A New Dose-intense Epoetin Alfa Regimen Effective in Anemic Cancer Patients Receiving Chemotherapy: An Open-label, Non Randomized, Pilot Study

Transcription

1 A New Dose-intense Epoetin Alfa Regimen Effective in Anemic Cancer Patients Receiving Chemotherapy: An Open-label, Non Randomized, Pilot Study DANIELE SANTINI 1, BRUNO VINCENZI 1, ANNALISA LA CESA 1, VLADIMIR VIRZI 1, FRANCESCA NAVAJAS 1, VINCENZO MALAFARINA 1, GIORDANO DICUONZO 1, ROBERTO CASSANDRO 2, VINCENZO ESPOSITO 3,4, VINCENZO MONTESARCHIO 3,4, ANGELA M.GROEGER 4,5,6 and GIUSEPPE TONINI 1 1 Medical Oncology, University Campus Bio-Medico, Rome; 2 Institute of Cardio-Thoracic Research, Respiratory Section. V. Monaldi Hospital, Naples; 3 Third Division of Infective Diseases, D. Cotugno Hospital, Naples, Italy; 4 International Society for the Study of Comparative Oncology (ISSCO), Silver Spring, MD, U.S.A.; 5 Division of Vascular Surgery, Cardarelli Hospital, Naples, Italy; 6 Department of Cardio-Thoracic Surgery, University of Vienna, Vienna, Austria Abstract. Background: Chronic anemia is a well-recognized complication of both cancer and cytotoxic treatments and is associated with symptoms (e.g., fatigue, dyspnea) that may induce or exacerbate functional deterioration. The use of recombinant human erythropoetin (rhuepo epoetin alfa) clearly increased haemoglobin (Hb) levels, decreased transfusion needs and allowed recovery of quality of life in anemic cancer patients (pts) undergoing chemotherapy (CT). The purpose of this open-label, non randomized, pilot study was to assess the safety and efficacy of an intensive 19-day epoetin alfa treatment in anemic patients with solid tumors receiving chemotherapy. Patients and Methods: Treatment: patients received a single induction s.c. dose of epoetin alfa 40,000 IU day 1 and twice a dose of 10,000 IU s.c. (8:00 a.m.- 8:00 p.m.) on days 3, 5, 8, 10, 12, 15, 17 and 19. The total dose of epoetin alfa per patient was 200,000 IU. Iron supplementation: 125 mg i.v. days and 8. Soluble transferrin receptor (stfr) levels were performed on days 1,8 and 15. This epoetin induction regimen was not followed by an epoetin maintenance therapy. Patients: Twenty-nine anemic (Hb 11.5 g/dl) pts with non myeloid malignancies undergoing CT were included in the study. Results: At baseline the mean Hb level was 9.41 g/dl. On day 8, the mean Hb level increased to g/dl (p<0.0001), reaching Correspondence to: Prof. Giuseppe Tonini, MD, PhD, University Campus Bio-Medico, Via Emilio Longoni, 83, Rome, Italy. Tel: 0039/06/ , Fax: 0039/06/ , g.tonini@unicampus.it Key Words: Anemia, epoetin alfa. g/dl on day 15 (p<0.0001). On days 22 and 29, the mean Hb levels increased to and g/dl, (p=0.002 and 0.033, respectively). No patient received blood transfusions. The global mean increase of Hb level was 1.64 g/dl (basal to d 29). It was defined as a major response: an increase of Hb levels > 1.5 g/dl. A rate of 62% (18/29 patients) of major responses was observed on day 21. Moreover, 25/29 patients (86.2%) presented an increase of Hb levels > 1 g/dl after 21 days. On days 8 and 15, the mean stfr levels had increased significantly ( p=0.021 and 0.001, respectively). The increase of mean stfr level after 15 days correlated significantly with the increase of mean Hb level in the first two weeks of epoetin therapy (p=0.05). Epoetin alfa has been well tolerated so far in the study. Conclusion: The results of the present study suggest that an induction dose of 40,000 IU of epoetin alfa, followed by 8 maintenance doses of 20,000 IU each, may improve the standard response in terms of both time to response and Hb increase. Moreover, the Hb levels seemed to increase after epoetin therapy discontinuation (d22-29). The incidence and extent of anemia in cancer patients is influenced by several factors: the type of malignancy, the myelosuppressive nature of the anticancer therapy and the presence of coexisting morbidities (1,2). Many cancer patients are anemic at baseline, particularly those with hematological malignancies. Moreover, the incidence and severity of anemia increases with successive rounds of chemotherapy and/or radiation therapy (3,4). Three erythropoietic agents: epoetin alfa, beta and darbepoetin alfa, are currently available for the treatment of anemia with different FDA-approved indications based on the clinical evidence submitted in the particular disease states (5-9) /2005 $

2 Table I. Demographic and clinical characteristics at caseline. Characteristics Epoetin alfa induction treatment (n=29) Mean age, yrs 60.3 (40-80) Sex, n Male 13 Female 16 Mean Hb (g/dl) 9.41 ± 1.10 (SD) Type of tumor Lung 4 Breast 9 Colorectal 10 Other 6 Stage of tumor Early 8 Advanced 21 Chemotherapy* 14 Transfusions* 3 * previous Recombinant human erythropoietin (rhuepo, epoetin alfa), in several placebo-controlled clinical trials and singlearm, community-based studies, increased Hb levels, decreased transfusion needs and improved QoL in anemic cancer patients undergoing chemotherapy when administered at dosages of either 10,000 IU three times per week or 40,000 IU once per week (10,11). The mean increase in Hb level was approximately 1 g/dl after 4 weeks and 2 g/dl after 8 weeks of epoetin alfa therapy, irrespective of the dosage regimen used (10,11). The doses of 20,000 IU three times per week or 60,000 IU once weekly are only administered to non-responder patients after 4 weeks of standard treatment. The ASH/ASCO guidelines suggest the use of 150 IU/Kg s.c. three times\week or 40,000 IU weekly plus oral iron supplementation at least for 4 weeks, considering doubling doses in non-responders, in anemic patients (Hb 10 g/dl) with non myeloid malignancies undergoing chemotherapy (12). An important factor in improving the effect of treatment with rhuepo is an optimal dose-schedule of the drug. A promising approach for future studies could be a higher dosage induction, given to achieve a more rapid response to anemia. A similar approach would be based on the evidence that the effect of rhepo on the erythropoietic system is dependent on its saturating concentration on erythroid progenitor cells and thus on both its dose and frequency of application. However, a more rapid response of anemia would have the advantages of being more convenient for patients, allowing an earlier selection of those who are likely to respond and allowing maintenance of a full dose-intensity of the chemotherapeutic protocol. Once the target level of hemoglobin is reached, the dose of rhepo and the route of administration could be reduced to maintain the same level. No specific guidelines for induction treatment are advised. When speed to response needs to be accelerated based on the clinical program of the patient, a few pilot studies have tested a higher epoetin alfa induction dose (13-16). These data favour a dose-response direct relationship for epoetin alfa. In fact, a recent dose escalation study on a platinumtreated population has shown a faster and higher increase in Hb level proportional with the increase of the weekly dose. The same study also demonstrated that the most efficient epoetin alfa schedule is the fractionated one. In fact 10,000 IU three times per week generates the highest Hb gain per 10,000 IU administered, with respect to one weekly dosage (16) In order to obtain a better response rate, speed and duration of response in anemic cancer patients, a new epoetin alfa regimen utilizing a 3-week induction fractionated dose was evaluated. This report describes the results of a pilot study conducted to examine the efficacy and safety of this dosing regimen in anemic cancer patients receiving chemotherapy. Patients and Methods Patient selection. Twenty-nine patients were enrolled. Requirements for inclusion were: a non-haematological malignancy, haemoglobin level 11.5 g/dl or less, to be receiving concomitant chemotherapy, 3 months or greater of life expectancy and to be able to understand and provide written informed consent. Exclusion criteria were uncontrolled hypertension, active infection, primary bone marrow malignancy and a known history of anemia caused by factors other than cancer or chemotherapy (i.e. iron or folate deficiencies, haemolysis, gastrointestinal bleeding, myelodisplastic syndromes). We also excluded patients who had previously received epoetin alfa, were planning to have a bone marrow transplant or were receiving peripheral-blood progenitor cell therapy. Baseline information were patients demographics, weight and blood pressure, tumor histology, current chemotherapy and radiation therapy regimens, and history of cisplatin chemotherapy regimens and transfusion use. During the screening phase of the study, demographic data were obtained, and medical history (including disease-related information) and 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. Soluble transferrin receptor (stfr) levels were performed on days 1, 8 and 15. Baseline demographic and clinical characteristics are reported in Table I. 670

3 Santini et al: Induction Epoetin in Anemic Cancer Patients First week Second week Third week 1Æ 3Æ 5Æ 1Æ 3Æ 5Æ 1Æ 3Æ 5Æ day day day day day day day day day Epoetin Epoetin Epoetin Epoetin Epoetin Epoetin Epoetin Epoetin Epoetin alfa alfa alfa alfa alfa alfa alfa alfa alfa 40,000 IU 10,000 IUx2 10,000 IUx2 10,000 IUx2 10,000 IUx2 10,000 IUx2 10,000 IUx2 10,000 IUx2 10,000 IUx2 Iron Iron Iron haemoglobin haemoglobin haemoglobin s-tfr s-tfr s-tfr Blood Blood Blood sampling sampling sampling Figure 1. Flow chart. Treatment plan. This was an open-label, non randomized pilot study in which anemic patients with solid tumors submitted to multicycle chemotherapy received a new dose-intense epoetin alfa induction regimen (EPREX, Ortho Biotech/Janssen-Cilag Inc.). Patients received one single induction s.c. dose of epoetin alfa 40,000 IU on day 1 and twice a dose of 10,000 IU s.c. (8:00 a.m.- 8:00 p.m.) on days 3, 5, 8, 10, 12, 15, 17 and 19. The total dose of epoetin alfa administered per patient was 200,000 IU. Iron supplementation: 125 mg i.v. on days 1 and 8. This epoetin induction regimen was not followed by an epoetin maintenance therapy. Hemoglobin levels were detected on days 1, 8, 15, 22 and 29 and soluble transferrin receptor (stfr) levels were performed on days 1, 8 and 15 (Figure 1). Efficacy endpoints. The efficacy endpoints were the evaluation of: the percentage of patients who achieved a major response defined as Hb increase 1.5 g/dl from baseline or a minor response defined as Hb increase 1 g/dl from baseline; the proportion of patients transfused after the first 3 weeks of treatment; the change in hemoglobin median level from baseline to last value (day 29); the determination of the time to treatment failure (response duration); the safety of the new dose-intensity epoetin alfa induction regimen; the predictive value of stfr levels. Results Responders. The percentage of patients who achieved a major response was 62% after a 3-week treatment and 69% after 4 weeks (Figure 2). Moreover, the proportion of patients who achieved a minor response was 86% after 3 weeks of treatment and 93% after 4 weeks (Figure 2). Transfusion requirements None during the 29 days of the protocol. Change in Hb levels. Mean Hb levels increased from 9.41 g/dl (±1.10, SD) to g/dl (±1.68, SD) after 3 weeks (day 22), and to g/dl (±1.72, SD) at day 29 (Figure 3). In particular, at baseline the mean Hb level was 9.41 g/dl. On day 8, the mean Hb level increased to g/dl (p<0.0001) and on day 15 reached g/dl (p<0.0001). On days 22 and 29, the mean Hb levels increased to and g/dl (p=0.002 and 0.033, respectively). The mean Hb gain in 4 weeks was 1.64 g/dl (Figure 4). Time to treatment failure (response duration). The median time to treatment failure was 9 weeks (95%C.I.: 5.78; 12.22) (Figure 5). Safety. All 29 patients were eligible for safety evaluation. The induction dosage regimen of epoetin alfa was welltolerated. Adverse events were unrelated to therapy and commonly occurring in patients undergoing chemotherapy. Twelve patients experienced serious adverse events, none of which were considered by the investigator to be related to epoetin alfa. Two patients reported an adverse event (respectively, blood hypertension and arthralgia/myalgia) that was considered by the investigator to be possibly related to epoetin alfa administration. Predictive value of stfr levels. On days 8 and 15, the mean stfr levels increased significantly (p=0.021 and 0.001, respectively). The increase of mean stfr level after 15 days correlated significantly with the increase of mean Hb level in the first 2 weeks of epoetin therapy (p=0.05). 671

4 Figure 2. Responders rate at day 22. Figure 4. Change in Hb from baseline. Figure 3. Hb levels over time. Discussion The new epoetin alfa regimen, utilizing a 3-week induction fractionated dose, was found to significantly increase Hb levels in patients receiving chemotherapy and was welltolerated. The evaluated induction treatment was faster than standard dosages in patients needing transfusion. In particular, the mean Hb increase was 1.5 g/dl after 3 weeks and 1.64 g/dl after 4 weeks of induction treatment, with 86% of patients gaining at least 1 g/dl. These results are 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 U/kg s.c. tiw or 10,000 20,000 U s.c. tiw (17, 18). Comparison of responders with other loading regimens (Table II) shows that epoetin alfa response is dosedependent: the higher the dose, the greater and faster the response. The few epoetin induction feasibility studies published in the literature, as the present paper, showed a dose-response curve with faster responses when a high dose of epoetin was administered over short times (13-15). Figure 5. Response duration. Cortesi et al. (13) performed a pilot study on a subset of solid tumor patients with a baseline Hb 8.2 g/dl. The induction treatment with epoetin alfa 40,000 twice a week for 2 weeks followed by no treatment allowed a Hb gain of 1.7 g/dl in 2 weeks and 2.9 g/dl in 6 weeks; the percent of responders was 82% at 6 weeks compared to 21% of a historical control group. Comparison to standard treatment revealed that there was also an advantage in chemotherapy compliance in the group quickly overcoming anemia. Furthermore, the present feasibility study demonstrated that a fractionated dose is more effective than one weekly administration (18-20). One-weekly epoetin alfa dosing has been widely adopted by oncologists in the U.S. and incorporated into treatment guidelines (17,18). In Patton et al s study (14), one weekly dosage of 60,000 IU epoetin alfa 672

5 Santini et al: Induction Epoetin in Anemic Cancer Patients Table II. Comparison among loading dose regimens. Drug Reference Pts Mean Hb Responders gain Rate at week 4 at week 4 (g/dl) ( 2g/dl) Epo alfa 40K Present % induction dose paper plus 60K/week (three times week) X 17 days Epo alfa Cortesi % 80K/week (week 6) (week 6) X 2 weeks Epo alfa 60K/week Patton nd X 4 weeks Epo alfa 60K/week Chap nd X 4 weeks Nesp 4.5 mcg/ Glaspy % Kg/week % (= 60K) X 4 weeks % for 8 weeks allowed a mean Hb increase of 1.1 g/dl in 4 weeks and 2.8 g/dl in 8 weeks in anemic cancer patients receiving chemotherapy. Chap et al. (15) performed an open-label, non randomized pilot study to evaluate the response rate of epoetin alfa at a dose of 60,000 IU weekly in anemic patients with non myeloid malignancies undergoing chemotherapy. The hemoblobin gain was 1.1 g/dl in 4 weeks and 2.6 g/dl in 8 weeks with respect to a mean baseline Hb concentration. Data from this pilot study suggest that a high induction dose (40,000 U) followed by high fractionated doses (10,000 x 2) three times a week may allow patients to more quickly achieve a significant increase in Hb level or a >12 g/dl target Hb level compared with epoetin alfa once per week. New studies evaluating a number of extended dosing schedules for epoetin alfa are underway. Some authors have investigated, with contrasting results, the role of serum soluble transferring receptor (stfr - a marker of functional iron deficiency), as well as of the early stfr increment (a quantitative measure of erythropoietic activity) in predicting epoetin response (21,22). In the present study, we demonstrated that the increase of mean stfr level after 15 days correlated significantly with the increase of mean Hb level in the first 2 weeks of epoetin therapy (p=0.05). In conclusion, these results establish the feasibility of a new epoetin alfa regimen utilizing a 3-week induction fractionated dose in anemic cancer patients undergoing chemotherapy. A variety of epoetin alfa doses, schedules and dosage regimens currently are being investigated in larger clinical studies. Further studies are required to define the most appropriate induction dosage of epoetin alfa. Acknowledgements We wish to thank Rosanna Macrina (University Campus Bio- Medico of Rome, Italy) for her writing, editorial and graphical support. References 1 Tchekmedyian NS: Anemia in cancer patients: significance, epidemiology, and current therapy. Oncology (Huntingt) 9(Suppl 10): Demetri GD: Anaemia and its functional consequences in cancer patients: current challenges in management and prospects for improving therapy. Br J Cancer 84(Suppl 1): 31-7, Groopman JE and Itri LM: Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 91(19): , Harrison LB, Shasha D and Homel P: Prevalence of anemia in cancer patients undergoing radiotherapy: prognostic significance and treatment. Oncology 63(Suppl 2): 11-8, Morreale A, Plowman B, DeLattre M, Boggie D and Schaefer M: Clinical and economic comparison of epoetin alfa and darbepoetin alfa. Curr Med Res Opin 20(3): , Adamson JW: Epoetin alfa: into the new millennium. Semin Oncol 25(3 Suppl 7): 76-9, Markham A and Bryson HM: Epoetin alfa. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in nonrenal applications. Drugs 49(2): , Glaspy J: Introduction. Improving the standard of care in the management of cancer-related anaemia: focus on darbepoetin alfa, a novel erythropoiesis-stimulating protein. Br J Cancer 84(Suppl 1): 1-2, Overbay DK and Manley HJ: Darbepoetin-alpha: a review of the literature. Pharmacotherapy 22(7): , Demetri GD, Kris M, Wade J, Degos L and Cella D: Qualityof-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 16: , Littlewood TJ, Bajetta E, Nortier JW, Vercammen E and Rapoport B: Epoetin Alfa Study Group. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19: , Rizzo JD, Lichtin AE, Woolf SH et al: American Society of Clinical Oncology. American Society of Hematology: Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20(19): , Cortesi E, Mancuso A, De Pasquale Ceratti A et al: Efficacy, safety, and clinical benefits of a loading dose of epoetin alfa in anemic patients receiving concomitant chemotherapy. Proc of ASH, 2002 abstract No

6 14 Patton J, Kuzur M, Liggett W et al: 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. Oncologist 9(1): Chap L, George M and Glaspy JA: Evaluation of epoetin alfa (Procrit ) 60,000 U once weekly in anemic cancer patients receiving chemotherapy. Proc of ASCO, 2002, abstract No Cella D, Zagari MJ, Vandoros C, Gagnon DD, Hurtz HJ and Nortier JW: Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol 21(2): , Glaspy J, Bukowski R, Steinberg D et al: Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 15: , Sabbatini P, Cella D, Chanan-Khan A et al: Cancer and treatment-related anemia. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, v Rockledge PA: National Comprehensive Cancer Network, Inc., 2002:ANEM-1-4, ANEM-A, MS-1-9, REF Shasha D and George M: Rapid hemoglobin response in anemic cancer patients undergoing chemotherapy or chemoradiation therapy receiving once-weekly epoetin alfa treatment. Blood 100: Abstract 3517, A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Italian Cooperative Study Group for rhuepo in Myelodysplastic Syndromes. Br J Haematol 103(4): , Tarng DC and Huang TP: Determinants of circulating soluble transferrin receptor level in chronic haemodialysis patients. Nephrol Dial Transplant 17(6): , Ziras N, Rozakou AJ, Potamianou A et al: Soluble transferrin receptor (stfr) as a predictor of response to prophylactic epoetin alfa (EPO) treatment in non-anemic cancer patients under chemotherapy. Preliminary results. Proc of ASCO, 2001, abstract No Received May 18, 2004 Revised September 27, 2004 Accepted October 18,