Adjuvant chemotherapy for endometrial cancer after hysterectomy

Nick Johnson; Andrew Bryant; Tracie Miles; Thomas Hogberg; Paul Cornes

doi:10.1002/14651858.CD003175.pub2

. Author manuscript; available in PMC: 2014 Sep 15.

Published in final edited form as: Cochrane Database Syst Rev. 2011 Oct 5;(10):CD003175. doi: 10.1002/14651858.CD003175.pub2

Adjuvant chemotherapy for endometrial cancer after hysterectomy

Nick Johnson ¹, Andrew Bryant ², Tracie Miles ¹, Thomas Hogberg ³, Paul Cornes ⁴

PMCID: PMC4164379 EMSID: EMS57246 PMID: 21975736

Abstract

Background

Endometrial adenocarcinoma (womb cancer) is a malignant growth of the lining (endometrium) of the womb (uterus). It is distinct from sarcomas (tumours of the uterine muscle). Survival depends the risk of microscopic metastases after surgery. Adjuvant (postoperative) chemotherapy improves survival from some other adenocarcinomas, and there is evidence that endometrial cancer is sensitive to cytotoxic therapy. This systematic review examines the effect of chemotherapy on survival after hysterectomy for endometrial cancer.

Objectives

To assess efficacy of adjuvant (postoperative) chemotherapy for endometrial cancer.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE up to August 2010, registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.

Selection criteria

Randomised controlled trials (RCTs) comparing adjuvant chemotherapy with any other adjuvant treatment or no other treatment.

Data collection and analysis

We used a random-effects meta-analysis to assess hazard ratios (HR) for overall and progression-free survival and risk ratios (RR) to compare death rates and site of initial relapse.

Main results

Five RCTs compared no additional treatment with additional chemotherapy after hysterectomy and radiotherapy. Four trials compared platinum based combination chemotherapy directly with radiotherapy. Indiscriminate pooling of survival data from 2197 women shows a significant overall survival advantage from adjuvant chemotherapy (RR (95% CI) = 0.88 (0.79 to 0.99)). Sensitivity analysis focused on trials of modern platinum based chemotherapy regimens and found the relative risk of death to be 0.85 ((0.76 to 0.96); number needed to treat for an additional beneficial outcome (NNT) = 25; absolute risk reduction = 4% (1% to 8%)). The HR for overall survival is 0.74 (0.64 to 0.89), significantly favouring the addition of postoperative platinum based chemotherapy. The HR for progression-free survival is 0.75 (0.64 to 0.89). This means that chemotherapy reduces the risk of being dead at any censorship by a quarter. Chemotherapy reduces the risk of developing the first recurrence outside the pelvis (RR = 0.79 (0.68 to 0.92), 5% absolute risk reduction; NNT = 20). The analysis of pelvic recurrence rates is underpowered but the trend suggests that chemotherapy may be less effective than radiotherapy in a direct comparison (RR = 1.28 (0.97 to 1.68)) but it may have added value when used with radiotherapy (RR = 0.48 (0.20 to 1.18)).

Authors’ conclusions

Postoperative platinum based chemotherapy is associated with a small benefit in progression-free survival and overall survival irrespective of radiotherapy treatment. It reduces the risk of developing a metastasis, could be an alternative to radiotherapy and has added value when used with radiotherapy.

Medical Subject Headings (MeSH): *Hysterectomy; Antineoplastic Combined Chemotherapy Protocols [*therapeutic use]; Chemotherapy, Adjuvant [mortality]; Endometrial Neoplasms [*drug therapy; mortality; therapy]; Randomized Controlled Trials as Topic

MeSH check words: Female, Humans

BACKGROUND

Description of the condition

Endometrial cancer is also known as adenocarcinoma of the endometrium, uterine cancer or womb cancer. This is a malignant growth of the lining (endometrium) of the womb (uterus) classified by the World Health Organization as C54. It is distinct from sarcomas (tumours of the uterine muscle). It is the seventh commonest cancer in women worldwide with approximately 290,000 cases annually and about 75,000 related deaths (Ferlay 2004; Ferlay 2010). It affects at least 1.5% of western women in their lifetime. The chance of surviving uterine cancer depends on the stage of the cancer when it is first diagnosed.

Endometrial cancer is classified into stages according to the microscopic pattern and its ability to invade into the uterine muscle. This also determines the risk of recurrence and treatment options. The common pathological type is an endometrioid adenocarcinoma but about 10% of endometrial cancers have a serous or clear cell appearance. A small percentage are the mixed mesenchymal mullerian malignant tumour (MMMT), also known as carcinosarcoma. Mixed mesenchymal malignant tumours were initially thought to be a mixed tumour involving sarcoma and epithelial malignancy but modern pathology now recognises that they are derived from a monoclonal epithelial cell that undergoes multilineage differentiation to include sarcomatous metaplasia. All these tumours behave differently from endometrioid cancers and have a relatively poor prognosis. The stage of the cancer is based on conventional pathology examination of the resected surgical specimen. The International Federation of Gynecological Oncology (FIGO) stage system was the UICC (Union for International Cancer Control) TNM system 6 (sixth edition) until 31 December 2009. From 1 January 2010 this was superseded by TNM system 7 (seventh edition, Sobin 2009). The differences are highlighted in Table 1. A cancer that has a low risk of recurring is a well-differentiated (Grade 1 or G1) pure endometrioid tumour that has not invaded into the uterine muscle (previously classified as FIGO stage 1a) or has only invaded up to half way (previously classified as FIGO stage 1b but since 2009 classified as stage 1a). These tumours are usually cured by hysterectomy only. Intermediate risk cancer is conventionally defined as a tumour confined to the body of the uterus but is either poorly differentiated (Grade 3 or G3) and early, invading less than 50% of the way through the uterine muscle or well/moderately differentiated (grade 1/2 or G2) with invasion more than 50% of the way through the uterus (formally classified at stage 1c, now stage 1b) and when there are no other risk factors. A small number of these tumours will recur. High-risk cancers have a higher risk of recurrence and adjuvant radiotherapy reduces the risk of recurrent disease in the pelvis (Johnson 2007; Kong 2007). There is no universally accepted definition of “high risk” but the risk factors include spread beyond the body of the uterus, deep invasion through the muscle, poorly differentiated or non endometrioid type, tumour seen in the vessels of the uterus (lymphvascular invasion) and advanced age.

Table 1.

Comparison of unified UICC staging systems for endometrial cancer: TNM sixth edition (to 2009) and seventh edition (from 2010 onwards)

Anatomic description of spread	Stage in TNM 6	Stage in TNM 7
Limited to endometrium	T1	T1
No invasion of myometrium	T1a	T1a
Invasion of < 1/2 of myometrium	T1b	T1a
Invasion of 1/2 or more of myometrium	T1c	T1b
Invades cervix	T2
Invades only glandular epithelium of endocervix	T2a	Ignore for staging purposes
Invades stroma of cervix	T2b	T2
Endometrial cancer extends outside of the uterus but is confined to the true pelvis	T3	T3
Tumour invades serosa and/or adnexa and/or positive peritoneal cytology	T3a	T3a
Vaginal metastases	T3b	T3b
Spread to lymph nodes	T3c	T3c
Spread to bladder or bowel mucosa	T4a	T4a
Distant extrapelvic metastases	T4bM1	T4bM1

Study	Percentage with node/adnexal/distant metastases Stage 3b+	death rate at censorship	Control arm	Comparative group	Radiotherapy dose (Gray)	Intervention arm chemotherapy	frequency of cycles
Hogberg	1.6%	23%	hysterectomy and pelvic radiotherapy	No additional treatment	> 44	cisplatin 50mg/m² + doxorubicin 50 mg/m² or epirubicin 75 mg/m² OR paclitaxel 175 mg/m² + epirubicin 60 mg/m² or doxorubicin 40 mg/m² + carboplatin AUC 5 OR paclitaxel 175 mg/m² + carboplatin AUC 5/6	4 cycles
J GOG 2033	24%	13%	hysterectomy and pelvic radiotherapy	No additional treatment	50	cyclophosphamide(333mg/m²), doxorubicin (40 mg/m²), cisplatin (50mg/m²)	every 4 weeks for 3 or more courses
GICOG	24%	35%	hysterectomy and pelvic radiotherapy	No additional treatment	45 to 50	Cyclophosphamide 600mgm² doxorubicin 45mgm² and cis-platin 50mgm²	every 28 days for five cycles
MaNGO	40%	20%	hysterectomy and pelvic radiotherapy	No additional treatment	45	cisplatin 50mg/m² + doxorubicin 60 mg/m²	every 3 weeks for 3 courses
GOG 34	42%	36%	hysterectomy	50 Gray pelvic radiotherapy	50	doxorubicin (45 mg/m²) up to a cumulative dose of 400	3 weekly
Kuoppala 2008	0	17%	hysterectomy	56gy pelvic radiotherapy divided into two schedules with about 4 weeks break	56	cisplatin 50 mg/m², epirubicin 60 mg/m², cyclophosphamide 500mg/m²	there chemotherapy cycles given before, during the break in radiotherapy and after radiotherapy
GOG 122	82%	56%	hysterectomy	30 Gray abdominal radiotherapy plus 50 Gray pelvic radiotherapy	50 +30 to upper abdomen	doxorubicin 60 mg/m² plus cisplatin 50 mg/m²	every 3 weeks for eight cycles.
GOG 150	Carcinosarcoma study. 56% were stage 3 and 4	41%	hysterectomy	30 Gray abdominal radiotherapy plus 50 Gray pelvic radiotherapy	50 + 30 to upper abdomen	Cisplatin (20 mg/m²/day×4 days) followed by a 1 hour infusion of ifosfamide (1.5g/m²/day IV×4 days) with mesna	every three weeks for three cycles

Methods	The collaborative Nordic and European study randomly studied the effect of adding a platinum based chemotherapy regimen to hysterectomy and radiotherapy for women with surgically excised endometrial cancer
Participants	The latest report provides data on 63 women from 12 EORTC centres. The eligibility criteria included histologically proven endometrial cancer of any type and infiltration to more than half the myometrial thickness. Women with positive peritoneal cytology and/or positive pelvic lymph nodes were also eligible and participants must have been fit to receive combination chemotherapy, have a WHO performance status of 0 to 2, adequate bone marrow, renal, hepatic and pulmonary function and give informed consent
Interventions	Early participants in the chemotherapy arm received four courses of cisplatin = 50mg/m² + doxorubicin 50mg/m² or epirubicin 75mg/m². Later in the trial, several regimens were allowed, of which cisplatin + doxorubicin, paclitaxel 175mg/m² + epirubicin 60mg/m² + carboplatin AUC 5, and paclitaxel 175mg/m² + carboplatin AUC 5/6 were most popular The control group were treated by pelvic radiotherapy ± vaginal brachytherapy to a dose of 44 Gray
Outcomes	The primary outcome was relapse free survival. The secondary endpoints were: Overall survival of patients treated with either radiation alone or radiation and chemotherapy given sequentially. To evaluate the addition of chemotherapy to the standard adjuvant treatment (radiotherapy) in terms of toxicity. To study whether the pattern of relapse will be influenced by the addition of chemotherapy.
Results (OS & PFS)	see the combined EORTC and NSGO table
Results (site of recurrence)	see the combined EORTC and NSGO table
Toxicity	see the combined EORTC and NSGO table
Notes	The data are still immature and the survival curves will evolve as later recruiters reach 5 years survival. The EORTC have not yet published the full report but early data are available from ASCO presentations and a report including the MaNGO trial is in the 2010 European Journal of Cancer
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence generation was organised by the EORTC headquarters using a minimisation procedure with the stratification factors for each centre
Allocation concealment (selection bias)	High risk	It is not possible to conceal treatment allocation from the participants but the treatment allocation will have been concealed from the data analysts
Blinding (performance bias and detection bias) All outcomes	Low risk	The data collection was by the EORTC data centre, an organisation of the highest scientific standard
Incomplete outcome data (attrition bias) All outcomes	Low risk	The trial has not yet been reported but the data will be analysed by the EORTC data centre, an organisation of the highest scientific standard
Selective reporting (reporting bias)	Low risk	The trial has not yet been reported but the data will be analysed by the EORTC data centre, an organisation of the highest scientific standard
Other bias	Unclear risk	The main issue are that details of the study population have not yet been formally published
Main problems with the trial as perceived by this analysis	Unclear risk	The trial has not yet been reported

Methods	NSGO-EC-9501 (in collaboration with EORTC −55991 - amendment 1) was a phase III open, randomised I national clinical trial
Participants	320 women from 13 Nordic centres with surgical stage I, II, IIIA (positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only) endometrial cancer participated. Women had histologically proven endometrial cancer of one of the following types: FIGO grade 3 (poorly differentiated endometrioid adenocarcinoma) with infiltration ≥ 50% of the myometrial thickness or any serous, clear cell or anaplastic carcinoma and women had to have had an endometrial cancer confined to the corpus cervix, regional lymph nodes or peritoneal fluid cytology. They were treated by hysterectomy, bilateral salpingo-oophorectomy and external beam radiotherapy. The trial recommended CT-based computer-aided 3-dimensional dose planning and four field technique. The prescribed dose to the target volume was at least 44 Gray. If other fractionations than 2.0 Gray five times per week were used, the dose was converted to a 2 Gray equivalent dose according to the linear quadratic formula. Brachytherapy was included as a part of the standard radiotherapy procedure in some centres and the decision to deliver brachytherapy was made before randomisation Women were excluded if there was: Any macroscopic postoperative residual tumour. Spread of disease on the surface or outside the uterus (Exceptions: macroscopically radically excised pelvic lymph nodes or positive peritoneal fluid cytology allowed). Macroscopic tumour involvement of the cervix at preoperative examination. Para-aortic lymph node involvement. Squamous carcinoma or small cell carcinoma with neuroendocrine differentiation. Preoperative irradiation. Previous or concurrent malignant disease except for curatively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin. Active infection or other serious underlying medical condition, which might prevent the patient from receiving treatment or to be followed Uncontrolled or potentially active site of pelvic infection (e.g. fistula or abscesses). Inadequate bone marrow, liver, or kidney function (WBC < 3.5×109/L, neutrophils < 1.5×109/L, platelets < 100×109/L S-creatinine > upper normal value, total S-bilirubin > 2 × upper normal value, estimated GFR < 50 ml/min according to Cockroft-Gault or Jeliffe for patients who will be treated with cisplatin. Previous extensive abdominal surgery or other condition that might give a substantial increase in the risk for complications from the radiation treatment or chemotherapy. Longer interval than 7 weeks between surgery and randomisation
Interventions	Women treated by Surgery and radiotherapy were allocated no additional treatment or chemotherapy. Chemotherapy was given before or after completion of the radiation. The decision about sequence had to be taken before randomisation. The following combinations were used: AP: Doxorubicin 50 mg/m² (epirubicin 75 mg/m²) and cisplatin 50-75 mg/m² q 3 weeks. Cisplatin could be substituted with carboplatin AUC 5-6. TP: Paclitaxel 175 mg/m²/3 hours and carboplatin AUC 5-6 q 3 weeks. TEC: Paclitaxel 175 mg/m²/3 hours, epirubicin 60 mg/m² (doxorubicin 40 mg/m²), and carboplatin AUC 5 q 3 weeks TAP: Doxorubicin 45 mg/m² and cisplatin 50 mg/m² day 1, paclitaxel 160 mg/m²/3 hours day 2, G-CSF 5 μg/kg/day starts on day 3 and continues for at least 10 days q 3 weeks (GOG-177 (46)). At least four cycles were planned.
Outcomes	The primary end-point was to compare progression-free survival of patients treated with either radiation alone or radiation and chemotherapy given sequentially. The secondary end-points were overall survival, toxicity and pattern of progression
Results (OS & PFS)	see the combined EORTC and NSGO table
Results (site of recurrence)	see the combined EORTC and NSGO table
Toxicity	see the combined EORTC and NSGO table
Notes	For follow-up, patients were seen 3 and 6 months after end of treatment, thereafter every 6 months for 5 years. Survival was calculated from the date of randomisation until the date of death. The progression-free survival was calculated as time elapsed from date of randomisation to date of progression or death of disease, whichever was the first registered event. Patients who died of non-disease-related causes were censored at time of death. Toxicity was graded according to CTC 1999
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisation was performed centrally by the study office at Linkoping University Hospital with stratification for centre and histology
Allocation concealment (selection bias)	Low risk	The data analysis was organised by the data centre at the NSGO. Although the statistician’s awareness of the group allocation has not been formally stated, it will have been of the highest quality and will have observed the usual rules
Blinding (performance bias and detection bias) All outcomes	High risk	It was not possible to conceal the treatment allocation from the participants
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The trial has not yet been reported
Selective reporting (reporting bias)	Low risk	There is no suggestion of selective reporting
Other bias	Low risk	There is no suggestion of bias
Main problems with the trial as perceived by this analysis	Low risk	The main issues are that the study population were a heterogenous group with very variable risk factors including some women with grade 1 disease, some with clear cell cancers and some with stage 3

Methods	See the tables for each study
Participants	The pivotal presentation at the 2007 ASCO meeting was the earliest report. This describes 382 women. 12% had stage 1a (intra endometrial/noninvasive cancer) 26% stage 1b, 49% stage 1c, 6% stage 2 and 1.6% stage 3 cancer. 27% had grade 1 or 2 cancer, 53% had grade 3 endometrioid cancer, 14% had grade 3 serous papillary or clear cell morphology and more data are needed on the other 6%. Most women had two or more of the risk factors: grade 3, deep myometrial invasion, or DNA non-diploidy. 378 women are described in the report published in the European Journal of Cancer. This report adds that brachytherapy was used in less than half the cases and unfortunately, we do not know if lymphadenectomy was performed in two thirds of cases
Interventions	See the tables for each study
Outcomes	See the tables for each study
Results (OS & PFS)	The latest report combined the results from the two trials and includes data on 378 women, 191 randomised to radiotherapy only and 187 allocated chemotherapy with radiotherapy. The HR for overall survival depending on randomisation (intention to treat) = 0.66 (95% CI; 0.40-1.08; P = 0.10). The hazard ratio for progression-free survival depending on randomisation after censoring deaths from intercurrent causes was 0.64 (95% CI; 0.41-0.99; P = 0.04)
Results (site of recurrence)	The latest report quotes disease progression in 46/191 (24%) radiotherapy arm 28/187 (15%) in the radiotherapy with additional chemotherapy arm. Therefore, it is best to rely on the latest report and accept that data added together from 3 trials, MaNGO and Hogberg. This quotes a rate of initial recurrence in the pelvis 11/267 for women allocated radiotherapy versus 5/267 for women allocated radiotherapy with additional chemotherapy. This number of distal and multiple sites of recurrence for women allocated radiotherapy was 52 and 7 respectively from 267 women allocated radiotherapy only and 35 and 3 respectively from 267 women allocated radiotherapy with additional chemotherapy
Toxicity	There was one treatment-related death 3 months after randomisation in a woman allocated no chemotherapy. No further details are available. There were eight serious adverse events in the chemotherapy arm. Two women had diarrhoea, one combined with neutropenia. Three women had neutropenia, one acquired pneumonia requiring respirator treatment, and another with associated nausea and vomiting. One woman had an allergic reaction to paclitaxel, one had an episode associated atrial fibrillation and one developed bilateral pulmonary emboli 24 days after the first cycle There was one serious adverse event in the no chemotherapy arm; an intestinal reaction with diarrhoea which led to cessation of radiotherapy after 36 Gray All serious adverse events resolved after appropriate treatment
Notes
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central randomisation was employed in accordance with good practice
Allocation concealment (selection bias)	Low risk	Analysis was by statisticians who had treatment allocation concealed
Blinding (performance bias and detection bias) All outcomes	High risk	It was not possible to conceal the treatment allocation from the participants
Incomplete outcome data (attrition bias) All outcomes	High risk	The compliance to radiotherapy was high, 182/191 (95%) and 178/187 (95%) received P44 Gray in the radiotherapy arm and radiotherapy-chemotherapy arm, respectively. Of the 187 patients assigned to chemotherapy, 136 (73%) received four treatment cycles as planned. Eighteen (9.6%) received no chemotherapy and data were not available from three women
Selective reporting (reporting bias)	Low risk	The trials have been reported in accordance with the Consort criteria
Other bias	Low risk	There is no suggestion of any bias
Main problems with the trial as perceived by this analysis	High risk	Data collection is still ongoing and the data from the trials have been merged, rather than reported separately

Methods	The Mario Negri Gynecologic Oncology group (MaNGO) collaborative clinical gynaecologic oncology group from 20 centres, mainly in the northern part of Italy organised ILIADE-III, a phase 3 randomised trial
Participants	The latest report describes 157 women with histologically confirmed endometrioid carcinoma, FIGO 1988 stage IIB, IIIA-C disease (stage IIIA with positive cytology alone without other risk factors was not included). They were excluded if the pathology was serous or clear cell carcinomas, if the performance status > 2. All women had a hysterectomy and removal of tubes and ovaries and lymphadenectomy was performed in about half (54%) of the cases. Pelvic radiotherapy involved 1.8 Gray fractions up to a total dose 45 Gray. The field was extended to L1/2 if there was a para-aortal metastases. Vaginal brachytherapy was added for women with cervical stromal involvement.
Interventions	Women were randomised to chemotherapy or no further treatment after hysterectomy and radiotherapy. Chemotherapy had to start within 30 days after surgery and consisted of doxorubicin 60mg/m2 + cisplatin 50 mg/m2 every 3 weeks for three cycles. The interval between chemotherapy and radiotherapy was less than 4 weeks. Women who did not receive chemotherapy had radiotherapy commenced within 40 days after surgery
Outcomes	The primary end-point was PFS. All times were counted from the time of randomisation. PFS was defined as the time to progression of endometrial cancer or death from all causes. Secondary end-points were OS; the time to death of all causes and cancer-specific survival (CSS); the time to death related to endometrial cancer. Survival differences between groups were expressed as hazard ratios and were analysed with univariate Cox proportional hazard models
Results (OS & PFS)	The overall survival appeared better but not significantly so in favour of women allocated additional chemotherapy The HR (95% CI) was 0.74; 0.36 to 1.52, representing 17/76 (22%) reported deaths with no chemotherapy versus 14/187 (18%) if is chemotherapy was used Similarly, the progression-free interval appeared better but not significantly so in favour of women allocated additional chemotherapy. The HR (95% CI) was 0.61; 0.33 to 1.12, representing 26 (34%) reported deaths with no chemotherapy versus 18 (23%) reported events if chemotherapy was used
Results (site of recurrence)	Disease progression for women in the MaNGO-trial were 24/76 (32%) and 15/80 (19%)
Toxicity	There were no treatment related deaths. Toxicity data were only available from 74 women. 12/74 (16%) developed grade 3/4 leucopenia, 4 (5%) suffered grade 3/4 nausea and vomiting
Notes
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed centrally by telephone at the Mario Negri Institute, Milan in blocks that balanced the treatment assignment within each site
Allocation concealment (selection bias)	Low risk	Randomisation was centrally organised and data were analysed using the intention-to-treat principles
Blinding (performance bias and detection bias) All outcomes	High risk	It is not possible to conceal the treatment allocation from the participants. The trial was supervised by the GOG Data Monitoring Committee without knowledge of treatment results
Incomplete outcome data (attrition bias) All outcomes	Low risk	The data have been reported in line with Consort guidance. For example we know that 76 women were allocated radiotherapy, 67 received it, 4 did not and the data are missing on a further 5 cases. Of the 80 allocated chemotherapy and radiotherapy, 71 Completed 3 cycles, 3 received less than 3 cycles, 2 did not receive any chemotherapy and data are missing fro 4 cases. Also of the 80, 74 received radiotherapy, 4 did not, data are missing on 2 cases and 2 further cases in this group had neither chemotherapy nor radiotherapy
Selective reporting (reporting bias)	Low risk	There is no suggestion of selective reporting.
Other bias	Low risk	Earlier presentations quote slightly different figures from the later ones but the differences are small and probably reflect maturity in the data rather than counting errors
Main problems with the trial as perceived by this analysis	Low risk	Like many of these studies, MaNGO recruited women with a variety of stages of disease, variety of surgical techniques and some of the data are missing. Overall, the quality of this trial was high and it has been coherently reported

Methods	After surgery, women were randomised centrally by the Finnish Cancer Registry to two groups: Both groups received pelvic radiotherapy. Group A had no additional treatment. Group B was given chemotherapy during gaps in radiation treatment. The first dose of chemotherapy was given 1 to 2 weeks after surgery and before radiotherapy. The second cycle was given after half of the radiotherapy had been given. The third treatment cycle followed 2 weeks after the radiotherapy
Participants	The study population consisted of 156 women with endometrial cancer treated in four Finnish university hospitals between April 1992 and April 1996. They were followed up until April 2001, Women had noninvasive or early myoinvasive (< 50%) grade 3 endometrial cancer or any grade cancer that was deeply myoinvasive (> 50%), involving the cervix or peritoneal washings (old FIGO stage 1c-lllA). Thirteen (18%) women allocated radiotherapy only had stage 2 disease compared to 21 (25%) women allocated chemotherapy with radiotherapy. Nine (12.5%) women allocated radiotherapy only had malignant cells in the pelvic washings compared to 10 (11.9%) of women allocated chemotherapy with radiotherapy. The rest had stage 1 disease The surgery included a total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy. 80% of women also had pelvic lymphadenectomy
Interventions	Women allocated only radiotherapy received a total dose of 56 Gray (2 Gray/fraction) delivered to the pelvis using a four-field technique. The treatment was divided in two courses 28 Gray each, separated by a pause of 3 weeks. The first course started 4 to 5 weeks following the operation Women allocated chemotherapy with the radiotherapy received three chemotherapy cycles consisting of cisplatin 50 mg/m² Cisplatin, epirubicin 60 mg/m² and cyclophosphamide 500mg/m². The first cycle was given after the final histopathological report was available, or 1 to 2 weeks after the operation. The second one was given during the pause in radiotherapy. The third course was given within 2 weeks after the completion of the second radiation course
Outcomes	The primary outcome was 5 year survival rate.
Results (OS & PFS)	During the five-year follow-up time 32 patients (20.5%) had recurrent disease. The recurrence rate was 22.6% in women allocated chemotherapy with radiotherapy and 18.0% in women allocated radiotherapy only. The difference is not statistically significant (P = 0.50) As calculated from the operation data, the median time to recurrence was 20 (range 8 to 60) months in women allocated chemotherapy compared to 15 (range 6 to 37) months in women allocated radiotherapy only (P = 0.17) Of the 32 patients with recurrent disease, only 6 stayed alive for the rest of the follow-up time. Twenty-six (81.2%) died of endometrial carcinoma. The median time interval from the recurrence to death was nine (range 2 to 22) months for women allocated chemotherapy with radiotherapy and eight (range 3 to 11) months for women allocated radiotherapy only. Even among the surviving patients, only two (one in each group) with a local recurrence were free of disease at the end of the follow-up. Fifteen women allocated chemotherapy with radiotherapy died and 11 of the women allocated radiotherapy only died. Consequently the disease-specific five-year survival was 82.1% and 84.7% respectively. The median survival for women allocated chemotherapy with radiotherapy was 37 (range 13 to 50) months compared to 23 (range 15 to 44) months for women allocated radiotherapy only (P = 0.148). The median disease-free survival was 25 months (range 12 to 49) for women allocated chemotherapy with radiotherapy and 18 (range 9 to 36) months for women allocated radiotherapy only (P = 0.13)
Results (site of recurrence)	The Kuoppala 2008 used chemotherapy sandwiched in between the radiotherapy courses. This trial reported a pure locoregional recurrence rate of 3.2% evenly distributed in the two groups, 3 women treated without chemotherapy of which 2 were alive after 5 years of follow up versus 2 treated by chemotherapy, of which one was alive after 5 years. In this trial chemotherapy did affect the distal recurrences rate, 13.8% versus 20.2%. Ten women (all died) developed a distal recurrence in the group not allocated chemotherapy compared to 17 (3 were still alive after 5 years of follow up) if chemotherapy had been used
Toxicity	Eight allocated both radiotherapy and chemotherapy required laparotomy for intestinal obstruction compared to 2 women treated by radiotherapy only Two patients in both groups experienced other major complications. One woman allocated chemotherapy with her radiotherapy suffered ureteric obstruction and one developed pelvic bone necrosis and bowel fistulation. One woman allocated radiotherapy only developed multiple gastric ulcerations causing serious malnutrition and another perforated her sigmoid colon. This was not attributable to recurrence Chemotherapy was implemented in three courses. The first, second and third treatment course could be administered according to the protocol 79 (94.0%), 70 (83.3%) and 64 (76.2%) women respectively. Of these, 6, 13 and 14 women respectively experienced grade 3 to 4 leucopenia. None suffered from grade 4 infection. There were two cases of sepsis and eight had Grade 3 infections. Nausea and vomiting were assessed as grade 3/4 in 5.6%. Grade 3 and 4 diarrhoea did not occur. Alopecia was severe (grade 3/4) in 49% of women. Liver and kidney functional test results remained within normal range throughout the chemotherapy
Notes
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Women were allocated treatment by the central Finnish Cancer registry
Allocation concealment (selection bias)	Low risk	Allocation was coded by group A or B.
Blinding (performance bias and detection bias) All outcomes	High risk	It is not possible to conceal the treatment allocation from the participants
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data were analysed on an intention to treat basis and all cases are accounted for In the group allocated chemotherapy with radiotherapy, 78 women (92.9%) were treated according to the protocol during the first period. Owing to intestinal symptoms one woman received only 20 Gray and another 22 Gray. One was treated with 49 Gray and another with 50 Gray in one period of radiotherapy. Two patients were not treated at all. In addition one patient had intestinal symptoms and one had infection, but both were nevertheless treated fully. During the second period the treatment was successful in 77 of women in this group (91.6%). Three had low leucocyte levels but were nevertheless treated according to protocol. Four patients complained of intestinal symptoms. Of, these, three were treated to the full dose but one received only 14 Gray. The second radiation period was omitted for one patient, because she developed sepsis. One refused the second treatment and four received none at all for unknown reasons Not all women received the prescribed radiotherapy dose, For women allocated radiotherapy only, 68 women (94.4%) received the full dose. One patient received 36 Gray and one was treated in one treatment period only with a dose of 45 Gray. Two patients refused the treatment and received no radiotherapy at all. During the second period 66 patients (91.6%) of the women allocated radiotherapy only were treated according to the protocol. Three suffered from intestinal symptoms but were treated to the full dose. However, there were another three patients treated to a suboptimal dose They received 11, 18 and 21 Gray, respectively. One patient was treated only during the first period and two patients opted to receive no radiotherapy at all
Selective reporting (reporting bias)	Low risk	There is no suggestion of selective reporting but that trial is old and was not reported according to CONSORT criteria
Other bias	Low risk	The groups were well matched.
Main problems with the trial as perceived by this analysis	Unclear risk	The trial design split the radiotherapy to include a break in treatment after delivering 26 Gray. This may allow metastatic deposits to recover especially in the group allocated radiotherapy. The split regimens would not be used in modern oncology and this limits the relevance of the data from this study

Methods	This was a GOG multicenter RCT. Women who had completed adjuvant radiotherapy, were randomised to receive no addition treatment or doxorubicin
Participants	224 women entered the study, 112 in each arm. Forty-three were deemed ineligible on review of the submitted data (appropriately so in our opinion) leaving 181 cases for evaluation. The original entry criteria were defined as primary, previously untreated, histologically confirmed invasive carcinoma of the endometrium stage I and II (occult), all histologic grades, with one or more of the following high-risk features: (1) equal to or greater than 50% myometrial invasion; (2) histologically documented pelvic or aortic node metastases; (3) histologically documented cervical extension without gross clinical evidence of cervical involvement; (4) adnexal metastases. All patients were required to undergo total abdominal hysterectomy, bilateral adnexectomy, selective pelvic and aortic lymph node dissection, and peritoneal cytology. Radiation therapy was started within 6 weeks of surgery. Women without aortic node metastases receive 5000 rads external beam therapy to the whole pelvis at 160 to 180 rads per day to a point 7 cm lateral to the midline of the pelvis at the widest transverse diameter. An 8 cm wide aortic field extended to the top of T10 was added to the pelvic field if there were para aortic lymph node metastases. The target dose to the aortic port was 4500 rads. Intracavitary therapy was not permitted
Interventions	After completion of radiation therapy, the patients were randomised to receive doxorubicin bolus therapy (60mg/m² starting dose) to a maximum cumulative dose of 500 mg/m² (although the methodology quotes 400mg/m² as the earlier upper limit, amended during the trial to 500mg/m² Between November 1977 and July 1986, 92 women were randomly allocated doxorubicin and 89 women were allocated no additional therapy entered the no-DOX arm
Outcomes	The primary outcomes investigated in this trial were survival and disease free interval
Results (OS & PFS)	The five-year survival rates for women with deep myometrial invasion, cervical involvement, and pelvic node metastases were similar (63% to 70%), whereas the rate for patients with aortic node metastases was 26%. The hazard ratios were reconstructed from the survival curves
Results (site of recurrence)	GOG 34 reported 16.3% of women (15/92) allocated to Doxorubicin had extrapelvic recurrence compared to 22.5% (20/89) not given chemotherapy. Data on the risk of pelvic recurrence is not available but it is said that there is no difference in rates
Toxicity	There were no cases of grade 3 or 4 cardiac toxicity. Twelve women (6.9%) developed small bowel obstruction after radiation therapy. There were three treatment related deaths in the group allocated doxorubicin chemotherapy and two in the radiotherapy-only arm
Notes
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	GOG statistical office supervised treatment allocation
Allocation concealment (selection bias)	Low risk	GOG statistical office supervised the analysis
Blinding (performance bias and detection bias) All outcomes	High risk	It is not possible to conceal the treatment allocation from the participants. The trial was supervised by the GOG Data Monitoring Committee without knowledge of treatment results
Incomplete outcome data (attrition bias) All outcomes	Low risk	This study was closed to patient entry in July of 1986 after concluding that successful completion was highly unlikely because of the reduced accrual rate and the surprisingly good recurrence-free survival rates of all but one high-risk category. In addition, the study was said to be flawed by the relatively large number of patients on the experimental regimen who, after randomisation, declined to receive any doxorubicin
Selective reporting (reporting bias)	Low risk	There is no suggestion of selective reporting but that trial is old and was not reported according to CONSORT criteria
Other bias	High risk	The most obvious imbalance is the higher frequency of pelvic node metastases and G3 lesions in the group allocated doxorubicin. Compliance in this study was a problem. Of the 92 women randomised to receive doxorubicin, 25 did not receive doxorubicin and 2 received only one course. This was usually due to patient refusal
Main problems with the trial as perceived by this analysis	Unclear risk	The low number of women receiving adequate chemotherapy will affect the statistical outcome of this group

Methods	This was a GOG multi centre randomised trial comparing doxorubicin-cisplatin (AP) chemotherapy with whole-abdominal irradiation (WAI) in women with stage III or IV endometrial carcinoma having a maximum of 2 cm of postoperative residual disease. A total of 190 were randomly assigned to receive AP and 198 women were assigned to receive WAI
Participants	Four hundred twenty-two women were entered between May 1992 and February 2000, of whom 388 were initially eligible. Women with FIGO stage III or IV endometrial carcinoma of any histology were eligible for this trial. Eligibility required total abdominal hysterectomy and bilateral salpingo-oophorectomy, surgical staging, tumour resection, no single site of residual tumour more than 2 cm and normal haematology and biochemistry. Nodal sampling was optional but women with para-aortic lymph nodes metastasis were required to have negative scalene node biopsies and chest computed tomography scans
Interventions	Chemotherapy consisted of doxorubicin 60 mg/m2 plus cisplatin 50 mg/m² every 3 weeks for eight cycles. The maximum allowable cumulative dose of doxorubicin was 420 mg/m². Therefore only cisplatin was to be infused during the eighth cycle. Hydration was maintained by administering normal saline at 500 ml/h for 2 hours before and after the cisplatin dose. Doxorubicin doses were reduced based on pretreatment blood counts, with dose levels reduced from 60 to 15 mg/m² in 15-mg/m² increments. Doses were re instituted with recovery of myelosuppression. Treatment interruption caused by myelosuppression exceeding 6 weeks required discontinuation of protocol therapy Whole abdominal radiation therapy (WAI) was delivered with an open-field anterior-posterior/posterior-anterior technique with up to 30 Gray in 20 daily fractions. Kidney blocks were used posteriorly but there was no liver shield. After WAI, women received a boost to the true pelvis or to an extended field encompassing pelvic lymph nodes (PLNs) and para-aortic lymph nodes (PALNs). A boost to both areas was administered to patients with positive PLN and no PALN sampling or patients with neither PLN nor PALN sampling. Pelvic (± para-aortic) boosts were accomplished using a four-field box technique with custom blocking to minimise the treated small-bowel volume. The boost dose was 15 Gray in 8 fractions. All fields were treated once daily, 5 days per week
Outcomes	The primary end point for comparison of the treatment regimens was PFS; OS was a secondary end point
Results (OS & PFS)	At the time of reporting the final analysis, 98 patients (51%) on the chemotherapy arm were alive compared to 76 women (38%) on the WAI arm. Women alive or deceased, without evidence of tumour progression included 97 (50%) and 93 (46%) in the AP and WAI arms, respectively, including 18 and 22 women, respectively, who died before documentation of tumour progression. The majority of deaths were attributed to cancer progression. The progression hazard ratio relative to the WAI arm, adjusted for stage, was 0.71 (95% CI, 0.55 to 0.91; P = .007). This adjusted relative hazard ratio was associated with a predicted increase in PFS at 60 months of 12% (50% for AP versus 38% for WAI). There was also a statistically significant difference in overall survival between the two arms. Subgroup analysis, presented at the IGCS in 2010 showed that this was independent of cervical stromal involvement of lymph node metastasis The hazard ratio of death relative to the WAI arm, adjusted for stage, was 0.68 (95% CI, 0.52 to 0.89; P = .004). This adjusted relative hazard estimate was associated with a predicted increase in survival at 60 months of 13% for patients on the AP arm versus WAI patients (55% versus 42%, respectively). Unadjusted Kaplan-Meier estimates of five-year PFS and OS were 42% and 53%, respectively, in the AP arm compared with 38% and 42%, respectively, in the WAI arm. The unadjusted hazard ratio recalculated from the survival curves of GOG 122 reveal that the overall survival hazard ratio is 0.74 (0.57, 0.96) and the progression-free survival hazard ration is 0.81 (0.63 to 1.05) Treatment hazard ratio with 95% CI by prognostic group is reproduced in Figure 11.
Results (site of recurrence)	The initial site of recurrence was limited to the pelvis in 27 women (13%), within the abdomen in 33 women (16%), and extra-abdominal or liver metastases in 45 patients (22%). Four women allocated whole abdominal radiotherapy and in two allocated chemotherapy arm, sites of initial recurrence were unknown. Of the 194 women given chemotherapy, 97 (50%) had documented tumour recurrence. The initial site of recurrence was limited to the pelvis in 34 patients (18%); 27 patients (14%) experienced disease recurrence within the abdomen, and, in 34 patients (18%), the first recurrence included extra-abdominal or liver metastases
Toxicity	Comparisons of grade 3 to 4 haematologic toxicities between AP and WAI were: WBC (62% versus 4%, respectively), absolute neutrophil count (< 85% versus 1%, respectively), platelets (21% versus 3%, respectively), and maximum haematologic toxicity (defined as percentage of patients who developed at least one grade 3 or 4 haematologic toxicity of any type; 88% versus 14%, respectively). The second most commonly reported acute toxicity was grade 3 to 4 GI toxicity, which was reported in 20% versus 13% of patients in the AP and WAI arms, respectively, and hepatic toxicity was reported in 1% versus 3% of patients in AP and WAI arms, respectively. Grade 3 to 4 cardiac and neurologic toxicities were seen in 15% and 7% of patients, respectively, receiving AP compared with 0% and less than 1% of patients, respectively, receiving WAI. Other infrequent grade 3 to 4 toxicities included hip osteonecrosis, vaginal vault necrosis, and dehydration (one patient each) in the WAI arm and ventral hernia (one patient) in the AP arm Quality of life was reported separately using the Fatigue Scale (FS), Assessment of Peripheral Neuropathy (APN), Functional Alterations due to Changes in Elimination (FACE), and Functional Assessment of Cancer Therapy-General (FACT-G), QoL measured at: pre-treatment, end of treatment (EOT), and 3 and 6 months post-treatment. Of 396 eligible patients, 317 provided a baseline QoL assessment. The AP arm produced a statistically significant survival benefit along with greater toxicities, including peripheral neuropathy persisting up to 6 months. WAI patients reported worse FS (P < 0.001) and FACE (P < 0.001) scores at EOT and poorer FACE scores 3 months post-treatment (P = 0.004) compared to AP patients. APN scores were significantly worse among AP patients at EOT, and 3 and 6 months post-treatment (P < 0.001 for all). There is no indication that FACT-G scores differed between the two arms at any assessment point
Notes	Treatment probably contributed to eight deaths on the AP arm (two patients had sepsis, two patients had congestive heart failure, and one patient each had sepsis plus left ventricular/aortic thrombus, hypoglycemic shock with myelosuppression, stroke secondary to congestive heart failure, and renal failure with severe thrombocytopenia) and five deaths on the WAI arm (one patient each had veno-occlusive liver disease, disease progression with hepatomegaly, aspiration and liver necrosis, renal and liver failure secondary to sepsis with severe ascites, and sepsis and liver failure)
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The GOG Statistical and Data Center randomly assigned therapy to each patient with equal probability of assignment to each treatment regimen. A balanced block randomisation was used to balance assigned treatment regimens within each institution
Allocation concealment (selection bias)	Low risk	The sequence of treatment assignments was concealed from institutions and patients until telephone registration with verification of eligibility
Blinding (performance bias and detection bias) All outcomes	High risk	The trial was supervised by the GOG Data Monitoring Committee without knowledge of treatment results. However, treatment allocation could not be concealed for the trial participants
Incomplete outcome data (attrition bias) All outcomes	Low risk	Reasons for the exclusion of 34 patients (15 on the WAI arm and 19 on the AP arm) included wrong stage (n = 3), double primary (n = 8), wrong cell type (n = 4), prior malignancy (n = 1), residual disease more than 2 cm (n = 1), incomplete lymph node sampling or laparoscopic surgery (n = 8), registration error (n = 1), and inadequate documentation of pathology (n = 8). The eight patients (four on each arm) deemed ineligible because of unilateral lymph node sampling or use of laparoscopic surgery are included in the analyses. Since this study was initiated, acceptance and use of laparoscopic surgery has widened, and these patients are otherwise eligible. Their inclusion does not change the study results
Selective reporting (reporting bias)	High risk	It was suggested at the ASCO annual meeting by Thomas 2003 that the data were originally presented with a focus on survival time when mortality reached 50% exaggerating the real differences between the two groups The GOG 122 data were reported to show a survival advantage to adjuvant chemotherapy over wide field whole abdominal external beam radiotherapy. Both at the initial data presentation and final publication two interpretations of the data were given. The data as randomised gave five-year outcomes: PFS raw RT 38% versus chemo 42% (P not given), stage-adjusted 38% versus 50% (SS); raw OS RT 42% versus chemo 53% (P not given), stage-adjusted (despite it being randomised trial) 42% versus 52% (SS). Since the rate of recurrence between the two arms differed by only 4% (54% versus 50%) it is unclear whether the differences are due to action on cancer or confounding effects
Other bias	High risk	The trial took 10 years to complete from 1992. As a consequence, the inclusion criteria were very broad. The study population included women with an exceptionally good prognosis after hysterectomy, others has an exceptionally bad prognosis. The adjuvant therapies are not optimal by current standards. A dose of 30 g in 20 fraction has only a 10% chance of eradicating upper abdominal disease. The survival curves converge and the benefit for chemotherapy is early and applies only to distant metastases. There was no stratification for risk, particularly site and volume of residuum and we do not know how well balanced the groups were with respect to specific risk factors. These criticisms were eloquently delivered by Thomas 2003 in a plenary session discussion available on the ASCO media player The authors of the definitive manuscript (GOG 122) say that the treatment arms were balanced in terms of patient characteristics but there are slight imbalances with respect to mixed cell type and FIGO stage. If anything, there were slightly more poor prognosis pathologies and more advanced stage cancer in the group allocated chemotherapy
Main problems with the trial as perceived by this analysis	High risk	This is predominantly a trial of advanced disease. Few participants had stage 1 or 2 cancer and the data may not be applicable to early disease The applicability of the “control” arm remains uncertain as this trial tests whole abdominal radiotherapy. The radiotherapy regimen used in GOG-122 was tested in only two prospective phase 2 studies, one of which reported after GOG-122 had completed randomisation. The first was GOG 9001 with ten women having whole abdominal radiotherapy with concomitant chemotherapy for resected stage pT3 to pT4 disease in 1990-1992. The second was GOG 94 and this is a description of 21 women with stage pT1 to pT4 endometrial cancer. In 2010, whole abdominal radiotherapy in remains outside the standard treatments suggested by major guideline groups (IOG (UK), National Cancer Institute, USA, National Comprehensive Cancer Network, Lukka 2006). These two factors may explain why the study did not change standard practice. Nevertheless this study fulfils the search criteria for the inclusion in this meta-analysis using the original unadjusted data

Methods	This randomised study was designed to assess whether adjuvant chemotherapy confers an advantage for overall and progression-free survival and on the incidence of local and distant relapses over standard pelvic radiotherapy in high-risk patients without residual tumour
Participants	A total of 491 women with high-risk endometrial carcinoma were consecutively referred to 29 institutions throughout Italy. A total of 345 patients were deemed eligible for this study, with 168 randomly assigned external RT and 177 adjuvant CT Women had histologically confirmed endometrioid, adenoacanthoma or adenosquamous carcinoma and FIGO stage Ic G3, IIa-bG3 with deep myometrial invasion (50% or more) or stage III disease following hysterectomy and bilateral salpingo-oopherectomy. To rule out FIGO stage IV disease all patients underwent chest radiography and abdominal-pelvic ultrasound. Women had to have had surgery as primary treatment and no previous neoadjuvant therapy Approximately 70% of the patients had myometrial invasion deeper than 50%. About one third of the patients had FIGO stage I-II disease. 8% had stage 2b cancer. Two thirds stage 3.22% in each group had stage 3c disease and about 40% had stage 3a disease
Interventions	Women were randomly allocated chemotherapy or radiotherapy after surgical staging and histological evaluation. Chemotherapy had to start within 30 days from surgery. Cyclophosphamide 600mg/m², adriamycin (doxorubicin) 45mg/m² and cis-platin 50mgm² (CAP regimen) were administered every 28 days for five cycles Radiotherapy had to start within 30 days after surgery. External radiation therapy was adopted for a total of 45 to 50 Gray in 5 to 7 weeks (1.7-2 Gray/day, 5 days/week). The upper limit of the pelvic field was at L5, the lower limit at the lower limit of the ischial tuberosity, and the lateral limits fell behind the border of the lateral and common iliac lymph nodes. Patients who had lymph node involvement received additional lumboaortic lymph node irradiation with the upper limit at LI, with 45 Gray in 5 to 7 weeks (1,5-1.8 Gray/day × 5days/ week)
Outcomes	The primary end points for this trial were overall survival, defined as the time from randomisation to death, irrespective of the cause, and progression-free survival, defined as the time from randomisation to the earliest tumour relapse, or death
Results (OS & PFS)	The hazard ratio (HR) for death after a median follow-up of 95.5 months for women in the chemotherapy group as compared with the radiotherapy group was 0.95 (95% confidence interval (CI), 0.66 to 1.36; P = 0.77). The HR for an event was 0.88 (95% CI, 0.63 to 1.23; P = 0.45). The 3, 5 and 7-year overall survivals were 76%, 66% and 62% in the chemotherapy group 78%, 69% and 62% in the radiotherapy group. The 3, 5 and 7-year progression-free survivals were, 68%, 63% and 60% and 69%, 63% and 56% respectively At the median follow-up time of 95.5 months (interquartile range 62 to 122 months), 135 events (recurrences or deaths, whichever came first) had occurred among the 340 randomised patients. There were 56 recurrences and 10 deaths as first event of the 174 patients on chemotherapy and 60 recurrences and nine deaths as first event of the 166 patients on radiotherapy. The overall number of observed deaths was 118 (35%). Fifty-nine in the RT arm and 59 in the CT arm The overall survival of the patients on chemotherapy was 76% (CI = 70% to 83%), 66% (CI = 59% to 73%) and 62% (CI = 55% to 70%) at the third, fifth and seventh year, respectively, and 78% (CI = 71% to 84%), 69% (CI = 61% to 76%) and 62% (CI = 54% to 71%) for patients on radiotherapy at the same time points. The progression-free survival of the patients on chemotherapy was 68% (CI = 61% to 75%), 63% (CI = 55% to 70%) and 60% (01 = 52% to 67%) at the third, fifth and seventh year, respectively and 69% (CI = 62% to 77%), 63% (CI = 55% to 70%) and 56% (CI = 46% to 63%) for patients on radiotherapy
Results (site of recurrence)	Chemotherapy delayed distant metastases and radiotherapy delayed local relapses but these trends did not achieve statistical significance. Among the 174 patients randomised to chemotherapy, the initial site of recurrence was distant in 27 (16%), local in 19 (11%), concurrent local and distant in eight (5%), and of unknown type in two (1%). Among the 166 patients randomised to radiotherapy the initial site of recurrence was distant (extra-abdominal or liver) in 35 (21%), local in 11 (7%), concurrent distant and local in nine (5%), and of unknown type in five (3%). Although this study was not powered to detect clinically significant differences in the incidence of relapses, chemotherapy seemed to prevent or delay distant relapses more than radiotherapy while radiotherapy seemed to prevent or delay local relapses in comparison with chemotherapy
Toxicity	Full details about the toxicity of chemotherapy with CAP is available for 123 women (80% of the 154 patients who had at least one course). Grades 2, 3 and 4 neutropenia occurred in 22 (18%), 38 (31%) and 5 (4%) patients, respectively; 36 patients (29%) had grade 2 anaemia, 5 (4%) had grade 3 anaemia; grade 2 and 3 thrombocytopenia was reported in five (4%) and two patients (2%), respectively. The incidence of nausea and vomiting was relatively low (grade 2 and 3 was reported for 29 (24%) and 12 (10%) patients, respectively, grade 4 for one patient). Other serious toxicities (grade 3) occurred in < 3 % of the patients randomised to CT. There were no treatment-related deaths Toxicity data are available for 146 (97%) of the 150 patients who started radiotherapy. Major late toxic effects were gastrointestinal, including five cases of bowel obstruction with three of these patients requiring surgical intervention, six cases of grade 3 radiation proctitis, and 13 reports of grade 3 diarrhoea (24 patients, 16%). Urinary tract complications (severe cystitis) were recorded in seven patients (5%)
Notes
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was carried out centrally by telephone at the L Mangiagalli Institute (Milan, Italy) and patients were stratified by institution and stage of disease
Allocation concealment (selection bias)	Low risk	It is very unlikely that there was any bias or allocation concealment during analysis of data but this is not clear in the reports
Blinding (performance bias and detection bias) All outcomes	High risk	It is not possible to conceal the treatment allocation from the participants
Incomplete outcome data (attrition bias) All outcomes	Low risk	131 (75%) of the 174 women assigned chemotherapy received five treatment cycles as planned and 154 (89%) received at least one cycle and were assessable for toxicity (six, four, four and nine women received only one, two, three and four courses of CAP, respectively, mainly because of excessive bone marrow toxicity). 12 women (7%) declined adjuvant chemotherapy 146 (88%) of the 166 women assigned radiotherapy completed treatment as planned. Only four women (2%) stopped treatment because of toxicity. Ten women (6%) declined treatment
Selective reporting (reporting bias)	Low risk	The trial is reported according to CONSORT criteria and there is no suggestion of any reporting bias
Other bias	Low risk	The two groups were similar across all categories.
Main problems with the trial as perceived by this analysis	Low risk	Threre are no serious flaws in this trial.

Methods	This trial utilised a straightforward randomisation comparing either pelvic irradiation or chemotherapy after initial surgical excision
Participants	A total of 475 women were randomised. Forty-one were deemed to be ineligible due to protocol violations such as myometrial invasion was less then 50% of the way through the myometrium, histology review revealed a sarcoma or rapid progression after enrolment. An additional 49 cases were excluded from analysis due to non-endometroid histology. The eligibility criteria for this study were International Federation of Gynecology and Obstetrics (FIGO- prior to 1998) stage IC-IIIC endometrial carcinoma with deeper than 50% myometrial invasion and absence of any prior chemotherapy, irradiation, or surgery for the treatment of any other cancer. Patients with stage II or III without deeper than 50% myometrial invasion were ineligible for this study. Patients were required to be under 75 years old, to have a WHO performance status of 0 to 3, and to have no residual visible tumour after an abdominal hysterectomy and bilateral salpingo-oophorectomy. Surgical staging consisted ideally of pelvic and/or para-aortic lymphadenectomy. 96% of women had a pelvic lymphadenectomy, 29% had a para-aortic lymphadenectomy
Interventions	The chemotherapy group received cyclophosphamide (333 mg/m²), doxorubicin (40 mg/m²), and cisplatin (50mg/m²) (CAP chemotherapy) every 4 weeks for 3 or more courses. Dose modifications of doxorubicin and cisplatin were as follows: a 25% reduction of both drugs was allowed for body weight less than 40 kg or age greater than 70 years old, and a 50% reduction was allowed in patients with G3 or G4 myelosuppression Pelvic irradiation was given in an open field using the anterio-posterior parallel opposing technique within 4 weeks of surgery. Forty-five to fifty Gray was given within 4 to 6 weeks, with 9 to 10 Gray of irradiation administered per week (5 working days per week). Subsequently, additional irradiations were performed in 11 cases (5.7%) with paraaortic lesions and in 6 patients (3.1%) who received brachytherapy
Outcomes	The primary endpoint was OS and secondary endpoints were PFS and the incidence of toxicity
Results (OS & PFS)	The PFS rate at 5 years was 83.5% in the PRT group and 81.8% in the CAP group. The hazard ratio was 1.07 (95% CI, 0.65 to 1.76:P = 0.73) The OS rate at 5 years was 85.3% in the PRT group and 86.7% in the CAP group. The hazard ratio was 0.72 (95% CI, 0.40 to 1.29; P = 0.27)
Results (site of recurrence)	Thirty-three recurrences (17%) occurred in the chemotherapy group compared to 30 recurrences (15%) in the radiotherapy group. The patterns of recurrence were similar in both treatment groups. Specifically, the incidence of intrapelvic recurrence sites, such as the pelvis or vagina, was 7.3% (14/192) in the chemotherapy group and 6.7% (13/193) in the radiotherapy group while the incidence of extrapelvic recurrence sites, such as the peritoneal cavity, liver, lung, para-aortic lymph nodes and others, was 16.1% (31/192) and 13.5% (26/193) respectively
Toxicity	G3 and G4 toxicities were experienced in 4.7% (9/192) of women given chemotherapy and 1.6% (3/193) of women allocated radiotherapy. Myelosuppression was the main problem for women given chemotherapy and bowel obstructions were the main complication in the radiotherapy group No treatment-related deaths occurred in either group.
Notes
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The treatment allocation involved simple randomisation. Each participant was assigned by central telephone system The study groups were remarkably well balanced for patient characteristics including age, postmenopausal status, co-morbidity, type of hysterectomy, postoperative stage, tumour grade, myometrial invasion, lymphovascular space invasion, cervical involvement, parametrial invasion, peritoneal cytology, adnexal metastasis, pelvic lymph node metastasis, and para-aortic lymph node metastasis. Treatment was completed in 98.9% (184/186) and 97.3% (183/188) of the patients in the PRT and CAP groups, respectively
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding (performance bias and detection bias) All outcomes	High risk	It is not possible to conceal the treatment allocation from the participants
Incomplete outcome data (attrition bias) All outcomes	Low risk	The initial enrolment involved 475 women. Forty-one were ineligible due to myometrial invasion of less than 50%, histological diagnosis of sarcoma, or rapid progression of disease after enrolment. An additional 49 patients with non-endometrioid histology were excluded. As a result, 385 patients were eligible for this trial. Seven patients in the PRT group did not receive PRT and 4 patients in the CAP group did not receive CAP Treatment was completed in 98.9% (184/186) and 97.3% (183/188) of the patients in the radiotherapy and chemotherapy groups, respectively. Pelvic radiation was defined as completed when the total radiation dose reached 40 Gray. Chemotherapy was said to have been completed when the number of cycles reached three. The median total doses were 50 Gray of pelvic irradiation and 1309 mg/m² cyclophosphamide, 120 mg/m² doxorubicin, and 180 mg/m² cisplatin. The median number of chemotherapy courses was 3, ranging from 1 to 7. The median duration of treatment was 5.1 weeks and 11.4 weeks in the radiotherapy and chemotherapy groups, respectively
Selective reporting (reporting bias)	High risk	The overall trial showed no significant difference with five-year PFS 83% versus 82%; OS 85% versus 87%. A subgroup analysis of 120 women in a high- to intermediate-risk group defined as (1) stage pTIc over 70 years old or with grade3 endometrioid adenocarcinoma or (2) stage pT2 or pT3a (positive cytology) was presented in the same publication. It suggested the chemotherapy group had a significantly higher PFS rate (83.8% versus 66.2%, log-rank test P = 0.024, hazard ratio 0.44) and higher OS rate (89.7% versus 73.6%, log-rank test P = 0.006, hazard ratio 0.24). Nevertheless this study fulfils the search criteria for the inclusion in this meta-analysis using the original unselected data
Other bias	Low risk	The broad inclusion criteria and subgroup analysis has been criticised but the authors have never deviated from their initial protocol and the groups are remarkably well matched However, the graphs depicting overall survival describe 122 women allocated radiotherapy but the graph related to PFS provides data on 123 women
Main problems with the trial as perceived by this analysis	High risk	Other trials have used higher doses of chemotherapy and used a 3 weekly cycle, not 4 weekly The other issue worth of note is the inconsistent data reporting. In the early ASCO presentations of this trial , 208 women were described as having low or intermediate risk disease and 67 women had high-risk disease. The full report published in 2008 has slightly different numbers. According to the manuscript, 190 women had low or intermediate risk disease, 120 had high intermediate risk group and 75 had high-risk disease Low intermediate risk was defined in the manuscript and as deeply invasive, well or moderately differentiated cancer. Of the 190 women reported in them anuscript, the progression-free survival was 94.5% and 87.5% (P = 0.11) and overall 5 year survival was 95% and 91% (P = .2) associated with radiotherapy and chemotherapy respectively. Earlier presentations described 89.6% and 87.2% The high intermediate risk group had deeply invasive poorly differentiated tumours and involved women over the age of 70 or they had stage 2 or 3a cancer. There were 120 women in the manuscript and there was significant progression-free survival advantage associated with chemotherapy HR = .44 (.20 to .97) High-risk disease was defined as stage 2 and 3a in the ASCO presentation of 67 women and they gained a substantial progression-free survival advantage (64.2% versus 84.5%; P = 0.06) and an overall survival benefit from adjuvant chemotherapy (80.3% versus 97.5% P = 0.02). This benefit was not confirmed in the final manuscript. In fact, the manuscript describes a progression-free survival rate in this group at 5 years of 78.6% and 64.4% (P = 0.17) and the overall survival rate at 5 years of 75.7% and 71.1% respectively. This is now a non significant trend in favour of radiotherapy. Presumably the data matured with time as more events were reached

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Death from any cause (HR)	6	Hazard Ratio (Random, 95% CI)	0.74 [0.62, 0.89]
1.1 Chemotherpay versus no additional treatment (all receive EBRT+surgery)	2	Hazard Ratio (Random, 95% CI)	0.68 [0.45, 1.02]
1.2 Chemotherpay v Radiotherapy	4	Hazard Ratio (Random, 95% CI)	0.76 [0.62, 0.92]
2 Death or recurrence (HR)	7	Hazard Ratio (Random, 95% CI)	0.75 [0.64, 0.89]
2.1 Chemotherpay versus no additional treatment (all receive EBRT+surgery)	3	Hazard Ratio (Random, 95% CI)	0.63 [0.44, 0.89]
2.2 Chemotherpay v Radiotherapy	4	Hazard Ratio (Random, 95% CI)	0.80 [0.66, 0.97]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Risk of death; Chemotherapy versus any other arm (RR)	8	2197	Risk Ratio (IV, Random, 95% CI)	0.88 [0.79, 0.99]
1.1 Chemotherpay versus no additional treatment (all receive EBRT+surgery)	4	871	Risk Ratio (IV, Random, 95% CI)	0.94 [0.72, 1.22]
1.2 Chemotherapy v radiotherapy	4	1326	Risk Ratio (IV, Random, 95% CI)	0.87 [0.76, 0.99]
2 Risk difference for death at 5 years for all trials	8	2197	Risk Difference (IV, Random, 95% CI)	−0.03 [−0.07, 0.00]
2.1 Chemotherpay versus no additional treatment (all receive EBRT+surgery)	4	871	Risk Difference (IV, Random, 95% CI)	−0.02 [−0.08, 0.03]
2.2 Chemotherapy v radiotherapy	4	1326	Risk Difference (IV, Random, 95% CI)	−0.04 [−0.10, 0.02]
3 Restricted to trials of conventional chemotherapy (RR)	6	1860	Risk Ratio (IV, Random, 95% CI)	0.85 [0.76, 0.96]
4 Risk difference restricted to trials of conventional chemotherapy	6	1860	Risk Difference (IV, Random, 95% CI)	−0.04 [−0.08, −0.01]
5 Analysis excluding unconventional radiotherapy regimens (RR)	5	1439	Risk Ratio (IV, Random, 95% CI)	0.96 [0.80, 1.16]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death from any cause; Chemotherapy versus radiotherapy (HR)	4		Hazard Ratio (Random, 95% CI)	0.76 [0.62, 0.92]
2 Death or recurrence; Chemotherapy versus radiotherapy (HR)	4		Hazard Ratio (Random, 95% CI)	0.80 [0.66, 0.97]
3 Overall 5 year survival; Chemotherapy versus radiotherapy (RR)	4	1326	Risk Ratio (IV, Random, 95% CI)	0.87 [0.76, 0.99]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death from any cause (HR) excluding mixed tumours (carcinosarcomas)	5		Hazard Ratio (Random, 95% CI)	0.74 [0.62, 0.89]
2 Overall 5 year survival (risk of death) excluding mixed tumours (carcinosarcomas) (RR)	7	1991	Risk Ratio (IV, Random, 95% CI)	0.89 [0.78, 1.02]
3 Overall 5 year survival (risk of death) excluding mixed tumours and trials of unconventional chemotherapy (RR)	5	1654	Risk Ratio (IV, Random, 95% CI)	0.85 [0.74, 0.98]

Methods	GOG orchestrated multicenter phase 3 randomised controlled trial
Participants	A total of 206 women with any stage of previously untreated locally confined mixed mesenchymal mullerian malignant tumour (primary carcinosarcomas of the uterus) were randomised to whole abdominal irradiation (WAI) arm (n = 105) or chemotherapy (n = 101) with Cispltain, Ifosfamide and mesna All women had a hysterectomy, bilateral salpingo-oopherectomy and optimal resection of all gross intra-abdominal/pelvic disease, including macroscopically involved pelvic and para-aortic nodes, leaving no residual disease any larger than 1 cm before randomisation Twenty-five cases were excluded from the analysis based on review of histology and one was excluded because the GOG committee felt there was inappropriate residual disease at randomisation
Interventions	Chemotherapy consisted of intravenous (IV) cisplatin (20mg/m2/day × 4 days) followed by a 1 hour infusion of ifosfamide (1.5g/m2/day IV × 4 days) with mesna (120 mg/m2 IV bolus over 15 min on day one, followed by 1.5 g/m2/day IV continuous infusion × 4 days beginning with day one) every 3 weeks for three cycles within 8 weeks following initial surgery Whole abdominal irradiation involved 30 Gray to the whole abdomen at 1 Gray per fraction, two fractions per day, and 5 days each week with a minimum of 6 hour between morning and afternoon fractions (hyperfractionation). Due to slow patient accrual, in August 1996, the dose fractionation schedule was changed to once-daily fractions of 1.5 Gray for 5 days each week to the same total dose to the whole abdomen of 30 Gray. Early recruits were given a pelvic boost of hyperfractionated 20 Gray. The fractionation schedule was also changed in August 1996 to once-daily fractions of 1.8 Gray for 5 days each week to a total dose of 19.8 Gray (cumulative true pelvic dose of 49.8 Gray)
Outcomes	Overall survival was defined as the time from randomisation to death from any cause or, for living patients, the date of last contact. The recurrence-free interval was assessed from the date of randomisation to the date when clinically evident disease was observed
Results (OS & PFS)	The estimated crude probability of recurring within 5 years was 58% (WAI) and 52% (CIM). Adjusting for stage and age, the recurrence rate was 21% lower for CIM patients than for WAI patients (relative hazard (RH) = 0.789, 95% confidence interval (CI): (0.530 to 1.176), P = 0.245, 2-tail test). The estimated death rate was 29% lower among the CIM group (RH = 0.712, 95% CI: 0.484 to 1.048, P = 0.085, two-tail test) The estimated crude probability of surviving at least five years following diagnosis was approximately 35% for those randomised to WAI versus 45% for those randomised to CIM. After adjusting for stage and age at diagnosis, the estimated death rate was 29% lower for CIM patients than WAI patients (RH = 0.712, 95% CI: 0.484 to 1.048). A similar result was obtained when all women (regardless of eligibility) were included in the analysis of survival for an intention-to-treat analysis (RH = 0.727, 95% CI: 0.503 to 1.050)
Results (site of recurrence)	There have been 112 recurrences reported from 206 women. These include 60 in the radiotherapy group and 52 in the chemotherapy group. There were slightly more vaginal recurrences in the CIM group and more abdominal recurrences in the WAI group, but these differences were not statistically significant The sites of first recurrence for women allocated radiotherapy included the vagina (4/105; 3.8%), pelvis (14/105; 13.3%), abdomen (29/105; 27.6%) and distant sites 13/105; 25.7%). The corresponding sites of first recurrence for women allocated chemotherapy was the vagina (10/101; 9.9%), pelvis (14/101; 13.8%), abdomen (19/101; 18.8%) and other distant sites (10/101; 23.8%)
Toxicity	Grade 3 or 4 acute anaemia (11 versus 1, P < 0.01) and neuropathy (central and peripheral) (9 versus 0, P < 0.01) occurred more often among those treated with CIM chemotherapy than radiotherapy. Regarding grade 2, 3 or 4 late effects, gastrointestinal events occurred more often among those treated with radiotherapy (WAI) than chemotherapy (10 versus 0, P < 0.001) Two women in the radiotherapy cohort died as a direct consequence of radiation hepatitis, while one patient in the chemotherapy arm died of an acute systemic blood infection which originated at the port site and was complicated by neutropenia
Notes
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was orchestrated by the central GOG office block randomisation based
Allocation concealment (selection bias)	Low risk	The authors confirm that treatment assignments remained concealed from randomisation code generation to registration
Blinding (performance bias and detection bias) All outcomes	High risk	It was not possible to blind the observers or participants to treatment allocation in this type of trial
Incomplete outcome data (attrition bias) All outcomes	Low risk	Primary outcome data were available on all 206 women and data on adverse events was available from 197/206 (96%) cases. A total of 232 women were randomised, but 26 were found to be ineligible and excluded (appropriately before analysis
Selective reporting (reporting bias)	Low risk	There is no suggestion of selective reporting and all important survival events have been reported
Other bias	Low risk	We have been unable to find any suggestion from any author that the study was biased
Main problems with the trial as perceived by this analysis	Low risk	The protocol for delivering radiotherapy changed midway through the study but this is unlikely to have any impact on the conclusions that can be derived from this study

Methods	see table for the separate studies
Participants
Interventions
Outcomes
Results (OS & PFS)
Results (site of recurrence)
Toxicity
Notes

Study	Reason for exclusion
Bruner	2007 This report describes quality of life in the GOG 122 trial. These data were included in the review but the manuscript has no data on the primary outcomes
Brunetto 2000	This was a trial examining the role of ifosfamide for uterine tumours but the morphology was not a simple adneocarinoma. The study population had advanced, persistent or recurrent carcinosarcoma of the uterus. Consequently the data were excluded as they do not address the primary management of a women presenting with a new cancer:
Deng 2000	This trial examined the effect of radiotherapy and chemotherapy on uterine morphology. It is not included in the analyses because there are no outcome data This study reported on the histological changes in 58 women treated for endometrial carcinoma with Estramustine phosphate (EMP) or radiotherapy. Estramustine (Emcyt, Estracit) is a chemotherapy agent commonly used to treat prostate cancer derived from estradiol with a nitrogen mustard-carbamate ester moiety that makes it an alkylating antineoplastic agent similar to mechlorethamine, with oestrogen-induced specificity. Women were randomly divided into three groups and clinically observed. Twenty-one women allocated oral Estramustine had 280 mg twice daily for 21 days before surgery and 19 women allocated radiotherapy received preoperative intra-cavity irradiation with half of the standard dosage. The control group involved 18 women who received surgical operation alone. The microscopic changes induced by irradiation were much heavier than those induced by chemotherapy. 5/21 women given Estramustine were found with no tumour lesion in the post operation samples, all of those five cases had strongly positive oestrogen receptors (++) and four of the five cases were well differentiated tumours before chemotherapy. In radiotherapy group, the tumour lesion disappeared in 6/19 cases, and five were moderately differentiated. No histopathological changes were seen in control group. Immunohistochemical tests revealed a significant decrease in oestrogen receptor staining after Estramustine and a decrease in ki- 67 index, especially for the oestrogen receptor positive tumours. The ki-67 index reduced significantly from 49.5% before to 35.1% after medication (P < 0.05).
Chauvergne 2008	This study compared different chemotherapy regimens but was excluded as the treatment allocation did not use a random allocation program
GCSF	The study population had advanced endometrial carcinoma, and the trial did not focus on the primary treatment after hysterectomy
GOG 107	This phase III trial examined the addition of doxorubicin to cisplatin in advanced endometrial carcinoma
GOG 156	The trial was never completed due to poor accrual
GOG 194	The trial was never completed due to poor accrual
Fujimura 2000	This study compared different chemotherapy regimens but is excluded as the treatment allocation did not involve a group that was not given chemotherapy The trial compared the outcome after randomly allocating women with deeply invasive (old stage 1C) endometrial endometrioid adenocarcinoma after hysterectomy either adjuvant CAP (cyclophosphamide, pirarubicin and cisplatin) or EP (etoposide and cisplatin). The five-year survival rate was 88.4% in the CAP group and 95.1% in the EP group; the difference between the two groups was not significant (P = 0.3496). The disease-free survival rate was 80.3% in the CAP group and 84.8% in the EP group (nonsignificant: P = 0.4533)
Omura	This was a study of women with stage I and II uterine sarcoma who were randomly allocated Doxorubicin (adriamycin) or no adjuvant chemotherapy. Participants did not have endometrial cancer
Samuels 2004	This was a randomised study of trabectedin given by different dosing schedules in patients with uterine leiomyosarcomas or liposarcomas, not cancers
Sutton 2000	This was a randomised trial comparing ifosfamide with ifosfamide + cisplatin involving 194 women with advanced or recurrent carcinosarcoma no longer amenable to control by surgery or radiotherapy
GOG 161	Phase III trial studied the addition of ifosfamide to paclitaxel in advanced uterine carcinosarcoma
Aapro 2003	This study recruited women with advanced inoperable or recurrent endometrial cancer and they were randomly assigned doxorubicin alone or in combination with cisplatin
Cohen 1984	This study recruited women with advanced, recurrent or residual endometrial adenocarcinoma considered incurable by radiation or surgery. Women were randomised to melphalan, 5-fluorouracil and megace or doxorubicin, cyclophosphamide and 5-fluorouracil
Edmonson 1987	This study recruited women with advanced cancer. Women with progestin-refractory, metastatic endometrial cancer were randomised to receive cisplatin alone or cisplatin in combination with doxorubicin and cyclophosphamide
Fleming 2004a	This study recruited women with advanced (stage III, IV) or recurrent endometrial cancer. They were randomised to receive doxorubicin and cisplatin or doxorubicin, cisplatin and paclitaxel with Granulocyte colony stimulating factor support
Fleming 2004b	This study recruited women with primary stage III, stage IV or recurrent endometrial carcinoma. They were randomised to receive doxorubicin and cisplatin or doxorubicin, paclitaxel and G-CSF support
Gallion 2003	This study recruited women with primary stage II, IV or recurrent endometrial carcinoma. They were randomised to standard-timed doxorubicin or circadian-timed doxorubicin and cisplatin
Horton 1978	This small study recruited women with measurable local extension or metastases not amenable to cure by surgery or radiotherapy. The women were randomised to receive doxorubicin or cyclophosphamide
Long 1995	This small study described in abstract form recruited women with advanced cancer. They were randomised to receive doxorubicin and cisplatin or doxorubicin, cisplatin, methotrexate and vinblastine
Pawinski 1999	This study recruited women with recurrent or metastatic disease. They were randomised to receive cyclophosphamide or ifosfamide
Thigpen 1994	This study recruited women with advanced cancer. Women had advanced or recurrent endometrial carcinoma no longer amenable to surgery or radiotherapy and were randomised to receive doxorubicin alone or in combination with cyclophosphamide
Thigpen 2004	This study recruited women with advanced cancer or recurrent endometrial carcinoma. They were randomised to treatment with doxorubicin alone or in combination with cisplatin

Trial name or title	A Phase III Trial of pelvic radiation therapy versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy
Methods	Randomisation to either pelvic radiotherapy or vaginal brachytherapy followed by 3 cycles carboplatin/paclitaxel
Participants	Women with high intermediate and high-risk stage I-II endometrial carcinoma
Interventions	Arm I: Active Comparator Patients undergo conventional or intensity-modulated pelvic radiotherapy once daily, 5 days a week, for 5 to 6 weeks (total of 25 to 28 fractions) in the absence of disease progression or unacceptable toxicity. Patients with stage II disease or stage I disease with a confirmed diagnosis of clear cell and/or papillary serous histology may also undergo 1 or 2 intravaginal (i.e., vaginal cuff) brachytherapy boost treatments Arm II: Experimental Patients undergo vaginal cuff brachytherapy comprising 3 to 5 high-dose rate brachytherapy treatments over approximately 2 weeks or 1 or 2 low-dose rate brachytherapy treatments over 1 to 2 days. Beginning within 3 weeks after initiating brachytherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 to 60 minutes on day 1. Chemotherapy repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity
Outcomes	Primary Outcome Measures: Duration of recurrence-free survival Secondary Outcome Measures: Duration of overall survival Cumulative incidences of vaginal recurrence, pelvic recurrence, distant (extra-pelvic) recurrence, and death from endometrial cancer Toxicity as assessed by NCI CTCAE v3.0 Quality of life as assessed by the FACT-G Physical and Functional Well-Being, FACT-En, FACT/GOG-Ntx, FACIT-F, PROMIS Fatigue-SF1, and FACT-Cx questionnaires
Starting date	March 2009
Contact information	Study Chair: D. Scott McMeekin, MD Oklahoma University Cancer Institute; Phone +1 405-271-8707 Investigator: Marcus E. Randall and Lucille P. Markey, Cancer Center at University of Kentucky, phone +1 859-257-7618
Notes

Trial name or title	A Randomized Phase III Trial of Cisplatin and Tumor Volume Directed Irradiation Followed by Carboplatin and Paclitaxel vs. Carboplatin and Paclitaxel for Optimally Debulked, Advanced Endometrial Carcinoma
Methods	Randomisation to either volume-directed radiotherapy with complex platinum based chemotherpay or 6 cycles conventional dose Carboplatin plus Paclitaxel. Additionally, tissue is stored for translational research
Participants	All women have surgical stage III or IVA endometrial carcinoma per FIGO 1988 staging criteria of any histological type. Surgical Stage III disease includes tumour invading the serosa, tumour in the adnexa, pelvic and/or para-aortic nodes, or vaginal involvement. Women with tumour cells in the pelvic washings as the only extra-uterine disease are eligible only if the histology is clear cell or serous papillary. Surgical Stage IVA includes patients with bladder or bowel mucosal involvement, but no spread outside the pelvis. Interim analysis in January 2011 shows that initial data was available from 61 women and all had stage 3 disease Partisipants have a GOG Performance Status of 0, 1, or 2 and are 18 years of age or older. Entry into the study is limited to no more than 8 weeks from the date of surgery. Surgery involves a hysterectomy and bilateral salpingo-oophorectomy. Pelvic lymph node sampling and para-aortic lymph node sampling are optional The volume of residual disease after surgery must be less than 2cm in any dimension
Interventions	Participants are randomly allocated to either Cisplatin 50 mg/m² IV Days 1 and 28 plus volume-directed radiotherapy followed by Carboplatin AUC 5* plus Paclitaxel 175 mg/m² q 21 days for 4 cycles with G-CSF support or Carboplatin AUC 6 plus Paclitaxel 175 mg/m² q 21 days for 6 cycles.
Outcomes	To determine if treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for 4 cycles (experimental arm) reduces the rate of recurrence or death (i.e. increases recurrence-free survival) when compared to chemotherapy consisting of carboplatin and paclitaxel for 6 cycles (control arm)
Starting date	The study opened to recruitment on June 29, 2009
Contact information	The study chairs for the GOG include Daniela Matei, Marcus E. Randall, David Mutch, Ursula A. Matulonis, Michael J. Birrer and Margaret Steinhoff. I-Chow Hsu represents the RTOG
Notes	The target recruitment is 804. By July 2010, 69 women had been recruited

Trial name or title	A Phase III intergroup trial on adjuvant therapy in radically operated endometrial cancer patients with high risk for micro-metastatic disease: 4 courses of adjuvant carboplatin/paclitaxel followed by radiation therapy versus 2 more courses of carboplatin/paclitaxel
Methods	Women are treated according to randomisation to either adjuvant radiotherapy (48.6 Gray in 1.8 Gray fractions) + para-aortic irradiation if pelvic N+ and para-aortal nodes NX or N+ or 2 additional cycles of adjuvant CT (carboplatin and paclitaxel) The randomisation occurs after surgery and before the routine adjuvant chemotherapy. Vaginal brachytherapy is added if stage II or higher with cervical engagement if extended hysterectomy with parametrial resection has not been performed
Participants	Women treated by hysterectomy, four courses of chemotherapy (carboplatin and paclitaxel) for histologically confirmed endometrial carcinoma (endometrioid, adenosquamous, serous or clear cell carcinoma) with no macroscopic remaining tumour after primary surgery (lymph node exploration optional), with one of the following postoperative FIGO 2009 stage and grade: a. stage IB grade 3, nodes not explored. c. Stage II all grades d. Stage IIIC1-2 (based only on positive nodes with no macroscopic remaining tumour) WHO-performance status 0-2;
Interventions	After randomisation all patients receive four courses of CT (carboplatin and paclitaxel). Thereafter women are treated according to randomisation Arm 1: Adjuvant radiotherapy (48.6 Gray in 1.8 Gray fractions) + para-aortic irradiation if pelvic N+ and para-aortal nodes NX or N+ Arm 2: 2 additional cycles of adjuvant CT (carboplatin and paclitaxel) Vaginal brachytherapy is added if stage II or higher with cervical engagement if extended hysterectomy with parametrial resection has not been performed
Outcomes	Primary: Overall survival (OS) Secondary: Progression-free survival (PFS), Failure-free survival (FFS; defined as relapse or death from endometrial carcinoma or of treatment complications, deaths of intercurrent causes censored), treatment toxicity, quality of life, translational research of predictive or prognostic factors
Starting date
Contact information	Thomas Hogberg, Department of Cancer Epidemiology, University Hospital, SE-221 85 Lund, Sweden. thomas.Hogberg@med.lu.se
Notes

Trial name or title	Randomised phase III trial comparing concurrent chemoradiation and adjuvant chemotherapy with pelvic radiation alone in high-risk and advanced stage endometrial carcinoma: PORTEC-3
Methods	Randomised controlled trial
Participants	Women with high-risk and advanced stage endometrial carcinoma Histologically confirmed endometrial carcinoma, with one of the following postoperative old FIGO stages and grade: Stage IB grade 3 with documented Lymphatic Vascular Space Invasion (LVSI) Stage 1C grade 3 Stage II grade 3 Stage IIIA or IIIC (IIIA based on peritoneal cytology alone is only eligible if grade 3) Stage IB or IC, stage II or stage III with serous or clear cell histology World Health Organization (WHO) performance status zero to two White Blood Cells (WBC) more than or equal to 3.0 × 10^9/L Platelets more than or equal to 100 × 10^9/L Bilirubin less than or equal to 1.5 × Upper Normalised Limit (UNL) Aspartate Aminotransferase (ASAT)/Alanine Aminotreansferase (ALAT) less than or equal to 2.5 × UNL Written informed consent
Interventions	Patients are randomised (1:1) to receive external beam pelvic radiotherapy (standard arm: 48.6 Gray in 1.8 Gray fractions), or pelvic radiotherapy with concurrent chemotherapy (two cycles of cisplatin) followed by adjuvant chemotherapy (four cycles of carboplatin and paclitaxel; experimental arm) This trial tests the addition of concurrent and adjuvant chemotherapy to postoperative radiation therapy
Outcomes	Five-year overall survival and failure-free survival
Starting date
Contact information	Dr C L Creutzberg. c.l.creutzberg@lumc.nl
Notes	http://www.clinicalresearch.nl/portec3/

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death from any cause; Chemotherapy versus no additional treatment (HR)	2		Risk Ratio (Random, 95% CI)	0.68 [0.45, 1.02]
2 Death or recurrence; Chemotherapy versus no additional treatment (HR)	3		Hazard Ratio (Random, 95% CI)	0.63 [0.44, 0.89]
3 Overall 5 year survival; Chemotherapy versus no additional treatment (RR)	4	871	Risk Ratio (IV, Random, 95% CI)	0.94 [0.72, 1.22]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Distant (extrapelvic) recurrence (RR; all trials)	7	2198	Risk Ratio (IV, Random, 95% CI)	0.79 [0.68, 0.92]
2 Distant (extrapelvic) recurrence; (Risk difference; all trials)	7	2198	Risk Difference (IV, Random, 95% CI)	−0.05 [−0.08, −0.01]
3 Distant (extrapelvic) recurrence excluding mixed tumours (RR; all trials)	6	1992	Risk Ratio (IV, Random, 95% CI)	0.79 [0.67, 0.94]
4 Pelvic recurrence (chemotherapy v no treatment) (RR)	2	690	Risk Ratio (IV, Random, 95% CI)	0.48 [0.20, 1.18]
5 Pelvic recurrence (chemotherapy v radiotherapy) (RR)	4	1327	Risk Ratio (IV, Random, 95% CI)	1.28 [0.97, 1.68]
6 Any recurrence (chemotherapy v no adjuvant treatment) (RR)	4	869	Risk Ratio (IV, Random, 95% CI)	0.64 [0.49, 0.84]
7 Any recurrence (chemotherapy v radiotherapy) (RR)	4	1327	Risk Ratio (IV, Random, 95% CI)	0.95 [0.83, 1.08]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death from any cause (HR) for subgroup serous/clear cell	2		Hazard Ratio (Random, 95% CI)	0.98 [0.68, 1.40]
2 Death or recurrence (HR) for subgroup serous/clear cell cancer	2		Hazard Ratio (Random, 95% CI)	0.84 [0.57, 1.23]

PERMALINK

Adjuvant chemotherapy for endometrial cancer after hysterectomy

Nick Johnson

Andrew Bryant

Tracie Miles

Thomas Hogberg

Paul Cornes

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors’ conclusions

BACKGROUND

Description of the condition

Table 1.

Description of the intervention

How the intervention might work

Why it is important to do this review

OBJECTIVES

METHODS

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Unpublished and grey literature

Handsearching

Correspondence

Language

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

RESULTS

Description of studies

Results of the search

Figure 1.

Included studies

Table 2.

Table 3.

Trials of adjuvant chemotherapy versus no additional therapy after surgery and radiotherapy

NSGO & EORTC

MaNGO

Kuoppala 2008

GOG 34

Trials of adjuvant chemotherapy versus radiotherapy after surgery

GOG 122

GICOG

J GOG 2033

GOG 150

Excluded studies

Ongoing studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

Effects of interventions

Overall effect of chemotherapy on survival rates

Figure 2.

Figure 3.

Figure 4.

Senstivity analysis

Senstivity analysis; separating the trials into comparisons of chemotherapy versus radiotherapy and chemotherapy versus no additional treatment

Comparing chemotherapy or radiotherapy