Back pain Digestive System Diarrhea 81 Nausea 70 70 Vomiting Stomatitis 62 Anorexia 51 Dyspepsia 17 13 Hematemesis Dysphagia 11 11 GI hemorrhage 8 Constipation Skin and Appendages Rash 70 45 Alopecia Pruritis 23 Musculo-skeletal System 21 Bone pain Arthralgia 11 Special Senses Eye hemorrhage 11 Cardiovascular System Hypertension 34 Tachycardia 11

Placebo (n=56) 80 23 36 20 36 20 9 18 66 66 57 63 57 20 7 7 5 11 73 45 13 5 4 0 32 9

LEUKINE Placebo (n=56) Events by Body System (n=53) Metabolic/Nutritional Disorders Bilirubinemia 30 27 25 23 Hyperglycemia 15 21 Peripheral edema Increased creatinine 15 14 15 9 Hypomagnesemia 13 16 Increased SGPT Edema 13 11 Increased alk. phosphatase 8 14 Respiratory System 23 13 Pharyngitis Epistaxis 17 16 15 14 Dyspnea 11 14 Rhinitis Hemic and Lymphatic System Thrombocytopenia 19 34 17 29 Leukopenia Petechia 6 11 Agranulocytosis 6 11 Urogenital System Hematuria 9 21 Nervous System Paresthesia 11 13 11 9 Insomnia Anxiety 11 2 Laboratory Abnormalities* 41 49 High glucose 27 36 Low albumin High BUN 23 17 Low calcium 2 7 17 8 High cholesterol

*Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratory measurements.

Table 8

Percent of AML Patients Reporting Events LEUKINE Events by Body System (n=52) Body, General Fever (no infection) 81 Infection 65 37 Weight loss Weight gain 8 19 Chills 12 Allergy Sweats 6 Digestive System Nausea 58 Liver 77 Diarrhea 52 Vomiting 46 Stomatitis 42 Anorexia 13 Abdominal distention 4 Skin and Appendages Skin 77 Alopecia 37

Placebo (n=47) 74 68 28 21 26 15 13 55 83 53 34 43 11 13 45 51

LEUKINE Placebo (n=47) Events by Body System (n=52) Metabolic/Nutritional Disorder Metabolic 58 49 Edema 25 23 Respiratory System Pulmonary 48 64 Hemic and Lymphatic System Coagulation 19 21 Cardiovascular System Hemorrhage 29 43 Hypertension 25 32 Cardiac 23 32 Hypotension 13 26 Urogenital System GU 50 57 Nervous System Neuro-clinical 42 53 Neuro-motor 25 26 Neuro-psych 15 26 Neuro-sensory 6 11

REFERENCES 11. Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colonystimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the southwest oncology group. JCO 1995; 13(7):1632-1641.

12. Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocyte-macrophage colonystimulating factor in cancer patients: A phase Ib clinical study. In Behring Institute Research Communications, Colony Stimulating Factors-CSF. International Symposium, Garmisch-Partenkirchen, West Germany. 1988; 83:107-118.

13. Estey EH, Dixon D, Kantarjian H, et al. Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with Ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1990; 75(9):1766-1769.

14. Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. NEJM 1987; 317:1545-1552.

15. Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte-macrophage colony stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78(5):1190-1197.

16. Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood 1989; 73(3):849-857. © 2008, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496. Licensed under Research Corporation Technologies U.S. Patent No. 5,602,007, and under Novartis Corporation U.S. Patent Nos. 5,942,221; 5,908,763; 5,895,646; 5,891,429; and 5,720,952.

Manufactured by:

Bayer HealthCare Pharmaceuticals, LLC. Seattle, WA 98101 US License No. 1791

6701801BS

(11981)

Revised April 2008

A SUSAN GOODIN, PHARMD, FCCP, BCOP

PATRICK MEDINA, PHARMD, BCOP

s this issue goes to press, cancer clinicians and researchers from around the world are gathering in Orlando, Florida, for the annual meeting of the American Society of Clinical Oncology.

The abstracts were recently released with reports of advances in cancer prevention, diagnosis, and treatment as well as in basic research leading to development of new therapies. At the same time, oncology pharmacists are preparing for the 5th Annual Meeting of the Hematology/Oncology Pharmacy Association, where exciting new developments in pharmacy research and practice will be presented.

The latest cancer statistics reported this week by the American Cancer Society attest to the progress being made in the fight against cancer. In 2006 (the latest year for which statistics are available), there were 181 cancer deaths per 100,000 people, down

from 184 in 2005. Although modest, these changes show a continuing downward trend in cancer deaths, attributed to earlier detection and improved treatment.

Not only are new treatments emerging for cancers such as advanced melanoma, as discussed in the article by LeAnn Norris, but new research is leading to reevaluation of older agents, such as gefitinib for non–smallcell lung cancer, as discussed in the continuing education article by Edward S. Kim and his colleagues. But, as their study shows, cancer therapies not only have to be compared in terms of safety and efficacy but also in terms of their impact on quality of life. As Karen Oishi points out in her commentary, patients and their families must be informed about the available treatment options, and preferences regarding treatments, their potential side effects, and cost must be considered.

The recent news reports of a mother and

Coming Soon CE article: Follow-up Care for Colorectal Cancer Survivors Setting Up a Chemotherapy Prep Area in a Community Practice Ixabepilone: A New Treatment for Metastatic Breast Cancer Overcoming Barriers to Appropriate Use of Opioids for Cancer Pain Reports from the 2009 Annual Meeting of the American Society of Clinical Oncology, the 5th Annual Conference of the Hematology/Oncology Pharmacy Association

For a free subscription go to www.theoncologypharmacist.com June 2009

her 13-year-old son who fled after a courtordered treatment for the son’s lymphoma illustrate how complex these decisions may be and how important it is to establish good communication with patients and their families.

The theme of the ASCO meeting this year is personalized medicine. Advances in understanding of the genetics and biology of cancer and identification of biomarkers have made it possible to tailor cancer treatments to the biological characteristics of the individual patient. But beyond this, the patient’s values, beliefs, preferences, and lifestyle must be taken into account as well, and treatment options must be clearly communicated to the patient and his or her family. In this capacity, pharmacists are essential to patient care playing an important role in counseling patients about treatment options and appropriate use.

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EDITORS’ LETTER

A Letter from the Editors

Vol. 2, No. 4

June 2009

Feature Articles CONTENTS

12

Departments

Skin Cancers

3

Editor’s Letter

5

Medical Minutes

6

In the Literature

Recent advances in the diagnosis and treatment of melanoma

15

Cancer Complications Current and emerging therapies for MRSA in patients with cancer

23

Continuing Education Oral biologic therapy versus chemotherapy for pretreated NSCLC

30

9

Safe Handling Initiative highlights the need for increased attention, education about occupational drug exposure

News Notes

28

Recent FDA Approvals

31

Oncology Drug Codes

33

Meetings

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Johns Hopkins Bayview Medical Center Baltimore, MD

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June 2009

MEDICAL MINUTES

Medical Minutes

BY JOHN SCHIESZER

Combining Chemo with a Common Virus May Help Patients with Advanced Cancer Researchers are now combining a drug developed from the naturally occurring reovirus with chemotherapy agents to help improve survival rates in patients with advanced cancers. The drug, Reolysin (Oncolytics Biotech Inc), is demonstrating promising results in combination with certain chemotherapeutic agents.

The reovirus preferentially replicates in cancer cells with an activated RAS pathway, while sparing normal cells. Approximately two thirds of all cancers have an activated RAS pathway, including most metastatic disease. Viral replication within cancer cells causes them to burst open, releasing more virus to infect other cells.

Results from a phase 1/2 trial of Reolysin combined with paclitaxel/carboplatin for patients with advanced cancers showed positive results. Fifteen head and neck cancer patients were treated, and all but one had prior platinum treatment. Of 12 patients evalu-

able for clinical response, five had partial response and four had had stable disease for periods ranging from 2 to 6 months.

For patients who have been followed for at least 6 months since their initial treatment, median progressionfree survival (PFS) is currently 6 months and overall survival is 7 months. The literature suggests that platinum-refractory patients typically have a PFS of approximately 2 months and a median survival range of 4.5 to 6.5 months. Although these data look good, the overall survival figure may, in fact, improve further as many of the patients are still alive.

These results have led Oncolytics Biotech to announce that its first pivotal phase 3 trial will use the same treatment combination in head and neck cancer patients who have failed traditional platinum-based therapies. The trial is expected to get under way within the next 4 to 6 months.

John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute.

He can be reached at medminutes@aol.com.

High-Dose Radiation May Help Improve Lung Cancer Survival Higher doses of radiation combined with chemotherapy may improve survival in patients with stage III lung cancer, according to researchers in Michigan. They have found that giving chemotherapy at the same time as radiation enhances the effect of both.

Increasing the dose of radiation over the course of treatment was also found to increase survival.

“When patients are diagnosed with stage III lung cancer, surgery is often not an option, and survival rates are typically quite low.

Finding new ways to improve survival, even in small increments, is crucial,” said senior study author Feng-Ming Kong, MD, PhD, who is an associate professor of radiation oncology at the University of Michigan, Ann Arbor.

Kong and his colleagues compared survival among 237 patients treated with radiation alone, with radiation followed by chemotherapy, and with radiation and chemotherapy given at the same time.

A total of 31 patients were also enrolled in a study in which the radiation dose was increased throughout the course of the treatment.

The researchers found that patients treated with radiation alone had the worst overall survival rates, living only an average of 7.4 months after diagnosis. intensity treatment category to $7131 for Adding chemotherapy increased surthose in the high-intensity category. vival to 14.9 months when it was adminSurvival rates across all intensity categories istered after completion of radiation and were similar.

15.8 months when administered at the “What this indicates is that some doctors same time as radiation.

After 5 years, are providing potentially unnecessary care, 19.4% of the patients receiving concuror care without measurable benefit to the rent chemotherapy were still alive, compatient. It makes sense to many doctors and pared with only 7.5% of patients receivpatients that more would be better, but, ing sequential chemotherapy. unfortunately, there can be unintended con“Our study shows chemotherapy helps, sequences or unneeded care,” said study and high-dose radiation helps. But it’s author Brent Hollenbeck, MD, who is an challenging to administer these treatassistant professor of urology at the ments at the same time because of the University of Michigan Medical School, potential toxicity associated with the Ann Arbor. high-dose radiation,” Kong explained.

The study found that patients treated The Michigan researchers are curmore aggressively had more imaging procerently assessing use of positron-emission dures and more invasive surgical procedures. tomography imaging during the course The aggressively treated patients were also of lung cancer treatment to personalize nearly twice as likely to require major medhigh-dose radiation therapy in individical interventions, and were 2.5 times more ual patients.

As the tumor becomes likely to undergo radical cystectomy. smaller during treatment, increasing the “By reducing unnecessary healthcare, we radiation dose will become more toleracan reduce wasteful spending, which will ble because it will be targeting a smaller lessen the cost burden of bladder cancer, one area.

The researchers believe this strateof the most expensive cancers to treat from gy could lead to improved treatment diagnosis to death,” Hollenbeck explained. outcomes in many patients.

More Intense Bladder Cancer Treatment Does Not Appear to Improve Survival Although aggressive therapy may be beneficial for some cancers, that does not appear to be the case for patients with early bladder cancer. A new study of thousands of patients with early-stage bladder cancer has found that despite enduring more invasive tests and medical procedures, patients who were treated aggressively for early-stage bladder cancer had no better survival than patients who were treated less aggressively. In addition, the aggressively treated patients were more likely to undergo major surgery to have their bladder removed.

In this study, researchers gathered data from the Surveillance, Epidemiology and End Results (SEER) Medicare database to identify patients who were diagnosed with early-stage bladder cancer between 1992 and 2002 and the physician primarily responsible for their care (Hollenbeck BK, et al. J Natl Cancer Inst. 2009;101:543-545).

They identified 20,713 patients and 940 physicians. Each doctor included in the study had treated at least 10 patients for bladder cancer. The researchers found that average per-patient treatment expenditures ranged from $2830 for physicians in the low-

June 2009

G REEN H ILL H EALTHCARE C OMMUNICATIONS

5

IN THE LITERATURE

In the Literature

was funded by GlaxoSmithKline.

Grunberg SM, et al. Lancet Oncol.

May 8, 2009. Epub ahead of print.

Concise Reviews of Studies Relevant to Cancer Care ■ Cancer Survivors More Likely ■ Cetuximab plus FOLFIRI Reduces Risk of Progression of Metastatic Colorectal Cancer Background: Researchers investigated the efficacy of cetuximab plus FOLFIRI (irinotecan, fluorouracil, and leucovorin) as first-line treatment for metastatic colorectal cancer. The researchers also sought to find associations between the mutation status of the Kirsten rat sarcoma (KRAS) gene and clinical response to cetuximab.

Design: Patients with epidermal growth factor receptor–positive colorectal cancer with unresectable metastases were randomized to receive FOLFIRI either alone or in combination with cetuximab.

Summary: This study adds to the growing number of reports showing the significant association between KRAS mutation status and tumor response.

The researchers found that cetuximab benefit was limited to patients with wild-type KRAS tumors. However, they found no significant difference in overall survival. Grade 3/4 adverse events, which were more frequent with the combination therapy, included skin reactions, infusion-related reactions, and diarrhea.

Takeaway: Cetuximab plus FOLFIRI increased progression-free survival by 1.2 months in patients with metastatic colorectal cancer wild-type KRAS tumors.

Van Custem E, et al. N Engl J Med. 2009;360:1408-1417.

Takeaway: The three-drug regimen (casopitant mesylate, dexamethasone, ondansetron) significantly reduces CINV in patients receiving highly emetogenic chemotherapy compared with the two-drug regimen (dexamethasone, ondansetron). This study

E RBITUX

■ Addition of Casopitant Mesylate Reduces CINV Background: Management of chemotherapy-induced nausea and vomiting (CINV) remains an issue for patients receiving highly emetogenic chemotherapy. The addition of casopitant mesylate to a regimen of dexamethasone and ondansetron may help prevent delayed-phase CINV. Design: In a multicenter, randomized, double-blind, placebo-controlled trial, chemo-naïve patients with malignant solid tumors were randomized to receive placebo, single oral dose (150 mg) of casopitant mesylate, or 3-day intravenous (90 mg on day 1) plus oral (50 mg on days 2 and 3) casopitant mesylate. The primary end point was the proportion of patients without vomiting, retching, or use of rescue medications in the first 120 hours.

Summary: More patients in the casopitant groups achieved complete response after cycle 1 (66% in the placebo group, 86% in the oral casopitant group, and 80% in the intravenous plus oral casopitant group). This improvement was sustained over multiple cycles.

Adverse events included neutropenia, febrile neutropenia, and dehydration.

6

G REEN H ILL H EALTHCARE C OMMUNICATIONS

®

to Be Unemployed Background: Almost half of all cancer survivors are younger than 65 years, a group for which cancer and its treatment could alter employment opportunities. However, the association between survivorship and employment status is unknown.

Design: Researchers performed a meta-analysis using data found through a systematic search of studies published between 1966 and June 2008 from the MEDLINE, CINAHL, PsycINFO, and OSH-ROM databases. Meta-regression analysis was performed to assess associations of unemployment with cancer type, country of origin, average age at diagnosis, and background unemployment rate.

Summary: Cancer survivors were 1.37 times more likely to be unem-

(cetuximab): FOR PATIENTS WITH HEAD AND NECK C ANCER

ERBITUX + RT: 26% reduction in Risk of Death from SCCHN1,2

Important Safety Information1 Infusion Reactions I Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest I Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Cardiopulmonary Arrest I Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy Pulmonary Toxicity I Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed Dermatologic Toxicities I In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects ERBITUX Plus Radiation Therapy and Cisplatin I The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2 ) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

June 2009

■ Gemcitabine and Vinorelbine Effective in Children with Hodgkin’s Disease Background: Both gemcitabine and vinorelbine have significant singleagent response rates in pediatric patients with heavily pretreated relapsed/refractory Hodgkin’s disease.

The efficacy and toxicity of a combination of these two agents (ie, GV) were assessed for this population by the Children’s Oncology Group.

Design: In a phase 2 trial, patients

received, on days 1 and 8 of each 21day cycle, vinorelbine 25 mg/m2/dose via intravenous (IV) push before gemcitabine 25 mg/m2/dose IV over 100 minutes. Response (including complete response, very good partial response, partial response) was evaluated every two cycles.

Summary: In patients aged 10.7 to 29.4 years who had received at least two prior chemotherapy regimens, some having undergone prior autologous stem-cell transplantation, measur-

ERBITUX + RT (%) (n = 208)

able responses were seen in 76% of assessable patients. Hematologic toxicity was prominent in all treatment cycles. Nonhematologic grade 3 and 4 toxicity was less common.

Takeaway: GV is an effective and well-tolerated reinduction regimen for children with relapsed or refractory Hodgkin’s disease. Further evaluation of GV in this population is warranted.

Cole PD, et al; for the Children’s Oncology Group. J Clin Oncol. 2009;27: 1456-1461.

RT Alone (%) (n = 212)

No. (%) of Patients ERBITUX + RT (n = 211)

Grades 1-4

RT Alone (n = 213)

Delivery of planned RT dose Adequate delivery per protocol Inadequate delivery per protocol

184 (87.2) 27 (12.8)

187 (87.8)

Grade 3/4

Grades 1-4

Grade 3/4

Mucositis/stomatitis

93

56

94

52

Dysphagia

65

26

63

30

Xerostomia

72

5

71

3

Radiation dermatitis

86

23

90

18

26 (12.2) I

† No difference in radiation dose delivered between the 2 treatment groups in a randomized trial comparing ERBITUX + RT versus RT alone in patients with locally or regionally advanced SCCHN.2

The incidences of grades 3/4 xerostomia, mucositis/stomatitis, and radiation dermatitis were more frequent in the ERBITUX plus RT arm

INDICATIONS Head and Neck Cancer I ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck1 IERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed1 SCCHN = squamous cell carcinoma of the head and neck; RT = radiation therapy.

Electrolyte Depletion I Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary Late Radiation Toxicities I The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone.

The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms Pregnancy I In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus Adverse Events I The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus I The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection I The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) For more information, please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

References: 1. ERBITUX® (cetuximab) Package Insert. ImClone Systems Incorporated, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543; November 2008. 2. Bonner JA, Harari PM, Giralt J, et al.

Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567-578. 3. Data on file, Bristol-Myers Squibb, ERBI 001. © 2009, ImClone Systems Incorporated, New York, New York 10014, U.S.A. and Bristol-Myers Squibb Company, Princeton, New Jersey 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone Systems Incorporated.

693US09AB03511

June 2009

3/09

Please see brief summary of Full Prescribing Information including boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent page.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

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IN THE LITERATURE

ployed than healthy controls. Survivors of breast cancer, gastrointestinal cancers, and cancer of the female reproductive organs were at an increased risk for unemployment.

Takeaway: To improve employment outcomes, clinical and supportive services should be aimed at better management of symptoms, rehabilitation, and workplace accommodation for disabled survivors.

De Boer AGEM, et al. JAMA. 2009; 301:753-762.

IN THE LITERATURE

■ Adjuvant Chemotherapy Improves Survival in Older Women with Early-Stage Breast Cancer Background: In the United States, the average age at diagnosis of breast cancer is approximately 63 years, and most deaths occur in women 65 years or older. However, older women are underrepresented in clinical trials.

Design: Patients with stage I, II, IIIA, or IIIB breast cancer were randomized to receive either standard chemothera-

py or capecitabine. Endocrine therapy was recommended when applicable. A Bayesian statistical design was used to test the noninferiority of capecitabine as compared with standard chemotherapy. The primary end point was relapsefree survival.

Summary: At 2 years, patients who received capecitabine were twice as likely to have a relapse and almost twice as likely to die as patients who received standard chemotherapy. At 3 years, the rate of relapse-free survival

was 68% for patients who received capecitabine and 85% in those who received standard chemotherapy.

Takeaway: Standard adjuvant chemotherapy is superior to capecitabine in patients with early-stage breast cancer who are 65 years of age or older.

Muss HB, et al; for the CALB Investigators. N Engl J Med. 2009;360:2005-2065.

Erbitux® (cetuximab) Solution for intravenous use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.]

INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.]

Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients.

Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]

Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

8

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Know?

Did you

According to new American Cancer Society statistics, about 562,340 American men and women will die of cancer in 2009. The most common fatal cancers are cancers of the lung and bronchus, prostate, and colorectum in men and cancers of the lung and bronchus, breast, and colorectum in women.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.]

• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions with Erbitux (cetuximab) (incidence *25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials 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.

The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 1:

Incidence of Selected Adverse Events (*10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=212) (n=208) Grades Grades Grades Grades Body System Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole 56 4 49 5 Asthenia Fever1 29 1 13 1 Headache 19 <1 8 <1 Infusion Reaction2 15 3 2 0 Infection 13 1 9 1 1 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, high3 Aspartate Transaminase, high3 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, high3 Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneform Rash4 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3

4

Includes cases also reported as infusion reaction.

Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

June 2009

News Updates of Relevance to Everyday Oncology Practice ■ BRCA1 and BRCA2 Patents Challenged A potential landmark lawsuit was filed on May 12, 2009, in the federal court of New York against Myriad Genetics Laboratories, the manufacturer of BRACAnalysis, and the US Patent

Office. The suit challenges the decision to grant a patent on a gene to a single company. Plaintiffs argue that BRCA testing would improve if market forces were allowed to work, and that the restriction on competition blocks other companies to develop alterna-

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2: Incidence of Selected Adverse Events Occurring in *10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy BSC alone Erbitux plus BSC (n=274) (n=288) Body System Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology 89 12 16 <1 Rash/Desquamation Dry Skin 49 0 11 0 Pruritus 40 2 8 0 27 1 6 1 Other-Dermatology 21 0 4 0 Nail Changes Body as a Whole 89 33 76 26 Fatigue 30 1 18 <1 Fever Infusion Reactions3 20 5 13 <1 4 0 Rigors, Chills Pain Abdominal Pain 59 14 52 16 51 16 34 7 Pain-Other 33 4 11 0 Headache Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 29 2 19 1 Cough Gastrointestinal Constipation 46 4 38 5 39 2 20 2 Diarrhea Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 23 10 18 8 Other-Gastrointestinal Mouth Dryness 11 0 4 0 Infection 35 13 17 6 Infection without neutropenia Neurology Insomnia 30 1 15 1 15 6 9 2 Confusion Anxiety 14 2 8 1 Depression 13 1 6 <1 1

Adverse reactions occurring more frequently in Erbitux treated patients compared with controls.

Adverse events were graded using the NCI CTC, V 2.0.

Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusion related.

BSC = best supportive care

2 3

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%).

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

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

DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

June 2009

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations.

Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.

OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).

Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Erbitux® is a registered trademark of ImClone Systems Incorporated.

Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876 Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543

Copyright ©2008 by ImClone Systems Incorporated and Bristol-Myers Squibb Company. All rights reserved.

1236886A4 ER-B0001A-11-08

Rev November 2008

drome, which can lead to heart arrhythmias and sudden death (New York Times. May 12, 2009).

■ Sleep Problems May Lead to Increased Cancer Pain Pain and fatigue may be reduced by interventions to help patients with cancer deal with sleep problems and depressed mood. Further, pain management may help alleviate trouble sleeping. Stepanski and colleagues analyzed demographic, clinical, and patient-reported outcomes data from 11,445 cancer patients undergoing treatment in a large community oncology practice using structural equation modeling. The data were split so that a model was constructed using half of the patients; this model was then cross-validated on the remaining patients. Although fatigue was best represented as a latent variable, significant direct effects were found for trouble sleeping, depressed mood, and pain (J Sleep Med. April 15, 2009).

■ Risk for False-positive Findings with Multiple Cancer Screenings As the number of cancer screening tests increases, the likelihood for falsepositives may also increase, along with diagnostic interventions. Researchers examined this cumulative risk, by analyzing data from patients participating in the ongoing Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Croswell and colleagues found that after 14 tests, the cumulative risk of having at least one false-positive is 60.4% and the cumulative risk of undergoing an invasive diagnostic procedure prompted by a false-positive result is 28.5% for men and 22.1% for women. Based on this likelihood, physicians should educate their patients about these risks during cancer screening discussions (Ann Fam Med. 2009;7:212-222).

■ FDA Invests in Product Safety The US Food and Drug Administration (FDA) has requested a budget of $3.2 billion to protect and promote the public health—a 19% increase over the current year’s budget. The 2010 request proposes two major initiatives: protecting America’s food supply and safer medical products. The safer medical products effort ($166.4 million) provides resources to improve the safety of human and animal drugs, medical devices, vaccines, blood, and other medical products by strengthening the safety and security of the supply chain for medical products. Included in this effort is the follow-on biologics and drug importation initiative ($5 million), which proposes a new authority for the FDA to approve follow-on biologics and provides funding for the FDA to develop policies to allow Americans to buy drugs approved in other countries (www.fda.gov/bbs/topics/ NEWS/ 2009/NEW02013.html).

G REEN H ILL H EALTHCARE C OMMUNICATIONS

9

NEWS NOTES

News Notes

tives, as well as to interpret or compare gene sequences that involve the patented genes. Myriad has not yet responded publicly to the suit. The American Civil Liberties Union, which organized the lawsuit, pointed out that the problem is with the US Patent Office, not Myriad specifically.

Single companies also hold patents on the HFE gene, which is linked to hereditary hemochromatosis, the CFTR gene, which is linked to cystic fibrosis, and a genetic test on long QT syn-

PHARMACY PRACTICE

HOPA President Foresees Opportunities Continued from cover with others on the healthcare team.

Then I did my pharmacy practice residency at the University of California San Diego Medical Center and my oncology pharmacy practice residency at the University of Colorado. In 2004, I attended the Making a Difference in Oncology meeting and heard about HOPA, which was just being formed. I joined and immediately got involved in committee work within HOPA. That evolved into serving in leadership positions as secretary, president-elect, and now as president.

What have been some of the highlights of your year as HOPA president?

This has been a year of laying the foundation for the organization and watching the initial parts of the strategic plan come to fruition. HOPA is still a relatively young organization, and we’re still very much a member volunteer organization. As we grow, we rely on our members to take time out of their busy lives to get everything done.

HOPA has accomplished so many things this year it is hard to pick out the highlights. Last year when Jim Koeller was president, HOPA University was established; this year, the education and standards committee has developed programming that allowed our membership to have online access to continuing education programs. As HOPA Universtiy expands, we will be able to provide relevant and high-quality continuing education not only at annual meetings but also throughout the year.

As the organization moves forward, it is important that we are able to provide funding opportunities so the membership can do research, especially in areas were there are gaps in knowledge regarding oncology patient care and oncology pharmacy. The research committee has worked hard to establish an Investigator Research Award for which we hope to award sometime this year.

sessions offered at each organization’s annual meeting. In addition, we’ve been working with other oncology professional groups, including the American Society of Clinical Oncology and the Oncology Nursing Society, on developing standards for the safety of the administration of chemotherapy. We are looking to work with the American Association of Colleges of Pharmacy on the development of an oncology pharmacy curriculum guide to provide some standardization of what we as practitioners feel is important and needs to be communicated to pharmacy students.

The hope here is that students are exposed early and really understand what oncology pharmacy involves and what opportunities it offers.

Are there any plans to establish regional chapters of HOPA? There is nothing formally set up within HOPA to provide regional chapters, but some regional or state societies have asked for input in some of their programming and meetings. This is part of HOPA’s strategic plan and, as we move forward, we are looking at the viability of regional or local chapters within our own organization to allow exchange of ideas and education between members on a more frequent basis. At this point, with HOPA’s rapid growth, we’re spending a lot of time establishing necessary infrastructure within the organization, getting policies and procedures set up, and making sure committees have directions and are functioning at a high level.

What are some of the highlights that we can look forward to at this year’s meeting?

This year is going to be another great meeting with many learning opportunities. It’s been organized by an active program committee, with the goal of involving the membership more in the education process by having more debates, case discussions, and more

We’ve been looking at ways that pharmacists can be included as a provider of services and able to bill for their cognitive and other services.

We’ve also been working collaboratively with several outside organizations, such as the American Society of Health-System Pharmacists and the American College of Clinical Pharmacy, on how we can improve and streamline the oncology pharmacy board certification process. As a result, HOPA will now provide the testing and continuing education credit for the BCOP [boardcertified oncology pharmacist] specialty

10

diverse workshops with hands-on type activities to meet the needs of our different types of members. We’re trying to get to the nitty gritty of what we do as hematology/oncology pharmacists and how we do it and to get a lot of input from our membership. Our members are very talented and active, and we’re trying to tap into their expertise. At the opening session, Ernest Anderson from the Association of Community Cancer

G REEN H ILL H EALTHCARE C OMMUNICATIONS

We are having students do some volunteer work at the meeting, and we hope that once they see the great things we do on a daily basis, it will encourage them to consider a career in oncology pharmacy.

Centers will present the keynote address, providing us with a global, costeffectiveness perspective on cancer care, which is something we may not think about on a daily basis when we are taking care of patients. We will be having a town hall meeting to give the members a voice and allow them to discuss issues that are important to HOPA and hematology/oncology pharmacy. Additionally, HOPA is sponsoring the Run from the Sun, our first annual run/walk and charity drive benefiting the Richard David Kann Melanoma Foundation.

Does HOPA get involved in policy and legislative issues on the state or national level?

We have a legislative affairs committee, and they have been quite active this year, mostly at the federal level. For instance, they have written letters to the Centers for Medicare & Medicaid Services regarding funding for Medicare services and to the FDA regarding drug shortages. We are working with a group of 11 pharmacy organizations to support payment systems within pharmacy and to assess what impact the new funding that is going to be coming through with the federal stimulus package will have on pharmacy in general and on oncology pharmacy in particular. We’ve been looking at ways that pharmacists can be included as a provider of services and able to bill for their cognitive and other services. The president-elect of HOPA, Philip Johnson from Moffitt, has a passion for legislative issues, so I foresee that in the coming years there will be even more work done in the legislative realm.

Does HOPA have any plans to address the predicted oncology workforce shortage?

The HOPA board has just begun thinking about what this shortage will be and what impact it will have on oncology pharmacy. We’ve started talking about forming task forces to provide recommendations on how HOPA should approach this shortage. The shortage appears to be one that mostly affects physicians, physician assistants, nurse practitioners, and others who provide more direct, basic care more than some pharmacists. It may actually provide opportunities for oncology pharmacists to become more integrated into

patient care, allowing us to be more active mid-level practitioners. There’s going to be a need for that, and oncology pharmacists can provide high-quality direct patient care if given the opportunity. Another area where oncology pharmacy may see some gains would be in the area of research. If there are fewer practitioners to see patients, that means fewer people with time to do research, which opens a door for oncology pharmacists to do some rigorous research in the area of oncology pharmacy.

Does HOPA offer any research support or other programs for pharmacy students or residents to encourage them to get involved in oncology pharmacy?

HOPA has done a good job of reaching out to the residents. At our meeting every year we have a resident poster reception, which is very well attended.

A large majority of the oncology pharmacy practice residents across the country come to HOPA and present their residency projects. We offer merit-based travel grants to some of the residents so they can attend the meeting. We’ve tried to incorporate residents on every committee as well as several new practitioners so they can get involved in the organization early in their career and become part of the committee structure. HOPA realizes that it is important to train the future of our organization. This year, students from NOVA Southeastern University will serve as volunteers at the meeting, and we hope that once they see the great things we do on a daily basis, it will encourage them to consider a career in oncology pharmacy.

Any final comments?

I think HOPA is a great organization with wonderful and talented people.

Although we are relatively young, we are quite poised to become a leader in oncology care. We are working to develop standards and guidelines that will impact oncology patient care and outcomes. It has been a great honor to serve as president. I look forward to HOPA’s future successes and being a part of this outstanding organization throughout my career.

—Karen Rosenberg

June 2009

A pioneer in cancer innovation — exploring new directions

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A family of firsts — Our proven therapeutics are standards of care in 5 of the 6 leading causes of cancer mortality in the United States.

A robust pipeline — Our molecules in development target the fundamental mechanisms of cancer growth and include a HER dimerization inhibitor, a Hedgehog pathway inhibitor, an antibody–drug conjugate, and antibodies targeting cancer cell-surface antigens.

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Our goal is to fundamentally change the way cancer is treated — not just with incremental advances, but with new standards of care.

www.BioOncology.com

© 2009 Genentech USA, Inc. All rights reserved. 9708100 Printed in USA.

Skin Cancers

SKIN CANCERS

Recent Advances in the Diagnosis and Treatment of Melanoma

BY LEANN B. NORRIS, PHARMD, BCPS, BCOP SOUTH CAROLINA COLLEGE OF PHARMACY, COLUMBIA

M

ore than 75% of all skin cancer deaths are from melanoma.

Although this cancer is curable in early stages, treatment for advanced melanoma continues to be a challenge.1 Recently, significant advances were made in the areas of diagnostics, immunotherapy, and targeted therapies. This review examines studies presented at several national meetings in 2008, including the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) Congress, in addition to significant advances published in the literature.

New diagnostic tests Patient prognosis in melanoma is highly dependent on early diagnosis. In fact, 5-year survival rates are 45% in patients with an ulcerated melanoma >4-mm thick as compared with 95% in patients with thin melanoma (<1 mm).2 Early detection and surgical excision is currently the best treatment option in patients with thin melanoma. Optimization of early diagnosis is needed, however, as most pigmented skin lesions are hard to assess with the naked eye.3 Dermoscopy is one option that allows for cross-polarization of light, which makes the epidermis translucent and permits visualization of the epidermis and superficial epidermis.4,5 A metaanalysis of studies performed in the clinical setting was conducted to evaluate the accuracy of dermoscopy compared with the naked eye for diagnosis of cutaneous melanoma.6 The findings supported previous data that indicated that dermoscopy is indeed significantly better at differentiating between melanoma and nonmelanoma lesions. Like other techniques, appropriate use of dermoscopy requires training, but when used correctly, it can be extremely beneficial in identifying patients who need further evaluation.

New drugs/drug regimens Immunotherapy has been a mainstay in both adjuvant treatment for melanoma and metastatic disease. In the United States, interferon alfa-2b and interleukin-2 (IL-2) are currently the only two approved immunotherapeutic agents for melanoma. Disappointing response rates and undesirable toxicities, however, affect adherence rates and limit use of these agents.

12

During the 2008 ASCO meeting, promising data pertaining to new and current immunologic agents were presented supporting the future role of immunotherapy as the primary treatment for melanoma.

Antagonistic monoclonal antibodies The discovery of agents that block cytotoxic T lymphocyte antigen-4 (CTLA-4) has already demonstrated promising results in T-cell–mediated killing, antitumor T-cell immune function, and subsequent inhibition of tumor recurrence.7 Immune-related adverse events (IRAEs) are a unique phenomenon associated with CTLA-4

mumab with or without budesonide.

This study included treatment-naïve and previously treated patients with advanced melanoma. Study end points included overall survival, response rates, and grade 2 diarrhea or higher. Overall survival at 10.5 months was not reached, but 1-year survival rates were 58% (ipilimumab + budesonide) and 59.1% (ipilimumab + placebo). Treatment-naïve patients had a 1-year survival rate of 71%. Response rates were seen in both groups (ipilimumab + budesonide, 12.1%; ipilimumab + placebo, 15.8%), but no differences were seen in the incidence of grade 2-4 diarrhea in the 2 groups. One of the

Synergistic activity has been seen preclinically with anti-CD137 agents and other treatment options, such as chemotherapy, radiation, and antiCTLA-4 therapy. blockade. Unlike the current approved immunotherapeutic agents, CTLA-4 blockade and subsequent IRAEs have been linked to tumor efficacy. O’Day and associates presented data from a large multicenter phase 2 trial of ipilimumab in patients with advanced melanoma who had failed prior chemotherapy and/or IL-2. Patients received 10 mg/kg of this agent intravenously (IV) every 3 weeks for four cycles followed by maintenance treatment for patients with stable or responding disease every 12 weeks.

Overall median survival was 10.2 months, and 24 (57%) of 42 patients experienced stable disease that had not progressed at the time of presentation.

Of 155 patients, overall rate of disease control (stable disease + partial response + partial response) exceeded 27% (42/155). IRAEs occurred in 22% of patients (grade 3 or 4), with gastrointestinal and hepatic toxicities occurring in 8% and 7% of patients, respectively.

These data are encouraging when looking at overall survival and period of disease control.8 Another study sought to determine whether prophylactic budesonide would prevent IRAEs associated with antiCTLA-4 agents. Weber and colleagues presented results of a phase 2 trial evaluating the safety and efficacy of ipili-

G REEN H ILL H EALTHCARE C OMMUNICATIONS

most interesting findings was that tumors stopped growing in 30% of patients at the end of the 12-week period, with another 10% to 20% showing responses later.9 At ASCO, data were also presented on the other anti-CTLA-4 agent, tremelimumab, being studied for treatment of melanoma. Ribas and colleagues presented a late-breaking abstract that evaluated the role of chemotherapy (temozolamide or dacarbazine) versus tremelimumab alone as first-line therapy. This large, randomized trial included 655 patients with stage IIIc-IV melanoma. Tremelimumab, 15 mg/kg, was administered every day for 90 days in the treatment group compared with oral temozolamide, 200 mg/m2 on days 1 to 5 every 28 days, or dacarbazine, 1000 mg/m2 IV every 21 days, in the chemotherapy arm. Primary end points included overall survival, with secondary end points evaluating response, durable tumor response, 6month progression-free survival (PFS), and safety. Unfortunately, tremelimumab failed to demonstrate a significant improvement in overall survival compared with standard chemotherapy.

Overall survival with tremelimumab was 11.76 months versus 10.71 months for chemotherapy (with overlapping confidence intervals and hazard ratio =

1.04). Therefore, the data and safety monitoring board recommended early discontinuation after two thirds of the events had occurred. Response rates were similar at 9.1 versus 10.1. Additionally, 6-month PFS was similar (18.6 and 14.1) in the two arms. Diarrhea (43% overall), pruritus (25%), and rash (23%) were the most common toxicities in the tremelimumab arm. The authors concluded that tremelimumab failed to show overall survival benefits in stage IIIc-IV melanoma patients as first-line therapy.10

Agonistic monoclonal antibodies Several new immunologic agents are currently under investigation for the treatment of melanoma. A phase 1/2 study of BMS-663513 (4-1BB), a fully humanized anti-CD137 nonblocking agonist monoclonal IgG4 antibody, was conducted in patients with melanoma.

CD137 is expressed on a variety of cells and is thought to have several mechanisms of action. Additionally, synergistic activity has been seen preclinically with anti-CD137 agents and other treatment options, such as chemotherapy, radiation, and anti-CTLA-4 therapy. In both dose-finding phases of this study, patients with melanoma were enrolled and experienced minor dose-limiting toxicities and partial response rates of significant duration. Ongoing studies are investigating use of this agent in patients with metastatic melanoma.11 A phase 1 study of CD40, a novel target found on B-cell malignancies and many solid tumors, was conducted in patients with melanoma. Partial responses were seen in four (27%) of 15 patients, with one near-complete response that lasted for 18 months.

Unfortunately, CD40 activity may be lost as tumors become metastatic.

Therefore, studies are evaluating the potential of using CD40 therapy after initial therapy for optimal immune activation.12 Other phase 1 data were presented on an anti-programmed death (PD)-1 monoclonal antibody, PD-1(CD279).

PD-1 blockade augments the proliferation of melanoma-specific CD8 T cells.

Antitumor activity was found in one patient with a partial response, and four patients experienced tumor regressions. Interestingly, the one patient who experienced a partial response had failed chemotherapy, bevacizumab, and Continued on page 14

June 2009

STRONG. FROM THE START.

FOR A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When patients experience acute chemotherapy-induced nausea and vomiting (CINV) during their first cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3 ALOXI®: A single IV dose lasts up to 5 days after MEC4,5* The only IV 5-HT3 antiemetic specifically approved for prevention of both acute and delayed CINV associated with MEC6* Can be used with multiple-day chemotherapy regimens6† * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.

ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. Most commonly reported adverse reactions include headache (9%) and constipation (5%).

Please see the following brief summary of prescribing information.

REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al.

5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapyinduced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved Prevention of Moderately Emetogenic Chemotherapy-induced Nausea and Vomiting with Palonosetron, a Pharmacologically Novel 5-HT3 Receptor Antagonist: Results of a Phase III, Single-Dose Trial Versus Dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc. © 2008 Eisai Inc. All rights reserved. Printed in USA. AL349 A 10/08

www.ALOXI.com

Diagnosis and Treatment of Melanoma Continued from page 12

SKIN CANCERS

cetuximab. Major toxicities with this agent were similar to toxicities associated with anti-CTLA-4 therapy.13

Tyrosine kinase inhibitors Two phase 2 studies presented at ASCO involved multitargeted kinase inhibitors. Axitinib, a vascular endothelial growth factor receptor (VEGFR) ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy.

Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection.

ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists.

ADVERSE REACTIONS 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 reported in practice.

In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron.

Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1).

Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study.

In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear.

Dermatological: < 1%: allergic dermatitis, rash.

Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia.

Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

14

and platelet-derived growth factor receptor (PDGFR) inhibitor, was administered to 32 patients with refractory advanced melanoma. An objective response rate of 19% (6/32) was achieved. Stable disease occurred in 28% of patients, and 30% were progression free at 6 months. This study proved that further research is needed

to evaluate the effects of axitinib both alone and in combination with other agents for melanoma.14 Sunitinib, a c-kit (CD117) and multitargeted tyrosine kinase inhibitor, was evaluated in a phase 2 trial in pretreated metastatic uveal melanoma patients. Tumors were stained for c-kit activity. Overall, 15 patients, who had at least 10% c-kit

General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome.

Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.

Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.

Musculoskeletal: < 1%: arthralgia.

Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia.

Psychiatric: 1%: anxiety, < 1%: euphoric mood.

Urinary System: < 1%: urinary retention.

Vascular: < 1%: vein discoloration, vein distention.

Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. 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.

Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.

DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low.

Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.

In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase).

A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.

Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed.

Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.

Nursing Mothers It is not known whether palonosetron 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 and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established.

Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients.

Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated.

Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects.

Dosage adjustment is not necessary in patients with any degree of renal impairment.

Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.

Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized.

OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care.

Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.

Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.

PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information].

• Patients should be instructed to read the patient insert.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2008 Eisai Inc. All rights reserved. Printed in USA. AL350 10/08

staining, were treated with sunitinib.

One patient had an objective response rate and 10 patients had documented stable disease. PFS exceeded 5 months, and response durations and stable disease were >4 months. Although these data are preliminary, the study offers promising results and supports potential research in patients with hard-totreat uveal melanoma.15

Large clinical trials Interferon therapy has been a mainstay in the treatment of melanoma to decrease disease recurrence and slow disease progression. Pegylated interferon has a unique molecular structure that allows for a longer half-life, extended action, and once-weekly dosing. Although studied in other disease states, pegylated interferon use has not been established in the treatment of melanoma. In 2008, Eggermont and associates published data evaluating the benefit of pegylated interferon alfa-2b in resected stage III melanoma patients compared with observation. Peg-interferon was administered as 6 µg/kg per week for 8 weeks then 3 µg/kg per week for an intended duration of 5 years. The primary end point was recurrence-free survival with secondary end points including distant metastasis-free survival, overall survival, and safety. More than 1200 patients were enrolled in the study—608 patients in the interferon group and 613 in the observation group.

Pegylated interferon alfa-2b was administered for an overall median of 12 months. The 4-year rate of recurrencefree survival was 45.6% in the interferon group compared with 38.9% in the observation group. There was no significant difference, however, in overall survival between the two groups. Grade 3/4 adverse events occurred more frequently in the treatment group than in the observation group. The most common toxicities in patients treated with pegylated interferon alfa-2b included fatigue, hepatotoxicity, and depression.

Therefore, the toxicity profile is similar to the profile for interferon alfa-2b. The data suggest that pegylated interferon alfa-2b may have a role in the treatment of patients with resected stage III melanomas.16 In a phase 2 trial, McDermott and associates evaluated the efficacy and safety of the sorafenib/dacarbazine combination in patients with advanced melanoma.17 Patients enrolled in the study had stage III unresectable or stage IV melanoma. Patients received dacarbazine 1000 mg/m2 either with placebo or in combination with sorafenib, 400 mg, twice a day for a maximum of 16 cycles. The primary end point was PFS. Time to progression, response rate, and overall survival were secondary end Continued on page 29

June 2009

Current and Emerging Therapies for MRSA in Patients with Cancer

BY KATHRYN SCHULTZ, PHARMD, BCPS; AND EMILY MACKLER, PHARMD, BCOP UNIVERSITY OF MICHIGAN HEALTH SYSTEM, ANN ARBOR

T

here are many factors to consider when selecting a therapy for methicillin-resistant Staphylococcus aureus (MRSA) in patients with cancer, including, but not limited to: severity of illness, site of infection, presence of chemotherapy side effects, such as neutropenia and mucositis, drug interactions, adverse events, recent antibiotic therapy, previous infections and susceptibilities, and presence of indwelling catheters. Formal guidelines have not been published for the management of MRSA in cancer patients; however, the management of neutropenic fever and cancer-related infections has been addressed by the Infectious Diseases Society of America (IDSA) and the National Comprehensive Cancer Network (NCCN) in their published guidelines released in 2002 and 2008, respectively.1,2 In recent years, selection of antibiotics to treat MRSA has come into question. Glycopeptide-resistant MRSA was not recognized until 1996, almost 40 years after the introduction of vancomycin.3 However, concern for a potential vancomycin minimum inhibitory concentration (MIC) creep, clinical failure of vancomycin in the treatment of susceptible MRSA infections with increased MICs, and increasing incidence of vancomycin-resistant organisms, especially enterococci, has increased the need to consider alternative therapies.2-4 The repertoire of therapies to combat MRSA has increased over the past decade, and new therapies are continually in development.3-6 Organizations such as IDSA have made efforts to enhance appropriate prescribing of vancomycin by publishing guidelines for its use in neutropenic fever and catheter-related infections.1,7 The Centers for Disease Control and Prevention (CDC) also launched the Campaign to Prevent Antimicrobial Resistance in Healthcare Settings, which encourages thoughtful prescribing of vancomycin.8 The purpose of this campaign is to improve antimicrobial stewardship and prevent emergence of vancomycin-resistant organisms. These guidelines and the CDC campaign emphasize that vancomycin should be initiated only in specific situations and recommend deescalating empiric therapy by discontinuing vancomycin after

June 2009

72 hours based on clinical and microbiological data.1,2,7

MRSA prophylaxis The most common sites for MRSA infections are the skin and skin structure, the bloodstream, and the respiratory tract.2 Patients with cancer frequently have central venous catheters (CVCs) and thus are at a higher risk for CVC-related infection. Vancomycin is frequently used in regions where methicillin-resistant staphylococci are found in high incidence. In an effort to prevent CVC-related infections, the use of antibiotic lock therapy in certain cases to allow retention of a tunneled CVC (TCVC) or implantable device has been studied.7,9 Van de Wetering and van Woensel evaluated the efficacy of antibiotics in the prevention of early TCVC infections in oncology patients.9 Early TCVC infections are defined as those that develop within 45 days after placement of the catheter.

The researchers concluded that administration of teicoplanin or vancomycin

mens in preventing gram-positive infections has also been investigated.10-13 None of these regimens were specifically evaluated in patients with cancer, but decolonization has been evaluated as a preventive means of decreasing the incidence of MRSA infection. Intranasal mupirocin was evaluated with or without whole-body washing with chlorhexidine in all MRSA-colonized hospital and nursing home patients, and both agents were evaluated in MRSAcolonized intensive care unit (ICU) patients.10,11 In these studies, intranasal mupirocin with chlorhexidine body wash reduced skin colonization compared with mupirocin and placebo solution, but did not eradicate MRSA from other body sites. Therefore there was not a significant difference in the number of patients who were MRSA-free 30 days after treatment.10 In ICU patients, combination intranasal mupirocin and chlorhexidine bathing reduced the incidence of MRSA colonization during the hospitalization, but evaluation did not include

The repertoire of therapies to combat MRSA has increased over the past decade, and new therapies are continually in development. (two studies each) did not significantly decrease the incidence of gram-positive bacteremia when compared with placebo. However, when the TCVC was flushed with a vancomycin and heparin solution, the incidence of bacteremia was reduced compared with heparin flushing alone (odds ratio [OR] = 0.43; confidence interval [CI]: 0.21-0.87).9 Thus, prophylactic flushing of TCVC with a vancomycin/ heparin solution may prevent grampositive infections in oncology patients. It should be noted, however, that flushes were used in only five studies included in the systematic review.

Additionally, the NCCN does not endorse the use of vancomycin/ heparin solution flushes because of concerns that bacterial resistance would increase if this method were widely practiced.2 The value of other prophylactic regi-

longer time points for evaluation.11 A second body-wash solution, octenidine dihydrochloride, in combination with mupirocin was evaluated in hospitalized patients colonized with MRSA.12 This combination decreased MRSA colonization of tested body sites during the hospital stay. The degree of reduction varied by body site, nasal carriage showing the greatest reduction (88.5%).12 In the above-mentioned studies, the value of the therapeutic agents used for MRSA decolonization was determined by rates of skin decolonization, but one agent has been studied to determine whether it would prevent MRSA pneumonia.13 In a study by Silvestri and associates, oral vancomycin administered as a 4% gel to the oropharynx every 6 hours was evaluated in ICU patients who were expected to be intubated for >72 hours. The study found that over a 1-year period, there were significantly

fewer nosocomial lower airway infections in the vancomycin group compared with the control group (OR = 0.26; 95% CI: 0.08-0.88; P <.001). One MRSA infection was prevented for every seven patients treated with vancomycin gel.13 Although the efficacy of various MRSA prophylaxis regimens has been studied in the general hospital population and in ICU patients, the utility of these agents to prevent MRSA infections in patients with cancer has not specifically been studied, and their routine use is not recommended in cancer patients at this time.

MRSA treatment MRSA has historically been associated with patients in the hospital setting. More recently, however, community-associated strains of MRSA have emerged. As mentioned earlier, the most common sites for MRSA infections are the skin and skin structure, the bloodstream, and the respiratory tract.2 Therapeutic agents for treatment of MRSA include both intravenous (IV) and oral antibiotics. Many of the available oral antibiotics are options for patients with less-severe skin and skinstructure infections (SSSIs)or as stepdown therapy after a course of IV treatment. Oral agents that are available for the treatment of MRSA include doxycycline, trimethoprim-sulfamethoxazole (cotrimoxazole), clindamycin, and linezolid. Of the IV antibiotics available for treatment of MRSA infections, vancomycin has been the gold standard. Second-line therapies include linezolid, an oxazolidinone; daptomycin, a cyclic lipopeptide; and tigecycline, a glycylcycline. Because of its adverse event profile, quinupristin-dalfopristin, a streptogramin, is usually third-line (Table 1).1,3-5,7,14-19 When neutropenia confounds the clinical scenario, current guidelines recommend adding vancomycin to a neutropenic fever antibiotic regimen after 72 hours of continuing fever if grampositive cocci in clusters are found on a gram stain, MRSA is identified by culture, or if a patient is at high risk for infection with MRSA.1 Localized MRSA cellulitis in cancer patients is treated with recommended therapies for SSSIs as indicated by the

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Cancer Complications

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Table 1. Available Therapies for MRSA

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Recommended dosage and administration

Therapy

Mechanism of action

Vancomycin

Tricyclic glycopeptide inhibits 15 mg/kg IV q12h bacterial cell wall synthesis, Renal dose adjustment alters permeability of bacterial cell membrane and interferes with RNA synthesis

Supporting literature

Special considerations

MRSA bacteremia: first-line per IDSA guidelines1,7

Increasing resistance3,4

Bactericidal; slow, timedependent Quinupristindalfopristin (Q-D)

Inhibits early and late phases of protein synthesis of 50S ribosomal subunit, respectively Bactericidal

cSSSIs: 7.5 mg/kg IV q12h Catheter-related bacteremia: 1 g IV q12h vancomycin vs 7.5 mg/kg IV q8h Q-D15 VRE bacteremia: • 62% cancer patients 7.5 mg/kg IV q8h • Combined all staphylococcal infections (only 2 MRSA) Not FDA approved for • Phase 2 trial MRSA bacteremia • 1/2 Staphylococcus aureus in vancomycin group and 2/5 in 7.5-mg/kg Q-D group showed clinical response • MRSA not segregated from MSSA • Safety profiles comparable

Myalgia and arthralgia Venous reactions (50%) and change in infusion site required (70%) Inhibits 3A4

MRSA infections: Q-D 7.5 mg/kg IV q8h16 • Culture-proven MRSA • Various sources (bacteremia, catheter-related bacteremia, respiratory, etc) • All patients failed/intolerant to previous therapy • Administration adverse events led to discontinuation of therapy (20%) • Overall success 71.1% (n = 90) and 66.7% in patients clinically and bacteriologically evaluable Q-D 7.5 mg/kg IV q8h vs vancomycin 1 g IV q12h17 • Gram-positive nosocomial pneumonia • Patients with significant neutropenia (ANC <500/mm3) were excluded • Clinical success 56.3% vs 58.3% • Tendency for drug-related venous adverse events 28/145 vs 16/138 (P = .056) Linezolid

Oxazolidinone inhibits Pneumonia or cSSSIs: bacterial protein synthesis by 600 mg IV or PO q12h binding to the 70S initiation complex Bacteriostatic

Linezolid 600 mg IV q12h vs vancomycin 1g IV q12h18 • Neutropenic patients with cancer • No significant difference in clinical efficacy • Increased drug-related adverse events in vancomycin group (52/303 vs 72/300; P <.04) Linezolid 600 mg IV or PO q12h vs comparator group (vancomycin, oxacillin, dicloxacillin)14 • Increased risk of mortality in linezolid-treated catheterrelated bloodstream infections in seriously ill patients (78/363 vs 58/363) in 84 days after first dose

Daptomycin

Cyclic lipopeptide rapidly depolarizes bacterial cell membrane via formation of potassium efflux channels Bactericidal; rapid, concentration-dependent

Tigecycline

Glycycline inhibits 30S ribosomal subunit to inhibit protein translation

cSSSIs: 4 mg/kg IV q24h Bacteremia: 6 mg/kg IV q24h Renal dose adjustment

cSSSIs: Initial dose: 100 mg IV once, then 50 mg IV q12h

Bacteriostatic

IV and PO available Thrombocytopenia, specifically in treatment courses ≥14 days Risk of serotonin syndrome when concomitantly used with agents that increase serotonin concentrations such as serotonin agonists and selective serotonin reuptake inhibitors

Daptomycin 6 mg/kg IV daily vs low-dose gentamicin + antistaphylococcal penicillin or vancomycin19 • Staphylococcus aureus bacteremia ± endocarditis • Successful outcome 42 days after therapy: 44.2% vs 41.7% • Clinically significant renal dysfunction: 11% vs 26.3% (P = .004) • Successful outcome in patients with MRSA: 44.4% vs 31.8% (NS) • Any drug-related adverse events: 35% vs 42.2% (P = .29) • Serious adverse events: 51.7% vs 44.8% (P = .3)

Poor lung penetration and binds to lung surfactant

In vitro activity against MRSA5 No clinical studies evaluating use in the treatment of MRSA

Time-dependent killing

Increased creatine phosphokinase 2.8%-6.7% Rhabdomyolysis: case reports with 6 mg/kg IV q24h dosing Increased risk with acute renal failure or concomitant use of drugs that may cause rhabdomyolysis (ie, statins)

Drug achieves poor serum concentration—not recommended for treatment of bacteremia2

ANC indicates absolute neutrophil count; cSSSIs, complicated skin and skin-structure infections; FDA, US Food and Drug Administration; IDSA, Infectious Diseases Society of America; IV, intravenous; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; NS, not significant; PO, by mouth; RNA, ribonucleic acid; VRE, vancomycin-resistant enterococci.

Continued on page 18 16

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June 2009

# Teva is 1 in Oncology Products

View Teva’s complete line of oncology products at www.tevausa.com/oncology

Data derived from the use of information under license from the following IMS Health Information Service: IMS NSP Audit, MAT 9/08. Data is proprietary to IMS Health. ©2009, Teva Pharmaceuticals USA

8349 A

19 Hughes • Irvine, California 92618 800.729.9991 • www.tevausa.com

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Current and Emerging Therapies for MRSA Continued from page 16

IDSA guidelines.20 For initial therapy, IV vancomycin is used empirically, but treatment may be changed to oral therapies such as linezolid or clindamycin depending on sensitivities of the particular strain, if available, and if the patient’s condition is improved. However, patients are treated differently if they are immunocompromised (neutropenic, recent chemotherapy, cellmediated immunodeficiency). Treatment of an immunocompromised patient changes drug selection for SSSI to broad-spectrum empiric therapy that includes coverage of resistant gram-positive bacteria, such as MRSA. The therapy selected is typically vancomycin, but linezolid, daptomycin, or quinupristin/dalfopristin are alternative options.2,20 Treatment of community-acquired pneumonia in cancer patients follows the IDSA guidelines, but may be complicated by recent antibiotic therapy, increasing severity of illness, history of MRSA infection, or known colonization, thus necessitating the addition of vancomycin or linezolid and consideration of hospitalization for pneumonia.2,21 Hospital-acquired pneumonia in cancer patients, whether early or lateonset, tends to necessitate treatment as for late-onset pneumonia, especially if the patient has received antibiotics in the past 90 days, has had a recent hospitalization, or is from a healthcare-associated facility.2,22 The third common site of MRSA infections in cancer patients is the bloodstream. These infections are commonly associated with vascular access devices (VADs), because the device provides a potential site of infection.

The course of action for VAD infections depends on whether it is categorized as an entry-site or exit-site infection.2 VAD exit-site infections may be treated with antimicrobial therapy without the removal of the catheter. However, patients with a serious, catheter-related infection (tunnel or port pocket) should have the catheter removed immediately.2 Whether the MRSA infection is categorized as community-acquired or hospital-acquired, vancomycin is the first-line treatment for bacteremia in this population. Doxycycline and clindamycin are not recommended monotherapies for MRSA bacteremia because of increasing resistance.5 Additionally, linezolid is not recommended for catheter-related infections in light of the US Food and Drug Administration (FDA) alert (Table 1). Also, it is not FDA approved for bacteremia, thus adding to the limitations of drug selection for MRSA bacteremia.23

MRSA emerging therapies The increasing incidence of MRSA infections has led to a need for develop-

18

Table 2. Pipeline Drug Status Drug class

Agent

Approval status

Glycopeptide

Teicoplanin

Approved in Europe

Lipoglycopeptides

Telavancin

1/26/09: NDA submitted for nosocomial pneumonia 3/5/08: FDA accepted for review Theravance’s complete response to approvable letter for cSSSIs 12/7/06: NDA submitted for cSSSIs

Dalbavancin

9/9/08: Pfizer withdrew all marketing applications for cSSSIs in adults 12/21/07: Pfizer received an FDA approvable letter; working with the FDA to provide additional data on dalbavancin in regard to the noninferiority draft guidance for approval of antibiotics published by the FDA

Oritavancin

10/9/08: FDA sent a complete response letter stating that the company’s NDA did not demonstrate safety and efficacy for treatment of cSSSIs. FDA requested that a sufficient number of patients with MRSA as the cause of the cSSSI be enrolled to determine efficacy in that subset 12/8/08: FDA said insufficient data had been provided 02/08: NDA submitted for cSSSIs Phase 2 for catheter-related bacteremia

Cephalosporins

Ceftobiprole

11/26/08: FDA sent a complete response letter stating that the NDA for ceftobiprole could not be approved at this time and requested the company to audit work at the clinical sites 11/08: In the week prior to the FDA’s complete response letter, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended to the European Union that ceftobiprole be approved for cSSSIs 3/19/08: FDA requested more information about how ceftobiprole works 3/18/08: FDA issued approvable letter for cSSSIs and diabetic foot infections

Ceftaroline

10/27/08: Phase 3 results were presented at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting in Washington, DC. The abstract stated that ceftaroline was noninferior to vancomycin/aztreonam for the treatment of cSSSIs 02/07: Two phase 3 studies initiated for cSSSIs

Zinc metalloenzyme

Lysostaphin

No trials under way

cSSSIs indicates complicated skin and skin-structure infections; FDA, US Food and Drug Administration; NDA, new drug application.

Sources: References 23-28.

ment of new therapeutic options for MRSA (Table 2).23-28 There are a few new glycopeptides: teicoplanin, telavancin, dalbavancin, and oritavancin.

Teicoplanin is not currently available in the United States. In a study of patients with hematologic malignancies who presented with neutropenic fever, either teicoplanin or vancomycin was added after documentation of bacteremia due to gram-positive cocci.29 Therapeutic success was seen in 55 (87.3%) of 63 patients in the teicoplanin 6 mg/kg IV twice daily for 2 days, then once-daily arm and 56 (91.8%) of 91 patients in the vancomycin 15 mg/kg every 12 hours arm (P = .560). In bacteremia caused by staphylococci, successful outcome was seen in 45 (86.5%) of 52

G REEN H ILL H EALTHCARE C OMMUNICATIONS

patients treated with teicoplanin compared with 45 (93.8%) of 48 patients treated with vancomycin.

Telavancin, a lipoglycopeptide antibiotic, is active against MRSA. It has two mechanisms of action, which contribute to its bactericidal activity against MRSA. It inhibits cell-wall synthesis and depolarizes the bacterial cell membrane.6 In two recently published phase 3 trials, telavancin was at least as effective as vancomycin (91% vs 86%) in curing MRSA SSSIs.30 Adverse events of telavancin and vancomycin led to withdrawal from the study in 8% and 6% of patients, respectively. Phase 3 trials comparing telavancin with vancomycin for hospital-acquired pneumonia due to MRSA were completed in

May and June of 2007, respectively.23,24 Dalbavancin is a semisynthetic lipoglycopeptide effective against grampositive organisms including MRSA.31 The half-life of dalbavancin is longer than that of other glycopeptides at 9 to 12 days. A phase 2 prospective trial compared the safety and efficacy of two doses of dalbavancin given 1 week apart compared with vancomycin twice daily for 14 days in patients with catheter-related bloodstream infections. Of note, patients with prolonged neutropenia or those who had received immunosuppressant therapy were excluded. The overall success rate (combined clinical and microbiologic response) was greater with dalbavancin Continued on page 20

June 2009

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CANCER COMPLICATIONS

Current and Emerging Therapies for MRSA Continued from page 18

than with vancomycin (87% vs 50%; P <.05). Adverse events (oral candidiasis and diarrhea) were similar for the two drugs. No patients discontinued dalbavancin therapy, whereas two patients in the vancomycin arm withdrew from the study because of adverse events, including one with acute renal failure possibly related to vancomycin. Dalbavancin is a lipoglycopeptide, which may contribute to its efficacy in catheter-related bloodstream infections when staphylococcal organisms are imbedded in biofilms. Phase 3 studies are under way to further evaluate the safety of dalbavancin.

Oritavancin is a third lipoglycopeptide, for which a new drug application

between ceftobiprole and vancomycin, the only significant difference being a higer incidence of nausea in the ceftobiprole group (14% vs 8%; P <.05).32 A phase 2 study of ceftaroline evaluated its safety and efficacy compared with standard therapy, which included vancomycin, for treatment of cSSSIs.33 Ceftaroline was well tolerated, with 61.2% of the ceftaroline group experiencing an adverse event, similar to the 56.3% rate in the standard therapy group. Test of cure (TOC) was evaluated at predetermined time points after completion of therapy. Clinical cures at TOC were achieved in 96.7% of ceftaroline patients and 88.9% of standard therapy patients. Of microbiologic cul-

This structural difference makes lysostaphin a novel therapeutic agent for S aureus and, more importantly, antibiotic-resistant S aureus. was filed in 2008 for complicated skin and skin-structure infections (cSSSI).26 Phase 2 trials to demonstrate safety and efficacy of a once-daily agent versus an infrequent dosing schedule for the treatment of cSSSI were completed in May 2008. Although teicoplanin has been studied in treatment of bacteremia in neutropenic patients with hematologic cancers, the three lipoglycopeptides have not been studied in cancer populations. The FDA released a letter in December 2008 to the manufacturers of oritavancin requesting additional phase 3 studies that would include more patients with cSSSI that have MRSA identified as the causative organism in order to exhibit efficacy in this patient population.26 Cephalosporins have historically not been a therapeutic choice for treating MRSA. New cephalosporins, such as ceftobiprole and ceftaroline, however, are currently under development. These new agents provide broad-spectrum coverage that includes gram-positive, gram-negative, and anaerobic organisms with the added benefit of activity against MRSA and vancomycin-resistant staphylococci. The added coverage of MRSA is due to the high level of binding of these new cephalosporins to the penicillin-binding protein 2a.

Ceftobiprole has been evaluated in two phase 3 clinical trials for the treatment of cSSSIs and will be evaluated in phase 3 trials for hospital-acquired pneumonia, community-acquired pneumonia requiring hospitalization, and neutropenic fever in patients receiving chemotherapy.32 Ceftobiprole was found to be noninferior to vancomycin in treatment of cSSSIs. Similar safety and adverse event profiles were seen

20

tures that identified pathogens, 10 patients had MRSA, five in each treatment group. Clinical cure was achieved in 80% (4 of 5) of ceftaroline patients and 100% (5 of 5) of standard (vancomycin)-therapy patients.

While both new cephalosporins show promise for being effective against MRSA, it should be noted that trials to date have been of their use in treating cSSSIs; studies of their use in bacteremia and pneumonia have not been reported on or published. Interestingly, Ortho-McNeil withdrew its phase 2 study of ceftobiprole in the treatment of hospitalized patients with S aureus bacteremia because of lack of an appropriate patient population.28 At this point, no published studies are available that evaluate the use of MRSA-active cephalosporins in patients with cancer, but the manufacturers of ceftobiprole plan to conduct a study of its use in cancer patients with neutropenic fever.

Another agent under investigation, lysostaphin, is a zinc metalloenzyme that was first identified in 1964. The S aureus peptidoglycan cell wall contains a higher amount of glycine than other staphylococcal species, mainly because of the pentaglycine bridges, which provide the additional strength to the cell wall of S aureus.34 This structural difference makes lysostaphin a novel therapeutic agent for S aureus and, more importantly, antibiotic-resistant S aureus. Lysostaphin has the added advantage of being active against actively growing and nondividing cells, such as staphylococci in biofilms. Its activity is due to three enzymes: glycylglycine endopeptidase, endo-β-N–acetyl glucosamidase and N-acetyl-muramyl-L-alanine amidase. Lysostaphin has been studied for

G REEN H ILL H EALTHCARE C OMMUNICATIONS

the treatment of endocarditis synergistically with aminoglycosides, but it has the potential to be used for MRSA infections because of its unique specificity and activity against S aureus biofilms. However, it has not yet been evaluated in patients with cancer.

Conclusion Patients with cancer are prone to MRSA infections in the bloodstream, skin and skin structures, and respiratory tract. Selection of initial antibiotic therapy should take into consideration the local antimicrobial susceptibilities, site of infection, clinical condition of patient, drug allergies, and recent antibiotic use.2 There are no published guidelines for the management of MRSA infections in patients with cancer, but there are resources available from the IDSA and the NCCN to help guide antibiotic selection and prudent use of vancomycin.1,2,7,20 As more agents are developed to be effective against MRSA, it is important that we continue to evaluate them specifically for their place in treatment of patients with cancer.

References

1. Hughes WT, Armstrong D, Bodey GP, et al.

2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730-751.

2. National Comprehensive Cancer Network I. Prevention and treatment of cancer-related infections (1.2008). www.nccn.org/professionals/ physician_gls/PDF/infections.pdf. Accessed July 30, 2008.

3. Sakoulas G, Moellering RC Jr. Increasing antibiotic resistance among methicillin-resistant Staphylococcus aureus strains. Clin Infect Dis. 2008;46(suppl 5):S360-S367.

4. Tverdek FP, Crank CW, Segreti J. Antibiotic therapy of methicillin-resistant Staphylococcus aureus in critical care. Crit Care Clin. 2008;24: 249-260, vii-viii.

5. Cosgrove SE, Fowler VG Jr. Management of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2008;46(suppl 5):S386S393.

6. Naber CK. Future strategies for treating Staphylococcus aureus bloodstream infections.

Clin Microbiol Infect. 2008;14(suppl 2):26-34.

7. Mermel LA, Farr BM, Sherertz RJ, et al.

Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis. 2001; 32:1249-1272.

8. Centers for Disease Control and Prevention.

December 5, 2003. Fact sheet: 12 steps to prevent antimicrobial resistance among hospitalized adults. www.cdc.gov/drugresistance/healthcare/ ha/12steps_HA.htm. Accessed August 12, 2008.

9. van de Wetering MD, van Woensel JB. Prophylactic antibiotics for preventing early central venous catheter gram positive infections in oncology patients. Cochrane Database System Rev. 2007;(1):CD003295.

10. Wendt C, Schinke S, Württemberger M, et al.

Value of whole-body washing with chlorhexidine for the eradication of methicillin-resistant Staphylococcus aureus: a randomized, placebocontrolled, double-blind clinical trial. Infect Control Hosp Epidemiol. 2007;28:1036-1043.

11. Ridenour G, Lampen R, Federspiel J, et al.

Selective use of intranasal mupirocin and chlorhexidine bathing and the incidence of methicillin-resistant Staphylococcus aureus colonization and infection among intensive care unit patients. Infect Control Hosp Epidemiol. 2007;28: 1155-1161.

12. Rohr U, Mueller C, Wilhelm M, et al. Methicillin-resistant Staphylococcus aureus wholebody decolonization among hospitalized patients with variable site colonization by using mupirocin in combination with octenidine dihydrochloride. J Hosp Infect. 2003;54:305-309.

13. Silvestri L, van Saene HK, Milanese M, et al.

Prevention of MRSA pneumonia by oral vancomycin decontamination: a randomized trial.

Eur Respir J. 2004;23:921-926.

14. US Food and Drug Administration. March 16, 2007. Information for healthcare professionals: Linezolid (marketed as Zyvox). www.fda.gov/ cder/drug/InfoSheets/HCP/linezolidHCP.pdf.

Accessed August 12, 2008.

15. Raad I, Bompart F, Hachem R. Prospective, randomized dose-ranging open phase II pilot study of quinupristin/dalfopristin versus vancomycin in the treatment of catheter-related staphylococcal bacteremia. Eur J Clin Microbiol Infect Dis. 1999;18:199-202.

16. Drew RH, Perfect JR, Srinath L, et al. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy.

J Antimicrob Chemother. 2000;46:775-784.

17. Fagon JY, Patrick H, Haas DW, et al. Treatment of gram-positive nosocomial pneumonia: prospective randomized comparison of quinupristin/dalfopristin versus vancomycin. Nosocomial Pneumonia Group. Am J Respir Crit Care Med. 2000;161:753-762.

18. Jaksic B, Martinelli G, Perez-Oteyza J, et al.

Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infect Dis. 2006;42:597-607.

19. Fowler VG Jr, Boucher HW, Corey GR, et al.

Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653-665.

20. Stevens DL, Bisno AL, Chambers HF, et al.

Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-1406.

21. Mandell LA, Wunderink RG, Anzueto A, et al.

Infectious Diseases Society of America/ American Thoracic Society consensus guidelines on the management of communityacquired pneumonia. Clin Infect Dis. 2007;44 (suppl 2):S27-S72.

22. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and health-care associated pneumonia. Am J Respir Crit Care Med. 2005;171: 388-416.

23. ClinicalTrials.gov. Comparison of Telavancin and Vancomycin for Hospital-Acquired Pneumonia Due to Methicillin-Resistant Staphylococcus aureus (ATTAIN 1). www.clinicaltrials. gov/ct2/show/NCT00107952?term=telavancin &rank=2. Accessed August 12, 2008.

24. ClinicalTrials.gov. Comparison of Telavancin and Vancomycin for Hospital-Acquired Pneumonia Due to Methicillin-Resistant Staphylococcus aureus (ATTAIN 2). www.clinicaltrials. gov/ct2/show/NCT00124020?term=telavancin &rank=3. Accessed August 12, 2008.

25. Drugs.com. Pfizer to Withdraw Global Marketing Applications for Dalbavancin. www.drugs. com/nda/dalbavancin_080909.html. Accessed February 8, 2009.

26. Drugs.com. Complete Response Letter for Oritavancin. www.drugs.com/nda/oritavancin_0812 09.html. Accessed February 8, 2009.

27. Drugs.com. FDA Issues Approvable Letter for Ceftobiprole. www.drugs.com/nda/ceftobiprole_ 080318.html. Accessed August 12, 2008.

28. Drugs.com. FDA Issues Complete Response Letter for Ceftobiprole. www.drugs.com/nda/cefto biprole_080318.html. Accessed August 12, 2008.

29. D’Antonio D, Staniscia T, Piccolomini R, et al.

Addition of teicoplanin or vancomycin for the treatment of documented bacteremia due to gram-positive cocci in neutropenic patients with hematological malignancies: microbiological, clinical and economic evaluation. Chemotherapy.

2004;50:81-87.

30. Stryjewski ME, Graham DR, Wilson SE, et al.

Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms. Clin Infect Dis. 2008;46:1683-1693.

31. Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis. 2005; 40:374-380.

32. Anderson SD, Gums JG. Ceftobiprole: an extended-spectrum anti-methicillin-resistant Staphylococcus aureus cephalosporin. Ann Pharmacother. 2008;42:806-816.

33. Talbot GH, Thye D, Das A, et al. Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother. 2007; 51:3612-3616.

34. Kumar JK. Lysostaphin: an antistaphylococcal agent. Appl Microbiol Biotechnol. 2008;80:555-561.

June 2009

THANK THA ANK Y YOU O OU ffor or m making aking TThe he O Oncology ncology PPharmacist harmacist tthe he m most ost w widely idely rread ead aand nd requested requested newspaper newspaper of of the the ooncology ncology pharmacy pharmacy ccommunity ommunity

Join o over ver 10,000 10,0 000 of y your our o colleagues collea agues To T o ensure ensure u uninterrupted ninterrupted FREE FREE delivery delivery of of The The Oncology Oncology Pharmacist, Pharmacist, register att www.theoncologypharmacist.com register online online a www.theoncologypharmacist.com Written W ritten by by aand nd ffor or ooncology ncology p pharmacists harmacists ooffering ffering yyou ou the the following: following: Concise rreviews Concise eviews o off h hot ot ttopics opics iin n the the p peer-reviewed eer-reviewed literature literature b y clinical clinical sspecialists pecialists w ith k ey p oint ‘‘takeaways’ takeaways’ by with key point C overage o ey rresearch esearch sstudies tudies a nd on-the-scene on-the-scene rreports eports Coverage off k key and ffrom rom o ncology m edical m eetings oncology medical meetings C ontinuing e ducation a rticles a nd post-tests post-tests a o charge, charge, Continuing education articles and att n no o ffering y ou a convenient convenient w ay tto oo btain contact contact h ours offering you way obtain hours IInterviews nterviews w ith rrenowned enowned tthought hought lleaders eaders iin n tthe he o ncology with oncology p harmacy ccommunity ommunity pharmacy Coverage off llegislation and policy C overage o egislation a nd p olicy cchanges hanges that that affect affect cancer cancer care care iin ny our a reas of of p ractice your areas practice IICD-9-CM CD-9-CM a nd J-code J-code u pdates, s w ith F DA- a nd C ompendia-approved u ses and updates, with FDAand Compendia-approved uses

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YYour our Innovative Innovative PPartners artners iinn Medical Medical M Media edia

GASTROINTESTINAL CANCERS

Colon and Rectal Cancers Guidelines Continued from cover MD, Fox Chase Cancer Center, Philadelphia, Pennsylvania, and head of the NCCN committee for colon, rectal, and anal cancer guidelines.

“I think the KRAS story is probably the number one story of the guidelines,” Engstrom said during an interview. “I think the second one is the addition of the survivorship guidelines to our panel. I think other than lung cancer, really we’re the only cancer right now to have a full inclusion in the guidelines of survivorship. And then I think third is judging who’s resectable for liver metastasis.”

Several studies published in 2008 demonstrated that the status of the tumor KRAS gene is highly predictive of outcome with anti–epidermal growth factor receptor agents, such as cetuximab and panitumumab. However, these agents have been found to be effective only in colorectal cancer patients with tumors that express the normal (or wild-type) KRAS gene and not with tumors that express KRAS gene mutations.

So the colon and rectal cancers guide-

line updates include the recommendation that KRAS testing should be done for all patients diagnosed with metastatic colorectal cancer before finalizing their treatment plan, with these agents used only for those who have tumors with wild-type KRAS genes.

Said Engstrom, “I think the finding [from those studies] was an eye-opener to oncologists because we didn’t know why some patients didn’t respond before. Just like we have a lot of other agents that we don’t know why patients don’t respond to, such as irinotecan. Some of our patients do [respond] and some don’t. And now we’re starting to tease this apart with these molecular tests. I think this is an important new direction in the management of colorectal cancer.”

The guidelines’ new section on survivorship outlines principles for longterm follow-up care for patients in remission. In addition to monitoring these patients for disease-specific recurrence, the new guidelines stress the need for screening and monitoring for other cancers. Specifically, the guidelines state

that special attention should be paid to prevention of breast and cervical cancers among women survivors, while surveillance for prostate cancer should be stressed to male cancer survivors.

In addition, the survivorship section describes healthy lifestyle recommendations (especially exercise), the management of long-term treatment side effects, wellness counseling, and transferring care to a primary care physician.

“There are many survivors in the group of colorectal patients, and they’re a little bit neglected,” said Engstrom.

“Some of them have had colonoscopies. Many of them have had radiotherapy along with chemotherapy. I have patients that are out 20, 25, 30 years from their treatment of [colorectal] cancer and they still have some sequelae that they are living with. And nobody’s ever really talked to them about that. So I think these survivorship guidelines are important. The breast cancer patients are usually the model that we go by, but I think there are as many survivors in colorectal cancer as there are in breast cancer.”

The guideline updates also include a recommendation for the reevaluation of patients with initially unresectable metastatic colorectal disease to determine whether they would be suitable for resection following chemotherapy.

Specifically, the guidelines now include the words “potentially convertible” or “unconvertible,” which have been added to the definition of unresectable disease.

An up-front multidisciplinary team evaluation is now recommended, including a surgeon with resection expertise. “Before, we defined ‘resectable’ by what comes out, asking how many metastases are there and how large?” said Engstrom during his presentation. “Now we’re defining it by what stays in, such as preserving liver segments.”

In addition, the guideline updates provide new data on using cetuximab in treatment of patients with metastatic colorectal cancer, including in combination with specific chemotherapy drugs as an initial therapy option.

—Deborah Brauser

BREAST CANCER

Breast Cancer Guidelines Continued from cover advocates skin-sparing mastectomy, when possible, for breast reconstruction.

The updates were presented at the NCCN Annual Conference by Beryl McCormick, MD, of Memorial SloanKettering Cancer Center, New York, and Stephen B. Edge, MD, of Roswell Park Cancer Institute, Buffalo, New York.

DCIS and early breast cancer Family history suggestive of hereditary breast cancer is a reason to offer genetic counseling to patients with DCIS or early invasive breast cancer, the NCCN panel decided. Data suggest that women at high risk are increasingly opting for prophylactic mastectomy.

A Surveillance, Epidemiology and End Results (SEER) analysis of DCIS patients found the rate of bilateral mastectomy to be 6% in 1998 but 18% in 2005 (Tuttle TM, et al. J Clin Oncol. 2009; 1362-1367).

Patients with DCIS should also undergo mammography after excision, when there is uncertainty about the adequacy of excision, the panel said.

Radiotherapy recommendations Reflecting trends in whole breast ir-

22

radiation, the panel included a recommendation for computed tomography (CT)-based treatment planning, and gave the option for radiotherapy doses of 45 Gy to 50 Gy in 1.8 Gy to 2 Gy per fraction or a hypofractionated dose of 42.5 Gy at 2.66 Gy per fraction (ie, lower dose over a shorter period).

Trials have suggested that faster courses of radiotherapy will decrease the time to treatment initiation, reduce the cost of healthcare, and increase the proportion of women who complete radiotherapy after breast-conserving surgery. “We offer hypofractionation to our patients, and 60% opt for it,” McCormick said.

Radiotherapy should be considered after mastectomy in patients with one to three positive nodes, as this has been shown to reduce local recurrence and increase survival, the panel added.

The updated guidelines also contain an option for radiotherapy without additional radiation (boost) in early invasive breast cancer (stage I, IIA, or IIB or T3N1M0). The previous recommendation was for radiotherapy to the whole breast with boost. A European Organisation for Research and Treat-

G REEN H ILL H EALTHCARE C OMMUNICATIONS

ment of Cancer (EORTC) study of 5318 stage I and II patients found significant advantages to the boost except in patients aged 60 years and older (Bartelink H, et al. N Engl J Med. 2001; 345:1378-1387).

“Based on this study, the panel believed the boost had little biological value in older patients and should be optional for older patients with negative margins,” she said, adding that she often does include the boost for patients over 60 who have positive margins.

Local therapy for stage IV disease Another addition to the guidelines is the option for surgical resection and radiation therapy to the chest wall and internal mammary nodes for patients with stage IV or recurrent disease who were initially treated with mastectomy without radiation therapy.

This is supported by a database from EORTC 10801 and Danish Breast Cancer Cooperative Group 82TM of salvage treatment for local recurrence, which compared breast-conserving therapy (n = 66) to mastectomy (n = 67) in stage I and II patients (with the majority also receiving radiotherapy).

Out to 10 years, no difference in survival has emerged, with approximately 50% of both groups still alive, McCormick noted.

The panel also concluded that women who are diagnosed initially with metastatic disease may benefit from local breast surgery with or without radiation therapy. Generally, this palliative local therapy should be considered only after a response to initial systemic therapy, Edge said.

Studies have suggested that excision of a primary tumor (with negative margins) can impact survival in stage IV patients. For example, in a recent study, surgery reduced the risk of death by 51% (Bafford AC, et al. Breast Cancer Res Treat. 2009;115:7-12).

“Some 3% to 5% of women present with metastases at diagnosis, and their 5-year survival is 5% to 15%,” he noted. “Local therapy has historically been reserved for palliation in those with local progression of tumor, but for many patients, metastases are discovered only after surgery, on postoperative imaging.”

Increased survival after radiation as Continued on page 27

June 2009

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• The estimated time to complete this activity is 1 hour. Your continuing education certificate can be printed by following the directions online after successful completion of the post-test.

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LEARNING OBJECTIVES After completing this activity, the reader should be better able to: • Describe findings of phase 2 and phase 3 trials of gefitinib in non–small-cell lung cancer (NSCLC).

• Discuss the potential clinical implications of the INTEREST trial.

• Explain how patient characteristics such as race, sex, smoking history, and biomarkers such as epidermal growth factor receptor-gene-copy number may affect response to NSCLC therapy.

• Discuss management of skin toxicities associated with epidermal growth factor receptor inhibitor therapy

DISCLAIMERS The opinions or views expressed in this continuing education activity are those of the faculty and do not necessarily reflect the opinions or recommendations of the University of Nebraska Medical Center (UNMC), Center for Continuing Education.

TARGET AUDIENCE Registered pharmacists and other interested healthcare professionals, especially those caring for cancer patients.

While the University of Nebraska Medical Center, Center for Continuing Education is an ACPE-accredited organization, this does not imply endorsement by the UNMC or

COST This program is complimentary for all learners.

L

ung cancer remains a leading cause of cancer-related deaths worldwide and in the United States accounts for more cancer deaths than breast, colorectal, and prostate cancer combined.

The rate of lung cancer deaths is alarmingly high because patients usually present with advanced metastatic disease, which has limited treatment options. Standard treatment involves chemotherapy and supportive care, albeit with modest response rates and a high recurrence rate after standard first-line platinum-based doublet therapy.

Background The taxane docetaxel, at a dose of 75 mg/m2, is approved by the US Food and Drug Administration (FDA) for second-line treatment of advanced non–small-cell lung cancer (NSCLC). The pivotal trials that led to docetaxel’s approval for this indication demonstrated an improved survival and quality of life with docetaxel compared with best supportive care and compared with vinorelbine or ifosfamide chemotherapy. Side effects may include diarrhea, neuropathy, and

FACULTY/PLANNER DISCLOSURES It is the policy of the University of Nebraska Medical Center, Center for Continuing Education that all planners and faculty participating in continuing education activities provided by the University of Nebraska Medical Center, Center for Continuing Education are to disclose to the audience any real or apparent conflicts of interest with providers of commercial products and/or devices relating to the topics of this educational activity and also disclose discussion of labeled/unapproved uses of drugs or devices discussed in their presentation. The planners and faculty have been advised that this activity must be free from commercial bias and based upon all the available scientifically rigorous data from research that conforms to accepted standards of experimental design, data collection, and analysis.

June 2009

severe neutropenia. Other agents such as pemetrexed and erlotinib are also indicated for second-line treatment of NSCLC. Two randomized phase 2 trials (known as Iressa Dose Evaluation in Advanced Lung Cancer, or IDEAL 1 and 2) in patients with previously treated advanced NSCLC suggested that gefitinib—an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor that is taken orally—was efficacious and less toxic than chemotherapy in patients who had undergone prior treatment for NSCLC.1,2 Based on the data from these trials, gefitinib received accelerated approval by the FDA in 2003 as a single agent for patients with advanced lung cancer that progressed despite treatment with platinum-based and docetaxel chemotherapy. In 2005, however, a phase 3 trial (Iressa Survival Evaluation in Lung Cancer [ISEL]) showed that gefitinib compared with placebo did not improve survival in patients with NSCLC.3 The FDA subsequently altered gefitinib’s labeling, limiting its use to patients who were already receiving the drug and appeared to be benefitting from it.

The authors, reviewers, and planning committee members listed below have stated they have no significant or substantial relationship with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporter of this activity.

• Lois Colburn • Edward S. Kim, MD • Dawn Lagrosa • Brenda Ram, CMP • Lara J. Reiman • Karen Rosenberg • Jill Stein • Katie Tipton, PharmD, BCOP The following author has stated that she has the following financial relationships:

• Karen Oishi, RN, MSN, GNP, ANP, OCN, has received honoraria from sanofi-aventis, Genentech, and Novartis.

EDITORIAL BOARD Edward S. Kim, MD The University of Texas M.D. Anderson Cancer Center 1515 Holcombe Blvd.

Houston, TX 77030 Karen Oishi, RN, MSN, GNP, ANP, OCN Advanced Practice Nurse/Clinical Nurse Practitioner The University of Texas M.D. Anderson Cancer Center 1515 Holcombe Blvd.

Houston, TX 77030 Katie Tipton, PharmD, BCOP Clinical Pharmacy Specialist The University of Texas M.D. Anderson Cancer Center 1515 Holcombe Blvd.

Houston, TX 77030 PLANNING COMMITTEE Lois Colburn Executive Director Center for Continuing Education University of Nebraska Medical Center 986800 Nebraska Medical Center Omaha, NE 68198-6800 Brenda Ram, CMP Coordinator Center for Continuing Education University of Nebraska Medical Center 986800 Nebraska Medical Center Omaha, NE 68198-6800 Dawn Lagrosa Associate Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Lara J. Reiman Managing Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Karen Rosenberg Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Jill Stein 22 rue Malher Paris, France 75004

ACCREDITATION AND CONTACT HOURS STATEMENT The University of Nebraska Medical Center, Center for Continuing Education is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The ACPE provider number is 447-000-09-068-H04-P. To receive the 1 contact hour of continuing education credit, pharmacists should complete the activity requirements and evaluation at the conclusion of the activity. Approval is valid from the initial release date of June 15, 2009. The expiration date is June 15, 2010. A statement of credit will be available for printing online upon completion of the post-test with a score of 70% or better and the evaluation instrument.

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INTEREST study findings The Iressa in NSCLC Trial Evaluating Response and Survival versus Taxotere (INTEREST) was an open-label, phase 3 study that compared gefitinib with docetaxel in patients with locally advanced or metastatic NSCLC who had received at least one prior platinum-based chemotherapy regimen.4 Overall, 1466 patients were recruited from 149 centers in 24 countries and then randomized to gefitinib, 250 mg/day orally, or docetaxel, 75 mg/m2, administered as a 1-hour intravenous infusion every 3 weeks.

The two treatment groups were well matched in terms of demographic and clinical characteristics and were generally representative of a pretreated population with advanced NSCLC. There were two primary survival end points: survival in all treated patients and in those whose tumors had high EGFR-gene-copy number.

In the 1433 patients whose results were analyzed, efficacy rates were similar for gefitinib and docetaxel.

That is, gefitinib-treated patients had a median overall survival of 7.6 months versus 8.0 months in docetaxel-treated patients, while 32% of gefitinib and

34% of docetaxel patients were alive at 1 year, confirming noninferiority of gefitinib. The median progression-free survival (2.2 vs 2.7 months) and objective response rates (9.1% vs 7.6%) were also similar for the two groups.

The similar rates of overall survival were seen across multiple preplanned subgroups except in patients who received third-line treatment. In fact, patients who received third-line treatment had significantly longer survival with docetaxel than with gefitinib.

Gefitinib was better tolerated than docetaxel.

events prompting withdrawal from therapy (4% vs 11%), grade 3 to 4 adverse events (9% vs 41%), and adverse events resulting in death (1% vs 2%). The type of adverse event also differed between the two treatment groups.

Rash, acne, and diarrhea were more common with gefitinib, while hematologic toxic effects, asthenic disorders, and alopecia were more common with docetaxel.

Researchers also found that more gefitinib-treated patients had sustained and clinically relevant improvement in quality of life as assessed by Functional

More gefitinib-treated patients had sustained and clinically relevant improvement in quality of life as assessed by FACT-L total score.

Overall, gefitinib-treated patients experienced fewer treatment-related adverse events than docetaxeltreated patients (72% vs 82%), overall events (72% vs 82%), serious adverse events (4% vs 18%), adverse

Assessment of Cancer Therapy-Lung (FACT-L) total score. The FACT-L is a widely validated tool that measures quality of life in patients being treated for lung cancer using a patient-completed questionnaire.

COMMENTARY Oral Biologic Therapy versus Chemotherapy for Pretreated Non–small-cell Lung Cancer: A Pharmacist’s Perspective

BY KATIE TIPTON, PHARMD, BCOP The University of Texas M.D. Anderson Cancer Center, Houston

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ecurrent disease after primary therapy of non– small-cell lung cancer (NSCLC) has few effective treatment options. In patients with poor performance status or multiple comorbidities, practitioners must often choose between best supportive care and potential harm to the patient associated with treatment that offers poor response rates.

Docetaxel, pemetrexed, and erlotinib are the only drugs currently approved for second-line treatment of recurrent or metastatic lung cancer with response rates rarely reported to be greater than 10%. An optimal second-line treatment would have a mild side effect profile, increase quality of life, and provide improved response compared with traditional agents.

Treatments such as the oral tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib are generally well tolerated, but provide similar rates of response as chemotherapy.

Despite promising data from the phase 2 studies Iressa Dose Evaluation in Advanced Lung Cancer 1 and 2 (IDEAL 1; IDEAL 2),1,2 gefitinib was removed from the US drug market in June 2005 because of a lack in evidence of improved survival versus placebo as second-line therapy for NSCLC. The Iressa

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Survival Evaluation in Lung Cancer (ISEL) trial showed median survival of 5.6 and 5.1 months, respectively, for gefitinib and placebo.3 The study did show significant improvement in never-smokers and Asian patients for gefitinib, but no advantage for patients with adenocarcinoma or women. There has been much discussion of the issues that may have affected the trial’s outcomes. Specifically, 90% of the patient population was chemotherapy-refractory, and possible underdosing of gefitinib may have altered the outcomes of the trial.

Currently, the availability of gefitinib in the United States is limited. The drug is available through clinical trials and to patients who have and continue to benefit from gefitinib therapy. Recently, US trials have reexamined the use of gefitinib in NSCLC. The Iressa in NSCLC Trial Evaluating Response and Survival versus Taxotere (INTEREST) investigated the effectiveness of gefitinib in recurrent or metastatic NSCLC versus docetaxel, a standard treatment in the setting.4 The INTEREST study compared gefitinib with docetaxel in previously treated NSCLC patients.

Primary outcomes were noninferiority of gefitinib on

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overall survival (OS) for the entire population and superiority of gefitinib in patients with high epidermal growth factor receptor (EGFR)-gene-copy number by fluorescence in situ hybridization. Secondary outcomes included objective response rates and progression-free survival (PFS). All patients were previously treated with platinum-based regimens, with approximately 16% of patients in each arm having had received more than one treatment for metastatic or recurrent disease. At baseline, 53.8% and 56.3% of patients were chemotherapy-refractory to platinum-based chemotherapy, and 9.3% and 7.8% were refractory to paclitaxel-based regimens in the gefitinib and docetaxel arms, respectively.2 Fifty-seven percent of patients in the gefitinib arm and 59.6% of those in the docetaxel arm were refractory to their most recent chemotherapy. Nearly 55% of all patients had adenocarcinoma, and approximately 60% had a performance status of 1.

Median OS was similar in the two arms (8 months for gefitinib and 7.8 months for docetaxel), and the noninferiority hazard ratio for OS was 1.020 (96% confidence interval [CI]: 0.905-1.150). PFS and response rates were also similar.2 Superiority in OS

June 2009

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The two treatment groups had similar improvements in lung cancer symptoms.

The study additionally showed that individuals who had never smoked, women, persons of Asian ethnic origin, and those with adenocarcinoma lived longer than smokers, men, people of non-Asian ethnic origin, and those without adenocarcinoma. However, contrary to expectation, patients with these factors had a similarly long survival whether they were treated with gefitinib or docetaxel. Earlier research had suggested that docetaxel chemotherapy provided similar survival benefit in all patients.

Several biomarkers had been reported to help predict which patients are more likely to respond to EGFR inhibitor treatment. The INTEREST study found, for the most part, no link between treatment outcome and biomarkers.

It is important to note that the study differed in several respects from the ISEL study, which found no significant improvement in overall survival in gefitinibtreated patients with advanced NSCLC compared with placebo-treated patients. The ISEL trial enrolled a large number of patients who were refractory to chemothera-

was not observed for gefitinib in patients with a high EGFR-gene-copy number or any other subgroup.

Patients previously reported to have favorable response rates to EGFR inhibitors, such as those with adenocarcinoma, those of Asian ethnic origin, women, and never-smokers, had comparable outcomes regardless of treatment group. Such patients in both groups also experienced higher survival rates than those with other NSCLC histologies, those of non-Asian ethnic origin, men, and smokers. Patients with other NSCLC histologies, those of non-Asian ethnic origin, men, and smokers had similar survival rates with gefitinib and docetaxel treatment.2 These findings indicate that gefitinib is not inferior to US Food and Drug Adminstration–approved second-line treatments for NSCLC docetaxel in response rate, OS, or PFS. Although the findings from the INTEREST study raise questions about the ability to predict response to EGFR inhibitors, they offer evidence that gefitinib is a viable option for second-line treatment of metastatic/recurrent NSCLC. If reapproved, gefitinib will join the approved second-line options of docetaxel, pemetrexed, and erlotinib as well as unapproved alternatives of gemcitabine and vinorelbine. Choice of available second-line therapies is primarily dictated by a patient’s previous exposure to chemotherapy, comorbidities, hepatic and renal function, and performance status. Dosing convenience, potential drug interactions, and toxicities should also be considered.

Gefitinib may be offered to patients with poor performance status, renal dysfunction, and mild hepatic

June 2009

py. This population is notoriously difficult to treat and has a poor prognosis, which may account for the lack of significant improvement in the gefitinib group.

Clinical implications The management of advanced NSCLC remains a clinical challenge. However, an oral agent that rivals intravenous chemotherapy in terms of efficacy but has better tolerability and improves quality of life represents an important shift in the treatment paradigm for this disease and also offers patients an attractive treatment alternative.

What we now know: • Lung cancer is a key cause of cancer deaths worldwide. Standard therapy involves chemotherapy and supportive care, but response rates are suboptimal and disease recurrence is common.

• Docetaxel is widely used for second-line treatment of advanced NSCLC. • The molecularly-targeted oral agent gefitinib and cytotoxic intravenous chemotherapy with docetaxel are equally effective in advanced NSCLC. The

dysfunction or moderate-to-severe hepatic dysfunction due to liver metastases. Concomitant medications should be reviewed, however, to avoid drug interactions resulting in toxicities.

Oral TKIs such as gefitinib and erlotinib also present new challenges in toxicity management. Early intervention and management are instrumental to improving tolerability of the EGFR inhibitors gefitinib, erlotinib, and cetuximab. Most notably, dermatologic toxicity may affect a patient’s tolerance of therapy. Forty-three percent to 86% of patients experience dermatologic toxicities with EGFR inhibitors, and up to 16% may have grade 3 rash. In addition to appropriate dosing reductions, familiarity with treatment algorithms for management of dry skin and acnelike and maculopapular rash are necessary to assist oncologists in managing these toxicities.5,6 Little experimental evidence exists to support dermatologic toxicity management. A study by Scope and colleagues aimed to determine whether minocycline or tazarotene could reduce and prevent cetuximab-induced acnelike rash in patients with metastatic colorectal cancer.7 Forty-eight patients were randomized to receive either placebo or minocycline in addition to either topical tazarotene or placebo applied to one side of the face for a total of 8 weeks starting on day 1 of cetuximab therapy.

Fewer patients receiving minocyclines reported moderate-to-severe itching or rash. A significant difference in the number of facial lesions was observed, with a maximal effect near week 4 and a decline in effect by week 8. Although four patients receiving

two treatments provide similar overall survival, tumor response, and progression-free survival.

• Gefitinib decreases toxicity compared with docetaxel.

• Gefitinib improves quality of life more than docetaxel. In fact, it is the first agent that has been shown to improve quality of life more than a chemotherapy agent. ™

Jill Stein contributed to the preparation of this manuscript.

References 1. Fukuoka M, Yano S, Giannone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2003;21: 2237-2246.

2. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small-cell lung cancer. A randomized trial. JAMA. 2003;290:2149-2150.

3. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with advanced non-small-cell lung cancer: results from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet.

2005;366:1527-1537.

4. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet. 2008;372:1809-1818. ™

placebo required dose interruptions in cetuximab due to grade 3 rash, no patients receiving minocycline required interruptions. Tazarotene treatment had no benefit and caused significant skin irritation.

Nearly 33% of patients discontinued tazarotene therapy because of irritation. These data suggest benefit with approximately 1 month of prophylactic minocycline treatment and no advantage to use of tazarotene in management of EGFR-related rash.

References 1. Fukuoka M, Yano S, Giannone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2003;21: 2237-2246.

2. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small-cell lung cancer. A randomized trial. JAMA. 2003;290:2149-2150.

3. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366:1527-1537.

4. Kim ES, Hirsch V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372:1809-1818.

5. Chou LS, Garey J, Oishi K, Kim E. Managing dermatologic toxicities of epidermal growth factor receptor inhibitors. Clin Lung Cancer. 2006;8(suppl 1):S15-S22.

6. Hu JC, Sadeghi P, Pinter-Brown LC, Yashar S, Chiu MW. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management.

J Am Acad Dermatol. 2007;56:317-326.

7. Scope A, Agero AL, Dusza SW, et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol. 2007;25: 5390-5396.

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COMMENTARY Oral Biologic Therapy versus Chemotherapy for Pretreated Non–small-cell Lung Cancer: A Nurse’s Perspective

BY KAREN OISHI, RN, MSN, GNP, ANP, OCN The University of Texas M.D. Anderson Cancer Center, Houston

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ung cancer is the cause of approximately one third of all cancer-related deaths and is the number one cause of cancer deaths in the United States and worldwide.1,2 Traditionally, it has been a difficult disease to manage and treat, because lung cancer is usually diagnosed at an advanced stage and because we have a limited number of effective drugs. The oncology community constantly strives to better understand the biology of the disease and to develop better drugs. Several phase 3 trials indicate that current doublet chemotherapy regimens yield equivalent efficacies and similar toxicity profiles,3 and new-generation molecularly targeted therapies are emerging.

Gefitinib, the first epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor to reach the market, targets the specific physiologic pathway of tumor survival and proliferation. Later-introduced EGFR inhibitors approved for treatment of non– small-cell lung cancer (NSCLC) after at least one prior chemotherapy regimen include erlotinib, docetaxel, and pemetrexed. Since the negative results of the Iressa Survival Evaluation in Lung Cancer (ISEL) trial were reported in 2005,4 gefitinib has been slowly fading away from the domain of NSCLC treatment options.

The surprising results of the Iressa in NSCLC Trial Evaluating Response and Survival versus Taxotere (INTEREST) reported late last year has caused the oncology community to rethink the options for lung cancer therapy. This trial showed the statistical noninferiority of gefitinib compared with the previously approved second-line agent docetaxel.5 In light of these findings, the role of gefitinib is now being reassessed, and we are all asking what the study out-

comes will mean in clinical management of patients with NSCLC. The INTEREST study examined quality-of-life (QOL) measures, as well as the safety and tolerability of gefitinib and docetaxel.5 QOL is often overlooked in clinical trials, because the primary end point tends to evaluate the survival advantages exclusively. In NSCLC, achieving QOL is a very important goal, because most lung cancer patients experience many symptoms related to their disease.

Trial participants who received gefitinib and docetaxel showed improvements in their lung cancer symptoms, but significantly more patients had sustained and clinically relevant improvement in QOL with gefitinib.5 The results of the INTEREST study have raised more questions than answers for the lung cancer community. Will gefitinib be US Food and Drug Administration–approved and available as a secondline therapy? Will the positive INTEREST data have any influence on our selection of specific agents for treatment? Do second-line chemotherapy agents, such as docetaxel or pemetrexed, show efficacy equivalent to that of molecularly targeted agents, such as erlotinib and gefitinib? Is there a need for a head-tohead trial comparing erlotinib with gefitinib? How do we sequence second-line therapies to best benefit patients? Is there a need for molecular marker testing in patients receiving chemotherapy agents as well as targeted agents? Answers to these and other questions, will, I believe, lead in the next 5 or 10 years to more sophisticated and less controversial treatment algorithms for the NSCLC community.

As oncology nurses, we have the responsibility to inform and educate the public as well as patients

and their families about significant new findings that may potentially provide new options for lung cancer treatment. This enables patients to choose more suitable options from those that are available to them. If it gets the necessary approval, gefitinib will be among the options available to treat lung cancer, and we must be prepared for the possibility of a need to educate the oncology community about its use and potential side effects. Oncology nurses not only educate patients about available therapy options, but also help them decide which side effects they are willing to tolerate, for example, dermatologic (rash with EGFR inhibitors) versus gastrointestinal (nausea/vomiting with chemotherapies) toxicities. The INTEREST study shows the need for further study of QOL measures. Oncology nurses should be encouraged to pursue research on these measures, as we are advocates for our patients.

References 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108.

2. American Cancer Society. Cancer Statistics 2008 [PowerPoint presentation]. www.cancer.org/docroot/PRO/content/PRO_1_1_ Cancer_Statistics_2008_Presentation.asp. Accessed May 15, 2009.

3. Fossella FV, Devore R, Kerr RN, et al; for The TAX 320 NonSmall Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol.

2000;18:2354-2362.

4. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366:1527-1537.

5. Kim ES, Hirsch V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372:1809-1818.

REACH US ONLINE AT www.theoncologypharmacist.com • View current and past issues • Register to receive your free subscription • Access CE activities 26

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June 2009

Breast Cancer Guidelines local therapy in stage IV disease was also recently documented in a series in which overall survival at 3 years was 43% with treatment, versus 27% in the untreated arm (Le Scodan R, et al. J Clin Oncol. 2009;27:1375-1381).

Imaging issues addressed The panelists did not advocate the use of positron-emission tomography/CT scanning in the evaluation of newly diagnosed patients with earlystage disease, except in those clinical situations where other staging studies are equivocal or suspicious. Even then, biopsy is recommended, as always for accurate staging.

They further maintained that the value of magnetic resonance imaging (MRI) remains unclear, but they revised the guidelines to address the utility of dedicated breast MRI. The panel noted that MRI has a role in screening women at high risk, detecting disease in dense breasts, evaluating extent of disease, defining response to neoadjuvant therapy, and evaluating cases of axillary nodal adenocarcinoma but normal mammography.

Edge advised physicians, however, not to make surgical decisions on the basis of MRI findings, due to the high rate of false positives. Instead, biopsy and tissue sampling should help guide treatment decisions. He noted that MRI outperforms mammography in detecting second cancers. In one study, MRI found contralateral tumors in 3% of breast cancer patients (Lehman CD, et al. N Engl J Med. 2007;356:1295-1303).

MRI also helps select patients for breast-conserving therapy after neoadjuvant therapy by evaluating response to treatment and defining the extent of cancer; however, it also underestimates the amount of residual disease.

The use of MRI does lead to a change in therapy for some patients, Edge noted. In a meta-analysis of all retrospective literature on the topic, Houssami and colleagues showed that 11% of patients underwent more extensive surgery than originally planned, and 8% converted from lumpectomy to mastectomy (J Clin Oncol. 2008;26: 3248-3258). It is still unclear whether the rate of mastectomies is increasing in parallel with increased use of MRI, however. In an NCCN database, rates have been stable despite rising MRI use, according to Edge.

Evidence is also lacking to show that MRI actually affects outcomes, he noted. Although MRI does pick up lesions not seen on mammography, 80% are determined to be benign. â&#x20AC;&#x153;We may identify more lesions on MRI, but they may not be clinically significant or they may be controlled by the radiation we give,â&#x20AC;? he commented.

June 2009

postsurgical reconstruction using breast implants, autologous tissue (flaps), or a combination of the two (eg, latissimus/implant composite reconstruction). The options are to perform reconstruction in conjunction with New reconstruction guidelines mastectomy (immediate) or after the New guidelines have been added for completion of cancer treatment (de ' & # ) " ! $ #) ' & # ) " % *

layed). The preference for one over the other is based on factors such as the need for radiotherapy (delayed) and use of implants (immediate) McCormick noted. â&#x20AC;&#x153;Women who need radiotherapy should be identified at diagnosis, and reconstruction in those cases should be delayed,â&#x20AC;? she said.

The NCCNâ&#x20AC;&#x2122;s bottom line on MRI is that its value remains uncertain, the practice of obtaining MRI varies (and should meet standards for performance), and the downsides are real.

BREAST CANCER

Continued from page 22

â&#x201E;˘

Presents The Second Annual 2009 Curriculum for

CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals

SAGAR LONIAL, MD

Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, will proudly offer the multidisciplinary cancer team at your center a series of newsletters focusing on the challenges in treating patients with multiple myeloma.

Associate Professor of Hematology and Oncology Emory University

# Earn Continuing Education Credits # Eight part newsletter series

CLINICAL TOPICS: â&#x20AC;˘ Retreatment Settings â&#x20AC;˘ Maintenance Therapy â&#x20AC;˘ Do CRs Correlate to a Clinical Benefit?

â&#x20AC;˘ Perspectives on Relevant End Points of Clinical Trials â&#x20AC;˘ Stem Cell Mobilization â&#x20AC;˘ Cytogenic Testing in the MM Patient

â&#x20AC;˘ To Transplant or Not to Transplantâ&#x20AC;ŚThat is the Question â&#x20AC;˘ Sequencing Strategies in MM: Treatment with Case Studies

Each newsletter will feature: â&#x20AC;˘ Contributions from thought-leading physicians, pharmacists, and nurses

â&#x20AC;˘ Continuing Education credits available to physicians, pharmacists, and nurses

TO REQUEST FREE COPIES

! % " # &&& '

Maintenance Therapy Newsletter # # #

(" ! # " #

The purpose of this activity is to enhance knowledge concerning the treatment of patients with multiple myeloma (MM).

Global Education Group designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

! # $ This activity was developed for physicians, nurses, and pharmacists.

"# ! $!" " #

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Medical Learning Institute, Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.5 contact hours.

At the completion of this educational activity, participants should be able to: â&#x20AC;˘ Define the role of posttransplant maintenance therapy in the treatment of patients with multiple myeloma (MM) â&#x20AC;˘ Describe how novel agents for MM can be used to sustain response and possibly delay relapse in patients with MM â&#x20AC;˘ Interpret new data from clinical trials of maintenance regimens for MM as reported at the 2008 ASH annual meeting â&#x20AC;˘ Identify the risks and benefits associated with novel agents used in the maintenance setting, including increased toxicity and acquired drug resistance

"# ! ! ( " # MLI is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.

Completion of this activity provides for 1.5 contact hours (0.15 CEU) of continuing education credit. The universal program number for this activity is 468999-09-013-H01-P. Estimated time to complete this activity: 1.5 hours Date of original release: May 11, 2009 Valid for CME credit through: May 11, 2010

(" ! # # This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Medical Learning Institute, Inc. (MLI). Global is accredited by the ACCME to provide continuing medical education for physicians. % & ( &) % %'##"$& ) ! ' & "! $ !& $"

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27

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AUA Counters Mainstream Recommendations PROSTATE CANCER

Continued from cover The PSA test, as well as how it is used to guide patient care (ie, at what age men should begin regular testing, intervals at which the test should be repeated, and at what point a biopsy is necessary), are highly controversial. The AUA believes, however, that when offered and interpreted appropriately the PSA test may provide essential information for the diagnosis, pretreatment staging or risk assessment, and posttreatment monitoring of prostate cancer.

ment. “[The] panel carefully reviewed the most recently reported trials of PSA testing in both the United States and Europe before finalizing its guidelines.

The strengths and limitation of these trials are reviewed in the guidelines.”

In regard to biopsy, a continuum of risk exists at all values, and major studies have demonstrated that there is no safe PSA value below which a man may be reassured that he does not have biopsydetectable prostate cancer. Therefore,

According to the AUA, early detection and risk assessment of prostate cancer should be offered to well-informed men 40 years of age or older who have a life expectancy of at least 10 years.

The new Best Practice Statement the AUA does not recommend a single updates the AUA’s previous guidance, PSA threshold at which a biopsy should which was issued 9 years ago. Major be obtained. Rather, the decision to perchanges to the AUA statement include form a biopsy should take into account new recommendations about additional factors, including who should be considered for free and total PSA levels, PSA testing, as well as when PSA velocity and density, a biopsy is indicated followpatient age, family history, ing an abnormal PSA readrace/ethnicity, biopsy history, ing. According to the AUA, and comorbidities. In addiearly detection and risk tion, the AUA statement assessment of prostate cancer emphasizes that not all should be offered to wellprostate cancers require acinformed men 40 years of age tive treatment and that not or older who have a life Peter Carroll, MD all prostate cancers are lifeexpectancy of at least 10 years. A base- threatening. The decision to proceed to line PSA level above the median for age active treatments is one that men 40 is a strong predictor of prostate can- should discuss in detail with their cer. Such testing may not only allow for physician to determine whether active earlier detection of more curable can- treatment is necessary, or whether surcers, but may also allow for more effi- veillance may be an option for their cient, less frequent testing, according to prostate cancer. the AUA. “Prostate cancer comes in many Men who wish to be screened for forms, some aggressive and some not,” prostate cancer should have both a PSA said Carroll, who is professor and chair test and a digital rectal examination. of urology at the University of CaliforThe statement by the AUA also notes nia, San Francisco. “The AUA is comthat other factors, such as family histo- mitted to timely, expert, and appropriry, age, overall health, and ethnicity, ate care for men either with or at risk should be combined with the results of of getting prostate cancer and is prePSA testing and physical examination pared to revise these guidelines continto better determine the risk of prostate uously as new information becomes cancer. The statement recommends available.” that the benefits and risks of screening for prostate cancer should be discussed, Key points The Best Practice Statement by the including the risk of overdetection (detecting some cancers which may not AUA also clarifies a number of key points about the use of PSA in treatneed immediate treatment).

“The single most important message ment selection and posttreatment folof this statement is that prostate cancer low-up of prostate cancer patients: • Serum PSA predicts the response of testing is an individual decision that prostate cancer to local therapy. patients of any age should make in con• Routine use of a bone scan is not junction with their physicians and urolrequired for staging asymptomatic ogists. There is no single standard that men with clinically localized prosapplies to all men, nor should there be at tate cancer when their PSA level is this time,” said Peter Carroll, MD, chair ≤20.0 ng/mL. of the panel that developed the state28

G REEN H ILL H EALTHCARE C OMMUNICATIONS

• Computed tomography or magnetic resonance imaging scans may be considered for the staging of men with high-risk clinically localized prostate cancer when the PSA level is >20.0 ng/mL or when locally advanced or when the Gleason score is ≥8.

• Pelvic lymph node dissection for clinically localized prostate cancer may not be necessary if the PSA level is <10.0 ng/mL and the Gleason score is ≤6.

• Periodic PSA determinations should be offered to detect disease recurrence.

• Serum PSA should decrease and remain at undetectable levels after radical prostatectomy.

• Serum PSA should fall to a low level following radiation therapy, high-intensity focused ultrasound, and cryotherapy and should not rise on successive occasions.

• PSA nadir after androgen suppression therapy predicts mortality.

• Bone scans are indicated for the detection of metastases following initial treatment for localized disease, but the PSA level that should prompt a bone scan is uncertain.

Additional important prognostic information can be obtained by evaluation of PSA kinetics (velocity).

• The kinetics of PSA rise after local therapy for prostate cancer can help distinguish between local and distant recurrence.

“What is also important in this document is that we clearly acknowledge the risks of overdetection and overtreatment. I think that brings us in line with other groups,” Carroll said in an interview with The Oncology Pharmacist. “We are no longer recommending a single PSA cut point but to use PSA in conjunction with age, digital rectal examination, ethnicity, family history, and other PSA parameters. This is a more sensitive and specific way of diagnosing prostate cancer.”

William Catalona, MD, who is a professor of urology at Northwestern University, Chicago, said dropping the age for a baseline PSA to age 40 may be an important new approach because it can better guide clinicians by potentially providing significantly more information.

“I think it is important. Not so much for diagnosing prostate cancer at age 40, but for establishing a baseline so that you can get data for PSA velocity.

So, if you start at age 40, their PSA should be less than 1.0 ng/mL. After that, you can track it,” said Catalona in an interview with The Oncology Pharmacist. “I think early PSA velocity is a promising new marker for identifying men destined to die of prostate

cancer. It can help detect cancer earlier than we can now detect it using any other method. Perhaps we can now treat them and save their lives. This adds to our ability to identify the worse cancers early.” ™

—John Schieszer ™

Recent FDA

Approvals • Bevacizumab for Glioblastoma The US Food and Drug Administration (FDA) has granted accelerated approval of bevacizumab (Avastin, Genentech) for treatment of glioblastoma that has progressed following prior therapy. The accelerated approval is based on data from an openlabel phase 2 study of 167 patients with glioblastoma that had progressed following initial treatment with temozolomide and radiation. Of the 167 patients, 26% had a tumor response to bevacizumab, and the median duration of response was 4.2 months. The first antiangiogenesis therapy approved by the FDA, bevacizumab is also indicated for certain types of metastatic colorectal cancer, non–small-cell lung cancer, and HER2-negative breast cancer.

• Laser Surgery for Inoperable Brain Tumors The FDA has cleared the AutoLITT System (Monteris Medical) for use in neurosurgery. The first application of the technology is expected to be in treatment of otherwise inoperable brain tumors. The system uses a magnetic resonance imaging–guided laser probe, delivered through a small bur hole in the skull, to deliver laser interstitial thermal therapy (“LITT”) to heat and coagulate the tumor from the inside. Once coagulated, the treated tumor mass is dead.

• Full Approval for Dasatinib for CML The FDA has granted full approval for dasatinib (Sprycel, Bristol-Myers Squibb) for treatment of all phases of chronic myeloid leukemia (CML) in adults who are resistant or intolerant to prior therapies including imatinib.

The oral tyrosine kinase inhibitor was originally approved under accelerated approval regulations. The full approval was based in part on a phase 3 study showing 80% progression-free survival at 2 years in patients resistant or intolerant to imatinib. The drug is also approved for treatment of adults with Philadelphia chromosome–positive acute lymphoblastic leukemia.

June 2009

Diagnosis and Treatment of Melanoma points. Median PFS was 21.1 weeks in the dacarbazine + sorafenib arm versus 11.7 weeks in the placebo + dacarbazine arm; however, this did not reach statistical significance. There were statistically significant differences, however, in the PFS rates at 6 and 9 months. In addition, time to progression was 21.1 weeks versus 11.7 weeks in the placebo group. No differences in overall survival were seen, and the toxicity profile was manageable in both arms. Therefore, if phase 3 results are similar, sorafenib could potentially have a role in the treatment of stage III-IV melanoma.

At the ESMO Congress in 2008, results from the largest randomized phase 3 trial ever conducted in stage IV melanoma were presented.18 Patients were included in the study if they had either unresectable metastatic melanoma previously untreated with either a cytokine or chemotherapy for stage IV disease. Patients were treated with either temozolamide 150 mg/m2/day for 7 days, then 7 days off, or standard-dose dacarbazine progression. The primary end point was overall survival. Secondary end points included PFS, overall response rate, duration of objective response, and safety and tolerability.

Median overall survival failed to meet statistical significance at 9.13 months in the temozolamide arm and 9.36 months with dacarbazine. Median PFS was also unimpressive at 2.3 and 2.17 months, respectively. Response rates were higher in the temozolamide arm (14.5% vs 9.8%), but the duration of response was longer in the dacarbazine arm. The toxicity profile was worse in the temozolamide treatment arm, with more grade 3 and 4 toxicities. The authors concluded that temozolamide is an alternative to dacarbazine in unresectable metastatic melanoma patients. Toxicity profiles, however, may be more significant with temozolamide without any additional survival benefits.18

Immunol. 2006;18:206-213.

CD137 agonist monoclonal antibody, in patients 8. Oâ&#x20AC;&#x2122;Day SJ, Ibrahim R, DePril V, et al. Efficacy and (pts) with advanced cancer (CA). J Clin Oncol. safety of ipilimumab induction and maintenance 2008;26:133s. Abstract 3007. dosing in patients with advanced melanoma who 12. Vonderheide RH, Flaherty KT, Khalil M, et al. progressed on one or more prior therapies. J Clin Clinical activity and immune modulation in Oncol. 2008;26:488s. Abstract 9021. cancer patients treated with CP-870,893, a 9. Weber JS, Berman D, Siegel J, et al. Safety and novel CD40 agonist monoclonal antibody. J Clin efficacy of ipilimumab with or without prophylacOncol. 2007;25:876-883. tic budesonide in treatment-naive and previously 13. Brahmer JR, Topalian S, Wollner I, et al. Safety treated patients with advanced melanoma. J Clin and activity of MDX-1106 (ONO-4538), an Oncol. 2008;26:485s. Abstract 9010. anti-PD-1 monoclonal antibody, in patients 10. Ribas A, Hauschild A, Kefford R, Gomezwith selected refractory or relapsed malignanNavarro J, Pavlov D, Marshall M. Phase III, cies. J Clin Oncol. 2008;26:133s. Abstract 3006. open-label, randomized, comparative study of 14. Fruehauf JP, Lutzky J, McDermott DF, et al. tremelimumab (CP-675,206) and chemotherapy Axitinib (AG-013736) in patients with metasta(temozolomide [TMZ] or dacarbazine [DTIC]) in tic melanoma: a phase II study. J Clin Oncol. patients with advanced melanoma. J Clin Oncol.

2008;26:484s. Abstract 9006.

2008;26:485s. Abstract LBA9011.

15. Chan KR, Gundala S, Laudadio M, Mastrangelo

A, Sato T. A pilot study using 11. Sznol M, Hodi FS, Margolin K, et al.

Phase I M, Yamamoto study of BMS-663513, a fully human antisunitinib malate as therapy in patients with stage

IV uveal melanoma. J Clin Oncol. 2008;26:494s.

Abstract 9047.

16. Eggermont AM, Suciu S, Santinami M, et al.

Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomized phase III trial. Lancet.

2008;372:117-126.

17. McDermott DF, Sosman JA, Gonzalez R, et al.

Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. J Clin Oncol. 2008; 26:2178-2185.

18. Patel PM, Suciu S, Mortier L, et al. Extended schedule, escalated dose temozolamide versus dacarbazine in stage IV maligant melanoma: final results of the randomized phase II study (EORTC 18032). Ann Oncol. 2008;19(suppl 8):viii1-viii4. Abstract LBA8.

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References

1. Ries LAG, Melbert D, Krapcho M, eds. SEER Cancer Statistics Review, 1975-2005. Bethesda, MD: National Cancer Institute. http://seer.cancer. gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER Web site, 2008.

2. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

J Clin Oncol. 2001;19:3635-3648.

3. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004;351: 998-1012.

4. Menzies SW, Crotty KA, Ingvar C, McCarthy WH. An Atlas of Surface Microscopy of Pigmented Skin Lesions Dermoscopy. 2nd ed. Sydney, Australia: McGraw-Hill Australia; 2003.

5. Malvehy J, Puig S, Argenziano G, Marghoob AA, Soyer HP. International Dermoscopy Society Board. Dermoscopy report: proposal for standardization. Results of a consensus meeting of the International Dermoscopy Society. J Am Acad Dermatol. 2007;57:84-95.

6. Vestergaard ME, Macaskill P, Holt PE, Menzies SW. Dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. Br J Dermatol. 2008;159: 669-676.

7. Peggs KS, Quezada SA, Korman AJ, Allison JP. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin â&#x201E;˘

June 2009

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SKIN CANCERS

Continued from page 14

Safe Handling SAFE HANDLING

National Safe Handling Month Calls Attention to Need for Increased Awareness, Education about Occupational Drug Exposure

A

pril 2009 was designated the first-ever National Safe Handling Awareness Month in an effort to increase awareness of the risks of occupational exposure to chemotherapeutic agents and other hazardous drugs and educate healthcare providers on guidelines and safety measures that can minimize the risks. The initiative, supported by an unrestricted educational grant provided by Carmel Pharma, Inc., the maker of PhaSeal, included regional and national continuing education activities. The Oncology Pharmacist recently spoke with Byron Peters, RPh, and MiKaela Olsen, RN, MS, OCN, about ways to ensure safe handling of hazardous drugs in the clinical setting. Mr Peters is director of pharmacy, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.

Ms Olsen is an oncology and hematology clinical nurse specialist, at Johns Hopkins Hospital, Baltimore, Maryland.

The National Institute for Occupational Safety and Health, the Oncology Nursing Society, the American Society of HealthSystem Pharmacists, and other organizations have issued guidelines on safe handling. Why is this campaign to increase awareness needed?

Byron Peters (BP): Many people think that measures such as use of biological safety cabinets and personal protective equipment are enough.

But when we conducted an environmental wipe sample study some years Byron Peters, RPh ago, it was striking to see that despite doing everything we thought we were supposed to be doing, there was still surface contamination in a relatively new work environment (Harrison BR, et al. Am J Health-Syst Pharm. 2006;63:1763-1744). More and more studies are showing contamination in all areas of the workplace.

MiKaela Olsen (MO): Workplace health is becoming more of a concern in general across the country, and hazardous drugs are a part of that. Hazardous drugs are being increasingly MiKaela Olsen, RN, used for nonmaligMS,OCN nant diseases, and

30

nononcology providers may not be aware of the hazards of these drugs.

Another concern is the increasing use of potentially hazardous oral drugs that may carry risks similar to intravenously administered agents.

We need to recognize and take hold of this problem and ensure safe handling. Unfortunately, not everyone uses the recommended personal protective equipment when handling these agents.

There’s a huge knowledge deficit, and maybe peer pressure issues too. If more experienced staff in the department choose not to use protective equipment, their less experienced colleagues may not realize how important it is to do so or may feel it is not a priority.

How can institutions be sure that employees are following safe handling procedures?

MO: Monitoring of employees to determine whether they are experiencing any symptoms that may be related to hazardous drug exposure is important.

Employees may be experiencing nonspecific symptoms, such as headache, nausea, and eye or skin irritation, and may not necessarily associate them with exposure to a particular substance.

BP: We do need heightened awareness because people have been exposed, either knowingly or unknowingly.

Fifteen years ago, we did not have some of the environmental controls or engineering devices that we now have to protect us. We are making great strides.

We have containment isolators, better biological safety cabinets, and we know how frequently we have to inspect them. We also use a closed-system transfer device (CSTD) that has been clinically proven to reduce the risk of drug exposure (the PhaSeal System).

Studies have shown that when two levels of protection were implemented, subjects’ urine became negative for drug traces (Wick C, et al. Am J Health-Syst Pharm. 2003;60:2314-2320). We don’t know if we have the perfect solution, but at least based on what we know now, there are some additional steps that people can take to ensure safety.

The problem is that not everyone is using all the levels of protection we now have; some are not even at the minimum level.

What are some of the barriers to more widespread use of safe handling measures?

MO: I think that sometimes stems partly from the leadership of the facility.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Costs should not be a reason for not implementing safeguards. Providing a safe work environment is the cost of doing business.

We have to educate our leadership about the hazards of these drugs and the potential risks to employees. They need to develop policies to protect everyone in the environment from hazardous drugs, and implement those policies.

This shows that they are committed to protecting their employees.

BP: Unfortunately, I think part of the problem is probably financially motivated. Interventions cost money and may not be reimbursed. Costs, however, should not be a reason for not implementing safeguards. Providing a safe work environment is the cost of doing business and something that you just have to do.

What can nurses and pharmacists do to ensure proper handling of oral chemotherapy agents by patients and healthcare providers?

MO: There is less regulation safety measures for oral versus intravenous chemotherapy. In the Oncology Nursing Society Chemotherapy and Biotherapy course, we cover handling of oral chemotherapy drugs in the home and we discuss that in our teaching to nurses. Many institutions have patient education materials that they provide to the family about how to handle these drugs and to dispose of body excretions at home.

BP: When we as pharmacists dispense drugs to patients, part of the process involves counseling. We share information about safe handling, such as not breaking tablets in half, and how to dispose of the drugs. Interestingly, there are no regulations about packaging of hazardous drugs when dispensing.

Oral chemotherapy agents are packaged the same way as drugs like amoxicillin.

What practical steps can hospitals and other institutions take to ensure adherence to safe handling guidelines?

MO: It is the employee’s right to be informed about the risks, and they need to receive annual training about how to protect themselves. Women who are trying to conceive are pregnant or breast feeding and men who are trying to conceive need to be informed about

the risks and should be offered alternate duty if requested.

BP: Frequently we talk about specially trained and experienced nurses and pharmacists, but there are also other levels of people who come in contact with hazardous drugs, such as technicians, students, housekeeping staff, and those who ship and receive drugs. These individuals need to be trained on safe handling as well. Studies have shown that vials can come from the manufacturer with hazardous drugs on the outside of the container even when they are properly sealed.

MO: When these drugs are given, we may be unknowingly exposing staff, visitors, and caregivers. We have to think about the whole continuum and protect everyone in the environment. We have to look at this problem from the time the drug is delivered all the way to its proper disposal.

BP: The work surface contamination study we conducted got management’s attention. We’ve implemented a CSTD, the PhaSeal product. People realize that this is an added cost, but they understand that we are willing to do what is needed to do to protect our staff, our patients, and our visitors and to protect the environment. We try to take a leading role in our community showing that we understand the problem and will do whatever it takes to provide the utmost safety. The leadership has to make safe handling a priority. If you start at the top, it sends a good message to heighten awareness about the hazards of handling these drugs. You need to continue to reinforce policies with training programs, annual recertification, annual assessment of technique and competency, and in-service training.

For additional information on the safe handling of hazardous drugs and to hear more from Byron Peters and MiKaela Olsen, please view the archived Safe Handling Awareness Day CE webinar at www.carmelpharma usa.com/CE. Free CE credit for this archived webinar presentation is available for pharmacists, pharmacy technicians, nurses, and risk managers.

June 2009

™

™

ONCOLGY DRUG CODES

Oncology Drug Codes Medications Used for the Treatment of Colorectal Cancer

C

olorectal cancer is a term used to refer to cancer that starts in either the colon or the rectum. Colon cancer and rectal cancer have many features in common. The following sections will assist healthcare professionals and payers by providing appropriate coding, billing, and reimbursement information associated with the management of colorectal cancer.

153 Malignant neoplasm of colon Excludes: benign carcinoid tumor of colon (209.50-209.56) malignant carcinoid tumor of colon (209.10-209.16) 153.0 Hepatic flexure 153.1 Transverse colon 153.2 Descending colon Left colon 153.3 Sigmoid colon Sigmoid (flexure) Excludes: rectosigmoid junction (154.0) 153.4 Cecum Ileocecal valve 153.5 Appendix 153.6 Ascending colon Right colon 153.7 Splenic flexure 153.8 Other specified sites of large intestine Malignant neoplasm of contiguous or overlapping sites of colon whose point of origin cannot be determined Excludes: ileocecal valve (153.4) rectosigmoid junction (154.0) 153.9 Colon, unspecified Large intestine NOS 154 Malignant neoplasm of rectum, rectosigmoid junction, and anus Excludes: benign carcinoid tumor of rectum (209.57) malignant carcinoid tumor of rectum (209.17) 154.0 Rectosigmoid junction Colon with rectum Rectosigmoid (colon) 154.1 Rectum Rectal ampulla 154.2 Anal canal Anal sphincter Excludes: skin of anus (172.5, 173.5) 154.3 Anus, unspecified Excludes: anus: margin (172.5, 173.5) skin (172.5, 173.5) perianal skin (172.5, 173.5) 154.8 Other Anorectum Cloacogenic zone Malignant neoplasm of contiguous or overlapping sites of rectum, rectosigmoid junction, and anus whose point of origin cannot be determined

©iStockphoto.com/sx70

The following sections include: • Associated ICD-9-CM codes used for the classification of colorectal cancer • Drugs that have been FDA-approved in the treatment of colorectal cancer Please note: if a check mark appears in the FDA column it will NOT appear in the Compendia section even if a drug is included in the NCCN (National Comprehensive Cancer Network) Drugs & Biologics Compendium • Drugs included in the NCCN Drugs & Biologics Compendium for off-label use in colorectal cancer. NCCN is recognized by the Centers for Medicare & Medicaid Services (CMS) as a referencing source • Corresponding HCPCS/CPT codes and code descriptions • Current code price (AWP-based pricing) • Most recent ASP plus 6% (Medicare allowable) • Possible CPT administration codes for each medication.

Associated ICD-9-CM Codes Used for Colorectal Cancer

June 2009

G REEN H ILL H EALTHCARE C OMMUNICATIONS

31

ONCOLOGY DRUG CODES

FDAapproved for colorectal cancer

NCCN Drugs & Biologics Compendium off-label use for colorectal cancer

Current code price (AWPbased pricing)

Medicare allowable (ASP + 6%), effective 4/1/09-6/30/09

CPT administration codes 96413, 96415

Generic (brand) name

HCPCS code: code description

bevacizumab (Avastin)

J9035: injection bevacizumab, 10 mg

✓

$68.75

$57.40

capecitabine (Xeloda)

J8520: capecitabine, oral, 150 mg

✓

$7.35

$5.28

N/A

capecitabine (Xeloda)

J8521: capecitabine, oral, 500 mg

✓

$24.50

$17.51

N/A

cetuximab (Erbitux)

J9055: injection, cetuximab, 10 mg

✓

$60.00

$49.73

96413, 96415

floxuridine (FUDR)

J9200: injection, floxuridine, 500 mg

$121.50

$58.08

96422, 96423, 96425

fluorouracil (Adrucil)

J9190: injection, fluorouracil, 500 mg

✓

$3.44

$1.55

irinotecan (Camptosar)

J9206: injection, irinotecan, 20 mg

✓

$32.82

$18.30

96413, 96415

leucovorin calcium

J0640: injection, leucovorin calcium, per 50 mg

✓

$3.75

$0.87

96372, 96374, 96409

oxaliplatin (Eloxatin)

J9263: injection, oxaliplatin, 0.5 mg

✓

$12.26

$9.54

96413, 96415

panitumumab (Vectibix)

J9303: injection, panitumumab, 10 mg

✓

$106.09

$84.29

96413, 96415

✓

96409

References • HCPCS Level II Expert; 2009 • CPT 2009; 2008 • ICD-9-CM for Professionals, Volumes 1 & 2; 2009 • The Drug Reimbursement Coding and Pricing Guide, Vol 6, No 2; RJ Health Systems International LLC; 2nd Quarter 2009 • FDA-approved indication (from products’ prescribing information) • NCCN • American Cancer Society • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC., Wethersfield, Connecticut • CMS-Medicare allowable 2nd Quarter 2009 (effective dates 4/1/09-6/30/09).

Prices listed herein are effective as of May 1, 2009.

ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; HCPCS, Healthcare Common Procedure Coding System; NCCN, National Comprehensive Cancer Network.

This information was supplied by:

The Most Comprehensive HCPCS/CPT Drug and Product Reimbursement Coding and Pricing Service Available!

ReimbursementCodes.com is an online HCPCS/CPT reimbursement coding and pricing service that provides up-to-date reimbursement information.

You have the ability to accurately match reimbursement to the corresponding date of service for every claim!

• Drugs which are injected subcutaneously, intramuscularly, or intravenously • Selected orally administered chemotherapeutic and antiemetic agents • Nutritional agents and ostomy care products • Drugs administered via nebulizers or other DME equipment • Radiopharmaceuticals Plus a fast and efficient avenue to HCPCS/CPT coding and reimbursement information!

• In billable units matching the CMS- and AMA-established reimbursement code description • A validated pricing methodology • Includes all price changes that have occurred for each code, along with the effective date of the change(s) Does your revenue stream run as productively as possible?

Contact RJ Health Systems, and mention The Oncology Pharmacist.

PO BOX 290616, Wethersfield, CT 06109 • T: (860) 563-1223 • F: (860) 563-1650 • www.RJHealthSystems.com

32

G REEN H ILL H EALTHCARE C OMMUNICATIONS

June 2009

JULY 2009

OCTOBER 2009

©iStockphoto.com/Michael Mattner

1-4 CHICAGO, ILLINOIS Lynn Sage Breast Cancer Symposium www.lynnsagebreastcancer.org

8-11 TORONTO, CANADA

©iStockphoto.com/Sam Valtenbergs

International Academy of Oral Oncology 2nd World Congress www.iaoo2009.com

9-10

©iStockphoto.com/Will Dozier

SAN FRANCISCO, CALIFORNIA NCCN Academy for Excellence and Leadership in Oncology www.nccn.org

11-12

BOSTON, MASSACHUSETTS Understanding New Technologies and Managing Oncology Care Needs www.cancerlearning.com

AUGUST 2009

21-23

WASHINGTON, DC 8th International Congress on Targeted Therapies in Cancer www.cancerlearning.com

SEPTEMBER 2009

11-12

ST. LOUIS, MISSOURI Translational Advances in Radiation Oncology and Cancer Imaging Symposium www.astro.org June 2009

4-7 SAN DIEGO, CALIFORNIA 8-9 DALLAS, TEXAS 29th Annual Oncology Nurses Symposium www.scripps.org

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information.

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].

Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved.

Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk.

Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.]

Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan.

Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.]

Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina.

[See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some

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cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy.

[See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma 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. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses.

Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.]

Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses.

Table 1 Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%).

Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs.

1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. 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.

Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure.

Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection.

Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women.

Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, activecontrolled trials, 927 patients received Rituxan in combination with chemotherapy.

Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) greater. No overall differences in effectiveness were observed between these Respiratory System 38 4 Any Adverse Events 99 57 patients and younger patients. Cardiac adverse reactions, mostly supraventricular 86 10 Increased Cough 13 1 Body as a Whole arrhythmias, occurred more frequently among elderly patients. Serious pulmonary Fever 53 1 Rhinitis 12 1 Chills 33 3 Bronchospasm 8 1 adverse reactions were also more common among the elderly, including Infection 31 4 Dyspnea 7 1 Asthenia 26 1 Sinusitis 6 0 pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Headache 19 1 Metabolic and Nutritional Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 B-cell NHL did not include sufficient numbers of patients aged 65 and over to Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 determine whether they respond differently from younger subjects.

Flushing 5 0 LDH Increase 7 0 OVERDOSAGE There has been no experience with overdosage in human clinical Heme and Lymphatic System 67 48 Digestive System 37 2 Lymphopenia 48 40 Nausea 23 1 trials. Single doses of up to 500 mg/m2 have been given in dose-escalation Leukopenia 14 4 Diarrhea 10 1 Neutropenia 14 6 Vomiting 10 1 clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Thrombocytopenia 12 2 Nervous System 32 1 Impairment of Fertility No long term animal studies have been performed to Anemia 8 3 Dizziness 10 1 Skin and Appendages 44 2 Anxiety 5 1 establish the carcinogenic or mutagenic potential of Rituxan or to determine Night Sweats 15 1 Musculoskeletal System 26 3 Rash 15 1 Myalgia 10 1 potential effects on fertility in males or females. PATIENT COUNSELING Pruritus 14 1 Arthralgia 10 1 INFORMATION Patients should be provided the Rituxan Medication Guide and Urticaria 8 1 Cardiovascular System 25 3 Hypotension 10 1 provided an opportunity to read prior to each treatment session. Because caution Hypertension 6 1 should be exercised in administering Rituxan to patients with active infections, it is b a Adverse reactions observed up to 12 months following Rituxan. Adverse reactions graded for severity by important that the patient’s overall health be assessed at each visit and any NCI-CTC criteria. questions resulting from the patient’s reading of the Medication Guide be In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and discussed. Rituxan is detectable in serum for up to six months following up to 6 months after Rituxan infusion. Rituxan in Combination With completion of therapy. Individuals of childbearing potential should use effective Chemotherapy Adverse reactions information below is based on 1250 patients contraception during treatment and for 12 months after Rituxan therapy. who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs.

3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions Revised 9/2008 (4835505) were reported more frequently (≥5%) in patients receiving Rituxan following CVP Jointly Marketed by: compared to patients who received no further therapy: fatigue (39% vs. 14%), Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs.

7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With ©2008 Biogen Idec Inc. and Genentech, Inc. 7140917 October 2008

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33

MEETINGS

Meetings

For previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

When planning a treatment course for DLBCL

Take the essential path toward improved survival

Cumulative Cumulative Proportion Proportion Surviving Surviving

RITUXAN+CHOP is proven to prolong survival in DLBCL

47% INCREASE

1.0

in 7-year OS in GELA* trial 1,2

0.8 0.6 0.4 R-CHOP (n=202) CHOP† (n=197) p =0.0004

0.2 0 0 Years

1

2

3

4

5

6

7

8

• At 7 years, 8 cycles of RITUXAN+ CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1 • At 5 years, 8 cycles of RITUXAN+ CHOP increased OS from 46% to 58% compared with CHOP alone5

BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5 RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.0% for CHOP).5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).5

Please see brief summary of prescribing information on adjacent page.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previously untreated elderly (age ≥60 years) DLBCL patients.3,4 †CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone.

References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al.

Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc. 5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

PROVE N. POWE R FU L.

©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved.

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