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R E V I E W Erythropoietic Agents in the Management of Cancer Patients Part 1: Anemia, Quality of Life, and Possible Effects on Survival Robert E. Smith, Jr., MD rythropoietin is the major regulator of erythropoiesis: In normal subjects, when hemoglobin concentrations decrease to < 12 g/dL, levels of endogenous erythropoietin increase [1]. This is primarily achieved by recruitment of additional peritubular renal cells, augmenting erythropoietin production by dedicated peritubular cells [2]. In patients with chronic renal failure who have an impaired ability to produce endogenous erythropoietin, replacement therapy with erythropoietic agents resulted in normalization of hemoglobin levels [3, 4]. The use of erythropoietic agents to correct anemia has also been studied extensively in patients with cancer. Anemia (as defined by a hemoglobin concentration < 12 g/dL) is a common occurrence in oncology patients, and the endogenous erythropoietic response to anemia is diminished in cancer-related anemia [5, 6]. The causes of anemia in cancer patients are multifactorial and may be related to chemotherapy (myelosuppressive chemotherapies, as well as nephrotoxic platinum-based therapy) [7] or neoplastic bone marrow infiltration [8]. There is also the anemia of chronic disease (ie, inflammatory cytokines that suppress erythropoiesis and erythropoietin production) [9–13]. This review will briefly summarize the principal findings regarding the use of erythropoietic agents to correct anemia in oncology patients and identify several areas of continuing investigation in optimizing the use of erythropoietic agents for that purpose, and then review the theoretical basis and clinical data regarding the use of erythropoietic agents in patients with cancer to impact survival or cognitive function. E Correspondence to: Robert E. Smith, Jr., MD, President, South Carolina Oncology Associates, 1301 Taylor Street, Suite 1-A, Columbia, SC 29201; telephone: (803) 296-5721; fax: (803) 296-5741; e-mail: [email protected] J Support Oncol 2003;1:249–259 VOLUME 1, NUMBER 4 © 2003 BioLink Communications n NOVEMBER/DECEMBER 2003 Abstract Erythropoietic agents have been shown to be well tolerated and highly effective in correcting the anemia associated with cancer. Studies aimed at optimizing their use in this regard are ongoing and are evaluating the potential value of early dose intensification through “frontloading” schedules, the feasibility of reducing the frequency of dosing, and the value of early initiation of erythropoietic agents to prevent anemia. The potential for erythropoietic therapy to contribute to survival in cancer patients also is being investigated. Anemia is an independent poor prognostic factor in several cancer settings, such as head-and-neck, lung, and cervical cancer. In patients with B-cell chronic lymphocytic leukemia, it is possible that the period of stable disease—that is, postponement of the need for cytotoxic chemotherapy—may be prolonged when patients are “downstaged” through correction of their anemia. In addition, anemia may affect the patient’s quality of life in ways that impact compliance and/or the ability to tolerate therapy. Retrospective analysis of large phase III trials designed to evaluate the effect of erythropoietic agents on anemia in cancer patients has reported a trend toward improved survival among patients who received erythropoietic therapy. Trials to evaluate how correction of anemia in cancer patients might impact survival are ongoing. In this first installment of a two-part article, the author reviews the clinical data supporting the use of erythropoietic agents for the management of the fatigue due to anemia, the effect of anemia control on quality of life, and the evidence available so far that control of such anemia may actually lengthen survival. In the next issue, Dr. Smith will discuss the possible role of erythropoietic agents in neuroprotection and neurotherapy, including cognitive dysfunction in cancer patients. Erythropoietic Agents for Management of Chemotherapy-Induced Anemia RANDOMIZED PHASE III TRIALS IN ANEMIC CANCER PATIENTS Dr. Smith is Co-Director, South Carolina Cancer Center, and President, South Carolina Oncology Associates, Columbia, South Carolina Several studies have shown that, despite the complex pathophysiology of anemia in cancer patients, erythropoietic agents can ameliorate anemia in this patient population [14–17]. Four large, randomized, placebo-controlled phase III trials evaluated the biologic and clinical activity of www.SupportiveOncology.net 249 Table 1 Randomized Phase III Trials of Erythropoietic Agents for the Treatment of Anemia in Cancer Patients STUDY Abels 14 Littlewood et al15 Vansteenkiste et al16 Hedenus et al17 PATIENT POPULATION Anemia with solid and hematologic malignancies associated with chemotherapy or chronic anemia of cancer Anemic patients with solid tumors or hematologic malignancy associated with non–platinum-based chemotherapy Anemic lung cancer patients receiving platinum-based chemotherapy Anemic patients with lymphoproliferative malignancies PATIENT ARMS (TOTAL PATIENTS) TREATMENT (EVALUABLE PATIENTS) Non-chemotherapy (124) Epoetin alfa, 100 IU/kg SC TIW for 8 wk (63) Placebo (55) Non–cisplatin-based chemotherapy (157) Epoetin alfa, 150 IU/kg SC TIW for 12 wk (79) Placebo (74) Cisplatin-based chemotherapy (132) Epoetin alfa, 150 IU/kg SC TIW for 12 wk (63) Placebo (61) Epoetin alfa, 150–300 IU/kg SC (251) Placebo (124) Non–platinum-based chemotherapy (375) CLINICAL OUTCOME Statistically significant increase in hematocrit vs placebo for all 3 strata (P < 0.04) Statistically significant decrease in percentage of patients requiring transfusions and number of units transfused in months 2 and 3 for chemotherapytreated patients receiving rHuEPO vs placebo (P < 0.005 and P = 0.009, respectively). No change in percentage of patients transfused or number of units transfused among non-chemotherapy patients Epoetin alfa therapy resulted in significantly decreased transfusion requirements (P = 0.0057), increased hemoglobin levels (P < 0.001), and improved quality of life (P < 0.05). Platinum-based chemotherapy (320) Darbepoetin alfa, 2.25– 4.5 µg/kg per week SC for 12 wk (156) Placebo (158) Chemotherapy (344) Darbepoetin alfa, 2.25– 4.5 µg/kg per week SC for 12 wk (174) Placebo (170) Darbepoetin alfa therapy resulted in a statistically significant decrease in number of transfusions (P < 0.001), fewer units of blood transfused (P < 0.001), and decreased incidence and severity of fatigue (P = 0.019). Darbepoetin alfa therapy resulted in a statistically significant increase in patients achieving a hemoglobin response (P < 0.001), a decrease in number of patients receiving transfusions (P < 0.001), and significantly decreased fatigue (P < 0.001). The improvement in fatigue correlated with changes in hemoglobin levels. Abbreviations: SC = subcutaneously; TIW = three times per week; rHuEPO = recombinant human erythropoietin. Erythropoietic Agents: Anemia, QOL, Survival erythropoietic agents in the management of anemia in cancer patients (Table 1). The studies employed different erythropoietic agents (epoetin alfa [Procrit] and darbepoetin alfa [Aranesp]), used varied criteria to define anemia, included different patient populations, had nonuniform definitions for response to treatment, and had differing study endpoints. Despite these variations, the patterns of response seen across the trials were highly reproducible: improvements in measures of erythropoiesis from baseline (hemoglobin or hematocrit) that translated into decreased transfusion requirements in months 2 and 3, with decreased fatigue and improved quality of life. OPEN-LABEL, COMMUNITY-BASED STUDIES In addition, four large, community-based, openlabel, nonrandomized studies of erythropoietic agents were conducted in anemic cancer patients with nonmyeloid malignancies who were receiving 250 www.SupportiveOncology.net chemotherapy [18–21]. The studies had similar designs and endpoints (Table 2). Despite differences in the erythropoietic agents prescribed (epoetin alfa and darbepoetin alfa), as well as doses and schedules, all four studies reported very similar improvements in mean hemoglobin change uncorrected for transfusion (Table 3). In all of the studies, quality of life (as measured by the mean change in the linear analog score or in the FACT-Fatigue [Functional Assessment of Cancer TherapyFatigue] scale) significantly improved during erythropoietic therapy. In three studies [19–21], improvements in quality of life correlated with improvement in hemoglobin levels (for patients with objective responses or stable disease following chemotherapy). Quality-of-life improvement was most clearly seen in patients who achieved hemoglobin concentrations ≥ 12 g/dL or an increase ≥ 2 g/dL from baseline [20]. The findings in these community-based studies were consistent THE JOURNAL OF SUPPORTIVE ONCOLOGY Table 2 Community-Based Studies of Erythropoietic Agents for the Treatment of Cancer-Related Anemia: Study Designsa GLASPY ET AL18 (n = 2,342) Open-label, nonrandomized Anemic Nonmyeloid malignancies Chemotherapy Epoetin alfa Initial dose: 150 U/kg SC TIW Increase to 300 U/kg SC TIW if inadequate response at wk 8 Retrospective tumor response analysis (subset) Effect on: • Hemoglobin • Transfusion requirements • Quality of life (linear analog scale) DEMETRI ET AL19 (n = 2,370) GABRILOVE ET AL20 (n = 2,964) VADHAN-RAJ ET AL21 (n = 1,173) Open-label, nonrandomized Anemic (Hgb ≤ 11.0 g/dL) Nonmyeloid malignancies Chemotherapy Epoetin alfa Initial dose: 10,000 U SC TIW Increase to 20,000 U SC TIW if Hgb rise < 1 g/dL at wk 4 Prospective tumor response analysis Effect on: • Hemoglobin • Transfusion requirements • Quality of life (linear analog scale, FACT-An) Open-label, nonrandomized Anemic (Hgb ≤ 11.0 g/dL) Nonmyeloid malignancies Chemotherapy Epoetin alfa Initial dose: 40,000 U SC QW Increase to 60,000 U SC QW if Hgb rise < 1 g/dL at wk 4 Prospective tumor response analysis Effect on: • Hemoglobin • Transfusion requirements • Quality of life (linear analog scale, FACT-An) Open-label, nonrandomized Anemic (Hgb ≤ 11.0 g/dL) Nonmyeloid malignancies Chemotherapy Darbepoetin alfa Initial dose: 3 µg/kg SC Q2W Increase to 5 µg/kg SC Q2W if Hgb rise < 1 g/dL at wk 6 N/A Effect on: • Hemoglobin • Transfusion requirements • Quality of life (FACT-Fatigue subscale and energy numerical grade) Abbreviations: FACT-An = Functional Assessment of Cancer Therapy–Anemia; Hgb = hemoglobin; SC = subcutaneously; QW = every week; Q2W = every two weeks; TIW = three times per week.; N/A= not applicable a Modified from Crawford22 with those reported in the randomized, placebocontrolled phase III trials and confirmed that erythropoietic agents are effective in the management of anemia in cancer patients, independent of tumor type or chemotherapy regimen. clinical trials, the incidence of death and the proportion of patients withdrawing from the trial due to an adverse effect did not differ between patients receiving erythropoietic agents and those receiving a placebo [14–17]. ADVERSE EFFECTS OF ERY THROPOIETIC AGENTS EVOLVING ISSUES IN THE USE OF ERYTHROPOIETIC AGENTS Numerous cancer patients have received erythropoietic agents in both controlled and open-label clinical trials and in community practice [14–21], and they have been well tolerated. The incidence and severity of adverse events have not differed from those observed in patients receiving a placebo, except for shortness of breath, edema, hypertension, and injection-site reactions [23], and even they were not clinically significant. In controlled Dose-escalation schedules. Historically, erythropoietic agents have been administered at a fixed dose (1 or 3 times per week for 12 weeks), and if an adequate hematologic response was not seen at week 4 or week 8, the dose was increased. Studies with darbepoetin alfa in cancer-associated anemia reported a correlation between the dose of darbepoetin alfa and both the proportion of patients who met the criteria for hematologic Smith Table 3 Community-Based Studies of Erythropoietic Agents for the Treatment of Cancer-Related Anemia: Effect on Hemoglobin Levelsa GLASPY ET AL18 Baseline Final Mean change from baseline a b 9.5 g/dL 11.3 g/dL 1.8 g/dLb DEMETRI ET AL19 9.3 g/dL 11.3 g/dL 2.0 g/dLb GABRILOVE ET AL20 9.5 g/dL 11.3 g/dL 1.8 g/dLb VADHAN-RAJ ET AL21 10.4 g/dL 12.4 g/dL 2.1 g/dL* Modified from Crawford22 Significantly (P < 0.001) greater than baseline VOLUME 1, NUMBER 4 n NOVEMBER/DECEMBER 2003 www.SupportiveOncology.net 251 Erythropoietic Agents: Anemia, QOL, Survival response and the rapidity of that response [24]. These data are consistent with the hypothesis that higher doses of erythropoietic agents, administered early in therapy, would result in a higher proportion of patients achieving an earlier response. This “front-loading” hypothesis is currently being investigated [25–29]. Optimizing the frequency of dosing. In early studies, erythropoietic agents were dosed 3 times per week (TIW) for 12 weeks. Gabrilove [20] and others [30–32] reported that a dose of 40,000 IU of epoetin alfa administered once weekly (with escalation to 60,000 IU at week 4 if the hemoglobin rise was < 1 g/dL) appeared to produce an acceptable clinical response. Chemotherapy-induced anemia also has been treated successfully utilizing darbepoetin alfa in a once-every-2-week (Q2W) regimen [21, 28–30] or once-every-3-week (Q3W) regimen [33, 34]. Currently, 200 µg Q2W has been adopted as the most common dose and schedule for darbepoetin alfa. Further exploration of schedules that would minimize the frequency of administration without sacrificing efficacy is ongoing. Prevention of anemia. A number of studies have looked at the use of erythropoietic agents prophylactically in patients at risk for anemia [35–40]. In these randomized trials, early treatment with erythropoietic agents consistently resulted in statistically significant decreases in the mean hemoglobin fall, which translated into decreases in the number of patients receiving red blood cell (RBC) transfusions and the units of RBCs transfused per patient. These findings were consistent whether the patient population was receiving platinumbased chemotherapy or non–platinum-based therapy and whether the patient population was one in which baseline anemia is common (small-cell lung cancer [SCLC]) or relatively uncommon (patients receiving adjuvant therapy for breast cancer) (Table 4). Further evaluation of the clinical and economic impact of early treatment with erythropoietic agents in patient populations at risk for anemia is warranted. Erythropoietic Therapy: Impact on Survival THEORETICAL BASIS FOR AN IMPACT ON SURVIVAL IN CANCER PATIENTS Hypoxia and cancer survival. Approximately 25%–50% of patients with certain major non- 252 www.SupportiveOncology.net myeloid tumors (namely, breast, lung, and gynecologic cancers and lymphoma) treated with a single agent or a standard chemotherapy regimen experience severe (≥ grade 3) anemia [41]. Hemoglobin levels < 13 g/dL have been associated with tumor hypoxia [42], and more pronounced anemia (hemoglobin < 10 g/dL) has been associated with impaired local control and decreased survival in specific cancers treated with radiotherapy-based regimens [43–46]. A comprehensive meta-analysis found that median survival times were longer for non-anemic cancer patients in all of the studies evaluated [47]. Overall, the estimated increased risk of death was 65% in patients with cancer and anemia, compared with cancer patients without anemia, suggesting that, at least in some cases, anemia may be an independent predictor of survival in patients with cancer. The theoretical basis for the clinical impact of low hemoglobin levels relates to the cellular regulation of oxygen delivery. Hypoxia results in an increased expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) within hours of hypoxic stress. HIF-1 alpha dimerizes with constitutively expressed HIF-1 beta to form a transcription factor that regulates increased expression of a number of genes, including erythropoietin (EPO), vascular endothelial growth factor (VEGF), glucose transporters, glycolytic enzymes, transferrin, and the transferrin receptor [48]. Under well-oxygenated conditions, HIF-1 alpha is ubiquitinated and degraded after being bound by the product of the von Hippel-Lindau tumor suppressor gene (VHL). Congenital deficiency of or mutation in VHL leads to an increased incidence of cancer, suggesting that chronic and/or inappropriate activation of the HIF-1 alpha response may be central to the initiation or progression of some tumors [49]. Mechanism(s) of hypoxia impact on cancer survival. The up-regulation of HIF-1 alpha in response to hypoxia may affect the survival of cancer patients in one or more ways: 1. HIF-1 alpha expression results in upregulation of proangiogenic factors that support tumor growth, metastasis, and resistance to chemotherapy [50]. 2. Hypoxia results in resistance to free radicals formed subsequent to ionizing radiation therapy and/or chemotherapy [51, 52]. 3. Hypoxia increases resistance to apoptosis [49]. 4. Hypoxia impacts survival by impacting the host, resulting in reduced tolerance to therapy, THE JOURNAL OF SUPPORTIVE ONCOLOGY Table 4 Erythropoietic Agent Prophylaxis of Chemotherapy-Induced Anemia STUDY ERYTHROPOIETIC AGENT DOSE AND SCHEDULE PATIENTS (n) CHEMOTHERAPY DESIGN ten Bokkel Huinink et al37 Ovarian cancer (118) 6 cycles of platinumbased combination therapy Randomized, openlabel, controlled trial vs standard management 150 or 300 U/kg 3 × week up to Hgb = 15 g/dL de Campos et al36 SCLC (36) 6 cycles of VICE Randomized, openlabel, controlled trial vs standard management 150 or 300 U/kg 3 × week up to Hgb = 15 g/dL Del Mastro et al38 Breast cancer (62) 6 cycles of CEF 150 or 300 U/kg 3 × week up to Hgb = 15 g/dL Dunphy et al39 Head and neck or lung cancer (29) Carboplatin and paclitaxel Randomized, openlabel, controlled trial vs standard management Randomized, openlabel, controlled trial vs standard management Thatcher et al40 SCLC (130) 6 cycles of platinumbased combination therapy Randomized, openlabel, controlled trial vs standard management 150 or 300 U/kg 3 × week up to Hgb = 15 g/dL 150 or 300 U/kg 3 × week up to Hgb = 15 g/dL RESULTS EPO arms had a statistically significant prolongation in time to first transfusion and a decrease in the percentage of patients receiving transfusions. EPO arms had a statistically significant decrease in number of patients receiving transfusions, number of RBC units/transfusion episode, and total number of RBC units transfused. EPO arms had a statistically significant decrease in clinically significant anemia and mean Hgb decrease. EPO arms had a statistically significant decrease in mean Hgb fall by the end of 2 cycles of therapy and a decrease in the proportion of transfused patients at study end. EPO arms had a statistically significant decrease in the number of patients experiencing anemia, as well as the number of patients transfused. Abbreviations: SCLC = small-cell lung cancer; VICE = vincristine, ifosfamide, carboplatin, and etoposide; CEF = cyclophosphamide, epirubicin, and fluorouracil; EPO = epoetin alfa; Hgb = hemoglobin reduced immune function, and reduced quality of life [49]. In preclinical murine models, hypoxic tumor cells were two- to six-fold more chemoresistant than normoxic tumor cells [53]. Hemoglobin levels < 10 g/dL have been reported to be associated with impaired local control rates and survival rates in head-and-neck as well as cervical cancer patients receiving radiotherapy-based treatment regimens [43–44, 54]. Furthermore, retrospective analyses of head-and-neck cancer patients treated with radiotherapy demonstrated that hemoglobin levels are an independent prognostic factor for survival [55]. Similar data have been reported for cervical cancer patients and non–small-cell lung cancer (NSCLC) patients treated with chemoradiotherapy [47, 54, 56]. Potential consequences of erythropoietic agents on cancer cell growth. Theoretically, if tumor cells have active erythropoietin receptors (EPO-R), erythropoietic agents might stimulate neoplastic cell growth. Several authors have demonstrated in vitro stimulation of erythroleukemic cell lines expressVOLUME 1, NUMBER 4 n NOVEMBER/DECEMBER 2003 ing EPO-R [57–59] and stimulation of myeloma cells expressing EPO-R [60, 61]. However, exposure to an erythropoietic agent did not affect in vitro colony formation or the percentage of S-phase cells in panels of tumor cells [62, 63], and had no additive effect on the cell lines’ response to granulocyte-macrophage colony stimulating factor (GMCSF) or interleukin-3 (IL-3). To date, there are no data supporting the hypothesis that erythropoietic agents can accelerate nonmyeloid cancer progression in animal models or humans. When progression of disease has been reported in patients with myeloma or acute myelogenous leukemia (AML), there has been no indication of a causal relationship [23]. Smith Clinical Data on the Impact of Erythropoietic Agents on Survival of Cancer Patients Pilot studies have reported that the correction of anemia (via RBC transfusions or erythropoietic agents) in patients receiving potentially curative radiotherapy for cervical and/or head-and-neck www.SupportiveOncology.net 253 Erythropoietic Agents: Anemia, QOL, Survival cancer resulted in improved survival [64–66]. In two large, randomized phase III trials where survival was a secondary endpoint, the treatment arm receiving erythropoietic agents showed trends toward longer overall and progression-free survival [15, 67]. The Littlewood study. Littlewood et al [15] randomized 375 patients with solid or nonmyeloid hematologic malignancies and a hemoglobin level < 10.5 g/dL (or ≥ 10.5 g/dL but < 12.0 g/dL after a hemoglobin decrease of ≥ 1.5 g/dL per cycle since the start of chemotherapy) in a double-blind, placebo-controlled trial. The randomization was 2:1. Patients received epoetin alfa starting at 150 IU/kg TIW for up to 28 weeks (n = 251) or placebo (n = 124) and were eligible for a dose increase at week 4 if there was an inadequate initial response. Patient demographics were generally comparable between the two arms. The three most common malignancies (breast, non-Hodgkin’s lymphoma, and myeloma) were present in similar percentages in the two arms, and the overall distribution of chemotherapy regimens within specific malignancy types was generally balanced between the epoetin alfa and placebo groups (Table 5) [15]. Although not a primary endpoint and added as a secondary endpoint after the start of the study, survival was assessed 12 months after the last patient enrolled had completed the study. At a median follow-up of 26 months, the median overall survival was 17 months among the patients treat- Table 5 Most Frequent (≥ 20% Overall) Chemotherapeutic Agents Used for the Three Most Common Tumor Types in the Study Reported by Littlewood et al15 EPOETIN ALFA (n = 251) TUMOR TYPE/CHEMOTHERAPEUTIC AGENT NUMBER Breast Cancer Cyclophosphamide Fluorouracil Epirubicin Methotrexate Non-Hodgkin’s lymphoma Cyclophosphamide Vincristine Doxorubicin Myeloma Melphalan Vincristine Doxorubicin 254 PLACEBO (n = 124) PERCENT NUMBER 44.9 39.7 26.9 18.0 13 16 8 9 63.4 58.5 53.7 11 9 5 n = 78 35 31 21 14 n = 36 n = 41 26 24 22 36.1 44.4 22.2 25.0 n = 21 n = 37 21 11 12 PERCENT 52.3 42.9 23.8 n = 25 56.8 29.7 32.4 www.SupportiveOncology.net 13 5 4 52.0 20.0 16.0 Table 6 Secondary Endpoint Survival Assessment Reported by Littlewood et al15 EPOETIN ALFA, n (%) Alive at follow-upa Died Lost to follow-upa a 94 (37%) 155 (62%) 2 (1%) PLACEBO, n (%) 41 (33%) 82 (66%) 1 (1%) Median follow-up of 26 months ed with epoetin alfa and 11 months among the placebo-treated patients (Table 6). The Kaplan-Meier 12-month estimate of survival was 60% for the epoetin alfa group and 49% for the placebo group, with a log-rank test showing a trend in overall survival favoring epoetin alfa (P = 0.13). A similar trend in favor of the patients given epoetin alfa was seen in both those with hematologic malignancies and those with solid tumors. The Vansteenkiste study. Retrospective data regarding a possible survival impact were also reported by Vansteenkiste et al [67]. They reported on a double-blind, phase III trial that randomized anemic patients (hemoglobin ≤ 11 g/dL) with lung cancer receiving platinum-containing chemo therapy to receive darbepoetin alfa or placebo. Randomization was stratified to balance the treatment groups by tumor type (NSCLC vs SCLC) and geographic region. Although they were secondary endpoints, data on tumor progression and survival status were collected quarterly for 1 year after the last patient enrolled had completed treatment. The median overall survival was 46 weeks (range, 39–53 weeks) among darbepoetin alfa patients and 34 weeks (range, 29–40 weeks) among placebo patients. The median time to disease progression or death was 23 weeks (range, 19–31 weeks) for patients treated with darbepoetin alfa and 20 weeks (range, 17–23 weeks) for those receiving a placebo. Analysis of the tumor strata showed a more pronounced effect of darbepoetin alfa on time to treatment failure or death among SCLC patients, with an 11-week time to disease progression prolongation in the darbepoetin alfa arm compared with the placebo arm (Table 7). A CAVEAT Neither of the phase III trials discussed above was designed or powered to evaluate survival endpoints. The variables that have a known influence on survival (stage of disease, marrow involvement, THE JOURNAL OF SUPPORTIVE ONCOLOGY intensity of chemotherapy, and use of radio therapy) were not controlled for or stratified in the studies. These retrospective analyses of survival endpoints do, however, serve to generate hypotheses concerning the benefit of correcting hemoglobin levels in cancer patients undergoing chemotherapy. Randomized phase III trials testing these hypotheses are currently ongoing. Table 7 TREATMENT ARM Darbepoetin alfa Median, wk Range, wk Placebo Median, wk Range, wk WHEN ANEMIA MAY AFFECT CHOICE OF TREATMENT Erythropoietic therapy also may affect survival in diseases where the presence of anemia may be a factor in therapeutic strategies. For instance, anemia is common in patients with chronic lymphocytic leukemia (CLL) and may be due to one or more of several factors: extensive bone marrow infiltration, hypersplenism, blood loss, auto immune hemolysis, deficiency of hematopoietic cofactors, and/or the anemia of chronic disease. Both the Rai and Binet staging systems identify anemia as an indicator of disease progression [68, 69]. Consistent with the finding that increased severity of anemia indicates disease progression in B-cell chronic lymphocytic leukemia (B-CLL), National Cancer Institute guidelines state that patients with hemoglobin levels < 10 g/dL are candidates for chemotherapy [70]. Randomized, controlled studies have reported that erythropoietic agents can ameliorate the anemia seen in CLL patients, as measured by increased hemoglobin levels and decreased transfusion requirements [71–74]. Correction of anemia also may result in “downstaging” of CLL patients. Pangalis et al [75] evaluated whether the “downstaging” of B-CLL patients by correction of disease-related anemia could prolong the time to cytotoxic therapy and potentially offer a survival advantage. The study enrolled 32 Rai stage III or IV B-CLL patients who had had no treatment for CLL at least 1 month prior to study entry, an ECOG performance status ≤ 2, a life expectancy of at least 6 months, and were clinically stable for at least 1 month prior to study entry. Anemia was defined as a hematocrit < 32% on two occasions 2 weeks apart. Of the 32 patients enrolled, 11 were anemic at baseline and 14 developed anemia while on the study (median of 53.5 months after being enrolled in the study; range 17–120 months). The baseline (at the time anemia was diagnosed) hemoglobin level among the 25 patients who experienced aneVOLUME 1, NUMBER 4 n NOVEMBER/DECEMBER 2003 Smith Median Time to Disease Progression or Death Reported by Vansteenkiste et al67 SCLC NSCLC 33 26–41 18 16–26 21 16–26 19 16–23 Abbreviations: SCLC = small-cell lung cancer; NSCLC = non–small-cell lung cancer mia was a median of 9.4 g/dL (range, 5.9–9.9 g/dL). Treatment with epoetin alfa included both an induction phase (150 IU/kg TIW for a maximum of 12 weeks, with dose escalation permitted to 300 IU/kg TIW) and a maintenance phase (150 IU/kg weekly). A complete response to epoetin alfa was defined as a hematocrit level ≥ 38%, whereas a partial response was defined as an increase > 6% from baseline with a hematocrit < 38%. Of the 25 evaluable patients, 18 (72%) achieved a complete response and 2 (8%) had a partial response. Among the 20 responders, 18 experienced prolonged responses (median of 30.8+ months; range 27.5–64+ months) and 2 died of infection while still maintaining their hematocrit levels. At the completion of the induction period, 19 of 20 patients were “downstaged”: 6 to Rai stage 0; 9 to Rai stage 1; and 4 to Rai stage II. During a median of 31+ months follow-up (range, 25 to 65+ months), antileukemic therapy was required in 4 of the 20 responding patients, and corticosteroid therapy for autoimmune hemolysis in a fifth Table 8 Rai Stage Prior to and After Completion of the Induction Phase of Erythropoietic Agent Administrationa ERYTHROPOIETIC AGENT ADMINISTRATION RAI STAGE 0 I II III IV a b PRIOR, n (%) AFTER 3 MONTHS, n (%) 0 0 0 24 (96%) 1 (4%) 6 (24%) 9 (36%) 4 (16%) 5 (20%) 1 (4%)b From Pangalis et al75 Without anemia www.SupportiveOncology.net 255 Erythropoietic Agents: Anemia, QOL, Survival patient was needed (Table 8). The median overall survival of the 25 evaluable patients had not been reached as of publication of the Pangalis paper, and the 2- and 3-year survival rates were 96% and 78%. The reported median overall survival of Rai stage III patients is approximately 3 years, although the B-CLL population is heterogeneous and longer survival times have been reported [68, 69, 76]. These data are consistent with the hypothesis that “downstaging” B-CLL by correction of disease-related anemia may prolong the time to cytotoxic therapy and offer a survival advantage; however, these results also could be due to a subset selection of patients with less aggressive disease. Given the low toxicity, high response rate, and prolonged response duration and time to chemotherapy reported with erythropoietic therapy in this trial, a randomized prospective study specifically designed to evaluate the impact of erythropoietic agents on survival in B-CLL patients would seem to be warranted. Summary Erythropoietic agents have been shown to be well tolerated and highly effective in correcting the anemia associated with cancer. Studies aimed at optimizing their use in this regard are ongoing and are evaluating the potential value of early dose intensification through “frontloading” schedules, the feasibility of reducing the frequency of dosing, and the value of the early initiation of erythropoietic therapy in patients at risk for anemia. The potential for erythropoietic agents to contribute to survival in cancer patients is being investigated. Anemia is an independent poor prognostic factor in several cancer settings. Preclinical and clinical data have shown improved local control and survival in head-and-neck and cervical cancer patients who are managed with erythropoietic agents or RBC transfusions to correct their anemia while they are undergoing potentially curative chemoradiotherapy. In patients with B-CLL, it is possible that the time to cytotoxic chemotherapy may be prolonged when patients are “downstaged” through correction of their anemia. Hypoxia may contribute to improved cancer cell survival, proliferation, metastases, and resistance to therapy. In addition, anemia may affect the quality of life of the patient in ways that impact compliance and/or the ability to tolerate therapy. Retrospective analysis of large phase III trials designed to evaluate the effect of erythropoietic agents on anemia in cancer patients has reported a trend toward improved survival among patients managed with erythropoietic agents. Prospective, randomized trials to evaluate a possible survival impact of correcting anemia in cancer patients by means of erythropoietic agent therapy are ongoing. Editor’s note: Part 2 of this review—the possible role of erythropoietic agents as neuroprotectants/neurotherapeutics—will appear in the next issue of The Journal of Supportive Oncology. References 1. Finch CA. Erythropoiesis, erythropoietin and iron. Blood 1982;60:1241–1246. 2. Koury ST, Koury MJ, Bondurant MC, et al. 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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;19:2865–2874. 16. Vansteenkiste J, Pirker R, Massuti B, et al. Double blind placebo controlled randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002;94:1211–1220. 17. Hedenus, M, Adriansson M, San Miguel T, Continued on page 258 THE JOURNAL OF SUPPORTIVE ONCOLOGY P E E R V I E W P O I N T Commentary by Matti S. Aapro, MD D r. Smith’s paper reviews most of the existing evidence of a relationship between sustained correction of anemia in cancer patients by various erythropoietic agents available today and the quality-of-life improvement experienced by these patients. He also could have mentioned the positive data for epoetin beta [1]. Clearly, the majority of practicing hematologists and oncologists agree with the existing evidence and are convinced that epoetins will not only decrease the need for transfusions (the official cancer-related indication) but also help patients cope with the disease and its treatment. There are, however, discordant voices, sometimes because the data have evolved too quickly between evaluation of studies and guideline publication. For some other experts the data require scrutiny, as much of the old data come from studies with methodological problems [2]. Nevertheless, anyone who has had the opportunity to observe patients who respond to epoetin therapy and transform themselves from “zombies” to almost normal, active adults knows that at least a proportion of cancer patients derive considerable benefit from the administration of epoetins. PHARMACOECONOMIC AND OTHER ISSUES IN EUROPE The pharmacoeconomic issues in regard to the use of these agents and their reimbursement are widely debated in Europe, at least, and the complexities of these calculations go beyond the scope of this commentary. But to quote, with a slight change, a prominent colleague:“Given the negative impact of anemia in cancer patients and the benefits derived from rhEPO treatment, it can no longer be justified that so few European patients are given the chance to receive this therapy, especially as more convenient and cost-effective epoetin regimens are now available” [3]. The adverse event related seemingly to the European market version of epoetin alfa (Eprex) needs a mention. This product has been implicated in the development of pure red blood cell aplasia (PRCA ) in patients with chronic renal failure, although recently the number of reported cases has decreased dramatically [4]. Subjected to considerable scrutiny from health authorities, Eprex, which is similar but not exactly the same VOLUME 1, NUMBER 4 n NOVEMBER/DECEMBER 2003 Smith as its US counterparts Epogen and Procrit, now carries a warning against its subcutaneous use in patients with chronic renal failure. Epogen and Procrit, as well as epoetin beta (NeoRecormon), have been implicated in a very small number of cases compared with Eprex. With the accumulated evidence available up to July 2003, darbepoetin alfa (Aranesp) has not been associated with any increase of PRCA [5]. Should the number of cases associated with Eprex continue to decrease, it will be reassuring for all, but the explanation of the phenomenon might continue to escape us. PROSPECTIVE DATA ARE NEEDED Smith discusses one of the most fascinating developments for the practitioner and the patient, namely, the simplification of the treatment schedule, which could soon mean that epoetin will be administered once every 3 weeks, along with chemotherapy. Of course, in a review article, one has to make choices as to what data to include, but I believe the evidence that has led the National Comprehensive Cancer Network to advocate the maintenance of hemoglobin levels above 12 g/dL in elderly patients, as well as issues surrounding quality of life and anemia in the elderly, who represent the majority of our patients—should have been mentioned [6]. Smith’s excellent paper does discuss the laboratory and indirect clinical evidence that leads one to believe that there should be not only a direct correlation between hemoglobin level and local tumor-control rate by radiation therapy but also between hemoglobin level and patient survival after chemotherapy, or even without chemotherapy, as in some intriguing data on B-cell chronic lymphocytic leukemia. Although there is a body of highly suggestive retrospective data, one of the first studies designed to evaluate these hypotheses ended earlier than it should have as, very surprisingly, the independent data monitoring committee realized that more early deaths occurred in the epoetin alfa arm of the study than in the placebo arm [7]. Another negative study has also been reported in patients with head and neck cancer [8]. However, many other studies are ongoing, with probably better designs, and their results are eagerly awaited. 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