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Gastric carcinoma and gastro-oesophageal junction (GC/GEJ) carcinoma remain a significant global problem, with patients presenting with symptoms often found to have advanced or metastatic disease. Treatment options for these patients have broadened in recent years with new chemotherapy agents, agents targeting angiogenic pathways and the development of immune checkpoint inhibitors (ICIs). Most initial advances have occurred in the refractory setting, where it is important to balance treatment benefits versus toxicity and patient quality of life. In the first-line treatment of advanced/metastatic GC/GEJ, platinum- and fluoropyrimidine-based chemotherapy protocols remain the backbone of therapy (with or without HER2- targeted therapy), with the FOLFIRI regimen offering an alternative in patients deemed unsuitable for a platinum agent. Microsatellite instability-high or mismatch repair-deficient cancers have been shown to benefit most from ICIs. In unselected patients previously treated with doublet or triplet platinum- and fluoropyrimidine-based chemotherapy and second-line chemotherapy with irinotecan or taxanes have formed the backbone of therapy with or without the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab in addition to paclitaxel. Beyond this, efficacy has been demonstrated with oral trifluridine/tipiracil and with single-agent nivolumab, in selected refractory patients. In this review, we highlight the positive evidence from key trials that have led to our current practice algorithm, with particular focus on the refractory advanced disease setting, discussing the areas of active research and highlighting the factors, including biomarkers and the influence of ethnicity, that contribute to therapeutic decision-making., Competing Interests: Competing Interests: All authors have no COI directly related to this work. BUT COI Statements from authors with industry unrelated to this work are as follows: Nick Pavlakis: Advisory Boards MSD, Merck, BMS, Takeda, Beigene, Astra Zeneca, Roche, Amgen, Novartis Speaking Honoraria Roche, Pierre-Faber Research Funding – to institution Bayer, Roche Christos Karapetis: Advisory Board Amgen, Astra Zeneca, Beigene, BMS, Eli Lilly, Eisai, Ipsen, Merck, MSD, Pierre Fabre, Roche, Takeda Timothy Price: Advisory Board MSD, Merck Serono, Pierre Fabre, BMS, Servier Radka Obermannova: Personal fee BMS, Merck, MSD, Servie Research support (to institution): Roche Florian Lordick: Honorari BMS, MSD, Roche, Astra Zeneca Lorraine Chantrill: Advisory Board Pierre Fabre, AstraZeneca, BMS, Merck, (© The Author(s), 2022.)

Aims: Gastric cancer with peritoneal involvement has a poor prognosis. Intraperitoneal (IP) paclitaxel has shown promising results in these patients. However, this approach has only been studied in the Asian population, and in combination with S-1. We investigated the maximum tolerated dose of IP paclitaxel, with a standard chemotherapy combination, in the Australian population., Methods: The study of the population included metastatic human epidermal growth factor receptor 2 (HER2) negative gastric adenocarcinoma with peritoneal involvement. Treatment included six 21-day cycles of cisplatin (80 mg/m 2 IV, day 1) plus capecitabine (1000 mg/m 2 PO BD, days 1-14) plus IP paclitaxel (days 1 and 8). IP paclitaxel doses for cohort 1-3 were 10, 20, and 30 mg/m 2 , respectively, in a 3 + 3 standard dose-escalation design., Results: Fifteen patients were enrolled of which 6 were female and the median age was 63. Two patients developed dose-limiting toxicities. No grade 4/5 toxicities were recorded. The maximum tolerated dose was not reached. Therefore, as defined by the study protocol, the recommended phase-2 dose for IP paclitaxel was determined to be 30 mg/m 2 . The 12-month survival rate was 46.7%, and the median survival was 11.5 months (interquartile range [IQR]: 15.3-6.9)., Conclusions: IP paclitaxel is safe in combination with cisplatin and capecitabine and the recommended phase-2 dose is 30 mg/m 2 ., (© 2021 John Wiley & Sons Australia, Ltd.)

Objectives: Nab-paclitaxel has radiosensitizing antitumor efficacy in pancreatic cancer. We aimed to establish maximum tolerated dose (MTD) of nab-paclitaxel with radiotherapy in unresectable locally advanced pancreatic cancer., Methods: In a phase I dose escalation trial patients received weekly nab-paclitaxel for 6 weeks with external beam radiotherapy (EBRT). 3 + 3 design was used with nab-paclitaxel doses: 25 mg/m 2 (cohort 1), 50 mg/m 2 (cohort 2), 75 mg/m 2 (cohort 3), and 100 mg/m 2 (cohort 4). Primary endpoint was MTD. Secondary objectives were progression-free survival and overall survival., Results: Fourteen patients were recruited. Median age was 69 years (range, 40-86). Grade 1/2 toxicities were nausea (93%), vomiting (54%), diarrhea (57%), and fatigue (69%). There were no dose limiting toxicities (DLT) in cohorts 1 to 3. In cohort 4, DLTs of febrile neutropenia and enterocolitis were observed in patient 1. Subsequent DLT of febrile neutropenia and enterocolitis occurred in patient 5 in the expanded cohort. Following chemoradiotherapy median progression-free survival was 4.7 months (95% confidence interval, 2.5-27.5) and median overall survival was 10.8 months (95% confidence interval, 6.37-25.2)., Conclusions: Nab-paclitaxel and EBRT was well-tolerated at doses below 100 mg/m 2 . The MTD and recommended phase II study dose for nab-paclitaxel with EBRT is 75 mg/m 2 in this disease., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Nivolumab improves disease control and survival in advanced NSCLC in patients with good performance status (PS), but there is limited data on its efficacy in patients with poor PS., Aim: Primary objective of the study was to evaluate the efficacy and safety of nivolumab and examine the influence of PS on outcomes., Methods and Results: Retrospective analysis of patients treated with single-agent nivolumab for advanced NSCLC at a single institution was performed. Sixty-six patients treated with nivolumab were identified (33 male) with a median age of 68.5 years. Fifty-six (85%) patients were current or former smokers and 17 (26%) had brain metastasis. All patients had received prior chemotherapy, 39 (59%) patients received one and 27 (41%) had ≥2 prior lines of therapy. Median overall survival (OS) was 7.1 months (95%CI 3.61-11.3) in the overall study population. OS of patients with PS ≥2 at the start of treatment was 3.04 months (95%CI 1.64-7.36) as compared to 10.23 months (95%CI 7.06-18.9) with PS ≤1. The overall response rate was 7% (four patients had a partial response), 23 (40%) patients had stable disease; the overall disease control rate (partial response and stable disease) was 47%. Twenty-six (40%) patients had PS ≥2 at the start of treatment and 2 (8%) of these patients developed a partial response, 4 (15%) had stable disease; the overall disease control rate was 23%. Fourteen (58%) patients with PS ≥2 had disease progression at the time of first disease response evaluation. In the overall population, 20% of patients experienced grade ≥3 treatment-related adverse events (TRAEs), most commonly pneumonitis, hepatitis, and colitis. Fourteen TRAEs led to treatment discontinuation, 9 (23%) adverse events (AEs) in patients with PS ≤1 and 5 (19%) with PS ≥2. Fourteen (21%) patients died within 30 days of the last nivolumab treatment., Conclusion: There was no significant difference in toxicity leading to treatment discontinuation between the poor and good PS groups, but survival was shorter with poorer PS. PS appears to be an important prognostic factor and remains a relevant discriminator in the selection of treatment with immunotherapy for lung cancer., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Effective targeting of RAS mutations has proven elusive until recently. Novel agents directly targeting KRAS G12C have shown promise in early-phase clinical trials that included patients with metastatic colorectal cancer. Prior reports have suggested that G12C mutation may be predictive of poor outcome., Objective: Assessment of the specific characteristics and prognostic implications of individual RAS mutation subtypes in patients with metastatic colorectal cancer., Patients and Methods: Retrospective review of individual RAS mutation types from the South Australian Metastatic Colorectal Registry between 2006 and 2020., Results: Of the 5165 patients entered onto the registry, 2305 (45%) had RAS mutation results available. 772 (33%) had a RAS mutation. The nature of the RAS mutation was available in 668 (87% of those with RAS mutation). Rare mutations (outside codons 12 and 13) made up 12.6% of the total. There were numerical differences in survival between the specific RAS mutation subgroups, with the longest median overall survival (30 months) observed in those with G12S mutations. However, there was no statistical difference in survival when comparing the various RAS mutations, including the comparison of G12C to G12S (p = 0.38). Patients with cancer harbouring rare RAS mutations had a median survival of 30 months., Conclusions: Whilst the G12S mutation was associated with the longest survival numerically, the observed survival for patients with the most common RAS mutations (G12C, G12V, G12A, G12D and G13D) did not significantly differ., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Chemotherapy can cause premature menopause which may result in adverse effects such as fertility loss, osteoporosis, cardiovascular disease and menopausal symptoms. It is thus very important that women are provided with accurate information regarding their risk of premature menopause as a consequence of proposed chemotherapy. Unfortunately, at present there are no reliable tools which can be applied in clinical practice to estimate the risk of premature menopause in women undergoing chemotherapy, beyond age of the patient and form of chemotherapy utilized., Aim: This was a pilot study to determine whether AMH levels pre and during chemotherapy are able to predict for chemotherapy induced menopause, and to assess quality of life and menopausal symptoms., Methods and Results: Premenopausal women between 18 to 45 who were planned to undergo gonadotoxic chemotherapy with curative intent for either breast cancer or haematologic malignancy were recruited from a single centre. AMH, FSH, LH and oestradiol levels were recorded prior to commencement of therapy, during and following completion of chemotherapy. Menstrual status, menopausal symptoms and quality of life data were collected at baseline and during follow-up. Twenty two women were recruited. The baseline AMH was higher in women who regained menses post-chemotherapy (median 23.1 vs 9.9 pM (P = .06). Menopausal symptoms were significantly higher at 1 year post diagnosis than at baseline however quality of life was similar., Conclusion: AMH may be useful for predicting chemotherapy induced menopause. Further research is still required to determine the place of such testing for patient counselling and management., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Introduction: This is a phase 1, open-label, single-centre, uncontrolled, dose-escalation study to evaluate the feasibility, tolerability and pharmacokinetic profiles of a single dose of liposomal curcumin, administered via an existing tunnelled indwelling pleural catheter (TIPC) directly to the tumour site in individuals with diagnoses of malignant pleural effusion. Primarily, we aim to determine a maximum tolerated dose of liposomal curcumin administered via this method., Methods and Analysis: We will use a 3+3 expanded cohort for predefined dose-escalation levels or until a predefined number of dose-limiting toxicities are reached. Participants will be administered a single dose of liposomal curcumin (LipoCurc, SignPath Pharma) via their existing TIPC as a sequential enrolling case series with the following dose cohorts: 100, 200 and 300 mg/m 2 . Primary endpoints are determination of the maximum tolerated dose within the predetermined dose range, and determination of the feasibility of intrapleural administration of liposomal curcumin via an existing TIPC. Secondary endpoints include determination of the safety and tolerability of intrapleural administration of liposomal curcumin, median overall survival, effects on quality of life and on feelings of breathlessness, and the pharmacokinetics and concentrations of curcumin from the plasma and the pleural fluid. Important inclusion criteria include age ≥18 years, an existing TIPC, a pleural biopsy or pleural fluid cytology-proven diagnosis of malignant pleural effusion and for whom no antitumour therapy of proven benefit is available or has been previously declined, eastern cooperative group performance status <2., Ethics and Dissemination: The study protocol has been approved by the Southern Adelaide Local Health Network Human Research Ethics Committee (HREC) (approval number: HREC/20/SAC/11). Study results will be published in peer-reviewed journals, and presented at conferences, in field of medical oncology and respiratory medicine., Trial Registration Number: ACTRN12620001216909., Protocol Version Number: V.1.0., Competing Interests: Competing interests: SK, AF, AJH, SN, CSK, BD, none declared. PS, is the Vice President and Chief Science Officer of Sign Path Pharma Inc, US., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG)., Methods: A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1-2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4-5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours; incidence of toxicity; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection; cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping; inter-observer agreement on mrTRG scoring and pathTRG scoring; studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018., Discussion: When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations., Trial Registration: ANZ Clinical Trials Register ACTRN12617001087347. (www.anzctr.org.au, registered 26/7/2017) Protocol Version: 1.1 (June 2017).

Objectives: Some early studies indicated lower survival with longer time from diagnosis to cancer treatment, but others showed the reverse. We investigated time to treatment of colorectal cancer and associations with survival., Setting and Participants: Clinical registry data for colorectal cancer cases diagnosed in 2000-2010 at four major public hospitals in South Australia and treated by surgery (n=1675), radiotherapy (n=616) and/or systemic therapy (n=1556)., Design: A historic cohort design, with rank-order tests for ordinal clinical and sociodemographic predictors and multiple logistic regression for comparing time from diagnosis to treatment. Unadjusted Kaplan-Meier estimates and adjusted Cox proportional hazards regression were used to investigate disease-specific survival by time to treatment., Outcome Measures: Time to treatment and survival from diagnosis to death from colorectal cancer., Results: Treatment (any type) commenced for 87% of surgical cases < 60 days of diagnosis, with 80% having surgery within this period. Of those receiving radiotherapy, 59% began this treatment < 60 days, and of those receiving systemic therapy, the corresponding proportion was 56%. Adjusted analyses showed treatment delay >60 days was more likely for rectal cancers, 2006-2010 diagnoses, residents of northern than other metropolitan regions and for surgery, younger ages <50 years and unexpectedly, those residing closer to metropolitan services. Adjusting for clinical and sociodemographic factors, and diagnostic year, better survival occurred in < 2 years from diagnosis for time to treatment >30 days. Survival in the 3-10 years postdiagnosis generally did not differ by time to treatment, except for lower survival for any treatment >90 days for surgical cases., Conclusions: The lower survival < 2 years from diagnosis for treatment < 30 days of diagnosis is consistent with other studies attributed to preferencing more complicated cases for earlier care. Lower 3-10 years survival for surgical cases first treated >90 days from diagnosis is consistent with previously reported U-shaped relationships., Competing Interests: Competing interests: DR reports grants from Cancer Council SA, during the conduct of the study., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Gastric cancer with peritoneal metastasis has a poor outcome. Only a few studies have specifically investigated this group of patients. Japanese researchers have shown that chemotherapy with intraperitoneal paclitaxel (IPP) and oral S-1 (tegafur/gimeracil/oteracil) is active and well tolerated. These results have been achieved in a specific genetic pool (Japanese population), using regimens that may not be available in other parts of the world. We have designed this phase I trial to investigate IPP in combination with a standard chemotherapy combination in these patients., Methods: We use a 3+3 expanded cohort dose escalation until a predefined number of dose-limiting toxicities are reached. Patients will have an intraperitoneal catheter placed surgically after trial enrolment. Chemotherapy includes a maximum of six cycles (21 days) of capecitabine (X) (1000 mg/m 2 two times a day, days 1-14)+cisplatin (C) (intravenous 80 mg/m 2 day 1) and IPP (days 1 and 8) with the following doses: cohort-1: 10 mg/m 2 , cohort-2: 20 mg/m 2 and cohort-3: 30 mg/m 2 . Primary endpoint is to determine the maximum tolerated dose of IPP. Secondary endpoints include determining the safety and tolerability of IPP in combination with C and X, overall response rates, ascites response rate, progression-free survival, overall survival and effects on quality of life.Important inclusion criteria include age ≥18 years, human epidermal growth factor receptor 2 non-amplified gastric adenocarcinoma with histological or cytology-proven peritoneal involvement and adequate organ function. Exclusion criteria include previous malignancy within 5 years, recent abdominal or pelvic radiation treatment, significant abdominal adhesions or sepsis., Ethics and Dissemination: The study is approved by Southern Adelaide Clinical Human Research Ethics Committee. A manuscript will be prepared for publication on the completion of the trial. This study will be conducted according to the Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) annotated with TGA comments (Therapeutic Goods Administration DSEB July 2000) and in compliance with applicable laws and regulations. The study will be performed in accordance with the NHMRC Statement on Ethical Conduct in Research Involving Humans (© Commonwealth of Australia 2007), and the NHMRC Australian Code for the Responsible Conduct of Research (©Australian Government 2007), and the principles laid down by the World Medical Assembly in the Declaration of Helsinki 2008., Trial Registration Number: ACTRN12614001063606., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with chronic hepatitis B are at risk of reactivation of viral hepatitis during chemotherapy. We report a case of hepatitis B reactivation occurring in association with single-agent gemcitabine chemotherapy in the absence of significant myelosuppression. Gemcitabine is a nucleoside analog that can affect cell-mediated immunity, and this may contribute to an increased risk of reactivation of hepatitis B. We advise caution when administering chemotherapy to patients who are hepatitis B surface antigen positive, even when using relatively nontoxic palliative single-agent cytotoxic drugs. Monitoring of liver function tests will identify hepatitis, and measurement of hepatitis B DNA levels may help distinguish chemotherapy-induced hepatitis from hepatitis B virus reactivation.