Results of a randomised Phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer.

BACKGROUND: OCTOVA compared the efficacy of olaparib (O) versus weekly paclitaxel (wP) or olaparib + cediranib (O + C) in recurrent ovarian cancer (OC). AIMS: The main aim of the OCTOVA trial was to determine the progression-free survival (PFS) of olaparib (O) versus the oral combination of olaparib plus cediranib (O + C) and weekly paclitaxel (wP) in recurrent ovarian cancer (OC). METHODS: In total, 139 participants who had relapsed within 12 months of platinum therapy were randomised to O (300 mg twice daily), wP (80 mg/m2 d1,8,15, q28) or O + C (300 mg twice daily/20 mg daily, respectively). The primary endpoint was progression-free survival (PFS) of olaparib (O) versus olaparib plus cediranib (O + C) or weekly paclitaxel (wP). The sample size was calculated to observe a PFS hazard ratio (HR) 0.64 in favour of O + C compared to O (20% one-sided type I error, 80% power). RESULTS: The majority had platinum-resistant disease (90%), 22% prior PARPi, 34% prior anti-angiogenic therapy, 30% germline BRCA1/2 mutations. The PFS was increased for O + C vs O (O + C 5.4 mo (2.3, 9.6): O 3.7 mo (1.8, 7.6) HR = 0.73; 60% CI: 0.59, 0.89; P = 0.1) and no different between wP and O (wP 3.9 m (1.9, 9.1); O 3.7 mo (1.8, 7.6) HR = 0.89, 60% CI: 0.72, 1.09; P = 0.69). The main treatment-related adverse events included manageable diarrhoea (4% Grade 3) and hypertension (4% Grade 3) in the O + C arm. DISCUSSION: OCTOVA demonstrated the activity of O + C in women with recurrent disease, offering a potential non-chemotherapy option. TRIAL REGISTRATION: ISRCTN14784018, registered on 19th January 2018 http://www.isrctn.com/ISRCTN14784018 .

The clinicopathological characteristics and survival outcomes of primary expansile vs. infiltrative mucinous ovarian adenocarcinoma: a retrospective study sharing the experience of a tertiary centre.

Background: Mucinous ovarian carcinomas (MOCs) are rare ovarian tumours accounting for 3% of all epithelial ovarian carcinomas (EOCs). They are either expansile or infiltrative, based on the tumour's histological pattern of invasion. MOCs have a distinct molecular profile, natural history, chemo-sensitivity, and prognosis compared to other EOCs. The aim of this study was to describe patient and tumour characteristics, as well as survival outcomes of expansile and infiltrative primary MOCs. Methods: This was a retrospective cohort study conducted at a tertiary cancer centre. Patients had surgery for primary MOC between Jul 1, 2010 and Oct 28, 2022. All patients discussed at the Oxford multidisciplinary team (MDT) meeting with a diagnosis of MOC were included. We excluded patients with mucinous metastatic carcinoma (MMC), dual histological diagnoses, those who died before treatment was initiated, and patients with incomplete records. Results: A total of 47 patients were identified and 14 were excluded. Out of the remaining 33 MOCs, 23 (70.6%) were expansile and 10 (30.4%) were infiltrative. The median follow-up was 37 months (95% CI: 14.1-69.8). Patients with infiltrative tumours were older than those with expansile tumours (median age 62 vs. 55 years, P=0.049). Infiltrative tumours were diagnosed at a more advanced International Federation of Gynaecology and Obstetrics (FIGO) stage compared to expansile tumours: FIGO stage II/III 50% vs. 8.2% (P=0.002). We found paired-box gene 8 (PAX8) more frequently expressed in expansile tumours (75% vs. 37.5%, P=0.099). Adjuvant treatment was administered in 50% of patients with infiltrative disease, compared to only 13% of those with expansile disease (P=0.036). 80% of patients who have relapsed had received adjuvant chemotherapy, compared to 17.2% of patients without relapse (P=0.012). At 3 years, there was a statistically significant difference in progression-free survival (PFS) (94.7% vs. 65.6%, P=0.02) between the expansile and infiltrative groups, but no difference in overall survival (OS) (88.8% vs. 90%, P=0.875). Conclusions: Patients with infiltrative tumours were older, more likely to have bilateral tumours and more likely to have an advanced FIGO stage at diagnosis. Adjuvant treatment was more likely to be administered to patients with infiltrative tumours, however, this did not prevent relapse. PFS at 3 years was significantly higher in patients with expansile tumours. PAX8 was more frequently expressed by expansile tumours.

A population-scale temporal case-control evaluation of COVID-19 disease phenotype and related outcome rates in patients with cancer in England (UKCCP).

Patients with cancer are at increased risk of hospitalisation and mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the SARS-CoV-2 phenotype evolution in patients with cancer since 2020 has not previously been described. We therefore evaluated SARS-CoV-2 on a UK populationscale from 01/11/2020-31/08/2022, assessing case-outcome rates of hospital assessment(s), intensive care admission and mortality. We observed that the SARS-CoV-2 disease phenotype has become less severe in patients with cancer and the non-cancer population. Case-hospitalisation rates for patients with cancer dropped from 30.58% in early 2021 to 7.45% in 2022 while case-mortality rates decreased from 20.53% to 3.25%. However, the risk of hospitalisation and mortality remains 2.10x and 2.54x higher in patients with cancer, respectively. Overall, the SARS-CoV-2 disease phenotype is less severe in 2022 compared to 2020 but patients with cancer remain at higher risk than the non-cancer population. Patients with cancer must therefore be empowered to live more normal lives, to see loved ones and families, while also being safeguarded with expanded measures to reduce the risk of transmission.

Association of SARS-CoV-2 Spike Protein Antibody Vaccine Response With Infection Severity in Patients With Cancer: A National COVID Cancer Cross-sectional Evaluation.

Importance: Accurate identification of patient groups with the lowest level of protection following COVID-19 vaccination is important to better target resources and interventions for the most vulnerable populations. It is not known whether SARS-CoV-2 antibody testing has clinical utility for high-risk groups, such as people with cancer. Objective: To evaluate whether spike protein antibody vaccine response (COV-S) following COVID-19 vaccination is associated with the risk of SARS-CoV-2 breakthrough infection or hospitalization among patients with cancer. Design, Setting, and Participants: This was a population-based cross-sectional study of patients with cancer from the UK as part of the National COVID Cancer Antibody Survey. Adults with a known or reported cancer diagnosis who had completed their primary SARS-CoV-2 vaccination schedule were included. This analysis ran from September 1, 2021, to March 4, 2022, a period covering the expansion of the UK's third-dose vaccination booster program. Interventions: Anti-SARS-CoV-2 COV-S antibody test (Elecsys; Roche). Main Outcomes and Measures: Odds of SARS-CoV-2 breakthrough infection and COVID-19 hospitalization. Results: The evaluation comprised 4249 antibody test results from 3555 patients with cancer and 294 230 test results from 225 272 individuals in the noncancer population. The overall cohort of 228 827 individuals (patients with cancer and the noncancer population) comprised 298 479 antibody tests. The median age of the cohort was in the age band of 40 and 49 years and included 182 741 test results (61.22%) from women and 115 737 (38.78%) from men. There were 279 721 tests (93.72%) taken by individuals identifying as White or White British. Patients with cancer were more likely to have undetectable anti-S antibody responses than the general population (199 of 4249 test results [4.68%] vs 376 of 294 230 [0.13%]; P < .001). Patients with leukemia or lymphoma had the lowest antibody titers. In the cancer cohort, following multivariable correction, patients who had an undetectable antibody response were at much greater risk for SARS-CoV-2 breakthrough infection (odds ratio [OR], 3.05; 95% CI, 1.96-4.72; P < .001) and SARS-CoV-2-related hospitalization (OR, 6.48; 95% CI, 3.31-12.67; P < .001) than individuals who had a positive antibody response. Conclusions and Relevance: The findings of this cross-sectional study suggest that COV-S antibody testing allows the identification of patients with cancer who have the lowest level of antibody-derived protection from COVID-19. This study supports larger evaluations of SARS-CoV-2 antibody testing. Prevention of SARS-CoV-2 transmission to patients with cancer should be prioritized to minimize impact on cancer treatments and maximize quality of life for individuals with cancer during the ongoing pandemic.

COVID-19: Third dose booster vaccine effectiveness against breakthrough coronavirus infection, hospitalisations and death in patients with cancer: A population-based study.

PURPOSE: People living with cancer and haematological malignancies are at an increased risk of hospitalisation and death following infection with acute respiratory syndrome coronavirus 2. Coronavirus third dose vaccine boosters are proposed to boost waning immune responses in immunocompromised individuals and increase coronavirus protection; however, their effectiveness has not yet been systematically evaluated. METHODS: This study is a population-scale real-world evaluation of the United Kingdom's third dose vaccine booster programme for cancer patients from 8th December 2020 to 7th December 2021. The cancer cohort comprises individuals from Public Health England's national cancer dataset, excluding individuals less than 18 years. A test-negative case-control design was used to assess the third dose booster vaccine effectiveness. Multivariable logistic regression models were fitted to compare risk in the cancer cohort relative to the general population. RESULTS: The cancer cohort comprised of 2,258,553 tests from 361,098 individuals. Third dose boosters were evaluated by reference to 87,039,743 polymerase chain reaction coronavirus tests. Vaccine effectiveness against breakthrough infections, symptomatic infections, coronavirus hospitalisation and death in cancer patients were 59.1%, 62.8%, 80.5% and 94.5%, respectively. Lower vaccine effectiveness was associated with a cancer diagnosis within 12 months, lymphoma, recent systemic anti-cancer therapy (SACT) or radiotherapy. Patients with lymphoma had low levels of protection from symptomatic disease. In spite of third dose boosters, following multivariable adjustment, individuals with cancer remain at an increased risk of coronavirus hospitalisation and death compared to the population control (OR 3.38, 3.01, respectively. p < 0.001 for both). CONCLUSIONS: Third dose boosters are effective for most individuals with cancer, increasing protection from coronavirus. However, their effectiveness is heterogenous and lower than the general population. Many patients with cancer will remain at the increased risk of coronavirus infections even after 3 doses. In the case of patients with lymphoma, there is a particularly strong disparity of vaccine effectiveness against breakthrough infection and severe disease. Breakthrough infections will disrupt cancer care and treatment with potentially adverse consequences on survival outcomes. The data support the role of vaccine boosters in preventing severe disease, and further pharmacological intervention to prevent transmission and aid viral clearance to limit the disruption of cancer care as the delivery of care continues to evolve during the coronavirus pandemic.

Vaccine effectiveness against COVID-19 breakthrough infections in patients with cancer (UKCCEP): a population-based test-negative case-control study.

BACKGROUND: People with cancer are at increased risk of hospitalisation and death following infection with SARS-CoV-2. Therefore, we aimed to conduct one of the first evaluations of vaccine effectiveness against breakthrough SARS-CoV-2 infections in patients with cancer at a population level. METHODS: In this population-based test-negative case-control study of the UK Coronavirus Cancer Evaluation Project (UKCCEP), we extracted data from the UKCCEP registry on all SARS-CoV-2 PCR test results (from the Second Generation Surveillance System), vaccination records (from the National Immunisation Management Service), patient demographics, and cancer records from England, UK, from Dec 8, 2020, to Oct 15, 2021. Adults (aged ≥18 years) with cancer in the UKCCEP registry were identified via Public Health England's Rapid Cancer Registration Dataset between Jan 1, 2018, and April 30, 2021, and comprised the cancer cohort. We constructed a control population cohort from adults with PCR tests in the UKCCEP registry who were not contained within the Rapid Cancer Registration Dataset. The coprimary endpoints were overall vaccine effectiveness against breakthrough infections after the second dose (positive PCR COVID-19 test) and vaccine effectiveness against breakthrough infections at 3-6 months after the second dose in the cancer cohort and control population. FINDINGS: The cancer cohort comprised 377 194 individuals, of whom 42 882 had breakthrough SARS-CoV-2 infections. The control population consisted of 28 010 955 individuals, of whom 5 748 708 had SARS-CoV-2 breakthrough infections. Overall vaccine effectiveness was 69·8% (95% CI 69·8-69·9) in the control population and 65·5% (65·1-65·9) in the cancer cohort. Vaccine effectiveness at 3-6 months was lower in the cancer cohort (47·0%, 46·3-47·6) than in the control population (61·4%, 61·4-61·5). INTERPRETATION: COVID-19 vaccination is effective for individuals with cancer, conferring varying levels of protection against breakthrough infections. However, vaccine effectiveness is lower in patients with cancer than in the general population. COVID-19 vaccination for patients with cancer should be used in conjunction with non-pharmacological strategies and community-based antiviral treatment programmes to reduce the risk that COVID-19 poses to patients with cancer. FUNDING: University of Oxford, University of Southampton, University of Birmingham, Department of Health and Social Care, and Blood Cancer UK.

A Phase Ib Open-Label, Dose-Escalation Study of NUC-1031 in Combination with Carboplatin for Recurrent Ovarian Cancer.

PURPOSE: NUC-1031 is a first-in-class ProTide modification of gemcitabine. In PRO-002, NUC-1031 was combined with carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: NUC-1031 was administered on days 1 and 8 with carboplatin on day 1 every 3 weeks for up to six cycles. Four dose cohorts of NUC-1031 (500, 625, and 750 mg/m2) with carboplatin (AUC4 or 5) were investigated. Primary endpoint was recommended phase II combination dose (RP2CD). Secondary endpoints included safety, investigator-assessed objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and pharmacokinetics. RESULTS: A total of 25 women with recurrent ovarian cancer, a mean of 3.8 prior lines of chemotherapy, and a median platinum-free interval of 5 months (range: 7-451 days) were enrolled; 15 of 25 (60%) were platinum resistant, 9 (36%) were partially platinum sensitive, and 1 (4%) was platinum sensitive. Of the 23 who were response evaluable, there was 1 confirmed complete response (4%), 5 partial responses (17%), and 8 (35%) stable disease. The ORR was 26% and CBR was 74% across all doses and 100% in the RP2CD cohort. Median PFS was 27.1 weeks. NUC-1031 was stable in the plasma and rapidly generated high intracellular dFdCTP levels that were unaffected by carboplatin. CONCLUSIONS: NUC-1031 combined with carboplatin is well tolerated in recurrent ovarian cancer. Highest efficacy was observed at the RP2CD of 500 mg/m2 NUC-1031 on days 1 and 8 with AUC5 carboplatin day 1, every 3 weeks for six cycles. The ability to deliver carboplatin at AUC5 and the efficacy of this schedule even in patients with platinum-resistant disease makes this an attractive therapeutic combination.

Maximal effort cytoreductive surgery for disseminated ovarian cancer in a UK setting: challenges and possibilities.

OBJECTIVE: To assess surgical morbidity and mortality of maximal effort cytoreductive surgery for disseminated epithelial ovarian cancer (EOC) in a UK tertiary center. METHODS/MATERIALS: A monocentric prospective analysis of surgical morbidity and mortality was performed for all consecutive EOC patients who underwent extensive cytoreductive surgery between 01/2013 and 12/2014. Surgical complexity was assessed by the Mayo clinic surgical complexity score (SCS). Only patients with high SCS ≥5 were included in the analysis. RESULTS: We evaluated 118 stage IIIC/IV patients, with a median age of 63 years (range 19-91); 47.5 % had ascites and 29 % a pleural effusion. Median duration of surgery was 247 min (range 100-540 min). Median surgical complexity score was 10 (range 5-15) consisting of bowel resection (71 %), stoma formation (13.6 %), diaphragmatic stripping/resection (67 %), liver/liver capsule resection (39 %), splenectomy (20 %), resection stomach/lesser sac (26.3 %), pleurectomy (17 %), coeliac trunk/subdiaphragmatic lymphadenectomy (8 %). Total macroscopic tumor clearance rate was 89 %. Major surgical complication rate was 18.6 % (n = 22), with a 28-day and 3-month mortality of 1.7 and 3.4 %, respectively. The anastomotic leak rate was 0.8 %; fistula/bowel perforation 3.4 %; thromboembolism 3.4 % and reoperation 4.2 %. Median intensive care unit and hospital stay were 1.7 (range 0-104) and 8 days (range 4-118), respectively. Four patients (3.3 %) failed to receive chemotherapy within the first 8 postoperative weeks. CONCLUSIONS: Maximal effort cytoreductive surgery for EOC is feasible within a UK setting with acceptable morbidity, low intestinal stoma rates and without clinically relevant delays to postoperative chemotherapy. Careful patient selection, and coordinated multidisciplinary effort appear to be the key for good outcome. Future evaluations should include quality of life analyses.

Biologicals in the upfront treatment of ovarian cancer: focus on bevacizumab and poly (adp-ribose) polymerase inhibitors.

Biologicals have made a major impact in the management of several cancers, but have hitherto had a negligible impact in ovarian cancer. Fortunately, ovarian cancer has been much more sensitive to cytotoxic chemotherapy than many cancers, so treatments were still available. However, improvements are required as more than 80% of patients who present with advanced ovarian cancer eventually will die as a result of their disease. The antiangiogenic antibody bevacizumab and the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib have recently been shown to improve progression-free survival of patients with ovarian cancer with better hazard ratios in certain groups than have been seen previously.

Intensity of lipid lowering with statins and brachial artery vascular endothelium reactivity after acute coronary syndromes (from the BRAVER trial).

The time course and differential effects of statin regimens on endothelial function after acute coronary syndromes (ACSs) are unknown and could contribute to the superiority of a more intense strategy. A subset of subjects who were enrolled in the PROVE IT-TIMI 22 trial (n = 50) underwent evaluation of vascular reactivity by high-resolution brachial ultrasound. Endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent sublingual nitroglycerin-mediated dilation (NMD) were measured at baseline and at 48 hours, 1 month, and 4 months after the initiation of 40 mg of pravastatin (n = 26) or 80 mg of atorvastatin (n = 24). After 4 months, low-density lipoprotein cholesterol was decreased by 32% in the atorvastatin group but was not different from baseline after ACS in the pravastatin group. C-reactive protein decreased similarly in the 2 groups. Brachial artery diameters at rest were similar in the 2 groups and at each time point of the trial. FMD and NMD increased significantly after 4 months by 27% and 24%, respectively (p <0.05), with no difference between groups. There was no correlation between the change in FMD and the change in lipids or C-reactive protein. In subjects who had received previous statin therapy (n = 15), there was no significant variation in FMD (p = 0.140) and NMD (p = 0.129). In conclusion, initiation of statin therapy soon after ACS is associated with improvements in endothelium-dependent and independent vascular reactivities after 4 months.

Quality of life after acute myocardial infarction among patients treated at sites with and without on-site availability of angiography.

BACKGROUND: Previous studies have compared the treatment and outcome of patients with acute myocardial infarction (AMI) admitted at sites with and without availability of angiography. Although mortality rates do not differ, it is unknown if quality of life (QOL) and functional status differ. METHODS: We measured QOL and functional status in patients with AMI treated within Québec at 5 sites with (n = 253) and 5 sites without (n = 334) angiography. RESULTS: At admission, clinical characteristics, complication rates, and baseline measures of QOL and functional status were similar at sites with and without angiography. During hospitalization, patients treated at sites with angiography were more likely to undergo an invasive cardiac procedure than patients admitted at sites without angiography (angiography, 63% vs 26%; percutaneous transluminal coronary angioplasty, 33% vs 13%; and coronary artery bypass graft, 12% vs 5%). At 30 days and 6 months after AMI, QOL was slightly superior at sites with angiography, but by 1 year, most measures of QOL were back to baseline at both types of sites and were similar between the 2 groups. At 6 months, most standard health-related QOL components were similar; only physical and emotional role limitations were higher at sites with angiography. Return to work occurred earlier (at 30 days, 23% vs 12%), and a lower proportion of patients was readmitted for angina (within 1 year after AMI, 12% vs 18%) at sites with angiography. CONCLUSIONS: In the early post-AMI period, the QOL of patients admitted at sites with angiography was higher than that of patients admitted at sites without angiography. However, by 1 year, the QOL and functional status of patients was similar in both groups. Differences in QOL were greatest when differences in treatment were greatest, lending support to a positive albeit small association between an early invasive approach to post-AMI care and improved QOL.