International Journal of Radiation Oncology*Biology*Physics
Clinical investigationCervixA phase III randomized trial of postoperative pelvic irradiation in stage IB cervical carcinoma with poor prognostic features: Follow-up of a gynecologic oncology group study
Introduction
The surgical or radiotherapeutic treatment of Stage IB cancer of the uterine cervix is predicated by the tumor’s character to confine itself to the cervix, and then spread in a progressive and predictable manner through regional lymphatics. Thus, in instances where lymph nodes are negative, treatment failures in Stage IB with disease apparently still localized would suggest faulty radiotherapeutic or surgical technique (1, 2).
Metastasis to lymph nodes has long been identified as a major prognostic factor in early stage cervical cancer. However, certain histopathologic features of cervical carcinomas have been shown to be independent risk factors for locoregional failures related to disease retained in lymphatic plexi, irrespective of lymph node status. These features include large tumor diameter (LTD), deep stromal invasion (DSI), and presence of tumor in the capillary lymphatic spaces (CLS). A Gynecologic Oncology Group (GOG) study of 575 women estimated that such risk factors existed in 25% of all Stage IB cancers and that these factors increased the risk of recurrence from 2% to 31% at 3 years (3). Earlier, external irradiation (RT) had been proposed to be of benefit in reducing recurrences in this group of patients (4). This prospect led to the development of the current study, GOG Protocol 92 (5). The hypothesis to be tested was that postoperative external-beam RT to the standard pelvic field reduces recurrence and improves the recurrence-free interval in women with Stage IB cervical cancers with negative lymph nodes and certain poor prognostic features treated by radical hysterectomy and pelvic lymphadenectomy.
The study was designed with a primary endpoint of disease recurrence, defined as the length of time from study entry until disease recurrence. In the initial report of this study (5), 60 patients had recurred and 48 patients had died, including 4 who died of non–cancer-related causes. At that time, only preliminary results of survival were presented. Since that report, 7 additional recurrences have been observed and 19 additional deaths have occurred (including 4 additional non–cancer-related deaths). The purpose of this report is to provide final results of analysis of overall survival and to update the results on recurrence-free interval, on the basis of an extended follow-up period, for the patients enrolled in GOG Protocol 92. This report also discusses the possible reasons for differences between recurrence and survival results.
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Methods and Materials
Detailed information on patient eligibility, randomization, treatment details, and methods for this study have been published previously (5) and are summarized briefly here as necessary. Patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB primary cervical carcinoma and 2 or more risk factors, defined as DSI, CLS tumor involvement, and tumor diameter of 4 cm or more (large tumor diameter = LTD), were eligible for this study.
The eligibility criteria arose from a
Recurrence
Table 2 shows first recurrences by site of recurrence and treatment regimen. Since the time of the initial report (5), 7 additional disease recurrences (3 in RT arm and 4 in OBS arm) were observed, and the initial results have not changed substantially. A significant reduction in risk of recurrence with RT vs. OBS (HR = 0.54; 90% CI = 0.35 to 0.81; p = 0.007) was seen. Both local (13.9% vs. 20.7%) and distal (2.9% vs. 8.6%) recurrence rates were lower in RT vs. OBS.
Figure 1 shows the cumulative
Discussion
The results from retrospective studies have disagreed as to the value of postoperative irradiation in node-negative Stage IB cervix cancer. As discussed in the previous publication (5), complications were a major concern. Although the difference in Grade 3 or 4 AEs in the current report was not statistically significant at the traditional 0.05 level (6.6% vs. 2.1%, p = 0.083), it was notable enough to warrant that the clinician will need to weigh whether the postoperative RT complications
Conclusion
The continued demonstration of long-term significantly reduced recurrence risk (p = 0.007) and progression/death risk (p = 0.009) should be of help to clinicians and patients in deciding the initial management of node-negative Stage IB cervical cancer. Several possible attributes of the trial might partially explain the apparent disparity in significance levels (OS, p = 0.074), including several which have been described here. The particular effectiveness of adjunctive RT in reducing the
Acknowledgments
The authors thank Dr. Christopher S. Lange of the Department of Radiation Oncology, SUNY Downstate Medical Center, for his insights and many helpful discussions.
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This study was supported by National Cancer Institute Grants CA 27469 and CA 37517.