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Journal of Clinical Oncology, Vol 23, No 36 (December 20), 2005: pp. 9377-9386
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.01.8507
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Efficacy and Safety Analysis of Epoetin Alfa in Patients With Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

Thomas Grote, Allen L. Yeilding, Rene Castillo, Dean Butler, Ellioth Fishkin, David H. Henry, Michael DeLeo, Kenneth Fink, Daniel J. Sullivan

From the Forsyth Regional Cancer Center, Winston-Salem, NC; Private practice, Birmingham, AL; Ochsner Cancer Institute, New Orleans, LA; Dial Research Associates, Brentwood, TN; Trinitas Hospital, Elizabeth, NJ; Joan Karnell Cancer Center, PA Hospital, Philadelphia, PA; Berkshire Hematology Oncology, Pittsfield, MA; Eisenhower Army Medical Center, Gordon, GA; and Johnson & Johnson Pharmaceutical Research & Development LLC, Raritan, NJ.

Address reprint requests to Thomas Grote, MD, Forsyth Regional Cancer Center, 1010 Bethesda Court, Winston-Salem, NC 27103; e-mail: tgrote{at}phoa.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: This randomized, double-blind, placebo-controlled trial (N93-004) evaluated the effects of epoetin alfa on tumor response to chemotherapy and survival in patients with small-cell lung cancer (SCLC).

PATIENTS AND METHODS: Adult patients with hemoglobin ≤ 14.5 g/dL starting chemotherapy received epoetin alfa 150 U/kg or placebo subcutaneously 3 times weekly until 3 weeks after completion of chemotherapy. Survival was assessed for 3 years. The primary end point was the proportion of patients with complete or partial response after three chemotherapy cycles.

RESULTS: The trial was terminated prematurely after 224 of a projected 400 patients were accrued. Baseline characteristics were similar between groups. Epoetin alfa and placebo patients (n = 109 and n = 115, respectively) had mean baseline hemoglobin of 12.8 g/dL and 13.0 g/dL, respectively. Overall tumor response was similar between the epoetin alfa and placebo groups after three chemotherapy cycles (72% and 67%, respectively; 95% CI of difference, –6% to 18%) and after completion of chemotherapy (60% and 56%, respectively; 95% CI of difference, –9% to 17%). Epoetin alfa and placebo groups had similar median overall survival (10.5 and 10.4 months, respectively) and overall mortality (91.7% and 87.8%, respectively; hazard ratio, 1.172; 95% CI, 0.887 to 1.549; P = .264). Hemoglobin was maintained in the prechemotherapy range in epoetin alfa patients, but decreased substantially in placebo patients. Fewer epoetin alfa patients than placebo patients required transfusion.

CONCLUSION: These results suggest that in newly diagnosed patients with SCLC epoetin alfa does not affect tumor response to chemotherapy or survival. However, the early trial closure makes these conclusions preliminary.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
Erythropoietin receptors have been detected in a multitude of cancer cells, including lung cancer cells.1 In an analysis of human lung carcinomas, expression of erythropoietin-binding sites were identified in large-cell anaplastic carcinomas, small-cell carcinomas, epidermoid carcinomas, adenocarcinomas, and metastases.2 These observations led to questions regarding the potential impact of epoetin alfa therapy on tumor cell growth. In 1993, when epoetin alfa was approved for the treatment of anemia associated with chemotherapy in patients with nonmyeloid malignancies, it was theorized that epoetin alfa might have a clinically relevant effect on tumor cell growth through epoetin-receptor binding. If so, this could be evident as a diminished response rate to chemotherapy in patients initially receiving chemotherapy for lung cancer.

Conversely, treatment of anemia may be beneficial in patients receiving cancer therapy. Recent data indicate that anemia is an independent prognostic factor for survival in patients with cancer, with an overall estimated increased relative risk of death of 65%.3 The negative effects of anemia may be especially important in patients with lung cancer, as the incidence of anemia is generally higher in these patients compared with patients with other types of malignancies.4,5

At the time that epoetin alfa was approved for the treatment of anemia associated with chemotherapy in patients with nonmyeloid malignancies, Johnson & Johnson Pharmaceutical Research and Development LLC (Raritan, NJ) initiated a placebo-controlled study evaluating the potential for epoetin alfa to affect solid tumor growth. This study was designed to evaluate tumor response at a predetermined timepoint, following the initiation of chemotherapy for newly diagnosed small-cell lung cancer (SCLC).


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
Study Design and Patients
This randomized, double-blind, parallel group, placebo-controlled trial (N93-004) was conducted at 35 sites (including private practices, hospital oncology units, and academic institutions) in the United States. The study consisted of a double-blind treatment phase, with up to 12 cycles of chemotherapy for the assessment of hematologic response and tumor response to chemotherapy, followed by 3 years of double-blind follow-up for the assessment of survival.

Patients were eligible for study participation if they met the following inclusion criteria: age ≥ 18 years with newly diagnosed, histologically-documented, measurable and assessable, limited- or extensive-stage SCLC; scheduled to receive at least three cycles of chemotherapy with etoposide/cisplatin; Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2; life expectancy ≥ 3 months; and baseline Hb ≤ 14.5 g/dL. Patients were excluded from the study for the following reasons: previous cytotoxic chemotherapy or radiotherapy or scheduled to receive curative-intent radiation therapy during the first three chemotherapy cycles; clinically significant uncontrolled underlying disease not attributable to underlying malignancy; uncontrolled hypertension; or evidence of untreated iron, folate, or vitamin B12 deficiency, or ongoing hemolysis. All patients provided written informed consent. Before initiation of the study, the protocol and the statement of informed consent were approved by the institutional review boards at each participating site. The study was conducted in accordance with the Declaration of Helsinki, and patients or their legal representatives provided written consent to participate in the study.

Treatment Regimen
Eligible patients were randomly assigned 1:1 using a computer-generated randomization schedule to receive either epoetin alfa 150 U/kg or an equivalent volume of placebo administered subcutaneously (SC) 3 times weekly (TIW) until approximately 3 weeks after completing the final cycle of chemotherapy. The goal of epoetin alfa therapy was to maintain hemoglobin levels near baseline. If hemoglobin increased to more than 16 g/dL, the dose was withheld until hemoglobin decreased to less than 14 g/dL, then resumed at 75 U/kg SC TIW. Dose escalation was not permitted. Etoposide and cisplatin were administered every 3 weeks for ≥ 3 cycles (no other chemotherapy agents were permitted on study). The recommended starting dose of etoposide was 100 mg/m2 on days 1 to 3 of each cycle, and the recommended starting dose of cisplatin was 100 mg/m2 during each cycle (generally on day 1). The dose and schedule of etoposide and cisplatin chemotherapy could be varied as needed, based on toxicity or unrelated adverse events. After the third cycle of chemotherapy, patients continued to receive chemotherapy as appropriate for disease response. Per protocol, radiation therapy was not to start until after the third chemotherapy cycle.

Objectives and Assessments
The primary objective of the study was to determine the effect of epoetin alfa compared with placebo on tumor response in SCLC patients receiving etoposide and cisplatin. The primary end point was the proportion of patients in each group with a complete response (CR) or partial response (PR) after the third cycle of chemotherapy. Secondary objectives were to determine the effects of epoetin alfa on survival, erythroid parameters, and transfusion rates. Secondary end points were survival rates and duration, the proportion of patients with CR or PR after the final cycle of chemotherapy, changes in hemoglobin over time, RBC transfusions, and ECOG performance status scores.

Efficacy assessments included tumor staging, tumor response to chemotherapy (CR, PR, no response [NR], or progressive disease [PD]), survival, ECOG performance status, hematologic response (hemoglobin change from baseline to the end of cycle 3 and study end, as well as weekly hemoglobin levels), and RBC transfusion requirements (proportion of patients transfused, number of units transfused, and number of days to first transfusion).

Tumor staging was performed at baseline, after three cycles of chemotherapy, and at the final visit. Overall tumor response to chemotherapy was assessed after three cycles of chemotherapy and at the final visit using appropriate radiographic techniques, without central review of images. Definitions of tumor response were based on WHO criteria and modified from Miller et al.6 CR was defined as the total disappearance of all known malignant disease. PR was defined as (1) a ≥ 50% decrease in total tumor area (added products of bidimensional measurements of all measurable disease); and (2) no growth of any measurable lesion by more than 25% and no estimated growth of any unmeasurable but assessable lesions by more than 25%; and (3) no new lesions. NR (stable disease) was defined as (1) a less than 50% decrease and ≤ 25% increase in total tumor area of all measurable disease; (2) no growth of any measurable lesion by more than 25% and no estimated growth of any unmeasurable but assessable lesions by more than 25%; and (3) no new lesions. PD was defined as (1) a more than 25% increase in the size of at least one measurable malignant lesion or a more than 25% increase in the estimated size of any assessable but nonmeasurable lesion; or (2) a more than 25% increase in the estimated extent of assessable disease or a more than 25% increase in the estimated extent of unmeasurable disease; or (3) development of a new malignant lesion. Confirming the response by repeat testing at least 4 weeks after first assessment was not required.

Survival was assessed annually for up to 3 years after study completion or early withdrawal. Sites were instructed to collect patient survival data for 3 years and were contacted to obtain missing survival information. Survival duration was defined as the time from the date of the first dose of chemotherapy to the date of death. Patients without a date of death were censored on the date that the patient was last known to be alive. Evaluation of ECOG performance status was performed at baseline and at the final visit. Hematologic parameters were assessed immediately before the administration of chemotherapy on day 1, and weekly thereafter until 3 weeks after completing the final chemotherapy cycle. Iron status (serum iron, total iron binding capacity, and ferritin) was evaluated at screening and at the final visit. Safety was monitored by adverse-event (AE) reporting, clinical laboratory tests, vital sign measurements, and physical examination throughout the study. Treatment-emergent adverse events were coded in accordance with a modified World Health Organization Adverse Drug Reaction Terminology (WHOART) dictionary, in which the included term was the description most closely related to the investigator's terminology, the preferred term was a group of closely related included terms, and the body system was a broad category including related preferred terms.

Statistics
To demonstrate noninferiority of epoetin alfa to placebo for the primary end point, the absolute overall tumor response rate (ORR) in the epoetin alfa group could not be ≥ 15% below that in the placebo group after three cycles of chemotherapy. Given a power of 90% and a significance level of.05 (one-sided), the sample size needed to detect a significant difference between groups was 200 patients per study arm (accounting for a dropout rate of 5%). For tumor response, 95% CIs using the normal approximation to the binomial distribution were calculated. Kaplan-Meier estimates were generated for survival over the entire course of the study and follow-up, and for on-study transfusions. All efficacy data were analyzed for the intent-to-treat (ITT) population, which was defined as all randomly assigned patients. The safety population comprised all randomly assigned patients who received at least one dose of the study drug and for whom safety data were available.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
Patient Demographics and Baseline Characteristics
The study was prematurely terminated by Johnson & Johnson Pharmaceutical Research and Development with approval from the US Food and Drug Administration because of slow recruitment and suboptimal enrollment. At the time of early study termination, 224 patients of a planned 400 patients had been enrolled. The ITT population comprised 109 patients in the epoetin alfa group and 115 patients in the placebo group who were recruited between July 15, 1993, and May 6, 2002 (when the study was discontinued). The disposition of all patients is presented in Table 1. The most common cause for discontinuation was completing the planned course of chemotherapy (43% of patients). Baseline demographics and clinical characteristics were generally similar between groups (Table 2). In total, 86% of patients were white, 55% were men, and patients had a mean age of 63.8 years. Extensive-stage SCLC was present at baseline in 66% of epoetin alfa patients versus 59% of placebo patients, and the mean number of days since diagnosis was similar between groups (13.0 days v 12.7 days). The majority (70%) of patients had ECOG performance status 0 to 1. For all patients, mean hemoglobin (± standard deviation [SD]) was 12.9 ± 1.52 g/dL.


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  		Table 1. Patient Disposition

 

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  		Table 2. Patient Demographics and Baseline Characteristics

 
Exposure to Cytotoxic Therapy and Study Medication
Exposure to cytotoxic therapy (chemotherapy and radiation therapy) for each group is listed in Table 3. The intensity of administered chemotherapy was similar between groups. In both groups, 72% of patients received at least three cycles of chemotherapy, and the mean number of chemotherapy cycles received was 4.0 in the epoetin alfa group and 4.1 in the placebo group (median, four chemotherapy cycles in each case; range, one to 12 cycles). The median duration of exposure to epoetin alfa or placebo was 13.4 weeks (range, 0.1 to 39.4 weeks) and 13.4 weeks (range, 0.1 to 44.6 weeks), respectively. After the first week of therapy, the median weekly dose of epoetin alfa ranged from 440.0 U/kg SC to 451.5 U/kg SC for all weeks in which there were at least 10 patients who continued to receive study medication.


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  		Table 3. Exposure to Cytotoxic Therapy

 
Tumor Response
The overall tumor response rate (ORR; defined as CR + PR) after the third chemotherapy cycle was 72% (95% CI, 64% to 81%) in the epoetin alfa group and 67% (95% CI 58% to 76%) in the placebo group (Table 4). The observed difference in ORR of 6% (95% CI, –6% to 18%) excluded the prespecified limit of –15%, indicating that the ORR in the epoetin alfa group was not lower than the ORR in the placebo group. In patients with extensive-stage and limited-stage SCLC, observed differences in ORR were 13% (95% CI, –2% to 29%), and –6% (95% CI, –25% to 13%), respectively (Table 4).


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  		Table 4. Tumor Response Rates

 
After the final cycle of chemotherapy, ORR was 60% (95% CI, 50% to 69%) in the epoetin alfa group and 56% (95% CI, 47% to 65%) in the placebo group, with an observed difference in ORR of 4% (95% CI, –9% to 17%). In patients with extensive-stage and limited-stage disease, observed differences in ORR were 1% (95% CI, –15% to 18%) and 11% (95% CI, –9% to 31%), respectively (Table 4).

Survival
A total of 201 of the 224 enrolled patients died before the end of the 3-year follow-up period. The overall mortality rate was 91.7% (100 of 109 patients) in the epoetin alfa group and 87.8% (101 of 115 patients) in the placebo group (hazard ratio, 1.172; 95% CI, 0.887 to 1.549; P = .264); median survival times (based on Kaplan-Meier estimates) were 10.5 months and 10.4 months, respectively (Fig 1). The most frequent cause of death in both groups was disease progression (epoetin alfa group, 91%; placebo group, 84%). No other cause of death in either group was reported more frequently than once.



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  		Fig 1. Kaplan-Meier plot of survival over time. () One month = 28 days.

 
Hemoglobin Levels Over Time
Mean baseline hemoglobin levels (epoetin alfa group, 12.8 g/dL; placebo group, 13.0 g/dL) were maintained in the epoetin alfa group during the first 22 weeks of study (mean weekly hemoglobin range, 11.3 g/dL to 12.7 g/dL), whereas the mean hemoglobin decreased in the placebo group to a minimum of 9.9 g/dL at week 14 (Fig 2). At the time of median exposure to study drug (13 weeks), mean change in hemoglobin was –0.2 g/dL in the epoetin alfa group and –2.9 g/dL in the placebo group. Mean hemoglobin at the end of cycle 3 was 12.5 g/dL and 10.6 g/dL in the epoetin alfa group and placebo groups, respectively, and mean final hemoglobin was 12.2 g/dL and 10.3 g/dL, respectively (mean difference in hemoglobin between groups at both timepoints, 1.9 g/dL; 95% CI, 1.4 to 2.4).



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  		Fig 2. Mean hemoglobin (Hb) levels and 95% CI over time.

 
Transfusion Requirements
Over all chemotherapy cycles, fewer epoetin alfa patients (26 of 109 patients; 24%) than placebo patients (42 of 115 patients; 37%) required RBC transfusions (hazard ratio, 0.597; 95% CI, 0.365 to 0.977). This difference between groups became evident after cycle 3; the proportion of patients transfused through cycle 3 was the same in each group (18%). Kaplan-Meier estimates of the time to first transfusion showed that the probability of transfusion was greater in the placebo group starting at month 3 (Fig 3). The mean number of units transfused across all cycles was similar between the epoetin alfa (mean, 0.5 units; SD, 3.6 units) and placebo groups (mean, 0.4 units; SD, 0.7 units). One patient in the epoetin alfa group had an abdominal aortic aneurysm requiring 37 units of blood.



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  		Fig 3. Kaplan-Meier plot of time to first transfusion.

 
ECOG Performance Status
The distribution of ECOG performance status scores was similar between treatment groups at baseline and at study end. All but two patients (98%) in the epoetin alfa group and all patients (100%) in the placebo group had an ECOG performance status score of ≤ 2 at baseline (mean ± SD baseline scores, 1.2 ± 0.7 and 1.1 ± 0.7, respectively). At study end, 71% of patients in each group had an ECOG score ≤ 2 (mean final scores, 1.6; SD, 1.3; and mean, 1.7; SD, 1.1, respectively).

Safety
Safety data were available for all 224 randomly assigned patients. The incidence and pattern of AEs were similar between groups. The most frequently reported AEs in the epoetin alfa group were nausea, vomiting, alopecia, granulocytopenia, constipation, and fatigue (Table 5). Anemia was reported at least twice as often in the placebo group as in the epoetin alfa group, as were dyspnea and dizziness. Fatigue was also reported more frequently in the placebo group. The most common severe AEs in the epoetin alfa and placebo groups were, respectively, alopecia (19%; 10%), nausea (16%; 10%), vomiting (13%; 10%), granulocytopenia (11%; 7%), dehydration (9%; 2%), and dyspnea (4%; 8%). There were no notable differences in the types or frequencies of serious AEs (SAEs) between treatment groups, and virtually all SAEs were considered to be unrelated to or of a doubtful relationship with the study medication. The most frequently reported SAEs occurring in more than 10% of patients were "aggravated malignant neoplasms" (a phrase that comprised several terms including metastatic lung cancer, death as a result of cancer or disease progression, aggravated neoplasms, and so on; epoetin alfa, 72%; placebo, 71%), granulocytopenia (epoetin alfa, 21%; placebo, 17%), dehydration (epoetin alfa, 16%; placebo, 16%), fever (epoetin alfa, 15%; placebo, 21%), vomiting (epoetin alfa, 13%; placebo, 7%), and nausea (epoetin alfa, 11%; placebo, 7%).


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  		Table 5. Treatment-Emergent Adverse Events Occurring in ≥ 20% of Patients

 
Discontinuation of study medication due to AEs was more common in the placebo group than in the epoetin alfa group (28% v 21%, respectively). For most of these patients, the AE was considered unrelated to study treatment. Four patients in each treatment group experienced treatment-limiting AEs considered possibly related to study treatment. In the epoetin alfa group, these AEs included increased sweating (two reports), thrombosis, chest pain, constipation, hypotension, dyspnea, and vomiting (one report each). In the placebo group, these AEs included tremor, grand mal convulsions, coma, pulmonary embolism, and reduced creatinine clearance (one report each).

Thrombovascular events (TVEs), including all superficial and catheter-related TVEs and events that could possibly have an underlying thrombovascular origin, were reported in 22% of epoetin alfa patients and 23% of placebo patients during the study period. Clinically relevant TVEs (including such events as deep venous thrombosis, pulmonary embolism, myocardial infarction, and cerebrovascular accident, but excluding reported TVEs for which there was no clinical information available to definitely relate the event to a thrombovascular origin) were reported in 11% of epoetin alfa patients and 10% of placebo patients (Table 6).


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  		Table 6. Clinically Relevant TV

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Appendix
 Authors' Disclosures of...
 REFERENCES
 
Despite early study termination as a result of suboptimal enrollment, the overall tumor response rate was not lower for the epoetin alfa group compared with the placebo group (the 95% CI for the difference between groups did not include –15%). This is consistent with the study hypothesis that epoetin alfa did not decrease tumor response by at least 15%. Follow-up of patients for up to 3 years after the study treatment period indicated that survival rates and survival duration among epoetin alfa- and placebo-treated patients were similar over at least 12 months from the start of the study. Apparent divergence in the survival curves, shown in Figure 1, was noted after the study treatment period and after month 12.

The interpretation of a possible divergence in survival curves after 12 months is difficult. Relevant patient data were only collected during the period of chemotherapy and study-drug administration. After completion or discontinuation from the treatment phase of the study, patients could receive other therapies at the discretion of their physician, including commercially available epoetin alfa. In addition, a higher proportion of patients in the epoetin alfa group versus the placebo group had extensive-stage SCLC at diagnosis (66% v 59%).

Because of the known association of anemia and poorer survival rates, several recent studies have examined the more aggressive investigational use of erythropoietic agents to potentially improve survival rates in patients with cancer. These studies treated patients earlier, sometimes when they were not anemic, and generally targeted higher hemoglobin levels than is recommended for the routine treatment of chemotherapy-induced anemia. Two recently published studies using such approaches have revealed a potentially deleterious effect on survival.7,8 The first was a prospective, randomized, double-blind, placebo-controlled study of 939 patients with metastatic breast cancer and baseline hemoglobin ≤ 13 g/dL receiving first-line chemotherapy.7 At the onset of chemotherapy, patients were treated with epoetin alfa (n = 469) or placebo (n = 470) for 12 months to maintain hemoglobin within the range of more than 12 g/dL to less than 14 g/dL, even after chemotherapy was stopped. Study drug administration was terminated early, after all patients had been enrolled, because of a significantly lower 12-month survival rate in the epoetin alfa group than in the placebo group (70% v 76%; P = .0117). This difference was mainly due to an increase in mortality in the epoetin alfa group relative to placebo in the first 4 months of the study (8.7% v 3.4%). This included a greater number of early deaths among epoetin alfa patients attributed to disease progression (6% v 3%) or TVEs (1% v 0.2%) compared with placebo patients. A blinded review of the data indicated that more of the deaths in the epoetin alfa–treated patients during the first 4 months of the study may have been as a result of TVEs.

The second study was a randomized, double-blind, placebo-controlled study evaluating the effect of maintenance of normal hemoglobin with epoetin beta versus placebo on cancer control and survival in patients with head and neck cancer undergoing radiotherapy.8 Women with baseline hemoglobin of less than 12 g/dL or men with baseline hemoglobin of less than 13 g/L received epoetin beta or placebo to attain a target hemoglobin of ≥ 14 g/dL or ≥ 15 g/dL, respectively. Compared with placebo, the adjusted relative risk of locoregional tumor progression in the epoetin beta group was 1.69 (95% CI, 1.16 to 2.47; P = .007), with an adjusted relative risk of death of 1.39 (95% CI, 1.05 to 1.84; P = .02).

Although it is possible that the two studies demonstrating a deleterious effect on survival could reflect an adverse effect of erythropoietic agents on tumor growth, other factors should be considered. For instance, in both of those studies target hemoglobin levels were higher than those used in routine clinical practice. Conversely, in the current study, epoetin alfa dose escalation was not permitted, resulting in a mean hemoglobin near the 12 g/dL level. In the recent epoetin alfa study,7 patients were treated for up to a year; in the epoetin beta study,8 although the treatment duration was shorter, hemoglobin increases of 2 g/dL in a 1-week period were allowed. In some patients treated with epoetin alfa, rapid increases in hemoglobin and treatment to a high target hemoglobin level have been associated with higher rates of TVEs than would be expected from the routine use of epoetin alfa.7,9

To examine this phenomenon further, several companies that manufacture and market erythropoietin receptor–agonists undertook extensive analyses of epoetin alfa, epoetin beta, and darbepoetin alfa data in patients with cancer and anemia treated according to current prescribing guidelines worldwide. These analyses revealed no evidence of a deleterious effect of these agents on tumor progression or survival when used according to standard prescribing guidelines. These analyses did confirm a previously known modest increase in the rate of TVEs in patients receiving erythropoietic therapy (epoetin alfa,10 epoetin beta,11 darbepoetin alfa12). For epoetin alfa, a combined analysis was conducted of data from 10 completed, randomized, double-blind, placebo-controlled studies evaluating the use of epoetin alfa for supportive anemia care in 1,976 patients with cancer and anemia receiving chemotherapy for which full patient-level survival data were available. The point estimate of the hazard ratio for on-study mortality was 0.99 (CI, 0.76 to 1.28), demonstrating that mortality for epoetin alfa recipients was indistinguishable from that for placebo recipients. Tumor response and rate of disease progression were also similar between the groups. Thus, when used for the approved indication and within established guidelines for target hemoglobin levels, epoetin alfa therapy has a well-defined and acceptable risk profile.10 Similar mortality findings were also reported for the other erythropoietin receptor–agonists.

Preclinical data on the promotion of tumor growth by erythropoietic agents are also controversial. In certain tumor cell lines and xenografts expressing both erythropoietin and its receptor, it has been suggested that erythropoietin signaling may promote cancer progression.13-16 In addition, several investigators have suggested a link between the expression of the erythropoietin receptor and tumor proliferation.13,15,17,18 However, several of these studies required suprapharmacologic doses of erythropoietic agents to obtain a minimal response,13,19 and many in vitro studies have shown no such relationship.20-23 Importantly, no causal relationship between epoetin alfa and cancer progression in humans has been demonstrated.24,25 The results of the current study support the premise that epoetin alfa administered at a dose of 150 U/kg SC TIW does not affect tumor response to chemotherapy or median survival in patients with SCLC receiving cisplatin-based chemotherapy. However, in light of recent studies suggesting impaired survival relative to placebo in patients with metastatic breast cancer7 or patients with head and neck cancer8 treated to higher target hemoglobin levels, clinicians should consider maintaining a target hemoglobin of 12 g/dL during epoetin alfa therapy, as recommended by the American Society of Hematology/American Society of Clinical Oncology and the National Comprehensive Cancer Network's evidence-based guidelines for cancer- and treatment-related anemia.26,27 Further studies designed to specifically evaluate the effect of erythropoietic agents on survival are warranted.


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
Authors' Disclosures of...
 REFERENCES
 
The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF (via Adobe® Acrobat Reader®) version.

Alabama.
Luigi F. Bertoli, MD, James C. Barton, MD, Ronald C. McCoy, MD, Ruth Atkinson, MD, James Barton, MD, John Hankins, MD, Jimmie Harvey, MD, Lisa Larson, MD, James Lasker, MD, Dice Lineberry, MD, Luis Pineda, MD, Kent Tucker, MD, Kevin Windsor, MD, Birmingham; James P. Daugherty, MD, PhD, Sally P. Green, MD, Michael J. Norgard, MD, Hemant K. Patel, MD, K. Lemone Yielding, MD, Florence; Rudolph M. Navari, MD, Bruce Johnson, MD, George M. Perrine, MD, Franc Wallace, MD, Birmingham; Allan Yielding, MD, William D. Wise, Birmingham.

California.
Peter D. Eisenberg, MD, Robert Pakter, MD, David Gullion, MD, Bobbie Head, MD, PhD, Greenbrae; L. Wayne Keiser, MD, James Harris, MD, Marek Bozdech, MD, Helen Collins, MD, Paul J. Dugan, MD, Julius M. Jaffee, MD, James Long, MD, Daniel P. Mirda, MD, Harry B. Richardson, MD, Thomas Stanton, MD, Mark Turrill, MD, Santa Rosa; H. Jeffrey Lawrence, MD, Neil Toribara, MD, Patricia Cornett, MD, Bonnie Jensen, MD, San Francisco; Kevin P. Ryan, MD, Deborah G. Tracy, MD, Major Bowyer, Travis AFB.

Connecticut.
Nicholas Daniak, MD, Karen Hutchinson, MD, Ingram Roberts, MD, Larry Bersetin, MD, Kenneth Dressler, MD, Robert Folman, MD, Jerry Malefatto, MD, Pasquale Perillie, MD, Glen Reznikoff, MD, Martin Roseman, MD, David Witt, MD, Bridgeport.

District of Columbia.
James D. Ahlgren, MD, Catherine Broome, MD, Gertrud W. Mergner, MD, Philip Cohen, MD, Craig M. Kessler, MD, Peter Shields, MD, Robert S. Siegel, MD, Imad Tabbara, MD, Washington; Dennis Priebat, MD, Marion H. Jordan, MD, Anna C. Alt-White, RN, Anthony Arcenas, MD, Steven Krasnow, MD, Lawrence S. Lessin, MD, David Perry, MD, Robert Wadleigh, MD, Washington.

Florida.
Roberto Arevelo-Araujo, MD, Frank J. Zaccaria, New Port Richey; Craig J. Badolato, MD, Sally P. Green, MD, Craig Deligdish, MD, Melbourne; Samuel Gross, MD, Francis DeTure, MD, Roy M. Ambinder, MD, Raul Castillo, MD, Philip Dunn, MD, Paul Garrett Jr., MD, Vasundhara Iyengar, MD, Arnold Miller, DO, David Molthrop, MD, Rebecca Moroose, MD, Jorge Otoya, MD, Robert Reynolds, MD, Michael Roberts, MD, David Smith, MD, Lee Zehngebot, MD, Orlando; Leonard A. Kalman, MD, Paul Kaywin, MD, Harold S. Golstein, MD, Peter L. Citron, MD, Alan D. Feinberg, MD, Alberto F. Larcada, MD, Martin E. Liebling, MD, Mark E. Oren, MD, Howard W. Wallach, MD, Grace Wang, MD, Miami; Harvey Sher, MD, PA, A. Allen Seals, MD, Jacksonville.

Georgia.
Teresa A. Coleman, MD, Kenneth I. Fink, MD, Col. Kent M. Plowman, MC, Raj R. Gupta, MD, Fort Gordon.

Illinois.
John W. Kugler, MD, John A. McCallister, MD, Stephen A. Cullinan, MD, James B. Gerstner, MD, James A. Knost, MD, Michael H. Veeder, MD, Allen M. Vukov, MD, Peoria; William J. Popovic, MD, Vernon Hermsen, Guillermo Rodriguez Jr., MD, Belleville.

Indiana.
Laurence Bates, MD, James Lingeman, MD, Wm. Dugan, Redmond Hogan, Greg Smith, Randall Trowbridge, Indianapolis.

Kansas.
Raj Sadasivan, MD, William Bartholome, MD, Kansas City.

Louisiana.
Rene A, Castillo, MD, Richard J. Gralla, MD, George A. Pankey MD, John T. Cole, MD, Archie W. Brown Jr., MD, Carl G. Kardinal, MD, Edwin A. McElroy, MD, Simi Rai, MD, New Orleans; David V. Schapira, MBChB, FRCP, M. Wayne Hurst, PhD, John Bickers, MD, Anthony Lowell, MD, Paul Schwarzenberger, MD, Chris Theodossiou, MD, Robert Veith, MD, Richard Vial, MD, Donna Walker, MD, New Orleans.

Massachusetts.
Michael J. DeLeo, MD, Richard Perera, MD, Jesse I. Spector, MD, Harvey Zimbler, MD, Pittsfield.

Minnesota.
Bruce F. Lewis, MD, William Goodall, MD, Kenneth Caldwell, MD, Thomas Ducker, MD, Rodger Johnson, MD, Irving Lerner, MD, John Schwerkoske, MD, John Wangsness, MD, St Paul.

Missouri.
Susan L. Luedke, MD, M. Robert Hall, MD, Rachel Borson, MD, Mark Stutz, MD, Rudolph Willis, MD, St. Louis; William Moriconi, MD, Ronald A. Gadde, St. Louis; Leonard A. White, MD, John F. Lindeman, MD, Alex Denes, MD, John R. Eckardt, MD, Alfred O. Greco, MD, Burton M. Needles, MD, St Louis.

Nebraska.
James A. Mailliard, MD, David L. Dworzack, MD, Samuel Mehr, MD, Sandra Chong, PharmD, Stephen Lemon, MD, Henry Lynch, MD, Raylene Rospond, PharmD, Omaha.

Nevada.
John Ellerton, MD, Paul V. Heeren, MD, Edgar A. Faylona, MD, Las Vegas.

New Jersey.
Ellioth H. Fishkin, MD, Elizabeth.

New York.
James A. Holland, MD, William J. M. Hrushesky, MD, Vernon J. King, MD, George Mosby, MD, Jeffrey Cooper, MD, Albany; Michael Schuster, MD, Steven Allen, MD, Thomas J. Degnan, Daniel R. Budman, MD, Stuart Lichtman, MD, Manhasset.

North Carolina.
Thomas H. Grote, MD, Carl S. Phipps, MD, Elms L. Allen, MD, Richard A. Brodkin, MD, Nick G. Chrysson Jr, MD, Judith O. Hopkins, MD, Eugene H. Paschold, MD, Marc L. Slatkoff, MD, Winston-Salem.

Ohio.
D. Randolph Drosick, MD, A. William Schreiner, MD, Robert Cody, MD, Douglas Hawley, MD, David Kirlin, MD, Wilfried Leder, MD, Philip Leming, MD, Cincinnati; Duane A. Sigmund, MD, Robert Means, MD, Cincinnati.

Pennsylvania.
Frank Andrews, MD, Rajneesh Nash, MD, Jane Raymond, MD, Richard K. Shadduck, MD, Zella Zeigler, MD, Pittsburgh; James F. Conroy, DO, Alexiss Sokil, MD, Isadore Brodsky, MD, Pamela Crilley, DO, Michael Styler, MD, David Topolsky, MD, Philadelphia; David H. Henry, MD, Vomrpd K. Bhutani, MD, Patricia Ford, MD, Michael Haut, MD, Bernard Mason, MD, David Mintzer, MD, Athur P. Staddon, MD, Philadephia.

South Carolina.
Francisco Gonzalez, MD, Edward W. Catalano, MD, James A. McFarland, MD, Cesar E. Vivanco, MD, Columbia.

Tennessee.
Lester L. Porter III, MD, Ronald Dean Butler, MD, W. Barton Campbell, MD, John A. Strupp, MD, Alan Cohen, MD, Ruth Lamar, MD, Patrick Murphy, MD, Nashville.

Texas.
Robert O. Kerr, MD, Mitchell R. Lestico, PharmD, John D. Doty, MD, Jerry D. Fain, MD, Richard E. Helmer, MD, Demetius F. Loukas Jr., MD, Gregory B. Smith, MD, Brenda L. Towell, MD, Thomas B. Tucker, MD, Dennis A. Tweedy, MD, John J. Whitaker, MD, J. Dudley Youman III, MD, Austin; John J. Nemunaitis, MD, Samuel P. Marynick, MD, Mammo Amare, MD, Thomas Anderson, MD, Joseph Bailes, MD, Larry Barker, MD, Alton J. Blow, MD, Joanne Blum, MD, Tammy Bordelon, MD, Barry Brooks, MD, Cynthia Cathcart, MD, Ernest Cochran, MD, Barry Cooper, MD, John Cox, MD, Randall Davis, MD, Claude Denham, MD, Lewis Duncan, MD, Gerald Edelman, MD, Timothy George, MD, Rudolf Good, MD, Kenneth Hancock, MD, Bonni Lee Harbaugh, MD, Sherron Helms, MD, Victor Hirsch, MD, Victor Horadam, MD, William Hyman, MD, Vinay Jain, MD, Stephen Jones, MD, Ronald Kerr, MD, Pankaj Khandelwal, MD, Gary Kimmel, MD, Robert Kirby, MD, Barry Luskey, MD, Billie Marek, MD, Kristi McIntyre, MD, Robert Mennel, MD, Douglas Orr, MD, R. Steven Paulson, MD, Mark Redrow, MD, Donald Richards, MD, Michael Savin, MD, Margaret Schottstaedt, MD, Todd D. Shenkenberg, MD, David Snyder, MD, Dilip Solanki, MD, James Strauss, MD, Gerardo Trillo, MD, James Turner, MD, David Watskins, MD, Robert Weisberg, MD, Charles White, MD, Dallas; David W. Ririe, Maj, USAF, MC, Kathy L. Christman, Maj, USAF, MC, Col Philip J. Perucca, MD, Jeffrey Allterton, MD, Charles Bane, MD, Mark C. DeLeon, MD, Gia Hong, MD, Elizabeth Horenkamp, MD, Thomas Johnson, MD, Stacy Lewis, MD, Earnest C. Lewis, MD, Michael Osswald, MD, David Powell, MD, Robert Prieto, MD, Mark Schroeder, MD, Paul Shaughnessy, MD, John Turner, MD, Sharon Wilks, MD, Lackland AFB.

Virginia.
Stefan M. Gorsch, MD, Faye Satterly, RN, Gordon Morris, MD, Robert Pritchard, MD, Chris Zazakos, MD, Charlottesville.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
REFERENCES
 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.


Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other
Dean Butler Johnson & Johnson (A)
Ellioth Fishkin Ortho-McNeil (A)
David H. Henry Ortho Biotech (A) Ortho Biotech (A) Ortho Biotech (B)
Kenneth Fink Ortho Biotech (A); Amgen (A)
Daniel J. Sullivan Johnson & Johnson Pharmaceutical Research & Development LLC (N/R)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) ≥ $100,000 (N/R) Not Required


   Acknowledgment
 
The authors would like to thank Thomson Scientific Connexions for editorial support in preparing this manuscript. This study (Protocol N93-004) was supported by Johnson & Johnson Pharmaceutical Research and Development LLC (formerly known as The R.W. Johnson Pharmaceutical Research Institute).


   NOTES
 
Supported by Johnson & Johnson LLC.

Presented in part in Grote T, Castillo R, Fishkin E, et al: Effects of early intervention with epoetin alfa in patients with small cell lung cancer (SCLC). Lung Cancer 41:S74,2003 (suppl 2; abstr O-252).

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
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10. Johnson & Johnson Pharmaceutical Research & Development LLC: Safety of erythropoietin receptor agonists (ERAs) in patients with cancer: Oncologic Drugs Advisory Committee briefing document. Submitted March 30, 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/cder04.html#Oncologic. Accessed October 27, 2005

11. Huber M: Epoetin beta in the treatment of anemia in cancer patients. Presented at the Oncologic Drugs Advisory Committee Meeting, Gaithersburg, MD, May 4, 2004. http://www.fda.gov/ohrms/dockets/ac/cder04.html#Oncologic. Accessed October 27, 2004

12. Amgen Inc: Aranesp (darbepoetin alfa) safety: Oncologic Drugs Advisory Committee briefing document. Thousand Oaks, CA, Amgen Inc. Submitted March 31, 2004. http://www.fda.gov/ohrms/dockets/ac/cder04.html#Oncologic. Accessed October 27, 2004

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