According to the NCCN recommendations for early cervical cancer, hysterectomy is indicated with dissection of the cervix, corpus, parts of the vagina and ligaments, and pelvic lymph nodes. In this meta-analysis, radical, extrafascial, or laparotomy hysterectomy with lymphadenectomy was completed within six to 12 weeks after chemoradiotherapy/radiotherapy in eight studies. We conducted this meta-analysis to evaluate the role of surgery in patients with locally advanced cervical cancer after chemoradiotherapy/radiotherapy. Survival status and side effects related to surgery were examined.
Clinical features
Radiotherapy/chemoradiotherapy followed by surgery could have different effects on survival status compared with chemoradiotherapy alone in patients with different stage disease in the eight manuscripts. However, surgery could have no effect on OS after radiotherapy/chemoradiotherapy.
According to Perez [
14], the five-year cause-specific survival of patients with bulky IB2 (>five centimetres), IIA (>five centimetres) or IIB disease was 61%, 63%, and 69%, respectively, after radiotherapy and 60%, 72%, and 65%, respectively, after radiotherapy followed by surgery (
p > 0.5). The ten-year OS of patients with bulky IB2 (>five centimetres), IIA (>five centimetres) or IIB disease was 61%, 68%, and 69% after radiotherapy and 44%, 72%, and 65% after radiotherapy followed by surgery (
p > 0.5). Recurrence and metastasis rates were reported for the subgroups as follows: stage IB: 10% and 14%; stage IIA: 17% and 20%; and stage IIB: 23% and 29%. Chemotherapy was not utilized in this study. A tumour diameter greater than five centimetres was considered bulky disease; this definition differs from that stated in the 2009 FIGO guidelines (>four centimetres). For those patients with a tumour diameter more than four centimetres but less than five centimetres, the survival status was not included. These results are worth exploring. According to Keys [
13], the five-year disease-free survival (DFS) and local recurrence (LR) rates were 62% and 53% in the surgery group and 14% and 27% in the chemoradiotherapy group for patients with stage IB2 disease (
p > 0.5). Surgery could reduce the LR rate, especially among those patients with four-, five- and six-centimeter tumours. In the study by Leguevaque [
12], the two-year DFS and recurrence rates were 66% and 49.7% in the surgery group and 22.4% and 36.4% in the chemoradiotherapy group (
p < 0.05). The pelvic region was the main site of recurrence, occurring in 46.7% of the surgery group at 14 months and 56.2% of the chemoradiotherapy group at 11 months. The death rate caused by cervical cancer was 16.4% in the surgery group and 20.4% in the chemoradiotherapy group (
p < 0.05), of which 45.4% and 77.8% of these cases were caused by pelvic recurrence (PR). As mentioned in this article, surgery was conducted in only patients who had a complete response (CR) or a residual tumour less than 50% of the initial size after chemoradiotherapy. Surgery did not improve OS but did increase DFS. In the study by Morice [
15], the three-year OS and event-free survival rates of 86% and 97%, respectively, and 72% and 89%, respectively, were not significantly different according to surgery group among CR patients after chemoradiotherapy. Progression-free survival (PFS) and OS were similar between the two groups (74.8% and 71.7% for chemoradiotherapy alone; 76.3% and 74.5% for surgery after chemoradiotherapy) in the study by Centina [
16]. According to Mazeron [
17], the five-year DFS was 75.6% and 77.4% in the two treatment groups (
p > 0.5), and the five-year OS was not statistically significantly different between the two treatment regimens. In the study by Fanfani [
18], the three-year DFS and OS were 62.9% and 68.3% versus 63.2% and 67.7% for two treatment regimens (
p > 0.5). The recurrence and death rates were 40.7% and 28.7% for chemoradiotherapy and 37.6% and 30.1% for surgery after chemoradiotherapy (
p < 0.05) among patients with stage IIIA and IIIB disease. Surgery after chemoradiotherapy significantly reduced the recurrence and death rates without any effect on DFS or OS. Based on the report by Darus [
19], the mean OS was 113.8 months (94.4–133.3 months) in the surgery group and 113.7 months (92.2–135.1 months) in the chemoradiotherapy group for patients with stage IB2 disease (
p > 0.5). The mean disease-free interval was 113.8 months (89.8–137.8 months) and 113.2 months (93.9–132.5 months) for the two groups (
p > 0.5). Surgery or brachytherapy could be performed depending on tumour shrinkage after external beam radiotherapy.
These studies indicate that the recurrence and death rates could be decreased by surgery after chemoradiotherapy/radiotherapy without affecting OS.
In this meta-analysis, the OS for radiotherapy/chemoradiotherapy combined with surgery was not increased compared with that for radiotherapy/chemoradiotherapy alone in patients with locally advanced cervical cancer. Hence, surgery is not recommended after radiotherapy/chemoradiotherapy. After excluding Daru’s data because the patients received surgery without brachytherapy, the final results for OS remained the same. The articles included in this meta-analysis mainly focused on stage IB-IIB disease, especially the report by Perez [
14]; hence, we conducted a subgroup analysis and found that the OS of patients with stage IB-IIB disease was not improved by radiotherapy/chemoradiotherapy combined with surgery. In 2016, a multicenter cohort study on chemoradiotherapy combined with image-guided brachytherapy in locally advanced cervical cancer showed promising results. The three- and five-year actuarial LC, pelvic control (PC), cancer-specific survival (CSS), and OS were 91% and 89%, 87% and 84%, 79% and 73%, and 74% and 65%, respectively. The three- and five-year actuarial LC rates for patients with stage IB, IIB, and IIIB disease were 98% and 98%, 93% and 91%, and 79% and 75%, respectively. The three- and five-year actuarial PC for patients with stage IB, IIB, and IIIB disease was 96% and 96%, 89% and 87%, and 73% and 67%, respectively. The five-year actuarial rates of grade three-five morbidity were 5%, 7%, and 5% for the bladder, gastrointestinal tract, and vagina, respectively [
20]. There were some analyses of patients who received surgery after chemoradiotherapy/radiotherapy without comparison to those who received radiotherapy/chemoradiotherapy alone. The nine-year DFS and OS rates were 81% and 85% for patients with stage IB2 to IVA disease [
21], the two-year LC was 91.7% for stage IIB to IIIA disease [
22], the five-year OS and DFS rates were 84% and 76% for IB2 to IVB adenocarcinoma [
23], the five-year DFS and OS rates were 83% and 90% for patients with stage IB2, IIA and IIB disease [
24], and the two- and five-year DFS rates were 80.4% and 72.2% for patients with stage IB2, IIA and IIB disease [
25]. Chemoradiotherapy was associated with excellent survival outcomes without severe side effects for locally advanced cervical cancer.
Side effects were reported in six studies in this meta-analysis, with data unavailable in the studies by Leguevaque [
12] and Morice [
15]. Grade one-two and/or three-four side effects were available in some articles. The digestive and/or urinary systems were involved in some studies. Unfortunately, more details regarding grade and affected system were not available. Consequently, side effects were not evaluated due to uncertainties in the data extraction. In the articles included in this meta-analysis, the results regarding side effects were different. In the research by Keys, grade three and four side effects occurred at a rate of 10% in both groups. The frequency of side effects was higher in the surgery group (63% versus 56%) [
13]. According to Darus, surgery did not increase toxicity, which was mainly grade one-two. More gastrointestinal toxicities occurred in the chemoradiotherapy group (41% versus 21%), but this difference was not statistically significant [
19]. In the publication by Fanfani, urinary and gastrointestinal complications were more prevalent after radiotherapy than after surgery (14.3% versus 0%). Grade one-two side effects occurred in 57.1% and 8.2% of the cases in the radiotherapy and surgery groups, respectively (
p < 0.05). The rate of vascular complications was 16.4% after surgery compared with 0% after radiotherapy. Grade one-two and three-four side effects occurred in 15% and 1.4% of the surgery group. Late vascular complications were similar in the two groups. Grade one-two and three-four urinary side effects occurred in 7.8% and 7.6% of the radiotherapy group and 9.6% and 4.1% of the surgery group. The rates of grade one-two and three-four gastrointestinal side effects were 6.5% and 2.6% in the radiotherapy group and 6.8% and 0% in the surgery group [
18]. In the study by Perez, grade three side effects occurred in 5–11% and 8–12% of patients in the radiotherapy and surgery groups. In the radiotherapy group, the following rates of side effects were reported: rectovaginal fistula, 1.5%; proctitis, 1.1%; small intestine obstruction, 1.8%; urethral stricture, 1.8%; and vesicovaginal fistula, 0.9%. In the surgery group, small intestine obstruction/perforation occurred in 4.2% of the cases, urethral stricture in 2.6%, vesicovaginal fistula in 1.6%, and rectovaginal fistula in 1.3% [
14]. In the research by Mazeron, the cumulative incidence of severe late morbidity was higher in the surgery group at two years (16.2% versus 4.3%) and at five years (2.5% versus 6.5%) [
17]. In the study by Centina, grade one-two side effects in the surgery group included proctitis and cystitis (50%), and the rate of grade three-four side effects was 2%. Six patients had an infection 30 days after surgery. In total, 3.4% of the patients underwent unilateral lymphocyst resection or drainage. Overall, 2.3% of the patients had a uretero-cutaneous fistula treated with surgery and double J-stent positioning [
16].
Other adverse effects of surgery were as follows. Hospital stay was prolonged by five days (range, four to six days). Median surgical time was four hours (four to six hours). Median blood loss was 450 ml (150–600 ml). Furthermore, 13.9% of patients received transfusions, 3.4% had a vascular laceration, 1.5% had a urethral tear, 2.3% had urethral stricture, 1.5% had wound dehiscence, and 1.5% had infection of the surgical wound [
16]. According to the research by Fanfani, the median operation time was 240 min (90–400 min), blood loss was 275 ml (100–3000 ml), and the total operative hospital stay was eight days (four to 18 days) [
18]. In developing countries, surgery increases the economic burden. Since the data were limited, more details remain to be investigated.
Limitations
There are some limitations to this meta-analysis. First, different chemotherapy regimens were administered, such as cisplatin, capecitabin, 5FU, carboplatin and gemcitabine. The effects of different chemotherapy regimens are unclear, but chemotherapy plays a crucial role in the tumour response to radiotherapy. Second, tumour response after chemoradiotherapy is a key factor in the decision to perform surgery [
26]. For example, in the study by Leguevaque, surgery was performed in only patients who had a CR or a residual tumour less than 50% of the initial tumour size after chemoradiotherapy. In the study by Morice, surgery was conducted in patients with a CR after chemoradiotherapy. Residual disease in the cervix at the end of radiotherapy is one factor to consider [
27,
28] in decision-making regarding surgery after radiotherapy. The response to radiotherapy/chemoradiotherapy was evaluated and sometimes repeated by gynaecological examination and/or MRI. Third, it has been reported that positive nodes are an independent prognostic factor for OS [
29]. A high rate of extra-cervical disease and pelvic and/or para-aortic node involvement is associated with more radiotherapy resistance and decreased OS despite a CR after chemoradiotherapy [
28]. The need for detecting positive nodes is emphasized before surgery. PET-CT was more promising than MRI at detecting positive nodes [
30], but repeat MRI can provide proof of residual disease [
31]. Fourth, squamous cell carcinoma and adenocarcinoma were investigated in this meta-analysis without separating the results by pathology category. Fifth, data on DFS, PFS, LC and recurrence rate were not available for the meta-analysis, and these results are still unknown. Finally, although surgery remains the first option for local relapse or an incomplete response to radiotherapy, the indications for surgery after radiotherapy/chemoradiotherapy are still controversial.