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Abstract
Objective Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction.
Methods A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3–5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival.
Results Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3–5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85–100%; n=29) and for cediranib 88% (IQR 76–93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4–11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1–20.4 months; n=17). Median follow-up was 12.4 months (8.9–not reached; n=17).
Conclusions The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated.
Trial registration number EudraCT 2016-004618-93
- Ovarian Cancer
Data availability statement
Data are available upon reasonable request.
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Data availability statement
Data are available upon reasonable request.
Footnotes
Presented at The data in this manuscript were presented at the 2022 European Congress of Gynaecological Oncology.
Contributors GCJ, CZ, and ARC designed the study. AW, AI, and RR were responsible for project management. AI, AW, AM, RDM, SK, JP, CW, VR, GA, ZS, JH, CM, RDM, ARC, and GCJ collected data. CP and AC analyzed the data. CZ analyzed post hoc data. CP, AM, AC, CZ, RDM, ARC, and GCJ interpreted the data, and wrote the manuscript. CP and AC had access to the raw data.
Funding The trial was sponsored by the University of Manchester and coordinated by Cardiff University Centre for Trials Research. The trial was funded by Astrazeneca, who also provided the investigational medicinal products (cediranib and olaparib). Astrazeneca had no role in designing the study, data collection, data analysis, interpretation of the results, writing of the statistical analysis final report, or the final decision to submit the manuscript.
Competing interests ARC and GCJ have received research funding for this and other investigator initiated studies from AstraZeneca. RDM is supported by a National Institute for Health Research Clinical Lectureship (CL-2022-06-002).
Provenance and peer review Not commissioned; externally peer reviewed.
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