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Epoetin Alfa 60,000 U Once Weekly Followed by 120,000 U Every 3 Weeks Increases and Maintains Hemoglobin Levels in Anemic Cancer Patients Undergoing Chemotherapy

^a Tennessee Oncology, Nashville, Tennessee, USA; ^b Ortho Biotech Products, L.P., Bridgewater, New Jersey, USA

Correspondence: Jeffrey Patton, M.D., Tennessee Oncology Southern Hills, 397 Wallace Road, Suite 201, Nashville, Tennessee 37211-8025, USA. Telephone: 615-333-2481; Fax: 615-781-3923; e-mail: jpatton{at}tnonc.com

	LEARNING OBJECTIVES

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After completing this course, the reader will be able to:

1. List the recommendations in current clinical practice guidelines on epoetin alfa dosing and administration regimens for patients with cancer and chemotherapy-related anemia.
   
2. Discuss the benefits associated with epoetin alfa therapy in cancer patients with anemia receiving chemotherapy, in terms of increased hemoglobin levels, lower transfusion needs, and improved quality of life.
   
3. Explain how higher initial doses of once-weekly epoetin alfa followed by less frequent maintenance dosing with epoetin alfa in anemic cancer patients undergoing chemotherapy may be beneficial, both to the patient and to the health care provider.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Purpose. Epoetin alfa administered s.c. three times weekly or once weekly increases hemoglobin (Hb) levels, decreases transfusion requirements, and improves quality of life in anemic cancer patients receiving chemotherapy. This study assessed the feasibility of using higher initial doses of once-weekly epoetin alfa followed by less frequent maintenance doses to increase and then maintain adequate Hb levels in this population.

Materials and Methods. In this open-label, nonrandomized, pilot study, anemic (baseline Hb 11 g/dl) cancer patients undergoing chemotherapy received initial doses of epoetin alfa of 60,000 U s.c. once weekly to increase Hb levels by at least 2 g/dl, followed by 120,000 U s.c. every 3 weeks to maintain Hb levels. The maximum treatment duration was 24 weeks.

Results. The mean baseline Hb level was 10.1 ± 0.8 g/dl (n = 20). Once-weekly dosing resulted in mean Hb level increases of 1.0 ± 1.1 g/dl by week 4 and 2.9 ± 1.9 g/dl by week 8; 86% and 79% of patients evaluable at week 8 and week 12, respectively, demonstrated increases of at least 2 g/dl (target Hb level of 12 g/dl). Thirteen patients (65%) received at least one maintenance dose; the mean Hb level increased from 12.8 ± 1.1 g/dl before starting maintenance therapy to 13.3 ± 1.4 g/dl at the last maintenance week. Both dosage regimens were well tolerated.

Conclusions. Once-weekly epoetin alfa at a dose of 60,000 U effectively increased Hb levels by week 8; 86% of patients achieved rises of at least 2 g/dl or Hb levels 12 g/dl. Moreover, epoetin alfa at doses of 120,000 U every 3 weeks maintained or increased Hb levels. Results from this pilot study suggest that higher initial once-weekly dosing of epoetin alfa followed by less frequent maintenance dosing appears to be feasible for treating anemia in cancer patients undergoing chemotherapy. Further evaluation of these and other epoetin alfa dosage regimens is warranted.

Key Words. Epoetin alfa • Anemia • Antineoplastic agents • Neoplasms • Erythropoietin • Drug administration schedule

	INTRODUCTION

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Anemia occurs frequently among patients with cancer and is often debilitating. The most common symptom associated with anemia is fatigue, which affects the majority of cancer patients at some point during the course of their disease and treatment. Many patients with cancer experience fatigue daily or report that fatigue significantly affects their daily routines [1, 2]. Clinical practice guidelines issued by the American Society of Hematology and the American Society of Clinical Oncology have recommended epoetin alfa as the standard treatment option for patients with chemotherapy-related anemia and hemoglobin (Hb) levels 10 g/dl [3]. For patients with Hb levels >10 g/dl but 12 g/dl, the use of epoetin alfa is optional, depending on clinical circumstances [3, 4]. In contrast, the National Comprehensive Cancer Network recommends the use of erythropoietic agents for the treatment of cancer-related or treatment-related anemia in patients with Hb levels 11 g/dl [4]. These guidelines were developed using the results of large, prospective, community-based trials and randomized, double-blind, placebo-controlled trials, which established the efficacy of epoetin alfa, administered at doses of 150–300 U/kg s.c. three times weekly (tiw) [5, 6], 10,000–20,000 U s.c. tiw [7], or 40,000–60,000 U s.c. once weekly (qw) [8], in significantly decreasing transfusion requirements, increasing Hb levels, and improving quality of life in anemic cancer patients receiving chemotherapy. In qw trials, weekly epoetin alfa doses of 40,000–60,000 U were shown to be as effective and well tolerated as the doses administered in the tiw studies [8, 9].

Epoetin alfa doses higher than those currently approved for use in the U.S. have been shown to be well tolerated and effective in increasing Hb levels in small numbers of patients with myelodysplastic syndromes [10–12] and sickle cell disease [13] and in patients undergoing autologous blood donation before open heart surgery [14]. In the U.S., epoetin alfa is approved for various dosing schedules across several disease states, including once-daily or qw administration to reduce the need for allogeneic blood transfusions in anemic patients scheduled to undergo elective surgery. However, epoetin alfa also has been shown to maintain Hb responses when administered every 2 weeks (q2w) in patients undergoing continuous ambulatory peritoneal dialysis [15], and q2w, every 3 weeks (q3w), every 4 weeks (q4w), or longer than q4w in patients with predialysis chronic kidney disease [16–18].

Dosing regimens of erythropoietic agents that employ higher starting doses and lower or less frequent maintenance doses are presently being explored for the treatment of cancer-related anemia. Such regimens have the potential to provide additional benefits to patients and health care providers beyond those currently demonstrated with standard step-up dosing. Hypothesized advantages include a more timely response to therapy, a greater proportion of patients responding, an opportunity to identify nonresponders earlier in the course of treatment, and a possible cost savings (or an improved cost-benefit ratio). Moreover, the transition to less frequent maintenance dosing once patients have achieved stabilization of Hb levels may be more convenient for both patients and health care providers.

The safety and efficacy of higher initial epoetin alfa dosing, as well as maintenance therapy administered q3w, have not been evaluated previously in patients with chemotherapy-related anemia. The objectives of this pilot study were to evaluate the feasibility of initial epoetin alfa dosing at 60,000 U qw to increase Hb levels safely in patients with chemotherapy-related anemia who are receiving chemotherapy and to evaluate whether maintenance therapy of 120,000 U q3w safely sustains the gains in Hb levels observed with this initial dosing regimen.

	MATERIALS AND METHODS

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Study Design and Treatment Regimen
This open-label, nonrandomized, pilot study was conducted at a single center (Tennessee Oncology; Nashville, TN) in the U.S. The protocol was approved by the TriStar Nashville Market Institutional Review Board, and all patients provided written informed consent before study participation. Patients were screened for entry between July 2001 and January 2002.

During the screening phase of the study, demographic data were obtained, and a medical history, including disease-related information, and a physical examination, including vital signs, weight, and Eastern Cooperative Oncology Group (ECOG) performance status, were performed for each patient. Routine hematology and chemistry series were done, including: complete blood count with differential, serum chemistry panel (including creatinine, electrolytes, albumin, aspartate aminotransferase, total bilirubin); serum iron, serum ferritin, and total iron binding capacity; serum folate; vitamin B₁₂; and a pregnancy test (if applicable, within 7 days of the first epoetin alfa dose).

Following study enrollment, recombinant human erythropoietin (epoetin alfa, PROCRIT^®; Ortho Biotech Products, L.P.; Bridgewater, NJ) was initiated at a dose of 60,000 U s.c. qw. Patients received their first doses of epoetin alfa before the start of their next chemotherapy cycle and then weekly thereafter. After a minimum of 8 weeks of qw epoetin alfa therapy, if their Hb levels had increased by 2 g/dl above baseline, patients were given a maintenance dose of 120,000 U epoetin alfa s.c. q3w (given in two injections). Patients were evaluated every 3 weeks for up to 24 weeks (total treatment duration). An additional follow-up visit took place 1 month after each patient completed study treatment. If, at any time during the initial phase (qw epoetin alfa) or the maintenance phase (q3w epoetin alfa), a patient’s Hb level increased to >15 g/dl, epoetin alfa was withheld until the Hb level decreased to 13 g/dl; treatment was then resumed at a dose that was reduced by 20,000 U (i.e., from 60,000 U qw to 40,000 U qw or from 120,000 U q3w to 100,000 U q3w). If a patient’s Hb level increased by more than 1.3 g/dl in a 2-week period, a similar dose reduction occurred at the physician’s discretion. Iron supplementation was permitted at the discretion of the physician.

At the initiation of therapy, Hb level, hematocrit value, and blood pressure were obtained within 3 days before the first epoetin alfa dose, then every week until Hb level was stabilized, then at the discretion of the physician thereafter. After maintenance dosing began, Hb, hematocrit, and blood pressure were monitored weekly for 6 weeks (approximately two maintenance doses) and at the physician’s discretion thereafter. In addition, complete blood count with differential; physical examination; ECOG performance status; serum chemistry panel; transfusion information since the last study visit; adverse events; and chemotherapy, radiation therapy, and other concomitant therapy administration were recorded at each visit.

Patients
Men and women at least 18 years of age who were receiving myelosuppressive chemotherapy for a nonmyeloid malignancy and who had baseline Hb levels 11 g/dl were eligible for study enrollment. Patients were not required to receive chemotherapy for the entire study duration. Patients were required to have an ECOG performance status 2 and a life expectancy of at least 6 months. Patients were ineligible if they were diagnosed with a myeloid malignancy or if they had any of the following: anemia due to factors other than cancer or chemotherapy (i.e., iron, B₁₂, or folate deficiencies; hemolysis; or gastrointestinal bleeding); a recent (within the past 3 months) or uncontrolled seizure disorder; brain metastases; a history of thrombotic vascular events; uncontrolled hypertension; or known hypersensitivity to human serum albumin or mammalian cell-derived products. Patients who were candidates for bone marrow or stem cell transplantation, who were receiving peripheral blood progenitor therapy, or who had been treated with epoetin alfa or any other erythropoietic agents within the previous 6 months also were ineligible. Other exclusion criteria included concomitant interleukin-11 therapy during the study period, serious intercurrent illness or significant history of medical disease within the past 2 years, and pregnancy or lactation.

Statistics
The study end points were hematologic response as measured by change in Hb level (primary) and transfusion requirements (secondary). Patients were considered evaluable for safety if they received at least one dose of study drug. Patients were evaluable for efficacy if they received at least one dose of study drug and met all inclusion/exclusion criteria at enrollment. A sample size of 20 patients was considered sufficient to provide descriptive statistics to characterize the change in Hb level and transfusion requirements observed with this dosing regimen. Continuous variables (including Hb level, change in Hb level, proportion of patients transfused, and units transfused per patient) were summarized by descriptive statistics. Categorical variables were summarized by frequency statistics. Because this was a pilot study, no statistical significance was attributed to the data collected. Patients who received transfusions during the study were not included in the primary analysis of mean Hb level (except baseline Hb level), mean change in Hb level, or percentage of patients demonstrating a hematopoietic response. A hematopoietic response was defined as an increase in Hb level of at least 1 g/dl at week 4 and also as an increase in Hb level of at least 2 g/dl or the achievement of an Hb level 12 g/dl at any subsequent time point during the study. All data were analyzed using SAS software (Cary, NC) or an equivalent statistical package.

Safety was evaluated by adverse event reporting, clinical examination, and laboratory evaluations. Adverse events were rated according to National Cancer Institute Common Toxicity Criteria and were coded according to the World Health Organization-Adverse Reaction Terminology (WHO-ART) coding dictionary for tabulation.

	RESULTS

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Demographics and Baseline Characteristics
Twenty anemic cancer patients receiving chemotherapy for nonmyeloid malignancies were enrolled in this study between July 2001 and January 2002. The baseline characteristics of those patients are shown in Table 1. The mean age was 60.1 ± 9.2 years, 75% of the patients were female, and the mean baseline Hb level was 10.1 g/dl. Eighty percent of patients had an ECOG performance status of 0 or 1, and 90% of patients had solid tumors. During the study, patients received chemotherapy for a mean of 13.5 ± 7.3 weeks, and 55% received a platinum-containing treatment regimen. Four patients also received radiation therapy while on study (average dose of 5,690 cGy). All 20 patients enrolled had received prior treatment with chemotherapy within 3 months of study initiation. The most common classes of chemotherapeutic agents received prior to study were taxanes (70% of patients), pyrimidine analogues (60%), and platinum compounds (55%). Two patients had received prior radiation therapy and 15 patients had undergone surgery within 3 months of study initiation.

View larger version (24K): [in this window] [in a new window]   Figure 1. Patient disposition.

Hematologic Parameters
Initial epoetin alfa qw dosing resulted in mean Hb level increases of 1.0 ± 1.1 g/dl by week 4 and 2.9 ± 1.9 g/dl by week 8 of the study for patients who did not receive transfusions (Fig. 2). In general, there was a steady increase in Hb level during initial therapy; overall, 50% (10/20) of the patients had increases in Hb levels of at least 1.0 g/dl from baseline to week 4, and 13 (86%) of the 15 patients had increases in Hb levels of at least 2 g/dl (or achieved an Hb level of 12 g/dl) at week 8. At week 12, 79% of patients had achieved increases in Hb levels of at least 2 g/dl or had achieved an Hb level 12 g/dl. The median time to Hb response (Hb increase >2 g/dl) was 5.5 weeks, and the median time to hematopoietic response (Hb increase >2 g/dl or Hb 12 g/dl) was 5 weeks.

View larger version (16K): [in this window] [in a new window]   Figure 2. Mean Hb levels at baseline, week 4, week 8, week 12, and last measurement. aWeek 4 and week 8 values represent mean Hb levels during initial qw dosing phase. bBy week 12, 10 patients had commenced q3w maintenance dosing. Hb values are rounded to the nearest 0.1 g/dl. Error bars represent standard deviations.

View larger version (18K): [in this window] [in a new window]   Figure 3. Mean Hb levels during epoetin alfa q3w maintenance phase. an values indicate the number of patients with an Hb value recorded for a given week; this may not be the same as the number of patients still on study or the number of patients receiving study drug that week. Hb values are rounded to the nearest 0.1 g/dl. Error bars represent standard deviations.

Safety
All 20 patients were eligible for safety evaluation. Overall, both the initial and maintenance dosage regimens of epoetin alfa were well tolerated. Ten patients experienced serious adverse events, none of which were considered by the investigator to be related to epoetin alfa. One patient reported an adverse event (arthralgia/myalgia) that was considered by the investigator to be possibly related to epoetin alfa administration. In addition, three deaths were reported during the study, all of which were attributed to disease progression.

	DISCUSSION

Top Learning Objectives Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
In this pilot trial, epoetin alfa administered at doses of 60,000 U s.c. qw effectively increased Hb levels in anemic patients with cancer who were receiving chemotherapy. The mean Hb level increase at week 4 during the qw dosing phase was 1.0 ± 1.1 g/dl. This is consistent with an increase in Hb of approximately 1 g/dl at week 4 achieved in previous studies of anemic cancer patients undergoing chemotherapy who received initial epoetin alfa doses of 40,000 U s.c. qw [8, 9, 19, 20], 150–300 U/kg s.c. tiw [5, 6], or 10,000–20,000 U s.c. tiw [7]. In the current study, the mean increase in Hb level of 2.9 ± 1.9 g/dl at week 8 of the 60,000 U s.c. qw dosing phase is higher than the Hb increase of almost 2 g/dl at week 8 reported in previous large community-based studies of tiw and qw dosing [5, 7, 8, 19, 20] and a randomized placebo-controlled study of tiw dosing [6], but similar to the Hb increase reported in another small pilot study in which patients with cancer-related anemia received a similar initial epoetin alfa dosage (60,000 U qw) for up to 16 weeks (mean Hb increase at week 8 of 2.6 ± 2.4 g/dl) [21]. In addition, in the current study, the mean Hb level increase at last value (2.9 ± 2 g/dl) was higher than increases reported in large community-based trials of epoetin alfa (range of 1.8–2.0 g/dl) [5, 7, 8, 20] and in a placebo-controlled study conducted in patients with cancer-related anemia (mean Hb level increase of 2.2 g/dl) [6]. The more robust Hb increase seen with higher starting doses of epoetin alfa may allow health care providers to identify nonresponders and make dose adjustment decisions earlier in the course of therapy.

Approximately two-thirds of patients with chemotherapy-induced anemia respond to epoetin alfa tiw therapy, with response rates ranging from 53%-70% [5–7]. The response rate to epoetin alfa 60,000 U qw in this study is higher (86% at week 8) than rates reported with epoetin alfa at doses of 40,000 U s.c. qw. These intriguing differences in Hb level increase and response rate at week 8, however, should be interpreted cautiously because of the small sample size in this pilot trial, and should be confirmed in larger clinical studies.

For all patients whose Hb levels increased by 2 g/dl during the qw dosing phase and who entered the maintenance phase, epoetin alfa administered q3w effectively maintained Hb levels (Fig. 2). These results demonstrate the feasibility of using less frequent epoetin alfa dosing for maintenance therapy in this population and support the need for continued evaluation of alternative epoetin alfa dosage regimens. Moreover, the mean weekly dose used in the maintenance phase of this study parallels the 40,000 U epoetin alfa dose administered qw in current practice. Evidence exists, however, that epoetin alfa has been administered in community oncology practices at qw, q2w, and q3w intervals [22]. Less frequent maintenance dosing with epoetin alfa (q2w, q3w, and q4w) also has been used successfully in patients with predialysis chronic kidney disease [16–18]. Taken with the once-daily and qw dosing recommendations in elective surgery patients, these data collectively reflect the flexibility of epoetin alfa dosing schedules.

Both the initial and maintenance dosing regimens of epoetin alfa appeared to be well tolerated in this study, with only one adverse event (arthralgia/myalgia) considered to be possibly related to epoetin alfa. Larger studies are warranted to fully evaluate the safety of higher starting and maintenance doses of epoetin alfa in cancer patients.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Once-weekly epoetin alfa dosing has been widely adopted by oncologists in the U.S. [22] and incorporated into treatment guidelines [3, 4]. Data from this pilot study suggest that higher qw starting doses of epoetin alfa may allow patients to more quickly achieve a 2-g/dl increase in Hb level or a >12 g/dl target Hb level compared with epoetin alfa at a dose of 40,000 U qw.

In addition, these results establish the feasibility of less frequent maintenance dosing in anemic cancer patients undergoing chemotherapy. Alternative dosing regimens may ultimately provide flexibility for prescribers in selecting a dose and schedule of administration based on individual patient needs and convenience, without compromising efficacy. A variety of epoetin alfa doses and dosage regimens currently are being investigated in larger clinical studies.

	ACKNOWLEDGMENT

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This research was supported by a grant from Ortho Biotech Products, L.P.

	REFERENCES

Top Learning Objectives Abstract Introduction Materials and Methods Results Discussion Conclusions References

 

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