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.

Efficacy of immune checkpoint inhibitors for metastatic colorectal cancer with microsatellite instability in second or latter line using synthetic control arms: A non-randomised evaluation.

PURPOSE: Immune checkpoint inhibitors (ICIs) appeared active in single-arm trials for patients with chemoresistant metastatic colorectal cancer (mCRC) harboring microsatellite instability (MSI). Given the paucity of randomised controlled trials (RCTs) in this setting, we evaluated the effect size of ICIs using intra-patients comparison and ARCAD database as historical controls. PATIENTS AND METHODS: Individual-patient data from NIPICOL and CheckMate 142 phase II trials that evaluated a combination of ICIs for MSI mCRC patients (N = 176) and from five non-ICI mCRC historical RCTs in second-line or latter (N = 4026) were analyzed. Firstly, promising of ICIs was identified using intra-patient comparison based on growth modulation index (GMI) defined the ratio of progression-free survivals (PFS) on ICIs and previous line of therapy. Survival outcomes of ICIs-treated patients were then compared with those matched non-ICIs treated from ARCAD database historical RCTs. RESULTS: Among ICIs-treated patients, median PFS on ICIs was 32.66 (range 0.10-74.25) versus 4.07 months (range 0.7-49.87) on prior therapy, resulting on median GMI of 4.97 (range 0.07-59.51; hazard-ratio (HR)= 0.16 (95 %CI=0.11-0.22, P < 0.001)). Compared to matched non-ICI patients, in third-line, median overall survival (OS) was not reached with ICIs versus 3.52 months with placebo (HR=0.20, 95 %CI=0.10-0.41, P < 0.001), and 6.51 months with active drugs (HR=0.30, 95 %CI=0.15-0.60, P = 0.001). In second-line, median OS was not reached with ICIs versus 11.7 months with chemotherapy+placebo (HR=0.12, 95 %CI=0.07-0.22, P < 0.001), and 16.3 months with chemotherapy+targeted therapy (HR=0.10, 95 %CI=0.05-0.19, P < 0.001). CONCLUSION: ICIs demonstrates high effect size for MSI mCRC patients in second-line and later. This work might be useful as an example of methodology to avoid RCTs when benefit from experimental therapy is likely to be high.

A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: The AGENT Trial.

PURPOSE: Suboptimal treatment outcomes with 5-fluorouracil (5-FU)/folate, the standard of care for metastatic colorectal cancer (mCRC), have generated interest in optimizing the folate. Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is an immediately active folate and may improve outcomes over the existing standard of care (leucovorin). EXPERIMENTAL DESIGN: AGENT was a randomized, phase III study (NCT03750786). Patients with mCRC were randomized to arfolitixorin (120 mg/m2 given as two intravenous bolus doses of 60 mg/m2) or leucovorin (400 mg/m2 given as a single intravenous infusion) plus 5-FU, oxaliplatin, and bevacizumab. Assessments were performed every 8 weeks. The primary endpoint was the superiority of arfolitixorin for overall response rate (ORR). RESULTS: Between February 2019 and April 2021, 490 patients were randomized (245 to each arm). After a median follow-up of 266 days, the primary endpoint of superiority for ORR was not achieved (48.2% for arfolitixorin vs. 49.4% for leucovorin, Psuperiority = 0.57). Outcomes were not achieved for median progression-free survival (PFS; 12.8 and 11.6 months, P = 0.38), median duration of response (12.2 and 12.9 months, P = 0.40), and median overall survival (23.8 and 28.0 months, P = 0.78). The proportion of patients with an adverse event of grade ≥3 severity was similar between arms (68.7% and 67.2%, respectively), as was quality of life. BRAF mutations and MTHFD2 expression were both associated with a lower PFS with arfolitixorin. CONCLUSIONS: The study failed to demonstrate clinical benefit of arfolitixorin (120 mg/m2) over leucovorin. However, it provides some useful insights from the first-line treatment setting, including the effect of gene expression on outcomes. SIGNIFICANCE: This phase III study compared arfolitixorin, a direct-acting folate, with leucovorin in FOLFOX plus bevacizumab in mCRC. Arfolitixorin (120 mg/m2) did not improve the ORR, potentially indicating a suboptimal dose.

Evaluation of Intratumoral Response Heterogeneity in Metastatic Colorectal Cancer and Its Impact on Patient Overall Survival: Findings from 10,551 Patients in the ARCAD Database.

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). PATIENTS AND METHODS: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. RESULTS: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. CONCLUSION: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes.

FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study.

PURPOSE: In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). PATIENTS AND METHODS: Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m2 or dl-LV 400 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 to 3,000 mg/m2 every 46 hours every 2 weeks, either with irinotecan 180 mg/m2 or with oxaliplatin 100 mg/m2 as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). RESULTS: Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P = .99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P = .64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P = .26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. CONCLUSION: Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.

Clinical and exploratory biomarker findings from the MODUL trial (Cohorts 1, 3 and 4) of biomarker-driven maintenance therapy for metastatic colorectal cancer.

PURPOSE: MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). We report findings from Cohorts 1 (BRAFmut), 3 (human epidermal growth factor 2 [HER2]+) and 4 (HER2‒/high microsatellite instability, HER2‒/microsatellite stable [MSS]/BRAFwt or HER2‒/MSS/BRAFmut/RASmut). METHODS: Patients with unresectable, previously untreated mCRC without disease progression following standard induction treatment (5-fluorouracil/leucovorin [5-FU/LV] plus oxaliplatin plus bevacizumab) were randomly assigned to control (fluoropyrimidine plus bevacizumab) or cohort-specific experimental maintenance therapy (Cohort 1: vemurafenib plus cetuximab plus 5-FU/LV; Cohort 3: capecitabine plus trastuzumab plus pertuzumab; Cohort 4: cobimetinib plus atezolizumab). The primary efficacy end-point was progression-free survival (PFS). RESULTS: Cohorts 1, 3 and 4 did not reach target sample size because of early study closure. In Cohort 1 (n = 60), PFS did not differ between treatment arms (hazard ratio, 0.95; 95% confidence intervals 0.50-1.82; P = 0.872). However, Cohort 1 exploratory biomarker data showed preferential selection for mitogen-activated protein kinase (MAPK) pathway mutations (mainly KRAS, NRAS, MAP2K1 or BRAF) in the experimental arm but not the control arm. In Cohort 3 (n = 5), PFS ranged from 3.6 to 14.7 months versus 4.0 to 5.4 months in the experimental and control arms, respectively. In Cohort 4 (n = 99), PFS was shorter in the experimental arm (hazard ratio, 1.44; 95% confidence intervals 0.90-2.29; P = 0.128). CONCLUSIONS: Vemurafenib plus cetuximab plus 5-FU/LV warrants further investigation as first-line maintenance treatment for BRAFmut mCRC. MAPK-pathway emergent genomic alterations may offer novel therapeutic opportunities in BRAFmut mCRC. Cobimetinib plus atezolizumab had an unfavourable benefit:risk ratio in HER2‒/MSS/BRAFwt mCRC. New strategies are required to increase the susceptibility of MSS mCRC to immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02291289.

Evaluating sex as a predictive marker for response to bevacizumab in metastatic colorectal carcinoma: Pooled analysis of 3,369 patients in the ARCAD database.

BACKGROUND: Previous studies suggest a possible sex-specific response to bevacizumab in metastatic colorectal carcinoma (mCRC), showing a benefit in males, while the effect in females is less significant. METHODS: Data from 3369 patients with mCRC enrolled on four first-line randomised trials testing chemotherapy with or without bevacizumab (2000-2007) were pooled. Association between sex and progression-free survival and overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction effect between sex and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut point of 60 years to evaluate the possible role of menopausal-related effects. RESULTS: Bevacizumab was associated with an improved median OS in males and females, with a 2.3- and 0.6-months benefit, respectively. Stratified by age, bevacizumab resulted in improved OS in males at both age categories. In females at or above the age of 60 (n = 731), bevacizumab resulted in improved OS. However, in females below the age of 60 (n = 634), OS benefit did not reach statistical significance (adjusted hazard ratio = 0.94, 95% confidence interval 0.74-1.20). CONCLUSIONS: Our results confirmed the OS benefit from the addition of bevacizumab to first-line chemotherapy in mCRC in both sexes. Among females, the benefit was less than 1 month. For females under the age of 60, there was no survival benefit. These findings could be used to relieve financial toxicity or be redistributed within healthcare systems for other health-related purposes.

Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials.

PURPOSE: Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. MATERIALS AND METHODS: We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. RESULTS: Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. CONCLUSION: In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

Impact of Preoperative Chemotherapy Features on Patient Outcomes after Hepatectomy for Initially Unresectable Colorectal Cancer Liver Metastases: A LiverMetSurvey Analysis.

Background: Prognostic factors have been extensively reported after resection of colorectal liver metastases (CLM); however, specific analyses of the impact of preoperative systemic anticancer therapy (PO-SACT) features on outcomes is lacking. Methods: For this real-world evidence study, we used prospectively collected data within the international surgical LiverMetSurvey database from all patients with initially-irresectable CLM. The main outcome was Overall Survival (OS) after surgery. Disease-free (DFS) and hepatic-specific relapse-free survival (HS-RFS) were secondary outcomes. PO-SACT features included duration (cumulative number of cycles), choice of the cytotoxic backbone (oxaliplatin- or irinotecan-based), fluoropyrimidine (infusional or oral) and addition or not of targeted monoclonal antibodies (anti-EGFR or anti-VEGF). Results: A total of 2793 patients in the database had received PO-SACT for initially irresectable diseases. Short (<7 or <13 cycles in 1st or 2nd line) PO-SACT duration was independently associated with longer OS (HR: 0.85 p = 0.046), DFS (HR: 0.81; p = 0.016) and HS-RFS (HR: 0.80; p = 0.05). All other PO-SACT features yielded basically comparable results. Conclusions: In this international cohort, provided that PO-SACT allowed conversion to resectability in initially irresectable CLM, surgery performed as soon as technically feasible resulted in the best outcomes. When resection was achieved, our findings indicate that the choice of PO-SACT regimen had a marginal if any, impact on outcomes.

Trajectories of body weight change and survival among patients with mCRC treated with systemic therapy: Pooled analysis from the ARCAD database.

BACKGROUND: Higher body mass index is associated with a higher incidence of colorectal cancer (CRC) but also with improved survival in metastatic CRC (mCRC). Whether weight change after mCRC diagnosis is associated with survival remains largely unknown. METHODS: We analysed individual patient data for previously untreated patients enrolled in five phase 3 randomised trials conducted between 1998 and 2006. Weight measurements were prospectively collected at baseline and up to 59.4 months after diagnosis. We used stratified multivariable Cox models to assess the prognostic associations of weight loss with overall and progression-free survival, adjusting for other factors. The primary end-point was a difference in overall survival (OS) between populations with weight loss and stable or increasing weight. FINDINGS: Data were available for 3504 patients. The median weight change at 3 months was -0.54% (IQR -3.9 … +1.5%). We identified a linear trend of increasing risk of death associated with progressive weight loss. Unstratified median OS was 20.5, 18.0, and 11.9 months (p < 0.001) for stable weight or gain, <5% weight loss, and ≥5% weight loss at 3 months, respectively. Weight loss was associated with a higher risk of death (<5% loss: aHR 1.18 [1.06-1.30], p < 0.002; ≥5% loss: aHR 1.87 [1.67-2.1], p < 0.001) as compared to stable or increasing weight at 3 months post-baseline (reference), while adjusting for age, sex, performance, and a number of metastatic sites. INTERPRETATION: Patients losing weight during systemic therapy for metastatic colorectal cancer have significantly shorter OS. The degree of weight loss is proportional to the observed increased risk of death and remains evident among underweight, normal weight, and obese individuals. On-treatment weight change could be used as an intermediate end-point. FUNDING: The creation and management of the database containing the individual patient data from the original randomised trials is supported by the Aide et Recherche en Cancérologie Digestive Foundation.

Efficacy of anti-epidermal growth factor receptor agents in patients with RAS wild-type metastatic colorectal cancer ≥ 70 years.

PURPOSE: Colorectal cancer (CRC) affects many older adults. We investigated the efficacy and safety of adding anti-epidermal growth factor receptor (EGFR) agents to doublet chemotherapy (DC) in older patients. METHODS: Patients with RAS wild-type (WT) metastatic CRC (mCRC) receiving first-line DC + anti-EGFR (n = 1191) or DC alone (n = 729) from seven trials in the Aide de Recherche en Cancerologie Digestive database were included. The prognostic and predictive effects of age were investigated. Progression-free and overall survival (OS) were evaluated between age groups (≥70 vs <70) for DC + anti-EGFR. In addition, outcomes were compared between DC+/-anti-EGFR within age groups in three trials with a DC alone arm. Subsequently, the same analysis was conducted for left-sided tumours. Adverse events grade ≥3 (G3+) were compared between age groups. RESULTS: Older (vs younger) patients receiving DC + anti-EGFR had similar progression-free survival (PFS) (8.7 vs 10.3 months; hazard ratio (HR) = 1.20 [0.96-1.49];p = 0.107) but inferior OS (21.3 vs 26.3; HR = 1.36 [1.08-1.72];p = 0.011). DC + anti-EGFR (vs DC alone) improved OS (23.9 vs 20.3; HR = 0.82 [0.70-0.95];p = 0.008) and PFS (11.2 vs 8.9; HR = 0.70 [0.60-0.82];p < 0.001) in younger but not older patients: OS (24.7 vs 17.6; HR [95% confidence interval {CI}] = 0.77 [0.58-1.04];p = 0.092) and PFS (9.1 vs 8.7; HR [95% CI] = 0.85[0.63-1.15];p = 0.287). In left-sided 'only' tumours, the following outcomes for older (vs younger) patients were observed. For DC + anti-EGFR, PFS 9 versus 11.2 months; HR1.10 (95% CI 0.83-1.46); p = 0.52, OS 25.6 vs 30.3 HR 1.32 (95% CI 0.97-1.79), p = 0.086. For DC + anti-EGFR (vs DC alone), PFS and OS for younger patients were 11.9 vs 9.2 months HR 0.60 (95% CI 0.47-0.78) p < 0.001 and 24.1 versus 23.3 months HR 0.84 (95% CI 0.67-1.04), respectively. For older patients, PFS and OS were 13.1 versus 8.5 months, HR 0.51 (95% CI, 0.28-0.93), P = 0.027 and 26.3 versus 16.5 months HR 0.49 (95% CI, 0.28-0.85), respectively. There was no significant difference in toxicity among different age groups. CONCLUSIONS: Older (vs younger) patients with mCRC RAS WT patients had comparable toxicity and efficacy with the addition of anti-EGFR agents to chemotherapy.

New curative approach using embolization followed by moderate-dose radiotherapy after surgical failure for large right heart metastasis.

PURPOSE: Cardiac metastasis is a rare fatal event. An intracavitary right tumor mainly in the ventricle is difficult to manage. Literature reports suggest that cardiac surgery in oligometastatic patients could offer median survival of 1 year. We investigated salvage treatment comprising transcoronary tumor embolization followed 15 days later by cardiac radiotherapy (40.5 Gy/15 fractions). CASES: We report two cases of severe right cardiac metastasis with a history of abdominal cancer managed by this salvage treatment following residual cardiac mass after previous cardiac surgery. CONCLUSION: Both symptomatic patients improved progressively and were locally controlled for at least 1 year without toxicity.

Clinical Trial Endpoints in Metastatic Cancer: Using Individual Participant Data to Inform Future Trials Methodology.

Meta-analysis based on individual participant data (IPD) is a powerful methodology for synthesizing evidence by combining information drawn from multiple trials. Hitherto, its principal application has been in questions of clinical management, but an increasingly important use is in clarifying trials methodology, for instance in the selection of endpoints, as discussed in this review. In oncology, the Aide et Recherche en Cancérologie Digestive (ARCAD) Metastatic Colorectal Cancer Database is a leader in the use of IPD-based meta-analysis in methodological research. The ARCAD database contains IPD from more than 38 000 patients enrolled in 46 studies and continues to collect phase III trial data. Here, we review the principal findings of the ARCAD project in respect of endpoint selection and examine their implications for cancer trials. Analysis of the database has confirmed that progression-free survival (PFS) is no longer a valid surrogate endpoint predictive of overall survival in the first-line treatment of colorectal cancer. Nonetheless, PFS remains an endpoint of choice for most first-line trials in metastatic colorectal cancer and other solid tumors. Only substantial PFS effects are likely to translate into clinically meaningful benefits, and accordingly, we advocate an oncology research model designed to identify highly effective treatments in carefully defined patient groups. We also review the use of the ARCAD database in assessing clinical response including novel response metrics and prognostic markers. These studies demonstrate the value of IPD as a tool for methodological studies and provide a reference point for the expansion of this approach within clinical cancer research.

Selinexor, a selective inhibitor of nuclear export, enhances the anti-tumor activity of olaparib in triple negative breast cancer regardless of BRCA1 mutation status.

Triple negative breast cancer (TNBC) is a deadly disease with limited treatment options. Selinexor is a selective inhibitor of nuclear export that binds covalently to exportin 1 thereby reactivating tumor suppressor proteins and downregulating expression of oncogenes and DNA damage repair (DDR) proteins. Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor approved for the treatment of patients with breast cancer harboring BRCA mutations. We examined the effects of co-treatment with selinexor and olaparib in TNBC cell lines. BRCA1 wildtype (BRCA1-wt) and BRCA1 mutant (BRCA1-mut) TNBC cell lines were treated with selinexor and/or olaparib and effects on cell viability and cell cycle were evaluated. The effects of treatment were also evaluated in mouse xenograft models generated with BRCA1-wt and BRCA1-mut TNBC cell lines. Treatment with selinexor inhibited cell proliferation and survival of all TNBC cell lines tested in vitro. This effect was enhanced following treatment of the cells with the combination of selinexor and olaparib, which showed synergistic effects on tumor growth inhibition in MDA-MB-468-derived (BRCA1-wt) and MDA-MB-436-derived (BRCA1-mut) xenografts. As co-treatment with selinexor and olaparib exhibits anti-tumor activity regardless of BRCA1 mutation status, the clinical implications of the combination warrant further investigation.

Clinicopathological and Molecular Characteristics of Early-Onset Stage III Colon Adenocarcinoma: An Analysis of the ACCENT Database.

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 < .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.

Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis.

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.

Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer.

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 < .001) and PFS (median = 8.6 vs 7.5 months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P < .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction < .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 < .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.

Treatment breaks in first line treatment of advanced colorectal cancer: An individual patient data meta-analysis.

BACKGROUND: Intermittent systemic anti-cancer therapy in patients with advanced colorectal cancer (aCRC) may improve quality of life without compromising overall survival (OS). We aimed to use individual patient data meta-analysis (IPDMA) from multiple randomised controlled trials evaluating intermittent strategies to inform clinical practice. We also aimed to validate whether thrombocytosis as a predictive biomarker identified patients with significantly reduced OS receiving a complete treatment break. PATIENTS AND METHODS: An IPDMA of intermittent strategy impact on survival was undertaken, including all relevant trials in which data were available. Intermittent strategies were classified into two groups: a planned stopping of all therapy ("treatment break strategy"; 6 trials; 2,907 patients) or to the same treatment omitting oxaliplatin ("maintenance strategy"; 3 trials; 1,271 patients). The primary analysis sample was of patients successfully completing induction therapy. Additionally, a pre-planned analysis of the predictive value of thrombocytosis on survival under a continuous versus an intermittent strategy was undertaken. RESULTS: All trials had comparable inclusion criteria. The overall IPDMA of intermittent therapy versus continuous therapy demonstrated no detriment in OS (HR = 1.03 [95% CI 0.93-1.14]), whether from complete break (HR 1.04 [95% CI 0.87-1.26]) or maintenance strategies (HR 0.99 [95% CI 0.87-1.13]). Thrombocytosis was confirmed as a marker of poor prognosis in aCRC, but did not predict for OS detriment from treatment break strategies (interaction HR = 0.97 [95% CI 0.66-1.40] compared to continuous therapy). CONCLUSION: The highest levels of evidence from this IPDMA indicate no detriment in survival for patients receiving an intermittent therapy strategy, either for maintenance or complete break strategies. Although, thrombocytosis is confirmed as a marker of poor prognosis, it is not predictive of poor outcome for patients treated with intermittent therapy. An intermittent chemotherapy strategy can therefore be applied irrespective of baseline platelet count and does not result in inferior OS compared to continuous chemotherapy.