Anemia in cervical cancers: Impact on survival, patterns of relapse, and association with hypoxia and angiogenesis

Purpose: The prognostic impact of anemia in cervical cancers is well established. We have investigated the impact of anemia on prognosis and patterns of relapse in cervical cancers. Furthermore, we analyzed the relationship between anemia, tumor hypoxia, and angiogenesis. Methods and Materials: Eighty-seven patients (mean age 58 years) with squamous cell cancer of the cervix (Stage IIB: n = 19; Stage IIIB: n = 59; Stage IVA: n = 9) were prospectively enrolled in the study from 1995 through 1999. Patients underwent definitive radiotherapy with a combination of external beam radiotherapy (45-50.4 Gy) and high-dose-rate brachytherapy (5 × 7 Gy). Tumor oxygenation was measured with the Eppendorf pO₂-histograph before radiotherapy and after 19.8 Gy. Angiogenesis was determined by measuring the microvessel density in pretreatment biopsies in 46 patients. The impact of tumor oxygenation (at 0 Gy and 19.8 Gy), hemoglobin (hb) level (at 0 Gy and 19.8 Gy), angiogenesis and clinical parameters on survival and relapse was investigated. Results: The 3-year overall survival rate (after a median follow-up of 42 months) was 57% for the whole group of patients, 72% for Stage IIB, 60% for Stage IIIB, and 22% for Stage IVA. The presence of pretreatment anemia had a significant impact on the relapse rate. However, the midtherapy hb level (at 19.8 Gy) had the strongest impact on local failure rate and survival: 3-year local failure rate was 6% in 20 patients with a hb > 13 g/dL at 19.8 Gy, 15% in 47 patients with an hb between 11 and 13 g/dL, and 67% in 20 patients with an hb < 11 g/dL, p = 0.0001. This was associated with a significant impact on the 3-year overall survival, 79% vs. 64% vs. 32%. Twenty-three tumors were poorly oxygenated at both measurements (oxygen pressure [median pO₂] < 15 mm Hg before therapy and at 19.8 Gy). This group had a significantly lower 3-year overall survival as compared with patients with high pO₂ before and/or at 19.8 Gy (38% vs. 68%, p = 0.02), and these poorly oxygenated tumors had also a significantly increased microvessel density. In a multivariate model, the midtherapy hb level maintained an overwhelming impact on local failure rate and survival. Conclusions: Hemoglobin level during radiotherapy was the strongest prognostic factor for local control and survival. We could further identify a poor prognostic subgroup with persisting hypoxia during radiotherapy, low hb levels, and increased angiogenesis. According to these findings, an association between anemia, poor tumor oxygenation, and angiogenesis is likely.