Differences in experiences of care between patients diagnosed with metastatic cancer of known and unknown primaries: mixed-method findings from the 2013 cancer patient experience survey in England.

OBJECTIVES: To explore differences in experiences of care reported in the Cancer Patient Experience Survey (CPES) between patients with cancer of unknown primary (CUP) and those with metastatic disease of known primary (non-CUP); to determine insights pertaining to the experiences of care for CUP respondents from free-text comments. DESIGN: Two separate, but related, studies, involving secondary analysis of existing data. Using frequency matching of CUP and non-CUP patients, statistical comparisons of responses to CPES questions were conducted. Free-text comments from CUP respondents were analysed thematically. SETTING AND PARTICIPANTS: The CPES questionnaire comprises 63 closed questions measuring 8 areas that relate to experience of care and 3 free-text questions. Questionnaires were mailed to all adult patients (aged ≥16 years) in England with cancer admitted to hospital between 1 September 2013 and 30 November 2013. RESULTS: Matched analysis of closed response items from 2992 patients found significant differences between CUP (n=1496) and non-CUP patients (n=1496): CUP patients were more likely to want more written information about their type of cancer and tests received, to receive their diagnosis from a general practitioner (GP) and have seen allied health professionals, but less likely to have understood explanations of their condition or had surgery. Freetext responses (n=3055) were coded into 17 categories and provided deeper insight regarding patient information and interactions with GPs. CPES data may include a preponderance of patients with favourable CUP subtypes and patients initially identified as CUP but whose primary was subsequently identified. CONCLUSIONS: These are the first large-scale studies to explore the experiences of care of CUP patients. The significant differences identified between the experiences of CUP and non-CUP patients suggest CUP patients require more psychosocial support and specific interventions to manage diagnostic uncertainty and the multiple investigations many CUP patients face. Substantial limitations were identified with the CPES data, emphasising the need for prospective studies

The feasibility of triggers for the integration of Standardised, Early Palliative (STEP) Care in advanced cancer: A phase II trial.

BACKGROUND: While multiple clinical trials have demonstrated benefits of early palliative care for people with cancer, access to these services is frequently very late if at all. Establishing evidence-based, disease-specific 'triggers' or times for the routine integration of early palliative care may address this evidence-practice gap. AIM: To test the feasibility of using defined triggers for the integration of standardised, early palliative (STEP) care across three advanced cancers. METHOD: Phase II, multi-site, open-label, parallel-arm, randomised trial of usual best practice cancer care +/- STEP Care conducted in four metropolitan tertiary cancer services in Melbourne, Australia in patients with advanced breast, prostate and brain cancer. The primary outcome was the feasibility of using triggers for times of integration of STEP Care, defined as enrolment of at least 30 patients per cancer in 24 months. Triggers were based on hospital admission with metastatic disease (for breast and prostate cancer), or development of disease recurrence (for brain tumour cohort). A mixed method study design was employed to understand issues of feasibility and acceptability underpinning trigger points. RESULTS: The triggers underpinning times for the integration of STEP care were shown to be feasible for brain but not breast or prostate cancers, with enrolment of 49, 6 and 10 patients across the three disease groups respectively. The varied feasibility across these cancer groups suggested some important characteristics of triggers which may aid their utility in future work. CONCLUSIONS: Achieving the implementation of early palliative care as a standardized component of quality care for all oncology patients will require further attention to defining triggers. Triggers which are 1) linked to objective points within the illness course (not dependent on recognition by individual clinicians), 2) Identifiable and visible (heralded through established service-level activities) and 3) Not reliant upon additional screening measures may enhance their feasibility

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

ICON 9-an international phase III randomized study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy

BACKGROUND: Two novel biological agents-cediranib targeting angiogenesis, and olaparib targeting DNA repair processes-have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy. PRIMARY OBJECTIVE: To assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse. STUDY HYPOTHESIS: Maintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone. TRIAL DESIGN: International phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm). MAJOR INCLUSION CRITERIA: Patients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy. PRIMARY ENDPOINTS: Progression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type. SAMPLE SIZE: 618 patients will be recruited. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03278717

Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer

PURPOSE: Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors.Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum refractory ovarian cancer (PPROC). EXPERIMENTAL DESIGN: Part I was a combination 3+3 dose-escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50-150 mg/day with three-weekly intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) for 6 cycles followed by maintenance afuresertib at 125mg/day until progression or toxicity. Part II was a single arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the maximum tolerated dose (MTD) defined in Part I in combination with PC for 6 cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose-escalation), and investigator-assessed overall response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Part II). RESULTS: Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities (DLTs) of grade 3 rash were observed, one at 125mg and two at 150mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. (etc -see manuscript for full version)

Impact of COVID-19 on cancer service delivery: results from an international survey of oncology clinicians.

To report clinician-perceived changes to cancer service delivery in response to COVID-19. Multidisciplinary Australasian cancer clinician survey in collaboration with the European Society of Medical Oncology. Between May and June 2020 clinicians from 70 countries were surveyed; majority from Europe (n=196; 39%) with 1846 COVID-19 cases per million people, Australia (AUS)/New Zealand (NZ) (n=188; 38%) with 267/236 per million and Asia (n=75; 15%) with 121 per million at time of survey distribution. Medical oncologists (n=372; 74%), radiation oncologists (n=91; 18%) and surgical oncologists (n=38; 8%). Eighty-nine per cent of clinicians reported altering clinical practices; more commonly among those with versus without patients diagnosed with COVID-19 (n=142; 93% vs n=225; 86%, p=0.03) but regardless of community transmission levels (p=0.26). More European clinicians (n=111; 66.1%) had treated patients diagnosed with COVID-19 compared with Asia (n=20; 27.8%) and AUS/NZ (n=8; 4.8%), p<0.001. Many clinicians (n=307; 71.4%) reported concerns that reduced access to standard treatments during the pandemic would negatively impact patient survival. The reported proportion of consultations using telehealth increased by 7.7-fold, with 25.1% (n=108) of clinicians concerned that patient survival would be worse due to this increase. Clinicians reviewed a median of 10 fewer outpatients/week (including non-face to face) compared with prior to the pandemic, translating to 5010 fewer specialist oncology visits per week among the surveyed group. Mental health was negatively impacted for 52.6% (n=190) of clinicians. Clinicians reported widespread changes to oncology services, in regions of both high and low COVID-19 case numbers. Clinician concerns of potential negative impacts on patient outcomes warrant objective assessment, with system and policy implications for healthcare delivery at large

Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors

SUMMARY: Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. TRIAL REGISTRATION: NCT01462175 (ClinicalTrials.gov), October 31, 2011. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10637-021-01141-2

Exercise during chemotherapy for ovarian cancer (ECHO) trial : design and implementation of a randomised controlled trial

Introduction Epidemiological evidence supports an association between higher levels of physical activity and improved cancer survival. Trial evidence is now needed to demonstrate the effect of exercise in a clinical setting. The Exercise during CHemotherapy for Ovarian cancer (ECHO) trial is a phase III, randomised controlled trial, designed to determine the effect of exercise on progression-free survival and physical well-being for patients receiving first-line chemotherapy for ovarian cancer. Methods and analysis Participants (target sample size n=500) include women with newly diagnosed primary ovarian cancer, scheduled to receive first-line chemotherapy. Consenting participants are randomly allocated (1:1) to either the exercise intervention (plus usual care) or usual care alone, with stratification for recruitment site, age, stage of disease and chemotherapy delivery (neoadjuvant vs adjuvant). The exercise intervention involves individualised exercise prescription with a weekly target of 150 minutes of moderate-intensity, mixed-mode exercise (equivalent to 450 metabolic equivalent minutes per week), delivered for the duration of first-line chemotherapy through weekly telephone sessions with a trial-trained exercise professional. The primary outcomes are progression-free survival and physical well-being. Secondary outcomes include overall survival, physical function, body composition, quality of life, fatigue, sleep, lymphoedema, anxiety, depression, chemotherapy completion rate, chemotherapy-related adverse events, physical activity levels and healthcare usage. Ethics and dissemination Ethics approval for the ECHO trial (2019/ETH08923) was granted by the Sydney Local Health District Ethics Review Committee (Royal Prince Alfred Zone) on 21 November 2014. Subsequent approvals were granted for an additional 11 sites across Queensland, New South Wales, Victoria and the Australian Capital Territory. Findings from the ECHO trial are planned to be disseminated via peer-reviewed publications and international exercise and oncology conferences

Tertiary lymphoid structures critical for prognosis in endometrial cancer patients

B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells shows presence of naive B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis shows association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence show L1CAM expression in mature TLS, independent of L1CAM expression in the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank are evaluated, TLS are found in 19%. L1CAM expressing TLS are most common in mismatch-repair deficient (29/127, 23%) and polymerase-epsilon mutant EC (24/47, 51%). Multivariable Cox regression analysis shows strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker.Tertiary lymphoid structures (TLS) are associated with a reduced risk of cancer recurrence and improved response to immune checkpoint blockade in several tumor types. Here the authors identify L1CAM as a marker for mature TLS and show that the presence of TLS is associated with favorable prognosis in patients with endometrial cancer from the PORTEC-3 trial.Biological, physical and clinical aspects of cancer treatment with ionising radiatio