Prognostic value of patient reported outcomes in advanced gastro-oesophageal cancer: a systematic review.

To summarise the prognostic value of patient-reported outcomes (PROs) in advanced gastro-oesophageal (GO) cancer. We systematically searched multiple databases using search terms related to advanced GO cancer, PRO and prognosis. Studies examining the relationship between baseline PROs and prognosis were included. Two reviewers independently screened articles and extracted data on study design, survival and associations between PROs and survival, in both univariable and multivariable analyses. QUIPS was used for quality assessment. From 3004 studies screened, seven studies were eligible, comprising PRO data from 2761 of 3408 (81%) participants. Median survival times ranged from 4.5 to 9.5 months. Among participants with oesophageal squamous cell carcinoma (SCC), physical functioning, social functioning and fatigue (QLQ-C30) were associated with overall survival (OS) in one univariable analysis. Among three studies of participants with adenocarcinoma, univariable analyses revealed associations between OS and global quality of life (QOL), physical functioning, role functioning and social functioning; two studies showed association with pain. There was an association between emotional functioning, fatigue, lack of mobility, lack of self-care, appetite loss/anorexia and OS in one study. One multivariable analysis among participants with oesophageal SCC showed physical and social functioning was associated with OS. Among participants with adenocarcinoma, multivariable analyses showed associations between OS and physical functioning/lack of mobility, appetite loss/anorexia (three studies), global QOL, role functioning/lack of self-care, pain (two studies) and social functioning (one study). Physical functioning, role functioning, social functioning, pain, anorexia and global QOL were associated with OS in advanced GO cancer.

Estimating survival scenarios in advanced or metastatic gastric and oesophageal adenocarcinoma: a systematic review of randomised-controlled trials.

Background: We aimed to summarize survival data from RCTs in patients with GO adenocarcinoma; estimate and explain worst-, typical- and best-case-scenarios of survival time; and determine if simple multiples of median overall survival (mOS) could estimate these percentiles.Methods: We systematically searched RCTs of systemic therapies for GO adenocarcinoma published 2000-2022. The following key percentiles were extracted from overall survival curves: 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). We tested if these percentiles could be estimated by simple multiples of mOS: 0.25 of the median for the 90th percentile, 0.5 for 75th, 2 for 25th, and 3 for 10th.Results: We identified 44 trials (22,447 participants). For first line chemotherapy and immunotherapy combined (CI) trials (n = 3) worst-to-best case survival time ranged from 4 months to not reached, compared to 3-30 months for other trials (n = 27) and 1-23 months for subsequent line (n = 14). Simple multiples of mOS accurately estimated the following survival percentiles: 90th (n = 3/3 trials), 75th (n = 3/3) and 25th (n = 2/3) in first line CI trials. In other first line trials, the mOS accurately estimated the 90th survival percentile in n = 22/27 trials, 75th percentile in n = 26/27, 25th percentile 27/27 and 10th percentile in 22/27. Simple multiples of the mOS accurately predicted the 90th, 75th, 25th and 10th survival percentiles in majority of trials of second and subsequent line apart from chemotherapy and immunotherapy only trials.Conclusion: We provide realistic, evidence-based prognostic information as scenarios for survival time which can inform clinical decision-making. Simple multiples of the mOS accurately estimated the percentiles for most groups.

Framework for the Use of External Controls to Evaluate Treatment Outcomes in Precision Oncology Trials.

Advances in genomics have enabled anticancer therapies to be tailored to target specific genomic alterations. Single-arm trials (SATs), including those incorporated within umbrella, basket, and platform trials, are widely adopted when it is not feasible to conduct randomized controlled trials in rare biomarker-defined subpopulations. External controls (ECs), defined as control arm data derived outside the clinical trial, have gained renewed interest as a strategy to supplement evidence generated from SATs to allow comparative analysis. There are increasing examples demonstrating the application of EC in precision oncology trials. The prospective application of EC in conducting comparative studies is associated with distinct methodological challenges, the specific considerations for EC use in biomarker-defined subpopulations have not been adequately discussed, and a formal framework is yet to be established. In this review, we present a framework for conducting a prospective comparative analysis using EC. Key steps are (1) defining the purpose of using EC to address the study question, (2) determining if the external data are fit for purpose, (3) developing a transparent study protocol and a statistical analysis plan, and (iv) interpreting results and drawing conclusions on the basis of a prespecified hypothesis. We specify the considerations required for the biomarker-defined subpopulations, which include (1) specifying the comparator and biomarker status of the comparator group, (2) defining lines of treatment, (3) assessment of the biomarker testing panels used, and (4) assessment of cohort stratification in tumor-agnostic studies. We further discuss novel clinical trial designs and statistical techniques leveraging EC to propose future directions to advance evidence generation and facilitate drug development in precision oncology.

Angiogenesis Inhibitors and Immunomodulation in Renal Cell Cancers: The Past, Present, and Future.

Angiogenesis inhibitors have been adopted into the standard armamentarium of therapies for advanced-stage renal cell carcinomas (RCC), but more recently, combination regimens with immune checkpoint inhibitors have demonstrated better outcomes. Despite this, the majority of affected patients still eventually experience progressive disease due to therapeutic resistance mechanisms, and there remains a need to develop novel therapeutic strategies. This article will review the synergistic mechanisms behind angiogenesis and immunomodulation in the tumor microenvironment and discuss the pre-clinical and clinical evidence for both clear-cell and non-clear-cell RCC, exploring opportunities for future growth in this exciting area of drug development.

Immune checkpoint inhibitor-induced myocarditis, myositis, myasthenia gravis and transaminitis: a case series and review.

Immune checkpoint inhibitors have been incorporated into the treatment of various malignancies. An increasing body of literature is reporting rare but potentially fatal adverse events associated with these agents. In this case series, the authors report the clinical features and outcomes of seven patients who received immune checkpoint inhibitors for different solid organ malignancies and developed a tetrad of immune-related myocarditis, myositis, myasthenia gravis and transaminitis. Herein the authors review the literature and describe the current diagnostic and management approach for this overlapping syndrome. The authors' series highlights the importance of a high index of clinical suspicion, prompt comprehensive investigations, early multidisciplinary team involvement and initiation of immunosuppressive therapy when immune-related adverse events are suspected.

Cancer immunotherapy is used in the treatment of different cancer types. Immunotherapy activates the immune system to detect and attack cancer cells, but side effects may arise from the immune system inadvertently attacking normal tissues and organs. The increased use of immunotherapy has led to an increase in the reporting of rare but potentially life-threatening treatment-related side effects. In this case series, the authors report the clinical features and outcomes of seven patients who developed inflammation of the heart, muscles, nerve and muscle junctions and liver following treatment with immunotherapy. The authors review the scientific literature and discuss the current understanding of and management approach to this rare syndrome. The authors' report highlights the importance of a high degree of clinical suspicion, prompt comprehensive testing to confirm diagnosis, early involvement of experts from different specialties and early initiation of treatment in the management of this unique syndrome.

Clinical and molecular profile of young adults with early-onset colorectal cancer: Experience from four Australian tertiary centers.

BACKGROUND: Patients with early-onset colorectal cancer (EO-CRC) have unique characteristics. Contemporary data on the pathological and molecular features, and survival of EO-CRC are limited in the Australian context. AIM: To determine the demographic, histopathological and molecular characteristics of adults with EO-CRC, and their survival. METHODS: We conducted a retrospective study of adults aged 18-49 years with EO-CRC who were referred to the Illawarra Shoalhaven Local Health District, South Eastern Sydney Local Health District and Royal North Shore Hospital in New South Wales, Australia, between 2014 and 2018. RESULTS: Of 257 patients included, 94 (37%) patients presented with de novo metastatic CRC, 80% patients had near-average risk family history and 89% had a symptomatic presentation. In 159 patients with nonmetastatic disease at diagnosis, stage III disease (OR 3.88 [95% CI: 1.13-13.3]; p = .03) and the presence of perineural invasion (PNI) (OR 6.63 [95% CI: 2.21-19.84]; p = .001) were risk factors associated with the development of metastatic disease. Among 94 patients with de novo metastatic disease, 43 (43%) and 12 (14%) patients harbored a KRAS or BRAF V600E mutation, respectively. The median overall survival was 29.6 months (95% CI: 20.4-38.7). BRAF mutation was associated with inferior survival (HR 3.00 [95% CI: 1.30-6.94]; p = .01). CONCLUSION: The prevalence of KRAS and BRAF mutations in our cohort is similar to the overseas experience. Stage III disease at diagnosis, presence of PNI and BRAF mutation are adverse prognostic indicators. A better understanding of the molecular landscape is needed for this patient cohort, so as to better tailor prevention strategies, screening and treatment pathways.

Efficacy of immune checkpoint inhibitors in older adults with advanced stage cancers: A meta-analysis.

OBJECTIVES: There is uncertainty whether older patients derive a similar benefit from immune checkpoint inhibitors (ICI) as younger patients. We performed a meta-analysis of ICI trials in advanced cancers to better estimate treatment benefit in the older population. MATERIALS AND METHODS: We performed an electronic search for randomized trials of ICI, either as monotherapy or in combination with other agents. Hazard ratios (HR) for subgroups defined by different age cut-offs were extracted. Pooled overall survival (OS) treatment estimates were calculated using the inverse variance weighted method. RESULTS: In nineteen trials comparing ICI monotherapy versus non-ICI treatment, there was no significant treatment-age interaction (age ≥ 65 years: N = 6064, HR 0.73; age < 65 years: N = 7250, HR 0.79; P-interaction = 0.27). Findings were similar at older age cut-offs of 70 years (age ≥ 70 years: N = 433, HR = 0.93; age < 70 years: N = 169, HR = 0.95; P-interaction = 0.91) and 75 years (age ≥ 75 years: N = 139, HR = 0.75; age < 75 years: N = 1133, HR = 0.61; P-interaction = 0.72) respectively, and for trials of ICI combination therapy. CONCLUSION: ICI therapy improves OS in both younger and older patients with advanced cancers, and the magnitude of improvement does not depend on age. Patient selection for ICI therapy should be done based on performance status and adequate organ function independently of age.