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

https://doi.org/10.1016/S0360-3016(03)00123-8Get rights and content

Abstract

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.

Introduction

The prognostic impact of anemia in cervical cancers is well established. In the comprehensive first report on this topic in 1965, Evans and Bergsjø published results on more than 1000 patients treated for cervical cancers with radiotherapy in the period from 1940 through 1958 at the Radium Hospital in Oslo (1). Patients with a pretreatment hemoglobin (hb) level of less than 11 g/dL had a significantly poorer overall survival as compared with patients with a hb level of 11 g/dL or more. Moreover, Evans and Bergsjø found a more or less linear relationship between low hb levels and reduced survival for anemic patients, e.g., the lower the hb, the higher was the failure rate. Numerous investigations have supported their findings in cervical cancers and other solid tumors 2, 3, 4, 5, 6, 7. In a recent meta-analysis, anemia was found to be an independent prognostic factor for increased death rates also in various solid tumors (head-and-neck, lung, prostate) as well as in lymphomas (8).

As a consequence of the data in cervical cancers, the impact of keeping the hb above 12 g/dL by transfusions has been investigated in a randomized study in the early 1980s at the Princess Margaret Hospital (2). This trial recruited patients with locally advanced cervical cancers treated with definitive radiotherapy. The study showed an advantage in terms of local control for the transfusion group but was stopped after recruiting 132 patients. There was no stratification by tumor volume or stage, and the results of this study have therefore been criticized and are not necessarily a proof that transfusions improve the therapeutic efficacy (9).

Despite the association between anemia and poor prognosis in patients who are treated with definitive radiotherapy for locally advanced cervical cancers, there is no clear evidence whether anemia exerts an independent prognostic impact or whether anemia represents only an epiphenomenon indicating that anemia is linked to adverse prognostic factors such as large tumor volume (9). Moreover, it is unclear how far correcting anemia might impact on prognosis. A recent large retrospective investigation from seven centers in Canada supports the assumption that anemia during radiotherapy is more important than pretreatment hb levels and that there is no difference between spontaneously high hb levels and hb levels after transfusions (10).

Tumor hypoxia offers a possible and attractive radiobiologic explanation for the prognostic impact of anemia. Already in their first report, Evans and Bergsjø discussed an impact of anemia on tumor oxygenation as a cause for increased failure rates in anemic patients (1). Intratumoral hypoxia can be measured with experimental techniques. Höckel et al. demonstrated that hypoxic cervical cancers have a poorer prognosis than better oxygenated tumors 11, 12. Other research groups have confirmed their data, and poor tumor oxygenation has been identified as an independent and major risk factor for treatment failure 13, 14, 15. Poor tumor oxygenation is also associated with an increased risk of nodal disease (16). However, a causative role of hypoxia remains controversial (17).

Angiogenesis has been also identified as a prognostic factor in cervical cancers (18). Most of the clinical investigations have determined angiogenesis by measuring the vascularization grade (microvessel density [MVD]) in histologic specimen as first described by Weidner et al. 19, 20. Highly vascularized tumors (with a high MVD) have in general a poorer prognosis than tumors with lower vascularization.

Our investigation mainly concentrated on the impact of anemia on prognosis and relapse patterns in cervical cancers. Moreover, we investigated the possible relationship between anemia, tumor hypoxia, and angiogenesis.

Section snippets

Patient population

Eighty-seven patients with squamous cell cancer of the cervix underwent prospective evaluation of hypoxia and various prognostic factors in our department in the period between 1995 through 1999. Part of the results with special emphasis on the relation between p53 status and tumor hypoxia have recently been published in this journal (21).

The mean age of the patient population was 58 years (range 35–80 years). All patients were treated with curative intent and followed thereafter in our

Overall survival and patterns of relapse

The overall survival rate for the whole group of patients was 57% after 3 years. The overall survival according to FIGO stage was 72% for Stage IIB, 60% for Stage IIIB, and 22% for Stage IVA. Thus, Stage IVA was a significant risk factor, whereas no significant differences were observed between stages IIB and IIIB.

Thirty-six patients (41%) relapsed. There were 19 local relapses as first site of failure (including patients who were never locally controlled or had a complete remission of less

Discussion

The prognostic impact of anemia in cervical cancers is well established. Nevertheless, the pathophysiologic mechanisms are controversially discussed even in the recent literature. Some retrospective investigations have found an independent impact of anemia on prognosis in multivariate analysis 5, 6, 8, 10, 24. Other researches assume that the prognostic significance of anemia results from an association between anemia and tumor volume and that anemia does not exert an independent impact (9).

Our

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