Shi, Qian

Background: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs). Design: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions. Results: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland ( p = 0.0034 and p < 0.001, respectively), with median difference of 3–4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients ( p < 0.001). Conclusions: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.

Abstract Background Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing. Methods Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided. Results Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P &lt; .001), disease-free survival (HR = 0.91, 95% CI = 0.84 to 0.98; P = .01), and survival after recurrence (HR = 0.88, 95% CI = 0.80 to 0.97; P = .008) in the analysis without molecular markers; however, age at onset of CC lost its prognostic value when outcome was adjusted for molecular markers. Conclusion Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.

Abstract Background Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients. Methods PTS data of 9277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemotherapy, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs chemotherapy alone). All statistical tests were 2-sided. Results Compared with right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 vs 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67 to 0.76; P &lt; .001) and PFS (median = 8.6 vs 7.5 months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P &lt; .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction &lt; .001); left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53 to 0.66; PFS HRadj =0.68, 95% CI = 0.61 to 0.75) but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75 to 0.97; P = .01; PFS HRadj = 0.77, 95% CI = 0.67 to 0.88; P &lt; .001) but not for right-sidedness. Conclusions The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.

Abstract Background: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer–specific survival. Methods: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer–specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components. Results: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer–specific survival (HD, −1.15; 95% CI, −2.76 to 0.47 per 100,000 person-years; P = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location. Conclusions: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer–specific survival. Impact: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.

Given the Food and Drug Administration's (FDA's) acceptance of master protocol designs in recent guidance documents, the oncology field is rapidly moving to address the paradigm shift to molecular subtype focused studies. Identifying new “marker‐based” treatments requires new methodologies to address the growing demand to conduct clinical trials in smaller molecular subpopulations, identify effective treatment and marker interactions, and control for false positives. We introduce our methodology, Hierarchical Bayesian Clustering Design of Multiple Biomarker Subgroups (HCOMBS), a two‐stage umbrella Phase II design with effect size clustering and information borrowing across multiple biomarker‐treatment pairs. HCOMBS was designed to reduce required sample size, differentiate between varying effect sizes, and control for operating characteristics in the multi‐arm setting. When compared to independently applied Simon's Optimal two‐stage design, we showed through simulations that HCOMBS required less participants per treatment arm with a well‐controlled family‐wise error rate and desirable marginal power. Additionally, HCOMBS features a statistical approach that simultaneously conducts clustering and hypothesis testing in one step. We also applied the proposed design on the alliance brain metastases umbrella trial.

Abstract Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs &gt;70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (&gt;70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age &gt;70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin &lt;12 g/dL, ECOG PS ≥2, and elevated β2-microglobulin. Median follow-up was 5.6 years. Patients &gt;70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients &gt;70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P &lt; .001). Age &gt;70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients &gt;70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.

Abstract Background First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed to assess the prognostic and predictive impact of BRAFmt on the efficacy of targeted therapies with first-line chemotherapy. Methods Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomly assigned whenever possible. Results A total of 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%), and 3759 double wild type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] = 1.46, 95% confidence interval [CI] = 1.30 to 1.64) and patients with double wild-type tumors (HRadj = 2.14, 95% CI = 1.94 to 2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy with or without anti-epidermal growth factor receptor (anti-EGFR) (HRadj = 0.96, 95% CI = 0.71 to 1.30; and HRadj = 0.85, 95% CI = 0.66 to 1.14, respectively). Conclusions Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.

Abstract Disease progression after frontline therapy for Diffuse large B‐cell lymphoma (DLBCL) is a clinically significant event. Patients who experience early progression or have refractory disease have especially poor outcomes. Simple, clinically applicable prognostic tools are needed for selecting patients for consideration for novel therapies and prognostication in the relapsed/refractory (R/R) setting. Model building was performed in patients from the Surrogate endpoints in aggressive lymphoma (SEAL) consortium with disease progression after frontline immunochemotherapy. The primary endpoint was overall survival (OS) measured from date of progression. Validation was performed in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and Danish National Lymphoma Register (LYFO) cohorts. Model performance was assessed using time‐dependent concordance indices (c‐statistic) and calibration with metrics evaluated at 2 years from progression. Note, 1234 of 5112 patients treated with frontline immunochemotherapy in the SEAL consortium developed progressive disease. Time to progression on immunochemotherapy and age at progression were strongly associated with post‐progression OS (both p < 0.001). A prognostic model was developed incorporating spline fit for both variables. The model had good concordance in the discovery (0.67) and validation sets (LYFO c = 0.64, MER c = 0.68) with generally good calibration. Time to progression on frontline therapy is strongly associated with post‐progression OS in DLBCL. We developed and validated a simple to apply clinical prognostic tool in the R/R setting. The useful prediction of expected outcomes in R/R DLBCL and can inform treatment decisions such as considerations for CAR‐T therapy as well as trial designs. The model is available in smartphone‐based point of care applications.

PURPOSE: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. PATIENTS AND METHODS: Four of the six studies in the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. RESULTS: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). CONCLUSION: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.