Optimizing Treatment for Cervical Cancer

Abstract

There are a number of ways in which surgery, radiation therapy, and more recently chemotherapy have been employed in the treatment of locally advanced cervical cancer. The evidence in favor of chemoradiation in cervical cancer was summarized in a meta-analysis of 19 trials which showed improvement with the concomitant administration of chemotherapy and radiation (CRT), not only in survival (by >10% at 5 years) but also in both local and distant recurrence rates. These results validate the National Cancer Institute Alert (USA) in February 1999, which was based on preliminary evidence from five randomized trials, and stated that concomitant chemoradiotherapy should be considered for the majority of patients with cervical cancer. However, patients with locally advanced disease with negative para-aortic nodes accounted for the majority of those selected for these trials, and the benefits of the addition of chemotherapy to radiation were clearer in stages I and II disease. Acute and late toxicity remain areas of concern. The role of surgery is also undergoing re-evaluation, both in early disease where surgery may offer equal survival to radiation with reduced morbidity, and in more locally advanced cases where recent data have shown surgery preceded by chemotherapy achieves similar gaines in absolute survival compared with radiation alone. The trials involving CRT differed in size, design, accrual period and chemotherapeutic agent used, and there has been extensive debate about optimization of the radiation dose and whether chemotherapy in some of the trials compensates for inadequate radiation dose. However, these factors would not account for the improvement in distant relapse rates observed. Similarly, surgical expertise has been shown to be a major factor affecting outcome in radical procedures, and recent developments in more conservative surgery also improve morbidity in selected cases. The alternative strategy of neoadjuvant chemotherapy prior to surgery (NACT-S) has been evaluated extensively in South America and Italy in groups similar to those in which CRT has been shown to be effective. Although the data are promising, the evidence base for outcome compared with radiation alone is much smaller, and there have been no direct comparisons with CRT. The chemotherapy in CRT may be acting predominantly through a cytotoxic effect as distinct from having a sensitization effect, and hence the rationale for these two approaches (CRT and NACT-S) may be broadly similar, that is, early control of systemic disease as well as additional local control to that achieved by either surgery or radiation alone. The sequential use of further chemotherapy after these strategies is under development. In early disease, surgery and radiation therapy are comparable in terms of efficacy, and the preference for surgery is based on reduced morbidity and the potential to preserve fertility. The addition of platinum-based chemotherapy, either prior to surgery or with radiation improves survival and distant recurrence rates in more locally advanced cases up to stage IIb, or in those patients with adverse risk factors. The available data are insufficient to recommend routine adoption of CRT in earlier (stage Ia2) or more advanced cases (stages III or IV). However, with the enrolment of over 4000 women in randomized trials and mature follow-up, chemoradiation has become an established treatment.