Anemia is a common occurrence in cancer patients, resulting from

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1 1072 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 Daniel Shasha, M.D. 1 Martine J. George, M.D. 2 Louis B. Harrison, M.D. 1 1 Department of Radiation Oncology, Beth Israel Medical Center, New York, New York. 2 Clinical Affairs, Ortho Biotech Products, L.P., Bridgewater, New Jersey. Supported by a grant from Ortho Biotech Products, L.P. Address for reprints: Daniel Shasha, M.D., The Charles & Bernice Blitman Department of Radiation Oncology, Beth Israel Medical Center, 10 Union Square East, New York, NY 10003; Fax: (212) ; dshasha@bethisraelny.org Dr. Shasha and Dr. Harrison are members of the Speaker s Bureau for Ortho Biotech, Inc. Dr. George was an employee of Ortho Biotech, Inc. Received March 10, 2003; revision received May 30, 2003; accepted June 3, BACKGROUND. The current study was performed to prospectively evaluate the effectiveness, clinical outcomes, and safety of once-weekly (QW) recombinant human erythropoietin (r-huepo [epoetin- ]) in anemic cancer patients with nonmyeloid malignancies who were receiving radiation therapy (RT) concomitantly or sequentially with chemotherapy (CT). METHODS. A total of 777 anemic patients (hemoglobin [Hb] 11 g/dl) were enrolled in this multicenter, open-label, nonrandomized, 16-week study. Patients initially received epoetin- at a dose of 40,000 units (U) subcutaneously QW, escalating to a dose of 60,000 U QW if the Hb increased to 1 g/dl after 4 weeks. Endpoints were changes in hematologic and quality of life (QOL) parameters. RESULTS. Among the 442 patients evaluable for hematologic response, the mean increase in Hb from baseline to the time of final evaluation was g/dl (P 0.05). An increase in Hb of 2 g/dl, in the absence of blood transfusions, occurred in 68.3% of patients (278 of 407 patients) who were on the study for 30 days. The overall response rate (Hb increase 2 g/dl or Hb 12 g/dl in the absence of blood transfusions) was 74.0% (301 of 407 patients). In 359 patients who were evaluable for QOL assessment, epoetin- therapy was found to significantly (P 0.05) improve mean Linear Analog Scale Assessment (LASA) scores for energy level, ability to perform daily activities, and overall QOL from baseline to the time of final evaluation. QW epoetin- therapy was found to be well tolerated. CONCLUSIONS. Treatment with QW epoetin- was found to increase Hb levels, decrease transfusion requirements, and improve functional status and QOL in anemic patients with nonmyeloid malignancies who were receiving RT concomitantly or sequentially with CT. Clinical benefits and the safety profile of QW epoetin- in this setting appear to be similar to those observed in anemic cancer patients receiving CT. Cancer 2003;98: American Cancer Society. KEYWORDS: radiation oncology, quality of life (QOL), anemia, neoplasm, epoetin-, hemoglobin (Hb). Anemia is a common occurrence in cancer patients, resulting from the disease itself or from chemotherapy (CT) and/or radiation therapy (RT). The incidence and severity of CT-induced anemia vary relative to the chemotherapeutic agent(s) used, the schedule and intensity of treatment, and whether the patient has received prior myelosuppressive CT and/or RT. 1 3 Patients receiving platinum-containing CT typically require more transfusions to correct anemia compared with patients receiving nonplatinum CT. 4 Many patients presenting for RT already are anemic; during a course of RT, the 2003 American Cancer Society DOI /cncr.11616

2 Epoetin- for Chemoradiation Patients/Shasha et al incidence of anemia may increase to as high as 80% depending on the tumor type. 5 Anemia often is accompanied by fatigue, with the severity of fatigue appearing to be correlated with the severity of anemia. 6 Fatigue is experienced by most cancer patients and is associated with significant functional and psychosocial impairment As a result, fatigue and impaired quality of life (QOL) may interfere with therapy, leading to a reduction or delay in CT or RT dosing, or even withdrawal from treatment, because of patient distress. In addition to fatigue and QOL effects, low hemoglobin (Hb) levels are associated with a reduction in tumor oxygen levels that, in turn, may lead to a decreased rate of local tumor control and decreased survival after RT To our knowledge the relation between tumor hypoxia and anemia is not fully understood, but hypoxic cells are two to three times more resistant to RT than those with normal oxygenation, and surviving cells can reestablish tumors in situ. 18 As a result, low Hb levels are associated with resistance to RT, decreased drug cytotoxicity, and increased rates of local recurrence. 18 Support for the relation between low Hb levels and low locoregional control has been provided by several studies across a variety of tumor types, including cervical carcinoma, head and neck carcinoma, 22,23 and other solid tumors. 15,16,24,25 Hence, correcting anemia may increase tumor oxygenation and enhance tumor radiosensitivity and locoregional tumor control, as well as improve QOL. Because low Hb levels are associated with poor tumor control, severely anemic (Hb 10 g/dl) cancer patients may receive red blood cell (RBC) transfusions prior to RT. RBC transfusions have an immediate effect on Hb levels, but the limitations of this approach include a short half-life for transfused RBCs, blood bank restrictions, increased risk of infections and fever (and associated costs), and possibly immunosuppression. 26 Otherwise, the treatment of anemia is not routine in most patients undergoing curative-intent RT. Several studies of cancer patients with anemia at the initiation of RT indicate that the use of recombinant human erythropoietin (r-huepo [epoetin- ]), which is biologically and immunologically indistinguishable from endogenous erythropoietin, increases Hb levels and decreases transfusion requirements during RT Several large community-based studies have demonstrated that epoetin- effectively corrects anemia and improves QOL in anemic patients with nonmyeloid malignancies who are receiving CT, 31,32 including a recent study using once-weekly (QW) epoetin- dosing that produced improvements in Hb levels and QOL similar to those noted with a dosing schedule of three times weekly, which should lead to added patient and physician convenience. 33 The objective of the current study was to prospectively evaluate the effectiveness, safety, and clinical outcomes of QW epoetin- therapy in the treatment of anemia in cancer patients with nonmyeloid malignancies who are receiving RT either concurrently or sequentially with CT. MATERIALS AND METHODS Patients The current study enrolled patients from communitybased practices or academic institutions in the U.S. Patients eligible for the study were adult (age 18 years) cancer patients with anemia (Hb 11 g/dl) and with histologically confirmed nonmyeloid malignancies who were receiving RT either concomitantly or sequentially with CT and who had a life expectancy of 6 months. Patients were required to have received at least 4000 centigrays (cgy) of radiation within 8 weeks prior to baseline and/or were scheduled to receive a total RT dose of at least 4000 cgy and/or a course of RT lasting 4 weeks during the 16-week study. Patients also had to be willing and able to complete a QOL questionnaire (the 100-mm Linear Analog Scale Assessment [LASA]). Informed consent was obtained from all eligible patients. Patients were excluded if they had brain metastases, uncontrolled hypertension, known hypersensitivity to mammalian cell-derived products or human albumin, or anemia (due to iron, B 12, or folate deficiencies; hemolysis; or gastrointestinal bleeding). Candidates for bone marrow or stem cell transplantation, patients receiving peripheral blood progenitor cell therapy, and patients who had received epoetin- therapy within 6 months of study enrollment also were excluded. Study Design The current study was a prospective, multicenter, open-label, single-arm, nonrandomized, 16-week study. The protocol and informed consent form were approved by the Western Institutional Review Board (a centralized institutional review board located in Olympia, WA) or by the local Institutional Review Board. Baseline assessments (obtained within the 10- day period immediately preceding the first dose of epoetin- ) included patient demographics, weight, blood pressure, Hb and hematocrit (Hct) levels, transfusion history (within the prior 6 months), current and previous RT and CT therapy, Eastern Cooperative Oncology Group (ECOG) performance status, tumor type/histology, and identification of the primary site of malignancy.

3 1074 CANCER September 1, 2003 / Volume 98 / Number 5 Treatment Regimen Patients initially received 40,000 units (U) of epoetin- (PROCRIT, Ortho Biotech Products, L.P., Bridgewater, NJ) subcutaneously (SC) QW. If the Hb increased 1 g/dl after 4 weeks of therapy, the epoetin- dose was increased to 60,000 U SC QW. This dose escalation occurred at Week 5, starting with the fifth weekly dose. If the Hb was 13 g/dl at any time during the study, epoetin- was discontinued until a Hb level of 12 g/dl was reached; treatment then was resumed at 75% of the original dose and was titrated accordingly. If Hb increased by 1.3 g/dl during any 2-week period, the epoetin- dose was decreased. Patients received QW epoetin- dosing for up to 16 weeks. Functional and/or actual iron deficiency is a potentially limiting factor for normal erythropoiesis. Consequently, the iron status of enrolled patients, including transferrin saturation (serum iron iron binding capacity) and serum ferritin, were evaluated throughout the study as clinically indicated. Deficient patients were to receive supplemental iron as needed to support erythropoiesis stimulated by epoetin-. The formulation of iron supplements depended on the preference of the patient and physician. Efficacy and Safety Assessments The primary efficacy endpoints were the hematologic parameters of Hb, Hct, number of transfusions, and number of units transfused. Hematologic response to QW epoetin- therapy was defined as an increase in Hb of 2 g/dl or the achievement of a Hb level of 12 g/dl at any point during the study, in the absence of a transfusion within the previous 30 days. Secondary efficacy endpoints were QOL parameters using self-reported LASA scores for energy level (Energy), ability to perform daily activities (Activity), and overall well-being (Overall QOL). During the study, Hb and Hct levels (completed before the start of each cycle of CT and RT) were measured at Weeks 2, 4, 8, 12, and 16. Blood pressure was monitored at Weeks 4, 8, 12, and 16. Transfusion requirements and the duration and total dose of RT and CT administered were assessed at Week 4 and every 4 weeks thereafter. Patient-reported functional capacity and QOL were measured by LASA at baseline, Week 8, and Week 16 (or on early discontinuation). LASA evaluations were completed before any studyrelated assessments were performed. On completion of the study at Week 16, or if a patient withdrew from treatment prematurely, the ECOG performance status also was recorded. If RT or CT was discontinued during the study, a patient could remain on study and continue to receive epoetin-. At the time of discontinuation of RT or CT, a final Hb, Hct, and LASA evaluation was performed. Patients could be withdrawn from the study for any of the following reasons: development of severe adverse reaction to epoetin-, development of significant intercurrent illness, disease progression, or patient or physician request. Laboratory values and vital signs were assessed every 4 weeks. Adverse events were recorded throughout the study, and were summarized by severity, body part, and possible relationship to epoetin-. Adverse events were rated as not related, possibly related, probably related, or definitely related to epoetin- therapy. Statistical Analysis Descriptive statistics (i.e., mean, standard deviation [SD], median, range, and interquartiles) were used to summarize continuous variables, including baseline characteristics of the study population. Categoric variables were presented as frequency statistics (i.e., frequencies, percentages, and cumulative percentages). Parametric (i.e., Student t test) and nonparametric (i.e., Wilcoxon signed rank test) statistics were used to test for differences from baseline. Repeated measures analysis was used to determine changes in the Hb, Hct, transfusion rate, and QOL. All data were analyzed using SAS software (SAS Institute Inc., Cary, NC) or an equivalent software package. RESULTS Demographics A total of 777 patients were enrolled onto the study; 442 patients were evaluable for hematologic response (i.e., had at least 2 Hb assessments) and 359 patients were evaluable for QOL assessments (i.e., had at least 2 QOL assessments). The remaining patients were not evaluable for hematologic or QOL response for the following reasons: did not meet eligibility criteria (n 26), removed because of unclear RT data (n 5), did not meet the RT dose requirement (n 121), did not meet the RT dose requirement and received RT for 4 weeks (n 161), and did not receive CT (n 22). An additional 82 patients were not evaluable for QOL response because they had fewer than 2 QOL assessments. A total of 151 patients withdrew before the completion of the study (Table 1). Baseline demographics and characteristics of the 442 evaluable patients are presented in Table 2. At baseline, the mean Hb of the evaluable patients was g/dl; 10.2% of the patients were transfused in the 6 months prior to the initiation of epoetin- therapy. The distribution of tumor types at baseline among evaluable patients is presented in Table 3. The

4 Epoetin- for Chemoradiation Patients/Shasha et al TABLE 1 Reported Reasons for Early Patient Withdrawal from Study (n 151) TABLE 3 Distribution of Evaluable Patients by Tumor Type (n 442) Reason No. of patients % of withdrawals Tumor type No. (%) a Disease progression Physician decision Patient noncompliance Death Patient request 10 7 Adverse event 10 7 Lost to follow-up 7 5 Intercurrent illness 3 2 Inadequate hemoglobin response 2 1 TABLE 2 Patient Baseline Demographics and Clinical Characteristics of Evaluable Patients (n 442) Characteristic Value Gender, % Male 42.8 Female 57.2 Mean age (yrs) 61.7 Mean Hb, g/dl 9.9 Mean Hct, % 29.8 LASA, mm a Activity level 41.9 Energy level 41.4 Overall QOL level 47.2 ECOG performance status (n 441) 0 (25%) 1 (49%) 2 (20%) 3 (6%) 4( 1%) Transfusion rate (%) 10.2% Hb: hemoglobin; Hct: hematocrit; LASA: Linear Analog Scale Assessment; QOL: quality of life; ECOG: Eastern Cooperative Oncology Group. a Expressed on a 100-mm scale, with 0 representing the lowest self-perception of each parameter and 100 representing the highest perception. majority of patients (97.6%) had nonhematologic malignancies; the lungs were the most common disease site (41.6% of patients). Chemotherapy and Radiation Therapy Evaluable patients received a variety of chemotherapeutic agents concurrently with epoetin- therapy, with the most common being carboplatin and paclitaxel (Table 4). RT doses received by evaluable patients are shown in Table 5. The mean RT dose received overall (prior to and during epoetin- therapy) was 5502 cgy. Patients with head and neck carcinoma received the highest mean RT dose (6447 cgy), whereas patients with hematologic malignancies received the lowest mean RT dose (4478 cgy). Nonhematologic tumors Lung 184 (41.6) Gastrointestinal 93 (21.0) Breast 66 (14.9) Head and neck 35 (7.9) Gynecologic 30 (6.8) Genitourinary 14 (3.2) Sarcoma 5 (1.1) Brain 3 (0.7) Adrenal gland 1 (0.2) Adenocarcinoma 1 (0.2) Hematologic tumors Non-Hodgkin lymphoma 4 (0.9) Multiple myeloma 3 (0.7) Hodgkin disease 1 (0.2) Unknown 3 (0.7) a One patient had two tumors: lung and gastrointestinal. TABLE 4 Top 10 Chemotherapeutic Agents Administered Concurrently With Epoetin- Therapy Agent Carboplatin 160 Paclitaxel Fuorouracil 122 Cisplatin 107 Etoposide 67 Doxorubicin 43 Cyclophosphamide 41 Leucovorin 39 Gemcitabine 19 Vinorelbine 19 No. of patients Hematologic Response A total of 442 patients were evaluable for hematologic response. There was a significant increase in the mean Hb level from baseline to the time of final evaluation ( g/dl [P 0.05] for final vs. baseline Hb level) (Table 6). The mean final Hb level of evaluable patients was g/dl. Similarly, there was a significant increase in the Hct level from baseline to the time of final evaluation (from 29.8% to 36.0%; P 0.05). Significant increases in Hb from baseline to the time of final evaluation were observed regardless of tumor response determined at the time of final evaluation (P 0.05). Secondary analyses of mean Hb and mean change in Hb also were performed to take into account the effect of transfusions on Hb. In one method, Hb measurements that were preceded by transfusion in the past 28 days were considered missing and were ex-

5 1076 CANCER September 1, 2003 / Volume 98 / Number 5 TABLE 5 Radiotherapy Dosage (cgy) Received in Patients Receiving Chemotherapy, Radiotherapy, and Epoetin- No. Mean Minimum Median Maximum All patients Lung Breast Gynecologic Gastrointestinal Genitourinary Head and neck Hematologic cgy: centigrays. TABLE 6 Hematologic Responses and Transfusion Rates in Anemic Patients Receiving RT Either Concomitantly or Sequentially with CT Who were Treated with QW Epoetin- Interval Mean Hb, g/dl (n) Mean Hct, %(n) % patients transfused (n) a Mean no. of units transfused per patient transfused Baseline 9.9 (442) 29.8 (441) 10.2 (442) 2.20 Week (434) b 31.7 (433) b 7.2 (442) b 2.22 Month (427) b 33.2 (425) b 12.8 (437) 2.43 Month (404) b 35.4 (402) b 9.3 (410) 2.26 Month (353) b 36.4 (353) b 4.7 (360) b 2.77 Month (306) b 36.8 (306) b 4.9 (306) b 2.72 RT: radiation therapy; CT: chemotherapy; QW: once-weekly; Hb: hemoglobin; Hct: hematocrit. a The baseline transfusion rate was the rate of recorded transfusions in the 6 months prior to the study. b Statistically significantly different from baseline, P cluded from the analysis. In the second method, a last-value-carried-forward approach was used, in which missing Hb values were replaced with pretransfusion Hb values. In both analyses, mean Hb change values at weeks 4, 8, 12, and 16 were consistent with the values calculated in the original analysis, varying at most by 0.1 g/dl at any time point. Among the patients who were on study for 30 days and who did not receive a transfusion during that time, 68.3% (278 of 407 patients) had a Hb increase 2 g/dl over baseline and 5.7% (23 of 407 patients) achieved a Hb level 12 g/dl without a 2-g/dL change. The response rate to epoetin- at a dose of 40,000 U QW was 52.8% (215 of 407 patients); the overall response rate increased to 74.0% (301 of 407 patients) when patients who required dose escalation had their epoetin- dosage increased to 60,000 U QW. In total, 154 patients (34.8%) required an increase in the epoetin- dose (from 40,000 U QW to 60,000 U QW) during the study. Transfusion Use The percentage of evaluable patients requiring transfusions decreased significantly from baseline to Month 4 (10.2% to 4.9%; P 0.05) (Table 6). A similar, significant reduction in the percentage of patients requiring transfusions also was observed in a recent community-based study of QW epoetin- in anemic patients with nonmyeloid malignancies who were receiving CT. 33 LASA The total number of patients who were evaluable for QOL responses was 360, but 1 patient had QOL assessments at Weeks 8 and 16 only and was not included in the analysis. For the remaining 359 patients, the mean baseline LASA scores ( standard deviation [SD]) for energy level ( mm), ability to perform daily activities ( mm), and overall QOL ( mm) were all 50 mm, suggesting patient-perceived functional impairment at baseline. Final LASA scores demonstrated statistically significant improvements from baseline (Table 7). Mean changes in LASA scores from baseline to the time of final evaluation ( SD) were mm for energy level, mm for ability to perform daily activities, and mm for overall QOL

6 Epoetin- for Chemoradiation Patients/Shasha et al TABLE 7 Mean Change (Baseline to Final Evaluation) in LASA Scores and Corresponding Effect Size (n 359) QOL parameter Mean change (mm) % improvement a Effect size b Overall QOL 14.2 c Energy 16.4 c Activity 16.5 c LASA: Linear Analog Scale Assessment; QOL: quality of life. a Percent improvement was calculated by dividing the mean change by the mean baseline value. b Effect size was calculated by dividing mean change by baseline standard deviation. c P 0.05 vs. baseline. FIGURE 2. Percentage change in Eastern Cooperative Oncology Group (ECOG) performance status score from baseline to the final value stratified by change in the hemoglobin (Hb) level. a: indicates a statistically significant change from baseline (P 0.05). b: indicates that 13 patients with a missing baseline Hb value, final Hb value, or ECOG score were excluded from the study. whom the Hb level increase was 2 g/dl demonstrated a slight mean improvement in status. FIGURE 1. Percentage change in Linear Analog Scale Assessment (LASA) scores stratified by changes in the hemoglobin (Hb) level from baseline. a: indicates a statistically significant change from baseline (P ), adjusted for multiple comparisons. b: indicates a statistically significant difference from the previous Hb change group (P ). QOL: quality of life (P 0.05). The percentage changes in the means for these parameters were 38.5%, 38.5%, and 29.4%, respectively, with observed effect sizes of 0.74, 0.66, and 0.56, respectively. Patients who experienced increases in their Hb level also experienced statistically significant QOL improvements (Fig. 1). The greatest improvement in QOL parameters occurred in patients with an Hb increase 2 g/dl and up to 4 g/dl. The difference was statistically significant from the improvements observed in patients with an Hb increase of 0 2 g/dl (P ). Similar improvements were observed in anemic cancer patients receiving CT who were treated with QW epoetin-. 33 The percentage change in ECOG performance status score by Hb change from baseline to the time of final evaluation is shown in Figure 2. Patients whose Hb level decreased or whose Hb level increased between 0 2 g/dl appeared to experience statistically significant decreases in the percentage change in ECOG performance status score (P 0.05), indicating a worsening of status, whereas patients in Safety Safety was evaluated in 772 patients who received 1 or more doses of epoetin-. QW epoetin- was reportedly well tolerated. Adverse events were similar to those commonly reported among cancer patients receiving comparable RT and CT regimens. Adverse events reported to occur in 10% of patients were granulocytopenia (13.9%), fatigue (13.6%), nausea (14.0%), and emesis (11.5%). Only 20 of the 1642 (1.2%) reported adverse events were classified as possibly (18 events) or probably (2 events) related to epoetin- treatment. Of the 151 patients who withdrew from the study before completion, 10 withdrew because of adverse events. The adverse events and rates generally were similar to those observed in anemic CT patients receiving QW epoetin-. 33 DISCUSSION QW epoetin- therapy (40,000 U SC for 4 weeks with an increase to 60,000 U as needed) was found to significantly increase Hb and Hct levels in patients receiving RT either sequentially or concurrently with CT and was well tolerated. Calculations of mean Hb and mean change in Hb from baseline remained consistent at all relevant time points, regardless of the method used to account for the effect of transfusions on Hb. The percentage of responders (patients who had an increase in Hb 2 g/dl or who achieved a Hb level 12 g/dl in the absence of blood transfusions) in this patient population was 74.0%. QW epoetin- was effective in increasing Hb levels regardless of the dose and type of RT or CT, or the tumor response.

7 1078 CANCER September 1, 2003 / Volume 98 / Number 5 Furthermore, the increase in Hb levels was associated with a significant decrease in the percentage of patients requiring transfusions during the study period, and with significant improvements in patient-reported scores for energy level, ability to perform daily activities, and overall QOL. QW epoetin- elicited QOL improvements in this patient group despite the doses of RT they were receiving with concomitant or sequential CT. Previous studies of epoetin- in anemic patients undergoing RT had suggested a trend toward improvements in QOL parameters, but had not demonstrated statistically significant improvements; however, the studies were small and limited in their ability to detect QOL changes. 28,29 Because of limitations in enrolling sufficiently large numbers of patients to our study in a timely manner, adequately powered regression analyses to adjust for potentially confounding variables on QOL assessments were not possible. The current study was similar in design to the recently reported large, community-based study of QW epoetin- in anemic cancer patients receiving CT. 33 In both studies, very similar changes were observed in hematologic endpoints: mean change in Hb level (1.9 g/dl vs. 1.8 g/dl, respectively), overall response rates (74% vs. 68%, respectively), and statistically significant decreases in transfusion use. In addition, in both studies, QOL parameters measured by LASA were significantly and consistently improved from baseline, with the improvements similar in magnitude. Effect sizes for the impact of QW epoetin- on these QOL parameters in the current study (range, ) were in the moderate-to-large range, slightly higher than those observed in the QW epoetin- study in anemic cancer patients receiving CT but similar to those observed in an early communitybased study in which a dose of epoetin- was given 3 times weekly to anemic cancer patients receiving CT. 32 Effect sizes in this range suggest clinically meaningful changes. Therefore, the improvements in hematopoietic response and QOL parameters appear to be generally consistent across anemic cancer patient populations with regard to both settings and epoetin- dosing schedules. Anemia can have a considerable negative effect on QOL and may be an impediment to locoregional tumor control and survival in patients receiving curative-intent RT. Based on the results of the current study, the use of QW epoetin- in patients undergoing chemoradiation appears to be efficacious in correcting anemia, decreasing transfusion requirements, and improving QOL, and is well tolerated. The hematologic response and improvements noted in QOL with the use of QW epoetin- were similar to those observed in studies of anemic cancer patients receiving CT alone who were treated with the same epoetin- dosing schedule. Many patients presenting for or undergoing RT develop mild-to-moderate anemia that is readily correctable, 5 and the use of epoetin- in patients undergoing chemoradiation may provide an opportunity to improve treatment outcomes and patient well-being. 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