Epoetin Alfa in Cancer Patients: Evidence-Based Guidelines

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1 954 Journal of Pain and Symptom Management Vol. 22 No. 5 November 2001 Review Article Epoetin Alfa in Cancer Patients: Evidence-Based Guidelines Robert Turner, MD, Peter Anglin, MD, Ronald Burkes, MD, Félix Couture, MD, William Evans, MD, Glenwood Goss, MD, Robert Grimshaw, MD, Barbara Melosky, MD, Alexander Paterson, MD, and Ian Quirt, MD, for the Canadian Cancer and Anemia Guidelines Development Group Division of Clinical Hematology (R.T.), University of Alberta Hospital, Edmonton, Alberta; Division of Medical Oncology/Hematology (P.A.), Toronto, Ontario; Division of Medical Oncology/Hematology (R.B.), Mount Sinai Hospital, Toronto, Ontario; Department of Hematology-Oncology (F.C.), Centre Hospitalier Universitaire de Québec Pavillon Hotêl-Dieu, Québec City, Québec; Interdepartmental Program of Oncology, University of Ottawa (W.E.) and Ottawa Regional Cancer Centre (W.E.), Ottawa, Ontario; Lung Cancer Program (G.G.), Ottawa Regional Cancer Centre, Ottawa, Ontario; Division of Gynecology and Oncology (R.G.), Queen Elizabeth II Health Sciences Centre Victoria Site, Halifax, Nova Scotia; British Columbia Cancer Agency (B.M.), Vancouver, British Columbia; Department of Medicine (A.P.), Tom Baker Cancer Center, Calgary, Alberta; and Princess Margaret Hospital, University Health Network (I.Q.), Toronto, Ontario, Canada Abstract Anemia is a common cause of cancer-related fatigue. A systematic review of the literature was performed to establish guidelines on the use of epoetin alfa for the treatment of anemia. The evidence in support of these guidelines was selected, reviewed, and summarized by the members of the Canadian Cancer and Anemia Guidelines Development Group. The effects of epoetin alfa on quality of life (QOL) in patients with cancer were examined in 5 randomized, placebocontrolled trials and 2 large, open-label, nonrandomized, community-based studies. The effects of epoetin alfa on red blood cell transfusion requirements were examined in 19 randomized controlled trials (RCTs) with 21 comparisons. All trials compared epoetin alfa to a suitable control group, examined specified outcome measures that could be analyzed, and studied patients with cancer who were receiving chemotherapy. Trials involving patients with hematologic malignancies originating in the bone marrow were excluded. Outcome measures included 1) quality of life (QOL) (as measured by scales including the Linear Analogue Self- Assessment [LASA] and the Functional Assessment of Cancer Therapy [FACT] subscales), and 2) transfusion requirements (as measured by the proportion of patients requiring transfusion and amount of transfusion). The analysis confirmed that epoetin alfa produced statistically significant and clinically relevant improvements in QOL in patients with cancer. The overall relative risk ratio for transfusion among patients receiving epoetin alfa was calculated to be 0.60 (95% Cl, ; P ), representing a 40% reduction in the proportion of patients requiring transfusion. These results support recommendations for Address reprint requests to: Robert Turner, MD, Cross Cancer Institute, University Avenue NW, Edmonton, Alberta T6G 1Z2, Canada. Accepted for publication: January 20, U.S. Cancer Pain Relief Committee, /01/$ see front matter Published by Elsevier, New York, New York PII S (01)

2 Vol. 22 No. 5 November 2001 Evidence-Based Guidelines for Epoetin Alfa in Cancer Patients 955 the use of epoetin alfa in patients with cancer-related anemia. J Pain Symptom Manage 2001;22: U.S. Cancer Pain Relief Committee, Key Words: Anemia, cancer, epoetin alfa, fatigue, quality of life Introduction The treatment of cancer has historically focused more on issues of survival and managing acute severe toxicities than on quality of life (QOL). In recent years, improvements in cancer care have allowed oncologists and patients to focus on QOL as a central issue. However, many studies have reported that cancer-related fatigue is frequently not mentioned by patients, not assessed by physicians, and not adequately addressed as an integral part of the treatment plan. 1 Yet, fatigue is a symptom that has a substantial impact on QOL. A survey of 913 cancer patients 2 found that 78% reported moderate or severe fatigue, while only 48% reported nausea and 42% reported pain. Fatigue had the greatest impact on various measures of QOL, such as ability to work, financial burden, and family and social life; poor QOL was reported to greatly limit patients satisfaction with treatment. Curt et al. 3 also found that patients decisively ranked fatigue as the longest lasting and most disruptive symptom to their everyday lives, and that fatigue had severe economic repercussions for both cancer patients and caregivers who had to take time off work to assist them. Cancer-related fatigue is multidimensional and challenging to define. In an effort to provide standardization, Cella et al. 4 have proposed diagnostic criteria for a new International Classification of Diseases diagnosis of cancerrelated fatigue. Cancer-related fatigue in any given individual is generally the outcome of various contributing factors. These may include: The underlying disease itself Treatments for the disease Intercurrent disorders (e.g., anemia, infection, renal or hepatic failure, malnutrition) Sleep disorders Immobility or lack of exercise Chronic pain Use of centrally acting drugs Psychosocial factors. Hence, the evaluation and management of fatigue is complex and requires that the clinician consider various etiologies and devise a methodical and comprehensive plan to manage fatigue effectively. 5 One of the most important causes of cancerrelated fatigue is anemia. Cancer-related anemia per se also has many possible etiologies. Although chemotherapy regimens are well-known contributing factors in this regard, there is a paucity of literature on chemotherapy-induced anemia. Studies of toxicities associated with chemotherapy regimens often do not report anemia that is Grade 2 or lower (Hb 80 g/l). However, Groopman and Itri 6 reviewed a wide range of published chemotherapy trials and found incidences of Grade 3 and 4 anemia as high as 75% with some traditional chemotherapy regimens (e.g., CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] for non- Hodgkin s lymphoma). The incidence of anemia is also reported to be high with newer chemotherapeutic agents, some of which are highly cytotoxic. Hence, chemotherapy-induced anemia is an important contributing factor to poor QOL in cancer patients. Epoetin alfa (recombinant human erythropoietin) is an established treatment of anemia in patients with chronic renal disease: it improves Hb (hemoglobin) levels, diminishes red blood cell transfusion requirements, and improves quality of life. Evidence from RCTs also suggests this agent is effective in improving anemia in patients with HIV, surgical patients, and patients with anemia due to cancer or chemotherapy. Epoetin alfa is currently approved in Canada for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the disease itself, or to the effect of concomitantly administered chemotherapy. 7

3 956 Turner et al. Vol. 22 No. 5 November 2001 Table 1 Summary of Clinical Trials Examining the Effect of Epoetin Alfa on Red Blood Cell Transfusion Requirements in Patients with Cancer Receiving Chemotherapy Study/Tumor Type Hb Criteria at Entry (g/l) rhuepo Dosing Regimen Treatment Groups (n) Number Requiring Transfusion (mean units/ patient) P Value Abels et al., Gebbia et al., Head and neck, small cell lung Gamucci et al., Cascinu et al., Crawford et al., Small cell lung Thatcher et al., Small cell lung before CT 90 during CT Normal 105 Welch et al., Normal Ovarian advanced de Campos et al., Small cell lung Ehmer et al., Wurnig et al., Bone Del Mastro et al., Breast 3x/wk 12 wk 3x/wk x 3 CT cycles 3x/wk 12 wk 100 IU/kg SC 3x/wk 9 wk Non-cispl epo (79) Non-cispl pb (74) Cisplatin epo (64) Cisplatin pb (61) Carbo/Cisplatin epo (8) Carbo/Cisplatin pb (9) Cisplatin epo (21) Cisplatin (17) Cisplatin epo (50) Cisplatin pb (49) 75 IU/kg SC once daily 6 CT cycles Non-Pt epo (14) Non-Pt pb (13) 3x/wk Pt epo 150 (42) 300 IU/kg SC 3x/wk Pt epo 300 (44) x 6 CT cycles Pt (44) 300 IU/kg SC 3x/wk Pt epo (15) for up to 6 CT cycles Pt (15) Carbo epo 150 (12) 3x/wk 6 cycles Carbo epo 300 (12) 300 IU/kg SC Carbo (12) 3x/wk 6 cycles Anemic 5000 IU/day SC Pt epo (57) Pt (51) Non-Pt epo (44) Non-Pt (37) Total epo (101) Total (88) 110 trigger for rhuepo therapy 120 Kurz et al., Gynecological Csáki et al., Oberhoff et al., or 135 Ovarian, breast, lung with a 1.5 drop in preceding CT cycle Thatcher et al., Small cell lung ten Bokkel Huinink et al., Ovarian Varan et al., trigger for rhuepo therapy 600 IU/kg IV 2 /wk 20 wk 3x/wk 6 CT cycles IU/kg SC 3x/wk 12 wk 3x/wk 12 wk 5000 IU/day SC 12 wk (Approx 450 IU/kg/wk) 3x/wk 6 cycles 300 IU/kg SC 3x/ wk 6 cycles 3x/wk 6 cycles 300 IU/kg SC 3x/wk 6 cycles 3x/wk 2 mo Pt/Non-Pt epo (15) Pt/Non-Pt (14) Non-Pt epo (31) Non-Pt (31) Pt/Non-Pt epo (23) Pt/Non-Pt pb (12) CT epo (12) CT (8) Pt epo (57) Pt (51) Non-Pt epo (44) Non-Pt (37) Pt/Non-Pt epo 150 (42) Pt/Non-Pt epo 300 (44) Pt/Non-Pt (44) Pt epo 150 (46) Pt epo 300 (42) Pt (34) Pt/Non-Pt epo (17) Pt/Non-Pt (17) 32 (2.03) 36 (2.75) 34 (3.56) 42 (4.01) 0 4 NA 10 (0.30) 28 (1.8) (4) 8 (5.4) (2.1) 14 (8.4) (0.75) 3 (1.0) P 0.01 NS NA NA NA P 0.05 epo 150 P epo 300 P 0.01 NS P P 0.28 P 0.02 P 0.01 (for mean units/patient) NA P NS P 0.04 NA P 0.05 P (compared to control) P NS P (continued)

4 Vol. 22 No. 5 November 2001 Evidence-Based Guidelines for Epoetin Alfa in Cancer Patients 957 Table 1 Continued Study/Tumor Type Hb Criteria at Entry (g/l) rhuepo Dosing Regimen Treatment Groups (n) Number Requiring Transfusion (mean units/ patient) P Value Littlewood et al., Carabantes et al., Small cell lung, ovarian 105 3x/wk 6 cycles 4 wk post-ct IU/kg SC 3x/ wk 6 cycles 4 wk post-ct Non-Pt epo (251) Non-Pt pb (124) Pt epo (20) Pt (15) P P Abbreviations: carbo, carboplatin; CT, chemotherapy; epo, epoetin alfa; IV, intravenous; NA, not available; Non-cispl, non-cisplatin chemotherapy; Non-Pt, non-platinum-based chemotherapy; NS, not significant; pb, placebo; Pt, platinum-based (including cisplatin) chemotherapy; rhuepo, recombinant human erythropoietin; SC, subcutaneous. Methods In order for treatment recommendations to be adopted, they must be supported by evidence from RCTs. In this case, studies were reviewed that (a) examined the effects of epoetin alfa treatment on functional capacity and QOL, and/or (b) explored its effects on transfusion requirements in patients with cancer. MEDLINE (January 1985 to September 1999), CANCERLIT (January 1985 to August 1999), HealthStar (February 1997 to September 1999), and Cochrane Library (1999 Issue 2) databases were searched using the terms erythropoietin and cancer. The Proceedings of the 1997, 1998, and 1999 Annual Meetings of the American Society of Clinical Oncology (ASCO) were also searched for reports of completed trials. To examine the effects of epoetin alfa on red blood cell transfusion requirements, trials were selected if they were RCTs, compared epoetin alfa with a suitable control group, specified analyzable outcome measures, and studied patients with cancer who were receiving chemotherapy. In addition, one open-label study by Quirt et al. 8 and one of the three RCTs reported by Abels et al. 9 dealt with cancer patients who were not receiving chemotherapy. Trials involving patients with hematologic malignancies originating in bone marrow were excluded. In order to obtain a precise estimate of the effect of epoetin alfa on transfusion requirements in patients receiving chemotherapy, a meta-analysis was performed by Cancer Care Ontario. 10 Data from the RCTs was pooled using the Meta-analyst software provided by Dr. Joseph Lau (Boston, MA). The overall effect of erythropoietin is expressed as a risk ratio, the ratio of the risk of target events in treated patients to the risk of target events in untreated patients. Estimates 1.0 favored control (no erythropoietin or placebo), and estimates 1.0 favored experimental (erythropoietin). A broad range of RCTs were included in the meta-analysis; therefore, a random effects model was selected because the variations between the RCTs in patient factors (tumor type, hematologic status, chemotherapy regimen), epoetin alfa dose, and methodology were expected to produce statistical heterogeneity. Results The literature search yielded 19 RCTs that met the criteria for eligibility. Characteristics and outcomes of the RCTs are summarized in Table 1. To examine the effects of treating anemia with epoetin alfa on QOL, 5 randomized, placebo-controlled trials and 2 large, open-label, nonrandomized, community-based studies were examined. The characteristics and results of these studies are summarized in Table 2. Crosssectional analyses of data pooled from the community-based studies were also reviewed. RCTs That Included QOL Assessment Several RCTs examined QOL using various validated instruments. One of these is the LASA, a 100 mm line along which patients mark their response to questions such as How

5 958 Turner et al. Vol. 22 No. 5 November 2001 Study/Tumor type Abels et al., Kurz et al., Gynecological Thatcher et al., Small cell lung Littlewood et al., Carabantes et al., Small cell lung, ovarian Glaspy et al., Non-myeloid tumors Demetri et al., Non-myeloid tumors Table 2 Studies of the Effects of Epoetin Alfa on Quality of Life in Patients with Cancer Hb Criteria at Entry (g/l) Epoetin Alfa Dosing Regimen 3x/wk 12 wk 100 IU/kg SC 3x/wk 8 wk IU/kg SC 3x/wk 12 wk 3x/wk 6 cycles 300 IU/kg SC 3x/wk 6 cycles 3x/wk 6 cycles 4 wk post-ct IU/kg SC 3x/wk 6 cycles 4 wk post-ct Anemic IU/kg SC 3x/wk 4 mo IU SC 3x/wk 16 wk Treatment Groups (n) Non-cispl epo (79) Non-cispl pb (74) Cisplatin epo (64) Cisplatin pb (61) No CT epo (63) No CT pb (55) Pt/Non-Pt epo (23) Pt/Non-Pt pb (12) Pt/Non-Pt epo 150 (42) Pt/Non-Pt epo 300 (44) Pt/Non-Pt (44) Non-Pt epo (251) Non-Pt pb (124) Pt epo (20) Pt (15) N 2342; 1498 evaluable for QOL N 2370 QOL Outcome Measures QOL Results LASA LASA Energy Energy Improved Activity Activity Improved Overall QOL Overall QOL P 0.05 compared to placebo General 10- item questionnaire LASA Energy Activity Overall QOL WHO performance score LASA Energy Activity Overall QOL FACT-G FACT-F FACT-An SF-36 Nottingham Health Profile LASA Energy Activity Overall QOL LASA Energy Activity Overall QOL FACT-An FACT-An subscale P NS Overall QOL for 150 IU/ kg vs. baseline P 0.05 WHO P NS LASA Energy P Activity P 0.01 Overall QOL P 0.01 FACT-G P 0.05 FACT-F P 0.01 FACT-An P 0.01 SF-36 P NS EnergyP 0.03 Mobility P 0.04 Days of restricted activity P 0.04 LASA Base Termination Energy * Activity * Overall QOL * LASA Base Termination Energy * Activity * Overall QOL * FACT-An P FACT-An subscale P Abbreviations: CT, chemotherapy (platinum- or non-platinum-based); epo, epoetin alfa; FACT, Functional Assessment of Cancer Therapy scale; FACT-An, FACT anemia subscale; FACT-F, FACT fatigue subscale; FACT-G, FACT general subscale; Hb, hemoglobin; LASA, Linear Analogue Self- Assessment scale; Non-cispl, non-cisplatin chemotherapy; Non-Pt, non-platinum-based chemotherapy; NS, no significant differences between groups; pb, placebo; Pt, platinum-based (including cisplatin) chemotherapy; QOL, quality of life; rhuepo, recombinant human erythropoietin; SC, subcutaneously; SF-36, Medical Outcomes Study Short Form-36; WHO, World Health Organization performance score. *Refers to a significant difference in the linear analogue score. would you rate your energy level in the past week? This type of scale has a long history of use in pain and symptom reporting. 11 The FACT measurement system 12 was developed from the FACT-General (FACT-G), which consists of 29 general questions that examine four domains of QOL (physical, functional, emotional, and social well-being). The FACT- Fatigue (FACT-F) is comprised of the FACT-G with 13 additional questions relating to fatigue. The FACT-Anemia (FACT-An) is comprised of the FACT-G with 13 additional questions relating to fatigue and 7 questions relating to nonfatigue consequences of anemia. 13 The anemia subscale consists of only the 13 fatigue and 7 non-fatigue questions. The FACT scales have been used by large cooperative oncology groups to measure QOL, and have documented reliability and validity. Their results are highly correlated with those of the LASA. 14 European Epoetin Alfa Study. The largest and most recent randomized, placebo-controlled trial by Littlewood et al. 15 examined the bene-

6 Vol. 22 No. 5 November 2001 Evidence-Based Guidelines for Epoetin Alfa in Cancer Patients 959 fits of epoetin alfa on QOL, transfusion requirements, and anemia in 375 patients with cancer receiving non-platinum-based chemotherapy (Table 3). One of the main focal points in the QOL assessment was fatigue, which is associated with the decrease in Hb induced by treatment. QOL was assessed by the FACT measurement system, including FACT-An, FACT-G, FACT-F, and LASA, which were specifically designed to assess mental and physical component summaries of the Medical Outcomes Study Short Form-36 (SF-36), a generic instrument. Five QOL scales were chosen, a priori, for analysis due to their sensitivity to Hb levels: Total FACT-G, FACT-An Fatigue, LASA-Energy, LASA-Daily Activities, and LASA-Overall QOL. QOL analyses (N 349) were based on changes in scores from baseline to the last assessment. The relevant clinical secondary endpoints such as Hb and hematocrit levels and reticulocyte counts were also evaluated at the last assessment. At last assessment, the FACT-An Fatigue subscale, and LASA Energy, Daily Activities and Overall QOL had improved in the epoetin alfatreated group and deteriorated in the placebo group. The between-group differences were clear and significant for each of these parameters (LASA-Energy, P 0.001; LASA-Daily Activities, P 0.01; LASA-Overall QOL, P 0.01; FACT-G, P 0.05; FACT-F, and FACT-An, P 0.01). The SF-36 scales showed a trend in favor of epoetin alfa, but did not reach statistical significance. The differences seen were not altered by adjusting for subjects who died during the study. Epoetin alfa, transfusion requirements, and QOL: Early results. Abels et al. 9 conducted one of the first placebo-controlled trials of epoetin alfa in Analyzing efficacy results from 206 epoetin alfa-treated patients and 190 placebo-treated patients, investigators showed that epoetin alfa therapy increased hematocrit (P 0.004) and reduced transfusion requirements (P 0.009) compared to placebo. A retrospective QOL analysis indicated that LASA scores for energy level, ability to perform daily activities, and overall quality of life improved in epoetin alfa-treated patients (n 159) from prestudy to final evaluation compared to corresponding changes in placebo-treated patients (n 143). Epoetin alfa treatment was associated with a statistically significant improvement in overall QOL compared to placebo (P 0.05), with a trend to better energy and daily activity levels. Subgroup analysis showed that improvement in QOL was greater in those patients who responded to epoetin alfa treatment. Epoetin alfa in platinum-based chemotherapy. Carabantes et al. 16 studied 35 patients with small cell lung cancer or ovarian cancer receiving platinum-based chemotherapy. These patients all had initial Hb levels 115 g/l, which decreased to 115 g/l after 1 2 cycles of therapy. QOL was evaluated using the Nottingham Health Profile (a validated instrument). Of the 28 evaluable patients, only those in the epoetin alfa-treated group showed significant improvement in scores for energy (P 0.03), mobility (P 0.04), and days of restricted activity (P 0.04). Thatcher et al. 17 examined the ability of epoetin alfa treatment to prevent decline in Hb levels in 130 patients undergoing cyclic chemotherapy for small cell lung cancer. The impact on QOL was assessed with a three-item questionnaire that dealt with energy level, daily activity, and overall QOL. Significant improvement was seen in overall QOL (P 0.05). There were no significant differences in scores for energy level or daily activity. Kurz et al. 18 evaluated the ability of epoetin alfa to increase Hb levels and decrease transfusion requirements in 35 patients with gynecological cancers, most of whom were receiving platinum-based chemotherapy regimens. The effect of epoetin alfa on QOL parameters was also assessed using a visual analogue scale for a 10-item standardized questionnaire. QOL scores were calculated as the average value of weeks 4, 8, and 12 minus the pretreatment value. The ratings on these parameters did not differ significantly between epoetin alfa-treated and placebo groups. Open-Label Community-Based Studies Initial RCTs showing improvement in QOL with epoetin alfa were followed by three large, open-label, nonrandomized, communitybased studies involving over 5000 patients. Glaspy et al. 19 used a dose of 150 IU/kg, administered SC three times per week, Demetri et al. 14 used a dose of 10,000 IU SC three times per week, and Gabrilove et al. 20 used a dose of

7 960 Turner et al. Vol. 22 No. 5 November ,000 IU SC once weekly. The primary goal of these studies was to examine the applicability of the hematological and QOL findings to a broader patient population. These communitybased studies, using both the LASA and FACT scales, showed correction of anemia with epoetin alfa yielded statistically and clinically meaningful improvements in QOL. A direct relationship was seen between Hb level and improvements in QOL, and this association was independent of tumor response. Demetri et al. 14 further showed that data from the FACT-An questionnaire correlated well with the LASA (r 0.72). Patients with an overall QOL increase of 10 mm on the LASA showed a significant improvement in the FACT-An (e.g., patients achieved a 22% increase in FACT-An energy level, a positive, one-level change on the Likert scale, an attitude scale indicating a positive/negative change). Results generated by Gabrilove et al. 20 with once-weekly administration corroborated those of studies with threetimes-per-week regimens. A Canadian open-label study by Quirt et al., 8 involving 183 anemic cancer patients not receiving concomitant chemotherapy, demonstrated similar findings. Among patients who responded to treatment with epoetin alfa, Hb levels were significantly increased, while transfusion requirements were significantly reduced. In addition, both overall QOL scores on the LASA and FACT-An scales improved significantly. Maintenance of Hb Levels There is evidence to support that maintaining Hb levels at or above 120 g/l directly benefits the QOL of patients with cancer. 14 Accurate assessment of QOL is important when evaluating comparative treatments and when making decisions about future treatments. Cella 13 examined how well the FACT-An and FACT-F subscales could assess QOL in cancer patients suffering from fatigue and other anemiarelated symptoms. He concluded that low Hb levels ( 120 g/l) were associated with greater fatigue and poorer overall QOL. He also concluded that, even after accounting for fatigue, low Hb levels ( 120 g/l) were associated with decreased ability to work. A technique known as incremental analysis (or marginal benefit analysis) can be used to quantify the additional gain (or loss) in a given patient s QOL associated with each 10 g/l increase in the patient s Hb level. In an effort to identify the Hb levels necessary for optimal QOL, Cleeland et al. 21 applied incremental analysis to the data from two previous studies involving anemic cancer patients receiving epoetin alfa and chemotherapy. They reported a statistically significant (P 0.01), nonlinear relationship between Hb level and QOL. The largest improvement in QOL for each 10 g/l change in Hb (range: g/l) was seen when the Hb level increased from 110 to 120 g/l (range: g/l). This relationship was seen even after controlling for tumor type and status, transfusions, number of days on study, and extent of chemotherapy and radiotherapy. A statistically significant relationship was also observed between higher Hb levels and better FACT-An subscale scores for physical and functional well being, as well as LASA scores for energy and activity levels. Frequency and Risk Factors for Transfusion In 1997, the Krever Commission 22 reported on the safety of the blood system in Canada and presented recommendations about blood and blood alternatives. Recommendations dealing with the patient s right to decide included: The licensing bodies of the medical profession require in their standards of practice that the treating physician obtain the informed consent of the patient to the administration of blood and blood products... that patients in Canada... will be informed of the risks and benefits of, and alternatives to, allogeneic blood transfusion. These recommendations are consistent with the Canadian Medical Association Guidelines for Red Blood Cell and Plasma Transfusion, 23 which states: Anemia should not be treated with red blood cell transfusions if alternative therapies with fewer potential risks are available and appropriate. Skillings et al. 24,25 examined factors that would select for patients at high risk for receiving transfusions. Both univariate and multivariate analyses demonstrated that a baseline Hb 100 g/l was a strong risk factor for transfusion. Abels et al., 26 studying patients receiving mainly platinum-based chemotherapy, performed a multivariate logistic regression analysis. The study suggested the composite variable of baseline Hb level and change in Hb from baseline

8 Vol. 22 No. 5 November 2001 Evidence-Based Guidelines for Epoetin Alfa in Cancer Patients 961 to the start of the second chemotherapy cycle predicted the risk of transfusion. Patients with baseline Hb levels of 110 g/l that experienced no drop in Hb had a 79% risk of transfusion, compared to patients with baseline Hb levels of 130 g/l and no Hb drop who had a 37% risk of transfusion. Patients with a baseline Hb of 150 g/l with no drop in Hb after the first cycle of chemotherapy had an 8% risk of transfusion. Patients with baseline Hb levels of 110 g/l that dropped 10 g/l had 90% risk for transfusion. In those with baseline Hb levels of 130 g/l that dropped 20 g/l, the risk was 86%. Baseline Hb appeared to be the more important risk factor for patients with lower Hb. For patients with higher Hb, the change in Hb from baseline to the beginning of the second cycle seemed to be the more important risk factor. The RCTs that evaluated the effectiveness of epoetin alfa showed treatment with this agent reduced transfusion requirements and improved Hb or hematocrit levels. This was true whether the patient was already anemic (and receiving chemotherapy), or not yet anemic (prior to the start of chemotherapy). No studies have directly compared the effects of early and late initiation of epoetin alfa treatment. However, those studies that evaluated the effects of epoetin alfa administered before anemia developed reported lower transfusion rates than those studies in which epoetin alfa was initiated once anemia had developed or when Hb levels were already on the decline. 10 Effects of Epoetin Alfa on Red Blood Cell Transfusion Requirements: Results of Meta-analysis Meta-analysis of the effects of epoetin alfa on red blood cell transfusion requirements involved 1845 patients in 18 studies with 21 comparisons. The overall effect of epoetin alfa on the proportion of patients requiring transfusion was expressed as a relative risk ratio with a 95% confidence interval (CI). Because the target event in these studies, i.e., requirement for transfusion, was an undesirable one, risk ratios 1.0 would favor the control groups, while risk ratios 1.0 would favor the epoetin alfa groups. The overall relative risk ratio was 0.60 (95% Cl, ; P ), representing a 40% reduction in the proportion of patients requiring transfusion in the groups treated with epoetin alfa. Survival Benefits: Preliminary Findings Preliminary reports suggest that treating cancer-related anemia may confer survival as well as QOL benefits. Grogan et al. 27 showed cervical cancer patients receiving radiotherapy with or without concurrent chemotherapy, whose average weekly nadir Hb levels during treatment were 110 g/l, had significantly worse 5-year survival rates than those whose levels were at least 120 g/l. Glaser et al. 28 reported a worse prognosis in anemic patients with primary head and neck squamous cell carcinomas treated with neoadjuvant radiochemotherapy. In both cases, correction of anemia (with transfusion in the first study and epoetin alfa in the second) appeared to overcome the negative prognostic effect of Hb levels. It has been hypothesized that anemia increases tumor hypoxia and therefore confers a relative radioresistance, the mechanisms of which are still unknown. 29 Low Hb levels have been linked to a poorer prognosis in cancer patients receiving radiochemotherapy. The study by Littlewood et al, although not statistically powered to evaluate the effect of epoetin alfa on survival, indicated survival benefits in anemic cancer patients receiving non-platinum-based chemotherapy treated with epoetin alfa compared to placebo patients (P 0.128, log rank test). 30 Safety Therapy with epoetin alfa is well tolerated. Adverse effects related to epoetin alfa have been reported as rare and generally mild. No statistically significant differences were seen in the percentage of patients treated with epoetin alfa compared to corresponding incidence in placebo-treated patients over a 3 month period in the study by Abels et al. 9 (n 413). Although thrombotic/vascular events and hypertension have been reported in patients treated with epoetin alfa in clinical trials, these events have been rarely reported in cancer patients. Pain at the site of injection, skin rash, flu-like symptoms, and increase in blood pressure have also been seen in clinical trials. Summary Cancer-related fatigue plays an important role in the QOL of cancer patients. Cancer-related anemia is one of the chief causes of fatigue in

9 962 Turner et al. Vol. 22 No. 5 November 2001 these patients. The treatment, or preferably the anticipatory prevention, of cancer-related anemia is an important target for improving and maintaining QOL among cancer patients. The relationship between Hb levels and fatigue varies greatly between individual patients; hence, the decision to treat a particular patient s anemia rests on clinical judgment that encompasses the patient s entire clinical profile. The volume of literature reviewed proved unequivocally that epoetin alfa increases Hb, decreases transfusion, and improves QOL. One critical element of the clinical profile is the rate of descent of Hb level; rapid drops ( 15 g/l in 3 4 weeks) are more likely to precipitate fatigue and other symptoms of anemia than slower drops. However, in any given patient, Hb levels that correspond to optimal QOL are generally higher than levels that ordinarily trigger transfusion. Therefore, if symptoms of anemia sufficient to impair functional capacity or QOL are anticipated, delay in treatment is likely to incur losses in QOL. This is particularly true if epoetin alfa is to be used, given that its onset of action is about 4 weeks following initial administration. The conventional therapy for chemotherapyor disease-related anemia in patients with cancer is red blood cell transfusion. However, there are several reasons why transfusion may not be an optimal treatment option. These reasons may range from clinical circumstances (risk of iron overload, prevention of alloimmunization, difficulty of venous access, desire to avoid longterm complications in the setting of a curable malignancy) to patient preferences (which may be based on logistical circumstances, religious convictions, or other factors). Hence, the acceptability of transfusion as a treatment option can only be assessed in the context of the individual. In such cases, there is sufficient evidence to recommend that epoetin alfa be used as a treatment option (see Table 3 and Figure 1). Recommendations Because fatigue greatly decreases QOL among patients with cancer and because anemia is an important cause of cancer-related fatigue, the treatment or preferably the anticipatory prevention of cancer-related anemia is an important part of improving and maintaining the QOL of cancer patients. The relationship between hemoglobin (Hb) levels and fatigue varies greatly between individual patients. Thus, the decision to treat a particular patient s anemia rests on clinical judgment that encompasses the patient s entire clinical profile. Epoetin alfa treatment is not indicated for the acute correction of Hb levels that are descending very rapidly or are low enough to be life-threatening. In non-emergency situations, the clinician should consider the rate of descent of Hb levels and the likelihood that delay in treatment is likely to incur loss in QOL (particularly because the onset of action of epoetin alfa is about 4 weeks after therapy begins). In any given patient, however, the Hb levels that correspond to optimal QOL are generally higher than the levels that would ordinarily trigger transfusion. There is evidence from RCTs to recommend epoetin alfa as a safe, effective treatment for Table 3 Suggested Algorithm for Dosing and Administration of Epoetin Alfa 45,46 (see Figure 1) Patient Selection Criteria Symptomatic anemia affecting functional capacity/qol. OR Low baseline Hb levels ( 100 g/l) at the start of cancer chemotherapy. OR Baseline Hb levels ( 120 g/l) where symptoms of anemia sufficient to impair functional capacity or QOL are anticipated. OR A drop in Hb of g/l per cycle of chemotherapy where at least three cycles remain to be administered. AND Anemia directly or indirectly related to malignancy but NOT caused by hemolysis, gastrointestinal bleeding, and iron or folate deficiencies. Pre-Therapy Monitoring 1. Serum ferritin should be 100 g/l and transferrin saturation should be at least 20%. Supplemental iron may be required to maintain levels that will support erythropoiesis. 2. Serum folate should be assessed, as deficiency can blunt response. 3. Baseline reticulocyte count should be measured.

10 Vol. 22 No. 5 November 2001 Evidence-Based Guidelines for Epoetin Alfa in Cancer Patients 963 Fig. 1. Dosage regimen. Note: If Hb is rising more than 20g/L per month, the dose should be reduced by approximately 25%. A number of trials have rounded the IU/kg dose and have obtained similar results; 10,000 IU replaces the 150 IU/kg dose, and 20,000 IU replaces the 300 IU/kg dose. Gabrilove et al. 20 have shown similar results by administering 40,000 IU once weekly (instead of a three-times-weekly dosing schedule), increasing after 4 weeks to 60,000 IU once weekly for 4 weeks if the endpoints have not been achieved. patients with cancer in whom: Symptoms of anemia, sufficient to impair functional capacity or QOL are anticipated or present, or Anemia sufficient to require red blood cell transfusion is anticipated or present, or Transfusion is not an acceptable treatment option for medical reasons or because of patient choice. Acknowledgments The development of these guidelines and the technical support and assistance of Integrated Healthcare Communications Inc. in preparing this manuscript were funded through an unrestricted educational grant from Janssen-Ortho Inc. The opinions expressed by the editors or contributors do not necessarily reflect the views of the sponsor. Any persons or companies engaged to work on this publication do not assume liability for content. References 1. Communication about fatigue between cancer patients and their physicians. [Abstract 2331] Proc Am Soc Clin Oncol 1999;18:604a. 2. Ashbury FD, Findlay H, Reynolds B, McKerracher K. A Canadian survey of cancer patients experiences: are their needs being met? J Pain Symptom Manage 1998;16: Curt G, Breitbart W, Cella D, et al. Impact of cancer-related fatigue on the lives of patients. [Abstract 2214] Proc Am Soc Clin Oncol 1999;18: 573a. 4. Cella D, Peterman A, Passik S, Jacobsen P, Breitbart W. Progress toward guidelines for the management of fatigue. Oncology 1998;12: Portenoy RK, Itri LM. Cancer-related fatigue: guidelines for evaluation and management. Oncologist 1999;4: Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999;91: EPREX Product Monograph. JANSSEN- ORTHO Inc. Toronto, ON: August 19, Quirt I, Kovacs M, Burdette-Radoux S, et al. Epoetin alfa reduces transfusion requirements, increases hemoglobin (Hb) and improves quality of life (QofL) in cancer patients with anemia who are not receiving concomitant chemotherapy. [Abstract 2295] Proc Am Soc Clin Oncol 1999;18:594a. 9. Abels RI, Larholt KM, Krantz KD, Bryant EC. Recombinant human erythropoietin (r-huepo) for the treatment of the anemia of cancer. Blood cell growth factors: their present and future use in hematology and oncology. Proceedings of the Beijing Symposium. Dayton, OH: AlphaMed Press; 1991: Update Bulletin. Erythropoietin in the manage-

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