Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study. Impact of nutrition on outcome: a prospective randomized controlled trial in patients with head and neck cancer undergoing radiotherapy. Clinical and in vitro effects of recombinant human erythropoietin in patients receiving intensive chemotherapy for small-cell lung cancer. Erythropoietin for patients undergoing radiotherapy: a pilot study. Weekly administration of epoetin beta for chemotherapy-induced anemia in cancer patients: results of a multicenter, Phase III, randomized, double-blind, placebo-controlled study. Erythropoietin reduces anemia and transfusions: A randomized trial with or without erythropoietin during chemotherapy. Double-blind, placebo-controlled study of quality of life, hematologic end points, and safety of weekly epoetin alfa in children with cancer receiving myelosuppressive chemotherapy. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer.
This open-label, randomized phase III study was designed to investigate the effects of erythropoietin alfa (EPO) in addition to adjuvant chemotherapy and pelvic radiotherapy (CRT) in patients with stage IB to II cervical cancer who had undergone radical hysterectomy.
                Two hundred fifty-seven patients were randomly assigned to four cycles of carboplatin/ifosfamide chemotherapy followed by external-beam pelvic radiotherapy (CRT group) or four cycles of carboplatin/ifosfamide chemotherapy and EPO followed by pelvic radiotherapy and EPO (CRT + EPO group). The primary end point was recurrence-free survival (RFS). Secondary end points included overall survival (OS), change in hemoglobin levels, and safety, including thromboembolic events.
                The estimated 5-year RFS rates were 78% for patients receiving CRT + EPO and 70% for patients receiving CRT. There was no statistically significant difference in RFS, although a trend favoring patients treated with CRT + EPO was observed (hazard ratio [HR], 0.66; 95% CI, 0.39 to 1.12; log-rank P = .06). Exploratory analyses suggest a benefit with CRT + EPO for patients with stage IB to IIA disease (HR, 0.39; 95% CI, 0.18 to 0.85; P = .014) or patients with complete resection (HR, 0.55; 95% CI, 0.31 to 0.98; P = .039). OS was similar in both groups (HR, 0.88; 95% CI, 0.51 to 1.50; log-rank P = .63). Patients treated with EPO maintained higher hemoglobin levels throughout CRT. No significant differences in safety profiles were observed between the two groups. Incidence of thrombovascular events was low (2%) and comparable between both groups.
                This study confirms that EPO can be added safely to CRT in patients with cervical cancer, but it failed to demonstrate a significant benefit in RFS and OS. We aimed to determine the effect of dietary counseling or oral supplements on outcome for patients with cancer, specifically, nutritional outcome, morbidity, and quality of life (QOL), during and 3 months after radiotherapy.
                Seventy-five patients with head and neck cancer who were referred for radiotherapy (RT) were randomized to the following groups: group 1 (n = 25), patients who received dietary counseling with regular foods; group 2 (n = 25), patients who maintained usual diet plus supplements; and group 3 (n = 25), patients who maintained intake ad lib. Nutritional intake (determined by diet history) and status (determined by Ottery's Subjective Global Assessment), and QOL (determined by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 [EORTC QLQ-C30]) were evaluated at baseline, at the end of RT, and at 3 months.
                Energy intake after RT increased in both groups 1 and 2 (p < or = .05). Protein intake also increased in both groups 1 and 2 (p < or = .006). Both energy and protein intake decreased significantly in group 3 (p < .01). At 3 months, group 1 maintained intakes, whereas groups 2 and 3 returned to or below baseline levels. After RT, >90% of patients experienced RT toxicity; this was not significantly different between groups, with a trend for reduced symptomatology in group 1 versus group 2/group 3 (p < .07). At 3 months, the reduction of incidence/severity of grade 1+2 anorexia, nausea/vomiting, xerostomia, and dysgeusia was different: 90% of the patients improved in group 1 versus 67% in group 2 versus 51% in group 3 (p < .0001). After RT, QOL function scores improved (p < .003) proportionally with improved nutritional intake and status in group 1/group 2 (p < .05) and worsened in group 3 (p < .05); at 3 months, patients in group 1 maintained or improved overall QOL, whereas patients in groups 2 and 3 maintained or worsened overall QOL.
                During RT, nutritional interventions positively influenced outcomes, and counseling was of similar/higher benefit; in the medium term, only counseling exerted a significant impact on patient outcomes.
                Copyright 2005 Wiley Periodicals, Inc. Recombinant human erythropoietin (r-Hu-EPO) is known to be effective in untreated cancer patients. Here we assess the possibility that r-Hu-EPO may also prevent or reduce anemia in patients who receive cytotoxic chemotherapy.
                Thirty-six patients with small-cell lung carcinoma (SCLC) were enrolled onto a three-arm, randomized trial to investigate the effect of r-Hu-EPO on hemoglobin (Hb) levels and RBC and platelet (Plt) transfusions during chemotherapy. Bone marrow progenitors were studied before and after treatment. Two groups of patients received r-Hu-EPO at a dose of either 150 IU/kg (group 150) or 300 IU/kg (group 300) three times per week for the duration of chemotherapy. A control group did not receive r-Hu-EPO (group O). A maximum of six cycles of a chemotherapy regimen that consisted of vincristine, ifosfamide, carboplatin, and etoposide (VICE) were given to all patients. Hematologic parameters were measured weekly, and RBC or Plt transfusions were given for Hb levels less than 9 g/dL and Plt counts less than 20 x 10(9)/L.
                Hb levels decreased in all patients, but onset of anemia was delayed in groups that received r-Hu-EPO (P = .002). A total of 116 U RBC were transfused in group 0, 54 in group 150, and 52 in group 300 (P = .017). In addition, there was a nonsignificant trend toward higher Plt counts and fewer Plt transfusions in patients who received r-Hu-EPO.
                r-Hu-EPO at a dose of either 150 or 300 IU/kg three times weekly delays the onset of anemia and reduces RBC transfusion requirements in patients who undergo intensive chemotherapy for SCLC. A possible effect of r-Hu-EPO on platelet numbers deserves further study. To evaluate the feasibility and efficacy of using recombinant human erythropoietin (rhEPO) to correct decreased hemoglobin levels in patients undergoing radiotherapy and to get an estimate of its influence on the efficacy of radiotherapy.
                Fifty patients with cancer of the head and neck and the pelvis were randomized before radiotherapy to different rhEPO treatments (none, 3 x 150 U/kg per week i.v., 3 x 300 U/kg per week i.v. and 3 x 150 U/kg per week s.c.). Hematological parameters were evaluated weekly and the locoregional tumor control rates were determined in 38 patients with head and neck cancer.
                rhEPO-treated patients showed a significant increase in their hemoglobin values (0.7 g/100 ml per week). The rhEPO response was comparable for patients with cancer of the head and neck and the pelvis. A delayed recovery was seen when iron deficiency or impaired iron mobilization was present. No serious toxicity was observed. Locoregional tumor control was improved, although not statistically significantly, in those head and neck cancer patients who experienced a rapid rise of hemoglobin.
                Low hemoglobin levels can be safely and quickly corrected with rhEPO. This may improve the effectiveness of radiotherapy. The efficacy and safety of weekly administration of epoetin beta (EPO) for chemotherapy-induced anemia (CIA) patients was evaluated.
                One hundred and twenty-two patients with lung cancer or malignant lymphoma undergoing chemotherapy were randomized to the EPO 36 000 IU group or the placebo group. Hematological response and red blood cell (RBC) transfusion requirement were assessed. Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire.
                Mean change in hemoglobin level with EPO increased significantly over placebo (1.4 +/- 1.9 g/dl versus -0.8 +/- 1.5 g/dl; P < 0.001). The proportion of patients with change in hemoglobin level > or =2.0 g/dl was higher for EPO than those for placebo (P < 0.001). After 4 weeks of administration, the proportion of RBC transfusion or hemoglobin level <8.0 g/dl was significantly lower for EPO than those for placebo (P = 0.046). The changes in the FACT-An total Fatigue Subscale Score (FSS) were less deteriorated with EPO than those with placebo. Progressive disease (PD) did not influence the change in hemoglobin level but there was less decrease in FSS in non-PD patients. No significant differences in adverse events were observed. Thrombovascular events and pure red cell aplasia related to EPO were not observed. Retrospective analysis of survival showing the hazard ratio of EPO to placebo was 0.94.
                Weekly administration of EPO 36 000 IU significantly increased hemoglobin level and ameliorated the decline of QOL in CIA patients over the 8-week administration period. Anemia has been reported to develop during preoperative chemotherapy with paclitaxel and carboplatin. The use of recombinant human erythropoietin (EPO) has been shown to reduce anemia and subsequent packed red blood cell transfusions. The current study is a report of a Phase III, prospective, randomized trial with or without EPO that confirms the original observations of less anemia and fewer transfusions in those patients randomized to receive EPO concurrently with paclitaxel and carboplatin.
                Thirty patients with advanced head and neck or lung carcinoma were treated with 2 courses of paclitaxel, 230 mg/m(2), and carboplatin, 7.5 mg/mL/minute, repeated every 21 days. The treatment group was comprised of 15 patients randomized to receive concurrent EPO, 150 U/kg, 3 times per week; in patients deemed nonresponsive the dose was increased to 300 U/kg and 450 U/kg in subsequent courses. The control group was comprised of 15 patients randomized not to receive EPO.
                Twenty-seven patients were evaluable. After 2 courses of chemotherapy the mean hemoglobin decrease was 1.2 g/dL in the EPO group versus 2.8 g/dL in the control group (P = 0.037). There was a highly significant decrease in hemoglobin over time in patients who did not receive EPO (P = 0.008). After 4 courses of chemotherapy, fewer patients were transfused in the EPO arm: 2 of 13 (15%) in the EPO treatment group versus 5 of 14 (36%) in the control group.
                There was significantly less anemia and transfusions were reduced by 50% in patients randomized to receive EPO during chemotherapy with paclitaxel and carboplatin.
                Copyright 1999 American Cancer Society. To evaluate the effects of once-weekly epoetin alfa (EPO) on health-related quality of life (HRQOL), hemoglobin (Hb), transfusions, and tolerability in children with cancer.
                Anemic patients 5 years to 18 years of age receiving myelosuppressive chemotherapy for nonmyeloid malignancies, excluding brain tumors, received intravenous EPO 600 units/kg to 900 units/kg or placebo once-weekly for 16 weeks. Patients and parents completed the pediatric health-related quality-of-life generic scales (GS) and cancer-specific scales (CS).
                One hundred eleven patients received EPO and 111 patients received placebo. Mean final values for GS total score (P = .763 among patients; P = .219 among parents) and CS domain scores (P > or = .238; P > or = .081, respectively) were not significantly different between treatment groups. EPO-treated patients had greater increases in Hb overall (P = .002) and were more likely to be transfusion free after 4 weeks (38.7% v 22.5%; P = .010). Change in Hb was correlated with change in PedsQL-GCS total score in the EPO group (r = 0.242; P = .018), but was not in the placebo group (r = 0.086; P = .430). Adverse events were comparable between treatment groups.
                This study confirmed the tolerability and hematologic benefits of once-weekly EPO in children with cancer. No significant difference in HRQOL was detected between treatment groups, but a significant positive correlation was observed between Hb changes and HRQOL changes in the EPO group. Additional studies are warranted to assess HRQOL when anemia is managed optimally in children with cancer. To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC).
                Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m(2)/day)/carboplatinum (70 mg/m(2)) on days 1--5 and 29--33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 microg, days 15--19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1--3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors).
                This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: +/- G-CSF, p = 0.0072).
                With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication. Patients with cervical cancer frequently suffer from anemia. This two-stage, adaptive-design study investigated the effect of anemia correction with epoetin beta on treatment outcomes. Patients with stage IIB-IVA cervical cancer received radiochemotherapy (RCT) and were randomized to epoetin 150 IU/kg three times weekly (n = 34) or standard care (control; n = 40) for up to 12 weeks. Primary end point for stage 1 aimed to establish a correlation between anemia correction and treatment failure (no complete response or relapsing within 6 months after RCT initiation) as a proof of concept before moving into stage 2. Secondary end points included progression/relapse-free survival, overall survival, response to RCT, hemoglobin (Hb) response, and safety. Median baseline Hb was 11.4 and 11.6 g/dL in epoetin and control groups, respectively. At treatment end point, median Hb increased by 1.3 g/dL with epoetin, but decreased by 0.7 g/dL in the control group (P < 0.0001). No significant correlation between Hb increase and treatment failure was demonstrated. There were no significant differences between epoetin and control groups in progression/relapse-free survival (29.4% vs 32.5% patients with events; P = 0.96), overall survival (23.5% vs 12.5% patients with events; P = 0.22) or overall complete response (53% vs 58%; P = 0.86). Adverse events were well matched between groups. This study shows that epoetin beta rapidly, effectively, and safely increases Hb levels in patients with cervical cancer receiving RCT. No positive correlation of Hb increase and improvement in clinical outcomes could be demonstrated.
There are strong suggestions that RT plus EPO has a negative influence on outcome as opposed to RT alone. However, the target haemoglobin concentration, which was higher than recommended in four of the five included RCTs, may have had a significant role. Nevertheless, based on these findings EPO should not be administered as an addition to RT outside the experimental setting for patients with head and neck cancer.