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Clinical Evidence of the Importance of Hypoxia in Radiotherapy

In solid tumors, it is estimated that the hypoxic cell fraction ranges from less than 1% to greater than 50%. In one of the most elegant studies that has assessed the impact of tumor hypoxia on therapeutic outcomes after radiation, Brizel and colleagues directly measured the partial pressure of oxygen (pO2) content of tumors, using an oxygen electrode.[7]

In this study, 59 patients with head and neck cancer undergoing primary radiation therapy with or without neck dissection underwent direct pO2 measurements of the tumor, either at the primary site or at the lymph node site. For those patients with a median pO2 greater than 10 mm Hg (n=18), local control was achieved in 82% of the cases, with an overall survival rate of 80%. For those with hypoxic tumors (<10 mm Hg; n=34), local control was achieved in only 41% of the cases with an overall survival rate of 46%. Both these differences were significant (P </= .01). Of interest, in the same study, Brizel and colleagues were able to show a correlation between hypoxic cell populations and the likelihood of being anemic.

In the DAHANCA II trial,[6] male patients with pharyngeal cancers were randomized in a phase III trial to split-course radiation, with or without misonidazole as an hypoxic cell sensitizer. In this study, misonidazole did appear to improve the locoregional control rate, but in the subanalysis, an even more important variable seemed to be the hemoglobin level. For the misonidazole group, the locoregional control rate was 61% for patients with a hemoglobin level greater than 14.5 g/dL but only 28% for patients with a hemoglobin level less than 14.5 g/dL. In the placebo group, the locoregional control rate was 41% for those with a hemoglobin level greater than 14.5 g/dL and only 14% for those with a hemoglobin level less than 14.5 g/dL. The difference between these two groups yields a factor of approximately 3, which is the predicted value from the laboratory studies of oxygen enhancement ratio, a fact that makes these results intriguing.

In addition to these pivotal studies, a number of other clinical trials have demonstrated a relationship between anemia and its impact on local control and survival in glottic laryngeal carcinoma,[8] locally advanced non-small cell lung cancer,[9] and stage III/IV head and neck cancer.[10] In a trial of patients with early stage glottic laryngeal cancer, a multivariable analysis of 9 factors showed that only pretreatment hemoglobin level was an important factor for local control and survival. In the study by Kumar and colleagues,[10] intra-arterial cisplatin was administered, along with external beam radiation, to patients with advanced head and neck cancer. Again, in a multivariable analysis of outcome measures, pretreatment hemoglobin levels were highly correlated with response rate at the primary site and lymph nodes, as well as with failure-free survival and overall survival. Analysis of the locoregional failure-free survival vs the pretreatment hemoglobin levels is outlined in Figure 6. A similar relationship existed between the hemoglobin level and overall survival. In addition to the trials evaluating the effect on the respiratory tract, the importance of pretreatment hemoglobin level has also been demonstrated in radiation trials of patients with bladder, anal, prostate, and cervical cancer. The conclusion drawn from these studies is that tumor hypoxia and anemia are both negative and related factors that reduce the efficacy of radiation therapy.[10,11]

Figure 6. Correlation between pretreatment hemoglobin levels and response rate at primary site and lymph nodes in patients with advanced head and neck cancer.

To determine whether treatment of anemia with improvement of hemoglobin levels can influence outcome, the Radiation Therapy Oncology Group has initiated a phase III trial in head and neck cancer patients receiving radiation therapy. Patients will be randomized to receive 40,000 IU of erythropoietin subcutaneously at weekly intervals during radiation therapy, and compared with a group receiving standard supportive care to assess whether improvement of hemoglobin levels during therapy will affect outcomes. Since most of the data have been correlated so far only with pretreatment hemoglobin levels, which may be a surrogate end point for other poor prognostic features, this prospective, randomized intervention trial should substantially improve our understanding of the relationship between anemia and treatment outcomes for patients receiving radiation therapy.

Warmly, lillian
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