Radiol Oncol 2005; 39(2): 133-40. Managing anemia with epoetin alfa in patients with rectal cancer Vaneja Velenik , Irena Oblak , Veronika Kodre 1Department for Radiotherapy, Institute of Oncology, Ljubljana, Slovenia 2Janssen-Cilag Slovenia, Division of Johnson & Johnson d.o.o., Ljubljana, Slovenia Background. Anemia is one of the most challenging problems in clinical oncology due to its high prevalence among the patients with malignant diseases. The purposes of our study were: (1) to assess the potential of epoetin alfa therapy to prevent the decline in Hb concentrations that typically accompanies chemotherapy/radiotherapy (ChT/RT) of the patients with rectal cancer; (2) to test the hypothesis that the use of epoetin alfa significantly reduces the transfusion requirements in the patients with rectal cancer treated with ChT/RT after surgery, and (3) to evaluate the safety profile of the administration of epoetin alfa in the clinical setting. Methods. Sixty patients who underwent surgery for rectal cancer were prospectively enrolled. Group A consisted of 39 patients with Hb concentrations ^13 g/dl at the start of ChT/RT following surgery, and group B of 17 patients with Hb concentrations >13 g/dl at the start of ChT/RT following surgery, but whose Hb concentrations fell below 13 g/dl during the ChT/RT protocol. The starting dose of epoetin alfa in both groups was 10,000 IU subcutaneously (sc) three times a week (tiw). The following major parameters were evaluated: (1) change in Hb concentrations relative to the baseline as measured at 4-week intervals, (2) allogenic blood transfusion requirements in relation to Hb concentrations, and (3) incidence and severity of adverse events and their potential relationship to epoetin alfa administration. Results. The study protocol was completed in 56/60 patients. In group A, a statistically significant increase in Hb concentration (p<0.001) was observed after the first 4 weeks of epoetin alfa treatment compared to the baseline values, with the mean increase of Hb concentration of 1.97 g/dl ± 0.91 g/dl and Hb concentrations remained significantly increased through the whole study (p=0.0017). In group B, a continuous decrease in Hb concentrations was observed during the first weeks of therapy, reaching the level of statistical significance after 3 weeks of postoperative treatment. After the initiation of epoetin alfa treatment, an increase of Hb concentrations and their maintenance at ^12 g/dl was observed also in group B. Not a single patient enrolled in the study needed transfusion. None of described adverse events was connected to the epoetin alfa treatment. Conclusions. The results of the present study show that epoetin alfa is safe and effective in maintaining Hb concentrations during the adjuvant therapy in rectal cancer patients. It significantly increases Hb concentrations and reduces transfusion requirements in the patients receiving chemoradiotherapy after surgery for rectal cancer. Key words: rectal neoplasms - radiotherapy - drug therapy; anemia - drug therapy; epoetin alfa 134 Velenik V et al / Anemia and epoetin alfa in patients with rectal cancer Received 3 May 2005 Accepted 18 May 2005 Correspondence to: Vaneja Velenik, M. D., Department of Radiation Oncology, Institute of Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia; Phone: +386 1 232 3063; Fax: +386 1 431 41 80; E-mail: vvelenik@onko-i.si Introduction Anemia is one of the most challenging clinical problems in clinical oncology due to its high prevalence among the patients with malignant diseases. ,2 It is now recognized as an independent prognostic factor for patient’s survival and can also have a considerable negative effect on patient’s quality of life. ,1 Generally, clinical studies have shown that recombinant human erythropoietin (epoetin alfa) administered once weekly or three times a week improves hemoglobin (Hb) levels, decreases transfusion requirements, 1,4,7,1 improves quality of life, 7, and may also improve the survival in the patients with cancer-related anemia. 4,7,2 However, despite such efficient approach to the anemia management, a comprehensive survey indicated that only 36% of patients with solid tumors who were anemic received treatment for their anemia. Moreover, treatment of anemia was initiated at lower Hb levels than recommended (mean Hb level of 9.6 g/dl for solid tumors). Accordingly, it is mandatory to assess the feasibility and safety of the administration of epoetin alfa in each individual type of cancer. The purposes of our study were: (1) to assess the potential of epoetin alfa therapy to prevent the decline in Hb value that typically accompanies chemotherapy/radiotherapy (ChT/RT) of the patients with rectal cancer; (2) to test the hypothesis that the use of epoetin alfa significantly reduces the transfusion requirements in the patients with rectal cancer treated with ChT/RT after surgery, and (3) to evaluate the safety profile of administration of epoetin alfa in the clinical setting. Methods Sixty patients who underwent rectal cancer surgery were prospectively enrolled in the study between March 2002 and December 2003 (Table 1). The following inclusion criteria were used: - histologic confirmation of adenocarcinoma of the rectum (pathohistological stage II and III) that were amenable to postoperative ChT/RT; - age above 18 years; - WHO performance status 0-2; - Hb level <13 g/dl; - serum transferrin saturation (TSAT) >20%. Exclusion criteria were: uncontrolled or severe cardiovascular disease, including recent (<6 months) myocardial infarction; uncontrolled hypertension (diastolic blood pressure >95 mm Hg); congestive heart failure; uncontrolled or unexplained seizures; major illness Table 1. The study population Group N Description Mean age/Range (years) Gender (male/female) A 39 Hb level ^ 13 g/dl at the start of the Cht/RT treatment following surgery; enrolled at the start of the Cht/RT 64.8±14 19 M/20 F B 17 Hb level >13 g/dl at the start of Cht/RT treatment following surgery; enrolled during the Cht/RT 68.5±9.5 11M/6F All 56 Patients with Hb^13 g/dl treated for rectal cancer with Cht/RT after surgery 66.6±11.7 30 M/26 F ChT/RT - chemo-radiotherapy; N - number of patients Radiol Oncol 2005; 39(2): 133-40. Velenik V et al / Anemia and epoetin alfa in patients with rectal cancer 135 or infection within the preceding month, history of thrombotic or other vascular events during the preceding 6 months; known hypersensitivity to epoetin alfa or one of its components; pregnancy, lactation, or inadequate method of contraception in females with childbearing potential. Surgical procedures were as follows: abdominoperineal resection (APR; 23 patients), low anterior resection (LAR; 28 patients), anterior resection (RRA; 6 patients), Hartman’s palliative resection (2 patients) and coloanal anastomosis (CA; 1 patient). After surgery, all patients were treated on adjuvant setting at the Institute of Oncology in Ljubljana, Slovenia, following the protocol outlined below and approved by the Protocol Review Board and Committee for Medical Ethics at the Institute of Oncology. All patients were informed about the study protocol. At the enrolment, baseline data (history, physical and laboratory tests) were collected in all patients, including complete blood cell count, reticulocyte count, levels of serum iron, folate and vitamin B12, transferin saturation (TSAT) and ferritin. On the basis of Hb concentration, the patients were divided into two groups. Group A consisted of 39 patients with Hb level L13 g/dl at the start of the ChT/RT, and group B of 17 patients with Hb level >13 g/dl at the start of the ChT/RT following surgery, but whose Hb fell below 13 g/dl during the ChT/RT. Chemo-radiotherapy protocol The patients were treated following the combined ChT/RT protocol as shown in Figure 1. During 25 weeks, the patients received 6 cycles of chemotherapy with 5-fluorouracil (5-FU), 425 mg/m /day intravenously (iv), and Ca-folinat, 50 mg/day iv both during the days 1-5. Because of concomitant irradiation during the 4th cycle of ChT, the doses of 5-FU and Ca-folinat were reduced to 75% level for this cycle only. The cycles were repeated every 28 days. The patients were irradiated with 10-15 MV linear accelerator photon beams to a tumor dose of 50.4 Gy and daily fractions of 1.8 Gy, applied five-times/week. Epoetin alfa administration protocol In group A, the treatment with epoetin alfa started on day 1 of ChT/RT, whereas in group B, epoetin alfa was administered during the course of ChT/RT when a patient’s Hb concentration decreased below 13 g/dl. The starting dose of epoetin alfa was 10,000 IU subcutaneously (sc) three times a week (tiw). Hb concentration was monitored regularly at monthly intervals during chemotherapy and weekly during ChT/RT. If the Hb concentration increased by less than 1 g/dl from the baseline after 4 weeks of initiating epoetin alfa, the dose of the drug was increased to 20,000 IU sc tiw. In case of the increase of Hb concentration by more than 2 g/dl per month, the dose of epoetin alfa was reduced to 10.000 IU biw. surgery Week 1-4 Week 5-8 Week 9-12 Week 12-16 Week 17-20 Week 21-25 ChT cycle 1 ChT cycle 2 ChT cycle 3 ChT cycle 4 +RT ChT cycle 5 ChT cycle 6 Group A: epoetin alfa from week 1 Group A: epoetin alfa if Hb<13 g/dl Inclusion / Exclusion criteria ChT cycle: Chemotherapy cycle; RT: Radiotherapy Figure 1. Protocol of the study Radiol Oncol 2005; 39(2): 133-40. 136 Velenik V et al / Anemia and epoetin alfa in patients with rectal cancer The administration of epoetin alfa was interrupted when Hb concentration increased above 14 g/dl and was initiated again when it fell below 12 g/dl at a dose of 10.000 IU twice a week (biw). The application of epoetin alfa was abolished if the treatment with epoetin alfa was not effective (no expected rise in Hb level after dose escalation) or in cases of developing a severe adverse reaction related to epoetin alfa. All patients included in the study would be transfused if Hb concentration was <10 g/dl. Iron treatment, transfusion requirements and concomitant therapy The patient’s iron status, including transferrin saturation-TSAT (serum iron/iron binding capacity x 100; %) and serum ferritin (µg/L) was evaluated on weekly basis during ChT/RT, and on monthly basis during ChT. To avoid iron depletion of available stores and to support adequately erythropoiesis, stimulated by epoetin alfa, the patients with TSAT <20% and/or serum ferritin <100 µg/L required supplemental iron (300 mg elemental iron orally per day). Follow up In the postoperative phase, the patients were followed on weekly basis for a total of 25 weeks. Safety evaluations were carried out by clinical laboratory tests and by assessing the incidence and severity of treatment-related side effects. Statistical analysis The following parameters were evaluated: (1) change in Hb concentration relative to the baseline as measured at 4-week intervals, (2) blood transfusion requirements in relation to Hb level, and (3) incidence and severity of adverse events and their potential relationship Radiol Oncol 2005; 39(2): 133-40. to epoetin alfa administration. Hb concentration was presented as mean ± standard deviation (SD). Statistical analysis was performed using the two-sided paired t-test. A probability value of <0.05 was considered statistically significant. Results The study protocol was completed in fifty-six of sixty patients (56/60; 93.3%). The remaining four patients (4/60; 6.7%) included in the study were not included in statistical evaluations due to insufficient data. Forty-five of fifty-six patients (45/56; 80.3%) completed all six cycles of chemotherapy and radiation therapy as specified in the protocol. Eleven patients (11/56; 19.7%) received less than six cycles of ChT (5 cycles- 3 patients; 4 cycles- 5 patients; 2 cycles- 3 patients) due to the appearance of adverse events (ileus, dehydration, nausea, leucopoenia, febrile neutropoe-nia, infection, cardial decompensation, radio-proctitis, mucositis). Haan Hb valuaa tar patients In lbs Oraupa A and B 15,0 T----------------------------------------------------------------------------------------------- 10,0------------------------------------------------------------------------------------------------- 5,0------------------------------------------------------------------------------------------------- X 0,0-1-------------------1-------------------1-------------------1-------------------1-------------------1 0 4 8 12 16 20 weeks ^—Average Group A Average Group B Figure 2. Mean hemoglobin (Hb) concentrations in the patients treated with epoetin alfa in groups A and B. In group A, Hb levels were statistically increased from the enrolment in the study onwards. In group B, an initial decrease in Hb concentrations (weeks 0 through 3) was observed. After the initiation of the treatment with epoetin alfa, mean Hb concentrations in group B also reached the level of 12 g/dl till the end of the treatment. Velenik V et al / Anemia and epoetin alfa in patients with rectal cancer 137 Hematological response In group A, a statistically significant increase in Hb concentration (p<0.001) was observed after the first 4 weeks of epoetin alfa treatment compared to the baseline values, with the mean increase of Hb concentration of 1.97 g/dl ± 0.91 g/dl. As shown in Figure 2, Hb concentrations remained significantly increased from the initial values through the rest of the treatment (p=0.0017). In group B, a continuous decrease in Hb concentrations was observed during the first weeks of the therapy, reaching the level of statistical significance after 3 weeks of postoperative treatment, (p=0.006). After the initiation of epoetin alfa treatment, an increase of Hb concentrations (on average 0.7 g/dl ± 0.4 g/dl/4 weeks) and their maintenance at ^12 g/dl were observed (Figure 2). Figure 3 illustrates the frequency of Hb readings <13 g/dl in the patients from group A compared with those from group B during RT part of the protocol. In group A, a progressively smaller share of patients with Hb values <13 g/dl was registered during RT. None of the patients had Hb concentrations <13 g/dl at the Share of patients with Hb < 13 g/dl during radiotherapy (KT) ¦ Group A u Group B Figure 3. Prevalence of patients with hemoglobin (Hb) concentration <13 g/dl during the RT part of the protocol. In group A, a progressively smaller share of patients with Hb concentrations <13 g/dl during RT was observed and with none of the patients with Hb values 13 g/dl at the end of RT. In group B, the share of patients with Hb concentration <13 g/dl progressively increased during RT. 6 week of the irradiation. On the other hand, in group B, the share of patients with Hb concentrations <13 g/dl progressively increased during RT. In this subgroup, epoetin alfa was typically initiated during the 3rd week of RT. Transfusion requirements Not a single patient enrolled in the study needed transfusion. Safety and tolerability of epoetin alfa Nine adverse events that occurred in 6 patients who completed the study were recorded: ileus, dehydration, nausea, leucopoenia, febrile neutropoenia, infection, cardial decompensation, radioproctitis, and mucositis. None of the described adverse events was connected to the epoetin alfa treatment. Discussion In the present study, we tested the efficacy and feasibility of epoetin alfa administration in the patients receiving chemo-radiotherapy after surgery for rectal cancer. Our results demonstrate that, also in the patients with this type of cancer, epoetin alfa effectively increases and maintains Hb concentration during ChT/RT at the clinically requested level. None of the patients enrolled in our study required transfusion despite the aggressiveness of the treatment protocol. The results of our study corroborate the findings of randomized controlled trials with epoetin alfa in the treatment of anemia in other solid and hematological malignancies. These studies have consistently shown an increase in Hb concentrations, a decrease in transfusion requirements, and an improvement in patient’s energy level, their ability to maintain daily activities, and their overall quality of life. 1,4,7,13-19,21-24 Our results also confirmed an excellent safety profile of epoetin alfa. Although Radiol Oncol 2005; 39(2): 133-40. 138 Velenik V et al / Anemia and epoetin alfa in patients with rectal cancer thrombotic/vascular events and hypertension have been reported previously in the patients treated with epoetin alfa, no such events were observed in our population of patients. Recent studies on ovarian and lung cancer patients receiving cisplatin-based chemotherapy have demonstrated that higher Hb concentrations exerted a positive effect on patient’s tolerability of chemotherapy. The patients with low Hb-concentrations due to either the disease itself or myelotoxicity of chemotherapy had a lower capacity to compensate for treatment toxicity. In addition, our results indicate that the epoetin alfa treatment is particularly beneficial in combined treatment protocols. The major challenge remains how to identify the patients who would most likely develop anemia during the combined therapy and who are candidates for prophylactic epoetin alfa treatment. The benefits of epoetin alfa prophylaxis in the context of current clinical guidelines, which recommend starting with epoetin therapy at the Hb concentration range of 10-11 g/dl, 3,3 are yet to be defined. Anemia is a major cause of fatigue which is clinically manifested in 40-80% of patients with malignancies 5,20,3 and usually critically influences the quality of their lives. Indeed, fatigue is at least as common among the most reported bothersome symptoms in the patients with cancer as the pain is. 3,5,1 On the other hand, many authors have reported that the problem of cancer-related fatigue is frequently not assessed adequately because it is not mentioned by patients, assessed by physicians, or not addressed to as an integral part of the treatment evaluation protocols. Obviously, it is of critical importance to identify the fatigue in each individual patient and to offer him appropriate therapeutic option to alleviate it. Hypoxia in the tumor has been recognized as a key regulator of tumor growth. Sustained hypoxic environment in a growing tumor may trigger changes that can result in a more Radiol Oncol 2005; 39(2): 133-40. aggressive phenotype of tumor cells. Many studies have demonstrated a reduced probability of local control and worse survival results in the patients with hypoxic tumors, treated with ChT and/or RT. In case of RT, the reduction in radiosensitivity of tumor cells should be seriously considered when the oxygen partial pressure in a tumor decreases below 25-30 mmHg. In general, a two- to threefold higher radiation dose is required to kill completely the hypoxic cells, compared with well-oxygenated cells, a difference referred to as the oxygen enhancement effect. The increase in Hb concentrations, which improves the oxygen-carrying capacity of blood, is also correlated with better response to chemotherapy. To conclude, the results of the present study show that epoetin alfa is safe and effective in maintaining Hb concentrations during the adjuvant therapy of rectal cancer patients. It significantly increases Hb concentrations and reduces transfusion requirements in the patients receiving chemoradio-therapy after surgery for rectal cancer. Acknowledgements The authors wish to thank Aleš Ambrožič, PhD, Darja Ambrozič, MD, Rok Hren, PhD, Sanja Bizilj, MPhar, and Katarina Verhnjak, MSc Pharm for their assistance they offered during the preparation of this work. References 1. Groopman JE, Itri M. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999; 91: 1616-34. 2. Ludwig H, Fritz E. Anemia in cancer patients. Semin Oncol 1998; 25(Suppl 7): 2-6. 3. Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage non-small cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991; 9: 1618-26. Velenik V et al / Anemia and epoetin alfa in patients with rectal cancer 139 4. Blohmer JU, Wurschmidt F, Petry U, Weise G, Sehouli J, Kimming R, et al. Results with sequential adjuvant chemo-radiotherapy with vs. without epoetin alfa for patients with high-risk cervical cancer: Results of a prospective, randomized, open and controlled AGO- and NOGGO-intergroup study. [Abstract]. Ann Oncol 2004; 15: 477PD. 5. Carro JJ, Salas M, Ward A, Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 2001; 91: 2214-21. 6. Graf W, Bergstrom R, Pahlman L, Glimelius B. Appraisal of a model for prediction of prognosis in advanced colorectal cancer. Eur J cancer 1994; 30: 453-57. 7. Litllewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapaport B. 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 2001; 19: 2865-74. 8. Van Belle SJP, Cocquyt V. Impact of haemoglobin levels on the outcome of cancers treated with chemotherapy. Crit Rev Oncol Heamatol 2003; 47: 1-11. 9. Motzer RJ, Bacik J, Schwartz LH. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004; 22: 454-63. 10. Obermair A, Handisurya A, Kaider A, Sevelda P, KUlble H, Gitsch G. The relationship of pretreat-ment serum hemoglobin level to the survival of epithelial ovarian carcinoma patient. Cancer 1998; 83: 726-31. 11. Ramalingam S, Belani CP. Meaningful survival in lung cancer patients. Semin Oncol 2002; 29: 125-31. 12. Pangalis GA, Siankantaris MP, Angelopoulou MK, Vassilakopoulos TP, Dimopoulou MN, Kontopidou FN, et al. Downstaging Rai stage III B-chronic lymphocytic leukemia patients with the administration of recombinant human erythropoietin. Haematologica 2002; 87: 500-6. 13. Cella D. Factors influencing quality of life in cancer patients: anemia and fatigue. Semin Oncol 1998; 25(3 Suppl 7): 43-6. 14. Crawford J. Anemia and lung cancer. Lung Cancer 2002, 38: S75-8. 15. Curt GA, Breitbart W, Cella D, Groopman JE, Horning SJ, Itri LM, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue coalition. Oncologist 2000; 5: 353-60. 16. Del Mastro L, Venturini M. Strategies for the use of epoetin alfa in breast cancer patients. Oncologist 1998; 3: 314-8. 17. Demetri GD, Kris M, Wade J, Degos L, Cella D. Quality of life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. J Clin Oncol 1998; 16: 3412-25. 18. Aapro M, Bajetta E, Freund M, Lttlewood TJ, Nortier JWR, Rapoport B. Is there a possible survival benefit to increasing hemoglobin levels with epoetin alfa during chemotherapy? EJC Supplements 2004; 2: 20-8. 19. Abels R. Erythropoietin for anemia in cancer patients. Eur J Cancer 1993; 29A(Suppl 2): S2-8. 20. Bentzen SM, Johansen LV, Overgaard J, Thames HD. Clinical radiobiology of squamous cell carcinoma of the oropharynx. Int J Radiat Oncol Biol Phys 1991; 20: 1197-206. 21. Gabrilove JL, Cleeland CS, Livingston RB, Sarokhan B, Winer E, Einhorn LH. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001; 19: 2875-82. 22. Glaspy J, Bukowski R, Steinberg D, Taylor C, Tchekmedian S, Vadhan-Raj S. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 1997; 15: 1218-34. 23. Shasha D, George MJ, Harrison LB. Once weekly dosing of epoetin ? increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy. Cancer 2003; 98: 1072-9. 24. Thatcher N, De Campos ES, Bell DR, Steward WP, Varghese G, Morant R, et al. Epoetin alfa prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br J Cancer 1999; 80: 396-402. 25. Bohlius JF, Langesiepen S, Schwarzer G, Bennett CL, Engert A. Does erythropoietin improve overall survival in the treatment of patients with malignant diseases? Results of comprehensive metaanalysis. [Abstract]. Blood 2003; : 709. Radiol Oncol 2005; 39(2): 133-40. 140 Velenik V et al / Anemia and epoetin alfa in patients with rectal cancer 26. Glaser CM, Millesi W, Kornek GV, Lang S, SchŁll B, Watzinger F, et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of the preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001; 50: 705-15. 27. Johnson & Johnson. Background information for Oncology Drugs Advisory committee meeting. 4 May 2004. Gaithesburg, MD. Safety of erythropoietin receptor agonists (ERAs) in patients with cancer. At: http//:www.fda.gov/ohrms/dockets/ac/ 04/briefing/4037B2_02_JohnsonJohnson-Procrit.PDF. Accessed 23.09.2004. 28. Ludwig H, Birgegard G, Barret-Lee P, Birgegard G, Bokemayer C, Gascon P, et al. The European Cancer Anaemia Survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 2004; 40: 2293-306. 29. ICH harmonised tripatite guideline for good clinical practice. Article 16. Brookwood Medical Publications LTD; 1996. p. 87. 30. Fazekas JT, Scott C, Marcial V, Davis LW, Wasserman T, Cooper JS. The role of hemoglobin concentration in the outcome of misonidazole-sensitized radiotherapy of head and neck cancers: based on RTOG trial # 79-15. Int J Radiat Oncol Biol Phys 1989, 17: 1177- 81. 31. Tarnawski R, Skladowski K, Maciejewski B. Prognostic value of hemoglobin concentration in radiotherapy for cancer of supraglottic larynx. Int J Radiat Oncol Biol Phys 1997; 38: 1007-11. 32. Van Acht MJ, Hermans J, Boks DE, Leer JW. The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal carcinoma. Radiother Oncol 1992; 23: 229-35. 33. National Comprehensive Cancer Network (NC-CN). Clinical practice guidelines in oncology. Cancer-related fatigue. Version 1.2003. Available at http://www.nccn.org/physician_gls/fguidelines.html. 34. Rizzo JD, Lichitin AE, Woolf SH, Seidenfeld J, Bennet CL, Cella D, et al. 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 2002; 19: 4083-107. 35. Blitzer PH, Wang CC, Suit HD. Blood pressure and hemoglobin concentration: multivariate analysis of local control after irradiation for head and neck cancer. [Abstract]. Int J Radiat Oncol Biol Phys 1984; 10(Suppl 2): 98. 36. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997; 38: 285-9. 37. Nordsmark M, Overgaard J. A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy. Radiother Oncol 2000; 57: 39-43. 38. Turner R, Anglin P, Burkes R, Couture F, Evans W, Goss G, et al for Canadian Cancer and Anemia Guidelines Development Group. Epoetin alfa in cancer patients: evidence-based guidelines. J Pain Symptom Manage 2001; 22: 954-65. 39. Freedman LS, Honess DJ, Bleehen NM, Adams GE, Dische S, Henk JM. Does initial hemoglobin level modify the efficacy of radiosensitizers? An analysis of the MRC misonidazole studies in head and neck cancer and cervix cancer. Int J Radiat Biol Relat Stud Phys Chem Med 1987; 52: 965-7. 40. Horsman MR, Overgaard J. The oxygen effect. In: Steel GG, editor. Basic clinical radiobiology. London: Edward Arnold Publ; 1993. p. 81-8. 41. Kumar P. Tumor hypoxia and anemia: Impact on the efficacy of radiation therapy. Semin Hematol 2000; 4: 4-8. 42. Fyles AW, Milosevic M, Wong R, Kavanagh MC, Pintilie M, Sun A, et al. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol 1998; 48: 149-56. 43. Denekamp J, Waitea A. The potential for improving radiotherapy outcome by improving the oxygen supply to solid tumors. Strahlenther Onkol 1996; 172(Suppl.2): 22-3. 44. Vigario G, Kurohara SS, George FW. Association of hemoglobin levels before and during radiotherapy with prognosis in uterine cervix cancer. Radiobiology 1973; 106: 649-52. Radiol Oncol 2005; 39(2): 133-40.