This study involved 2 primary outcomes (overall survival and recurrence-free survival) and 18 explanatory variables (2 measures, average and nadir, for each of the perichemotherapy, perioperative, and total Hb levels, plus their corresponding graded Hb variables, and 3 variables for the number of blood transfusion: total, perichemotherapy, and perioperative and their corresponding categorical variables). Because of the correlations among the variables, no Bonferroni correction was performed. The most significant finding in this study was the relationship between the perichemotherapy average Hb levels as a categorical variable and recurrence-free survival (P = 0.003).
The principal finding of our study is that 95% of patients undergoing primary treatment have evidence of anemia; during this time period, 26% had severe (grade 3–4) anemia. In the perioperative period, 45% of patients received a blood transfusion, whereas only 19% of patients in the perichemotherapy period received a blood transfusion. The average Hb within the perichemotherapy period was associated with recurrence-free survival (P = 0.03) (Table 3; Fig. 1). Average Hb as a categorical variable within the perichemotherapy period was also associated with overall survival (P = 0.015) (Table 3; Fig. 2). Finally, the total number of transfusion was associated with poor recurrence-free survival as a continuous variable (P = 0.026). There were no significant findings in the perioperative period.
Erythropoietin and other erythropoiesis-stimulating agents (eg, darbepoetin, CERA-Epo) were found to improve QOL, increase Hb levels, decrease the need for transfusions, and prevent chemotherapy delay or dose modifications,1,8,12,23,26,30,32–34 but were expensive and associated with possible adverse effects,8,23 including increased mortality.35–37 Erythropoietin is currently not recommended for use in patients with cancer for the treatment of anemia,3,4,38 making blood transfusion the currently accepted criterion-standard treatment.
Many studies have sought to determine the critical threshold for blood transfusions. A large multicenter randomized controlled trial looked at a restrictive (Hb <70 g/L) versus a liberal (Hb < 100 g/L) transfusion strategy.44,45 The authors found overall mortality was significantly lower in the restrictive strategy group (22.2 vs 28.1%, P = 0.05).44 In a separate analysis of cardiovascular patients, the authors found that those who had severe ischemia in the restrictive group had a nonsignificant lower absolute survival rate. They concluded that a restrictive transfusion protocol was beneficial to all patients who had not had angina or an acute myocardial infarction.45 The American Society of Clinical Oncology and the American Society of Hematology guidelines recommend starting treatment with Hb values less than 100 g/L.46,47 Current literature provides no consensus about the optimum level of Hb for which to initiate transfusion in oncology patients.
Multiple studies in oncology have observed worse outcomes (decreased survival and increased recurrence) in people who received transfusions with multiple malignancies.8,9,14–19 Patients with lower Hb levels may have more aggressive or advanced disease.8–10,17 Initial studies in renal transplant patients suggested a benefit from an altered immune function.22,28
Gastrointestinal cancers are well studied with regard to transfusions. Transfusions have been associated with an increased rate of recurrence and death from malignancy in colorectal cancer.25–28 Amato and Pescatori21 performed a Cochrane review of 36 randomized controlled trials of perioperative transfusion in colorectal cancer patients. This meta-analysis found an increased recurrence rate in transfused patients with an odds ratio of 1.42 (1.20–1.67). Because of the theory of immunosuppression from transfusion, 2 randomized controlled trials were performed in colorectal patients comparing allogenic transfusion to nonimmunogenic autologous transfusions. Both studies48,49 found no between-groups differences, but the risk of recurrence increased with either form of transfusion. Blood transfusion in the perichemotherapy period had no effect in colorectal patients.47
In our population, only 19% of patients received a transfusion in the perichemotherapy period, whereas 45% received a transfusion in the perioperative period. Total transfusions did have an association with recurrence-free survival; however, there was no association with overall survival. Our results differ from the reported colorectal literature with no association of nadir, average Hb, or transfusion in the perioperative period.
Minimal research has been performed in gynecologic oncology on the issue of blood transfusions. The majority of research regarding anemia and transfusion has revolved around cervical cancer, with a rate of anemia of 18% to 82%.10,29,30 Anemia was associated with decreased QOL, increased transfusion rates, increased pelvic recurrence rates, increased tumor stage/size/lymph node status, decreased metastatic-free survival, and decreased survival.10,29,30,42,50,51 Anemia in cervical cancer is therefore either a marker for more aggressive disease, higher tumor burden, or a direct cause of hypoxia and radioresistance.16,24,42 Grogan et al42 tried to clarify this with a multicenter retrospective study of 605 patients in Canada. The authors confirmed that anemia was associated with decreased 5-year survival rate and increased recurrence rates. However, transfusion at a specific level had equivalent survival to those who achieved those levels spontaneously.42 It is well supported that anemia in cervical cancer is a poor prognostic factor for survival and outcome.
Anemia in ovarian cancer has been studied in several retrospective series. Obermair et al52 first examined anemia in 206 patients and found that Hb levels of less than 120 g/L were an independent poor prognostic factor for overall and progression-free survival. The same group reported a subsequent analysis of 553 patients and found that anemia was a poor prognostic indicator only in stage 1–2 disease.53 Several other groups have also shown a poor prognosis for anemia for overall survival on univariate analysis; however, the association diminishes with a multivariate analysis.54,55 Kumagai et al56 examined the incidence and prognosis of anemia with dose-dense taxol (JGOG 3016 trial). They found a rate of grade 3–4 anemia of up to 56% in the dose-dense-taxol group, but did not find any association with progression-free survival and were unable to analyze transfusion data. Several small studies have identified age, pretreatment Hb levels, and type of chemotherapy as risk factors for transfusion in ovarian cancer.57,58
The main limitations of our study relate to its retrospective design. We are limited by available data resulting in reporting and recall bias and possible changes in practice over the time of the study. There may also have been a selection bias that is unknown; clear rules for patient selection for transfusion were not in the available charts. It is possible that patients who received transfusions had more comorbidities than did patients not receiving transfusions; however, if this was the case, we would expect transfused patients to do significantly worse than patients who did not receive blood. The study was also limited by a relatively small sample and limited data on patient comorbidities and concurrent medical conditions.
Several other factors should be noted about our findings. Within the total average Hb group, there was no grade 3–4 anemia seen (Table 2). This is likely an anomaly due to transfusions, resulting in a mean value greater than 80 g/L, and represents our center’s transfusion protocols. Because of the difficulties of averages, a decision was made to also analyze nadir values, which were more representative of the true severity of the anemia. Three different time frames were analyzed (perichemotherapy, perioperative, and total) to be able to compare our results to both general oncology and colorectal literature.
Our study is the first retrospective analysis of the effects of blood transfusion on ovarian cancer survival. There appears to be an association of recurrence-free survival and overall survival with average Hb in the perichemotherapy period. These trends are significant only for grade 2–4 anemia. Although maintaining average Hb greater than 80 g/L portends an improved overall survival, transfusion does not seem to have any effect. The role of transfusion should therefore be limited to symptomatic patients while giving 1 unit at a time. This finding is in agreement with the current ACP guidelines and would decrease overtransfusion and minimize complications. Further prospective studies will need to confirm these results.
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APPENDIX Detailed explanation of excluded patients
- 4 had no documented pathologic diagnosis
- 4 had non-ovarian/peritoneal/fallopian primary cancers
- 22 had no data
- 23 were treated outside of Alberta
- 1 had inappropriate stage
- 1 had no diagnosis date
- 3 had borderline ovarian tumors