Search

Background: Immunotherapy is used routinely for treating deficient mismatch repair (dMMR) colon cancer (CC). This case series highlights an emerging safety issue, where patients develop bowel obstruction associated with immunotherapy response., Patients and Methods: Patients with dMMR CC who developed bowel obstruction while responding to immunotherapy were retrospectively identified. Data on patient, disease, treatment, and response-specific factors were explored for potential risk factors. Overall treatment numbers were used to estimate incidence., Results: Nine patients from eight European centres were included. Common features were hepatic flexure location (5/9), T4 radiological staging (6/9), annular shape (8/9), radiological stricturing (5/9), and endoscopic obstruction (6/9). All received pembrolizumab and obstructed between 45 and 652 days after starting treatment. Seven patients underwent surgical resection; one was managed with a defunctioning stoma; and one was managed conservatively. One patient died from obstruction. Radiological response was seen in eight patients, including two complete responses. Pathological response was seen in all seven who underwent resection, including four complete responses. The overall incidence of immunotherapy response-related obstruction in these centres was 1.51%., Conclusions: Bowel obstruction associated with immunotherapy response may represent a rare treatment-related complication in dMMR CC. Clinicians must recognise this safety signal and share experience to maintain patient safety., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Treating older adults with cancer is increasingly important in modern oncology practice. However, we currently lack the high-quality evidence needed to guide optimal management of this heterogeneous group. Principally, historic under-recruitment of older adults to clinical trials limits our understanding of how existing evidence can be applied to this group. Such uncertainty is particularly prevalent in the management of colon cancer (CC). With CC being most common in older adults, many patients also suffer from frailty, which is recognised as being strongly associated with poor clinical outcomes. Conducting clinical trials in older adults presents several major challenges, many of which impact the clinical relevance of results to a real-world population. When considering this heterogeneous group, it may be difficult to define the target population, recruit participants effectively, choose an appropriate trial design, and ensure participants remain engaged with the trial during follow-up. Furthermore, after overcoming these challenges, clinical trials tend to enrol highly selected patient cohorts that comprise only the fittest older patients, which are not representative of the wider population. FOxTROT1 was the first phase III randomised controlled trial to illustrate the benefit of neoadjuvant chemotherapy (NAC) in the treatment of CC. Patients receiving NAC had greater 2-year disease-free survival compared to those proceeding straight to surgery. Outcomes for older adults in FOxTROT1 were similarly impressive when compared to their younger counterparts. Yet, this group inevitably represents a fitter subgroup of the older patient population. FOxTROT2 has been designed to investigate NAC in a full range of older adults with CC, including those with frailty. In this review, we describe the key challenges to conducting a robust clinical trial in this heterogeneous patient group, highlight our strategies for overcoming these challenges in FOxTROT2, and explain how we hope to provide clarity on the optimal treatment of CC in older adults., Competing Interests: Disclosure ZC has received grants from Celgene, MSD, Amgen, and Takeda (via institution). MS has received a grant from Yorkshire Cancer Research to support provision of a clinical trial (via institution). MB has received payment/honoraria from Laboratoires Pierre Fabre, Amgen, and Servier, is Co-lead of Audit for the National Bowe Cancer Audit (England and Wales), and author of the National Institute for Health and Care Excellence (NICE) Colorectal Cancer Guideline. JR has received grants from Bristol Meyers Squibb, Laboratoires Pierre Fabre, Servier, HUB Organoids, and Cleara Biotech (via institution), consulting fees from Bayer, Bristol Meyers Squibb, Merck-Serono, Laboratoires Pierre Fabre, and Servier (via institution), payment/honoraria from Bristol Meyers Squibb, Laboratoires Pierre Fabre, and Servier (via institution), and support for attending meetings from Servier. JR is also a member of advisory boards for the PelvEx and MEND-IT trials, and a member of the ONCODE clinical advisory board. CP has received consulting fees from Nordic Pharma (via institution). JT has received payment/honoraria from Astellas Pharma Inc., Bristol Meyers Squibb, MSD, Merck & Co., Roche, Laboratoires Pierre Fabre, Novartis, and Servier, support for attending meetings from Laboratoires Pierre Fabre, MSD, and Servier, and is a member of advisory boards for Bristol Meyers Squibb, MSD, Merck & Co., Roche, Laboratoires Pierre Fabre, Novartis, and Servier. JB has received grants from Cancer Research UK, the National Institute for Health and Care Research, Medical Research Council, and Roche, and is Chair of the advisory board for the NIHR By-Band-Sleeve trial and the NIHR Health Technology Assessment General Funding Committee. DAC has received grants from Yorkshire Cancer Research (via institution) and support for attending meetings from Celgene. JFS has received consulting fees from Seagen, payment/honoraria from Laboratoires Pierre Fabre, Merck-Serono, and Servier, and support for attending meetings from Servier and Bristol Meyers Squibb. JFS is also a member of advisory boards for Elevation Oncology, Laboratoires Pierre Fabre, and Zentalis Pharmaceuticals. JFS, JB, and DM have received support from Yorkshire Cancer Research for the FOxTROT 2 trial, on which this manuscript is based (via institution). All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Primary tumour location (PTL) is being adopted by clinicians to guide treatment decisions in metastatic colorectal cancer (mCRC). Here we test PTL as a predictive marker for panitumumab efficacy, and examine its relationship with an extended biomarker profile. We also examine rectal tumours as a separate location., Patients and Methods: mCRC patients from the second-line PICCOLO trial of irinotecan versus irinotecan/panitumumab (IrPan). PTL was classified as right-PTL, left-PTL or rectal-PTL. PTL was assessed as a predictive biomarker for IrPan effect in RAS-wild-type (RAS-wt) patients (compared with irinotecan alone), then tested for independence alongside an extended biomarker profile (BRAF, epiregulin/amphiregulin (EREG/AREG) and HER3 mRNA expression)., Results: PTL data were available for 1180 patients (98.5%), of whom 558 were RAS-wt. High HER3 expression was independently predictive of panitumumab overall survival improvement, but PTL and EREG/AREG were not. IrPan progression-free survival (PFS) improvement compared with irinotecan was seen in left-PTL [hazard ratio (HR) = 0.61, P = 0.002) but not right-PTL (HR = 0.98, P = 0.90) (interaction P = 0.05; RAS/BRAF-wt interaction P = 0.10), or in rectal-PTL (HR = 0.82, P = 0.20) (interaction P = 0.14 compared with left-PTL; RAS/BRAF-wt interaction P = 0.04). Patients with right-PTL and high EREG/AREG or HER3 expression, had IrPan PFS improvement (high EREG/AREG HR = 0.20, P = 0.04; high HER3 HR = 0.33, P = 0.10) compared with irinotecan. Similar effect was seen for rectal-PTL patients (high EREG/AREG HR = 0.44, P = 0.03; high HER3 HR = 0.34, P = 0.05)., Conclusions: RAS-wt patients with left-PTL are more likely to have panitumumab PFS advantage than those with right-PTL or rectal-PTL. However, an extended biomarker panel demonstrated significant heterogeneity in panitumumab PFS effect within a tumour location. AREG/EREG and HER3 mRNA expression identifies patients with right-PTL or rectal-PTL who achieve similar PFS effect with panitumumab as left-colon patients. Testing could provide a more reliable basis for clinical decision making. Further validation and development of these biomarkers is required to optimise routine patient care., Clinical Trial Registration: ISRCTN identifier: ISRCTN93248876., Competing Interests: Disclosure JS has received speaker fees from Merck Serono and has served on advisory committees for Roche and Pierre Fabre. The other authors have declared no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

The presence of peritoneal metastases in patients with advanced colorectal cancer is associated with poor prognosis but the mechanisms for this are unclear. This review summarises the current knowledge of the pathophysiology, clinical features, prevalence, prognosis, and molecular biology of peritoneal metastases and the risk factors for the development of peritoneal metastases following resection of a primary colorectal tumour. Furthermore, the evidence for treatment strategies are described including cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, early post-operative intraperitoneal chemotherapy, sequential post-operative intraperitoneal chemotherapy and emerging novel strategies. Active areas of research should include the identification of individuals at high risk of peritoneal metastases after curative resection of primary tumour, development of a surveillance program for high-risk patients, optimisation of systematic therapies and further investigation of the use of intraperitoneal chemotherapy., Competing Interests: Declaration of competing interest JS – speaker fees Merck Serono; advisory board - Pierre Fabre, Roche; CME – GI Connect. NPW - consultancy fees from Eisai., (Copyright © 2019. Published by Elsevier Ltd.)

Background: To improve strategies for the treatment of BRAF-mutant advanced colorectal cancer (aCRC) patients, we examined individual data from patients treated with chemotherapy alone in three randomised trials to identify points on the treatment pathway where outcomes differ from BRAF wild-types., Patients and Methods: 2530 aCRC patients were assessed from three randomised trials. End-points were progression-free survival, response rate, disease control rate, post-progression survival (P-PS) and overall survival. Treatments included first-line oxaliplatin/fluorouracil (OxFU) and second-line irinotecan. Clinicians were unaware of BRAF-status., Results: 231 patients (9.1%) had BRAF-mutant tumours. BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic. Compared with wild-type, BRAF-mutant patients treated with first-line OxFU had similar DCR (59.2% versus 72%; adjusted OR = 0.76, P = 0.24) and PFS (5.7 versus 6.3 months; adjusted HR = 1.14, P = 0.26). Following progression on first-line chemotherapy, BRAF-mutant patients had a markedly shorter P-PS (4.2 versus 9.2 months, adjusted HR = 1.69, P < 0.001). Fewer BRAF-mutant patients received second-line treatment (33% versus 51%, P < 0.001), but BRAF-mutation was not associated with inferior second-line outcomes (RR adjusted OR = 0.56, P = 0.45; PFS adjusted HR = 1.01, P = 0.93). Significant clinical heterogeneity within the BRAF-mutant population was observed: a proportion (24.3%) had good first-line PFS and P-PS (both >6 months; OS = 24.0 months); however, 36.5% progressed rapidly through first-line chemotherapy and thereafter, with OS = 4.7 months., Conclusions: BRAF-mutant aCRC confers a markedly worse prognosis independent of associated clinicopathological features. Chemotherapy provides meaningful improvements in outcome throughout treatment lines. Post-progression survival is markedly worse and vigilance is required to ensure appropriate delivery of treatment after first-line progression., (© The Author 2016. 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.)