An Open Labeled Two Arm Study to Evaluate the Feasibility, Quality of Life, Safety and Efficacy of Darbepoetin as Compared to Erythropoietin Inpatients with Chemotherapy Induced Anemia in Patients with Gastro Intestinal Malignancies. **Suresh V S Attili, *B B Ananda, **Chinna Babu S, **Kamireddy Suresh. * Department of Surgical Oncology, BRA Medical College, Bangalore. ** Department of Clinical Research, ClinSync, Hyderabad. ABSTRACT Aim: An open labeled two arm study to evaluate the feasibility, quality of life, safety and efficacy of Darbepoetin as compared to Erythropoietin in patients with chemotherapy induced anemia of Gastro intestinal malignancies. Methods: This study was conducted in two hospitals in patients with metastatic GI malignancies who have chemotherapy induced anaemia. The selection of GI malignancies is due to lack of EPO receptors in malignant cells, there by reducing the adverse risk of erythropoietic agents on disease outcomes. The subjects have received chemotherapy and erythropoietic agents as per standard guidelines. Results: A total of 42 patients with chemotherapy induced anaemia were randomized in 1:1 ratio to either Darbepoetin or conventional erythropoietin arms. Darbepoetin has shown to improve the Health related Quality of Life when compared to erythropoietin. There is no statistically significant differences in the mean raise of haemoglobin during the study period or cost of therapy or incidence of adverse events in either arms. Conclusion: The current study indicates that it is feasible to give either of the erythropoietic agents in the gastrointestinal cancer patients with chemotherapy induced anaemia and there are no differences among the Darbepoetin or conventional erythropoietin. Though the current study is not designed or powered to evaluate the disease free survival compared to historical controls, it appears that administration of erythropoietic agents as per standard guidelines do not affect the disease outcomes in gastro intestinal malignancies. Introduction Keywords: Chemotherapy induced anaemia, gastrointestinal cancers, India. Anaemia is a common morbidity in cancer patients due to primary disease or secondary to the treatment (mostly chemotherapy occasionally due to radiation). A systematic review of 60 articles reporting the survival of cancer patients in relation to anaemia and haemoglobin concentration found a 65% higher relative risk of death Corresponding author: Dr AVS Suresh, Department of Medical Oncology, BIBI General Hospital and Cancer Centre, Malakpet, Hyderabad. Fax 91 40 23424122, Email: sureshattili@yahoo.com 289
Suresh VS Attili for anaemic patients than for non-anaemic patients. 1 Multiple attempts were made to correct anaemia with hope to improve survival and quality of life. Its management with erythropoietic agents presents many unresolved issues. Littlewood et al., 2 found that the median survival duration, was 17 months for patients treated with epoetin Alfa compared with 11 months for patients treated with placebo. However, that trial was neither designed nor powered for a survival end point. These findings were challenged by two major negative studies MF 4449 and INT 7. 3,4 Based on these results FDA issued warring that erythrocyte stimulating agents have actually Increased Mortality and/or risk of tumour progression in cancer patients receiving chemotherapy. However, results from studies MF 4449 and INT 7 need to be interpreted with caution for following reasons: In the head and neck concurrent chemo radiation protocol (MF4449) Darbepoetin was used. 3 1. More than 30% of patients did not receive radiation therapy as per protocol, and a further 8% had major protocol violations. 2. No statistically significant differences in disease progression or survival end points were seen when the data was analysed for the group of patients who did receive radiation therapy as per protocol. 3. Some of these subjects on Darbepoetin continued to receive it even after the completion of the chemotherapy duration and the thrombotic events happening post treatment also contributed to the inferior results. 4. More rhuepo-treated patients than placebo-treated patients had certain unfavourable characteristics. Similarly in breast cancer study, (INT-76) 4 subjects received first-line chemotherapy with erpex, was terminated early because of a higher mortality in the epoetin Alfa treatment arm than in the placebo arm at 12 months. However these results are attributed to the higher incidence of fatal thrombotic and vascular events in the rhuepo arm, which in turn were due to continuation of Epoitin therapy beyond reaching the target haemoglobin. Though the greater incidence of breast cancer progression in rhuepo-treated patients (6% vs. 3%) might also have contributed, the exact impact of the epoitin on survival cannot be interpreted with certainty. There are two major well designed studies on going to answer this question of survival by clearly defining the duration of therapy and target haemoglobin levels as well as balancing the disease and therapy related variables in either arms. 5,6 However, in view of several cultural and logistic reasons these agents are still being prescribed with clear information regarding possible side effects to the subjects across the globe. Regarding the issue of which erythropoietic agent is superior, there is limited retrospective data available, that showed no difference. As Darbepoetin can be given once 3 weeks matching with chemotherapy in contrary to conventional erythropoietin, which means more comfort to subjects, this open labeled two arm study was conducted to evaluate the feasibility, quality of life, safety and efficacy of Darbepoetin as compared to Erythropoietin in patients with chemotherapy induced anemia. Methods- The study was conducted at BIBI general hospital and cancer center along with BRA medical college. A total of 42 subjects were randomized in 1:1 ratio into conventional erythropoietin arm or Darbepoetin arm. Local EC approved Informed Consent form, with a clear statement that the drug may shorten the life expectancy was administered, explained and consent was obtained before the subject s participation in the study. The key eligibility criteria include - Subjects with chemotherapy induced anemia in GI malignancies, [defined as Hb less than 12 gm/dl, adequate transferrin and ferritin levels] who are able to give written informed consent, Aged 18-65, with Life expectancy of > 6 months, and adequate marrow, hepatic renal and cardiac condition were enrolled in to the study with key exclusion criteria of CHF- class III/IV, Past history of CAD or uncontrolled hypertension, Major surgery less than 12 weeks, Hemoglobinopathies, Hyperparathyroidism, Active infective/ inflammatory pathology, Pregnant and lactating females. All the patients received standard chemotherapy with DCF/5FU Cisplatin/ Folfox-4 as per the indication according to the NCCN guidelines. 7 At least a total of four or more cycles need to be received by the subjects after diagnosis of chemotherapy induced anemia. Stool for occult blood was tested to make sure that subjects do not have active blood loss and those with GI blood loss were excluded from analysis. The subjects were analyzed for the hemoglobin levels at intervals of one week for conventional erythropoietin arm and 3 weekly for Darbepoetin arm and QOL were administered at the time of Erythropoietin injection. Quality of life questionnaire- indigenously developed and validated QOL in Telugu was used to assess the 290
Erythropoietic Agents in GI Malignancies symptomatology of subjects. Two specific modules assessed were symptoms related to cancer and anemia, which were analyzed separately from the global QOL. 8 Cost effective analysis- We calculated the cost involved in management of anemia and related symptoms, travel/professional charges for the administration of the injections as well. We excluded the costs of the chemotherapy and management of other conditions as the scope of this study is evaluating the two forms of erythrocyte growth factor. Treatment received- patients on once 3 weekly Darbepoetin received 300 mcg matching with the chemotherapy schedule. And epoitin was used as at 40,000 U weekly (QW) with a dose increase to 60,000 U in patients with inadequate responses. The dose adjustments of erythrocyte growth factor administered in the study are as follows: 1. If previous Hb level is documented below 7 gm/dl after first dose, the dose should be increased by 50% of the previous dose. 2. Decrease the dose by 25% if Hb increase more than 1.0 gm/dl in a 3 week period. 3. Increase the dose by 25% if the raise of Hb is less than 1.0 gm/dl in a week period until one researches the target range. 4. Decrease the dose by 25% if a previous Hb level is > 11.5 gm/ dl. 5. Doses are to be with held if the previous Hb reading >12gm/dl until Hb< 12gm/ dl at which time study agent are to be restarted at a dose 25 % lower than the time the study agent was discontinued. 6. If previous Hb level is documented below 10 gm/dl after achieving the target range the dose should be increased by 25 %. Statistical analysis- Medicalc version 7.0 for Windows (MedCalc Software, Mariakerke, Belgium) was used for the analysis. The parameters were compared between two arms using students T test. Primary end point(s)- mean Hb during treatment period. Safety end points- Incidence of AEs, related to erythrocyte stimulating factor or anaemia related and overall number of AEs irrespective of grade. Secondary- QOL, Median transfusion requirement, cost of therapy as defined above. Results- The baseline demographics of the subjects were represented in table 1. The baseline parameters of the both groups are similar with a slight preponderance of patients with gastro-esophageal cancer in the Darbepoetin group compared to conventional erythropoietin arm where there are more colorectal cancer patients. The mean change in the hemoglobin, QOL, cost effective analysis were represented in the Table-2. The global QOL overall score suggests a better (statistically significant??/ clinically??) QOL for the Darbepoetin arm. However, the anemia related QOL score suggests no differences in Table 1: Baseline parameters of patients Parameter Darbepoetin arm [N=21] Conventional Erythropoietin [N=21] Male: Female 2:1 2:1 Age (Mean ±SD) 46.2±9.4 (years) 42.5±10.6 (years) ECOG performance status One Two Carcinoma gastro-oesophageal 67% (14) 71% (15) 71% (15) 52% (11) Colorectal cancer 48% (10) Baseline Hb levels 3.1±1.6 gm/dl 3.1±1.6 gm/dl 291
Suresh VS Attili Table2: Comparison of Quality of life, Cost analysis and response to chemotherapy and Erythropoietic agents Parameter Darbepoetin arm [N=21] Conventional Erythropoietin [N=21] QOL mean change + 14.8±5.4 (in scale) + 13.1±4.9 (in scale) Anaemia related + 3.8±1.2 (in scale) + 3.9±1.3 (in scale) Average cost 15,946.8±1982.4 (Rupees) 15,328.4±2046.6 (Rupees) Response to therapy Complete remission Partial Remission Stable Disease 5% (1) 0% (0) 43% (9) Progressive disease Mean time to Hb>11 16.2±5.4 (days) 18.6±7.2 (days) Mean Increase in Hb levels 3.1±1.5 gm/dl 2.9±1.4 gm/dl Mean Hb during therapy 12.3± 1.6 gm/dl 11.9± 1.3 gm/dl Mean transfusion requirement 0.6± 0.3 0.6± 0.4 QOL, which indicates that both agents are good in bringing back the hemoglobin to normal values. anemia related QOL there were no differences which indicates that either of the agents was good in bringing back the hemoglobin to normal values. After careful evaluation the multiple injections in conventional arm was considered for this minor difference in the QOL. Similarly the subjects on the Darbepoetin had lesser hospital visits which is the reason why, though it is more expensive, the overall cost of therapy in either arms is not different. The mean transfusion requirements to correct the hemoglobin and mean hemoglobin levels, mean time to achieve target hemoglobin are not different in either arm. The incidence of adverse events was represented according to system and CTC AE grade. 9 The only thrombotic event (venous tumor thrombus) observed in the conventional erythropoietin arm was tumor related and not related to the study drug. There are no other differences observed in the incidence of any adverse events in either arm and these are not different from the routine adverse events observed while on therapy (data not represented). Discussion The issue of erythropoietic stimulating factors in the treatment of chemotherapy induced anemia is highly controversial with majority of data favoring not to use as there is a potential for reduced survival period and disease progression free periods. 3,4, 10,11 It was hypothesized that erythropoietin (EPO) receptor expression on cancer cells may be responsible for this observation. Many subsequent articles have highlighted the limitations of those studies. 12 However there are two large well designed randomized placebo controlled studies going on, which may answer this issue. 5,6 Pending the results of these, many oncologists are using these agents across the globe due to various reasons from patient preferences for not using blood products, to other logistic reasons. In view of the controversies of expression of EPO receptors in breast, lung and other cancer types and potential risks of using these agents that may adversely affect the cancer outcome the current study is designed in subjects with GI malignancies not known to express these receptors. 10 Our results suggested that both these agents are equally effective and Darbepoetin is favoured in view of fewer hospital visits and fewer injections. There is significant reduction in the transfusion requirement, as well as hospital stay due to anaemia related complaints. The results also suggested that both the agents help in improving the quality of life in patients (GI malignancies) with chemotherapy induced anaemia. There is no increased risk of any adverse events observed in the present study due to addition of erythrocyte growth factor agents. However, due to small sample size deriving 292
Erythropoietic Agents in GI Malignancies conclusions regarding no or minimal risk of adverse events related to erythrocyte growth factor agents may not be appropriate and two larger studies, 5,6 may provide conclusions. When we looked for the response to therapy [partial vs. complete vs. stable disease vs. progressive disease] in either arms it is not different and is very much similar to the hospital records. Hence, though not planned, we took the matched hospital records to look for the progression free survival in either arm versus controls (we assume response to therapy is surrogate for the progression free survival). As the study is not designed to look for the survival end points, it was not formally analyzed. However, as the results are interesting they are briefly mentioned here. There is no difference as far as progression free survival is concerned in either arms and when compared to the existing matched hospital records. For gastro esophageal cancers it is 8.3±1.6 vs. 8.6±1.7 vs. 8.5±1.4 months in the hospital control group vs. Darbepoetin vs. Conventional erythropoietin arms and for colorectal cancers it is 14.6±3.4 vs. 14.3±2.8 vs. 14.5±3.1 months respectively). And we assume that it could be a surrogate of overall survival as well. Conclusions The current study indicates that it is feasible to give either of the erythropoietic agents in the gastrointestinal cancer patients with chemotherapy induced anaemia and there are no differences among the Darbepoetin or conventional erythropoietin. Though the current study is not designed or powered to evaluate the disease free survival compared to historical controls, it appears that administration of erythropoietic agents as per standard guidelines do not affect the disease outcomes in gastro intestinal malignancies. References 1. Caro JJ, Salas M, Ward A et al. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 2001;91:2214 2221. 2. Littlewood TJ, Bajetta E, Nortier JW et al. 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 ClinOncol 2001;19:2865 2874. 3. Henke M, Laszig R, Rube C et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double- blind, placebo-controlled trial. Lancet 2003;362:1255 1260. 4. Leyland-Jones B. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 2003;4:459 460. 5. Anemia Treatment for Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Receiving Chemotherapy. Clinical trials.gov identifier NCT00858364 6. A Study of Epoetin Alfa Plus Standard Supportive Care Versus Standard Supportive Care Only in Anemic Patients With Metastatic Breast Cancer Receiving Standard Chemotherapy. Clinical trials.gov identifier NCT00338286 7. Data accessed via www.nccn.org/professionals/physician_gls/ default.asp 8. C. J. Devaraj, V. Satya Suresh Attili, UllasBatra, Kamal Singh Saini, et al VALIDITY OF AN INDIGENOUSLY DEVELOPED QUALITY OF LIFE (QOL) QUESTIONNAIRE IN CANCER PATIENTS OF SOUTH INDIA. Annals of Oncology 17 (Supplement 9): ix279 ix282, 2006 9. Common Terminology Criteria for Adverse Events v3.0 (CTCAE), Publish Date: August 9, 2006 accessed at http://www.eortc.be/ services/doc/ctc/ctcaev3.pdf 10. FRANCIS FARRELL,a ADRIAN LEEb, The Erythropoietin Receptor and Its Expression in Tumor Cells and Other Tissues. The Oncologist 2004;9(suppl 5):18-30 11. Henke M, Mattern D, Pepe M, et al: Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J ClinOncol 24:4708-4713, 2006 12. Biete Sola A, Calvo Manuel FA, ClavoVaras B, et al: Erythropoietin in cancer treatment: Considerations about Henke s article. ClinTranslOncol 7:332-335, 2005 Lancet 363:81-82, 2004 293