Using serum CA125 to assess the activity of potential cytostatic agents in ovarian cancer

Objective: New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis. Methods: Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10. Results: From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0I0149 and 0I0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0I001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56. Conclusions: Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer.Peer reviewedFinal Accepted Versio

Combined direct hysteroscopic and real-time ultrasound guidance facilitating safe insertion of intra-uterine brachytherapy applicator for locally advanced cervical cancer with significant endocervical stenosis: A novel collaborative approach

Locally advanced cervical cancer is treated with combined chemoradiation (CCRT) – with the radiotherapy component comprising delivery of both external beam (EBRT) and intra-uterine brachytherapy (IUBT). Following initial pelvic and tumour irradiation via EBRT, secondary tissue fibrosis can obliterate the vagina and / or endocervical canal. 30–88% of women will develop some degree of stenosis, with complete stenosis reported in up to 11% of patients – making accessing the uterine cavity to insert brachytherapy applicators challenging and high risk (Bran et al., 2006). This can result in inadvertent uterine perforation, occurring in 2–10% of cases (Irvin et al., 2002); with subsequent abandonment of both the procedure and proceeding to IUBT to complete treatment. Omission of IUBT confers an at least 10% reduction in overall survival (Karlsson et al., 2017).Whilst ultrasound-guided insertion has been previously described (Van Dyk et al., 2021), we present a surgical video demonstrating a novel technique. We instead utilise a combination of both real-time ultrasound and direct hysteroscopic guidance to achieve successful IUBT applicator insertion following CCRT in a patient with stage IIa1 SCC cervix and previous failed insertion attempt due to complete stenosis of the endocervical canal. We demonstrate how post-radiation changes can be safely navigated – avoiding morbidity from procedural complications and ensuring successful outcome.Our case supports a collaborative approach to complex gynaecological cancer cases; with the combined skills of the oncology, radiology and surgical teams maximising patient safety – and optimising oncological treatment. Use of portable hand-held hysteroscopic devices would increase the feasibility of replicating our described technique in brachytherapy suites, mitigating need for theatre capacity; with MDT discussion central to the planning and staffing of cases

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

Acknowledgements: We thank the patients, and the families and friends who supported them, for participating in this trial; our ethics committee, our independent data and safety monitoring committee and the trial management group for their advisory roles; the PARTNER trial consortium members, past and present (Supplementary Information); and I. Cizaite for preparing and proofreading the manuscript. This trial was sponsored by Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, and financed by a project grant from AstraZeneca, who also supplied olaparib. Cancer Research UK provided peer review and endorsement for the study and financed the sample collections for the translational studies, which will be reported separately. We also acknowledge the National Institute for Health and Care Research Cambridge Biomedical Research Centre and the Cancer Research UK Cambridge Centre for their financial support for staff and infrastructure costs. The funders had no role in data collection or analysis. Once the trial group had interpreted the data, the results were then shared with the AstraZeneca scientists. In addition, we thank the Cancer Molecular Diagnostics Laboratory and The Precision Breast Cancer Institute Team for their support for sample collection; Cambridge Tissue Bank (NIHR203312) for sample assessment and diagnostics; Cambridge Clinical Trials Centre – Cancer Theme for their core staff support; the clinical trials support staff at all participating sites; and Addenbrookes Charitable Trust for financing the post of the chief investigator (2015–2018). We acknowledge Cancer Research UK (CRUKE/14/048) and AstraZeneca (1994-A093777).PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576

Quality of life after breast-conserving therapy and adjuvant radiotherapy for non-low-risk ductal carcinoma in situ (BIG 3-07/TROG 07.01): 2-year results of a randomised, controlled, phase 3 trial

BackgroundBIG 3-07/TROG 07.01 is an international, multicentre, randomised, controlled, phase 3 trial evaluating tumour bed boost and hypofractionation in patients with non-low-risk ductal carcinoma in situ following breast-conserving surgery and whole breast radiotherapy. Here, we report the effects of diagnosis and treatment on health-related quality of life (HRQOL) at 2 years.MethodsThe BIG 3-07/TROG 07.01 trial is ongoing at 118 hospitals in 11 countries. Women aged 18 years or older with completely excised non-low-risk ductal carcinoma in situ were randomly assigned, by use of a minimisation algorithm, to tumour bed boost or no tumour bed boost, following conventional whole breast radiotherapy or hypofractionated whole breast radiotherapy using one of three randomisation categories. Category A was a 4-arm randomisation of tumour bed boost versus no boost following conventional whole breast radiotherapy (50 Gy in 25 fractions over 5 weeks) versus hypofractionated whole breast radiotherapy (42·5 Gy in 16 fractions over 3·5 weeks). Category B was a 2-arm randomisation between tumour bed boost versus no boost following conventional whole breast radiotherapy, and category C was a 2-arm randomisation between tumour bed boost versus no boost following hypofractionated whole breast radiotherapy. Stratification factors were age at diagnosis, planned endocrine therapy, and treating centre. The primary endpoint, time to local recurrence, will be reported when participants have completed 5 years of follow-up. The HRQOL statistical analysis plan prespecified eight aspects of HRQOL, assessed by four questionnaires at baseline, end of treatment, and at 6, 12, and 24 months after radiotherapy: fatigue and physical functioning (EORTC QLQ-C30); cosmetic status, breast-specific symptoms, arm and shoulder functional status (Breast Cancer Treatment Outcome Scale); body image and sexuality (Body Image Scale); and perceived risk of invasive breast cancer (Cancer Worry Scale and a study-specific question). For each of these measures, tumour bed boost was compared with no boost, and conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy, by use of generalised estimating equation models. Analyses were by intention to treat, with Hochberg adjustment for multiple testing. This trial is registered with ClinicalTrials.gov, NCT00470236.FindingsBetween June 1, 2007, and Aug 14, 2013, 1208 women were enrolled and randomly assigned to receive no tumour bed boost (n=605) or tumour bed boost (n=603). 396 of 1208 women were assigned to category A: conventional whole breast radiotherapy with tumour bed boost (n=100) or no boost (n=98), or to hypofractionated whole breast radiotherapy with tumour bed boost (n=98) or no boost (n=100). 447 were assigned to category B: conventional whole breast radiotherapy with tumour bed boost (n=223) or no boost (n=224). 365 were assigned to category C: hypofractionated whole breast radiotherapy with tumour bed boost (n=182) or no boost (n=183). All patients were followed up at 2 years for the HRQOL analysis. 1098 (91%) of 1208 patients received their allocated treatment, and most completed their scheduled HRQOL assessments (1147 [95%] of 1208 at baseline; 988 [87%] of 1141 at 2 years). Cosmetic status was worse with tumour bed boost than with no boost across all timepoints (difference 0·10 [95% CI 0·05–0·15], global p=0·00014, Hochberg-adjusted p=0·0016); at the end of treatment, the estimated difference between tumour bed boost and no boost was 0·13 (95% CI 0·06–0·20; p=0·00021), persisting at 24 months (0·13 [0·06–0·20]; p=0·00021). Arm and shoulder function was also adversely affected by tumour bed boost across all timepoints (0·08 [95% CI 0·03–0·13], global p=0·0033, Hochberg adjusted p=0·045); the difference between tumour bed boost and no boost at the end of treatment was 0·08 (0·01 to 0·15, p=0·021), and did not persist at 24 months (0·04 [–0·03 to 0·11], p=0·29). None of the other six prespecified aspects of HRQOL differed significantly after adjustment for multiple testing. Conventional whole breast radiotherapy was associated with worse body image than hypofractionated whole breast radiotherapy at the end of treatment (difference –1·10 [95% CI –1·79 to –0·42], p=0·0016). No significant differences were reported in the other PROs between conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy.InterpretationTumour bed boost was associated with persistent adverse effects on cosmetic status and arm and shoulder functional status, which might inform shared decision making while local recurrence analysis is pending