International Journal of Gynecological Cancer:
The Effects of Anemia and Blood Transfusion on Patients With Stage III-IV Ovarian Cancer
Altman, Alon D. MD, FRCSC*; Liu, Xiao-Qing MD, MSc*†; Nelson, Gregg MD, PhD, FRCSC‡; Chu, Pamela MD, MBA, FRCSC‡; Nation, Jill MD, FRCSC‡; Ghatage, Prafull MBChB, FRCSC, FACOG‡
*Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Winnipeg Health Sciences Centre & CancerCare Manitoba; and †Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba; and ‡Tom Baker Cancer Centre & Foothills Medical Centre and Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Calgary, Calgary, Alberta, Canada.
Address correspondence and reprint requests to Alon D. Altman, MD, FRCSC, RS 406, 810 Sherbrook St, Winnipeg, Manitoba, Canada R3A 1R9. E-mail: firstname.lastname@example.org.
The authors declare no conflicts of interest.
Received May 5, 2013
Accepted July 17, 2013
Objectives: The objective of this study was to examine the overall and recurrence-free survival in patients with advanced ovarian cancer based on hemoglobin and blood transfusions.
Methods: A retrospective chart review was performed between 2003 and 2007 on patients with pathologically confirmed stage 3–4 ovarian, fallopian, or peritoneal cancers. Data were collected on date of diagnosis, recurrence and death, stage, grade, age, surgery, estimated blood loss, hemoglobin (nadir and average levels), and number of blood transfusions.
Results: Two hundred sixteen patients were included in the final analysis. In the perichemotherapy, perioperative, and total time frames, 88%, 81%, and 95% of patients were anemic, and 9%, 22%, and 26% of the patients had severe anemia. After adjusting for age, stage, and optimal debulking status, the perichemotherapy hemoglobin level as a continuous variable was weakly associated with recurrence-free survival (adjusted hazard ratio [AHR], 0.98; P = 0.03), and as a categorical variable with both recurrence-free survival (AHR, 2.49; P = 0.003) and overall survival (AHR, 1.91; P = 0.02). The total number of transfusions was also weakly associated with poor recurrence-free survival (AHR, 1.06; P = 0.03).
Conclusions: Our study is a retrospective analysis of the effects of anemia and transfusion on ovarian cancer. The rates of anemia in chemotherapy patients are higher than previously reported. Although maintaining average hemoglobin greater than 80 g/L during chemotherapy portends an improved overall survival, blood transfusion does not have any effect. The role of transfusion should therefore be limited to symptomatic patients while giving 1 unit at a time. Further prospective studies will be needed to confirm these results.
Anemia is a common and significant complication associated with poor performance status, decreased functional capacity, and poor quality of life (QOL).1–4 Multiple approaches have been used to improve anemia including erythropoietin (EPO), red blood cell (RBC) transfusion, perioperative hemodilution, iron supplementation, and intraoperative extracorporeal red cell salvage.5–7
The incidence of anemia in patients with solid tumors is 38% to 59%.1,2,8,9 The cause of anemia in cancer patients is multifactorial and includes acute or chronic hemorrhage, postoperative hemodilution, tumor-related hemolysis, changes in iron metabolism, deficiencies of folic acid and vitamin B12, suppression of erythroid precursors by tumor-related cytokines, postradiation therapy effects, or current chemotherapy effects.8,10–12 Groopman and Itri3 performed a large review of chemotherapy-induced anemia in adults and found that 49% of ovarian cancer patients were anemic by their sixth cycle of chemotherapy.
Recent studies have shown that EPO is related to increased mortality,8 with subsequent use of blood transfusion as the primary treatment method for anemia. A study performed by the American College of Physicians (ACP) showed that 67% of RBC transfusions were unjustified5,13 and introduced guidelines stating that threshold-driven transfusion strategies should be avoided, and blood should be given on a unit-by-unit basis.
Multiple studies in the oncology literature have observed worse outcomes in people who received transfusions with soft tissue sarcoma,14 solid tumors,15 and colorectal, head and neck,9 prostate, cervical, bladder, lymphoma, and lung cancers.8,16–19 Possible mechanisms of action include transfusion-related immunosuppression,17,20 cytokine release,6,9,20–24 or proangiogenesis with vascular epithelial growth factor.9
Transfusions have been associated with increased rates of recurrence and death 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). A similar association has never been examined in ovarian cancers.
Limited research has been performed in gynecologic oncology on the issue of blood transfusions, with the majority revolving around cervical cancer.10,29,30 A large retrospective study of transfusions in 125 women with gynecologic malignancies showed improved disease-free interval and survival rate in women who did not receive blood. The largest limitation to this study remains that the majority of patients included had cervical cancer (58.4%).20 There is insufficient evidence to guide the gynecologic oncologist in decisions regarding transfusion policies and thresholds in ovarian cancer patients. Many studies in advanced ovarian cancer accept high rates of complications for noncurative treatments that prolong life by a few months. Simple changes in transfusion policies may therefore result in improved survival rates14 with low complication rates. To clarify this issue, we performed a retrospective cohort study.
MATERIALS AND METHODS
This retrospective cohort study was performed at the Tom Baker Cancer Centre in Calgary, Alberta, Canada, between 2003 and 2007. Charts were reviewed from electronic medical records (ARIA oncology information system) and all available paper records. Inclusion criteria included any adult women (>18 years old) with stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancers. To be eligible for inclusion into the study, the patient’s chart must have had 3 years of possible survival data. Charts were excluded if they had a diagnosis of germ cell, metastatic, or sex cord stromal tumors of the ovaries, or if the primary site of disease was unknown.
A sample size calculation was attempted based on available oncology literature. A standard α of 0.05 and a β of 0.20 were obtained. Based on GOG 111,31 we assumed a median survival time for stage III-IV ovarian/peritoneal cancer of 38 months. The hazard ratio from the only retrospective trial performed in gynecologic oncology20 was 1.67, giving a sample size of 90 patients per arm. Given the rate of anemia was 49% in ovarian cancer patients,3 we expect the rate of anemia to be approximately equal in a random sample of the population. There are ∼70 patients per year who met the inclusion criteria. Because not all the patients had adequate information, we expanded our study search to encompass 5 years, ending in 2007 to allow for a 3-year survival analysis.
Our primary research question was: In women with ovarian or peritoneal cancer undergoing chemotherapy, is the number of blood transfusion or hemoglobin (Hb) level associated with worse outcomes? The primary outcome of this study was to examine the overall survival. The secondary outcome was recurrence-free survival.
Overall survival was defined as the interval from the date of initial diagnosis to the date of death or last known contact. Recurrence-free survival was defined as the interval from the date of initial diagnosis to the date of first recurrence or last known contact. No distinction was made between cancer-related and non–cancer-related deaths. Data were also collected on age, stage, grade, type of surgery, optimal debulking (defined as <1 cm), estimated blood loss (in mL), and tumor histology. Hemoglobin measurements and number of transfusions from every cycle of chemotherapy, preoperatively, intraoperatively, and postoperatively were recorded. Research ethics committee approval was received on January 26, 2010 (approval #25131).
The data were categorized into 3 treatment periods: total, perioperative, and perichemotherapy. The perioperative time period was defined as the interval from the date of surgery (including immediate preoperative blood work) to the date of subsequent chemotherapy. The perichemotherapy time period was defined as the interval from the date of first chemotherapy dose (including prechemotherapy blood work) to the last chemotherapy dose (with any associated blood work in the 3 weeks following). The variables examined included nadir, average Hb levels, and number of transfusions. All were analyzed for overall survival and recurrence-free survival, as both categorical and continuous variables. Nadirs and average Hb levels were classified according to the National Cancer Institute grading system: grade 1 (100–120 g/L), grade 2 (80–100 g/L), grade 3 (60–80 g/L), and grade 4 (<60 g/L).3,8 Because there were so few patients in the grade 4 category for the nadir Hb measures and in the grade 3 and 4 categories for the average Hb measures (Table 1), analyses were performed using the combined categories (combined grade 3 and 4 for the nadir variables and combined grade 2, 3, and 4 for the average variables). Pairwise relationship was investigated between the 2 outcomes and the explanatory variables of interest plus the potential covariates such as age, grade, stage, optimal debulking, estimated blood loss, and type of surgery performed using a Cox proportional hazards model. The same model was then performed accounting for age, stage, and optimally debulking status; cancer grade, estimated blood loss, and type of surgery were not associated with the outcomes of interest. All data were analyzed using SAS v9.2 (Cary, NC).
Two hundred seventy-four charts were reviewed; 58 patients were excluded, resulting in 216 patients in the final analysis. Two hundred ten had perichemotherapy Hb data, and 188 had perioperative data; 216 patients had results for overall survival, and 184 had recurrence data. Patients’ average age was 61.3 years (range, 30–91 years). Most patients (87%) had advanced-stage (stage 3C or 4) ovarian cancer; 58% were classified as grade 3, and 63% were optimally debulked (Table 2). In this data set, 93 patients received neoadjuvant chemotherapy. All patients were initially started on standard doses of carboplatin and paclitaxel, with 3 exceptions (1 pegylated liposomal doxorubicin, 1 cisplatin/topotecan, and 1 doxorubicin/cyclophosphamide). Neoadjuvant chemotherapy did not affect the rates of anemia. Twenty-two patients also received adjuvant intravenous/intraperitoneal chemotherapy. Because of difficulties accounting for blood transfusions when looking at Hb levels, both the nadir and average Hbs were examined in this study (Table 1). In the perichemotherapy period, 88% of patients were anemic; 9% had severe (grade 3–4) anemia. Perioperatively, the rate of anemia increased to 81%, with 22% having severe anemia. Overall, 95% of patients had evidence of anemia during the course of their initial treatment, and 26% had grade 3 or 4 anemia in this time period (Table 1). In our population, 98 patients (45%) received a transfusion in the perioperative period, 40 patients (19%) received a transfusion in the perichemotherapy period, and 115 patients (53%) received a transfusion overall. No patients in our study received EPO.
Perichemotherapy average Hb, as a continuous variable, was found to be weakly associated with recurrence-free survival (adjusted hazard ratio [AHR] of 0.98; 95% confidence limit, 0.96–0.998) (P = 0.03). The categorical variable for the perichemotherapy average Hb levels also related to recurrence-free survival (P = 0.003) (Table 3; Fig. 1). Perichemotherapy average Hb levels, as a categorical variable, were also associated with overall survival (P = 0.015). Total number of transfusion, as a continuous variable, was found to be associated with recurrence-free survival (AHR, 1.06 with 95% confidence limit of 1.01–1.11; P = 0.026) (Table 3). All other outcomes, including all nadir values, were not statistically significant (Table 3).
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.
The cause of anemia in cancer patients is multifactorial.8,10–12 Chemotherapy-induced anemia is quite common (9%–84% of patients2,9,23) secondary to the effects of myelosuppression on bone marrow erythroid precursors1,3,9,10,12 and damage to renal tubular cells.8,10,12 Groopman and Itri3 found a 49% rate of anemia in ovarian cancer. Our rate of overall anemia was 95%, and the rate of perichemotherapy anemia was 88%. These rates are higher than reported in previous oncology literature. Anemia can be graded according to absolute Hb levels and concomitant signs and symptoms. Grades 3 and 4 anemias have an incidence of 2% to 35%9; our rate was 9% in the perichemotherapy period, 22% in the perioperative period, and 26% overall.
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.
Although generally benign and well tolerated, transfusions have inherent risks.3,5,8,23,24,39–41 The risks associated with allogenic transfusions have led to a growing reluctance to transfuse blood.10,42 A study performed by the ACP showed that 67% of RBC transfusions were unjustified.5,13 As a consequence, ACP guidelines were introduced stating that threshold-driven transfusion strategies should be avoided and that blood should be given on a unit-by-unit basis based on the duration and degree of anemia, amount of blood loss, extent of the surgical procedure, the volume status, and the end-organ perfusion.3,5,43
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
A survey of 548 Society of Gynecologic Oncology members by Price et al5 found that the average prechemotherapy transfusion threshold was 79 ± 0.7 g/L with a mean transfusion of 1.9 ± 0.5 units of blood. Thirty-one percent of respondents would not transfuse until the Hb decreased below 70 g/L, and most physicians would transfuse 2 units. A retrospective study of 125 women with gynecologic malignancies and transfusions was reported in 2004.20 The disease-free interval and survival rate were significantly better in women who did not receive blood; persistent disease and recurrence were more common in the transfused group. The largest limitation to this study remains that the majority of patients included had cervical cancer.20 Finally, a large retrospective study was reported in abstract form at the 2011 Society of Gynecologic Oncology meeting. This study looked at 581 patients with ovarian cancer and examined the relationship of EPO-stimulating agents and survival. These authors found that exposure to EPO-stimulating agent increased the likelihood of recurrence and death.37 Our results differ from these findings, with no significant associations seen between transfusions and recurrence rate or overall survival.
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
Ovarian cancer; Blood transfusion; Gynecologic surgery; Anemia; Chemotherapy
© 2013 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
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