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© 2003 American Society for Clinical Oncology Risk Model Predictive of Severe Anemia Requiring RBC Transfusion After Chemotherapy in Pediatric Solid Tumor PatientsFrom the Pediatric Oncology Unit, INSERM U590, the Statistics department, and the Medical Oncology Unit, Centre Léon Bérard, Lyon Cedex, France. Address reprint requests to Perrine Marec-Berard, MD, Centre Léon Bérard, 28 rue Laennec, 69373 Lyon Cedex 08, France; e-mail: marec{at}lyon.fnclcc.fr.
Purpose: Severe anemias requiring RBC transfusions is a frequent complication of chemotherapy. A model elaborated by Ray-Coquard et al in adults pointed to three independent risk factors for RBC transfusion: performance status (PS) more than 1, hemoglobin less than 12 g/dL, and prechemotherapy absolute lymphocyte count (ALC)  700/µL. This model is tested on a pediatric population. Patients and Methods: One hundred nineteen children with solid tumors consecutively admitted for conventional chemotherapy throughout 1 year were included. The study end point was the RBC-transfusion risk in the month following chemotherapy. Only one course was considered for each patient. Age, sex, number of courses, platinum-containing regimens, PS, and hemoglobin and lymphocyte count at day 1 were tested in univariate and multivariate analyses.
Results: Thirty-one (26%) of 119 children required RBC transfusion within 31 days of chemotherapy. Three factors correlated to transfusion risk in the univariate analysis: PS more than 1 (P < .001), hemoglobin less than 12 g/dL (P = .007), and pretreatment ALC Conclusion: The risk model elaborated for adults may also segregate children at high risk of postchemotherapy RBC transfusion, thus facilitating assessment of risk of transfusion and/or prophylactic erythropoietin support.
ONE-THIRD OF all adults with solid tumors or hematologic malignancies (lymphomas) receiving conventional chemotherapy will require RBC transfusion. In a recent European pediatric survey, 80% of children receiving chemotherapy were reported anemic regardless of tumor type, and 95% of children requiring treatment received blood transfusion.1 However, transfusions of allogeneic blood may be associated with various short- or long-term adverse effects. Recombinant erythropoietin (rhEPO) administration may prove an alternative to RBC transfusion for preventing anemia. However, due to the extra cost of the treatment and inconveniences for children, it should be proposed only to patients at high risk of developing anemia.
A risk model validated in 1999 by Ray-Coquard et al2 on adult patients of the Elypse study, identified three independent factors for the risk of requiring transfusion within 31 days from initiation of chemotherapy: performance status (PS) more than 1, hemoglobin less than 12 g/dL, and prechemotherapy absolute lymphocyte count (ALC) The purpose of this study was to investigate this model in a pediatric cohort of children with solid tumors receiving conventional chemotherapy at the Centre Léon Bérard (CLB) of Lyon.
Patient Selection A retrospective monocentric study of the hematological consequences of chemotherapy was conducted in children treated in the CLB at Lyon from January 2000 to December 2000. This retrospective group included all pediatric patients consecutively treated with chemotherapy in the CLB 2000 cohort, who matched the selection criteria. These selection criteria were: age less than 18 years, having solid tumor, and receiving chemotherapy. Patients receiving a continuous chemotherapy regimen or concomitant cytokine treatments were not included. High-dose chemotherapy regimens requiring bone-marrow or peripheral-blood stem cell reinjection were also considered as exclusion criteria. Each patient was included only once. For each patient, only the first course of chemotherapy delivered in 2000 was taken into consideration. Information about the use of RBC transfusion in the 31 days following chemotherapy was collected.
Data concerning histology, chemotherapy regimen, sex, age, and Eastern Cooperative Oncology Group (ECOG) PS were collected. The correspondence between the Lansky score, the Karnofski score, and the ECOG scale3,4 is presented in Table 1
Criteria for RBC Transfusion The end point of the study was the transfusion of RBC for severe anemia within 31 days from the start of chemotherapy administration. In this pediatric population, RBC transfusion was given when hemoglobin levels were lower than 7 g/dL, or in case of poorly tolerated anemia with hemoglobin level less than 10 g/dL (shock, sepsis, cardiopathy, pulmonary disturbance).
Chemotherapy Regimens
Statistical Analysis
Of 122 children who received one or more chemotherapy courses between January 1, 2000 and December 31, 2000, there were 119 (69 males, 50 females) who fulfilled the selection criteria. Three children were excluded because of receiving prophylactic granulocyte colony-stimulating factor treatment. The median age of patients in the cohort was 8 years (range, 2 months to 18 years). Diagnosis included 25 brain tumors, 17 neuroblastomas, 15 osteosarcomas, 12 Wilms’tumors, 12 sarcomas, 10 Ewing sarcomas, seven non-Hodgkin’s lymphomas, six Hodgkin’s diseases, and 15 patients with other histology.
Univariate Analysis
In univariate analysis, PS greater than 1, hemoglobin level less than 12 g/dL, and ALC less than 700/µL immediately before initiation of chemotherapy (day 1) were found to be significantly (P < .05) related with the risk of RBC transfusion, whereas age (± 8 years), sex, Cisplatin-containing regimen, and number of previous chemotherapy courses did not correlate to the risk of transfusion (Table 2  ). Tumor type, baseline platelet, WBC or polymorphonuclear neutrophils count were not found correlated to the incidence of RBC transfusion.
Multivariate Analysis
Risk Model
The calculated probability of receiving RBC transfusion within 31 days from chemotherapy was high, with three risk factors (96%): intermediate with two risk factors (53% to 77%), low with only one risk factor (10% to 26%), and very low when no risk factor was present (2%; Table 3 ). The difference in the occurrence of transfusion between the four groups of the cohort was found to be highly significant (P < .001).
Anemia is a common complication in patients receiving chemotherapy, with incidence rates ranging from 2% to 78% for solid tumors, and as high as 63% for hematological malignancies in adult populations.5 Decreased hemoglobin counts could give rise to several symptoms such as fatigue, exhaustion, and impaired quality of life,6 and may worsen disease prognosis.7,8 The pragmatic objective of this study was to identify risk factors for chemotherapy-induced severe anemia requiring RBC transfusion in a population of children with various cancer types treated with different chemotherapy regimens, to select patients who might benefit from prophylactic treatment or more intensive surveillance. Tumor site, baseline hemoglobin level, RBC count, parameters of iron metabolism, and toxicity of chemotherapy had previously been reported as risks factors for anemia in adult cancer patients.9–12 Ray-Coquard et al2 have identified pretreatment risk factors capable of segregating adult patients at increased risk of severe anemia requiring RBC transfusion (SARRT). The reproducibility of this model in two validation groups of patients, as well as the large number of patients analyzed suggest that this risk model may be used to identify candidate patients for prophylactic measures or focused surveillance between chemotherapy courses. In this study, a similar strategy was used to identify children at high risk for severe anemia after cytotoxic chemotherapy: simple clinical and biologic risk factors for SARRT were tested in a univariate analysis and in a multivariate analysis. Independent risk factors were then used to delineate a risk model for SARRT. Using this strategy, the same three independent risk factors identified in the adult population were demonstrated to be predictive for the risk of SARRT in the pediatric population (ie, hemoglobin level, PS, and lymphocyte count). Of note, the relative risks associated with these three factors were slightly different in the pediatric and adult populations. Lymphopenia was the strongest predictor of SARRT in the pediatric model, followed by hemoglobin level and PS, while, in the adult population hemoglobin level was associated with a three-fold higher relative risk of SARRT as compared with performance status and lymphopenia. In the pediatric model, given the CIs of their odds ratios, a similar weight was given to these three predictive factors. This pediatric risk model based on the three risk factors also identified in an adult cohort2 was found capable of distinguishing subgroups of children with a significantly different risk of RBC transfusion: children with none, one, two, or three of these independent risk factors had respective incidences of SARRT of 0%, 17%, 59%, and 100%, respectively. The two highest-risk groups (patients with two or three risk factors) comprised 31 (26% of the 119 patients) of all children included in this study: 20 (66%) of these children indeed required transfusion within 1 month. Two-thirds of all children receiving transfusions were identified as belonging to these two highest-risk groups. This index does not depend on the number of chemotherapy courses previously received; therefore, it could be applied to any patient matching the inclusion criteria at any step of the treatment program. Before the availability of erythropoietin treatment, RBC transfusions has been the standard treatment of severe anemia of cancer patients; however, RBC transfusion are associated with numerous adverse effects, including the transmission of infectious diseases, and have only a limited capacity to ameliorate the symptoms of anemia. Erythropoietin may represent a more physiologic treatment option, especially in the long-term treatment of cancer- and cancer treatment–associated anemia.5 rhEPO treatment has been shown to improve quality of life in adult patients with chemotherapy, regardless of disease type and response to chemotherapy.13–15 The efficacy of rhEPO in children receiving chemotherapy is controversial. Few small studies (mostly nonrandomized) with heterogeneous recruitment, objectives, and evaluation criteria failed to demonstrate efficacy.16–20 Besides, children do not like shots, and existing epoietin preparations have very low patient acceptance. For these reasons, available evidence is insufficient, and there is provider reluctance to recommend the use of parenteral erythropoietin therapy in children.21 Three large, multicenter clinical trials testing the efficacy and safety of epoietin alfa in anemic children with cancer are currently underway—one in Europe and two in the United States. Still, it will be useful to identify children patients at high risk for SARRT, to propose primary prophylaxis of this complication with rhEPO in a population of patients in which this strategy could be both clinically justified and cost-effective. The present model could be useful in routine clinical practice for this purpose. In addition, this model could also be used for patient selection in subsequent randomized study focusing on high-risk cohorts of patients.
The authors indicated no potential conflicts of interest.
1. Michon J: Incidence of anemia in pediatric cancer patients in Europe: Results of a large, international survey. Med Pediatr Oncol 39:448–450, 2002[CrossRef][Medline]
2. Ray-Coquard I, Le Cesne A, Rubio MT, et al: Risk model for severe anemia requiring red blood cell transfusion after cytotoxic conventional chemotherapy regimens: The Elypse 1 Study Group. J Clin Oncol 17:2840–2846, 1999 3. Lansky SB, List MA, Lansky LL, et al: The measurement of performance in childhood cancer patients. Cancer 60:1651–1656, 1987[CrossRef][Medline] 4. Verger E, Salamero M, Conill C: Can Karnofsky performance status be transformed to the Eastern Cooperative Oncology Group scoring scale and vice versa? Eur J Cancer 28:1328–1330, 1992[CrossRef] 5. Ludwig H: Anemia of hematologic malignancies: What are the treatment options? Semin Oncol 29:45–54, 2002[Medline]
6. Estrin JT, Schocket L, Kregenow R, et al: A retrospective review of blood transfusions in cancer patients with anemia. Oncologist 4:318–324, 1999 7. Caro JJ, Salas M, Ward A, Goss G: Anemia as an independent prognostic factor for survival in patients with cancer: A systemic, quantitative review. Cancer 91:2214–2221, 2001[CrossRef][Medline] 8. Ludwig H, Pecorelli S: Suboptimal hemoglobin levels: Do they impact patients and their therapy? Audience responses. Semin Oncol 27:18–19, 2000[Medline] 9. Skillings JR, Sridhar FG, Wong C, et al: The frequency of red cell transfusion for anemia in patients receiving chemotherapy: A retrospective cohort study. Am J Clin Oncol 16:22–25, 1993[Medline]
10. Del Mastro L, Venturini M, Lionetto R, et al: Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy-induced anemia. J Clin Oncol 15:2715–2721, 1997
11. Fein DA, Lee WR, Hanlon AL, et al: Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol 13:2077–2083, 1995 12. Hensley ML, Lebeau D, Leon LF, et al: Identification of risk factors for requiring transfusion during front-line chemotherapy for ovarian cancer. Gynecol Oncol 81:485–489, 2001[CrossRef][Medline]
13. Gabrilove JL, Cleeland CS, Livingston RB, et al: Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: Improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 19:2875–2882, 2001
14. Littlewood TJ, Bajetta E, Nortier JW, et al: 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 19:2865–2874, 2001 15. Demetri GD, Kris M, Wade J, et al: Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: Results from a prospective community oncology study—Procrit Study Group. J Clin Oncol 16:3412–3425, 1998[Abstract] 16. Beck MN, Beck D: Recombinant erythropoietin in acute chemotherapy-induced anemia of children with cancer. Med Pediatr Oncol 25:17–21, 1995[Medline] 17. Bolonaki I, Stiakaki E, Lydaki E, et al: With recombinant human erythropoietin in children with malignancies. Pediatr Hematol Oncol 13:111–121, 1996[Medline] 18. Leon P, Jimenez M, Barona P, Sierrasesumaga L: Recombinant human erythropoietin for the treatment of anemia in children with solid malignant tumors. Med Pediatr Oncol 30:110–116, 1998[CrossRef][Medline] 19. Csaki C, Ferencz T, Schuler D, Borsi JD: Recombinant human erythropoietin in the prevention of chemotherapy-induced anaemia in children with malignant solid tumours. Eur J Cancer 34:364–367, 1998[CrossRef][Medline] 20. Henze G, Michon J, Morland B, et al. Phase III randomized study: Efficacy of epoetin alfa in reducing blood transfusions in newly diagnosed pediatric cancer patients receiving chemotherapy. Proc Am Soc Clin Oncol 21:387, 2002 (abstr 1547)
21. Corazza F, Beguin Y, Bergmann P, et al: Anemia in children with cancer is associated with decreased erythropoietic activity and not with inadequate erythropoietin production. Blood 92:1793–1798, 1998 Submitted September 24, 2002; accepted September 25, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher’s exact test. A logistic regression analysis, including the parameters studied in the univariate analysis, was performed using the logistic regression program of SPSS; a backward regression procedure was used with a P value less than .10 for entry. The risk factors and the end point were dichotomized; only the number of chemotherapy courses was coded into three groups. This multivariate analysis was performed in the 119 patients of the CLB 2000 pediatric series. A risk model was established using the independent risk factors identified in the multivariate analysis. 
