Is The Maintenance of Oxic Cancer ... Toxic?
Abstract & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationship to this field of study.
Synopsis: Thromboembolism (TE) is common in patients with uterine cervix cancer receiving primary therapy with chemoradiation. A study designed to raise endogenous hemoglobin by use of recombinant human erythropoietin (R-HUEPO) was inconclusive as a result of premature closure based on TE concerns.
Source: Thomas G, et al. Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol. 2008;108:317-325.
The primary purpose of this phase III study was to determine if maintenance of hemoglobin values above 12 g/dL by use of R-HUEPO during chemoradiotherapy (weekly cisplatin) for advanced cervix cancer was associated with improved outcomes (progression-free and overall survival and local control rates) relative to maintenance of hemoglobin values above 10 g/dL by way of non-R-HUEPO methods. The study accrued 114 of the intended 460 before being prematurely closed in deference to safety concerns raised by the sponsor. One hundred nine evaluable patients were equally randomized. Slight imbalances in accrual were noted due to incomplete randomization. Median follow-up was 37 months. PFS and OS were similar between the randomized cohorts (PFS at 3 years: 65% (control) vs 58% (R-HUEPO), OS at 3 years: 75% (control) vs 61 (R-HUEPO)). TE was diagnosed in 15 patients (14%); 4/52 (control) vs 11/57 (R-HUEPO), p = NS. No deaths due to TE were registered. A translational objective to measure platinum-adducts as a prognosticator of outcome identified that high values were associated with poor PFS and OS. The authors concluded that the study identified TE as common complication of this disease and that unfortunately, due to premature closure, the relationship between high hemoglobin values and outcome are unassessable.
Commentary
Sometimes a really good idea, founded by sound hypothesis-generating information and elevated to the level of a multi-institutional randomized controlled trial just…backfires! To illustrate this point, I'll try to outline the steps leading to the development of this protocol (also known as GOG-191): first, the association between tissue oxygenation and radiation has been known for years and the formation of free-radicals from interaction of radiation particles and oxygen is responsible for the efficacy of the modality; second, a substantial proportion of cervix cancer patients presenting for therapy are anemic with nearly a quarter being under 10.0 g/dL; third, acute anemia resulting from cervical bleeding is commonly associated with locally advanced disease and is most likely to levy an impact on tumor hypoxia; fifth, hypoxia, when measured directly is associated with radioresistance; sixth, hypoxia in the tumor microenvironment is additionally responsible for the secretion of vascular endothelial growth factor (VEGF) and angiopoietins (Ang-2), two powerful mediators of angiogenesis; seventh, local control was demonstrated to be improved in patients maintained by blood transfusion to be no greater than 12.5 g/dL; and eighth, two large studies of hemoglobin values and survival demonstrated an incremental stepwise improvement in survival for each 1 g/dL increase above 10 g/dL, with optimal levels being above 12 g/dL, achieved either by transfusion or spontaneously. The current study was set to address whether transfusion, replaced by R-HUEPO, could demonstrate the same findings. Well intentioned, and while incomplete, the study results did not demonstrate a significantly higher rate of TE with R-HUEPO. Nevertheless, the results from two (at the time) and now four randomized controlled trials in other solid tumors have demonstrated an inferior survival outcome in patients receiving R-HUEPO during their planned radiotherapy. So, safety concerns aside, the relationship of raised hemoglobin via R-HUEPO and improved survival may not be solid. However, the mistake in interpretation here would be that this data disprove the hypothesis of the relationship of hemoglobin and survival. It is of relevance to note that epoietin receptors have been identified on tumor cells. Activation of these receptors by R-HUEPO can stimulate cellular pathways responsible for proliferation, migration and clonogenicity. As such, this interaction in the microenvironment could circumvent the improved ability of radiation-induced cell kill normally achieved in the presence of oxic conditions. Much more work is necessary in this regard although it is unfortunately unlikely the study will be repeated.
The primary purpose of this phase III study was to determine if maintenance of hemoglobin values above 12 g/dL by use of R-HUEPO during chemoradiotherapy (weekly cisplatin) for advanced cervix cancer was associated with improved outcomes (progression-free and overall survival and local control rates) relative to maintenance of hemoglobin values above 10 g/dL by way of non-R-HUEPO methods.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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