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Purpose: The aim of this randomized, placebo-controlled, two-stage, phase II/III trial was to determine the efficacy of an oral cannabis extract in adults with refractory nausea and/or vomiting during moderately or highly emetogenic, intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Here, we report results of the prespecified combined analysis including the initial phase II and subsequent phase III components., Patients and Methods: Study treatment consisted of oral capsules containing either tetrahydrocannabinol 2.5 mg plus cannabidiol 2.5 mg capsules (THC:CBD) or matching placebo, taken three times a day from days -1 to 5, in addition to guideline-consistent antiemetics. The primary measure of effect was the difference in the proportions of participants with no vomiting or retching and no use of rescue medications (a complete response) during hours 0-120 after the first cycle of chemotherapy on study (cycle A)., Results: We recruited 147 evaluable of a planned 250 participants from 2016 to 2022. Background antiemetic prophylaxis included a corticosteroid and 5-hydroxytryptamine antagonist in 97%, a neurokinin-1 antagonist in 80%, and olanzapine in 10%. THC:CBD compared with placebo improved the complete response rate from 8% to 24% (absolute difference 16%, 95% CI, 4 to 28, P = .01), with similar effects for absence of significant nausea, use of rescue medications, daily vomits, and the nausea scale on the Functional Living Index-Emesis quality-of-life questionnaire. More frequent bothersome adverse events of special interest included sedation (18% v 7%), dizziness (10% v 0%), and transient anxiety (4% v 1%). There were no serious adverse events attributed to THC:CBD., Conclusion: THC:CBD is an effective adjunct for chemotherapy-induced nausea and vomiting despite standard antiemetic prophylaxis, but was associated with additional adverse events. Drug availability, cultural attitudes, legal status, and preferences may affect implementation. Future analyses will evaluate the cost-effectiveness of THC:CBD.

Objective: To evaluate the efficacy of sequential treatment with ipilimumab and nivolumab following progression on nivolumab monotherapy in individuals with advanced, non-clear-cell renal cell carcinoma (nccRCC)., Materials and Methods: UNISoN (ANZUP1602; NCT03177239) was an open-label, single-arm, phase 2 clinical trial that recruited adults with immunotherapy-naïve, advanced nccRCC. Participants received nivolumab 240 mg i.v. two-weekly for up to 12 months (Part 1), followed by sequential addition of ipilimumab 1 mg/kg three-weekly for four doses to nivolumab if disease progression occurred during treatment (Part 2). The primary endpoint was objective tumour response rate (OTRR) and secondary endpoints included duration of response (DOR), progression-free (PFS) and overall survival (OS), and toxicity (treatment-related adverse events)., Results: A total of 83 participants were eligible for Part 1, including people with papillary (37/83, 45%), chromophobe (15/83, 18%) and other nccRCC subtypes (31/83, 37%); 41 participants enrolled in Part 2. The median (range) follow-up was 22 (16-30) months. In Part 1, the OTRR was 16.9% (95% confidence interval [CI] 9.5-26.7), the median DOR was 20.7 months (95% CI 3.7-not reached) and the median PFS was 4.0 months (95% CI 3.6-7.4). Treatment-related adverse events were reported in 71% of participants; 19% were grade 3 or 4. For participants who enrolled in Part 2, the OTRR was 10%; the median DOR was 13.5 months (95% CI 4.8-19.7) and the median PFS 2.6 months (95% CI 2.2-3.8). Treatment-related adverse events occurred in 80% of these participants; 49% had grade 3, 4 or 5. The median OS was 24 months (95% CI 16-28) from time of enrolment in Part 1., Conclusions: Nivolumab monotherapy had a modest effect overall, with a few participants experiencing a long DOR. Sequential combination immunotherapy by addition of ipilimumab in the context of disease progression to nivolumab in nccRCC is not supported by this study, with only a minority of participants benefiting from this strategy., (© 2023 BJU International.)

Background: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older., Methods: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm., Results: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events., Conclusions: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations., Competing Interests: HWS acknowledges institutional research funding from AbbVie and Bristol-Myers Squibb and has received honoraria from Eli Lilly. ABH serves on the advisory board of Caris Life Sciences and WIRB-Copernicus Group, and is supported by research grants from AbbVie, Alnylam Pharmaceuticals and Cellularity. BME serves on the advisory board and as a consultant for Alpheus Medical, Curtana Pharmaceuticals, Ellipses Pharma, Global Coalition for Adaptive Research, ImmunoGenesis, Medicenna, MedQIA, Monteris, Neosoma, Sagimet Biosciences, Sapience Therapeutics, Servier Pharmaceuticals, Siemens and Sumitomo Pharma Oncology, serves as a consultant for Carthera and Chimerix, and is supported by a research grant from Siemens. HG serves on the advisory board of Merck Serono, and serves as a consultant for Curis and Telix Pharmaceuticals. HL acknowledges institutional research funding from Pfizer, and has received honoraria from AstraZeneca. JRS acknowledges institutional research funding from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Cancer Australia, Cancer Institute NSW, Merck Serono, National Health and Medical Research Council of Australia, Pfizer and Roche. ZL serves on the scientific advisory committee of Merck Sharp Dohme, has received honoraria from AstraZeneca, Bristol-Myers Squibb and Roche, and has received travel funding from Pfizer. MK acknowledges institutional research funding from AbbVie, Bristol-Myers Squibb and Specialized Therapeutics, and has received honoraria from AbbVie, Bristol-Myers Squibb, Eli Lilly, Ipsen, Pfizer and Roche., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel., Methods: ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99 m Tc and an Eastern Cooperative Oncology Group performance status score of 0-2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m 2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42., Findings: Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63-74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67-69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58-0·84]; p<0·0001), with 5-year overall survival of 57% (0·53-0·61) in the control group and 67% (0·63-0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3-4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1-3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment., Interpretation: The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients., Funding: Astellas Pharma., Competing Interests: Declaration of interests CJS received institutional research grants from Bayer, Sanofi, Astellas Pharma (Pfizer), Dendreon, and Janssen and personal consulting fees from Bayer, Astellas Pharma, Janssen, CellCentric, Point Biopharma, Pfizer, Novartis, Genentech (Roche), Bristol Myers Squibb, Lilly, Hengrui Europe Biosciences, and AstraZeneca. MRS received institutional research grants from Astellas Pharma, Amgen, AstraZeneca, Bionomics, Bristol Myers Squibb, Celgene, Medivation, MSD, Pfizer, Roche, Sanofi, and Tilray. KNC received institutional research grants from AstraZeneca, Bayer, Novartis, Pfizer, Point Biopharma, Roche, and Janssen; personal consulting fees from AstraZeneca, Bayer, Novartis, Pfizer, Point Biopharma, and Roche; institutional consulting fees from Janssen; and honoraria from Janssen and AstraZeneca. SC had stock or ownership interests in Clovis Oncology; received honoraria from Novartis and Clovis Oncology; had a consulting or advisory role for Astellas Pharma, Bayer, Pfizer, Janssen-Cilag, BeiGene, and Novartis; and received payment for speakers’ bureaus from Janssen-Cilag and Sanofi (Aventis). MF had a leadership or fiduciary role as a board director for the Royal Australasian College of Surgeons. LGH received institutional research grants, honoraria, and Support for meetings or travel from Astellas Pharma. NJL was on the data safety monitoring board or advisory board for Thoracic Oncology Group of Australia; had a leadership or fiduciary role as a deputy director for Cancer Trials New Zealand; and was a member of the executive committee for New Zealand Society for Oncology. JM had a leadership or fiduciary role as a treasurer for the Irish Society of Medical Oncology; and was a chairman for National Annual Conferences. RM had stock or ownership interests in Bayer; received honoraria from Sanofi, Janssen, Astellas Pharma, Bristol Myers Squibb, MSD, Pfizer, Novartis, and Clovis Oncology; had a consulting or advisory role for MSD Oncology; received research funding from Janssen, Bayer, and Astellas Pharma; provided expert testimony for Pfizer; and received support for meetings or travel from Janssen-Cilag, Roche, and Ipsen. SAN received honoraria from Janssen, Bayer, MSD, AstraZeneca, and Advanced Accelerator Application. FP received honoraria from Bayer and AstraZeneca. DWP received institutional research funding from Medivation, Bristol Myers Squibb, Roche, Exelixis, MSD, Pfizer, Astellas Pharma, Bayer, Symvivo, and Amgen; personal consulting fees from Bristol Myers Squibb, Pfizer, MSD, Cipla, Astellas Pharma, and MSD (Pfizer); institutional consulting fees from Pfizer and MSD; honoraria from Bayer and MSD (Pfizer); and support for meetings or travel from Bristol Myers Squibb, Astellas Pharma, Pfizer, Amgen, MSD (Pfizer), and Janssen. MNR was on the data safety monitoring board or advisory board for Pfizer, Ipsen, EMD, Serono, MSD, and Bayer. SKS received research grants from Novartis/AAA, Genentech, AstraZeneca, Pfizer, and MSD; honoraria from AstraZeneca, Bristol Myer Squibb, MSD, and Janssen; and was on the data safety monitoring board or advisory board as the chair for the data safety monitoring committee at Novartis. AlvT had a leadership or fiduciary role as the head of department for the Te Whatu Ora hospital. THT received honoraria from AstraZeneca. AlvT received honoraria from Novartis and Gilead; support for meetings or travel from MSD, Lilly, Astellas Pharma, and Ipsen; and was on the data safety monitoring board or advisory board for Amgen, Novartis, and MSD. FV-B received institutional research grants from Janssen, MSD, and Seagen and consulting fees from Janssen, MSD, AstraZeneca, and Bayer. AYZ received institutional research grants from Astellas Pharma, Amgen, AstraZeneca, Bionomics, Bristol Myers Squibb, Celgene, Medivation, MSD, Pfizer, Roche, Sanofi, and Tilray; personal consulting fees from MSD; honoraria from MSD, Astellas Pharma, Bayer, Pfizer, Mundipharma, Janssen, and AstraZeneca; and was on the data safety monitoring board or advisory board for MSD, Astellas Pharma, and Bayer. RRZ received honoraria from AstraZeneca and Pfizer. IDD is the director and chair of the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP); and a member or chair of advisory boards for Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, MSD (Pfizer), MSD, Pio Therapeutics, Roche, and Xennials Therapeutics (all honoraria are paid directly to ANZUP). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Men who initially present with localized prostate cancer and later develop metachronous metastases have a better prognosis than men with de novo metastatic disease and often have a low burden of disease on conventional imaging. Some have disease amenable to metastasis-directed therapy for lymph node or bone metastases, a strategy used by some because no documented overall survival (OS) benefit of combination systemic therapy in this setting. We report data for patients prospectively classified as "M0" at initial diagnosis from the interim analysis of the ENZAMET trial, with 34 mo of median follow-up for survivors. A total of 312 (28%) of the 1125 enrolled patients were classified as M0 at diagnosis, and 205 (66%) of the 312 patients had low-volume disease at study entry as per the CHAARTED criteria. The hazard ratio for OS, that is, HR(OS), was 0.56 (95% confidence interval [CI]: 0.29-1.06) with the addition of enzalutamide for all patients with metachronous metastatic hormone-sensitive prostate cancer, and for the low-volume subset the HR(OS) was 0.40 (95% CI: 0.16-0.97). The 3-yr OS was 83% without and 89% with enzalutamide for all patients with metachronous metastases, and 83% and 92%, respectively, for the low-volume subset. Intensification of hormonal therapy should strongly be considered for these men. PATIENT SUMMARY: Many men present with prostate cancer that has spread to distant sites beyond the prostate gland years after their initial diagnosis and treatment, while others have distant spread at the time the cancer is diagnosed. On average, men whose cancer comes back years after the initial diagnosis often survive much longer than men whose cancer has been found to spread to distant sites when it is first diagnosed. In this report, we demonstrate strong evidence for the first time that the survival of men whose cancer comes back years later is improved when drugs such as enzalutamide or apalutamide are added to testosterone suppression in this setting., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The management of metastatic colorectal cancer patients with a poor performance status (PS) continues to be a clinical dilemma, with the potential activity and safety of treating this population remaining poorly understood. Few of these patients are enrolled onto clinical trials, and poor PS is often multifactorial., Patients and Methods: We analyzed the Treatment of Recurrent and Advanced Colorectal Cancer registry to describe treatment practices and outcomes in poor (Eastern Cooperative Oncology Group [ECOG] PS 2) and very poor PS (ECOG PS > 2) patients to explore the relationship between age, tumor burden, comorbidities, and PS, and to evaluate the benefit of systemic therapy. Standard descriptive statistical methods, Kaplan-Meier analysis, and a multivariate Cox regression model were used., Results: Of 2769 registry patients (diagnosed January 2009 to June 2018), 329 (12%) and 182 (7%) patients had a poor and very poor PS, respectively. Good PS patients were more likely to receive systemic therapy than poor and very poor PS patients (85%, 55%, and 21.5%, P < .0001), but clinician assessed response was observed in all subsets (53%, 41%, and 29%, P = .0003). Treatment with chemotherapy was associated with longer median overall survival across PS groups. Exploratory analysis based on comorbidity score and tumor burden subgroups demonstrated a consistently positive overall survival association with treatment. Benefit was observed where poor overall survival was attributable to medical comorbidities and to tumor burden., Conclusion: In routine clinical care, a substantial proportion of poor and very poor PS patients receive active treatment, which is often associated with meaningful clinical benefit., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This multicentre, randomised, double-blinded, placebo-controlled, phase II/III trial aimed to evaluate an oral THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract for prevention of refractory chemotherapy-induced nausea and vomiting (CINV). Here we report the phase II component results., Patients and Methods: Eligible patients experienced CINV during moderate-to-high emetogenic intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Study treatment consisted of one cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) three times daily, from days -1 to 5, and 1 cycle of matching placebo in a crossover design, then blinded patient preference for a third cycle. The primary end point was the proportion of participants with complete response during 0-120 h from chemotherapy. A total of 80 participants provided 80% power to detect a 20% absolute improvement with a two-sided P value of 0.1., Results: A total of 81 participants were randomised; 72 completing two cycles were included in the efficacy analyses and 78 not withdrawing consent were included in safety analyses. Median age was 55 years (range 29-80 years); 78% were female. Complete response was improved with THC:CBD from 14% to 25% (relative risk 1.77, 90% confidence interval 1.12-2.79, P = 0.041), with similar effects on absence of emesis, use of rescue medications, absence of significant nausea, and summary scores for the Functional Living Index-Emesis (FLIE). Thirty-one percent experienced moderate or severe cannabinoid-related adverse events such as sedation, dizziness, or disorientation, but 83% of participants preferred cannabis to placebo. No serious adverse events were attributed to THC:CBD., Conclusion: The addition of oral THC:CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC:CBD to placebo. Based on these promising results, we plan to recruit an additional 170 participants to complete accrual for the definitive, phase III, parallel group analysis., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12616001036404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370473&isReview=true., Competing Interests: Disclosure PG: Research funding to institution—ASLAN Pharmaceuticals (Inst), Boston Biomedical (Inst), Eisai (Inst), Eisai (Inst), Five Prime (Inst), Genentech (Inst), Gilead Sciences (Inst), Halozyme (Inst), Medimmune, MSD (Inst), Pfizer (Inst), Pfizer (Inst), Specialised Therapeutics, Tigermed (Inst), Tilray (Inst), Zucero. MS: Research funding to institution—Amgen (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bayer (Inst), Bionomics (Inst), Bristol-Myers Squibb (Inst), Celgene (Inst), Medivation (Inst), Merck Sharp & Dohme (Inst), Pfizer (Inst), Roche (Inst), Sanofi (Inst), Tilray (Inst); Travel, Accommodations, Expenses—Medivation/Pfizer. NL: Consulting or Advisory Role—Camurus, Indivior, Mundipharma; Speakers' Bureau—PCM Healthcare Ltd; Research funding to institution—Camurus (Inst). AM: Travel, Accommodations, Expenses—Roche. AT: Travel, Accommodations, Expenses—Ipsen. JS: Research funding to institution—AbbVie (Inst), Amgen (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bayer (Inst), Bristol-Myers Squibb (Inst), Merck Serono (Inst), Pfizer (Inst), Roche (Inst). RM: Research funding to institution—Edwards Life Sciences (Inst). IO: Consulting or Advisory Role—Aucentra, Con Ca Pty Ltd, VieCure; Speakers' Bureau—Pierre Fabre (Inst). IM: Honoraria—Janssen; Patents, Royalties, Other Intellectual Property—Kinoxis Therapeutics. CG: Honoraria—Novotech; Consulting or Advisory Role—AbbVie (Inst), Bristol-Myers Squibb (Inst), Ipsen (Inst), Merck Sharp & Dohme (Inst), Novotech, Pfizer (Inst); Research funding to institution—Amgen (Inst), Bristol-Myers Squibb (Inst), Merck Sharp & Dohme (Inst); Travel, Accommodations, Expenses—Astellas Pharma, Astellas Pharma, Merck Sharp & Dohme. SC: Employment—GenesisCare; Stock and Other Ownership Interests—GenesisCare; Honoraria—Tetra Health; Consulting or Advisory Role—All Vascular, AstraZeneca/MedImmune, Bayer, Ipsen, Merck; Speakers' Bureau—Merck, Novartis/Ipsen; Travel, Accommodations, Expenses—Bristol-Myers Squibb, MedLab. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. All rights reserved.)

Purpose: Lifirafenib is an investigational, reversible inhibitor of B-RAF V600E , wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF - or K-RAS/N-RAS -mutated solid tumors., Methods: During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion., Results: The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF -mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAF V600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAF V600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAF V600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF -mutated non-small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS -mutated endometrial cancer and K-RAS codon 12-mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS -mutated colorectal cancer (n = 20)., Conclusion: Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAF V600 -mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS -mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.

Background: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer., Methods: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events., Results: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group., Conclusions: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Hepatic resectional surgery remains a highly specialized area of general surgery usually reserved for completion at tertiary metropolitan referral centres. Port Macquarie, on the Mid North Coast of New South Wales, is the only regionally based hospital offering surgery of this nature in mainland Australia. The purpose of this study is to review the data for patients undergoing hepatic resectional surgery in this non-metropolitan centre in order to illustrate that these operations can be carried out safely in a regional setting with comparable results to tertiary-level centres., Methods: A retrospective review of consecutive patients undergoing elective hepatic resections at Port Macquarie from February 2008 to 31 October 2015 was completed. Pre-morbid patient clinical and demographic factors, histopathological details, post-operative complications, survival and mortality data were all noted., Results: A total of 66 consecutive elective liver resections were performed during the study period. Metastatic colorectal cancer was the most commonly observed pathology (n = 33, 50.0%). The 90-day mortality was 4.5% (n = 3) whilst 17 patients (n = 17, 25.8%) experienced major complications (Clavien-Dindo grade 3 or 4). The median overall survival following hepatectomy for colorectal metastases was 48 months (95% confidence interval 37-59 months)., Conclusion: Our study shows excellent morbidity, mortality and survival for hepatic resectional surgery performed in a regional centre and is comparable data to major metropolitan centres. Our study confirms that major hepatic resectional surgery in this setting is safe and effective., (© 2016 Royal Australasian College of Surgeons.)

Background: There is strong interest in testing lifestyle interventions to improve cancer outcomes; however, the optimal methods for achieving behavior change in large-scale pragmatic trials are unknown. Here, we report the 1-year feasibility results for exercise behavior change in the Canadian Cancer Trials Group CO.21 (CHALLENGE) Trial., Methods: Between 2009 and 2014, 273 high-risk stage II and III colon cancer survivors from 42 centers in Canada and Australia were randomized to a structured exercise program (SEP; n = 136) or health education materials (HEM; n = 137). The primary feasibility outcome in a prespecified interim analysis was a difference between randomized groups of ≥5 metabolic equivalent task (MET)-hours/week in self-reported recreational physical activity (PA) after at least 250 participants reached the 1-year follow-up. Secondary outcomes included health-related fitness., Results: The SEP group reported an increase in recreational PA of 15.6 MET-hours/week compared with 5.1 MET-hours/week in the HEM group [mean difference = +10.5; 95% confidence interval (CI) = +3.1-+17.9; P = 0.002]. The SEP group also improved relative to the HEM group in predicted VO2max (P = 0.068), 6-minute walk (P < 0.001), 30-second chair stand (P < 0.001), 8-foot up-and-go (P = 0.004), and sit-and-reach (P = 0.08)., Conclusions: The behavior change intervention in the CHALLENGE Trial produced a substantial increase in self-reported recreational PA that met the feasibility criterion for trial continuation, resulted in objective fitness improvements, and is consistent with the amount of PA associated with improved colon cancer outcomes in observational studies., Impact: The CHALLENGE Trial is poised to determine the causal effects of PA on colon cancer outcomes. Cancer Epidemiol Biomarkers Prev; 25(6); 969-77. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial., Patients and Methods: Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point., Results: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin., Conclusion: The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further., Clinical Trials Number: Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Abiraterone improves survival, relieves pain, improves quality of life and extends time to prostate-specific antigen (PSA) progression in patients with metastatic castration-resistant prostate cancer (mCRPC). A consensus-based guide for using abiraterone in patients with mCRPC has been developed by Australian clinicians with expertise in prostate cancer, based on their experience and supported by published data. Recommendations were developed for eight key topics: abiraterone administration; steroid administration and duration of use; concomitant medications and drug interactions; timing of testing and monitoring response; safety in different populations; potential toxicities; precautions and contraindications; and referral and multidisciplinary care. Abiraterone is taken orally in a fasting state. Symptoms associated with mineralocorticoid excess are managed by coadministration of low-dose prednisone or prednisolone. Potassium levels, blood pressure and liver function need to be tested frequently during the early treatment phase. Response to treatment is monitored based on symptoms, radiological imaging and PSA levels. Potential adverse consequences of long-term steroid therapy on bone and metabolic health need to be screened for and managed. Advanced prostate cancer is best managed by a multidisciplinary team and early referral should be considered. Questions about the potential use of abiraterone in early disease and in combination with other therapies are being addressed in ongoing clinical trials., (© 2014 Wiley Publishing Asia Pty Ltd.)

Background: Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone., Methods: In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m(2) intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 μmol/mol creatinine vs ≥60 μmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497., Findings: Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%])., Interpretation: The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients., Funding: Bristol-Myers Squibb., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC., Patients and Methods: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m(2) dose every three weeks, Results: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6-99 weeks) and 1-year survival was 71%., Conclusions: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

Objective: To map clinical oncology services in regional and rural Australia., Design and Setting: A self-administered survey was sent to 161 regional hospitals administering chemotherapy (RHAC) in Australia. RHAC were categorised by state, Hospital Peer Group and the Australian Standard Geographical Classification (ASGC) Remoteness Areas classification., Main Outcome Measure(s): Survey data provided percentage and aggregate figures about availability of medical, radiation and surgical oncologists, chemotherapy nurses, breast cancer nurses, palliative care physicians and allied health professionals according to remoteness and state. Chemotherapy prescribing practices, adherence to occupational health and safety guidelines and availability of multidisciplinary clinics were also explored., Results: A 98% survey completion rate was achieved. Significant deficiencies in service provision were identified in RHAC. Only 21% of RHAC reported a resident medical oncology service, 7% had a radiation oncology unit, and 6% had a resident surgical oncologist. Only 24% of RHAC reported a dedicated palliative care specialist and 39% identified a dedicated oncology counselling service. Other issues included administration of chemotherapy by nurses outside a recognised facility or by nurses without recognised oncology training, limited availability of funded breast care nurses and lack of multidisciplinary clinics., Conclusion: Survey data highlight marked cancer service deficiencies in rural and regional Australia. It is not unreasonable to conclude that these deficiencies might contribute to poorer outcomes for cancer patients living in these areas. The results suggest the need for short- and long-term measures to improve access to best-practice cancer services for patients living in regional, rural and remote areas of Australia.

Background: Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease., Methods: This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m(2), day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B(12), folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804., Findings: All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4.3 months [95% CI 4.1-4.7] vs 2.6 months [1.7-2.8]; hazard ratio [HR] 0.50, 95% CI 0.42-0.61, p<0.0001) and overall survival (13.4 months [11.9-15.9] vs 10.6 months [8.7-12.0]; HR 0.79, 0.65-0.95, p=0.012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0.0001), specifically fatigue (22 [5%] vs one [1%], p=0.001) and neutropenia (13 [3%] vs 0, p=0.006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0.0001)., Interpretation: Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer., Funding: Eli Lilly.

International research suggests complementary therapy usage is common in women with breast cancer. Comparable data do not exist for Australia. A self-completed questionnaire was used to survey Australian women with breast cancer about their usage of complementary therapies. The survey was mailed to members of two breast cancer consumer advocacy groups, and assessed type of therapy used, reasons for use, and sources of information about complementary therapies. Of 367 respondents with breast cancer, 87.5% had used complementary therapies, with many using four or more therapies. Most commonly used were vitamin supplements (54.2%), support groups (49.8%), massage (41.4%) and meditation (38.7%). Common reasons for use included improving physical (86.3%) and emotional (83.2%) wellbeing and boosting the immune system (68.8%). Women sought information about complementary therapies from a variety of sources. The range of therapies used and the diverse reasons for use emphasise the need for reliable, evidence-based information about complementary therapies for women and clinicians.

Background: Oral capecitabine achieves a superior response rate with an improved safety profile compared with bolus 5-fluorouracil-leucovorin (5-FU/LV) as first-line treatment for patients with metastatic colorectal cancer. We report here the results of a large phase III trial investigating adjuvant oral capecitabine compared with 5-FU/LV (Mayo Clinic regimen) in Dukes' C colon cancer., Patients and Methods: Patients aged 18-75 years with resected Dukes' C colon carcinoma were randomized to receive 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily, days 1-14 every 21 days (n = 993), or i.v. bolus 5-FU 425 mg/m(2) with i.v. leucovorin 20 mg/m(2) on days 1-5, repeated every 28 days (n = 974)., Results: Patients receiving capecitabine experienced significantly (P <0.001) less diarrhea, stomatitis, nausea/vomiting, alopecia and neutropenia, but more hand-foot syndrome than those receiving 5-FU/LV. Fewer patients receiving capecitabine experienced grade 3 or 4 neutropenia, febrile neutropenia/sepsis and stomatitis (P <0.001), although more experienced grade 3 hand-foot syndrome than those treated with 5-FU/LV (P <0.001). Capecitabine demonstrates a similar, favorable safety profile in patients aged <65 years or > or = 65 years old., Conclusions: Based on its improved safety profile, capecitabine has the potential to replace 5-FU/LV as standard adjuvant treatment for patients with colon cancer. Efficacy results are expected to be available in Keywords: Adjuvant treatment, capecitabine, chemotherapy, colorectal cancer

A 47-year-old woman developed pulmonary eosinophilia from the use of maloprim as malaria prophylaxis. The diagnosis was confirmed by bronchoalveolar lavage (BAL) and transbronchial lung biopsy. Her condition improved with drug withdrawal and steroid therapy. With the increased use of pyrimethamine and dapsone in the treatment of human immunodeficiency syndrome (HIV) infection, this form of drug allergy may become more common.