Abstract
Packed red blood cell (PRBC) transfusions are used to treat anemia in patients with cervical cancer undergoing radiotherapy (RT) owing to concerns of hypoxia-induced radioresistance. In the absence of high-quality evidence informing transfusion practices for patients receiving external beam RT (EBRT) and brachytherapy, various arbitrary hemoglobin target levels are used worldwide. To develop consensus statements to guide PRBC transfusion practices in patients with cervical cancer receiving curative-intent RT with EBRT and brachytherapy. This international Delphi consensus study was completed between November 1, 2019, and July 31, 2020. A total of 63 international clinical experts in gynecologic radiation oncology were invited; 39 (62%) accepted and consented to participate. Consensus building was achieved using a 3-round anonymous Delphi consensus method. Participants rated their agreement or disagreement with statements using a 5-point Likert scale. An a priori threshold of 75% or more was required for consensus. The preplanned primary outcome of this study was to assess hemoglobin transfusion thresholds and targets for both EBRT and brachytherapy by expert consensus. Response rates of 100% (39 of 39), 92% (36 of 39), and 97% (35 of 36) were achieved for the first, second, and third rounds of surveys, respectively. Twenty-three experts (59%) practiced in Canada, 11 (28%) in the United States, 3 (8%) in South America, 1 (3%) in Europe, and 1 (3%) in Asia. Consensus was reached for 44 of 103 statements (43%), which were combined to form the final 27-statement consensus guideline. No specific hemoglobin transfusion threshold was agreed on by consensus for EBRT or brachytherapy. By consensus (89% [31 of 35]), a hemoglobin transfusion target for patients who receive a PRBC transfusion should be 9 g/dL or more and less than 12 g/dL. This study presents the first international expert consensus guideline informing PRBC transfusion practices for patients with cervical cancer undergoing EBRT and brachytherapy. A minimum hemoglobin transfusion target of 9 g/dL was endorsed to balance tumor radiosensitivity with appropriate use of a scarce resource. Randomized clinical trials are required to evaluate the optimal transfusion threshold and target that maximize clinical benefit in this patient population.
Highlights
Cervical cancers are generally considered radiosensitive, underlying tumor hypoxia may be associated with radioresistance for a subset of patients.[1,2] A low hemoglobin level in this patient population caused by anemia of chronic disease, vaginal bleeding, and/or concurrent chemotherapy has been associated with poor local control rates, despite definitive radiotherapy (RT).[3]
54 Patients received packed red blood cell transfusion (PRBCT) Hemoglobin level during RT was associated with disease-specific survival (DSS), pelvic control (PC), and metastasis-free survival (MFS) Patients who responded to PRBCT showed improved PC (P = .02) Hemoglobin level was corrected in only 18.5% of patients who received PRBCT Persistent anemia despite PRBCT showed significantly decreased DSS (P = .005), PC (P = .001), and MFS (P = .048) Median overall survival (OS) in patients who received PRBCT of 16.1 mo vs no PRBCT of 27.9 mo (P = .006)
350 (14%) Patients received pre-RT PRBCT 522 (21%) Patients received PRBCT during RT PRBCT associated with poorer freedom from central recurrence (FFCR) (P < .001), freedom from distant metastasis (FFDM) (P = .008), and DSS
Summary
Cervical cancers are generally considered radiosensitive, underlying tumor hypoxia may be associated with radioresistance for a subset of patients.[1,2] A low hemoglobin level in this patient population caused by anemia of chronic disease, vaginal bleeding, and/or concurrent chemotherapy has been associated with poor local control rates, despite definitive radiotherapy (RT).[3] Several studies have described an association between hemoglobin level and hypoxia, the direct mechanism of the association remains obscure.[4,5,6] Despite conflicting evidence regarding its benefit, the administration of packed red blood cell (PRBC) transfusion(s) before RT for patients with cervical cancer and anemia has historically been associated with higher local control and overall survival (OS).[7,8,9,10] this practice is not informed by any recent randomized data, it is hypothesized to increase tumor radiosensitivity by improving tumor oxygenation, thereby facilitating the formation of reactive oxygen species that indirectly induce permanent DNA damage and trigger cancer cell death.[7,9,11,12,13,14,15] This rationale is often used to justify the use of PRBC transfusions prior to and during RT for malignant neoplasms of the cervix, with the purpose of maintaining hemoglobin levels above a prespecified and often arbitrary threshold throughout treatment.[16]
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