The role of post-radiation hysterectomy after definitive chemoradiotherapy in management in advanced cervical cancer have been debated for years for lacking prospective studies. Several retrospective studies demonstrated post-radiation might improve the outcomes, however the results were conflicting[13–15]. Moreover the majority pathology in these studies was SCC rather than AC, these results had limitations in illuminating the efficacy of hysterectomy for cervical AC patients.
In our study, we found surgery following CCRT provided a superiority in AC patients on 3-year OS (68.6% vs. 52.8%, p = 0.044), compared with non-surgery group. This was consistent with the findings of a previous study from our hospital based on a smaller patient population, that 3-year PFS and LPFS also had a trend to increase in surgery group[16]. However, clinical response after CCRT was not balanced in present study, which could influence the outcomes. Thus, subgroup analysis was conducted. In subgroup analysis of patients with non-CCR after CCRT, we found a significantly better 3-year PFS and DMFS in surgery group than non-surgery group. The lack of statistic significance of OS and LPFS might be partially explained by the smaller number of patients in the current study. A few researchers also testified surgery improved the outcomes of cervical cancer patients with residual tumor after CCRT[17, 18]. Pervin reported 40 patients with FIGO IIB-IIIB cervical cancer, who received post-radiation hysterectomy to control residual tumor. At 5 years follow up, 90% of patients remained disease free, indicating surgery might be an effective treatment for patients with residual cervical cancer[17]. Another retrospective study involving 192 patients with advanced cervical cancer, showed significantly fewer recurrences in patients with post-CCRT surgery comparing with those did not (16.7% vs. 31.7%)[13]. Although the above studies were mainly aimed at patients with SCC, our present study also showed the advantages of surgery in obliterating the residual lesions after radiotherapy and significantly improving the 3-year PFS and 3-year DMFS of AC patients. On the contrast, our study found surgery did not bring survival benefits to patients with CCR after CCRT. These results reflected those studies of Keys et al. who reported no significant clinical benefits in the use of post-radiation surgery in a randomized trial among patients with cervical cancer. Nevertheless, they suggested the patients with a bulky tumor (> 2 cm) might benefit from post-radiation hysterectomy by reducing the pelvic recurrence from 27–15%[19]. One explanation was that bulky remnant after treatment have been proved to be predictive factor for survival outcomes. Castelnau-Marchanda demonstrated in their study including 58 patients with cervical cancer treated by CCRT followed by hysterectomy, the 4-year OS and DFS rates were significantly decreased in patients with macroscopic residual disease (greater than 1 cm) in contrast to patients with microscopic residua or complete response[20]. Another French multicentric retrospective study of 54 women with cervical adnocarcinoma IB2 to IIIB, reported the rate of recurrences reached 17% in patients with no residual tumor or tumor smaller than 1 cm versus 30% in patients with residual tumor bigger than 1 cm[21]. Thus, elimination of residual tumors should play a positive role in improving local control and potentially increasing OS rate. For patients with CCR have been proved to have a better prognosis, adjuvant surgery might not lead to a statistically greater difference in survival.
The clinical evaluation of persistent tumor after chemoradiotherapy, has not been easy. Theoretically, cervical biopsy pathology is the gold standard for diagnosis. However, histological and cytological modificaitons after radiotherapy, sometimes affects the interpretation of pathology. And due to the inconvenience of the procedure, MRI is still the first choice for detecting residual disease after primary treatment, though the differentiation of residual tumor from post-radiated change is sometimes also difficult. Previous studies showed the false negative rate and false positive rate of MRI to detect post-chemoradiation residual disease in cervical cancer were about 11 ~ 15% and 17 ~ 29%[22, 23]. And in terms of functional imaging, Ferrandina conducted a prospective study comparing MRI and PET/CT in the detection of residual disease after chemotherapy for locally advanced cervical cancer, showing the sensitivity was higher for MRI than for PET/CT (86.1% vs. 63.1%, p = 0.002), while the specificity was higher for PET/CT than for MRI (35.5% vs. 80.6%, p = 0.002)[24]. Since imaging alone for evaluation was less satisfactory[15], we expected to improve the accuracy of evaluation by combining plevic examination with radiology. In the present study, 16 of 19 patients with partial response after CCRT through clinical evaluation, were pathological proven with residual tumor. For patients declared as CCR, residual tumor was noted in 44.4% (12/27) cases after surgery. Thus, we found a high sensitivity of 84.2% to predict residual tumor after CCRT through clinical evaluation, but the false negative rate was relatively high. According to our present study, the CCR patients had a better outcome regardless of the use of surgery or not, in that case, we still considered joint examination of imaging and physical examination as the primary method of evaluating the clinical response after CCRT. And non-CCR patients would potentially benefit from post-radiation surgery.
During the median follow-up of 44 months, 32 (56.1%) recurrences developed in non-surgery group and 22 (42.3%) in the surgery group. We found no significant differences of failure pattern between the two groups, though post-surgery group seemed to have a lower rate of local recurrence (17.3% vs. 31.5%). Distant metastasis was the major way of recurrence. Recurrences occurred after a median interval of 29 months in non-surgery group and 40 months in surgery group.
Surgery related morbidity was another concern for post-radiation hysterectomy. Some previous studies reported a high morbidity after post-radiation surgery, while the others showed similar incidence of severe side effects[19, 25]. Incidence of Grade 3–4 gastrointestinal and genitourinary morbidity events were 8.6% -10.4% and 8.6%-10% in patients with locally advanced cervical cancer treated with CCRT followed by hysterectomy, according to Houvenaeghel and Castelnau-Marchand[18, 20]. Severe urinary and gastro-intestinal toxicities occurred in 3.7% and 2.7% of the whole population in our study, and no significant differences between the surgery and non-surgery group. One patient in non-surgery group died of severe intestinal obstruction and secondary infection after CCRT. The incidence was lower than previous studies, which might benefit from the wide application of intensity modulated radiotherapy. And it might also result from small population size. Nonetheless, our findings indicated a tolerable long-term toxicity of this multimodality treatment.
The strengths of our study were the relatively large number of pure cervical AC population, the homogeneity of radiation treatment and long-term follow-up. The weakness was its retrospective nature, a single institution experience and the lack of integrity of medical records. Baseline characteristics between the two study groups were not well balanced which might influence the outcomes, especially the proportion of patients received consolidation chemotherapy. Due to the less chemosensitivity of AC and lack evidence for consolidation chemotherapy improving survival outcomes in AC patients, we reckoned chemotherapy could not explain the survival difference between the surgery and non-surgery groups. And due to the limitation of sample size, matching method was not feasible to use in this study.