Cross-trial comparisons for the adjuvant treatment of MSI colorectal cancer: dare to dream the future scenarios.

The remarkable outcomes achieved with neoadjuvant checkpoint inhibitors for patients diagnosed with MSI colorectal cancer hold the potential to revolutionize the treatment landscape in this context. Specifically, the combination of nivolumab plus ipilimumab in colon cancer and dostarlimab in rectal cancer has led to an unprecedented rate of complete pathological and clinical responses. Notably, these responses have been further substantiated by the absence of relapses, with a 0% relapse rate observed during the first year of follow-up. The significance of these achievements becomes even more apparent when compared to the relatively high relapse rates, ranging from 11% to 28%, observed in MSI colorectal cancer cases treated neoadjuvantly with chemo(radio)therapy. However, it is crucial to exercise caution when interpreting such exceptional responses in oncology, especially within a short follow-up period. The future implications of these findings will depend on how the data mature over time. In this manuscript, we attempt to explore the potential scenarios that may unfold in the near future.

Development and validation of a predictive score for diagnosing prostate cancer in primary care.

BACKGROUND: Prostate cancer (PCa) represents the fifth cause of death in the male population worldwide. The prostate-specific antigen (PSA) test demonstrated poor accuracy to assess the presence of PCa. Thus, the PSA testing paradigm should be moved from the systematic screening approach to the early identification of men who are harbouring clinically significant disease. Accurate clinical-based tools to predict PCa should therefore be developed for general practice. We derived and validated a PCa predictive score using a primary care data source. METHODS: Using the Italian Health Search Database, we formed a cohort of men aged 45-90 years in the period between 2002 and 2015. These patients were followed up until 31 December 2022. Those with less than a 5-year follow-up were excluded. The cohort was randomly divided into 'derivation' and 'validation' samples in a 1:1 ratio. Along with the demographic and clinical determinants forming the score, we investigated the role of PSA kinetics in the prediction accuracy. RESULTS: In a cohort of 529,082 men aged 45+ years, we identified 14,524 cases of PCa (incidence rate = 2.71 per 1000 person-years; 95% confidence interval = 2.67-2.80). The prediction accuracy of the PCa-HScore featured an explained variation of 12% and a discrimination power of 70%. The calibration slope was almost equal to 1 (p = 0.951, tested for equivalence against the 'perfect' slope) and the PSA kinetics did not improve the prediction accuracy. CONCLUSIONS: The PCa-HScore might guide the prescription of PSA and/or other clinical strategies in those men reporting certain levels of risk. A related decision support system could therefore be implemented in primary care.

Standardizing data collection in adjuvant colon cancer trials: A consensus project from the IDEA and ACCENT international consortia and national experts.

BACKGROUND: Despite contributions provided by the recent clinical trials, several issues and challenges still remain unsolved in adjuvant colon cancer (CC). Hence, further studies should be planned to better refine risk assessment as well as to establish the optimal treatment strategy in the adjuvant setting. However, it is necessary to request adequate, contemporary and relevant variables and report them homogeneously in order to bring maximal information when analyzing their prognostic value. MATERIAL AND METHODS: The project was devised to gain a consensus from experts engaged in the planning, accrual and analyses of stage II and III CC clinical trials, to identify mandatory and recommended baseline variables in order to i) harmonize future data collection worldwide in clinical trials dedicated to adjuvant treatment of CC; ii) propose guidance for Case Report Forms to be used for clinical trials in this setting. A total of 72 questions related to variables that should be reported and how to report them in adjuvant clinical trials were approved and then voted to reach a final consensus from panelists. RESULTS: Data items on patient-related factors, histopathological features, molecular profile, circulating biomarkers and blood analyses were analyzed and discussed by the whole expert panel. For each item, we report data supporting the acquired consensus and the relevant issues that were discussed. Nineteen items were deemed to be mandatory for resected stage III patients and 24 for resected stage II disease. In addition, 9 and 4 items were judged as recommended for stage III and II, respectively. CONCLUSION: In our opinion, these 28 variables should be used and uniformly reported in more comprehensive CRFs as research groups design future clinical trials in the field of adjuvant colon cancer.

Oxaliplatin-Based Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 12 Trials.

PURPOSE: A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS: We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS: A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION: In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis.

BACKGROUND: The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS: A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION: LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.