Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.

Malignant bowel obstruction: effectiveness and safety of systemic chemotherapy.

OBJECTIVES: Although systemic chemotherapy is often administered to patients with malignant bowel obstruction (MBO), its benefit remains unknown. This study assessed the outcomes of patients who received systemic chemotherapy as part of MBO treatment. METHODS: For this retrospective cohort study, data were extracted from records of patients hospitalised due to MBO in a tertiary cancer centre from 2008 to 2020. Eligible patients were not candidates for surgery and received systemic chemotherapy targeting the underlying malignancy causing MBO. Primary objective was to assess patient outcomes after chemotherapy; secondary objectives were rates of intestinal function recovery, hospital discharge and grade ≥3 toxicities. The primary endpoint was overall survival (OS). RESULTS: A total of 167 patients were included: median age was 55 (18-81) years, 91% had an Eastern Cooperative Oncology Group (ECOG) performance status ≥2, 75.5% had gastrointestinal tumours and 70% were treatment-naive. The median OS after chemotherapy was 4.4 weeks (95% CI 3.4 to 5.5) in the overall population. No OS difference was observed according to treatment line (p=0.24) or primary tumour (p=0.13). Intestinal function recovery occurred in 87 patients (52%), out of whom 21 (24.1%) had a reobstruction. Hospital discharge was possible in 74 patients (44.3%). Grade≥3 adverse events occurred in 26.9% of the patients, and a total of 12 deaths (7%) attributed to toxicities were observed after chemotherapy. CONCLUSIONS: MBO was associated with a dismal prognosis in this mostly treatment-naive population. The administration of chemotherapy yielded a significant risk of toxicities, whereas it did not appear to provide any relevant survival benefit in this scenario.

Carboplatin-based chemoradiotherapy in advanced cervical cancer: an alternative to cisplatin-based regimen?

OBJECTIVE: To evaluate the results of treatment with cisplatin or carboplatin concomitant with radiotherapy (RT) in cases of locally advanced cervical cancer (CC). METHODS: This study is a retrospective analysis of medical records of 184 patients with cervical cancer stage IIB-IVA who were treated at Instituto do Câncer do Estado de São Paulo from May 2008 to December 2012. All patients received complete pelvic region external-beam RT with weekly cisplatin (cis-RT, 40mg/m(2); n=159) or carboplatin (carbo-RT, AUC 2; n=25), followed by high-dose-rate intracavitary brachytherapy (HDR-ICBT). Primary endpoint was progression free survival; secondary endpoints were overall survival and overall response rate, which includes complete and partial responses. RESULTS: Five or more chemotherapy cycles were administered to 87.3% and 84% of the cis-RT- and carbo-RT- treated patients, respectively (p=0.749). Estimated 3-years progression free survival was 59% in the cis-RT group vs 40% in the carbo-RT group (p=0.249). Estimated 3-years overall survival was 70% in the cis-RT group vs 68% in the carbo-RT group (p=0.298). Overall response rate (95.3% cis-RT vs 95.4% carbo-RT; p=0.911) and grade ≥3 toxic effects (8.5% cis-RT vs 11.8% carbo-RT; p=0.757) were similar. In multivariate analysis, only the overall response rate was a significant predictor of survival. CONCLUSIONS: Patients with advanced cervical cancer who are treated with carbo-RT have similar 3-years overall survival, progression free survival, overall response rate, and toxic effects when compared to cis-RT-treated patients. Carbo-RT may be an alternative treatment in patients that cannot receive cisplatin.

Neoadjuvant chemotherapy with six cycles of carboplatin and paclitaxel in advanced ovarian cancer patients unsuitable for primary surgery: Safety and effectiveness.

OBJECTIVE: Three cycles of neoadjuvant chemotherapy (NACT) followed by interval debulking (ID) surgery is an alternative for patients with advanced ovarian cancer unresectable disease. This study aimed to determine the efficacy and safety of six cycles of NACT followed by cytoreduction. METHODS: Retrospective analysis of all patients with advanced epithelial ovarian cancer, tubal carcinoma, or primary peritoneal carcinoma treated with platinum based NACT between January 2008 and February 2012. RESULTS: Eighty-two patients underwent NACT; 78% and 18.2% had extensive stage IIIC or IV disease at diagnosis, respectively. Their median age was 60 years (41-82). On histology, serous adenocarcinoma was found in 90.2%. Patients did not receive chemotherapy after debulking surgery. 35.4% suffered grade 3/4 toxicity; the most commonly observed toxicities were hematologic and nausea. After NACT, 23.1% experienced clinical complete response, 57.4% partial response, and 12.1% disease progression. Complete resection of all macroscopic and microscopic disease (R0) was performed in 63.7%. Surgical complications were uncommon; however, four (6.2%) patients needed a second procedure due to operative complications and 18 (27.3%) needed blood transfusion after debulking. Over a median follow-up period of 19.2 months, median overall survival and chemotherapy-free interval were 37.5 months (confidence interval not reached) and 16 months, respectively. CONCLUSION: Six cycles of neoadjuvant carboplatin and paclitaxel was safe and effective and did not increase perioperative or postoperative complications in patients with stage IIIC/IV disease who were unsuitable for optimal PDS. The overall survival of this cohort was higher than that of those treated with ID surgery.