Journal of Hematology Oncology Pharmacy | September 2012 VOL 2, NO 3 by The Oncology Pharmacist

SEPTEMBER 2012 VOL 2 I NO 3

JOURNAL OF

HEMATOLOGY ONCOLOGY ™ PHARMACY TM

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

ORIGINAL RESEARCH

Effects of a Reduced Dose of Pegfilgrastim on the Incidence of Febrile Neutropenia and Bone Pain: A Retrospective Analysis Lew Iacovelli, BS, PharmD, BCOP, CPP; Richard Harms, PharmD, RPh; May Mo, MS

Testicular Germ-Cell Tumors: A History of “If You Don’t Cure the First Time, Try, Try Again” Patrick J. Kiel, PharmD, BCPS, BCOP; Christopher A. Fausel, PharmD, BCPS, BCOP; Kellie L. Jones, PharmD, BCOP

Medication Therapy Management in the Outpatient Cancer Center Amanda Moss, PharmD; Katie Won, PharmD, BCOP; Lynn Weber, PharmD, BCOP

WWW.JHOPONLINE.COM

XGEVA®, THE FIRST AND ONLY RANK LIGAND INHIBITOR TO PREVENT SREs

INDICATION M<:K6® ^h ^cY^XViZY [dg i]Z egZkZci^dc d[ h`ZaZiVa"gZaViZY ZkZcih ^c eVi^Zcih lî] WdcZ bZiVhiVhZh [gdb hda^Y ijbdgh# M<:K6 ^h cdi ^cY^XViZY [dg i]Z egZkZci^dc d[ h`ZaZiVa" gZaViZY ZkZcih ^c eVi^Zcih lî] bjaiêaZ bnZadbV#

IMPORTANT SAFETY INFORMATION Hypocalcemia M<:K6® XVc XVjhZ hZkZgZ ]nedXVaXZb^V# 8dggZXi ® egZ"Zm^hi^c\ ]nedXVaXZb^V eg^dg id M<:K6 igZVibZci# Bdcîdg XVaX^jb aZkZah VcY VYb^c^hiZg XVaX^jb! bV\cZh^jb! VcY kîVb^c 9 Vh cZXZhhVgn# Bdcîdg ® aZkZah bdgZ [gZfjZcian l]Zc M<:K6 ^h VYb^c^hiZgZY lî] di]Zg Ygj\h i]Vi XVc Vahd adlZg XVaX^jb aZkZah# >c i]Z edhibVg`Zi^c\ hZii^c\! hZkZgZ ]nedXVaXZb^V ]Vh WZZc gZedgiZY# 6Yk^hZ eVi^Zcih id XdciVXi V ]ZVai]XVgZ egd[Zhh^dcVa [dg hnbeidbh d[ ]nedXVaXZb^V#

Osteonecrosis of the Jaw (ONJ) DhiZdcZXgdh^h d[ i]Z _Vl DC? XVc dXXjg ^c ® eVi^Zcih gZXZ^k^c\ M<:K6 ! bVc^[Zhi^c\ Vh _Vl eV^c! dhiZdbnZaî^h! dhiZî^h! WdcZ Zgdh^dc! iddi] dg eZg^dYdciVa ^c[ZXi^dc! iddi]VX]Z! \^c\^kVa jaXZgVi^dc! dg \^c\^kVa Zgdh^dc# EZgh^hiZci eV^c dg hadl ]ZVa^c\ d[ i]Z bdji] dg _Vl V[iZg YZciVa hjg\Zgn bVn Vahd WZ bVc^[ZhiVi^dch d[ DC?# EZg[dgb Vc dgVa ZmVb^cVi^dc VcY Veegdeg^ViZ ® egZkZci^kZ YZci^hign eg^dg id i]Z ^cî^Vi^dc d[ M<:K6 ® VcY eZg^dY^XVaan Yjg^c\ M<:K6 i]ZgVen# 6Yk^hZ eVi^Zcih gZ\VgY^c\ dgVa ]n\^ZcZ egVXi^XZh# 6kd^Y ^ckVh^kZ YZciVa ® egdXZYjgZh Yjg^c\ igZVibZci lî] M<:K6 # EVi^Zcih l]d VgZ hjheZXiZY d[ ]Vk^c\ dg l]d YZkZade ® h]djaY gZXZ^kZ XVgZ Wn V YZci^hi DC? l]âZ dc M<:K6 dg Vc dgVa hjg\Zdc# >c i]ZhZ eVi^Zcih! ZmiZch^kZ YZciVa hjg\Zgn id igZVi DC? bVn ZmVXZgWViZ i]Z XdcYî^dc#

7VhZY dc Xa^c^XVa ig^Vah jh^c\ V adlZg YdhZ d[ Pregnancy YZcdhjbVW! eVi^Zcih lî] V XgZVi^c^cZ XaZVgVcXZ aZhh i]Vc (% bA$b^c dg gZXZ^k^c\ Y^Vanh^h VgZ Vi \gZViZg LdbZc h]djaY WZ VYk^hZY cdi id WZXdbZ egZ\cVci l]Zc g^h` d[ hZkZgZ ]nedXVaXZb^V XdbeVgZY id eVi^Zcih lî] ® iV`^c\ M<:K6 # >[ i]Z eVi^Zci ^h egZ\cVci dg WZXdbZh cdgbVa gZcVa [jcXi^dc# I]Z g^h` d[ ]nedXVaXZb^V Vi i]Z egZ\cVci l]âZ iV`^c\ i]^h Ygj\! i]Z eVi^Zci h]djaY WZ gZXdbbZcYZY Ydh^c\ hX]ZYjaZ d[ &'% b\ ZkZgn ) lZZ`h Veeg^hZY d[ i]Z ediZci^Va ]VoVgY id i]Z [Zijh# ]Vh cdi WZZc ZkVajViZY ^c eVi^Zcih lî] V XgZVi^c^cZ XaZVgVcXZ aZhh i]Vc (% bA$b^c dg gZXZ^k^c\ Y^Vanh^h# ©2012 Amgen Inc. All rights reserved. 07/12 64002-R5-V1 G69091-R1-V1 www.XGEVA.com

SUPERIORITY XGEVA® delayed the median time to first SRE in a prespecified integrated analysis across 3 head-to-head studies vs zoledronic acid1

PERCENTAGE OF PATIENTS WITHOUT SRE

I^bZ id [^ghi HG:! ZkVajViZY ^c bdgZ i]Vc *!+%% eVi^Zcih&!' VA® 120 mg Q4W (n = 2,862) XGEV zoledronic acid 4 mg Q4W (n = 2,861)

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: e: 19.4 months h

40 30

& &, ,

Median time: e 27.7 months h

G>H@ G>H@ G:9J8I>DC G:9J8I>DC

HR = 0.83 (95% CI: 0.76–0.90) P < 0.0001†

0 0

Reduction in risk of first SRE in 3 individual studies 7gZVhi XVcXZg/ &- kh odaZYgdc^X 3 VX^Y P 2 %#%&%! hjeZg^dgîn EgdhiViZ XVcXZg/ &- kh odaZYgdc^X VX^Y P 2 %#%%-! hjeZg^dgîn 3 Di]Zg hda^Y ijbdgh dg bjaiêaZ bnZadbV/ &+ kh odaZYgdc^X VX^Y P 1 %#%%&! cdc^c[Zg^dgîn0 3 P 2 %#%+%! CH [dg hjeZg^dgîn · HjWVcVanh^h d[ di]Zg hda^Y ijbdgh / &. kh odaZYgdc^X VX^Y 2 P 2 %#%()! hjeZg^dgîn · M<:K6® ^h cdi ^cY^XViZY [dg i]Z egZkZci^dc d[ HG:h ^c eVi^Zcih lî] bjaiêaZ bnZadbV *Excluding breast and prostate cancer. † P value for superiority.

STUDY STUDY MONTH Data from three international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.3

SUBCUTANEOUS INJECTION

NO DOSE ADJUSTMENTS

PRECISE ACTION

XGEVA® is not cleared by the kidneys and does not require dose adjustments, regardless of renal function3-8

XGEVA® acts precisely to bind XGEVA® is administered once to RANK Ligand, a key mediator every 4 weeks as a single, 120 mg of bone resorption, to inhibit subcutaneous injection3 3 osteoclast activity

Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.3 Adverse Reactions I]Z bdhi Xdbbdc VYkZghZ gZVXi^dch ® ^c eVi^Zcih gZXZ^k^c\ M<:K6 lZgZ [Vi^\jZ$Vhi]Zc^V! ]nede]dhe]ViZb^V! VcY cVjhZV# I]Z bdhi Xdbbdc hZg^djh VYkZghZ gZVXi^dc lVh YnhecZV# I]Z bdhi Xdbbdc VYkZghZ gZVXi^dch gZhjai^c\ ^c Y^hXdci^cjVi^dc lZgZ dhiZdcZXgdh^h VcY ]nedXVaXZb^V# 9jg^c\ edhi VeegdkVa jhZ! hZkZgZ hnbeidbVi^X ]nedXVaXZb^V! ^cXajY^c\ [ViVa XVhZh ]Vh WZZc ^YZci^ÃZY#

Please see brief summary of Prescribing Information on the following page.

REFERENCES: 1. Lipton A, Siena S, Rader M, et al. Comparison of denosumab versus zoledronic acid for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials. Ann Oncol. 2010;21(suppl 8):viii380. Abstract 1249P and poster. 2. Data on file, Amgen. 3. XGEVA® (denosumab) prescribing information, Amgen. 4. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:10591066. 5. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2:645-653. 6. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493-507. 7. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010;24:23-39. 8. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50:793-807.

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25Â°C/77Â°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/ Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis. Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on ďŹ ndings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth (see Use in Specific Populations). There are no adequate and well controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: t )ZQPDBMDFNJB (see Warnings and Precautions) t 0TUFPOFDSPTJT PG UIF +BX (see Warnings and Precautions) The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. 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 other clinical trials and may not reďŹ&#x201A;ect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 â&#x20AC;&#x201C; 41) and median duration on-study was 13 months (range: 0.1 â&#x20AC;&#x201C; 41). Of patients who received Xgeva, 46% were female. EightymWF QFSDFOU XFSF 8IJUF )JTQBOJD -BUJOP "TJBO BOE #MBDL 5IF median age was 63 years (range: 18 â&#x20AC;&#x201C; 93). Seventy-ďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in Severity (Trials 1, 2, and 3) which RANK ligand (RANKL) expression was turned off by gene removal Xgeva Zoledronic Acid (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?). In cynomolgus monkeys dosed subcutaneously with Body System n = 2841 n = 2836 denosumab throughout pregnancy at a pharmacologically active dose, there % % was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other ďŹ ndings in offspring included absence of axillary, inguinal, mandibular, GASTROINTESTINAL and mesenteric lymph nodes; abnormal bone growth, reduced bone Nausea 31 32 strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants Diarrhea 20 19 had measurable blood levels of denosumab (22-621% of maternal levels). GENERAL Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on Fatigue/ Asthenia 45 46 tooth eruption, though dental dysplasia was still apparent; axillary and inguinal INVESTIGATIONS lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in )ZQPDBMDFNJBb 18 9 multiple tissues was seen in one recovery animal. There was no evidence of )ZQPQIPTQIBUFNJBb 32 20 maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was NEUROLOGICAL no fetal NOAEL (no observable adverse effect level) established for this study )FBEBDIF 13 14 because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node RESPIRATORY agenesis and led to postnatal impairment of dentition and bone growth. Dyspnea 21 18 Pregnant RANKL knockout mice showed altered maturation of the maternal Cough 15 15 mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). a Adverse reactions reported in at least 10% of patients receiving Xgeva in Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Trials 1, 2, and 3, and meeting one of the following criteria: Measurable concentrations of denosumab were present in the maternal milk t "U MFBTU HSFBUFS JODJEFODF JO 9HFWB USFBUFE QBUJFOUT PS of cynomolgus monkeys up to 1 month after the last dose of denosumab t #FUXFFO HSPVQ EJGGFSFODF FJUIFS EJSFDUJPO PG MFTT UIBO BOE NPSF (â&#x2030;¤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk than 5% greater incidence in patients treated with zoledronic acid and because of the potential for serious adverse reactions in nursing infants compared to placebo (US Prescribing Information for zoledronic acid) from Xgeva, a decision should be made whether to discontinue nursing or b Laboratory-derived and below the central laboratory lower limit of discontinue the drug, taking into account the importance of the drug to the normal [8.3 â&#x20AC;&#x201C; 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant 2.2 â&#x20AC;&#x201C; 2.8 mg/dL (0.71 â&#x20AC;&#x201C; 0.9 mmol/L) for phosphorus] mice lacking the RANK/RANKL signaling pathway that have shown altered Severe Mineral/Electrolyte Abnormalities maturation of the maternal mammary gland, leading to impaired lactation t 4FWFSF IZQPDBMDFNJB DPSSFDUFE TFSVN DBMDJVN MFTT UIBO NH E- PS MFTT QPTUQBSUVN )PXFWFS JO DZOPNPMHVT NPOLFZT USFBUFE XJUI EFOPTVNBC than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and throughout pregnancy, maternal mammary gland development was normal, 1.3% of patients treated with zoledronic acid. Of patients who experienced with no impaired lactation. Mammary gland histopathology at 6 months of severe hypocalcemia, 33% experienced 2 or more episodes of severe age was normal in female offspring exposed to denosumab in utero; however, hypocalcemia and 16% experienced 3 or more episodes (see Warnings and development and lactation have not been fully evaluated (see Nonclinical Precautions and Use in Specific Populations). Toxicology [13.2] in Full Prescribing Information). t 4FWFSF IZQPQIPTQIBUFNJB TFSVN QIPTQIPSVT MFTT UIBO NH E- PS MFTT Pediatric Use. Xgeva is not recommended in pediatric patients. The safety than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and and effectiveness of Xgeva in pediatric patients have not been established. 7.4% of patients treated with zoledronic acid. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in (the target of Xgeva therapy) with a construct of osteoprotegerin bound to 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic Fc (OPG-Fc) at doses â&#x2030;¤ 10 mg/kg was associated with inhibition of bone growth acid group (see Warnings and Precautions). When events occurring during and tooth eruption. Adolescent primates treated with denosumab at doses an extended treatment phase of approximately 4 months in each trial are 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human included, the incidence of conďŹ rmed ONJ was 2.2% in patients who received dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the Xgeva. The median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero Postmarketing Experience. Because postmarketing reactions are to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth reported voluntarily from a population of uncertain size, it is not always malalignment, decreased neonatal growth, and an absence of axillary, inguinal, possible to reliably estimate their frequency or establish a causal mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered relationship to drug exposure. once exposure was ceased following birth; however, axillary and inguinal lymph The following adverse reactions have been identiďŹ ed during post approval nodes remained absent 6 months post-birth (see Use in Pregnancy). use of Xgeva: Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 t )ZQPDBMDFNJB Severe symptomatic hypocalcemia, including fatal cases. (44%) were 65 years of age or older. No overall differences in safety or efďŹ cacy were observed between these patients and younger patients. Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, Renal Impairment. In a trial of 55 patients without cancer and with varying less than 1% (7/2758) of patients with osseous metastases treated with degrees of renal function who received a single dose of 60 mg denosumab, denosumab doses ranging from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 weeks patients with a creatinine clearance of less than 30 mL/min or receiving for up to 3 years tested positive for binding antibodies. No patient with positive dialysis were at greater risk of severe hypocalcemia with denosumab binding antibodies tested positive for neutralizing antibodies as assessed using compared to patients with normal renal function. The risk of hypocalcemia at a chemiluminescent cell-based in vitro biological assay. There was no evidence the recommended dosing schedule of 120 mg every 4 weeks has not been of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical response associated evaluated in patients with a creatinine clearance of less than 30 mL/min or with binding antibody development. The incidence of antibody formation is receiving dialysis (see Warnings and Precautions, Adverse Reactions, and highly dependent on the sensitivity and speciďŹ city of the assay. Additionally, Clinical Pharmacology [12.3] in full Prescribing Information). the observed incidence of a positive antibody (including neutralizing antibody) OVERDOSAGE: There is no experience with overdosage of Xgeva. test result may be inďŹ&#x201A;uenced by several factors, including assay methodology, HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a sample handling, timing of sample collection, concomitant medications, and single-use vial. Store Xgeva in a refrigerator at 2Â°C to 8Â°C (36Â°F to 46Â°F) underlying disease. For these reasons, comparison of antibodies to denosumab in the original carton. Do not freeze. Once removed from the refrigerator, with the incidence of antibodies to other products may be misleading. Xgeva must not be exposed to temperatures above 25Â°C/77Â°F or direct DRUG INTERACTIONS: No formal drug-drug interaction trials have been light and must be used within 14 days. Discard Xgeva if not used within conducted with Xgeva. In clinical trials in patients with breast cancer the 14 days. Do not use Xgeva after the expiry date printed on the label. metastatic to bone, Xgeva was administered in combination with standard Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. anticancer treatment. Serum denosumab concentrations at 1 and 3 months PATIENT COUNSELING INFORMATION: and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal Advise patients to contact a healthcare professional for any of the following: telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence t 4 ZNQUPNT PG IZQPDBMDFNJB JODMVEJOH QBSFTUIFTJBT PS NVTDMF that various anticancer treatments affected denosumab systemic exposure and stiffness, twitching, spasms, or cramps (see Warnings and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months Precautions and Adverse Reactions) were not altered by concomitant chemotherapy and/or hormone therapy. The t 4ZNQUPNT PG 0/+ JODMVEJOH QBJO OVNCOFTT TXFMMJOH PG PS ESBJOBHF median reduction in uNTx/Cr from baseline to month 3 was similar between from the jaw, mouth, or teeth (see Warnings and Precautions and patients receiving concomitant chemotherapy and/or hormone therapy Adverse Reactions) t 1FSTJTUFOU QBJO PS TMPX IFBMJOH PG UIF NPVUI PS KBX BGUFS EFOUBM TVSHFSZ (see Clinical Pharmacology [12.2] in full Prescribing Information). (see Warnings and Precautions) USE IN SPECIFIC POPULATIONS: t 1SFHOBODZ PS OVSTJOH (see Warnings and Precautions and Use in Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Specific Populations) Xgeva can cause fetal harm when administered to a pregnant woman based on ďŹ ndings in animals. In utero denosumab exposure in cynomolgus Advise patients of the need for: monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, t 1SPQFS PSBM IZHJFOF BOE SPVUJOF EFOUBM DBSF along with evidence of absent lymph nodes, abnormal bone growth and t *OGPSNJOH UIFJS EFOUJTU UIBU UIFZ BSF SFDFJWJOH 9HFWB decreased neonatal growth. There are no adequate and well-controlled t "WPJEJOH JOWBTJWF EFOUBM QSPDFEVSFT EVSJOH USFBUNFOU XJUI 9HFWB studies with Xgeva in pregnant women. Women should be advised not Advise patients that denosumab is also marketed as ProliaÂŽ. Patients to become pregnant when taking Xgeva. If this drug is used during should inform their healthcare provider if they are taking Prolia. pregnancy, or if the patient becomes pregnant while taking this drug, the Amgen Manufacturing Limited, a subsidiary of Amgen Inc. patient should be apprised of the potential hazard to the fetus. Women One Amgen Center Drive who become pregnant during Xgeva treatment are encouraged to enroll Thousand Oaks, California 91320-1799 in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or their physicians ÂŠ2012 Amgen Inc. should call 1-800-77-AMGEN (1-800-772-6436) to enroll. All rights reserved. Printed in USA. Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and beneďŹ ts in 68257-R1-V1 continuing or discontinuing treatment with Xgeva.

EDITORIAL BOARD

CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCP Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

SECTION EDITORS CLINICAL CONTROVERSIES

ORIGINAL RESEARCH

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Assistant Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University, Atlanta, GA

REVIEW ARTICLES Scott Soefje, PharmD, BCOP Associate Director, Oncology Pharmacy Smilow Cancer Hospital at Yale New Haven Yale New Haven Hospital New Haven, CT

PRACTICAL ISSUES IN PHARMACY MANAGEMENT Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

FROM THE LITERATURE Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy Touro Universityâ&#x20AC;&#x201C;California Mare Island Vallejo, CA

EDITORS-AT-LARGE Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Oncology Clinical Specialist and Oncology Lead OHSU Hospital and Clinics Portland, OR

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice Samford University McWhorter School of Pharmacy Birmingham, AL

Sandra Cuellar, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

John M. Valgus, PharmD, BCOP, CPP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX

Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist University of Texas M. D. Anderson Cancer Center Houston, TX

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SEPTEMBER 2012

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ORIGINAL RESEARCH

76 Effects of a Reduced Dose of Pegfilgrastim on the Incidence of Febrile Neutropenia and Bone Pain: A Retrospective Analysis Lew Iacovelli, BS, PharmD, BCOP, CPP; Richard Harms, PharmD, RPh; May Mo, MS

Associate Publishers Joe Chanley joe@greenhillhc.com 732.992.1524 Cris Pires cris@engagehc.com 732.992.1896

85 Testicular Germ-Cell Tumors: A History of “If You Don’t Cure the First Time, Try, Try Again”

Production Manager Stephanie Laudien

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103 Medication Therapy Management in the Outpatient Cancer Center Amanda Moss, PharmD; Katie Won, PharmD, BCOP; Lynn Weber, PharmD, BCOP

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MISSION STATEMENT

109 Correction

The Journal of Hematology Oncology Pharmacy is an independent, peer-reviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals with highquality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

Journal of Hematology Oncology Pharmacy™, ISSN applied for (print); ISSN applied for (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Hematology Oncology Pharmacy™, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. E-mail: JHOP@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

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ORIGINAL RESEARCH

Effects of a Reduced Dose of Pegfilgrastim on the Incidence of Febrile Neutropenia and Bone Pain: A Retrospective Analysis Lew Iacovelli, BS, PharmD, BCOP, CPP; Richard Harms, PharmD, RPh; May Mo, MS Background: Pegfilgrastim 6 mg given 24 hours after chemotherapy reduces the incidence of febrile neutropenia (FN) in patients with nonmyeloid malignancies. Some clinicians have advocated reduced doses of pegfilgrastim to decrease the risk of pegfilgrastim-associated bone pain. Objective: To investigate the effects of pegfilgrastim doses equivalent to 3 mg or 6 mg on the incidence of FN and bone pain. Methods: This retrospective analysis included first-cycle data from 5 published clinical studies of pegfilgrastim administered at various weight-based doses. A total of 557 patients were evaluated, 22 of whom received a dose equivalent to a fixed dose of approximately 3 mg (“half dose”) and 66 of whom received a dose equivalent to a fixed dose of approximately 6 mg (“full dose”). The primary end point was the incidence of FN; the secondary end point was the incidence of bone pain adverse events (any grade and grade 3/4). Results: In this retrospective analysis of data from 5 clinical trials, the incidence of cycle 1 FN was 18.2% (95% confidence interval [CI], 5.2%-40.3%) in the half-dose group (N = 22) and 10.6% (95% CI, 4.4%-20.6%) in the full-dose group (N = 66). The incidence of bone pain of any grade was 45.5% (95% CI, 24.4%-67.8%) in the half-dose group versus 37.9% (95% CI, 26.2%-50.7%) in the full-dose group. The incidence of grade 3/4 bone pain was 7.6% (95% CI, 2.5%-16.8%) in the full-dose group; no patients in the half-dose group had grade 3/4 bone pain (95% CI, 0.0%-15.4%). J Hematol Oncol Pharm. 2012;2(3):76-81. Conclusion: In this retrospective study, patients who received the approximately half dose (3 mg) of pegfilgrastim had higher rates of FN and overall bone pain than patients who received www.JHOPonline.com the full dose (6 mg) of pegfilgrastim. Although these results have limitations, including a small Disclosures are at end of text sample size, further research is warranted.

egfilgrastim is a granulocyte colony-stimulating factor (G-CSF) that is indicated to reduce the incidence of febrile neutropenia (FN) in patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy that is associated with a clinically significant incidence of FN.1 In addition to reducing the incidence of FN, prophylactic pegfilgrastim has been shown to decrease FN-related hospitalizations and the use of anti-infectives and to facilitate administration of fulldose chemotherapy regimens2; pegfilgrastim is among the most frequently prescribed myeloid growth factors.3 Pegfilgrastim at a single fixed dose of 6 mg given 24 hours after chemotherapy is associated with predictable and consistent recovery of absolute neutrophil count (ANC),

Dr Iacovelli is Pharmacy Manager, Clinical Oncology Specialist and PGY2 Oncology Residency Program Director, Conehealth Cancer Center, Greensboro, NC; Dr Harms is Director of Medical Communications, Oncology Intl TA Head, and Ms Mo is Biostatistics Senior Manager, Amgen, Inc, Thousand Oaks, CA.

Journal of Hematology Oncology Pharmacy

and its safety and efficacy are comparable with filgrastim 5 µg/kg administered daily until recovery of ANC.4,5 Bone pain is the most often reported adverse event (AE) associated with G-CSF therapy, and it is generally mild to moderate in severity. In a retrospective analysis of 23 pegfilgrastim clinical trials, bone pain was most often reported in the first cycle of chemotherapy.6 In cycle 1, the incidence of bone pain of any grade was 35.1%, and the incidence of grade 3/4 bone pain was 3.3%. In addition, the incidence and severity of bone pain were similar between patients treated with pegfilgrastim and those treated with filgrastim.6 In an attempt to reduce the severity of bone pain, some clinicians have suggested reducing the recommended 6-mg dose of pegfilgrastim.7 Two small retrospective studies reported reductions in bone pain after empiric dose reduction of pegfilgrastim from 6 mg to 3 mg or 4 mg.7,8 The first study, a retrospective chart review reported in 2007, evaluated 34 patients with breast cancer who were treated with doxorubicincyclophosphamide-taxane (n = 12), with a dose-dense

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doxorubicin-cyclophosphamide-taxane (n = 13), or with other unspecified regimens (n = 9).8 Among the 32 of 34 patients who had dose reductions of pegfilgrastim (from 6 mg to 3 mg), there was a significant reduction in patient-reported bone pain severity.8 Although postchemotherapy white blood cell (WBC) counts were significantly lower with 3-mg pegfilgrastim, grade 3/4 neutropenia was not reported with either dose. However, the criteria (eg, severity of bone AEs) on which the decision to reduce the dose of pegfilgrastim was based were not described8; consequently, it is unclear whether the results were confounded. The second study, reported in 2008, evaluated 25 patients with breast cancer who experienced bone pain associated with normal or high leukocyte counts during recovery and subsequently had dose reductions to 4-mg pegfilgrastim.7 Patients were treated with adjuvant or with neoadjuvant chemotherapy (14 patients received doxorubicin/cyclophosphamide, followed by docetaxel) plus 6-mg pegfilgrastim. After the dose of pegfilgrastim was reduced, no bone pain was reported; however, the ANC data were insufficient to draw a conclusion regarding efficacy.7 The objective of this present retrospective analysis is to provide additional information regarding the effects of a reduced dose of pegfilgrastim on the incidence of FN (ie, efficacy) and bone pain (ie, safety). The analysis includes pooled clinical study data from patients with cancer who received chemotherapy and weight-based pegfilgrastim at doses equivalent to fixed doses of approximately 3 mg or 6 mg.

September 2012

Patients from weight-based dosing studies included in the analysis (N = 557) Pegfilgrastim dose range, mg

Pegfilgrastim dose category

<2.0 2.0–<2.5 2.5–<3.0 3.0–<3.5

Half dose, ~3.0 mg (N = 22)

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Figure 1 Allocation of Patients to Half-Dose or Full-Dose Pegfilgrastim Categories

Method Studies and Patients A review of the protocols and clinical study reports of 34 Amgen-sponsored pegfilgrastim interventional studies identified 5 clinical trials (3 of which were dose-finding studies) that randomly assigned patients to receive pegfilgrastim or filgrastim.4,9-12 Once-daily subcutaneous injections of filgrastim 5 µg/kg were given beginning 24 hours after chemotherapy administration and continued for up to 14 days or until ANC ≥10 × 109/L after the expected nadir, whichever occurred first.4,9-12 A single subcutaneous injection of pegfilgrastim per cycle was given 24 hours after chemotherapy administration at doses of 30, 100, or 300 µg/kg10; 30, 60, or 100 µg/kg9; 60 or 100 µg/kg11; and 100 µg/kg.4,12 For this present analysis, weight-based doses of pegfilgrastim were converted to equivalent “fixed” doses for the categorization of patients into approximate half-dose (~3 mg) and fulldose (~6 mg) groups (Figure 1). Patients from the 5 clinical trials were included in this analysis only if they fell into either of these 2 groups.4,9-12

The 557 patients enrolled in the 5 clinical trials were chemotherapy-naive, received previous adjuvant therapy, and/or received chemotherapy for their disease (Table 1).4,9-12 These studies included patients with stage II, III, or IV breast cancer who received doxorubicin/ docetaxel (AT),4,9 patients with non–small-cell lung cancer (NSCLC) who received carboplatin/paclitaxel (CP),10 and patients with lymphoma who received either cyclophosphamide/doxorubicin/vincristine/ prednisone (CHOP) or etoposide/methylprednisolone/ cisplatin/cytarabine (ESHAP).11,12 Patients were eligible for inclusion if they had adequate ANC or WBC counts (ANC ≥1.5 × 109 cells/L,4,10,12 ANC ≥2 × 109 cells/L,11 or WBC count ≥4 × 109 cells/L9); an adequate platelet count (either ≥100 × 109/L4,10-12 or ≥150 × 109/L9); and adequate renal, hepatic, and cardiac function. In addition, patients were required to be capable of self-care (Karnofsky performance status ≥70%10 or Eastern Cooperative Oncology Group performance status ≤24,9,11,12).

Full dose, ~6.0 mg (N = 66)

3.5–<4.0 4.0–<4.5 4.5–<5.0 5.0–<5.5 5.5–<6.0 6.0–<6.5 6.5–<7.0 7.0–<7.5 7.5–<8.0 ≥8.0

Note: The actual pegfilgrastim dose received was calculated by converting weight-based doses of pegfilgrastim to equivalent fixed doses. Patients were then assigned to a dose range and then a dose category according to the calculated weight-based dose received. Sources: References 4, 9-12.

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ORIGINAL RESEARCH

Patients were excluded if they had received recent (within 2-4 weeks of randomization4,9,12) or extensive (>25% of red bone marrow11) radiotherapy. In each study, informed consent was obtained from patients before enrollment, and an institutional review board at each participating center approved all study procedures.

End Points The primary end point for the present analysis was the incidence of FN, which was defined as a temperature of ≥38.2°C, with an ANC of <0.5 × 109/L. The secondary end point was the incidence of bone pain AEs (any grade and grade 3/4). AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA; version 11). AE preferred terms that were considered bone pain were predetermined and were used to identify bone pain–related AEs, such as “bone pain,” “back pain,” “neck pain,” “pain in hip,” “pain in shoulder,” “aching in limb,” and “pain in extremity” that occurred in the “musculoskeletal and connective tissue disorders” sys-

tem organ class. Pain-related preferred terms in other system organ classes (eg, “rib pain” in “repiratory, thoracic, and mediastinal disorders” and “toothache” in “gastrointestinal disorders”) were also identified as bone pain. Bone pain severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; version 3.0)13 as in the original studies. If a patient had multiple bone pain AEs in cycle 1, the severity of the AE with the highest CTCAE grade was considered as the bone pain severity for the cycle. Because of differences in the number of treatment cycles across the 5 studies, and because bone pain incidence is highest in the first cycle, only events occurring during the first chemotherapy cycle were evaluated. Homogeneity of studies was evaluated by examining the end point definitions of the individual studies.

Statistical Analyses Weight-based doses were converted to equivalent “fixed” doses using the following formula: dose (mg) =

Table 1 Pegfilgrastim and Filgrastim Use in Clinical Trials Included in This Analysis Growth factors received, N (%) Chemotherapy administered

Half-dose pegfilgrastim ~3 mg (N = 22)

Full-dose pegfilgrastim ~6 mg (N = 66)

AMG 97014410 Phase 1/2 NSCLC, thoracic cancer (N = 70)

11 (50)

6 (9)

AMG 9801479 Phase 2 Breast cancer (N = 124)

11 (50)

13 (20)

AMG 9802264 Phase 3 Breast cancer (N = 272)

0 (0)

38 (58)

AMG 99011712 Phase 2 NHL, Hodgkin lymphoma (N = 53)

ESHAP

0 (0)

4 (6)

AMG 99011811 Phase 2 NHL (geriatric population) (N = 38)

CHOP

0 (0)

5 (8)

Trial

AT indicates doxorubicin/docetaxel; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; CP, carboplatin/paclitaxel; ESHAP, etoposide/methylprednisolone/cisplatin/cytarabine; NHL, non-Hodgkin lymphoma; NSCLC, non–small-cell lung cancer.

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dose per kg (µg/kg) × baseline weight in kg per 1000. A total of 557 patients were categorized into dose groups according to the pegfilgrastim dose they received. Patients were then further categorized into the approximate half- or full-dose groups as follows: half-dose patients (N = 22) received doses between 2.5 mg and <3.5 mg (~3-mg dose), and full-dose patients (N = 66) received doses between 5.5 mg and <6.5 mg (~6-mg dose). Data analysis was performed using SAS Version 9.1 (SAS Institute; Cary, NC). Summaries of demographic data and baseline characteristics were generated by pegfilgrastim dose level (3 mg or 6 mg). Because of the limited sample size and low event rate, exact binomial confidence intervals (CIs) were calculated for the incidences of FN and bone pain in cycle 1 of chemotherapy.

Results and Discussion A non–evidence-based practice has emerged in which there have been attempts by physicians to mitigate pegfilgrastim-associated bone pain in patients with cancer by administering a dose of pegfilgrastim lower than the recommended 6-mg dose. In this study we analyzed pooled patient-level data from 5 clinical trials to investigate whether reduced pegfilgrastim dosing affects the incidence of FN and bone pain. Of the 557 patients with cancer enrolled in the 5 clinical trials and included in the present analysis (Table 1), 22 received the approximate 3-mg dose (“half dose”) of pegfilgrastim, and 66 received the approximate 6-mg dose (“full dose”) of pegfilgrastim. Patient demographics and baseline characteristics are shown in Table 2.4,9-12 Most patients had either NSCLC or breast cancer (a smaller proportion had non-Hodgkin lymphoma), and the majority received either CP or AT regimens. The half-dose group included a greater proportion of male patients, a higher mean body weight, and a greater proportion of patients with NSCLC who received CP.4,9-12 In contrast, the full-dose group included all 9 of the patients with lymphoma and a greater proportion of female patients with breast cancer who received AT. The incidence of FN, bone pain of any grade, and grade 3/4 bone pain for both dose groups during cycle 1 are shown in Figure 2. The 22 patients receiving the half dose of pegfilgrastim tended to have a higher incidence of FN during the first chemotherapy cycle (18.2%; 95% CI, 5.2%-40.3%) than the 66 patients receiving the recommended full dose of pegfilgrastim (10.6%; 95% CI, 4.4%-20.6%).4,9-12 The bone pain AEs (by MedDRA preferred term) were bone pain, arthralgia, pain in extremity, pain, back pain, noncardiac chest pain, and musculoskeletal pain. The incidence of bone pain of any grade during the first cycle of chemotherapy was 45.5% (95% CI, 24.4%-

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Table 2 Baseline Characteristics of Patients Who Received an Approximate Half Dose or Full Dose of Pegfilgrastima Characteristic

Half dose, ~3 mg (N = 22)

Full dose, ~6 mg (N = 66)

Women, N (%)

13 (59)

60 (91)

White, N (%)

19 (86)

50 (76)

Age, median yr (min-max)

59.0 (37-72)

53.5 (22-80)

Age-group ≥65 yr, N (%)

7 (32)

14 (21)

Weight, mean kg (SD)

83 (22)

66 (14)

11 (50)

6 (9)

11 (50)

51 (77)

0 (0)

9 (14)

Tumor type, N (%) NSCLC Breast cancer NHL a

Half-dose pegfilgrastim included doses between 2.5 mg and <3.5 mg, and full-dose pegfilgrastim included doses between 5.5 mg to <6.5 mg. NHL indicates non-Hodgkin lymphoma; NSCLC, non–smallcell lung cancer; SD, standard deviation. Sources: References 4, 9-12.

67.8%) among patients who received the half dose of pegfilgrastim and 37.9% (95% CI, 26.2%-50.7%) among patients who received the recommended full dose. No patients in the half-dose group (95% CI, 0%15.4%) and 7.6% (95% CI, 2.5%-16.8%) of patients in the full-dose group had grade 3/4 bone pain.4,9-12

The 22 patients receiving the half dose of pegfilgrastim tended to have a higher incidence of FN during the first chemotherapy cycle than the 66 patients receiving the recommended full dose of pegfilgrastim. The higher incidence of grade 3/4 bone pain could be attributed to the greater exposure to pegfilgrastim in the full-dose group. However, imbalances between the fulldose and the half-dose groups in the administration of chemotherapy regimens with potential to cause bone pain, such as doxorubicin, paclitaxel, and carboplatin,14-17 may also have been a contributing factor. A higher pro-

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Figure 2 Incidence of Febrile Neutropenia (A) and Bone Pain (B) in Patients Receiving Half-Dose (~3 mg) or Full-Dose (~6 mg) Pegfilgrastim B. Bone Pain

Bone pain incidence, % with 95% CI

Incidence of FN, % with 95% CI

A. Febrile Neutropenia

35 30 25 20

18.2% 10.6%

60 50

37.9%

40 30 20

0 Half dose (N = 22)

45.5%

7.6% 0.0% Half dose (N = 22)

Full dose (N = 66)

All grades

Half dose (N = 22)

Full dose (N = 66)

Grade 3/4

CI indicates confidence interval; FN, febrile neutropenia. Sources: References 4, 9-12.

portion of patients in the full-dose group than in the half-dose group received AT, whereas a higher proportion of patients in the half-dose group received CP. Considering that the response to chemotherapy and pegfilgrastim may differ between patients with solid tumors versus hematologic malignancies, we performed an ad hoc analysis, which showed that excluding the 9 patients with lymphoma had a negligible effect on the observed differences in the incidence of grade 3/4 bone pain between the full-dose and half-dose groups (data not shown). Previous studies have shown that the incidence of bone pain associated with pegfilgrastim is highest during the first chemotherapy cycle, then it generally decreases or resolves in subsequent cycles.6,18 Because of this decrease in the incidence of bone pain after cycle 1, ascribing the reduction of bone pain to a reduction in the dose of pegfilgrastim may be a confounded conclusion. The findings of the 2007 and the 2008 retrospective studies among patients with breast cancer who had empiric reductions of the pegfilgrastim dose in subsequent cycles as a result of bone pain7,8 should also be considered in light of this limitation: a decreased incidence of bone pain in later cycles would be expected

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even if the pegfilgrastim dose had remained at 6 mg. In a recent retrospective analysis that included 23 pegfilgrastim studies (1862 patients who received pegfilgrastim 100 Âľg or 6 mg once per chemotherapy cycle), the incidence of bone pain of any grade during the first cycle was 35.1% and the incidence of grade 3/4 bone pain was 3.3%.6 Of note, there is some overlap between the patient populations analyzed in the present analysis and those in the retrospective study by Gregory and colleagues,6 and all 5 studies included in the present analysis (Table 1) were included in the study by Gregory and colleagues.6

Limitations The current study had several limitations. First, the study was not large enough to detect statistically significant differences between the pegfilgrastim dose groups. Second, because this analysis included only trials with available patient-level data, the generalizability of the findings may be limited. Third, by pooling data from different existing trial data sets, the current analysis may not be well controlled for potential confounding factors such as tumor type and chemotherapy regimen.

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Fourth, because patients were categorized into the approximate fixed-dose treatment groups retrospectively based on the narrow ranges of weight-based pegfilgrastim doses administered, it was not possible to ensure balance in distribution of patients between the half-dose and full-dose groups. Finally, because bone pain was not a prespecified end point in the included trials, data regarding some important covariates related to bone pain, such as bone metastases and bone pain before entry into the trial, were not collected.

Conclusions In this retrospective study, patients who received the approximate half dose (3 mg) of pegfilgrastim had higher rates of FN and overall bone pain than patients who received the full dose (6 mg) of pegfilgrastim. Although these results have limitations, including a small sample size, further research is warranted. n Acknowledgments The authors would like to thank Margit Rezabek, DVM, PhD, and Benjamin Scott, PhD, whose work was funded by Amgen, Inc, for assistance in the preparation of this manuscript. Author Disclosure Statement Dr Iacovelli is a consultant to and has received honoraria from Amgen Inc. Dr Harms and Ms Mo are employees of and have stock in Amgen Inc.

References 1. Neulasta [prescribing information]. Thousand Oaks, CA: Amgen, Inc; 2010. 2. Renwick W, Pettengell R, Green M. Use of filgrastim and pegfilgrastim to support delivery of chemotherapy: twenty years of clinical experience. BioDrugs. 2009;23:175-186. 3. Falandry C, Campone M, Cartron G, et al. Trends in G-CSF use in 990 patients

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after EORTC and ASCO guidelines. Eur J Cancer. 2010;46:2389-2398. 4. Holmes FA, O’Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002;20:727-731. 5. Green MD, Koelbl H, Baselga J, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. 2003;14:29-35. 6. Gregory S, Schwartzberg L, Mo M, et al. Evaluation of reported bone pain in cancer patients receiving chemotherapy in pegfilgrastim clinical trials: a retrospective analysis. Community Oncol. 2010;7:297-306. 7. Paba C, Sachdev J, Kronish L, et al. Empiric dose reduction of pegfilgrastim in breast cancer patients receiving cytotoxic chemotherapy. J Clin Oncol. 2008;26:abstract 20636. 8. Bartelt ME, Harman S, Lower EE. Halved pegfilgrastim doses in adjuvant breast cancer patients associated with similar efficacy but reduced toxicity. Presented at: San Antonio Breast Cancer Symposium; December 13-16, 2007; San Antonio, TX. Abstract 2063. 9. Holmes FA, Jones SE, O’Shaughnessy J, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol. 2002;13:903-909. 10. Johnston E, Crawford J, Blackwell S, et al. Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol. 2000;18:2522-2528. 11. Grigg A, Solal-Celigny P, Hoskin P, et al. Open-label, randomized study of pegfilgrastim vs daily filgrastim as an adjunct to chemotherapy in elderly patients with non-Hodgkin’s lymphoma. Leuk Lymphoma. 2003;44:1503-1508. 12. Vose JM, Crump M, Lazarus H, et al. Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. J Clin Oncol. 2003;21:514-519. 13. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0. National Cancer Institute, US National Institutes of Health; August 9, 2006. 14. Kramer JA, Curran D, Piccart M, et al. Randomised trial of paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer: quality of life evaluation using the EORTC QLQ-C30 and the Rotterdam symptom checklist. Eur J Cancer. 2000;36:1488-1497. 15. Marsland TA, Garfield DH, Khan MM, et al. Sequential versus concurrent paclitaxel and carboplatin for the treatment of advanced non-small cell lung cancer in elderly patients and patients with poor performance status: results of two phase II, multicenter trials. Lung Cancer. 2005;47:111-120. 16. Boehmke MM, Dickerson SS. Symptom, symptom experiences, and symptom distress encountered by women with breast cancer undergoing current treatment modalities. Cancer Nurs. 2005;28:382-389. 17. Sierra J, Harms R, Mo M, Vogel CL. Evaluation of reported bone pain in patients (pts) receiving chemotherapy in pegfilgrastim clinical trials [abstract]. J Clin Oncol. 2009;27:9621. 18. Kubista E, Glaspy J, Holmes FA, et al. Bone pain associated with once-percycle pegfilgrastim is similar to daily filgrastim in patients with breast cancer. Clin Breast Cancer. 2003;3:391-398.

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R D IV O F AN D E US ION V O EO AT R P AN STR P A UT INI BC DM U S A

VELCADEHCP.COM

If you define value as an overall survival advantage: VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you define value as defined length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you define value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012 Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

VELCADE Indication and Important Safety Information INDICATION VELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated Closely monitor patients with risk factors for, or existing heart disease Acute diffuse infiltrative pulmonary disease has been reported Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on the next page of this advertisement. To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, 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: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

V-12-0095

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Testicular Germ-Cell Tumors

Background: Cancer of the testis consists of a diverse group of neoplasms, most of which are germ-cell tumors. Although testicular cancer comprises only 2% of all malignancies in the United States, it is the most common solid tumor in young men between the ages of 15 and 34 years. Advances in the management of testicular germ-cell tumors over the past 40 years have resulted in great improvement in the management of this disease. Objective: To review the historical and clinical significance of chemotherapy in the management of testicular germ-cell tumors. Discussion: The treatment of testicular germ-cell tumors involves 4 modalities, including surgery, radiation, chemotherapy, and observation. All patients with a testicular primary tumor will undergo a radical inguinal orchiectomy. The timing of the surgery is typically conducted before chemotherapy or radiation; however, some cases may warrant a delay in surgery to proceed with chemotherapy first, in which case the diagnosis is made clinically based on elevated tumor markers. Current advances in the management of patients with testicular cancer have resulted with a change from a disease with 90% mortality to a disease with almost a 90% cure rate with first-line chemotherapy. Long-term survival can also be achieved with second- and third-line chemotherapy regimens. J Hematol Oncol Pharm. Conclusion: With overall cure rates of more than 90%, this disease is the model of care for cur2012;2(3):85-98. able cancer. Patients with refractory or with relapsed disease can still be cured with second- or www.JHOPonline.com third-line chemotherapies with cisplatin-based regimens or with high-dose chemotherapy and Disclosures are at end of text transplantation. Pharmacists caring for this patient population must monitor for common toxicities associated with chemotherapy regimens.

n 2011 it was estimated that 8290 new cases of testicular cancer would be diagnosed in the United States.1 Cancer of the testis consists of a morphologically and clinically diverse group of neoplasms, most of which are germ-cell tumors. Although testicular cancer comprises only 2% of all malignancies in the United States, it is the most common solid tumor in men between the ages of 15 and 34 years.2 The incidence of testicular germ-cell tumors is highest in men of Scandinavian, German, and New Zealand descent, and it is principally observed in whites. The cause of testicular germ-cell tumors is unknown; nevertheless, the risk factors are known and include family

Dr Kiel is Clinical Pharmacy Specialist, Hematology/Stem Cell Transplant, Indiana University Simon Cancer Center-Indiana University Health; Dr Fausel is Clinical Director, Oncology Pharmacy Services, Indiana University Simon Cancer CenterIndiana University Health; Dr Jones is Clinical Associate Professor of Pharmacy Practice, Purdue University College of Pharmacy, Indiana University Simon Cancer Center-Indiana University Health.

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September 2012

history, cryptorchidism, Klinefelter’s syndrome, and testicular dysgenesis.3

Initial Presentation and Management The characteristic presentation of testicular germ-cell tumors is a painless testicular mass; however, most patients will present with symptoms of epididymitis and/or orchitis, which are painful and uncomfortable. A trial of antibiotics is usually prescribed to treat presumptive epididymitis, and if no response is observed, a testicular ultrasound is required. On ultrasound, the typical tumor is intratesticular and produces a hypoechoic mass. A radical inguinal orchiectomy with ligation of the spermatic cord is required for all patients with suspected testicular cancer. Transscrotal biopsy with orchiectomy is contraindicated, because of the potential to introduce metastatic spread. In addition, computed tomographic imaging of the chest, abdomen, and pelvis are required for staging of disease.3 Primary extragonadal disease comprises 10% of all testicular germ-cell tumors, which occurs most frequently in the mediastinum and retroperitoneum. Patients with

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Journal of Hematology Oncology Pharmacy

ORIGINAL RESEARCH

Table 1 American Joint Committee on Cancer Testicular Nonseminoma Guidelines Tumor stage Stage I IA IB IS Stage II IIA IIB IIC Stage III IIIA IIIB IIIC Serum tumor markers S1 S2 S3

Tumor type

Nodal status

Metastases

Serum tumor markers

pT1 pT2-4 Any pT/TX

N0 N0 N0

M0 M0 M0

S0 S0 S1-3

Any pT/TX Any pT/TX Any pT/TX

N1 N2 N3

M0 M0 M0

S0-1 S0-1 S0-1

Any pT/TX Any pT/TX Any pT/TX LDH <1.5 × normal 1.5-10 × normal >10 × normal

Any Any Any b-hCG (mIU/mL) <5000 5000-50,000 >50,000

M1a M0-1a M0-1b AFP (ng/mL) <1000 1000-10,000 >10,000

S0-1 S2 S0-3

AFP indicates alpha-fetoprotein; b-hCG, beta-human chorionic gonadotropin; LDH, lactate dehydrogenase; pT, primary tumor; TX, primary tumor cannot be assessed. Adapted from Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer Verlag; 2002.

mediastinal involvement may present with shortness of breath and chest pain, and potentially with superior vena cava syndrome. Patients with retroperitoneum involvement present with back pain or with an abdominal mass. Regardless of the presentation, a testicular ultrasound is required to diagnose the primary site of malignancy.3 Testicular germ-cell tumors are histologically classified as seminomatous or nonseminomatous.4 Approximately 50% of men present with seminoma histology and 50% present with nonseminomatous features. Nonseminomatous tumors are divided into 4 subclassifications, including choriocarcinoma, embryonal carcinoma, teratoma, and yolk sac tumor. Nonseminomas are more aggressive than seminomas, and when both are present, the management of nonseminoma takes precedence. Pathologic specimens often contain several mixed histologic entities.4 Common sites of metastases include the retroperitoneum, retroperitoneal lymph nodes, lungs, and brain.3 Serum tumor markers are used for diagnosis, staging, and assessing response to different modalities of treatment. These tumor markers are beta-human chorionic gonadotropin (b-hCG; normal range, <3 mIU/mL), alpha-fetoprotein (AFP; normal range, 0-25 ng/mL), and lactate dehydrogenase (LDH). AFP production is restricted to nonseminomatous germ-cell tumors, specifically embryonal carcinoma and yolk sac tumor. Eleva-

Journal of Hematology Oncology Pharmacy

tions in AFP may also occur during liver damage (infectious or drug- or alcohol-induced), hepatocellular carcinoma, and other gastrointestinal tract cancers. Elevated b-hCG may be observed in seminomatous and in nonseminomatous tumors; false-positive b-hCG results include cross-reactivity of the antibody with luteinizing hormone, hypogonadism, and marijuana use. The serum half-lives of b-hCG and AFP are 1 and 5 days, respectively. Increased levels of b-hCG occur in 40% to 60% of patients with metastatic nonseminomatous germ-cell tumors, and in 15% to 20% of patients with metastatic seminomas. LDH is less specific, but concentrations are increased in 60% of patients with nonseminomatous testicular cancer and in 80% of those with seminomatous testicular cancer.3 Testicular germ-cell tumors are treated based on the stage of disease and the risk factor classification.5,6 Stage I disease is confined to the testis; stage II disease includes spreading to the retroperitoneal lymph nodes; stage III is supradiaphragmatic disease, with nodal metastases to the posterior mediastinum or with supraclavicular region or hematogenous spread to nonnodal sites, particularly to the lungs. The American Joint Committee on Cancer has issued standard guidelines for testicular cancer staging (Table 1).5 The International Germ Cell Cancer Collaborative Group (IGCCCG) risk status criteria should be used in all clinical trials and in treatment deci-

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September 2012

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Testicular Germ-Cell Tumors

Table 2 The International Germ-Cell Cancer Collaborative Group Risk Categories Risk

Seminoma

Nonseminoma

Nonpulmonary visceral site Any b-hCG Any LDH Any primary site Nonpulmonary visceral site with metastases Any b-hCG Intermediate Any LDH Any primary site Good

Poor

N/A

Nonpulmonary visceral metastases absent Gonadal or retroperitoneal primary AFP <1000 ng/mL b-hCG <5000 mIU/mL LDH <1.5 × ULN Nonpulmonary visceral metastases absent AFP 1000-10,000 ng/mL b-hCG 5000-50,000 mIU/mL LDH 1.5-10 × ULN Mediastinal primary site Nonpulmonary visceral metastases present (ie, bone, liver, brain) LDH >10 × ULN

NOTE: Levels of tumor markers are postorchiectomy. AFP indicates alpha-fetoprotein; b-hCG, beta-human chorionic gonadotropin; LDH, lactate dehydrogenase; N/A, not applicable; ULN, upper limit of normal. Sources: References 6 and 7.

sions for patients requiring chemotherapy for advanced disease (Table 2).6,7

Evolution of Testis Cancer Treatment as a Clinical Model Although testicular germ-cell tumor only accounts for 2% of all malignancies, it is an important disease in oncology. It has been a model for multidisciplinary care and the systematic approach to clinical trial evaluation of chemotherapy agents in cancer (Figure 1).7-25 It has also been a testing ground for new antineoplastic drugs. The US Food and Drug Administration primarily approved cisplatin, ifosfamide, and etoposide based on evidence in testicular germ-cell tumors. These 3 chemotherapeutic agents are now common treatments for patients with many types of cancer, such as small-cell lung cancer, non–small-cell lung cancer, relapsed lymphoma, sarcoma, and head and neck cancers. The treatment of testis cancer represents a landmark achievement in cancer drug development, demonstrating dramatic improvements in cure rates with the use of multiagent chemotherapy. Research into the efficacy of combination chemotherapy for testicular germ-cell tumors began almost 40 years ago (Figure 1). The hypothesis was that malignant cells would rapidly develop drug resistance to single-agent therapy, leading to disease progression and subsequent death. The goal of combination chemotherapy was to (1) use drugs with single-agent activity based on different mechanisms of action, (2) use drugs with nonover-

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lapping toxicity, and (3) whenever possible, combine therapies with synergistic killing rather than with just additive effects. Initial therapy with actinomycin D produced 5% to 10% cure rates in the early 1960s.8 The discovery of vinblastine plus bleomycin as first-line therapy resulted in 25% long-term disease-free survival.9 The opportune discovery of cisplatin (formerly cis-diamminedichloroplatinum) and its incorporation into the management of patients who progressed from therapy with actinomycin D produced complete responses, with durable remissions.26 This led to the systematic incorporation of cisplatin with vinblastine and bleomycin (PVB), which produced complete remissions in 74% of patients with disseminated disease after first-line chemotherapy, and an additional 11% complete remissions after post-PVB surgical resection.10 Overall, this approach provided long-term disease-free survival of 64% at 30 months.10 All subsequent studies addressed clinically relevant questions, such as: • What is the number of cycles required for initial therapy? • Is maintenance therapy required? • Can cisplatin be substituted for carboplatin? The dogma of maintenance therapy with vinblastine was challenged and proved unnecessary after first-line treatment. As novel agents were discovered (most recently, etoposide) and were shown to be active in the preclinical arena, they were tested in patients with multiple relapsed disease, then as initial salvage therapy, and finally as frontline therapy. The standard PVB regimen was

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Figure 1 Evolution of Chemotherapy in Testis Cancer a Bleomycin demonstrates activity9

PVB vs BEP first-line cure 83%25 Ifosfamide shows activity in testis cancer16 Carboplatin for PVB studies begin Strategies based on serum cisplatin in the at Indiana marker monitoring begin19 first-line setting is University10 inferior12 VIP active in relapse7,15

1970

1980

Mithramycin + vinblastine Ifosfamide achieve responses9 clinical pharmacology7 Discovery of cisplatin10

BEP × 4 similar to BEP × 3 for good-risk disease13

Cisplatin enters phase 1/2 trials9

Actinomycin D monotherapy ± methotrexate and chlorambucil standard 5%-10% cure8

1960

VeIP or VIP as initial salvage therapy: 50% of relapsed patients alive at 4.7 years7 Landmark series of high-dose chemotherapy and stem-cell transplant: Double dose of 69% alive from second-line therapy, cisplatin more 44% alive from third-line therapy18 toxic and not more 24 effective

PVB cures 65% in first line11

Bleomycin and vinblastine produce 57% CR + 25% long-term survival24

Vinblastine maintenance negated25

Etoposide proves activity7

1990

TICE and stem-cell transplant23

2000

Dose-intense therapy with carboplatin begins25

EP × 3 is inferior to BEP × 320

Single-agent Paclitaxel activity carboplatin in relapse17 active12

Preclinical synergism with cisplatin and etoposide24

BEP × 3 is equivalent to EP × 414

2010

TIP regimen published18 VIP no better than BEP, alternative with underlying pulmonary disease21

Tandem transplant experience published22

Mesna is now given with all ifosfamide-containing regimens for testicular cancer. BEP indicates bleomycin, etoposide, cisplatin; CR, complete response; EP, etoposide, cisplatin; 2-mercaptoethane sulfonate sodium; PVB, cisplatin, vinblastine, bleomycin; TICE, paclitaxel, ifosfamide, carboplatin, etoposide; TIP, paclitaxel, ifosfamide, cisplatin; VeIP, vinblastine, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin.

then compared head to head with bleomycin, etoposide, and cisplatin (BEP), producing disease-free results in 74% and 83% of patients, respectively, with a noted survival advantage for advanced disseminated disease.11 Carboplatin was also investigated as a substitute for cisplatin in combination with bleomycin and etoposide for the treatment of patients with good-risk, metastatic, nonseminomatous disease.12 Chemotherapy consisted of 4 cycles of carboplatin with an area under the curve of 5 mg/mL/min, etoposide, and bleomycin (CEB) versus BEP. Complete responses were more common in patients receiving BEP (94.4%) compared with CEB (87.3%; P = .009), indicating that carboplatin should not be used as a standard of care.12 The primary end point of failure-free survival at 1 year was inferior for the carboplatin arm at 77% versus BEP at 91% (P <.001).12 Next, the number of cycles of BEP was evaluated in patients with good-risk disease in an effort to minimize the total number of cycles required for optimal treatment. The Southeastern Cancer Study Group trial demonstrated that 3 versus 4 cycles of BEP did not show

Journal of Hematology Oncology Pharmacy

a significant difference (P = .8) in overall survival (OS) or in disease-free survival (P = .93), with a median follow-up of 10.1 years.13 This changed the standard of care to consist of only 3 cycles of BEP in patients with good-risk disease.13 From here, salvage treatment continued to evolve to include novel agents and the incorporation of high-dose chemotherapy followed by stemcell transplantation.

Selection of Initial Treatment The treatment of testicular germ-cell tumors involves 4 different modalities—surgery, radiation, chemotherapy (Table 3),7,11,13-18,27,28 and observation. All patients with a testicular primary tumor will undergo a radical inguinal orchiectomy. The timing of the surgery is typically conducted before chemotherapy or radiation; however, some cases may warrant a delay in surgery to proceed with chemotherapy first (ie, when a patient is hemodynamically unstable). In that case, the diagnosis is made clinically based on elevated tumor markers. If orchiectomy is delayed, the procedure should be completed soon after chemotherapy, because the testes serve

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Testicular Germ-Cell Tumors

Table 3 Common Chemotherapy Regimens for Testicular Germ-Cell Tumors Regimen Standard first-line therapy BEP11,13 Bleomycin Etoposide Cisplatin EP14 Etoposide Cisplatin VIP7 Etoposide Ifosfamide Cisplatin Mesna Pegfilgrastim PVB11 Cisplatin Vinblastine Bleomycin Standard salvage therapy VIP15 Etoposide Ifosfamide Cisplatin Mesna Pegfilgrastim VeIP16 Vinblastine Ifosfamide Cisplatin Mesna Pegfilgrastim TIP17 Paclitaxel Ifosfamide Cisplatin Mesna Pegfilgrastim High-dose chemotherapy18 Carboplatin Etoposide Autologous stem-cell infusion Cisplatin + epirubicin27 Cisplatin Epirubicin Pegfilgrastim Paclitaxel + gemcitabine28 Paclitaxel Gemcitabine

Dose

Frequency

30 units IV bolus 100 mg/m2/day IV over 1 hr 20 mg/m2/day IV over 1 hr 100 mg/m2/day IV over 1 hr 20 mg/m2/day IV over 1 hr 75 mg/m2/day IV over 1 hr 1200 mg/m2/day IV over 2 hrs 20 mg/m2/day IV over 1 hr 120 mg/m2 IV bolus then 1200 mg/m2/day continuous IV 6 mg SC Historic regimen 20 mg/m2/day IV over 1 hr 0.15 mg/kg IV over 15 min 30 units IV bolus

75 mg/m2/day IV over 1 hr 1200 mg/m2/day IV over 2 hrs 20 mg/m2/day IV over 1 hr 120 mg/m2 IV bolus then 1200 mg/m2/day continuous IV 6 mg SC 0.11 mg/kg/day IV over 1 hr 1200 mg/m2/day IV over 2 hrs 20 mg/m2/day IV over 1 hr 120 mg/m2 IV bolus then 1200 mg/m2/day continuous IV 6 mg SC 250 mg/m2 IV over 24 hrs 1500 mg/m2/day IV over 1 hr 25 mg/m2/day IV over 0.5 hr 500 mg/m2 IV before ifosfamide and at 4 hrs and 8 hrs after 6 mg SC Repeat with granulocyte recovery, total of 2 cycles 700 mg/m2 daily over 0.5 hr 750 mg/m2 daily (undiluted) over 2 hrs Minimum 20 mg/m2/day IV 90 mg/m2 IV over 15 min 6 mg SC For platinum refractory disease 100-110 mg/m2 IV over 1 hr 1000 mg/m2 IV over 30 min

Every 3 wks for 3-4 cycles D1, D8, D15 or on D2, D9, D16 D1-D5 D1-D5 Every 3 wks for 4 cycles D1-D5 D1-D5 Every 3 wks for 4 cycles D1-D5 D1-D5 D1-D5 D1-D5 D7 Every 3 wks for 4 cycles D1-D5 D1-D2 D2, D9, D16 Every 3 wks for 4 cycles D1-D5 D1-D5 D1-D5 D1-D5 D7 Every 3 wks for 4 cycles D1-D2 D1-D5 D1-D5 D1-D5 D7 Every 3 wks for 4 cycles D1 D2-D5 D2-D5 D2-D5 D7 D –5, D –4, D –3 D –5, D –4, D –3 D0 Every 3 wks for 4 cycles D1-D5 D1-D5 D7 Every 4 wks for 6 cycles D1, D8, D15 D1, D8, D15

D indicates day of chemotherapy; IV, intravenous; mesna, 2-mercaptoethane sulfonate sodium; SC, subcutaneous.

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as a sanctuary site, and the ability to penetrate the testes with chemotherapy is extremely poor.

Stage I Seminoma In stage I seminoma, cancer is confined to the testes. After completing orchiectomy, treatment will depend on the histology (ie, seminoma or nonseminoma). Therapies to treat stage I seminoma include radiation, observation, or chemotherapy. Seminomas are exquisitely responsive to radiation therapy. Typical progression and spread of disease occur through the retroperitoneal lymph nodes; therefore, radiation is directed to the retroperitoneum, including the para-aortic lymph nodes and potentially the ipsilateral iliac nodes.29 Observation is also an acceptable management option in patients with stage I seminoma. In approximately 15% to 20% of patients, the disease will relapse while undergoing surveillance.3 Most relapses occur 12 to 15 months later (which is later than with nonseminoma).3 In a 15-year review of patients with stage I seminoma treated with adjuvant radiotherapy compared with patients with active surveillance, the 5-year relapse-free survival and OS were 95% and 100%, respectively.30 Some risk factors that have been hypothesized to increase the risk of relapse include primary tumor size >4 cm and rete testis invasion, but no randomized trials have prospectively evaluated these risks. Surveillance allows the avoidance of unnecessary treatment in the majority of patients whose disease would likely never recur; this will also avoid exposing them to toxicities of chemotherapy. Chemotherapy has been evaluated in stage I seminoma using single-agent carboplatin. Patients were randomized to radiation therapy to the para-aortic lymph nodes or to 1 cycle of carboplatin.31 After a median follow-up of 6.5 years, relapse-free survival rates were similar across groups (96% with radiation vs 94.7% with single-agent carboplatin; hazard ratio, 1.25; 90% confidence interval, 0.83-1.89). Toxicities were very similar across the groups. Based on these data, carboplatin has been added to the standard treatment guidelines for stage I seminoma.31

cure recurrent disease. When using observation for patients with nonseminomatous testicular cancer, it is likely that these patients will require both RPLND and chemotherapy at disease relapse. The retroperitoneum is the most common site of relapse in patients.19 Other common sites of recurrence include the lungs, brain, or other visceral sites. Because the retroperitoneum is a common site of relapsed disease, RPLND plays an invaluable role in the treatment of this disease.19 Observation should only be offered to a very compliant patient, because it is imperative to undergo routine, close monitoring.3 RPLND serves as a diagnostic procedure to define the presence or absence of disease, as well as to remove the most common area to find relapsed disease (Figure 2).19 This surgical procedure is associated with <1% mortality, and rare complications such as hemorrhage, bowel obstruction, and pulmonary embolism have been reported.32 The most common long-term morbidities associated with RPLND are retrograde ejaculation, infertility, and urinary and fecal incontinence resulting from nerve damage from the surgery. It is crucial to have an experienced surgeon for this surgery, who also uses nerve-sparing techniques to reduce long-term morbidity and ensures complete resection of the disease. With the use of nerve-sparing surgery, >95% of patients have preservation of antegrade ejaculation.32 Chemotherapy has been evaluated in patients with stage I nonseminoma. In the trial by de Wit and Fizazi, BEP for 2 cycles resulted in a 5% relapse rate and 1% death rate from disease after receiving chemotherapy.33 The German Testicular Cancer Study Group randomized 382 patients with stage I nonseminoma testicular cancer to 1 cycle of BEP or RPLND after orchiectomy.34 Because of toxicities associated with chemotherapy, postorchiectomy chemotherapy is not routinely used. There is, however, a group of patients in whom chemotherapy would be warranted, such as those with persistent elevated serum tumor markers after surgery but with no radiologic finding of disease.35,36 Chemotherapy in this group of patients would consist of 4 cycles of etoposide and cisplatin (EP) or 3 cycles of BEP.

Stage I Nonseminoma Radiation therapy does not play a role in the treatment of patients with stage I nonseminoma testicular cancer. Treatment modalities include observation, bilateral retroperitoneal lymph node dissection (RPLND), or chemotherapy. Approximately 25% to 30% of patients will relapse from their disease, and few patients will relapse after 2 years.19 Observation can be used to avoid the morbidity associated with RPLND surgery, with the understanding that cisplatin-based chemotherapy can

Stage II and III Seminoma In patients with stage II seminoma (stages IIA or IIB), the treatment of choice is radiation therapy.3 The radiation fields are similar to those for stage I treatment, but the fields are widened to include para-aortic or pelvic adenopathy. In patients with stage IIC good-risk disease, chemotherapy consisting of either 4 cycles of EP or 3 cycles of BEP is recommended.13,20 In seminoma, all stage III disease is considered good-risk disease, except in patients who have nonpulmonary visceral metastasis.

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Testicular Germ-Cell Tumors

Figure 2 Modified Bilateral Retroperitoneal Lymph Node Dissection

Panel A shows a standard dissection (dark outline). The anatomical locations of the lymph nodes are shown. Panel B shows a modified nerve-avoiding template for a right testicular tumor. Reprinted with permission from Bosl GJ, Motzer RJ. Testicular germ-cell cancer. N Engl J Med. 1997;337:242-254. All rights reserved. Published in N Engl J Med. 1997;337:242-253 as a courtesy of Memorial Sloan-Kettering Cancer Center.

Patients with stage III intermediate-risk seminoma who have nonpulmonary visceral metastasis should be given chemotherapy with 4 cycles of BEP. If relapse occurs, second-line chemotherapy is administered with a cure rate of >90% with advanced seminoma.19

Stage II and III Nonseminoma In stage II nonseminoma, if patients are experiencing persistent elevations of their tumor markers after orchiectomy, treatment consists of RPLND and/or chemotherapy.3 After surgery, more than 65% of patients

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will be cured of disease and not need chemotherapy.19 In patients with normal tumor markers, an RPLND alone is the standard of care.3 Close follow-up is important in these patients, and the decision to use adjuvant chemotherapy versus observation is based on the ability of the patient to adhere to close follow-up. Many patients will opt for adjuvant chemotherapy consisting of the standard BEP or EP regimens (Table 2). If the disease relapses during the observation period, chemotherapy with BEP or EP is administered. Clinical trial results have demonstrated equivalence between 4 cycles of EP

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Table 4 Overview of Initial Treatment Options Based on Stage of Disease Stage

Histology

Treatment modality

Regimen/frequency

Radiation Seminoma

Observation

Carboplatin every 3 wks × 2 cycles

Chemotherapy I Surgery (RPLND) Nonseminoma

Chemotherapy

BEP every 3 wks × 2 if persistent elevated tumor markers

Observation Radiation Seminoma

BEP every 3 wks × 3 cycles or EP every 3 wks × 4 cycles Chemotherapy (good risk)

II Surgery (RPLND) Nonseminoma

BEP every 3 wks × 3 cycles or EP every 3 wks × 4 cycles Chemotherapy

Seminoma III

Chemotherapy

BEP every 3 wks × 4 cycles

Chemotherapy (good risk)

BEP every 3 wks × 3 cycles or EP every 3 wks × 4 cycles

Chemotherapy (poor risk)

BEP every 3 wks × 4 cycles or VIP every 3 wks × 4 cycles

Nonseminoma BEP indicates bleomycin, etoposide, cisplatin; EP, etoposide, cisplatin; RPLND, retroperitoneal lymph node dissection; VIP, etoposide, ifosfamide, cisplatin. Adapted from Bosl GJ, Bajorin DF, Sheinfeld J, et al. Cancer of the testis. In: Devita VT, Lawrence TS, Rosenberg SA, et al, eds. Cancer: Principles and Practice of Oncology. Philadelphia, PA: Lippincott Williams and Wilkins; 2008:1463-1485.

and 3 cycles of BEP, and the hematologic and nonhematologic toxicities were similar.20 After a 10-year followup, no significant difference was observed in OS and disease-free survival (P = .80 and P = .93, respectively) between the treatment arms.13 Stage III nonseminomas are classified into good-, intermediate-, and poor-risk diseases. Although stage III is considered to be a metastatic disease, cisplatin-based chemotherapy will cure approximately 75% of patients with stage III disease.11 The standard chemotherapy for patients with good-risk stage III disease would consist of 3 cycles of BEP, with which approximately 90% of patients are cured.13 Treatment for intermediate-risk, nonseminomatous, metastatic testicular cancer has been evaluated in a randomized clinical trial consisting of 4 cycles of BEP versus 4 cycles of etoposide, ifosfamide, and cisplatin (VIP) in 84 patients.21 Complete response rates were similar between the treatment arms (79% vs 74%; P = .62, respectively), and after a follow-up of more than 7 years, relapse-free survival, disease-free survival, and OS rates were similar. The ifosfamide-containing arm did produce significantly more myelosuppression compared with the BEP arm. Based on toxicities and no overall efficacy advantage, 4 cycles of BEP are considered the standard of care for patients with intermediate-risk nonseminoma.

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In poor-risk disease, patients will receive chemotherapy consisting of 4 cycles of BEP or 4 cycles of VIP (Table 3). The VIP regimen would be chosen over BEP in patients with extensive lung disease. The use of bleomycin is avoided, because of the known pulmonary fibrosis that can occur.3 Also, worsening lung function could exclude patients from undergoing postchemotherapy resection of their disease. If patients have preexisting pulmonary dysfunction, they should not receive bleomycin. The 7year OS rate (VIP, 69% vs BEP, 67%) and the progression-free survival (PFS) rate (VIP, 64% vs BEP, 58%) are considered equivalent between the 2 groups, with VIP an alternative treatment option (Table 4).3

Posttreatment Follow-up After chemotherapy has been completed, patients follow up with radiologic tests and serum tumor markers to evaluate for residual disease. In the event of residual disease, it is imperative to remove it surgically. As many as 45% of the resected tumors will contain necrotic tissue, approximately 42% will contain teratoma (which can eventually transform to other malignancies, such as sarcoma), and approximately 10% of tissue will have viable tumor remaining (which is likely resistant to chemotherapy).37 If the surgical resection reveals residual disease, 2 additional cycles of chemotherapy can be

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Testicular Germ-Cell Tumors

considered.37 In patients with residual disease at sites other than the retroperitoneum, surgical resection is also extremely important, because there is a higher likelihood of teratoma outside of the retroperitoneum. This is especially true in patients with mediastinal testicular cancer, in whom any mediastinal mass would need to be surgically resected. The expectation is that after therapy the serum tumor markers will return to normal levels. However, there is a subgroup of patients in whom, despite appropriate therapy with orchiectomy and chemotherapy, tumor markers do not decline. In the past, chemotherapy had been traditionally offered to these patients. Two retrospective trials have been conducted in this patient population (ie, those with metastatic testicular cancer) to identify the role of surgery.38,39 In both trials, the 5-year OS rate was approximately 54% to 57% of patients who underwent surgery.38,39 The most important factor of successful treatment was complete resection of the disease. Factors identified to be poor predictors of response included increased b-hCG levels, serum AFP levels, redo RPLND, and testicular germ-cell cancer in the resected specimen.38,39 In select patients, surgical resection after persistent elevated serum tumor markers can achieve long-term success (ie, disease-free survival) and should be conducted by an experienced surgical oncologist.

Preclinical studies showed promise with ifosfamide as a single agent in refractory testicular germ-cell tumors; however, the initial clinical utility of drug administration was complicated by the high incidence of hemorrhagic cystitis requiring an antidote, 2-mercaptoethane sulfonate sodium (mesna).42 Now mesna is given with all ifosfamide-containing regimens for testicular cancer.42

Relapsed Disease In up to 35% of patients with testicular germ-cell tumors, the disease will relapse after standard treatment.19 These patients are candidates for salvage therapy, and the goal is still cure. The concept for salvage therapy has been to use cisplatin plus other active agents that were not initially used in first-line treatment. In 1978 etoposide was combined with cisplatin as salvage therapy for advanced, refractory testicular germ-cell tumors.40 Among 33 patients, 14 complete remissions and 15 partial remissions were observed, with dose-limiting toxicities being myelosuppression.40 Based on this experience, the Southeastern Cancer Study Group initiated a trial of etoposide and cisplatin, sometimes in conjunction with bleomycin and/or doxorubicin, for the treatment of refractory testicular germ-cell tumors.41 Of the 44 patients enrolled, 18 received cisplatin plus etoposide, and another 18 received cisplatin plus etoposide and bleomycin. The remainder included doxorubicin therapy. Of the total patients, 44% achieved a complete remission and 27% achieved a partial remission. The actuarial 5-year survival was 28%, with patients who achieved a complete response expected to have a 72% survival.41 This study proved that sustained disease-free survival after second-line therapy in relapsed metastatic disease is a realistic treatment goal.

TIP Building on the result of the VeIP trial,16 Memorial Sloan-Kettering Cancer Center (MSKCC) conducted a study substituting paclitaxel for vinblastine; patients with relapsed disease received paclitaxel, ifosfamide, and cisplatin (TIP) for 4 cycles.17 The efficacy of TIP was tested in 46 patients, wherein 70% achieved complete remission and a 2-year PFS of 65%. Myelosuppression was the primary toxicity, with 48% of patients requiring hospitalization for febrile neutropenia. This study was limited by the small number of patients and the lack of a control arm.17

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VIP and VeIP Given the clinical activity with other standard chemotherapeutic agents, the use of VIP or vinblastine, ifosfamide, and cisplatin (VeIP) was studied in patients with recurrent disease who received 2 previous cisplatincontaining regimens.43 Of the 56 evaluable patients, 21% attained a complete remission with a median response duration of 34 months.43 The addition of ifosfamide to the cisplatin-based chemotherapy provided a plausible option for achieving a sustained remission with third-line therapy. Accordingly, the VeIP regimen was evaluated as initial salvage therapy in 135 patients with progressive, metastatic, testicular germ-cell tumors after initial etoposide-cisplatinâ&#x20AC;&#x201C;based therapy.16 Approximately 50% of patients achieved a complete response, with a median PFS of 4.7 years, thereby establishing the combination of VeIP as an option for durable complete remissions in second-line metastatic disease.16

Tandem Stem-Cell Transplant The outlook for certain patients with testicular-cell tumors of poor prognosis and those harboring cisplatinrefractory disease, defined as progression within 4 weeks of initial cisplatin therapy, is less optimistic. Dose-intensive therapies were viewed as an option to overcome the drawbacks of traditional chemotherapy. However, the dose escalation of the most potent chemotherapy, cisplatin, is limited by nonmyelosuppressive toxicity, such as renal failure. Carboplatin, a second-generation platinum compound that showed activity in testicular germ-cell tumors with a dose-limiting toxicity of myelosuppression, was selected with

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etoposide for evaluation in the initial dose-intensive escalation followed by autologous stem-cell transplantation (ASCT). A brief experience with 25 patients showed that 52% of patients were disease free, with a median follow-up of 26 months.22 Einhorn and colleagues described 184 consecutive patients with metastatic testicular germ-cell tumors progressing after receiving cisplatin-based chemotherapy in 2007.18 Peripheral blood stem cells were collected, and patients underwent high-dose chemotherapy followed by stem-cell reinfusion for 2 cycles, which is referred to as a â&#x20AC;&#x153;tandem ASCT.â&#x20AC;? High-dose chemotherapy consisted of 2 cycles of carboplatin 700 mg/m2 and etoposide 750 mg/m2, both given intravenously 5, 4, and 3 days before peripheral blood stem cell infusion.18 At these doses of chemotherapy, most patients will develop severe lower gastrointestinal mucositis, leading to profound diarrhea, and severe prolonged nausea/vomiting, and will require close monitoring of renal function with electrolyte replacement as a result of the high-dose carboplatin and previous cisplatin exposure. For each cycle of high-dose chemotherapy, the minimum requirement was 1 million CD34+ cells per kilogram of body weight. After recovery of granulocyte and platelet counts, the second cycle of high-dose chemotherapy was given, unless a grade 4 nonhematologic toxic effect was present or if there was no response to the first course. The majority of patients who had complete or partial remission after receiving 2 cycles of high-dose chemotherapy and who had normal serum levels of bhCG and AFP received a daily maintenance oral dose of 50 mg/m2 etoposide for 21 consecutive days every 4 weeks for 3 cycles.18 Approximately 60% of patients attained complete remission without relapse. At 4 years, of the 135 patients who received the treatment as second-line therapy, approximately 69% attained prolonged disease-free survival compared with approximately 45% of patients who received transplant as third-line or later therapy.18 Of the 40 patients with platinum refractory disease, 45% remained free of disease for a median of 49 months.18 This observation provides data to support that patients with platinum refractory disease can still obtain sustained disease-free survival. Other published evidence documenting high-dose chemotherapy and stem-cell transplant has included the use of a few cycles of standard-dose chemotherapy followed by high-dose chemotherapy and autologous stemcell rescue. Pico and colleagues randomized platinumresistant patients to 4 cycles of cisplatin-, mesna-, and ifosfamide-based chemotherapies (N = 128) or 3 cycles of the same conventional-dose chemotherapy followed

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by carboplatin 0 mg/m2 to 550 mg/m2 based on creatinine clearance on day 1, etoposide 450 mg/m2, cyclophosphamide 1600 mg/m2, and mesna 3600 mg/m2 for 4 days followed 3 days later by stem-cell reinfusion (N = 135).44 No significant difference was observed between the groups with regard to event-free survival or OS (which was 53% at 3 years).44

Other Combination and Single-Agent Regimens Feldman and colleagues from MSKCC reported a phase 1/2 trial administering paclitaxel and ifosfamide every 14 days for 2 cycles followed by carboplatin 7 mg/ mL/min to 8 mg/mL/min plus etoposide 400 mg/m2 daily for 3 days and stem-cell rescue every 21 to 28 days for 3 cycles (N = 104).23 The 5-year OS and disease-free survival were 52% and 47%, respectively. Although Einhorn and colleagues18 and Feldman and colleagues23 used high-dose carboplatin and etoposide, the latter included an induction-like regimen, administering 3 rather than 2 high-dose cycles, a targeted area under the curve rather than using mg/m2, and did not use maintenance etoposide.23 High-dose chemotherapy produced durable remissions in more than 50% of patients with relapsed disease, confirming that the procedure is an effective salvage therapy. Gemcitabine in combination with oxaliplatin has been evaluated in a phase 2 clinical trial and yielded a response rate of 44% in cisplatin-refractory testicular germ-cell tumors.45 The combination of paclitaxel 110 mg/m2 and intravenous gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days has been studied as a salvage regimen.46 Hinton and colleagues conducted a phase 2 trial in patients with refractory testicular germ-cell tumors with the Eastern Cooperative Oncology Group evaluating this regimen in 28 patients.46 The baseline characteristics of this trial included patients whose disease had progressed after 2 previous cisplatin-based regimens or after highdose chemotherapy, had used 1 previous cisplatin-based regimen with either a mediastinal primary tumor, or had progression within 4 weeks of treatment with cisplatin. Responses were documented in 7 patients, including 3 complete responses, 2 of whom had no evidence of disease at the time of publication. Myelosuppression was the most frequently reported grade 3/4 toxicity, with 56% of patients developing neutropenia, 33% developing thrombocytopenia, and 11% developing anemia.46 In another combination trial of paclitaxel and gemcitabine, Einhorn and colleagues administered the combination to 32 patients with progressive disease after high-dose chemotherapy with ASCT.28 This regimen was third-line therapy in 25 patients, fourth-line therapy

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in 6 patients, and fifth-line therapy in 1 patient. A complete response was achieved in 6 (19%) patients, with 4 patients remaining disease-free between 20 and 57 months at the time of the studyâ&#x20AC;&#x2122;s publication. A partial response was achieved in 4 patients (12.5%); however, these patients all relapsed within 6 months.28 Novel single agents should continue to be evaluated in this setting for the rare patients who continue to progress despite first-, second-, and third-line therapy.

Toxicities with Treatment Toxicities are inherent with chemotherapy treatment. Both acute and delayed side effects are associated with the treatment of testicular germ-cell tumors and should be monitored and/or treated based on the toxicity the patient is experiencing (Table 5). Acute toxicities can happen immediately with therapy, and late toxicities are those that persist for more than 12 months after therapy.47 Cisplatin-based chemotherapy is a classically known highly emetogenic chemotherapy regimen, and nausea and vomiting can be devastating if not adequately prevented. Premedication with agents such as 5-HT3 antagonists, steroids, and/or aprepitant are important. Cisplatin can cause renal tubular damage, and it is imperative to appropriately hydrate the patient before and after receiving 5 days of cisplatin therapy.48 Combination chemotherapy utilized for the treatment of testicular germ-cell tumors can cause myelosuppression. Prophylactic colony-stimulating factors (CSFs) can be used to decrease the risk of febrile neutropenia (eg, pegfilgrastim). If a patient experiences febrile neutropenia, the patient should be treated according to the guidelines put forth by the Infectious Diseases Society of America.49 If the patient experiences neutropenic fever, the chemotherapy dose should not be lowered if the goal of therapy is cure. The use of CSFs should be incorporated to maintain dose intensity and should also be administered in the salvage setting.49 Erythropoietin-stimulating agents should be avoided in this setting, given the curative intent of the chemotherapy treatment.50 Another acute toxicity that a patient may experience is interstitial pneumonitis. This is different from the long-term pulmonary toxicity of pulmonary fibrosis.51-53 Long-term toxicities may include sterility, neuropathy, nephrotoxicity, pulmonary fibrosis, tinnitus, vascular toxicities, secondary malignancies, and late relapses. Sterility is an important adverse event in this patient population, because the men are young and have a long life expectancy. At diagnosis, more than 50% of patients have evidence of impaired spermatogenesis, with approximately 10% to 35% having some degree of infertility.52 Chemotherapy, as well as other modalities of

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Table 5 Treatment of Acute and Long-Term Toxicities Toxicity Acute Nausea/vomiting Myelosuppression Testosterone deficiency

Treatment

Interstitial pneumonitis

Stop offending agent/ give steroids

Long-term Sterility Neuropathy

Sperm banking Agents such as gabapentin

Nephrotoxicity

Prevent with hydration and avoidance of other nephrotoxic agents

Pulmonary fibrosis

Stop offending agent/ give steroids

Secondary malignancies Late relapse

Treat the secondary malignancy Surgery and/or chemotherapy

Antiemetics Colony-stimulating factors Testosterone replacement

Sources: References 50-52.

treatment such as abdominal radiation, can induce sterility; sterility can also be a side effect of RPLND.54 After treatment, follicle-stimulating hormone and luteinizing hormone levels can be elevated up to 2 years and can lead to azoospermia. After treatment, men can regain normal sperm counts and father children; however, this is not always certain. Therefore, sperm banking should be considered for males who wish to father children.51-54 Therapy should not be delayed for an extended period of time to undergo sperm banking, because testicular cancer is a rapid-growing disease when it is not treated.51-54 Neuropathy, which can result from treatment with both cisplatin and vinblastine, is a product of damage to sensory fibers, and causes numbness and tingling in the hands and feet.51-54 These toxicities may improve over time, or the patient may experience long-term problems. High-frequency hearing loss is associated with cisplatin therapy, and patients should be routinely monitored during therapy for changes in hearing.51-54 Pulmonary fibrosis is a classic toxicity associated with bleomycin therapy. Some patients may be more prone to pulmonary toxicity, such as those who smoke, those who have received previous chest radiation, those who have received large doses of bleomycin (>300 units), those who have had previous surgery (intubation), or those who have been exposed to high concentrations of oxygen.51,52 Resultant toxicities can include bronchiolitis obliterans or interstitial pneumonitis. Over time, lung

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ORIGINAL RESEARCH

function can be preserved in most patients; however, symptoms can persist in some patients. Treatment involves stopping the offending agent (bleomycin) and the administration of steroids for symptomatic relief. The patient may be evaluated before each dose of chemotherapy with pulmonary function tests to identify if changes need to be made to the bleomycin dosing; however, these tests have not proved to be significantly better in identifying clinical symptoms of pulmonary damage.3 As a late complication, a patient may experience signs of pulmonary fibrosis, unlike the acute toxicity with interstitial pneumonitis.51,52 Vascular toxicities can range from Raynaudâ&#x20AC;&#x2122;s phenomenon to cardiac problems, such as myocardial infarction (MI), thromboembolic disease, hyperlipidemia, hypertension, stroke, and metabolic syndrome.52,55 Raynaudâ&#x20AC;&#x2122;s phenomenon has been reported in up to 50% of patients and may persist for years after therapy.53 Bleomycin has traditionally been identified as the offending agent; however, data have demonstrated some association with cisplatin-induced hypomagnesemia.52 No formal treatment is available for this toxicity. Long-term cardiac toxicities have been identified in this patient population. In a report of 87 patients, 8% developed an MI, ischemia, or cerebrovascular event.55 This may seem like a small number of patients, but these toxicities are not frequently seen in men aged 30 to 42 years.55 Hyperlipidemia and metabolic syndrome have been documented in 80% and 40% of survivors, respectively.51 A full understanding of the mechanism of cardiovascular (CV) disease has not been fully elucidated, but some researchers believe some level of direct vascular injury may occur from radiation or chemotherapy. Other theories suggest that cytokine release, vascular injury, changes in electrolytes, or platelet aggregation may play a role. One report identified survivors of testicular cancer who received cisplatin-based chemotherapy and were 3 times more likely to develop metabolic syndrome compared with the general population.55 Because of these increased risks of CV events, it is important for patients to be appropriately screened and monitored for hypertension, hyperlipidemia, and metabolic syndrome, because education and screening information typically does not occur in this population. The risk of secondary malignancy is increased after treatment for testicular germ-cell tumors. Compared with the general population, survivors of testicular germcell tumors are at an approximately 30% increased risk of secondary malignancies when evaluated in population-based cancer registries over a 40-year time span.52 Among more than 40,000 patients who were followed for 11.5 years, 5.6% developed a secondary malignancy.56 Secondary solid tumors associated with this patient pop-

Journal of Hematology Oncology Pharmacy

ulation include cancers of the pleura, pancreas, stomach, bladder, and connective tissue. Leukemia is associated with combination chemotherapy, specifically etoposide and alkylating agents, such as ifosfamide and cyclophosphamide. The risk is increased based on dose. Doses of etoposide >2000 mg/m2 as opposed to doses â&#x2030;¤2000 mg/m2 incur more risk of leukemia (5-year risk, 2% vs 0.5%, respectively).52 Early after therapy, patients are at an increased risk of developing leukemia (3%-7% risk within 10 years of therapy); however, 10 to 20 years after treatment, the risk for leukemia is no different from that in the general population.51 One of the long-term challenges associated with treatment of testicular germ-cell tumors is late relapse. Most patients will recur within 2 years of treatment; however, 2% to 3% of patients will recur after this time period.51,52 In these scenarios, the disease is rarely curable with chemotherapy, and surgical resection is the standard treatment approach because most patients are refractory to chemotherapy.51,52 The most common sites of recurrence are the chest and retroperitoneum. Treatment in this scenario will depend on the previous therapies. Although almost all patients can be cured of their disease, many men struggle with long-term toxicities associated with therapy. Routine evaluation/screening should be conducted to evaluate for vascular, renal, otologic, neurologic, and reproductive toxicities associated with therapy. With the growing knowledge of long-term toxicities in this patient population (even after curing these individuals), it is important to understand the need for longterm follow-up to monitor the previously mentioned toxicities, and also the psychosocial morbidity associated with the diagnosis and treatment effects.51-53 The psychosocial needs can be related to fatigue, mental health, sexuality, employment, cognitive impairment, and quality of life. Institutions should have practice-based guidelines established to help monitor these patients throughout their life.

Practical Clinical Questions Question 1. How should we deal with chemotherapy drug shortages? Many pharmacies today are faced with the recurring problem of drug shortages. In most instances, there are alternate therapies for drug substitutions, but in the case of testicular germ-cell tumor treatment, this has been a dilemma that pharmacists and physicians have faced when chemotherapy has not been available. In 2010, bleomycin, carboplatin, cisplatin, and etoposide were all reported as being in short supply. In the fall of 2010, etoposide was on national backorder, and many centers faced an acute shortage of the drug that persisted for sev-

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September 2012

Vol 2, No 3

Testicular Germ-Cell Tumors

eral months. This is a disease for which treatment should not be delayed because of lack of a drug. Treatment delays can directly compromise the potential for cure, because of the high growth index of the tumor and the inherent sensitivity to chemotherapy. In patients deemed to be good risk by the IGCCCG (Table 2), PVB (Table 3) can be substituted for BEP. This regimen was the standard of care for the treatment of testicular germ-cell tumors in the 1980s before being compared with BEP.13 Toxicity was reported to be higher with the PVB regimen, including neuromuscular toxicity (eg, paresthesias, abdominal pain, myalgias), so patients must be counseled accordingly.16 In poor-risk patients, VIP (Table 4) can be substituted for BEP. This regimen has been studied extensively in the salvage/ relapse setting.16 Institutions should have a plan as to how to prioritize patients based on their drug supply, disease states, and the patient’s goal of therapy. If a facility is completely out of stock of one of these critical agents, every effort should be made to locate another site where a patient can receive complete treatment.

Question 2. How should cisplatin be dosed in patients with underlying dysfunction? Cisplatin causes renal tubular damage from the metabolism via glutathione conjugates and the production of reactive oxygen species, leading to proximal tubular damage.57 Patients are adequately hydrated before and after treatment to mitigate this toxicity. However, some patients may have preexisting renal dysfunction at baseline. The most important and most active drug of any of the chemotherapy regimens for testicular germ-cell tumors is cisplatin. With cure as the goal of treatment in this patient population, the decision has to be made to balance the toxicities of cisplatin, most of which are reversible, with the potential for compromising cure with any dose reduction of cisplatin. At our institution, we do not dose-adjust cisplatin based on one’s renal dysfunction. The most active drug of all of those discussed for the treatment of testicular cancer is cisplatin. By dose-reducing cisplatin, one could potentially compromise a patient’s success in being cured of the disease. The patients should be closely monitored in terms of laboratory values and input/output, and should receive adequate hydration before and after chemotherapy to protect from any further renal effects. Question 3. Is a bleomycin test dose really needed? This is an age-old question that continues to circulate among clinicians. The occurrence of hypersensitivity reactions has been reported; however, these reports date back to the 1970s. In a review by Lam, the question was asked, “Do we need routine bleomycin test dosing in the

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September 2012

21st century?”24 Based on the review of the literature, the recommendation is not to administer a test dose, because of the unpredictable onset of hypersensitivity and the timing of the reaction. At our institution, we do not administer a test dose to patients who are receiving bleomycin therapy.

Conclusion With overall cure rates of more than 90%, testicular germ-cell tumors are the model of care for curable cancer. Patients with refractory or relapsed disease after initial therapy still have the potential for cure with secondand third-line chemotherapies with cisplatin-based regimens or with high-dose chemotherapy followed by ASCT. Pharmacists caring for this patient population must monitor for common acute toxicities of the standard chemotherapy regimens for and long-term complications with cured patients, most of whom can live a normal life. n Author Disclosure Statement Dr Kiel, Dr Fausel, and Dr Jones reported no conflicts of interest.

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ORIGINAL RESEARCH

trial of the Genito-Urinary Group of the French Federation of Cancer Centers (GETUG T93BP). Ann Oncol. 2007;18:917-924. 15. Loehrer PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med. 1988;109:540-546. 16. Loehrer PJ Sr, Gonin R, Nichols CR, et al. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol. 1998;16:2500-2504. 17. Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol. 2005;23:6549-6555. 18. Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med. 2007;357:340-348. 19. Bosl GJ, Motzer RJ. Testicular germ-cell cancer. N Engl J Med. 1997;337: 242-254. 20. de Wit R, Roberts JT, Wilkinson PM, et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol. 2001;19:1629-1640. 21. de Wit R, Stoter G, Sleijfer DT, et al. Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic testicular non-seminoma: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group. European Organization for Research and Treatment of Cancer. Br J Cancer. 1998;78:828-832. 22. Broun ER, Nichols CR, Gize G, et al. Tandem high dose chemotherapy with autologous bone marrow transplantation for initial relapse of testicular germ cell cancer. Cancer. 1997;79:1605-1610. 23. Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol. 2010;28:1706-1713. 24. Lam MS. The need for routine bleomycin test dosing in the 21st century. Ann Pharmacother. 2005;39:1897-1902. 25. Einhorn LH. Curing metastatic testicular cancer. Proc Natl Acad Sci U S A. 2002;99:4592-4595. 26. Higby DJ, Wallace HJ Jr, Albert DJ, Holland JF. Diaminodichloroplatinum: a phase I study showing responses in testicular and other tumors. Cancer. 1974;33:1219-1225. 27. Bedano PM, Brames MJ, Williams SD, et al. Phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors. J Clin Oncol. 2006;24:5403-5407. 28. Einhorn LH, Brames MJ, Juliar B, Williams SD. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol. 2007; 25:513-516. 29. Jones WG, Fossa SD, Mead GM, et al. Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol. 2005;23: 1200-1208. 30. Alomary I, Samant R, Gallant V. Treatment of stage I seminoma: a 15-year review. Urol Oncol. 2006;24:180-183. 31. Oliver RT, Mead GM, Rustin GJ, et al. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol. 2011;29:957-962. 32. Beck SD, Bey AL, Birhle R, Foster RS. Ejaculatory status and fertility rates after primary retroperitoneal lymph node dissection. J Urol. 2010;184:2078-2080. 33. de Wit R, Fizazi K. Controversies in the management of clinical stage I testis cancer. J Clin Oncol. 2006;24:5482-5492. 34. Albers P, Siener R, Krege S, et al. Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I nonsemi-

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nomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol. 2008;26:2966-2972. 35. Culine S, Theodore C, Terrier-Lacombe MJ, Droz JP. Primary chemotherapy in patients with nonseminomatous germ cell tumors of the testis and biological disease only after orchiectomy. J Urol. 1996;155:1296-1298. 36. Davis BE, Herr HW, Fair WR, Bosl GJ. The management of patients with nonseminomatous germ cell tumors of the testis with serologic disease only after orchiectomy. J Urol. 1994;152:111-113; discussion 114. 37. Steyerberg EW, Keizer HJ, Fosså SD, et al. Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: multivariate analysis of individual patient data from six study groups. J Clin Oncol. 1995;13:1177-1187. 38. Beck SD, Foster RS, Bihrle R, et al. Outcome analysis for patients with elevated serum tumor markers at postchemotherapy retroperitoneal lymph node dissection. J Clin Oncol. 2005;23:6149-6156. 39. Albers P, Ganz A, Hannig E, et al. Salvage surgery of chemorefractory germ cell tumors with elevated tumor markers. J Urol. 2000;164:381-384. 40. Williams SD, Einhorn LH, Greco FA, et al. VP-16-213 salvage therapy for refractory germinal neoplasms. Cancer. 1980;46:2154-2158. 41. Hainsworth JD, Williams SD, Einhorn LH, et al. Successful treatment of resistant germinal neoplasms with VP-16 and cisplatin: results of a Southeastern Cancer Study Group trial. J Clin Oncol. 1985;3:666-671. 42. Wheeler BM, Loehrer PJ, Williams SD, Einhorn LH. Ifosfamide in refractory male germ cell tumors. J Clin Oncol. 1986;4:28-34. 43. Loehrer PJ Sr, Einhorn LH, Williams SD. VP-16 plus ifosfamide plus cisplatin as salvage therapy in refractory germ cell cancer. J Clin Oncol. 1986;4:528-536. 44. Pico JL, Rosti G, Kramar A, et al. A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann Oncol. 2005;16:1152-1159. 45. Kollmannsberger C, Beyer J, Liersch R, et al. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol. 2004;22:108-114. 46. Hinton S, Catalano P, Einhorn LH, et al. Phase II study of paclitaxel and gemcitabine in refractory germ cell tumor (E9897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2002;20:1859-1863. 47. Fosså SD, Gilbert E, Dores GM, et al. Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst. 2007;99:533-544. 48. Chabner BA, Amrein PC, Druker BJ, et al. Chemotherapy of neoplastic diseases. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006: 1315-1403. 49. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56-e93. 50. Rizzo JD, Brouwers M, Hurley P, et al. American Society of Hematology/ American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood. 2010;116: 4045-4059. 51. Pliarchopoulou K, Pectasides D. Late complications of chemotherapy in testicular cancer. Cancer Treat Rev. 2010;36:262-267. 52. Travis LB, Beard C, Allan JM, et al. Testicular cancer survivorship: research strategies and recommendations. J Natl Cancer Inst. 2010;102:1114-1130. 53. Abouassaly R, Fosså SD, Giwercman A, et al. Sequelae of treatment in longterm survivors of testis cancer. Eur Urol. 2011;60:516-526. 54. Vaughn DJ, Gignac GA, Meadows AT. Long-term medical care of testicular cancer survivors. Ann Intern Med. 2002;136:463-470. 55. Redig AJ, Munshi HG. Metabolic syndrome after hormone-modifying therapy: risks associated with antineoplastic therapy. Oncology (Williston Park). 2010;24: 839-844. 56. Travis LB, Fosså SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. 2005;97:1354-1365. 57. Hanigan MH, Devarajan P. Cisplatin nephrotoxicity: molecular mechanisms. Cancer Ther. 2003;1:47-61.

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Vol 2, No 3

MAY 2-5, 2013

THIRD ANNUAL CONFERENCE

Influencing the Patient-Impact Factor May 2-5, 2013 Westin Diplomat Hollywood, Florida

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TREANDA速 (bendamustine HCI) for Injection is his chemo.

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Single-agent TREANDA tripled median PFS* TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Survival distribution function

TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

P<.0001 HRâ&#x20AC; =0.27 (95% CIâ&#x20AC;¡: 0.17, 0.43)

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). â&#x20AC; HR=hazard ratio. â&#x20AC;¡ CI=confidence interval.

t 53&"/%" XBT DPNQBSFE XJUI DIMPSBNCVDJM JO B SBOEPNJ[FE PQFO MBCFM QIBTF USJBM JO USFBUNFOU OBÃ&#x2022;WF QBUJFOUT XJUI #JOFU TUBHF # PS $ 3BJ TUBHFT * *7 $-- XIP SFRVJSFE USFBUNFOU / t 53&"/%" JT BENJOJTUFSFE XJUI B DPOWFOJFOU EPTJOH TDIFEVMF o 5IF SFDPNNFOEFE EPTF GPS 53&"/%" JT NH N2 BENJOJTUFSFE JOUSBWFOPVTMZ PWFS NJOVUFT PO %BZT BOE PG B EBZ USFBUNFOU DZDMF VQ UP DZDMFT o *O UIF QIBTF USJBM QBUJFOUT SFDFJWFE DIMPSBNCVDJM BU B EPTF PG NH LH PSBMMZ PO %BZT BOE O PG B EBZ USFBUNFOU DZDMF VQ UP DZDMFT t *O UIF QJWPUBM QIBTF USJBM UIF NPTU DPNNPO OPO IFNBUPMPHJD BEWFSTF SFBDUJPOT GSFRVFODZ â&#x2030;¥ XFSF QZSFYJB OBVTFB BOE WPNJUJOH O 5IF NPTU DPNNPO IFNBUPMPHJD BCOPSNBMJUJFT GSFRVFODZ â&#x2030;¥ XFSF BOFNJB UISPNCPDZUPQFOJB OFVUSPQFOJB MZNQIPQFOJB BOE MFVLPQFOJB O

Important Safety Information t 4FSJPVT BEWFSTF SFBDUJPOT JODMVEJOH NZFMPTVQQSFTTJPO JOGFDUJPOT JOGVTJPO SFBDUJPOT BOE BOBQIZMBYJT UVNPS MZTJT TZOESPNF TLJO SFBDUJPOT JODMVEJOH 4+4 5&/ PUIFS NBMJHOBODJFT BOE FYUSBWBTBUJPO IBWF CFFO BTTPDJBUFE XJUI 53&"/%" 4PNF SFBDUJPOT TVDI BT NZFMPTVQQSFTTJPO JOGFDUJPOT BOE 4+4 5&/ XIFO 53&"/%" XBT BENJOJTUFSFE DPODPNJUBOUMZ XJUI BMMPQVSJOPM BOE PUIFS NFEJDBUJPOT LOPXO UP DBVTF 4+4 5&/ IBWF CFFO GBUBM 1BUJFOUT should be monitored closely for these reactions and treated promptly if any occur t "EWFSTF SFBDUJPOT NBZ SFRVJSF JOUFSWFOUJPOT TVDI BT EFDSFBTJOH UIF EPTF PG 53&"/%" PS XJUIIPMEJOH PS EFMBZJOH USFBUNFOU t 53&"/%" JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI B LOPXO IZQFSTFOTJUJWJUZ UP CFOEBNVTUJOF PS NBOOJUPM 8PNFO TIPVME CF BEWJTFE UP BWPJE CFDPNJOH QSFHOBOU XIJMF VTJOH 53&"/%" t 5IF NPTU DPNNPO OPO IFNBUPMPHJD BEWFSTF SFBDUJPOT GPS $-- GSFRVFODZ Ã¶ BSF QZSFYJB OBVTFB BOE WPNJUJOH 5IF NPTU DPNNPO IFNBUPMPHJD BCOPSNBMJUJFT GSFRVFODZ Ã¶ BSF BOFNJB UISPNCPDZUPQFOJB OFVUSPQFOJB MZNQIPQFOJB BOE MFVLPQFOJB

Discover the elements of efficacy and safety LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be â&#x2030;Ľ 1 x 109/L and the platelet count should be â&#x2030;Ľ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naĂŻve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in â&#x2030;Ľ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) Grade 3/4 All Grades Grade 3/4 All Grades Laboratory Abnormality n (%) n (%) n (%) n (%) 134 (89) 20 (13) 115 (82) 12 (9) Hemoglobin Decreased 116 (77) 16 (11) 110 (78) 14 (10) Platelets Decreased 92 (61) 42 (28) 26 (18) 4 (3) Leukocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Lymphocytes Decreased 113 (75) 65 (43) 86 (61) 30 (21) Neutrophils Decreased In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. 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: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant â&#x2030;ĽÂ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to â&#x2030;¤Â Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) â&#x2030;ĽÂ 1 x 109/L, platelets â&#x2030;ĽÂ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. t Aseptically SFDPOTUJUVUF FBDI 53&"/%" WJBM BT GPMMPXT t NH 53&"/%" WJBM "EE N- PG POMZ Sterile Water for Injection, USP t NH 53&"/%" WJBM "EE N- PG POMZ Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be VTFE t "TFQUJDBMMZ XJUIESBX UIF WPMVNF OFFEFE GPS UIF SFRVJSFE EPTF CBTFE PO NH N- DPODFOUSBUJPO BOE immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2â&#x20AC;&#x201C;0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The BENJYUVSF TIPVME CF B DMFBS BOE DPMPSMFTT UP TMJHIUMZ ZFMMPX TPMVUJPO t 6TF 4UFSJMF 8BUFS GPS *OKFDUJPO 641 GPS reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride *OKFDUJPO 641 GPS EJMVUJPO BT PVUMJOFE BCPWF /P PUIFS EJMVFOUT IBWF CFFO TIPXO UP CF DPNQBUJCMF t 1BSFOUFSBM drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8Â°C or 36-47Â°F) or for 3 hours when stored at room temperature (15-30Â°C or 59-86Â°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25Â°C (77Â°F) with excursions permitted up to 30Â°C (86Â°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ÂŠ2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 TRE-2511b (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation. Information. TRE-006 TREANDA

April 2012 August

ORIGINAL RESEARCH

Medication Therapy Management in the Outpatient Cancer Center Amanda Moss, PharmD; Katie Won, PharmD, BCOP; Lynn Weber, PharmD, BCOP Background: Medication therapy management (MTM) has been shown to improve patient outcomes. Patients with cancer are at high risk for adverse events caused by the toxicity and complexity of their medication regimens, and they may benefit from MTM services. Objectives: The primary objective was to document drug therapy problems, using an MTM model in an ambulatory oncology setting. A second objective was to evaluate the potential revenue from these services. Methods: MTM consults were conducted by 2 oncology pharmacists between January 1, 2010, and December 31, 2010, at Hennepin County Medical Center, Minneapolis, MN. A retrospective chart review of patient care notes was performed to collect data on drug therapy problems that were identified and resolved during the patient encounters. Results: A total of 107 patients were seen during 121 encounters. The sample included 60 females and 47 males. Most MTM billing claims were submitted to Medicaid (32%) or Medicare (27%), resulting in approximately $101 of potential revenue per visit. During an average of 33 minutes spent per encounter, 322 drug therapy problems were recognized (averaging 2.7 drug therapy problems per patient), of which 281 drug therapy problems were resolved in the original encounter. Because most patients were initially seen for chemotherapy teaching, the most prevalent category of drug therapy problem identified was Compliance/ J Hematol Oncol Pharm. Complex Regimen. 2012;2(3):103-107. www.JHOPonline.com Conclusion: It is feasible to incorporate the MTM model into current oncology pharmacy Disclosures are at end of text practice in the ambulatory setting. Pharmacists are able to submit billing claims for the service; as of yet, the revenue is undetermined.

ncology pharmacists specialize in the use of chemotherapeutic agents. These pharmacists practice in acute and ambulatory care settings to review chemotherapy treatment plans for accuracy and safety, provide clinical services to patients with cancer, and coordinate orders and prescriptions for chemotherapy and supportive medications. Oncology pharmacists also play an integral role in the formulary review of new chemotherapeutic agents, as well as in medication safety and proper handling of chemotherapeutic agents.1 Recently, the provision of medication therapy management (MTM) visits has been incorporated into current practice at Hennepin County Medical Center (HCMC), Minneapolis, MN, allowing for additional patient interaction in the outpatient setting. MTM is defined by the American Pharmacists Association as “a term used to describe a broad range of health care services provided by pharmacists, the medication experts on the health care team.”2 On average,

Dr Moss is a Doctor of Pharmacy candidate at the University of Minnesota College of Pharmacy, Minneapolis, MN; Dr Won and Dr Weber are Oncology Pharmacists at Hennepin County Medical Center, Minneapolis, MN.

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patients with cancer have 3 comorbidities and are taking 9.1 medications for cancer treatment, supportive care, and comorbid conditions.3 The use of multiple drug therapies increases the risk of altered pharmacokinetics and adverse drug reactions. Furthermore, because of prolonged treatment periods and the increased toxicity of antineoplastic agents, patients with cancer are prone to complications and decreased adherence.4 Face-to-face interaction with oncology pharmacists allows for medication reconciliation and disease state management, as well as for patient and family education to prevent nonadherence. Drug therapy problems can be identified, helping to ensure that the patient’s medication regimen is safe, minimally toxic, and appropriately effective to treat the patient’s oncologic condition. There is a need for research on MTM outcomes in the ambulatory oncology setting. To advance the incorporation of the MTM model into oncology pharmacy practice, we must document the feasibility and potential added value of performing MTM in this setting. The purpose of the current study is to describe an ambulatory oncology MTM practice and measure its impact, based on the identification and resolution of drug therapy problems. A secondary outcome is to report

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the amount billed per patient encounter, which represents potential revenue added by MTM services.

Methods A retrospective chart review was completed on all patients who underwent an MTM visit with an oncology pharmacist at HCMC between January 1, 2010, and December 31, 2010. There were no exclusion criteria, and all patients who had been seen during the study period were included in the analysis. Patients were referred to the pharmacists by oncologists or nurses from HCMC for medication review or for new patient teaching of chemotherapy and supportive care. HCMC is a Level 1 Trauma Center in Minneapolis, MN, and is considered a “safety-net” hospital, which provides care for lowincome, uninsured, and vulnerable populations. The infusion room within the Hennepin Comprehensive Cancer Center administers chemotherapy to between approximately 6 and 12 patients daily, Monday through Friday. Each patient encounter was documented and billed in the electronic health record, using the EpicCare EMR (Epic software; Verona, WI), and was also documented in an Excel spreadsheet for internal quality improvement purposes by 1 of the 2 oncology pharmacists. Data gathered in the spreadsheet included billing level, encounter time, patient insurance, drug therapy problems noted, oncologic disease, and reason for the encounter. The pharmacists also noted the patient name, medical record number, doctor, visit date, pharmacist name, and follow-up instructions. In addition to the spreadsheet data, the investigator reviewed all pharmacist notes for details on drug therapy problems and interventions. The primary outcome was measured by the number of drug therapy problems identified and recorded per patient encounter. Because of the many drug therapy problems available in the EpicCare EMR electronic health record oncology-specific drug therapy problem categories were created to ease the documentation process and highlight the most common drug therapy problems found in this patient population. The drug therapy problems were categorized as Indication/Prevention, Compliance/Complex Regimen, Drug Interaction, and Drug Safety Concern. Categories used to document drug therapy problems were used interchangeably at times because of similarities within the 4 of them and the complexity of drug therapy problems identified. Indication/Prevention focused on the need for additional drug therapy or the identification of unnecessary drug therapy. Additional drug therapy was suggested if a condition, such as nausea, was not addressed in the medication regimen, if there were preventive or prophylactic medications available, if a synergistic medication could be added, or if the treatment goal was not being

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achieved. Unnecessary drug therapy included the identification and discontinuation of medications with no medical indication and drug (eg, marijuana) use for recreation. Duplicate therapy, as well as medications that were being used for the treatment of avoidable adverse drug reactions, were also considered unnecessary. Compliance/Complex Regimen identified drug therapy problems within complex medication regimens, which can represent patient barriers to medication adherence. Drug therapy problems in this category pertained to insurance coverage, patient ability to afford the drug, and patient willingness to take the medication. In addition, pharmacists looked at the ability of the patient to take the medication by its specified route and to read and understand administration directions, and the pharmacists identified the need for adherence tools. Drug Interaction and Drug Safety Concern identified any drug therapy problems that involved the safety of the patient. Drug safety focused on the prevention of serious side effects and included making dose adjustments when needed, modifying dosing schedules, identifying possible drug–drug interactions, and making laboratory or drug monitoring recommendations. Drug therapy problems in the Drug Safety Concern category were identified and included allergic reactions, incorrect administration, complex regimens requiring stepwise increases or taper, and medications with undesirable effects. A secondary outcome was potential revenue gained from each MTM encounter and was measured by compiling the amount charged to the patient’s insurance. Billing levels were based on a predetermined amount dependent on the time spent and complexity of the encounter—taking into consideration the number of medications the patient is currently taking, the number of medical conditions present, the number of drug therapy problems that are identified, and the face-to-face time of the encounter—as specified by the Minnesota Health Care Programs (MHCPs). Billing level and insurance, if applicable, were documented in the EpicCare EMR patient care note, as well as in the Excel spreadsheet. Data collected by the 2 pharmacists were reviewed by the investigator, a pharmacist intern at HCMC, and analyzed using descriptive analyses (including numbers, percentages, and averages). This study was approved by the University of Minnesota Institutional Review Board, as well as by the Minneapolis Medical Research Foundation Institutional Review Board.

Results Over the course of 1 year, 107 patients were seen by a pharmacist in 121 patient encounters. The demographic characteristics of the patient population are displayed in Table 1. A total of 60 females and 47 males were includ-

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MTM in the Outpatient Cancer Center

Table 1 Baseline Demographic Characteristics

Table 2 Insurance Billed in Patient Encounters

Variable

Type of insurance

Result

N (%)

Patient encounters, N

121

Medicaid

39 (32.2)

Patients seen, N

107

Medicare

33 (27.3)

Private

27 (22.3) 18 (14.9)

Sex, N (%) Male

Uninsured

Female

Other

4 (3.3)

Average age, yrs

58.6

Total

121 (100.0)

Age range, yrs

22-89

Table 3 Classification of Drug Therapy Problems

Oncologic diseases of patients, N (%) Breast cancer

17 (15.9)