• © 1999 by American Society of Clinical Oncology

Concurrent Chemotherapy and Radiation: A Major Advance for Women With Cervical Cancer

IN THIS ISSUE OF the Journal of Clinical Oncology, Whitney et al¹ from the Gynecologic Oncology Group (GOG) report the results of a prospective randomized trial that compared concurrent radiation therapy, cisplatin, and fluorouracil with concurrent radiation and hydroxyurea in patients with locally advanced cervical cancer. Their study is one of five recently reported randomized trials that demonstrated improved survival and local control rates when concurrent cisplatin-containing chemotherapy was added to radiation treatment of cervical cancers.^2-5 Although these studies differed in their inclusion criteria, treatment specifics, and control treatments, each of the five demonstrated a 40% to 60% reduction in the relative risk of recurrence with cisplatin-containing chemoradiation. Rarely do oncologists receive such compelling support for a major change in treatment from so many studies over such a short period of time. For patients with locally advanced cervical cancer, these results provide the first major advance in treatment in at least 40 years. Spurred by these reports and their public health implications, the National Cancer Institute recently took the unusual step of disseminating a summary of the findings in a Clinical Alert.

Radiation therapy was first used to treat cervical cancer shortly after the discovery of radium. The subsequent development of high-energy linear accelerators for external treatment and improvements in brachytherapy techniques reduced complication risks and led to cure rates ranging from 90% to 95% for small stage IB1 tumors^6,7 and 30% to 50% for stage IIIB tumors.⁸ However, the standard treatment of locally advanced cancers has changed little since the 1970s. Although it is remarkable that even 50% of tumors that measure 7 cm or more in diameter can be cured with radiation alone, local relapse has continued to be the dominant cause of recurrence and death for patients with locally advanced cervical cancer. Since 1970, clinical research has focused on possible ways of improving the effectiveness of local treatment.

Some investigators have tried to improve local control by altering the method of radiation therapy delivery with, for example, neutron-beam irradiation or interstitial brachytherapy techniques. However, these treatments have not yet been demonstrated to improve outcome. More interest has centered on theoretical methods of sensitizing tumors to the cytotoxic effects of ionizing radiation. Because oxygen is one of the most potent radiation sensitizers, a number of investigators have explored ways to improve oxygen delivery to tumors with hyperbaric oxygen, transfusion, or drugs that increase the oxygen-carrying capacity of blood. Although 20 years ago a small study from Princess Margaret Hospital suggested that pelvic disease control could be improved with transfusion of anemic patients,⁹ this study has never been repeated. Studies of nitroimidazole hypoxic cell sensitizers have failed to demonstrate improvements in local control or survival of cervical cancer patients. The clinical relevance of tumor hypoxia remains controversial, but this continues to be an active area of study.

For at least 25 years, clinicians have been searching for ways of combining chemotherapy with radiation to improve pelvic disease control. Most of the early prospective randomized trials involved the use of neoadjuvant chemotherapy followed by radiation therapy. Despite encouraging tumor responses to various combination chemotherapy regimens, at least seven trials have now been reported providing little or no evidence of improvement in local control or survival.¹⁰ Investigators have speculated that drug toxicity, poor compliance with aggressive treatment, and accelerated repopulation of resistant clones of tumor cells might be contributing to this lack of benefit.

At the same time, several multi-institutional groups have explored the use of concurrent chemotherapy with radiation in an effort to capitalize on laboratory evidence that some drugs, including cisplatin, fluorouracil, mitomycin, and hydroxyurea, may sensitize tumor cells to the effects of radiation. Clinical studies of concurrent chemoradiation are complex, requiring careful cooperation between different specialists and with patients who are sometimes poorly oriented to the medical care system. Several studies have been hampered by frequent protocol violations. An early GOG study compared radiation alone with radiation and concurrent hydroxyurea.¹¹ This study seemed to show some benefit from the combination, but it has been criticized because many patients were treated without brachytherapy or with extremely low doses of radiation and because 93 (49%) of the 190 patients randomized were excluded from the analysis as ineligible or unassessable. For these reasons, some have questioned whether the value of hydroxyurea has ever been clearly demonstrated. Its inclusion in the control arms of the GOG studies reported by Whitney et al¹ and Peters et al⁴ may be considered a relative weakness of the two trials. Although the value of concurrent hydroxyurea may be questioned, the better survival achieved with combined radiation and cisplatin-containing chemotherapy provides convincing evidence of benefit, particularly in the context of four corroborating studies.

These five trials raise interesting questions that will undoubtedly be the subjects of future studies. Although all of the most successful treatments included cisplatin, of the four different cisplatin-containing regimens, only two were compared directly. It has yet to be determined which schedule achieves the most favorable therapeutic ratio and whether the inclusion of fluorouracil in the studies reported by Whitney et al¹ and Morris et al³ contributed importantly to the results. The latter study was the only one that prescribed concurrent chemotherapy with the brachytherapy portion of treatment. The importance of this is unclear, but the approach is attractive because 50% or more of the central dose of radiation is usually given during this part of the treatment. Extended-field irradiation (including the aortic nodes) has proven effective in the treatment of patients with known or suspected aortic node metastasis,¹² but its role needs to be clarified in the context of these new results.

Although compliance with required radiation therapy seemed to be similar in the arms of the Whitney et al² study, the large number of patients with incomplete or extremely protracted treatment in this and other multi-institutional trials is disturbing. A number of investigators have reported substantial decrements in local disease control when the total duration of radiation treatment exceeded 8 weeks.^13,14 The increasingly complex treatments required to successfully manage locally advanced cervical cancer pose special problems for its victims—women who are often economically disadvantaged with complicating personal and social problems. Efforts to improve patient education and support may provide some of the most important contributions to the treatment of this disease in the future.