Hysterectomy (radical) with neoadjuvant chemotherapy versus chemoradiotherapy alone

One multicentre RCT included 620 participants with FIGO Stage IB₂, IIA (greater than 4 cm) or IIB cervical cancer (EORTC 2019). Both patient groups received cisplatin‐based chemotherapy. In the NACT plus surgery group, women received neoadjuvant cisplatin‐based chemotherapy on day one. Treatment was repeated every 21 days. Within six weeks after the last chemotherapy course, and with a cumulative minimum of 225 mg/m², women underwent a type III to V Piver‐Rutledge radical hysterectomy. Women with positive lymph nodes or tumour invasion into the parametria or less than 5 mm from the resection borders after surgery received standard adjuvant external‐beam radiotherapy once daily, five days a week, for 5.0 to 5.6 weeks (25 to 28 treatment days) followed by external boost radiotherapy or brachytherapy for one or two days In the concurrent radiotherapy group, radiation consisted of 45 Gy to 50 Gy plus boost concurrent with weekly cisplatin chemotherapy (40 mg/m² per week). Adjuvant hysterectomy was allowed, but not recommended, in cases of histologically confirmed residual tumour. Participants in both groups were evaluated for OS at five years (primary endpoint) and OS, PFS, toxicity and quality of life (secondary endpoints).

Gupta 2018 was a single‐centre RCT that included women with cervical cancer Stage 1B₂, IIA or IIB disease. The NACT plus surgery group received three cycles of paclitaxel (175 mg/m²) and carboplatin (dosed to an area under curve of 5 to 6) once every three weeks. Participants underwent clinical response assessment after the second and third cycles of chemotherapy. Participants who had no response or disease progression at these time points crossed over to receive definitive CCRT, whereas responders underwent surgery three to four weeks after the third cycle of chemotherapy.

Participants assigned to the NACT plus surgery group underwent Piver‐Rutledge class III radical abdominal hysterectomy, bilateral pelvic lymphadenectomy and lower para‐aortic lymph node sampling by expert gynaecological oncologists. Surgery was abandoned in participants with intraoperative findings of either unresectable primary tumour or lymph node disease, and these participants were treated with definitive concurrent chemoradiation. Participants assigned to the concurrent chemoradiation group and those who were crossed over from the NACT plus surgery group received standard external‐beam radiation to the whole pelvis and brachytherapy. They received an external radiation dose of 40 Gy in 20 fractions with 2 Gy per fraction and a midline shield at 20 Gy, followed by intracavitary radiation to 'point A' as follows: either two applications of a low‐dose rate of 30 Gy each or five applications of a high‐dose rate of 7 Gy each. Radiation doses were modified to respect tumour, rectal and bladder constraints. These women also received five cycles of cisplatin (40 mg/m²), administered once every week starting with external‐beam radiotherapy. Participants in the NACT plus surgery group who underwent radical hysterectomy were given adjuvant therapy (radiotherapy or CCRT) as per protocol‐defined criteria, in accordance with published evidence. On the basis of histopathological evaluation of the surgical specimen, adjuvant chemoradiation was given in the presence of any one of the following features: lymph node metastasis, positive surgical margins or parametrial involvement. Adjuvant radiotherapy alone was given based on the presence of any two of the following features: deep cervical stromal invasion, lymphovascular invasion or tumour size greater than 4 cm. Participants in both groups were evaluated at protocol‐defined time points to evaluate response, monitor for relapse and assess toxicity.

In Khan 2014, both patient groups received platinum‐based chemotherapy. Participants assigned to the chemoradiotherapy group received external beam radiotherapy (EBRT; 45 Gy to 50 Gy) followed by brachytherapy. Participants assigned to the NACT plus surgery group, had radical hysterectomy and pelvic lymphadenectomy. Participants in both groups were evaluated for short‐term complications within 30 days of completion of treatment and long‐term complications that were reported within two years after treatment.

Hysterectomy (simple or radical) with neoadjuvant chemotherapy versus radiotherapy alone

Three RCTs randomised 571 women compared NACT and hysterectomy (simple or radical) versus radiotherapy alone (Benedetti‐Panici 2002; Chang 2000; Noriyuki 2010). Benedetti‐Panici 2002 included women with Stage IB₂ to III cervical cancer, Chang 2000 included women with IB to IIA bulky disease and Noriyuki 2010 had only women with Stage IIIB disease. The median age in each arm was similar in Benedetti‐Panici 2002 and Chang 2000 (range 46 to 52 years), whereas in Noriyuki 2010, women were significantly older in the radiotherapy arm (mean age 53 in the NACT and hysterectomy arm versus 60 years in the radiotherapy arm). All women in Benedetti‐Panici 2002 and Noriyuki 2010 and most in Chang 2000 had squamous cell cancers. In Benedetti‐Panici 2002 and Chang 2000, the Eastern Cooperative Oncology Group performance status was zero for most eligible women. Noriyuki 2010 did not report performance status.

In Benedetti‐Panici 2002, the NACT regimen was not predetermined; minimal requirements were a cisplatin‐containing regimen with a 240 mg/m² or greater total cisplatin dose with a maximum of two additional drugs, administered over six to eight weeks. After NACT, the women were clinically reassessed and classified as suitable or unsuitable for radical surgery. Participants who were unsuitable for radical surgery were treated with radiotherapy. Surgery consisted of radical hysterectomy (type III to V) plus systematic (at least 20 nodes to be resected) pelvic lymphadenectomy (aortic lymphadenectomy was optional). Postoperative radiotherapy was given in participants with positive surgical resection margins or metastatic nodes, or both. In the case of node metastasis, the choice of adjuvant treatment was based on the institution's policy (e.g. chemotherapy, external‐beam radiotherapy or no further therapy). Adjuvant treatment was given to 48 (29%) participants in the surgical group; 38 (23%) participants in the surgical group underwent adjuvant radiotherapy.

Conventional radiotherapy consisted of external‐beam, megavoltage radiotherapy (45 Gy to 50 Gy) to the whole pelvis over five to six weeks. In the presence of metastatic pelvic nodes an extra dose of 5 Gy to 7 Gy was administered. Low‐dose rate brachytherapy (20 Gy to 30 Gy to the tumour volume) was provided two to four weeks after external radiotherapy. Aortic node metastases, when present, were irradiated (45 Gy per five weeks, followed by a 5 Gy boost if residual disease was eventually detected) with extended fields encompassing pelvic and aortic volume or at the end of pelvic irradiation, in the case of a pelvic complete remission. Salvage treatments were allowed in women who showed progressive disease.

In Chang 2000, the NACT was cisplatin and vincristine, followed by bleomycin. Two to four weeks after the completion of NACT, participants underwent a type III radical abdominal hysterectomy and pelvic lymphadenectomy. The adnexae were usually left in women aged 40 years or less if the gross appearance of the adnexae was normal.

The radiotherapy usually included a combination of external radiotherapy and high‐dose rate brachytherapy; with 40 Gy to 44 Gy whole pelvic irradiation. The para‐aortic lymph nodes were not routinely included in the treatment field. Parametria received up to 50 Gy. If bulky tumour persisted after 44 Gy of irradiation, external‐beam doses to the lower pelvis were increased to 50 Gy to 54 Gy without central block followed by brachytherapy, or to 70 Gy without brachytherapy. The median cumulative dose to 'point A' in this treatment protocol was 70 Gy. Thirty‐seven participants were treated using this method. The postoperative radiotherapy was given by using techniques similar to those described above. The dose to the whole pelvis was 44 Gy to 45 Gy, and that to the true pelvis was 50 Gy to 54 Gy. After external radiotherapy, brachytherapy was given in two to three fractions with a total dose of 4 Gy/0.5 cm to 6 Gy/0.5 cm below the vaginal mucosa.

Participants in the NACT arm had a higher incidence of receiving adjuvant therapy with either radiotherapy or chemotherapy after the scheduled treatment than those in the radiotherapy arm, who received radical hysterectomy as the adjuvant therapy. Of the 68 women in the NACT arm, 62 underwent hysterectomy and 19 of those had adjuvant radiotherapy, six had adjuvant chemotherapy and two had chemoradiotherapy.

In Noriyuki 2010, the NACT regimen consisted of cisplatin, bleomycin and mitomycin for three courses every four weeks. If the tumour was surgically removable, a radical hysterectomy was performed with bilateral salpingo‐oophorectomy and pelvic lymphadenectomy, and then radiotherapy was given at 40 Gy to the whole pelvic region. If the tumour progressed or relapsed, combined chemotherapy of bleomycin, vincristine, mitomycin and cisplatin (BOPM) was given, and then irinotecan with cisplatin as the third line. If the local tumour was inoperable, radiotherapy was given at 40 Gy to the whole pelvic region with 20 Gy brachytherapy, followed by BOPM chemotherapy.

The radiotherapy group received radiotherapy to the whole pelvic region in 20 fractions totalling 40 Gy. The total dose delivered to 'point B' as a boost dose with midline shield coverage was 20 Gy. The total dose delivered by brachytherapy was 24 Gy to 30 Gy. The pelvic field extended from the upper margin of L5 to the mid‐portion of the obturator foramen or the lowest level of disease, with a 3 cm margin, and laterally 1.5 cm to 2 cm beyond the lateral margins of the bony pelvic wall. The duration of the radiotherapy was four weeks. In cases with local recurrence or progression of the primary lesion, chemotherapy was added, which included BOMP, irinotecan with cisplatin, and cisplatin or carboplatin alone. When distant metastasis occurred, the researchers added radiotherapy, or the single lesion was surgically removed.

All three studies assessed OS (Benedetti‐Panici 2002; Chang 2000; Noriyuki 2010), one study also assessed PFS (Benedetti‐Panici 2002) and two studies also assessed DFS (Chang 2000; Noriyuki 2010). However, the definition of DFS in Chang 2000 was absence of persistent or recurrent disease, so this appeared to be a combination of progression and DFS. It was possible to include all three studies in a meta‐analyses of OS and PFS or DFS as HR estimates were either explicitly reported, deduced (Parmar 1998), or obtained via personal correspondence (Noriyuki 2010). Benedetti‐Panici 2002 reported severe toxicity and complications and Chang 2000 reported tumour response to treatment and toxicity. Noriyuki 2010 did not report adverse events. None of the three studies reported quality of life outcomes.

Hysterectomy (simple or radical) with radiotherapy versus radiotherapy alone

Two studies, which included 374 women, compared preoperative radiotherapy and radical hysterectomy versus radiotherapy alone (Keys 2003; Perez 1987). Keys 2003 included 256 eligible women with Stage IB₂ disease (tumour size 4 cm to 8 cm); Perez 1987 included 118 women with Stage IIA disease as well as Stage IB (but women with a tumour more than 5 cm were excluded). The age distribution was comparable in the two groups in both trials, but additional information was not reported in Perez 1987. In Keys 2003, just over 75% of the women were 50 years old or under. Most women in both trials had squamous cell carcinoma of the cervix. Additional baseline information was not reported in the Perez 1987 trial; but the performance status of women in Keys 2003 was generally good (more than 76% in both arms with performance status of 0 and more than 20% with performance status of 1). Keys 2003 did not mention whether the participants were evaluated clinically or radiologically after radiotherapy in order to assess the tumour response and residual disease.

In Keys 2003, the daily fraction size was 180 Gy and external treatment carried to a total dose of 40 Gy for the radiation alone and 45 Gy for the adjuvant hysterectomy regimens. Both groups received brachytherapy one to two weeks after completing external treatment. The brachytherapy dose prescription was different between the treatment arms; the radiation alone group received 40 Gy with a total dose of 80 Gy to 'point A', while those who had hysterectomy received only 30 Gy with a total dose of 75 Gy to 'point A'. A minimum dose of 55 Gy was prescribed to 'point B' for both regimens. All irradiation was completed within 10 weeks. The surgical group then underwent simple hysterectomy with removal of tubes and ovaries, if present, two to six weeks after completion of all irradiation.

In Perez 1987, participants who were treated with preoperative radiotherapy and surgery received 20 Gy whole pelvis irradiation and one brachytherapy for 5000 to 6000 milligram‐hours (approximately 5 Gy to 6 Gy low‐dose rate given over six days), followed two to six weeks later by a radical hysterectomy and bilateral pelvic lymphadenectomy (up to the bifurcation of the common iliac vessels). The dose to the cervix was about 70 Gy and to the pelvic lymph nodes 30 Gy.

Treatment with irradiation alone in Perez 1987 consisted of 10 Gy to 20 Gy delivered to the whole pelvis and an additional parametrial dose to total of 50 Gy to the external iliac lymph nodes combined with two brachytherapy insertions for a total of approximately 7500 milligram‐hours (65 Gy to 70 Gy to 'point A'). The dose to the paracervical tissues was about 85 Gy and to the pelvic lymph nodes 60 Gy.

Keys 2003 assessed OS, pelvic‐free survival and the rate of pelvic recurrence. Perez 1987 assessed the five‐year tumour‐free actuarial survival, the sites of failure after therapy and treatment complications.

Hysterectomy (simple or radical) with chemoradiotherapy versus chemoradiotherapy alone

Morice 2012 included 61 women with FIGO Stage IB₂ or II cervical cancer with a complete clinical and radiological response after chemoradiotherapy, randomly allocated to the treatment arms: hysterectomy or no hysterectomy. The median age and stage distribution was similar in both groups (45 years in the chemoradiotherapy and hysterectomy arm and 44 years in the chemoradiotherapy and no hysterectomy arm). Half of the women had FIGO Stage IB₂ and half Stage II disease. More than 80% of participants in each group had squamous cell cancer. The performance status of the included women was not described.

Radiotherapy was delivered to the pelvis for a total dose of 45 Gy to 50 Gy, in five fractions of 1.8 Gy to 2 Gy per week, followed one to two weeks later by brachytherapy. Most women in both groups had one application of brachytherapy at 15 Gy. CCRT was cisplatin during external radiotherapy. A complete clinical and radiological response (based on magnetic resonance imaging (MRI)) was evaluated six to eight weeks after brachytherapy.

Hysterectomy could be performed via laparotomy or a laparoscopy and could be extrafascial or radical (type II according to the Piver classification) according to the preoperative examination. A selective or complete pelvic lymphadenectomy was optional and could be performed if lymphadenopathy was detected during surgery.

The trial gave HRs for OS and recurrence‐free survival as well as reporting the site of first recurrence. Morbidity was not reported after confirmation from the study authors. The median duration of follow‐up was 3.8 years (range 0.4 to 5.8 years) when the trial was closed early because of poor accrual.

Zheng 2017 included 102 participants with LACC and compared chemoradiotherapy and radical hysterectomy and pelvic lymph node dissection versus chemoradiotherapy alone. Fifty‐two participants were included in the hysterectomy arm and 50 in the chemoradiotherapy alone arm.

Women who met the inclusion criteria were first treated with CCRT.

The radiotherapy plan was as follows: the linear accelerator was used for external pelvic irradiation, and the intracavitary ¹⁹²Ir was used for radiotherapy. Stage 1: the whole basin irradiation before and after the field or left and right field irradiation, four or five times a week, each time 2.25 Gy or 1.8 Gy, pelvic centre total dose 30 Gy. Stage 2: the lead block protected the uterus, and the uterus continued to be irradiated from the front and back, five times a week, 1.8 Gy to 2.0 Gy each time, and the total periuterine dose was 15 Gy to 20 Gy. At the beginning of the second stage of external irradiation, intracavitary and the back of the cavity were performed at the same time once a week, with 4.6 Gy to 7.0 Gy at 'point A' and total of 35 Gy to 42 Gy at 'point A'. Chemotherapy regimen: cisplatin alone: 35 mg/m² to 40 mg/m², once a week. Surgical treatment: participants in the experimental group underwent radical surgery four to six weeks after the completion of CCRT. For radical total hysterectomy and pelvic lymphadenectomy, 3 cm of paracervical and vaginal tissues were removed.

The outcomes of the study included recurrence and OS rate using. As outcome indicators they used: short‐term efficacy evaluation: evaluate the efficacy according to the tumour regression before and after treatment; complete remission: complete regression of the tumour by gynaecological examination and imaging examination; partial remission: tumour volume reduction of 50% or less; stability of disease: tumour volume reduction of 50% or less; progression of disease: tumour enlargement or presence of new lesions. Complete remission plus partial remission indicated effective treatment.

Hysterectomy (radical) with chemoradiotherapy versus internal radiotherapy (brachytherapy) with chemoradiotherapy

Cetina 2013 included 211 women aged 18 to 70 years with a histological diagnosis of untreated FIGO Stage IB₂ to IIB cervical cancer and no evidence of para‐aortic lymph node involvement. It was reported that these 211 women were randomly allocated to either brachytherapy after external‐beam radiotherapy with chemotherapy or radical hysterectomy after external‐beam radiotherapy with chemotherapy. Women were ineligible for the study if they had previously received chemotherapy or radiotherapy. The median age, and stage distribution, was similar in both groups (44 years in the brachytherapy arm and 45 years in the hysterectomy arm). The median performance status (Karnofsky's) score was 90 and the median tumour size was 32 mm in both arms. Most participants in each treatment arm had FIGO Stage IIB disease (70% of participants in the brachytherapy arm and 74% in the hysterectomy arm). More than 80% of participants in each group had squamous cell cancer.

Participants received 50.4 Gy external‐beam radiotherapy to the entire pelvic region in 28 sessions of 1.8 Gy/day, five days/week, over the six weeks of chemotherapy. Immediately after completion of external‐beam radiotherapy with chemotherapy, participants in the brachytherapy underwent low‐dose rate brachytherapy of 30 Gy to 35 Gy delivered to 'point A', to result in a cumulative dose of 80 Gy to 85 Gy combining external‐beam radiotherapy and brachytherapy. The cumulative external‐beam radiotherapy and brachytherapy dose to 'point B' (the pelvic wall) was 55 Gy to 65 Gy.

Within four to six weeks after the external‐beam radiotherapy with chemotherapy, participants in the hysterectomy group were submitted to type III radical hysterectomy and bilateral pelvic lymph node dissection and para‐aortic lymph node sampling, if the multidisciplinary team judged the disease could be resected obtaining margins free of disease. Postoperative low‐dose rate brachytherapy was mandated in participants in the hysterectomy are only if the surgical specimen revealed positive surgical margins and was administered within four weeks after surgery at a median dose of 30 Gy to the vaginal mucosa delivered to a depth of 0.5 cm.

The trial gave HRs for OS and PFS. The trial also reported pathological response; operative complications; toxicity to chemoradiation with cisplatin and gemcitabine; long‐term complications; and late complications including proctitis, cystitis and hydronephrosis. Only late complications were reported in a breakdown by treatment arm. The median duration of follow‐up was 36 months (range 3 to 80 months).

Hysterectomy (radical) with neoadjuvant chemotherapy versus chemoradiotherapy alone

Reis Fihlo 2018 is an ongoing study and the final results will be available in 2023 (personal communication with the authors). Both participant groups (Stage IB₂, IIA, or IIB) will receive platinum‐based chemotherapy. Participants assigned to the NACT and radical hysterectomy group will receive chemotherapy every 21 days for six weeks. Within six weeks after the last chemotherapy course, women will undergo a type III to V Piver‐Rutledge radical hysterectomy. Women with positive lymph nodes or tumour invasion into the parametria or less than 5 mm from the resection borders after surgery will receive standard adjuvant external‐beam radiotherapy once daily, five days a week, for 5.0 to 5.6 weeks (25 to 28 treatment days) followed by external boost radiotherapy or brachytherapy for one or two days. Participants assigned to the CCRT group will receive standard therapy comprising cisplatin‐based chemotherapy once weekly for six weeks. Adjuvant hysterectomy will be allowed, but not recommended, in cases of histologically confirmed residual tumour. Participants in both groups will be evaluated for OS, PFS, toxicity of the regimens and quality of life.

CSEM 006 study is an ongoing study assessing DFS of women with Stage IIB cervical cancer randomised to NACT combined with surgery versus CCRT.

Hysterectomy (radical) with chemoradiotherapy versus hysterectomy with neoadjuvant chemotherapy versus chemoradiotherapy alone

Shanmugam 2019 is an ongoing RCT where all three participant groups with LACC will receive cisplatin and paclitaxel chemotherapy. Women assigned to the CCRT group will receive cisplatin (75 mg/m²) and paclitaxel (175 mg/m²) given within a three‐week interval between the two cycles along with concurrent radiotherapy of EBRT 50 Gy (2 Gy for 25 doses) followed by brachytherapy of 21 Gy (7 Gy for 3 doses) completed within eight weeks. Women assigned to the preoperative chemoradiation plus radical hysterectomy group will receive cisplatin (75 mg/m²) and paclitaxel (175 mg/m²) given within a three‐week interval between the two cycles along with concurrent radiotherapy of 50 Gy EBRT (2 Gy for 25 doses) followed by radical hysterectomy within three weeks after completion of radiotherapy. Women assigned to the preoperative chemotherapy plus radical hysterectomy group will receive cisplatin (75 mg/m²) and paclitaxel (175 mg/m²) given within a three‐week interval for three cycles followed by radical hysterectomy within three weeks after completion of chemotherapy. The outcomes of the study will be OS, PFS, overall response rate, complete clinical response, partial clinical response and quality of life.

For further details of the excluded studies see the Characteristics of excluded studies table.

Overall survival

Two studies, assessing 1253 participants, reported OS (EORTC 2019; Gupta 2018). There was no evidence of a difference in risk of death between women who received NACT plus hysterectomy and those who received chemoradiotherapy alone (HR 0.94, 95% CI 0.76 to 1.16; moderate‐certainty evidence; Analysis 1.1). The percentage of the variability in effect estimates that was due to heterogeneity rather than sampling error (chance) was not important (I² = 0%).

EORTC 2019 included 620 participants with Stage IB₂ to IIB cervical cancer and compared NACT plus surgery (314 participants) with standard chemoradiotherapy (312 participants). Five‐year OS was 72% in the NACT plus surgery arm and 76% in the standard chemoradiotherapy arm (difference 4.0%, 95% CI –4% to 12%; HR 0.87, 95% CI 0.65 to 1.17; P = 0.332). The trial reported 191 (31%) deaths with a median follow‐up of 8.2 years (interquartile range (IQR) 7.8 to 8.6). Five‐year OS was 72% in the NACT plus surgery arm and 76% in the standard chemoradiotherapy arm (difference 4.0%, 95% CI –4% to 12%). Additional radiotherapy was given to 113 (36.3%) participants in the NACT plus surgery arm. Additional surgery was performed in nine (2.9%) participants in the standard chemoradiotherapy arm.

Gupta 2018 included 633 women aged 18 to 65 years with histologically confirmed squamous cell carcinoma of the cervix with 1994 FIGO Stage IB₂, IIA or IIB disease. It compared NACT plus surgery with chemoradiotherapy. Five‐year OS rates in the NACT plus surgery group was 75.4% compared with 74.7% in the concurrent chemoradiation group (HR 1.03, 95% CI 0.75 to 1.40; P = 0.87).

Disease‐free survival

In Gupta 2018, five‐year DFS in the NACT plus surgery group was 69.3% compared with 76.7% in the concurrent chemoradiation group (HR 1.38, 95% CI 1.02 to 1.87; P = 0.038). In subgroup analyses, there was evidence of a difference in DFS detriment in the NACT plus surgery group in participants with FIGO Stage IIB disease, with a significant test of interaction between treatment effect and Stages IIA and IIB disease. In women with Stage IIB disease, the five‐year DFS rates in the NACT plus surgery group was 67.2% and concurrent chemoradiation group was 79.3% (unadjusted HR for DFS in the NACT plus surgery group 1.90, 95% CI 1.25 to 2.89; P = 0.003).

In EORTC 2019, the five‐year DFS in the NACT plus surgery group was 56.9% compared with 65.6% in the CCRT group (P = 0.021), mostly for Stage IIB disease. However, the authors noted that the first imaging measurement occurred systematically earlier in the neoadjuvant plus surgery arm than in the chemoradiotherapy arm.

Quality of life

None of the studies reported quality of life.

Severe adverse events

EORTC 2019 reported no toxic deaths. Short‐term severe adverse events (G3 or higher) occurred more frequently with NACT plus surgery (35%) than with chemoradiotherapy (21%; P < 0.001). In total, there were 198 serious adverse events (SAEs): 145 in the NACT plus surgery arm versus 53 in the standard chemoradiotherapy arm. Within the group of SAEs, there were 109 serious adverse reactions (SARs) with NACT plus surgery, and 35 SARs with chemoradiotherapy. Nearly all were chemotherapy related. In the NACT plus surgery arm, 238 (76%) women underwent surgery.

Main reasons for not having surgery as per protocol were toxicity (25/74, 34%), progressive disease (18/74, 24%) and insufficient response to NACT (12/74, 16%).

Overall survival

Meta‐analysis of three studies, assessing 571 participants, found that women who received NACT plus hysterectomy had a lower risk of death compared with women who received radiotherapy alone (HR 0.71, 95% CI 0.55 to 0.93; moderate‐certainty evidence; Analysis 2.1) (Benedetti‐Panici 2002; Chang 2000; Noriyuki 2010). The percentage of the variability in effect estimates that was due to heterogeneity rather than chance was not important (I² = 0%).

Progression‐free survival and disease‐free survival

Meta‐analysis of three studies, assessing 571 participants, found no difference in the risk of disease progression between women who received NACT plus hysterectomy and those who received radiotherapy alone (HR 0.75, 95% CI 0.53 to 1.05; moderate‐certainty evidence; Analysis 2.2) (Benedetti‐Panici 2002; Chang 2000; Noriyuki 2010). The percentage of the variability in effect estimates that was due to heterogeneity rather than chance might not have been important (I² = 20%).

Severe adverse events

Overall survival

In Keys 2003, there was no evidence of a difference in the risk of death between women who received radiotherapy plus extrafascial hysterectomy and those who received radiotherapy alone (HR 0.89, 95% CI 0.61 to 1.29; low‐certainty evidence).

Progression‐free survival

In Keys 2003, there was evidence of a difference in the risk of disease progression or death between women who received radiotherapy plus hysterectomy and those who received radiotherapy alone (HR 0.77, 95% CI 0.54 to 1.10; low‐certainty evidence).

Tumour‐free actuarial survival at five years

In Perez 1987, five‐year, tumour‐free actuarial survival for women with Stage IB was 80% with preoperative radiotherapy and surgery and 89% with radiotherapy alone. It was not reported how many women were Stage IB₁ and how many Stage IB₂ (the Stage IB₂ group was of interest for this Cochrane Review). Women with barrel‐shaped cervix (endocervical lesion with cervix diameter larger than 5 cm) were excluded. In Stage IIA, the five‐year tumour‐free survival was 79% in the preoperative radiotherapy and surgery group and 56% in the radiotherapy alone group. These differences were not significant (very low‐certainty evidence).

Quality of life

None of the studies reported quality of life.

Severe/serious adverse events

In the women with Stage IB disease in Perez 1987, only 1/48 (2%) women experienced a severe complication (grade 3) in the radiotherapy and surgery group (ureteral stricture) whereas 5/40 experienced severe complications in the radiotherapy alone group (including rectovaginal fistula, vesicovaginal fistula, ureteral stricture and pelvic infection). This difference was not significant. Similarly in women with Stage IIA disease, 5/14 (40%) women experienced a severe complication in the radiotherapy and surgery group (including proctitis, rectal stricture, small bowel stricture and ureteral stricture) whereas only 1/16 experienced a severe complication in the radiotherapy alone group (rectal stricture). This difference was not significant (low‐certainty evidence).

Keys 2003 stated that both treatment programmes were well tolerated and there did not appear to be a difference between groups in terms of adverse effects. There were 18/129 women with a grade 3 or 4 adverse effect in the hysterectomy and radiotherapy group and 19 cases in 18/121 women of severe adverse effects in the radiotherapy alone group. Two women in each group received no radiotherapy and were not included (low‐certainty evidence).

Overall survival

OS was inadequately reported in Zheng 2017 and it was not possible to calculate an HR. OS time of the chemoradiotherapy plus surgery group was 6 to 40 months, median survival time was 23 months and three‐year survival rate was 82.7%. Total survival time of the chemoradiotherapy group was 5 to 41 months, the median survival time was 22.5 months and the three‐year survival rate was 81.8%. The trial authors reported no evidence of a difference between arms (Chi² = 0.338, P = 0.56; very low‐certainty evidence).

The postoperative pathological data in the hysterectomy arm showed that the residual rate of non‐cancer was 82.7%, and the residual rate of cancer was 5.8%.

Progression‐free survival

PFS was inadequately reported in Zheng 2017 and it was not possible to calculate an HR. PFS time of the chemoradiotherapy plus surgery group was 3 to 40 months, median survival time was 23 months and three‐year survival rate was 73.1%. PFS time of the chemoradiotherapy alone group was 5 to 41 months, median survival time was 22 months and three‐year survival rate was 64.8%. There was no evidence of a difference between groups (Chi² = 0.092, P = 0.76; very low‐certainty evidence).

Morice 2012 reported no evidence of a difference in three‐year event‐free (death) survival rate (86% in the chemoradiotherapy plus hysterectomy group and 97% in the chemoradiotherapy alone group; log rank P = 0.15; very low‐certainty evidence).

Recurrence‐free survival at three years

Morice 2012 reported no evidence of a difference in three‐year event‐free (recurrence) survival rate (72% in the chemoradiotherapy plus hysterectomy group and 89% in the chemoradiotherapy alone group; log rank P = 0.17; low‐certainty evidence). We did not attempt to calculate an HR using the methods of Parmar 1998 due to this being a single trial analysis (very low‐certainty evidence).

The authors reported that morbidity was studied in a further publication, but when we contacted them, they could not provide data on morbidity.

Quality of life

The trial did not report quality of life.

Severe adverse events

The trial did not adequately report SAEs.

Overall survival

There was no evidence of a difference in the risk of death between women in the brachytherapy group and those in the radical hysterectomy group (HR 0.65, 95% CI 0.35 to 1.21; P = 0.19; low‐certainty evidence).

Progression‐free survival

There was no evidence of a difference in the risk of disease progression or death between women in the brachytherapy group and those in the radical hysterectomy group (HR 0.70, 95% CI 0.31 to 1.34; P = 0.24; low‐certainty evidence).

Quality of life

The study did not report quality of life.

Severe adverse events