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. Author manuscript; available in PMC: 2024 Dec 8.
Published in final edited form as: Lancet Oncol. 2020 Dec 22;22(2):277–288. doi: 10.1016/S1470-2045(20)30591-X

Objective responses to first-line neoadjuvant carboplatin−paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial

Robert D Morgan 1, Iain A McNeish, Adrian D Cook 2, Elizabeth C James 3, Rosemary Lord 4, Graham Dark 5, Rosalind M Glasspool 6, Jonathan Krell 7, Christine Parkinson 8, Christopher J Poole 9, Marcia Hall 10, Dolores Gallardo-Rincón 11, Michelle Lockley 12, Sharadah Essapen 13, Jeff Summers 14, Anjana Anand 15, Abel Zachariah 16, Sarah Williams 17, Rachel Jones 18, Kate Scatchard 19, Axel Walther 20, Jae-Weon Kim 21, Sudha Sundar 22, Gordon C Jayson 23, Jonathan A Ledermann 24, Andrew R Clamp 25,✉
PMCID: PMC7616995  EMSID: EMS177350  PMID: 33357510

Summary

Background

Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial.

Methods

ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC–IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB–IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125- evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with ClinicalTrials.gov, NCT01654146.

Findings

Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29 · 5 months (IQR 15 · 6−54 · 3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14·4 months (95% CI 9·2–28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1–20·1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13·8 months (95% CI 8·8–23·4; 544 events) and 9·7 months (5·8–14·5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response.

Interpretation

The RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient’s clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response.

Introduction

Ovarian cancer is the most common cause of gynaecological cancer-related death in Europe and North America.1 Although immediate primary surgery (IPS) followed by adjuvant platinum-based chemotherapy is considered the standard of care for women with advanced-stage disease, neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is a recognised treatment option for women in whom IPS is contraindicated. This therapeutic approach has been validated in three randomised, phase 3 trials, which reported non-inferior survival between IPS followed by adjuvant chemotherapy versus neoadjuvant chemotherapy followed by DPS in International Federation of Gynecology and Obstetrics (FIGO) stage III–IV ovarian cancer.2–5 Although the findings from these trials provide clear evidence for neoadjuvant chemotherapy followed by DPS in advanced disease, response rates to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) were not reported.2–5 The absence of published response evaluation data for neoadjuvant chemotherapy has contributed to wide variation in surgical practice in women with radiologically defined stable disease.6,7 Establishing robust and reproducible criteria for evaluation of response to neoadjuvant chemotherapy is pivotal in standardising DPS and improving outcomes for women with ovarian cancer.

ICON8 sought to determine whether first-line chemotherapy with dose-fractionated carboplatin plus paclitaxel improved progression-free survival and overall survival in women diagnosed with FIGO stage IC–IV epithelial ovarian cancer.8,9 The intention-to-treat primary progression-free survival analysis showed no significant difference in progression-free survival between standard three-weekly carboplatin plus paclitaxel versus either three-weekly or weekly carboplatin plus weekly paclitaxel.8 The eligibility criteria for ICON8 permitted women to enter the trial with a plan to receive neoadjuvant chemotherapy followed by DPS if this regimen was deemed the most appropriate management at local multidisciplinary case review. In these patients, both RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses to neoadjuvant chemotherapy were prospectively evaluated.10,11 In this post-hoc exploratory analysis of ICON8, we aimed to investigate whether objective treatment responses to neoadjuvant chemotherapy affected progression-free survival and cytoreduction rates, and could be used to predict patient survival and the effectiveness of DPS and thus guide surgical treatment decisions.

Methods

Study design and participants

ICON8 was an international, GCIG, multicentre, randomised, phase 3 trial in which patients were recruited from the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. At least one patient was recruited at each of the 117 hospitals (appendix pp 1–3). Inclusion criteria included newly diagnosed FIGO (1988) stage IC–IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB–IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum; age 18 years or older; an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; a life expectancy of more than 12 weeks; and adequate bone marrow, liver, and renal function (haemoglobin ≥90 g/L; platelet count ≥100 × 109 per L; absolute neutrophil count ≥1·5 × 109 cells per L; bilirubin ≤1·5 × upper limit of normal [ULN] and aspartate aminotransferase [AST] or alanine aminotransferase [ALT] ≤3 × ULN in the absence of parenchymal liver metastases or ≤5 × ULN in the presence of parenchymal liver metastases; and directly measured glomerular filtration rate [GFR] ≥30 mL/min or a calculated creatinine clearance ≥60 mL/min). Exclusion criteria included non-epithelial ovarian cancer; peritoneal cancer that was not Müllerian origin, including mucinous histology; borderline tumours or tumours of low malignant potential; previous systemic anticancer therapy for ovarian cancer; previous malignancies within 5 years before randomisation apart from adequately treated carcinoma in situ of the cervix, breast ductal carcinoma in situ, non-melanomatous skin cancer, previous or synchronous FIGO (2009) stage IA grade 1 or 2 endometrioid cancers with no lymphovascular space invasion; pre-existing grade 2 or worse neuropathy; any other disease or metabolic dysfunction that, in the opinion of the investigator, would put the participant at high-risk of treatment-related complications or prevent compliance with the trial protocol; previous radiotherapy to the abdomen or pelvis; planned intraperitoneal cytotoxic chemotherapy; planned maintenance treatment with systemic anticancer therapy following completion of protocol treatment and before protocol-defined progression; sexually active women of childbearing potential not willing to use adequate contraception; pregnant or lactating women who are breastfeeding; treatment with other investigational agents before protocol-defined progression; history or clinical suspicion of CNS metastases; and known hypersensitivity to carboplatin, paclitaxel, or their excipients (see appendix pp 4–5 for complete list of inclusion and exclusion criteria). In this post-hoc exploratory analysis, only patients who were planned to receive neoadjuvant chemotherapy followed by DPS were included.

All patients provided written informed consent before enrolment. The protocol had the appropriate national ethics committee approval for the countries in which the study was done. The trial was done in accordance with the national laws and regulations of the countries in which it was carried out. All protocol amendments were approved by relevant ethics committees and regulatory bodies (appendix pp 6−7). The trial was also done in accordance with Good Clinical Practice guidelines and provisions of the Declaration of Helsinki.

Randomisation and masking

Eligible patients were randomly assigned (1:1:1) using a minimisation method with a random element to one of three treatment groups. The minimisation was stratified by the following three factors: GCIG group (UK National Cancer Research Institute, Australia and New Zealand Gynaecological Oncology Group; Grupo de Investigación en Cáncer de Ovario y Tumores Ginecológicos de México; Korean Gynecologic Oncology Group; and Cancer Trials Ireland, formerly Irish Clinical Oncology Research Group), disease stage (FIGO stage IC high-grade serous, clear cell, or grade 3 carcinoma; FIGO stage IIA high-grade serous, clear cell, or grade 3 carcinoma; FIGO stage IIB; FIGO stage IIC; FIGO stage IIIA; FIGO stage IIIB; FIGO stage IIIC; and FIGO stage IV), and timing and outcome of surgery of IPS group (IPS plus FIGO stage IC–III with no visible residual disease; IPS plus FIGO stage IC–III with residual disease ≤1 cm; IPS plus FIGO stage IV or FIGO stage IC–III with residual disease >1 cm; no surgery currently planned; and DPS was planned). Patients were randomly assigned using the Medical Research Council Clinical Trials Unit at University College London (London, UK) randomisation telephone service. Patients and clinicians were not masked to their allocated group.

Procedures

Group 1 (the control group) received intravenous carboplatin area under the curve (AUC)5 or AUC6 (capped at 900 mg) and intravenous paclitaxel 175 mg/m2 by body surface area (capped at 350 mg) on day 1 of every 21-day cycle. Group 2 received intravenous carboplatin AUC5 or AUC6 (capped at 900 mg) on day 1 and intravenous dose-fractionated paclitaxel 80 mg/m2 by body surface area (capped at 160 mg) on days 1, 8, and 15 of every 21-day cycle. Group 3 received dose-fractionated intravenous carboplatin AUC2 (capped at 300 mg) and dose-fractionated intravenous paclitaxel 80 mg/m2 by body surface area (capped at 160 mg) on days 1, 8, and 15 of every 21-day cycle. The maximum number of cycles of chemotherapy was six.

Chemotherapy was interrupted for an absolute neutrophil count of less than 1·0 × 109 cells per L (groups 1 and 2 on day 1; group 3 on days 1, 8, and 15) or an absolute neutrophil count of less than 0.5 × 109 cells per L (group 2 on days 8 and 15), a platelet count of less than 75×109 per L (groups 1 and 2 on day 1; group 3 on days 1, 8, and 15), or a platelet count of less than 50 × 109 per L (group 2 on days 8 and 15). Treatment resumed without dose reduction if patients recovered from haematological toxicity within 7 days. If recovery occurred after 7 days or dose-limiting haematological toxicity occurred (grade 3 or 4 febrile neutropenia, grade 4 thrombocytopenia, or grade 3 thrombocytopenia with bleeding) protocol-defined dose reductions were recommended. The protocol defined dose levels for carboplatin and paclitaxel as 3-weekly carboplatin AUC5 (starting dose) and AUC4 (dose level –1) and AUC3·5 (dose level –2) by directly measured GFR or calculated GFR (Wright formula), or AUC6 (starting dose) and AUC5 (dose level –1) and AUC4·5 (dose level –2) by calculated GFR (Cockcroft-Gault or Jelliffe formulae); weekly carboplatin AUC2 (starting dose), AUC1·67 (dose level –1), and AUC1·5 (dose level –2); and weekly paclitaxel 80 mg/m2 (starting dose), 60 mg/m2 (dose level –1), and 45 mg/m2 (dose level –2). Dose levels could be amended for haematological and non-haematological toxicity. Chemotherapy was also interrupted for grade 2 or worse sensory or motor neuropathy, grade 3 or worse mucositis, grade 3 or worse increase in AST or ALT, grade 2 or worse rash or any other treatment-related grade 3 or worse adverse events. Paclitaxel was permanently discontinued if there was a delay in restarting paclitaxel for 3 weeks or longer due to grade 2 sensory or motor neuropathy, or grade 3 or worse sensory or motor neuropathy or any other treatment-related grade 4 or worse adverse events. Hypersensitivity reactions to carboplatin and paclitaxel were managed according to standard local practice. Docetaxel could not be used as a substitute for paclitaxel in patients who had hypersensitivity reactions that prohibited further administration of paclitaxel. Single-agent carboplatin was accepted as protocol treatment if patients were unable to tolerate paclitaxel. Three-weekly cisplatin (75 mg/m2 by body surface area) in combination with 3-weekly paclitaxel (80 mg/m2 by body surface area) could be used as a substitute for carboplatin in patients who had hypersensitivity reactions that prohibited further administration of carboplatin.

Protocol treatment was also discontinued due to any of the following reasons: progression while on therapy, unacceptable toxicity, inter-current illness that prevented further treatment, withdrawal of consent for treatment by the patient, or any alterations in the patient’s condition that justified the discontinuation of treatment in the investigator’s opinion.

The trial protocol strongly recommended that DPS was carried out as close to cycle 3 day 22 as possible, and within a maximum of 10 days after this, provided that haematological recovery had occurred. Only under exceptional circumstances, in which patients were deemed to be unsuitable for DPS following three cycles of neoadjuvant chemotherapy, could additional cycles of neoadjuvant chemotherapy be given. The maximum number of cycles of neoadjuvant chemotherapy permitted was six. The final decision to perform DPS was made by the local treating multidisciplinary team. The outcome of DPS was defined as either complete cytoreduction (R0; the absence of any macroscopically visible disease), optimal cytoreduction (largest deposit of residual disease ≤1 cm in diameter), or suboptimal cytoreduction (>1 cm diameter deposit of residual disease at the end of debulking surgery).12 Adjuvant chemotherapy was planned to commence between 1 and 6 weeks after DPS.

All patients recruited to ICON8 had cross-sectional imaging of the abdomen and pelvis with or without the thorax (preferably CT, but MRI was permitted) as part of all radiological tumour assessment. However, RECIST measurable disease was not required for trial entry. In the population of patients who received neoadjuvant chemotherapy followed by DPS, the baseline scan was carried out before randomisation and within 6 weeks before cycle 1, day 1 of neoadjuvant chemotherapy. Subsequently, cross-sectional imaging using the same imaging modality as the baseline scan was performed pre-operatively as part of the surgical planning process (the pre-surgical planning radiological tumour assessment), during cycle 3 or 4 of neoadjuvant chemotherapy. For patients undergoing DPS, a post-operative CT or MRI was done 4 weeks (±7 days) after surgery. In all trial patients, an end of primary treatment scan occurred within 6 weeks (±2 weeks) after day 1 of their last cycle of chemotherapy. At subsequent follow-up visits, cross-sectional imaging was performed only if there were clinical symptoms suggestive of relapse or progression, or if there was evidence of GCIG CA125 progression. Any patient with asymptomatic CA125 elevations and no radiological evidence of disease progression according to RECIST underwent routine 3-monthly repeat scans until protocol-defined disease progression. All patients recruited to ICON8 had serum CA125 concentration measured at baseline, within 7 days before cycle 1, day 1 of neoadjuvant chemotherapy, and then within 72 h before day 1 of each subsequent cycle of neoadjuvant chemotherapy. A pre-surgical serum CA125 concentration was requested within the protocol, but not mandated. Subsequently, CA125 concentrations were measured at each follow-up visit. The protocol did not mandate that serum CA125 had to be measured on the same day as the baseline or surgical planning scan.

All adverse events were graded according to US National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) and were collected at baseline, at every chemotherapy cycle, and at DPS. Only adverse events that occurred in the population of patients who had neoadjuvant chemotherapy followed by DPS are included in this post-hoc exploratory analysis of ICON8.

Outcomes

The co-primary outcomes of ICON8 were progression-free survival and overall survival. Secondary outcomes of ICON8 were toxicity, quality of life, and health economics. In the primary efficacy analysis, progression-free survival was calculated from the date of randomisation to the date of first clinical or radiological progression or death from any cause, whichever occurred first. In the primary efficacy analysis, overall survival was calculated from the date of randomisation to the date of death from any cause. The primary progression-free survival analysis, toxicity, and the quality-of-life analysis of ICON8 have been reported previously.8,9 In this post-hoc exploratory analysis, we assessed the RECIST and GCIG CA125 responses to platinum-based chemotherapy in women enrolled on ICON8 who were planned for neoadjuvant chemotherapy followed by DPS. In addition, we evaluated median progression-free survival in this patient cohort, using a landmark analysis, and compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses.

Statistical analysis

Sample size calculations for the main ICON8 trial have been reported previously.8 Because this analysis was exploratory, we did no formal power calculations. In this post-hoc exploratory analysis, we used a landmark method to assess progression-free survival, in which progression-free survival was calculated from the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death from any cause, whichever occurred first. We did not use asymptomatic elevations in CA125 to define disease progression.

Objective responses are reported according to RECIST and GCIG CA125 criteria.10,11 The RECIST response (investigator-assessed) was determined by comparing the baseline scan and the pre-surgical planning radiological tumour assessment. The GCIG CA125 response (centrally evaluated at the Medical Research Council Clinical Trials Unit at UCL) was determined by comparing the cycle 1, day 1 CA125 value with either the cycle 3 or 4, day 1 CA125 value or the pre-surgical CA125 value, whichever was the most recent value available. Patients were excluded from this post-hoc exploratory analysis if they did not have RECIST or GCIG CA125 measurable disease. Post-hoc sensitivity analyses of progression-free survival excluded patients who had planned DPS but did not then undergo surgery, and those with incomplete radiology data. Further post-hoc analyses were undertaken to investigate whether surgical response, CA125 response, and the presence of ascites could be combined to identify patients unlikely to benefit from DPS. A descriptive analysis of adverse events occurring before surgery was also undertaken.

Categorical variables are presented as number (%) with differences between groups analysed using the χ2 test. Missing data are indicated in tables, but are not included in the calculation of percentages. Continuous variables are presented as median (IQR). Time-to-event analyses used landmark analysis as described above and are presented using Kaplan-Meier curves and median (95% CI) event-free survival. Statistical significance was determined by a two-sided p value at the 95% level. All statistical analyses were done with Stata (version 16.1). The final trial database lock was on March 31, 2020.

This study is registered with ClinicalTrials.gov, NCT01654146.

Role of the funding source

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author (ARC) and trial statisticians (ADC and ECJ) had full access to all the data in the study. The corresponding author had final responsibility for the decision to submit for publication.

Results

Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8.8 779 (50%) of the 1566 women were planned to receive neoadjuvant chemotherapy followed by DPS after local multidisciplinary case review. Demographic data for this population are presented in table 1. The median follow-up for the population of patients who received neoadjuvant chemotherapy followed by DPS was 29·5 months (IQR 15·6–54·3). 130 (17%) of the 779 women in the neoadjuvant chemotherapy followed by DPS population had incomplete radiology follow-up data (104 women) or non-target lesions reported at baseline that were not described on subsequent follow-up imaging (26 women); these women were therefore excluded from this post-hoc exploratory analysis (figure 1). Of the remaining 649 women with complete RECIST-evaluable radiology datasets, 564 (87%) had measurable disease by RECIST (figure 1). Data from these 564 women were used to determine the RECIST response. Overall, 348 (62%) of 564 women had a RECIST complete or partial response following neoadjuvant chemotherapy, and the proportion of patients with a RECIST response did not differ between treatment groups (table 2). RECIST progressive disease during neoadjuvant chemotherapy occurred in 33 (6%) of 564 women (table 2). 156 (85%) of 183 women with RECIST stable disease had a reduction in the size of marker lesions, with a median reduction of 14% (IQR 5–23; figure 2A). 727 (93%) of 779 women in the neoadjuvant chemotherapy followed by DPS population had a baseline CA125 concentration that was 2×ULN (figure 1). Data from these 727 women were used to determine the GCIG CA125 response. 610 (84%) of the 727 women had a GCIG CA125 response to neoadjuvant chemotherapy and the proportion of responders did not differ across the treatment groups (table 2; figure 2B). Both RECIST and GCIG CA125 response data were available for 534 women (table 3). In the group of women with a GCIG CA125 response, a substantial proportion did not have a RECIST response: of 453 women with a GCIG CA125 response and RECIST-evaluable disease, 148 (33%) had RECIST stable or progressive disease (table 3). Of the same 453 women, 422 (93%) had a reduction in the size of the marker lesions.

Table 1. Baseline characteristics of patients undergoing neoadjuvant chemotherapy followed by delayed primary surgery.

Group 1 (n=257) Group 2 (n=263) Group 3 (n=259) Total (n=779)
Age, years 65 (59–70) 62 (54–68) 64 (55–69) 64 (56–69)
ECOG performance status
   0 105 (41%) 113 (43%) 93 (36%) 311 (40%)
   1 122(47%) 123(47%) 135 (52%) 380 (49%)
   2 28 (11%) 27 (10%) 31 (12%) 86 (11%)
   Missing 2 0 0 2
Histological type
   High-grade serous 199 (77%) 185 (70%) 194 (75%) 578 (74%)
   Low-grade serous 4 (2%) 7 (3%) 3 (1%) 14 (2%)
   Serous (no grade specified) 7 (3%) 8 (3%) 7 (3%) 22 (3%)
   Clear cell 4 (2%) 3 (1%) 5 (2%) 12 (2%)
   Endometrioid 1 (<1%) 2 (1%) 2 (1%) 5 (1%)
   Mucinous 0 3 (1%) 2 (1%) 5 (1%)
   Mixed 2 (1%) 3 (1%) 3 (1%) 8 (1%)
   Other 40 (16%) 52 (20%) 43 (17%) 135 (17%)
FIGO stage
   IC or IIA 1 (<1%) 1 (<1%) 2 (1%) 4 (1%)
   IIB or IIC 3 (1%) 4 (2%) 1 (<1%) 8 (1%)
   IIIA or IIIB 6 (2%) 13 (5%) 15 (6%) 34 (4%)
   IIIC 177 (69%) 171 (65%) 159 (61%) 507(65%)
   IV 70 (27%) 74 (28%) 82 (32%) 226 (29%)
Number of cycles of neoadjuvant chemotherapy received
   Four cycles or fewer 172(67%) 191 (73%) 184 (71%) 547 (70%)
   Five to six cycles 25 (10%) 27 (10%) 17 (7%) 69 (11%)
   Surgery not performed 40 (16%) 30 (11%) 42 (16%) 112 (14%)
   Surgery data missing 20 (8%) 15 (6%) 16 (6%) 51 (7%)
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Data are median (IQR), n (%), or n. ECOG=Eastern Cooperative Oncology Group. FIGO=International Federation of Gynaecology and Obstetrics. Group 1 received three-weekly carboplatin and paclitaxel, group 2 received three-weekly carboplatin and weekly paclitaxel, and group 3 received weekly carboplatin and weekly paclitaxel.

Figure 1. Trial profile for post-hoc exploratory analysis.

Figure 1

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CA125=cancer antigen 125. GCIG=Gynecologic Cancer InterGroup. RECIST=Response Evaluation Criteria in Solid Tumors (version 1.1). ULN=upper limit of normal.

Table 2. RECIST and GCIG CA125 response to neoadjuvant chemotherapy.

Group 1 Group 2 Group 3 Total
RECIST response
Complete response 8/182 (4%) 6/195 (3%) 7/187 (4%) 21 (4%)
Partial response 102/182 (56%) 119/195 (61%) 106/187 (57%) 327 (58%)
Stable disease 61/182 (34%) 60/195 (31%) 62/187 (33%) 183 (32%)
Progressive disease 11/182 (6%) 10/195 (5%) 12/187 (6%) 33 (6%)
Non-measurable disease at baseline 29 27 29 85
Total (including non-measurable) 211 222 216 649
GCIG CA125 response*
Yes 198/240 (83%) 204/243 (84%) 208/244 (85%) 610 (84%)
No 42/240 (18%) 39/243 (16%) 36/244 (15%) 117 (16%)
Total 240 243 244 727
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Data are n (%; non-measurable disease at baseline not included in denominator for RECIST response) or n. Group 1 received three-weekly carboplatin and paclitaxel, group 2 received three-weekly carboplatin and weekly paclitaxel, and group 3 received weekly carboplatin and weekly paclitaxel. CA125=cancer antigen 125. GCIG=Gynecologic Cancer InterGroup. RECIST=Response Evaluation Criteria in Solid Tumors (version 1.1).

*

All assessable patients had a baseline CA125 of twice the upper limit of normal range.

Figure 2. Waterfall plot showing percentage change in RECIST marker lesions (A) and GCIG CA125 level (B) from baseline, capped at 100%.

Figure 2

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(A) Dashed red lines represent 20% and –30% change in RECIST marker lesions from baseline. (B) Dashed red line represents –50% change in GCIG CA125 level from baseline. CA125=cancer antigen 125. GCIG=Gynecologic Cancer InterGroup. RECIST=Response Evaluation Criteria in Solid Tumors (version 1.1).

Table 3. RECIST and GCIG CA125 response to neoadjuvant chemotherapy.

GCIG CA125 response No GCIG CA125 response Missing Total
RECIST complete response 18 1 2 21
RECIST partial response 287 23 17 327
RECIST stable disease 127 51 5 183
RECIST progressive disease 21 6 6 33
RECIST non-measurable disease at baseline 66 13 6 85
Missing 91 23 0 114
Total (including missing) 610 117 36 763
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Data are n. CA125=cancer antigen 125. GCIG=Gynecologic Cancer InterGroup. RECIST=Response Evaluation Criteria in Solid Tumors (version 1.1).

To determine whether RECIST response to neoadjuvant chemotherapy could be used to predict patient survival or the effectiveness of DPS, progression-free survival and extent of surgical cytoreduction were evaluated according to RECIST response. A preplanned analysis of the primary progression-free survival analysis of ICON8 had already shown no significant difference in progression-free survival between the three neoadjuvant treatment regimens,8 and therefore all three groups were combined in this post-hoc exploratory analysis using a landmark method, which used time of pre-surgical planning radiological tumour assessment as the start point for progression-free survival. The median progression-free survival was 14·4 months (95% CI 9·2–28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1–20·1; 171 events) for patients with RECIST stable disease (figure 3A). It is notable that the survival outcomes determined using a landmark analysis are approximately 2 months shorter than those reported in the intention-to-treat primary efficacy analysis (appendix p 13).8 Data on surgical outcome were available for 536 (95%) of 564 women with RECIST-evaluable disease, of whom 67 (13%) did not undergo DPS (table 4). When including only those women who underwent DPS, the median progression-free survival was 15·0 months (95% CI 9·5–28·0; 273 events) for patients with a RECIST complete or partial response and 14·0 months (9·5–23·8; 143 events) for those with RECIST stable disease (appendix p 14). The 130 women with incomplete radiology follow-up data had a shorter median progression-free survival (12·5 months, 95% CI 7·5–17·2; 118 events) than the 649 women with a complete RECIST-evaluable radiology dataset (15·4 months, 10·1–25·3; 584 events; appendix p 15). In those women with RECIST-evaluable disease in the neoadjuvant chemotherapy followed by DPS population, median progression-free survival correlated with extent of surgical cytoreduction, and those who had complete (R0) cytoreductive surgery had the best median progression-free survival irrespective of RECIST response categorisation to neoadjuvant chemotherapy (appendix pp 16–17). 73 (42%) of 172 women with RECIST stable disease following neoadjuvant chemotherapy had complete cytoreduction, although this percentage was significantly lower than for those with a RECIST complete or partial response (187 [56%] of 335 women]; table 4; χ2 test for stable disease vs complete or partial response, p=0.0040). 14 (48%) of 29 women with RECIST progressive disease had complete cytoreduction (table 4).

Figure 3. Landmark Kaplan-Meier estimates of progression-free survival according to RECIST response (A) and GCIG CA125 response (B).

Figure 3

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CA125=cancer antigen 125. GCIG=Gynecologic Cancer InterGroup. RECIST=Response Evaluation Criteria in Solid Tumors (version 1.1).

Table 4. Outcome of cytoreductive surgery following neoadjuvant chemotherapy according to RECIST and GCIG CA125 response.

RECIST response GCIG CA125 response
Complete response Partial response Stable disease Progressive disease Total* Yes No Total
Residual disease: 0 cm (complete/R0 resection) 15/20 (75%) 172/315 (55%) 73/172 (42%) 14/29 (48%) 274/536 (51%) 290/576 (50%) 30/101 (30%) 320/677 (47%)
Residual disease: ≤1 cm (optimal) 3/20 (15%) 77/315 (24%) 44/172 (26%) 3/29 (10%) 127/536 (24%) 145/576 (25%) 19/101 (19%) 164/677 (24%)
Residual disease: >1 cm (suboptimal) 1/20 (5%) 33/315 (10%) 24/172 (14%) 2/29 (7%) 60/536 (11%) 72/576 (13%) 10/101 (10%) 82/677 (12%)
Inoperable (open and close surgery) 0 5/315 (2%) 3/172 (2%) 0 8/536 (1%) 8/576 (1%) 2/101 (2%) 10/677 (1%)
Surgery not performed 1/20 (5%)† 28/315 (9%) 28/172 (16%) 10/29 (34%) 67/536 (13%) 61/576 (11%) 40/101 (40%) 101/677 (15%)
Surgery data missing 1 12 11 4 28 34 16 50
Total (including missing) 21 327 183 33 564 610 117 727
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Data are n/N (%; surgery data missing not included in denominator) or n. CA125=cancer antigen 125. GCIG=Gynecologic Cancer InterGroup. RECIST=Response Evaluation Criteria in Solid Tumors (version 1.1).

*

Patients with RECIST non-measurable disease were not included (n=85).

†

Reason stated by investigator as “clinical decision”.

We did a similar analysis to determine the clinical impact of CA125 response assessment before DPS. The median progression-free survival (landmark analysis) was 13·8 months (95% CI 8·8–23·4; 544 events) for women with a GCIG CA125 response and 9·7 months (5·8–14·5; 111 events) for those without (figure 3B; appendix p 13). Data on surgical outcome were available for 677 (93%) of 727 women with GCIG CA125-evaluable disease, 101 of whom did not undergo DPS (table 4). When including only those women who underwent DPS, the median progression-free survival was 14·2 months (95% CI 9·3–25·0; 490 events) for those women with a GCIG CA125 response and 10·5 months (6·6–15·6; 73 events) for those without (appendix p 18). Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and in 30 (30%) of 101 women without (table 4; χ2 test comparing GCIG CA125 response vs no response, p<0·0001). DPS was not done in 40 (40%) of 101 women who did not have a GCIG CA125 response, compared with 61 (11%) of 576 women with a GCIG CA125 response (table 4; χ2 test comparing GCIG CA125 response vs no response, p<0·0001).

To determine whether combining the outcomes from both conventional response assessment modalities would identify a patient group unlikely to benefit from DPS, the rate of complete cytoreduction in patients with RECIST stable disease was evaluated according to GCIG CA125 response (appendix p 8). No significant difference in the rate of complete cytoreduction versus all other surgical outcomes was apparent (χ2 test comparing complete cytoreduction vs all other outcomes, p=0·18). However, notably, a greater number of women with RECIST stable disease and a GCIG CA125 response underwent surgery than those with RECIST stable disease and no GCIG CA125 response (109 [90%] of 121 women vs 32 [68%] of 47 women]), thereby making it challenging to draw any meaningful clinical conclusions (appendix p 8). The persistence of ascites has been shown to affect the outcomes of ovarian cancer surgery.13 In those ICON8 patients who had ascites at the commencement of neoadjuvant chemotherapy and had the best RECIST response of stable disease, the rate of complete cytoreduction versus all other surgical outcomes did not differ significantly between those groups with persistent or resolved ascites at pre-surgical imaging (χ2 test comparing complete cytoreduction vs all other outcomes, p=0·48; appendix p 8).

All adverse events in the neoadjuvant chemotherapy followed by DPS population that occurred during neoadjuvant chemotherapy and DPS, separated according to RECIST responses, are outlined in the appendix (pp 9–12). There were no differences in adverse events in patients with RECIST complete or partial response versus those with stable disease.

The number of reported non-high-grade serous cases with RECIST and/or GCIG CA125 measurable disease was too small to make any definitive conclusion regarding the differences in treatment response between each histological subtype.

Discussion

This exploratory analysis of treatment responses to first-line platinum-based neoadjuvant chemotherapy in women with newly diagnosed FIGO stage IC–IV epithelial ovarian cancer has several key findings. First, we showed that RECIST complete or partial response following neoadjuvant chemotherapy for predominantly high-grade serous carcinoma is approximately 60%. This response rate is lower than that often quoted to patients in the clinic, but is consistent with historically reported rates from other randomised, phase 3 trials investigating first-line carboplatin–taxane chemotherapy in smaller subsets of patients with measurable disease after upfront surgery.14,15 To our knowledge, data from this study represent the first and only prospective evidence reporting RECIST responses to first-line platinum-based neoadjuvant chemotherapy in epithelial ovarian cancer.

Second, we showed that a best response of RECIST stable disease following first-line platinum-based neoadjuvant chemotherapy should not preclude DPS. Median progression-free survival was similar between women with RECIST partial response and stable disease, and complete cytoreduction was achieved in 42% of women with RECIST stable disease who underwent DPS. This finding supports the use of DPS in all women with RECIST complete response, partial response, or stable disease, and is in keeping with the treatment protocols followed in the CHORUS and EORTC 55971 trials, which did not mandate a response to neoadjuvant chemotherapy before undergoing DPS.2,3 By contrast, the geographical variation seen in surgical management practice for advanced-stage ovarian cancer outside clinical trials6,7 indicates that lack of treatment response might negatively affect the decision to proceed with DPS—a factor that might also explain, in part, the higher proportion of patients with RECIST stable disease in ICON8 not undergoing surgery compared with those with a complete or partial response.

This exploratory analysis of ICON8 also showed that GCIG CA125 criteria inadequately document response to neoadjuvant chemotherapy. Although the prognosis of women without a GCIG CA125 response to neoadjuvant chemotherapy was worse than those who had a CA125 response, almost half (49%) of those patients with non-responding disease by GCIG CA125 criteria had at least optimal cytoreduction at DPS and 30% achieved complete cytoreduction—findings that were evident even in the subgroup of patients with RECIST stable disease. Therefore, GCIG CA125 criteria should not be used in isolation to determine which patients might be appropriate for DPS.

It should be noted that to reduce bias associated with comparing outcomes in different response cohorts, this exploratory analysis used a landmark method in which progression-free survival was determined from the date of pre-surgical planning radiological tumour assessment, as opposed to the intention-to-treat primary progression-free survival analysis, in which progression-free survival was determined from time of randomisation.8 For this reason, the progression-free survival values reported in this exploratory analysis cannot be directly compared with those reported in the primary analysis and are approximately 2 months shorter.

This large evaluation in a clearly defined patient population demonstrates the difficulties in using current well defined unidimensional radiological and biochemical response surrogates to assess the therapeutic impact of neoadjuvant chemotherapy in advanced high-grade ovarian cancer. Both response criteria imperfectly predict the ability to achieve complete or optimal cytoreduction at interval surgery—a more robust surrogate for survival, or indeed progression-free survival. We recommend therefore that RECIST and CA125 assessments should not be considered as standalone measures to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient’s clinical capacity (eg, performance status and comorbidities) to undergo cytoreductive surgery. This conclusion is unsurprising given the complex, multi-site, biologically heterogeneous nature of high-grade serous carcinoma.16,17 One notable limitation to this conclusion is that we have not considered more sophisticated evaluation methods for radiological and CA125 data. More detailed analysis of the trends in CA125 during neoadjuvant chemotherapy might demonstrate a more accurate percentage change or rate of change that correlates with RECIST response or provides enhanced discrimination of surgical outcomes at DPS.18 Equally, the development of volumetric or radiomics algorithms to analyse CT data might also improve our ability to provide meaningful predictors of outcome that can guide individual treatment decisions in the clinic.19

The data reported in this study have several identifiable limitations. Treatment responses, defined through RECIST and GCIG CA125, were not a predefined secondary outcome of the ICON8 trial. Nonetheless, response evaluation data were collected prospectively, and this exploratory analysis includes 83% complete data for RECIST and 93% complete data for GCIG CA125 outcomes. Although 17% of patients who had incomplete radiological follow-up had shorter progression-free survival than those with complete radiological data, this is unlikely to bias the overall conclusions of the study. Second, 20% of cases were described as serous (no grade specified) or other, and yet neoadjuvant chemotherapy is currently most frequently used in women diagnosed with FIGO stage IIIC–IV high-grade serous carcinoma. Notably, recruitment to the trial almost entirely predated the 2014 WHO reclassification of ovarian tumours, and we expect that the majority of unknown histiotypes would now be reclassified as high-grade serous carcinoma using current immunohistochemical panels.20 Third, treatment responses in other, rarer forms of epithelial ovarian cancer (eg, low-grade serous, clear cell, or endometrioid) remain insufficiently defined by our study because of the paucity of cases of these histological subtypes. Fourth, the BRCA1/2 status of enrolled patients was unknown, and yet tumours with BRCA1/2 mutations are often highly sensitive to platinum-based chemotherapy.21,22 Thus, the overall findings of this study might not be completely applicable to BRCA-mutant tumours. When ICON8 was originally opened, universal germline and somatic BRCA1/2 testing was not performed in all patients diagnosed with epithelial ovarian cancer and was instead restricted to those women with a high risk of hereditary ovarian or breast cancer.23,24 Moreover, none of the published phase 3 trials involving neoadjuvant chemotherapy evaluated BRCA1/2 status, and so the same criticism applies to all available datasets.2–4 We also recognise that combining patients with RECIST complete or partial responses might lead to underestimation of the survival outcomes of those patients with a complete response. Nonetheless, we took this approach in an exploratory setting and focused on differentiating patients with and without a conventional radiologically defined treatment response (complete or partial response vs stable or progressive disease), and the small proportion of patients with a RECIST complete response precluded a separate analysis of this group. It is also notable that ICON8 did not involve concurrent bevacizumab therapy as part of neoadjuvant chemotherapy.25–28 Indeed, the addition of bevacizumab to first-line carboplatin–paclitaxel neoadjuvant chemotherapy for epithelial ovarian cancer might improve treatment responses further, although this hypothesis has yet to be confirmed and might be uncovered in the follow-on phase 3 trial, ICON8b (NCT01654146).29,30 Additionally, it is noteworthy that 6% of patients planned for neoadjuvant chemotherapy followed by DPS had FIGO stage IC–IIIB ovarian cancer, whereas the standard of care approach for these FIGO stages’ of disease is IPS followed by adjuvant chemotherapy.31 For accuracy, the FIGO staging for all these patients was verified by each trial site, although no specific rationale for the local multidisciplinary team decision was collected. We expect that there were patient-specific factors (eg, performance status and comorbidities), disease-specific reasons (eg, widespread miliary peritoneal disease), or logistical factors at each trial site that led to this therapeutic approach being used in these cases. Finally, we acknowledge that the histological chemotherapy response score data for FIGO stage IIIC–IV high-grade serous carcinoma have not been collected in ICON8 as the chemotherapy response score system was published after completion of recruitment into ICON8.32 Therefore, chemotherapy response score reporting was not routinely undertaken at the time of the study.

In conclusion, this large exploratory analysis provides the first robust evaluation of response using internationally recognised radiological and biochemical criteria to neoadjuvant chemotherapy in a well annotated trial population of women with advanced ovarian cancer. It demonstrates that neither response modality should be used in isolation to determine a patient’s eligibility for DPS and that surgery, with the goal of complete cytoreduction, still provides clear clinical benefit for the majority of women with RECIST stable disease after three to four cycles of neoadjuvant chemotherapy. These findings should be validated prospectively in future clinical studies investigating neoadjuvant chemotherapy treatment strategies. We recommend that BRCA1/2 mutation status, chemotherapy response score, and the presence or absence of ascites before DPS are collected in appropriate cases to improve clinical usefulness.

Supplementary Material

Sup 1

Research in context.

Evidence before the study

Before this study, three randomised, phase 3 trials—CHORUS, EORTC 55971, and JCOG 0602—had shown that survival outcomes for women diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage III–IV ovarian cancer who were treated with three to four cycles of platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) were not inferior to those in women receiving immediate primary surgery followed by platinum-based adjuvant chemotherapy. However, none of these trials evaluated Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) responses to neoadjuvant chemotherapy. We searched PubMed and clinical trial registries, up to June 1, 2020, for studies that reported the RECIST or Gynecologic Cancer InterGroup (GCIG) CA125 response to neoadjuvant chemotherapy in epithelial ovarian cancer. We used search terms including “ovarian cancer”, “primary cytoreductive surgery”, “delayed primary surgery”, “interval debulking surgery”, “neoadjuvant chemotherapy”, “pre-operative chemotherapy”, “RECIST”, and “CA125”.

No prospective clinical trials were identified. We therefore concluded that there were no robust data to counsel patients about response rates or data to guide clinicians about proceeding with DPS based on RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer.

Added value of the study

In the international, multicentre, randomised, phase 3 ICON8 trial, 779 patients diagnosed with FIGO (1988) stage IC–IV epithelial ovarian cancer entered the trial with a plan to receive neoadjuvant chemotherapy followed by DPS. In these patients, RECIST and GCIG CA125 responses to neoadjuvant chemotherapy were gathered prospectively, allowing us to carry out a post-hoc exploratory analysis and report RECIST complete or partial responses and GCIG CA125 response rate following platinum-based neoadjuvant chemotherapy in predominantly FIGO stage III–IV high-grade serous carcinoma. Additionally, we were able to demonstrate that median progression-free survival was similar for women with RECIST complete or partial response and those with RECIST stable disease following platinum-based neoadjuvant chemotherapy.

Implications of all the available evidence

The data from the CHORUS, EORTC 55971, and JCOG 0602 trials, as well as this post-hoc exploratory analysis of ICON8, provide robust evidence that women diagnosed with FIGO stage III–IV epithelial ovarian cancer who are treated with platinum-based neoadjuvant chemotherapy should be considered for DPS even if they only have RECIST stable disease. Moreover, this post-hoc exploratory analysis of ICON8 demonstrates that neither RECIST nor GCIG CA125 response should be used in isolation to identify patients who are likely to benefit from DPS.

Acknowledgments

The trial was publicly funded by Cancer Research UK (CRUK) through the CRUK Clinical Trials Awards and Advisory Committee (C1489/A12127 and CA1489/A17092) and was supported by UK Medical Research Council core funding. The trial was also funded by the Irish Health Research Board, Irish Cancer Society, and Cancer Australia. The Medical Research Council was the trial sponsor and has delegated responsibility for the overall management of the ICON8 Trials Programme to the Medical Research Council Clinical Trials Unit at University College London (UK). The trial was part of the UK National Cancer Research Network portfolio. We acknowledge Experimental Cancer Medicine Centres and National Institute for Health Research Biomedical Research Centres for support at ICON8 centres in the UK. We thank all the women who participated in ICON8 and their families.

Funding

Cancer Research UK, UK Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Footnotes

Contributors

ARC, IAM, ECJ, J-WK, and JAL led and coordinated the main ICON8 study design. ARC, IAM, ECJ, ADC, J-WK, and JAL are members of the trial management group. IAM, RL, GD, RMG, JK, CP, CJP, MH, DG-R, ML, SE, JS, AA, AZ, SW, RJ, KS, AW, J-WK, SS, GCJ, JAL, and ARC contributed to recruitment and data collection in ICON8. For this exploratory analysis of ICON8, RDM, IAM, ADC, ECJ, and ARC analysed the data, which were interpreted by all co-authors. RDM, IAM, ADC, ECJ, and ARC drafted this manuscript, and the final version was approved by all co-authors.

Declaration of interests

RDM declares personal fees and travel expenses from AstraZeneca, outside the submitted work. IAM declares personal fees from Carrick Therapeutics, Clovis Oncology, Roche, Scancell, and Tesaro, and personal fees and grants from AstraZeneca, outside the submitted work.

RJ declares personal fees from Amgen, and personal fees and travel expenses from AstraZeneca, Clovis Oncology, and Tesaro, outside the submitted work. ML declares personal fees from Roche, outside the submitted work. AW declares personal fees from AstraZeneca and Roche, and personal fees and travel expenses from Tesaro, outside the submitted work. RMG declares personal fees from AstraZeneca, Clovis, GSK/Tesaro, Immunogen, and Sotio; travel or conference registration fees from AstraZeneca and GSK; and grants from Boehringer Ingelheim and Lilly/Ignyta, outside the submitted work. RMG is also a principal investigator for trials sponsored by AstraZeneca, GSK, Pfizer, Lilly, and Immunogen, outside the submitted work. SW declares personal fees and travel expenses from AstraZeneca, Clovis Oncology, and GSK, outside the submitted work. KS declares conference fees from GSK, outside the submitted work. ARC declares personal fees for AstraZeneca, Clovis Oncology, and GSK; research funding from AstraZeneca; and travel expenses from Clovis Oncology and Tesaro, outside the submitted work. All other authors declare no competing interests.

Contributor Information

Robert D Morgan, The Christie NHS Foundation Trust and University of Manchester, Manchester, UK.

Adrian D Cook, Medical Research Council Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.

Elizabeth C James, Medical Research Council Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.

Rosemary Lord, The Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, UK.

Graham Dark, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Rosalind M Glasspool, Beatson West of Scotland Cancer Centre, Glasgow, UK.

Jonathan Krell, Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.

Christine Parkinson, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Christopher J Poole, Arden Cancer Research Centre, University Hospital Coventry and Warwickshire NHS Trust, Coventry, UK.

Marcia Hall, Mount Vernon Cancer Centre, Northwood, UK.

Dolores Gallardo-Rincón, Instituto Nacional de Cancerología, Mexico City, Mexico.

Michelle Lockley, St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK.

Sharadah Essapen, Royal Surrey NHS Foundation Trust, Guildford, UK.

Jeff Summers, Maidstone and Tunbridge Wells NHS Trust, Kent, UK.

Anjana Anand, Nottingham University Hospitals NHS Trust, Nottingham, UK.

Abel Zachariah, Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK.

Sarah Williams, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

Rachel Jones, South West Wales Cancer Centre, Singleton Hospital, Swansea, UK.

Kate Scatchard, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

Axel Walther, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.

Jae-Weon Kim, Seoul National University College of Medicine, Seoul, South Korea.

Sudha Sundar, Pan Birmingham Gynaecological Cancer Centre and University of Birmingham, Birmingham, UK.

Gordon C Jayson, The Christie NHS Foundation Trust and University of Manchester, Manchester, UK.

Jonathan A Ledermann, UCL Hospitals NHS Foundation Trust and UCL Cancer Institute, London, UK.

Andrew R Clamp, The Christie NHS Foundation Trust and University of Manchester, Manchester, UK.

Data sharing

Data will be shared according to the Medical Research Council Clinical Trials Unit controlled access approach, based on the following principles: no data should be released that would compromise an ongoing trial or study; there must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose; investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers; the resources required to process requests should not be underestimated, particularly successful requests that lead to preparing data for release, and thus adequate resources must be available to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources; and data exchange complies with Information Governance and Data Security Policies in all the relevant countries. Researchers wishing to access data from the ICON8 should contact mrcctu.icon8and8b@ucl.ac.uk in the first instance.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Sup 1
EMS177350-supplement-Sup_1.pdf (756.5KB, pdf)

Data Availability Statement

Data will be shared according to the Medical Research Council Clinical Trials Unit controlled access approach, based on the following principles: no data should be released that would compromise an ongoing trial or study; there must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose; investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers; the resources required to process requests should not be underestimated, particularly successful requests that lead to preparing data for release, and thus adequate resources must be available to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources; and data exchange complies with Information Governance and Data Security Policies in all the relevant countries. Researchers wishing to access data from the ICON8 should contact mrcctu.icon8and8b@ucl.ac.uk in the first instance.

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