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

Marvin Rotman, IJROBP 2006;65:169
cervix_rotman_gog_postOp.gif (8650 bytes) 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.  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 planned pelvic dose was from 46 Gy in 23 fractions to 50.4 Gy in 28 fractions.

cervix_rotman_gog_postOp1.gif (8327 bytes) Results: The RT arm showed a statistically significant (46%) reduction in risk of recurrence and a statistically significant reduction in risk of progression or death (HR = 0.58. 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 . 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.
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. Earlier, external irradiation (RT) had been proposed to be of benefit in reducing recurrences in this group of patients. This prospect led to the development of the current study, GOG Protocol 92. 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.

External-beam RT without additional vaginal brachytherapy was to start 4 to 6 weeks after surgery. The median interval between randomization and beginning of pelvic RT was 14 days. Pelvic fields consisted of a 4-field technique with beam energies of at least 4 MeV, although 60Co could be used if the source-to-skin distance was 80 cm or greater. Total dose to be delivered was 46 Gy (in 23 fractions of 2.0 Gy) to 50.4 Gy (in 28 fractions of 1.8 Gy), 5 fractions per week. Treatment interruptions were to be no more than 1 week. The median duration of RT treatment was 5.7 weeks (range, 0.1–13.3 weeks) (excluding 9 patients who received no RT).

Treatment portals included the obturator, hypogastric, and external iliac lymphatics. The anteroposterior-posteroanterior (AP-PA) portals extended superiorly to the upper border of L5, inferiorly to the upper third of the obturator foramen, and laterally at least 1 cm beyond the margins of the bony pelvis at the widest plane through the pelvis. The lateral portal boundaries were superior and inferior (the same as the AP-PA boundaries), anterior (transverse line drawn through the pubic symphysis), and posterior (at least 4 cm beyond the cervical marker). The minimum anterior–posterior dimension of the lateral field was 9 cm, including the S2/S3 junction. 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 , 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 presented an acceptable cost-benefit ratio, despite the significantly higher recurrence rate (30.7% vs. 17.5%) and progression/death rate (35.0% vs. 21.9%) in the OBS arm. If a definite survival benefit had also been shown in this study (HR = 0.70, p = 0.074), the decision to use RT would be much easier.

The disparity between recurrence results and survival results in this study is surprising, given that survival comparison usually parallels recurrence comparisons in locally advanced cervix cancer trials. However, the sample size may have been too low. The study had 80% power to detect only risk reductions of 46% or greater in OS and did not find significant the 26% to 30% hazard reductions reported above.

Whereas many studies have pointed out the prognostic significance of CLS involvement, stromal invasion, and tumor size  either alone or combined, others have shown them to have little influence on recurrence rate or survival . A prior GOG study (of squamous cervical tumors) confirmed the prognostic significance of CLS involvement, stromal penetration, and tumor size

Two prognostic factors that seem to have become increasingly important in recent years have been cell type (adenocarcinomatous and adenosquamous tumors), and size (tumors 4 cm in diameter). In this study, the prevalence of both of these factors was higher in the RT arm, but these imbalances did not reduce the effectiveness of the RT arm (HR adjusted for cell type and tumor size = 0.60; 90% CI = 0.41 to 0.89; p = 0.016). Although tumor size contributes to risk of recurrence and mortality, in this study analysis of the effect of tumor size is precluded because of the confounding influence of the other eligibility criteria (small tumors required both of the other high-risk factors to be included, whereas large tumors required only 1 other factor). Lai et al. (19) reported that after control for confounding factors, histologic type (adenocarcinomatous and adenosquamous vs. squamous) was confirmed as an independent prognostic factor for reduced recurrence-free survival (RR = 1.28; p = 0.009) and OS (RR = 1.26; p = 0.0146) for Stage IB and II cervical cancer patients after primary radical surgery. When only Stage IB patients were considered (n = 521), histologic type was no longer a significant factor, although the relative risks for PFS and OS were 1.36 and 1.53, respectively (Lai, personal communication). In the current study, only 8.8% (3 of 34) of the patients with adenocarcinoma or adenosquamous tumors in the RT arm recurred vs. 44.0% (11 of 25) in the OBS arm. This outcome suggests that RT may be very valuable for such patients.
GI/GU complications

The reported incidence of GI/GU complications from use of postoperative irradiation has varied in the literature from 3% to 30% . The reasons for such a disparity are multiple and include differences in the reporting (all grades or just Grades 3 and 4) of complications. GI toxicity appears to be the most common and of greater concern, although bladder and ureteral toxicity cannot be ignored. The increase in Grade 3 to 4 complications reported in this study (6.6% RT and 2.1% OBS) may have been magnified by reporting bias. Lymphedema of the lower extremity (foot) was not considered in this study, although it has been reported by others as a significant complication of combined radical hysterectomy, lymphadenectomy, and irradiation

Landoni  reported in the Lancet that, in a study of 337 patients, the incidence of severe complications for surgery alone was not significantly different from those for combined surgery plus RT for Stage IB/IIA cervical cancer patients; and both were significantly more frequent than those seen in patients given RT alone (28% vs. 12%; p = 0.0004).

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.