Clinical outcomes of chemotherapy-based therapies for previously treated advanced colorectal cancer: a systematic literature review and meta-analysis.

PURPOSE: The purpose of this study was to evaluate clinical outcomes of standard therapies in previously treated, advanced colorectal cancer (CRC) patients. METHODS: A systematic literature review was conducted in Embase, MEDLINE, and CENTRAL databases (January 2000-July 2021), annual oncology conferences (2019-2021), and clinicaltrials.gov to identify studies evaluating the use of licensed interventions in second-line or later settings. The primary outcome of interest was objective response rate (ORR) and secondary outcomes included progression-free survival (PFS) and overall survival (OS). ORR was pooled using the Freeman-Tukey double arcsine transformation. For survival outcomes, published Kaplan-Meier curves for OS and PFS were digitized to re-construct individual patient-level data and pooled following the methodology described by Combescure et al. (2014). RESULTS: Twenty-three trials evaluating standard chemotherapies with or without targeted therapies across 4,791 advanced CRC patients contributed to our meta-analysis. In the second-line setting, the random effects pooled estimate of ORR was 22.4% (95% confidence interval (CI): 18.0, 27.1), median PFS was 7.0 months (95% CI: 6.4, 7.4), and median OS was 14.9 months (95% CI: 13.6, 16.1). In the third-line or later setting, the random effects pooled estimate of ORR was 1.7% (95% CI: 0.8, 2.7), median PFS was 2.3 months (95% CI: 2.0, 2.8), and median OS was 8.2 months (95% CI: 7.1, 9.1). CONCLUSION: Standard treatments have limited efficacy in the second-line or later setting with worsening outcomes in later lines. Given the global burden of CRC, further research into novel and emerging therapeutic options following treatment failure is needed.

Unreported and Overlooked: A Post Hoc Analysis of COPD Symptom-Related Attacks from the RISE Study.

Purpose: Moderate and severe COPD exacerbations are a significant health-care burden, but patients also experience "mild" exacerbations, or COPD symptom-related attacks, which often go unreported. We aimed to define and then determine the incidence of COPD symptom-related attacks and their impact on future risk of moderate/severe exacerbations, health-related quality of life (HRQoL), and lung function. The effect of COPD maintenance therapy on the attack definition was then evaluated by comparing budesonide/formoterol with formoterol alone. Patients and Methods: This post hoc analysis of the RISE study defined COPD symptom-related attacks as ≥2 consecutive days of both worsening symptoms and increased daily rescue medication use based upon thresholds of >2 and >4 short-acting ß2-agonist (SABA) inhalations/day above baseline. The impact of these events on subsequent moderate/severe exacerbation risk was estimated using a time-varying Cox proportional hazards model. The effects of COPD symptom-related attacks on St George's Respiratory Questionnaire (SGRQ) total score and pre-bronchodilator forced expiratory volume in 1 second (FEV1) were evaluated as average changes from baseline to first post-attack measurement. Rates of attacks were compared between treatment groups using negative binomial regression models. Results: COPD symptom-related attacks elevated the risk of subsequent moderate/severe exacerbations at both >2 and >4 inhalations/day above baseline (HR 1.86 and 2.21, respectively; p<0.0001), with a cumulative increase in risk with increasing attacks. HRQoL and lung function were reduced for patients with ≥1 versus no COPD symptom-related attacks at both rescue medication thresholds. There were fewer COPD symptom-related attacks with budesonide/formoterol versus formoterol alone, with no increased risk of pneumonia and lower respiratory tract infections. Conclusion: COPD symptom-related attacks are common and typically unreported. Importantly, these attacks can account for considerable morbidity and should not be regarded as "mild". Detection of such exacerbations may be valuable in identifying patients at greater risk and guiding preventive therapeutic interventions.