Anemia is a frequent complication of cancer and its associated treatment. Although its occurrence is well documented in the chemotherapy setting, the prevalence and nature of anemia in the radiation oncology setting
Drs. Shasha and Harrison provide an excellent review of the problem of anemia in patients receiving definitive radiotherapy. They also summarize their own original research on the prevalence of anemia in a typical radiation oncology practice. Their study confirms that there is an "epidemic" of anemia among oncology patients and suggests that the issue requires far more attention than it has received.
A Prognostic Indicator
It is well recognized that anemia is associated with decreased response, local control, and/or survival after radiotherapy, and the authors supply numerous references to support this premise. Many of these studies addressed the condition in the setting of radiotherapy alone, but is anemia still an important prognostic factor now that concurrent chemoradiation has supplanted radiotherapy alone for many-if not most-epithelial cancers? The Austrian experience cited by Drs. Shasha and Harrison is thus very important in support of this hypothesis.
At the University of Pennsylvania Medical Center, we have observed a strong relationship between hemoglobin level and response to preoperative chemoradiation in patients with bulky stage IIIA non-small-cell lung carcinoma. We treated 41 patients (all with mediastinoscopy-proven bulky stage IIIA disease) with neoadjuvant radiotherapy (45-50 Gy) and concurrent chemotherapy (either etoposide/cisplatin [Platinol] or carboplatin [Paraplatin]/paclitaxel [Taxol]). Our results are listed in Table 1. Pathologic complete or near-complete (only tiny microscopic residual foci) responses were seen in 12 of 23 patients with hemoglobin levels of 12.5 g/dL or more vs 3 of 18 responses in patients with hemoglobin levels < 12.5 g/dL. More studies are needed to determine the significance of anemia in the setting of concurrent chemoradiation.
A Frequently Uncorrected Problem
In light of the strong evidence of a relationship between anemia and outcome, why isn’t more emphasis placed on the correction of anemia? Drs. Shasha and Harrison provide several possible reasons, including:
Perhaps the most significant reason why the correction of anemia is still not a standard intervention is the failure of the academic and clinical research communities to prove that there is indeed a cause-and-effect relationship between anemia and poor tumor control. In Figure 1 of their article, Drs. Shasha and Harrison describe the traditional hypothesis that anemia leads to hypoxia, which, in turn, leads to radioresistance and poor outcome. However, an alternative explanation is that anemia/hypoxia-which may be present for months to years prior to cancer diagnosis and treatment-stimulates angiogenesis and, thus, tumor invasion and metastasis. In the angiogenesis model, correcting anemia at this late stage in a cancer’s natural history may be ineffective.
Finally, it is possible that anemia is merely a "marker" of a patient’s underlying comorbidity and performance status rather than an independent predictor of outcome. In fact, our experience in treating early-stage laryngeal cancer showed a strong correlation between anemia and death from intercurrent disease or second primary cancers.
Few Relevant Trials
Only large, prospective randomized trials can adequately answer these questions. To date, there have been few such studies. The most widely cited trial-in which local control and survival of anemic cervical cancer patients were improved with transfusion-has been criticized for its small size and inconclusive results when analyzed by intent-to-treat analysis. Preliminary results of a small randomized study of erythropoietin in head/neck cancer patients from the University of Chicago were disappointing. On a more positive note, a recent phase III trial (in a chemotherapy-alone setting) showed not only improved quality of life, but a trend toward improved survival for patients randomized to erythropoietin vs placebo.
The Radiation Therapy Oncology Group (RTOG) is conducting a large randomized trial in head and neck cancer, in which 372 patients will be randomized to erythropoietin or control. The design of this trial (RTOG 99-03), including stratification variables, is shown in Figure 1. The study is currently undergoing amendment to open accrual (with appropriate stratification) of patients who will receive concurrent cisplatin chemotherapy. Prospective studies such as RTOG 99-03 are critical to determining whether the correction of anemia significantly improves tumor control and survival as well as quality of life. Radiation oncologists should welcome and support these studies wholeheartedly.
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