Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial.

BACKGROUND: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy. METHODS: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50-74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032. FINDINGS: 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04-13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4-13·0; p=0·042) at 18 years (21% [95% CI 15·6-26·2] vs 14% [95% CI 10·5-17·4]). INTERPRETATION: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer. FUNDING: National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal

First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence

Four large randomised trials of paclitaxel in combination with platinum against a platinum-based control treatment have now been published in full, representing around 88% (3588 out of 4057) of patients randomised into the eight known trials of this question. There is substantial heterogeneity in the results of these four trials. Four main explanations for this heterogeneity have been proposed: differences in the extent and timing of ‘crossover’ to taxanes in the control groups; differences in the types of patient included; differences in the effectiveness of the research regimens used; differences in the effectiveness of the control regimens used. In this study we examine whether any of these explanations is consistent with the pattern of results seen in these trials. Each explanation suggests that a particular characteristic of each trial was responsible for the results observed. For each explanation the trials were split into groups according to that characteristic, in order to partition the total heterogeneity into that seen ‘within’ and ‘between’ groups of trials. If a particular explanation was consistent with the pattern of results, we would expect to see relatively little heterogeneity within each group of trial results viewed in this way, with most of the heterogeneity being between groups which are dissimilar with respect to the key characteristic. Heterogeneity ‘within’ and ‘between’ groups was formally compared using the F-ratio. If any explanation appeared to be consistent with the results of the trials, it was considered whether the explanation was also consistent with other evidence available about these regimens. Only one explanation appeared to be consistent with the pattern of results seen in these trials, and that was differences in effectiveness of the control arms used in these trials. This suggests that the very positive results in favour of paclitaxel/cisplatin seen in two of the trials may have been due to the use of a suboptimal control arm. There is no direct evidence about the relative effectiveness of the control arms used in these trials, but indirect evidence is consistent with the conclusion that the cyclophosphamide/cisplatin regimen used in two of the trials may be less effective than the control regimens used in the other trials. Specific concerns about the choice of a cyclophosphamide/cisplatin control arm in the first of these trials to report were raised before the results of the other trials were known, i.e. before any heterogeneity had been observed. Further investigation of this question would be useful. In the meantime, given all of the randomised evidence on the efficacy and toxicity associated with the regimens used in these trials, we conclude that single agent carboplatin is a safe and effective first-line treatment for women with advanced ovarian cancer

Randomised controlled trial comparing single agent paclitaxel vs epidoxorubicin plus paclitaxel in patients with advanced ovarian cancer in early progression after platinum-based chemotherapy: an Italian Collaborative Study from the ‘Mario Negri’ Institute, Milan, G.O.N.O. (Gruppo Oncologico Nord Ovest) group and I.O.R. (Istituto Oncologico Romagnolo) group

The aim of the study was to evaluate the role of epidoxorubicin plus paclitaxel combination (ET) vs single agent paclitaxel (T), as second-line chemotherapy treatment in advanced ovarian cancer patients in early progression within 12 months after platinum-based chemotherapy. From October 1994 up to June 1999, 234 patients from 34 Italian hospitals were randomised to receive: (A) epidoxorubicin (E) 80 mg m(-2) + paclitaxel (T) 175 mg m(-2) (3 h infusion), every 21 days for 4-6 cycles. (B) Paclitaxel 175 mg m(-2) (3 h infusion) every 21 days for 4-6 cycles. Evaluable for survival analysis were 106 and 106 patients in ET and T arm, respectively. Platinum-based monochemotherapy was the first-line treatment in 43% patients, while polichemotherapy containing anthracyclines was the preferred first-line therapy in 22% patients. The median time from the end of first-line therapy to randomisation was 3 months. Treatment was completed in 87 and 85% of T and ET arm, respectively. Haematological toxicity was significantly more common in ET group (ECOG grade 3-4 neutropenia: 37.4% in ET vs 18.2% in T arm). Neuropathies were similar in both arms (sensory: ECOG grade 2-3: 12.1% in ET vs 14.7% in T arm, motor: 6.1% in ET vs 5.3% in T arm). Objective response was achieved in 37.4% of patients in ET group and in 46.9% of patients in T arm. At a median follow-up of time of 48 months, a total of 180 patients progressed and 163 patients died. Survival analysis showed no difference between ET and T (median time to progression: 6 months for both regimens, median survival: 12 and 14 months for ET and T, respectively; hazard ratio for mortality of ET vs T: 1.17 (95% CI 0.86-1.59; P=0.33). The ET regimen does not seem to be more effective than T in refractory advanced ovarian cancer patients in early progression after platinum-based chemotherapy. Despite an acceptable response rate, the control of disease progression remains poor

Advanced epithelial ovarian cancer: 1998 consensus statements

Background: During an international workshop held in September 1998, a group of specialists in the field of ovarian cancer reached consensus on a number of issues with implications for standard practice and for research of advanced epithelial ovarian cancer. Methods: Five groups of experts considered several issues which included: biologic factors, prognostic factors, surgery, initial chemotherapy, second-line treatment, the use of CA 125, investigational drugs, intra-peritoneal treatment and high-dose chemotherapy. The group attempted to arrive at answers to questions such as: Are there prognostic factors, which help to identify patients who will not do well with current therapy? What is the current best therapy for advanced ovarian carcinoma? What directions should research take in advanced ovarian cancer? These issues were discussed in a plenary meeting. Results: One of the major conclusions drawn by the consensus committee was that in previously untreated advanced ovarian cancer, cisplatin plus paclitaxel has been shown to be superior to previous standard therapy with cisplatin plus cyclophosphamide (level I evidence). However, for many patients, carboplatin plus paclitaxel is a reasonable alternative because of toxicity and convenience considerations. Most participants felt that the benefits in terms of toxicity for the paclitaxel-carboplatin are such that its widespread adoption at this stage is justified. Until mature survival data are available a minority of investigators would recommend continued use of cisplatin plus paclitaxel, specifically for those patients with advanced disease with the best prognostic characteristics. For future clinical research in this area, new end points for randomised clinical trials, together with a new Trials Network, are proposed