Clinical investigation
Cervix
A 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

Parts of this article have been presented previously at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October 19–23, 2003, Salt Lake City, UT.
https://doi.org/10.1016/j.ijrobp.2005.10.019Get rights and content

Purpose: To investigate, in a phase III randomized trial, whether postoperative external-beam irradiation to the standard pelvic field improves the recurrence-free interval and overall survival (OS) in women with Stage IB cervical cancers with negative lymph nodes and certain poor prognostic features treated by radical hysterectomy and pelvic lymphadenectomy.

Methods and Materials: Eligible patients had Stage IB cervical cancer with negative lymph nodes but with 2 or more of the following features: more than one third (deep) stromal invasion, capillary lymphatic space involvement, and tumor diameter of 4 cm or more. The study group included 277 patients: 137 randomized to pelvic irradiation (RT) and 140 randomized to observation (OBS). The planned pelvic dose was from 46 Gy in 23 fractions to 50.4 Gy in 28 fractions.

Results: Of the 67 recurrences, 24 were in the RT arm and 43 were in the OBS arm. The RT arm showed a statistically significant (46%) reduction in risk of recurrence (hazard ratio [HR] = 0.54, 90% confidence interval [CI] = 0.35 to 0.81, p = 0.007) and a statistically significant reduction in risk of progression or death (HR = 0.58, 90% CI = 0.40 to 0.85, p = 0.009). With RT, 8.8% of patients (3 of 34) with adenosquamous or adenocarcinoma tumors recurred vs. 44.0% (11 of 25) in OBS. Fewer recurrences were seen with RT in patients with adenocarcinoma or adenosquamous histologies relative to others (HR for RT by histology interaction = 0.23, 90% CI = 0.07 to 0.74, p = 0.019). After an extensive follow-up period, 67 deaths have occurred: 27 RT patients and 40 OBS patients. The improvement in overall survival (HR = 0.70, 90% CI = 0.45 to 1.05, p = 0.074) with RT did not reach statistical significance.

Conclusions: Pelvic radiotherapy after radical surgery significantly reduces the risk of recurrence and prolongs progression-free survival in women with Stage IB cervical cancer. RT appears to be particularly beneficial for patients with adenocarcinoma or adenosquamous histologies. Circumstances that may have influenced the overall survival differences are considered.

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.

Section snippets

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.

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