Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial.

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.

Targeting PD-1/PD-L1 in biliary tract cancer: role and available data.

There is a critical need for novel therapies to treat patients with advanced biliary tract cancer (BTC). This systematic review summarizes the evidence-based knowledge for the potential role of PD-1 and PD-L1 monoclonal antibodies in the treatment of patients with early-stage and advanced BTC. An Embase database search was conducted, identifying 15 eligible phase II/III clinical trials for review. Results from recent phase III trials show a statistically significant overall survival (OS) benefit from the addition of PD-1/PD-L1 inhibitors to chemotherapy in the first-line management of advanced BTC. Future research should concentrate on the discovery of biomarkers to identify patients who would benefit most from these therapies.

The majority of patients with biliary tract cancer (BTC) present with advanced disease (disease that has spread) that cannot be cured. The current mainstay of treatment for advanced BTC is chemotherapy, which aims to prolong life expectancy to just under 12 months. The need for new, more effective treatments for advanced BTC is crucial. This systematic review summarizes the most recent clinical trials that have tested the use of newer drugs called immunotherapy (PD-1 and PD-L1 monoclonal antibodies) in the treatment of both early-stage and advanced BTC. Fifteen clinical trials have been included, each testing different immunotherapy drugs either alone or in combination with other anti-cancer treatments. Promising results from larger trials, have given hope for longer survival in patients with advanced BTC when treated with immunotherapy plus chemotherapy as their first-line treatment after diagnosis. However, further investigation is required to determine whether certain patients might benefit more than others and if immunotherapy drugs can also be given to patients at an earlier or later stage of their disease.

Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial.

PURPOSE: A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown. PATIENTS AND METHODS: Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies. RESULTS: Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy. CONCLUSIONS: A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious. See related commentary by Gonzalez-Ochoa and Oza, p. 2563.

Psychosexual Morbidity in Women With Ovarian Cancer: Evaluation by Germline BRCA Gene Mutational Status.

INTRODUCTION: Up to 75% of women with ovarian cancer experience psychosexual morbidity and approximately 15-20% of women with ovarian cancer have a germline BRCA1/2 mutation (gBRCAm). However, psychosexual morbidity remains unexplored in women with gBRCAm ovarian cancer. AIM: Given their younger age, genetic diagnosis, breast cancer risk, and increased prevalence of surgically-induced menopause, we aim to assess whether women with gBRCAm ovarian cancer experience distinct psychosexual morbidity. METHODS: Psychosexual morbidity was investigated in 2 cohorts of women with ovarian cancer: women with gBRCAm ovarian cancer vs women with gBRCA wildtype (gBRCAwt) ovarian cancer. Between August 2019 and March 2020, women with high-grade serous carcinoma of the ovary, Fallopian tube or primary peritoneum were approached in clinic or telephoned and invited to take part. Exclusion criteria included: women with alternative histology; women admitted from clinic; and women who lacked capacity to independently complete the questionnaire. The Female Sexual Function Index (FSFI) and background information were collected at a single time-point per patient. Scores below 26.55 were interpreted to suggest psychosexual dysfunction. MAIN OUTCOME MEASURE: Responses including total and domain FSFI scores, self-reported psychosexual problems and interest in psychosexual support were compared. RESULTS: Of 103 women approached, 53% returned questionnaires. In this exploratory analysis, women with gBRCAm ovarian cancer were significantly younger (51-60 years vs 61-70 years, gBRCAwt, P = .010). There was a trend towards increased prevalence of surgical menopause (57% vs 27%, P = .097) and breast surgery (53% vs 22%, P = .132, gBRCAm vs gBRCAwt, respectively). Women with gBRCAm ovarian cancer scored higher in the FSFI questionnaire, particularly women under 60 years (15.1 vs 2.7, P = .070), approaching significance. Women with gBRCAm ovarian cancer expressed more interest for face-to-face services (P = .018), especially psychosexual therapy (65% vs 30%) and more often felt the service was insufficient, approaching significance (71% vs 44%, gBRCAm vs gBRCAwt, respectively, P = .076). CONCLUSION: Women with gBRCAm ovarian cancer are younger, express more interest for specialist psychosexual support and potentially different psychosexual problems, warranting further exploration. Logue C, Pugh J, Foden P, et al., Psychosexual Morbidity in Women With Ovarian Cancer: Evaluation by Germline BRCA Gene Mutational Status. Sex Med 2022;10:100465.

Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study.

BACKGROUND: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. METHODS: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025). CONCLUSIONS: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

First-Line Management of Advanced High-Grade Serous Ovarian Cancer.

PURPOSE OF REVIEW: Epithelial ovarian cancer is a disease that encompasses a number of histologically and molecularly distinct entities; the most prevalent subtype being high-grade serous (HGS) carcinoma. Standard first-line treatment of advanced HGS carcinoma includes cytoreductive surgery plus intravenous paclitaxel/platinum-based chemotherapy. Despite excellent responses to initial treatment, the majority of patients develop recurrent disease within 3 years. The introduction of the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, and poly(ADP-ribose) polymerase (PARP) inhibitors into first-line management has changed the outlook for this lethal disease. In this review, we summarise the most recent clinical trials that determine current primary therapy of advanced HGS carcinoma and the ongoing trials that aim to change management in the future. RECENT FINDINGS: Recent phase III clinical trials have shown that delayed primary surgery after completing neo-adjuvant chemotherapy is non-inferior to immediate primary surgery, but could provide a survival benefit in FIGO (International Federation of Gynecology and Obstetrics) stage IV disease. The use of weekly intravenous chemotherapy regimens has not been proven to be more effective than standard 3-weekly regimens in Western patient populations, and the use of intraperitoneal chemotherapy remains controversial in the first-line setting. In contrast, newer systemic anti-cancer therapies targeting angiogenesis and/or HR-deficient tumours have been successfully incorporated into front-line therapeutic regimens to treat HGS carcinoma. Recent results from randomised trials investigating the use of PARP inhibitors as monotherapy and in combination with the anti-angiogenic agent, bevacizumab, have demonstrated highly impressive efficacy when combined with traditional first-line multi-modality therapy. Management of HGS carcinoma is evolving, but further work is still required to optimise and integrate tumour and plasma biomarkers to exploit the potential of these highly efficacious targeted agents.