In 2015, the United States Food and Drug Administration (FDA) approved uridine triacetate to treat overdose and severe toxicity of the fluoropyrimidine chemotherapy agents 5-fluorouracil (5-FU) and its oral prodrug capecitabine. Uridine triacetate is as an oral prodrug of uridine that competes with cytotoxic fluoropyrimidine metabolites for incorporation into nucleotides. Two million people worldwide start fluoropyrimidine chemotherapy each year, with 20-30% developing severe or life-threatening adverse effects, often attributable to a genetic predisposition such as dihydropyrimidine dehydrogenase deficiency. Whilst genetic prescreening is recommended prior to starting fluoropyrimidine agents, this only prevents 20-30% of early-onset life-threatening toxicity and so does not obviate the need for an antidote. Initial in-human studies established that uridine triacetate more than doubles the maximum tolerated weekly 5-FU bolus dose. A lack of clinical equipoise meant a placebo-controlled phase III trial was not ethical and so the phase III trials used historical controls. These found that uridine triacetate improved survival in those with fluoropyrimidine overdose and severe toxicity from 16% to 94%, with 34% able to resume chemotherapy within 30 days. Five case reports of delayed fluoropyrimidine toxicity demonstrate improvement following uridine triacetate treatment 120-504 h after last fluoropyrimidine administration, suggesting efficacy beyond the FDA licencing indications. Mechanistically uridine triacetate would be expected to be effective for overdose and severe toxicity of tegafur (a 5-FU prodrug), but there are no published case reports describing this. Uridine triacetate is available internationally through an expanded access scheme and has been available in the UK since 2019 on a named patient basis.

While epigenomic alterations are common in colorectal cancers (CRC), few epigenomic biomarkers that risk-stratify patients have been identified. We thus sought to determine the potential of ZNF331 promoter hypermethylation (mZNF331) as a prognostic and predictive marker in colon cancer. We examined the association of mZNF331 with clinicopathologic features, relapse, survival, and treatment efficacy in patients with stage III colon cancer treated within a randomized adjuvant chemotherapy trial (CALGB/Alliance89803). Residual tumour tissue was available for genomic DNA extraction and methylation analysis for 385 patients. ZNF331 promoter methylation status was determined by bisulphite conversion and fluorescence-based real-time polymerase chain reaction. Kaplan-Meier estimator and Cox proportional hazard models were used to assess the prognostic and predictive role of mZNF331 in this well-annotated dataset, adjusting for clinicopathologic features and standard molecular markers. mZNF331 was observed in 267/385 (69.4%) evaluable cases. Histopathologic features were largely similar between patients with mZNF331 compared to unmethylated ZNF331 (unmZNFF31). There was no significant difference in disease-free or overall survival between patients with mZNF331 versus unmZNF331 colon cancers, even when adjusting for clinicopathologic features and molecular marker status. Similarly, there was no difference in disease-free or overall survival across treatment arms when stratified by ZNF331 methylation status. While ZNF331 promoter hypermethylation is frequently observed in CRC, our current study of a small subset of patients with stage III colon cancer suggests limited applicability as a prognostic marker. Larger studies may provide more insight and clarity into the applicability of mZNF331 as a prognostic and predictive marker.

The log odds of positive lymph nodes (LODDS) was considered a superior staging system to N stage in colon cancer, yet its value in determining the optimal duration of adjuvant chemotherapy for stage III colon cancer patients has not been evaluated. This study aims to assess the prognostic value of a model that combines LODDS with clinicopathological information for stage III colon cancer patients and aims to stratify these patients using the model, identifying individuals who could benefit from varying durations of adjuvant chemotherapy.

A total of 663 consecutive patients diagnosed with stage III colon cancer, who underwent colon tumor resection between November 2007 and June 2020 at Sun Yat-sen University Cancer Center and Longyan First Affiliated Hospital of Fujian Medical University, were enrolled in this study. Survival outcomes were analyzed using Kaplan-Meier, Cox regression. Nomograms were developed to forecast patient DFS, with the Area Under the Curve (AUC) values of time-dependent Receiver Operating Characteristic (timeROC) and calibration plots utilized to assess the accuracy and reliability of the nomograms.

Multivariate analysis revealed that perineural invasion (HR = 1.776, 95% CI: 1.052-3.003, P = 0.032), poor tumor differentiation (HR = 1.638, 95% CI: 1.084-2.475, P = 0.019), and LODDS groupings of 2 and 1 (HR = 1.920, 95% CI: 1.297-2.842, P = 0.001) were independent predictors of disease-free survival (DFS) in the training cohort. Nomograms constructed from LODDS, perineural invasion, and poor tumor differentiation demonstrated robust predictive performance for 3-year and 5-year DFS in both training (3-year AUC = 0.706, 5-year AUC = 0.678) and validation cohorts (3-year AUC = 0.744, 5-year AUC = 0.762). Stratification according to this model showed that patients in the high-risk group derived significant benefit from completing 8 cycles of chemotherapy (training cohort, 82.97% vs 67.17%, P = 0.013; validation cohort, 89.49% vs 63.97%, P = 0.030).

The prognostic model, integrating LODDS, pathological differentiation, and neural invasion, demonstrates strong predictive accuracy for stage III colon cancer prognosis. Moreover, stratification via this model offers valuable insights into optimal durations of postoperative adjuvant chemotherapy.

The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery.

OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population.

Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]).

NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

This article is a summary of the French intergroup guidelines regarding the management of non-metastatic colon cancer (CC), revised in November 2022.

These guidelines represent collaborative work of all French medical and surgical societies involved in the management of CC. Recommendations were graded in three categories (A, B, and C) according to the level of evidence found in the literature published up to November 2022.

Initial evaluation of CC is based on clinical examination, colonoscopy, chest-abdomen-pelvis computed tomography (CT) scan, and carcinoembryonic antigen (CEA) assay. CC is usually managed by surgery and adjuvant treatment depending on the pathological findings. The use of adjuvant therapy remains a challenging question in stage II disease. For high-risk stage II CC, adjuvant chemotherapy must be discussed and fluoropyrimidine monotherapy or oxaliplatin-based chemotherapy proposed according to the type and number of poor prognostic features. Oxaliplatin-based chemotherapy (FOLFOX or CAPOX) is the current standard for adjuvant therapy of patients with stage III CC. However, these regimens are associated with significant oxaliplatin-induced neurotoxicity. The results of the recent IDEA study provide evidence that 3 months of treatment with CAPOX is as effective as 6 months of oxaliplatin-based therapy in patients with low-risk stage III CC (T1-3 and N1). A 6-month oxaliplatin-based therapy remains the standard of care for high-risk stage III CC (T4 and/or N2). For patients unfit for oxaliplatin, fluoropyrimidine monotherapy is recommended.

French guidelines for non-metastatic CC management help to offer the best personalized therapeutic strategy in daily clinical practice. Each individual case must be discussed within a multidisciplinary tumor board and then the treatment option decided with the patient.

High-risk stage III colon cancer has a considerably poorer prognosis than stage II and low-risk stage III colon cancers. Nevertheless, most guidelines recommend similar adjuvant treatment approaches for all these stages despite the dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis with intensive adjuvant treatment. Given the the proven efficacy of triplet chemotherapy in metastatic colorectal cancer treatment, the goal of this study is to evaluate the oncologic efficacy and safety of mFOLFIRINOX in comparison to those of the current standard of care, mFOLFOX 6, as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer after radical resection.

This multicenter, randomized (1:1), open-label, phase II trial will assess and compare the effectiveness and toxicity of mFOLFIRINOX and mFOLFOX 6 in patients with high-risk stage III colon cancer after radical resection. The goal of the trial is to enroll 312 eligible patients, from 11 institutes, aged between 20 and 70 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or between 70 and 75 with an ECOG performance status of 0. Patients will be randomized into two arms - Arm A, the experimental arm, and Arm B, the reference arm - and will receive 12 cycles of mFOLFIRINOX and mFOLFOX 6 every 2 weeks, respectively. The primary endpoint of this study is the 3-year disease-free survival, and secondary endpoints include the 3-year overall survival and treatment toxicity.

The Frost trial would help determine the oncologic efficacy and safety of adjuvant triplet chemotherapy for high-risk stage III colon cancers and ultimately improve prognoses.

ClinicalTrials.gov NCT05179889, registered on 17 December 2021.

Surgery with or without adjuvant chemotherapy is the standard treatment for early-stage colon cancer. However, evidence has recently emerged for neoadjuvant chemotherapy, with the results of randomised clinical trials sparking debates within multidisciplinary teams and splitting the gastrointestinal oncology community. Further to a systematic search of the literature, we provide a thorough and in-depth analysis of the findings from these trials, highlighting the advantages and disadvantages of neoadjuvant chemotherapy. We conclude that, while there is a potential value of moving systemic therapy from the post-operative to the pre-operative setting, the available evidence does not justify a shift in the treatment paradigm of early-stage colon cancer, and surgery with or without adjuvant chemotherapy should remain the standard approach for these patients.

Currently, 6 months of perioperative or adjuvant chemotherapy (ACT) is a standard treatment option after radical surgical removal of metachronous metastases in patients with metastatic colorectal cancer (CRC). Data show that ACT improves relapse-free survival in such patients, although no difference in overall survival rate was observed. We perform a systematic review to evaluate the efficacy of adjuvant chemotherapy after radical resection of metachronous metastases in CRC.

Colorectal cancer is an important cause of morbidity and mortality worldwide. The current treatment landscape includes chemotherapy, targeted therapy, immunotherapy, radiotherapy, and surgery. A key challenge to improving patient outcomes is the significant inter-patient heterogeneity in treatment response. Tumour organoids derived from the patients' tumours via surgically resected or endoscopically biopsied tissue, have emerged as promising models for personalised medicine. This review synthesises the findings, to date, of studies which have explored the efficacy of ex vivo organoid sensitivity testing for predicting treatment response. Most studies have focused on predicting the response to standard-of-care radiotherapy and chemotherapy options. There is strong evidence to support organoid sensitivity testing of ionising radiation, 5-fluorouracil, and irinotecan, and to a lesser extent, oxaliplatin and TAS-102. Fewer studies have used organoids to identify patients who are likely to benefit from novel treatment options that otherwise remain in clinical trials. This review also summarises recent advancements in organoid culture to include non-epithelial components of the tumour microenvironment, to allow testing of immunotherapy and certain targeted therapy options. Overall, further prospective trials will support the implementation of organoid-based personalised medicine for colorectal cancer patients in the future.

Lymphovascular invasion (LVI) and perineural invasion (PNI) can indicate poor survival outcomes in colorectal cancer, but few studies have focused on stage III colon cancer. The current study aimed to confirm the prognostic value of LVI and PNI and identify patients who could benefit from a complete duration of adjuvant chemotherapy based on the two pathological factors.

We enrolled 402 consecutive patients with stage III colon cancer who received colon tumor resection from November 2007 to June 2016 at Sun Yat-sen University Cancer Center. Survival analyses were performed by using Kaplan-Meier method with log-rank tests. Risk factors related to disease-free survival (DFS) and overall survival (OS) were identified through Cox proportional hazards analysis.

141 (35.1%) patients presented with LVI, and 108 (26.9%) patients with PNI. The LVI-positive group was associated with poorer 3-year DFS (86.5% vs. 76.3%, P = 0.001) and OS (96.0% vs. 89.1%, P = 0.003) rates compared with the LVI-negative group. The PNI-positive group showed a worse outcome compared with the PNI-negative group in 3-year DFS rate (72.5% vs. 86.7%, P < 0.001). Moreover, LVI-positive group present better 3-year DFS and OS rate in patients completing 6-8 cycles of adjuvant chemotherapy than those less than 6 cycles (3-year DFS: 80.0% vs. 64.9%, P = 0.019; 3-year OS: 93.2% vs. 76.3%, P = 0.002).

LVI is a superior prognostic factor to PNI in stage III colon cancer patients undergoing curative treatment. PNI status can noly predict the 3-year DFS wihout affecting the 3-year OS. Furthermore, LVI also represents an effective indicator for adjuvant chemotherapy duration.

Aberrantly methylated genes contribute to the landscape of epigenetic alterations in colorectal adenocarcinoma. The global CpG Island methylator phenotype (CIMP) and individually methylated genes are potential prognostic/predictive biomarkers. Research suggests an association between methylated DCR1 (mDCR1) and lack of benefit with irinotecan (IFL) treatment. We assessed the association between DCR1 methylation status and survival in patients receiving adjuvant fluorouracil/ leucovorin (5-FU/LV) or IFL. We analysed data from patients with stage III colon adenocarcinoma randomly assigned to adjuvant 5-FU/LV or IFL in CALGB 89803 (Alliance). The primary endpoint was overall survival (OS), and the secondary endpoint was disease-free survival (DFS). Using tumour sample DNA, we evaluated the association between survival, DCR1 methylation status, and molecular subgroups (BRAF, KRAS, mismatch repair status, CIMP status) using Kaplan-Meier estimator and Cox proportional hazard model. mDCR1 was observed in 221/400 (55%) colon cancers. Histopathologic features were similar between mDCR1 and unmethylated DCR1 (unDCR1) colon cancers. There was no difference in OS (p = 0.83) or DFS (p = 0.85) based on DCR1 methylation status. There was no association between methylation status and response to IFL . In patients with unDCR1 and KRAS-wildtype tumours, those who received IFL had a nearly two-fold worse DFS compared to patients who received 5-FU/LV (HR = 1.85, 95% CI (0.97-3.53, p = 0.06). This relationship was not notable among other subgroups. In stage III colon cancer patients, mDCR1 status did not associate with response to irinotecan. Larger studies may suggest an association between the iridocene response and molecular subgroups.

Limited and conflicting findings have been reported regarding the association between social support and colorectal cancer (CRC) outcomes. We sought to assess the influences of marital status and living arrangement on survival outcomes among patients with stage III colon cancer.

We conducted a secondary analysis of 1082 patients with stage III colon cancer prospectively followed in the CALGB 89803 randomized adjuvant chemotherapy trial. Marital status and living arrangement were both self-reported at the time of enrollment as, respectively, married, divorced, separated, widowed, or never-married, and living alone, with a spouse or partner, with other family, in a nursing home, or other.

Over a median follow-up of 7.6 years, divorced/separated/widowed patients experienced worse outcomes relative to those married regarding disease free-survival (DFS) (hazards ratio (HR), 1.44 (95% CI, 1.14-1.81); P =.002), recurrence-free survival (RFS) (HR, 1.35 (95% CI, 1.05-1.73); P = .02), and overall survival (OS) (HR, 1.40 (95% CI, 1.08-1.82); P =.01); outcomes were not significantly different for never-married patients. Compared to patients living with a spouse/partner, those living with other family experienced a DFS of 1.47 (95% CI, 1.02-2.11; P = .04), RFS of 1.34 (95% CI, 0.91-1.98; P = .14), and OS of 1.50 (95% CI, 1.00-2.25; P =.05); patients living alone did not experience significantly different outcomes.

Among patients with stage III colon cancer who received uniform treatment and follow-up within a nationwide randomized clinical trial, being divorced/separated/widowed and living with other family were significantly associated with greater colon cancer mortality. Interventions enhancing social support services may be clinically relevant for this patient population.

ClinicalTrials.gov Identifier: NCT00003835.

Over the past year, studies have demonstrated better ways of using the agents that we have to improve outcomes for patients with colon and Rectal cancers.

Current tools in predicting survival outcomes for patients with colon cancer predominantly rely on clinical and pathologic characteristics, but increasing evidence suggests that diet and lifestyle habits are associated with patient outcomes and should be considered to enhance model accuracy.

Using an adjuvant chemotherapy trial for stage III colon cancer (CALGB 89803), we developed prediction models of disease-free survival (DFS) and overall survival by additionally incorporating self-reported nine diet and lifestyle factors. Both models were assessed by multivariable Cox proportional hazards regression and externally validated using another trial for stage III colon cancer (CALGB/SWOG 80702), and visual nomograms of prediction models were constructed accordingly. We also proposed three hypothetical scenarios for patients with (1) good-risk, (2) average-risk, and (3) poor-risk clinical and pathologic features, and estimated their predictive survival by considering clinical and pathologic features with or without adding self-reported diet and lifestyle factors.

Among 1,024 patients (median age 60.0 years, 43.8% female), we observed 394 DFS events and 311 deaths after median follow-up of 7.3 years. Adding self-reported diet and lifestyle factors to clinical and pathologic characteristics meaningfully improved performance of prediction models (c-index from 0.64 [95% CI, 0.62 to 0.67] to 0.69 [95% CI, 0.67 to 0.72] for DFS, and from 0.67 [95% CI, 0.64 to 0.70] to 0.71 [95% CI, 0.69 to 0.75] for overall survival). External validation also indicated good performance of discrimination and calibration. Adding most self-reported favorable diet and lifestyle exposures to multivariate modeling improved 5-year DFS of all patients and by 6.3% for good-risk, 21.4% for average-risk, and 42.6% for poor-risk clinical and pathologic features.

Diet and lifestyle factors further inform current recurrence and survival prediction models for patients with stage III colon cancer.

The American Cancer Society and American Institute for Cancer Research recommend that cancer survivors limit intake of red and processed meats. This recommendation is based on consistent associations between red and processed meat intake and cancer risk, particularly risk of colorectal cancer, but fewer data are available on red and processed meat intake after cancer diagnosis.

To examine whether intake of unprocessed red meat or processed meat is associated with risk of cancer recurrence or mortality in patients with colon cancer.

This prospective cohort study used data from participants with stage III colon cancer enrolled in the Cancer and Leukemia Group B (CALGB 89803/Alliance) trial between 1999 and 2001. The clinical database for this analysis was frozen on November 9, 2009; the current data analyses were finalized in December 2021.

Quartiles of unprocessed red meat and processed meat intake assessed using a validated food frequency questionnaire during and 6 months after chemotherapy.

Hazard ratios (HRs) and 95% CIs for risk of cancer recurrence or death and all-cause mortality.

This study was conducted among 1011 patients with stage III colon cancer. The median (IQR) age at enrollment was 60 (51-69) years, 442 patients (44%) were women, and 899 patients (89%) were White. Over a median (IQR) follow-up period of 6.6 (1.9-7.5) years, we observed 305 deaths and 81 recurrences without death during follow-up (386 events combined). Intake of unprocessed red meat or processed meat after colon cancer diagnosis was not associated with risk of recurrence or mortality. The multivariable HRs comparing the highest vs lowest quartiles for cancer recurrence or death were 0.84 (95% CI, 0.58-1.23) for unprocessed red meat and 1.05 (95% CI, 0.75-1.47) for processed meat. For all-cause mortality, the corresponding HRs were 0.71 (95% CI, 0.47-1.07) for unprocessed red meat and 1.04 (95% CI, 0.72-1.51) for processed meat.

In this cohort study, postdiagnosis intake of unprocessed red meat or processed meat was not associated with risk of recurrence or death among patients with stage III colon cancer.

Numerous clinical studies in an adjuvant setting have been conducted and the combination therapy of 5-fluorouracil and oxaliplatin has been established as the standard treatment for Stage III and as an option for high-risk Stage II patients. Biologics such as bevacizumab and antiepidermal growth factor receptor antibodies have failed to show additional survival benefits. The indication of adjuvant chemotherapy has been determined according to the pathological stage. Nevertheless, a pathological diagnosis does not necessarily result in selection of the optimal treatment. To improve treatment decisions, many trials have aimed to stratify patients into treatment groups using genomic testing. Recently, gene signature, Immunoscore, and circulating tumor DNA (ctDNA) assays have been reported and among them, ctDNA was shown to be a promising accurate predictive marker for recurrence. Treatment of ctDNA-positive patients with aggressive chemotherapy may reduce recurrence rates. The ultimate goal is to accurately predict the risk of recurrence and to prevent recurrence in colon cancer patients. In this review we focus on the clinical development of adjuvant chemotherapy and stratification of patients according to risk of recurrence and the future direction of adjuvant chemotherapy.

KRAS and BRAF mutations are well-established predictive and prognostic factors in metastatic colorectal cancer, however their impact in the adjuvant setting has not yet been established.

We performed a meta-analysis of adjuvant phase III trials in patients with stage II and III colon cancer with available data on the impact of KRAS/BRAF mutations on both disease-free survival (DFS) and overall survival (OS). Trials were subgrouped based on whether adjustment for microsatellite instability (MSI) was performed and the subgroup effect was analyzed through a meta-regression. To increase the precision of the estimates, a joint DFS/OS (so-called 'multivariate') meta-analysis was performed. All statistical tests were 2-sided.

Nine trials were selected (QUASAR 2, PETACC-8, N0147, CALGB-89803, NSABP-C07, NSABP-C08, PETACC-3, QUASAR, MOSAIC) including a total of 10893 patients. In the primary meta-analysis, KRAS mutation was associated with poor DFS (pooled HR = 1.36, 95% CI = 1.15-1.61, P < .001) and OS (pooled HR = 1.27, 95% CI = 1.03-1.55, P = .03) and BRAF mutation was also associated with poor DFS (pooled HR = 1.33, 95% CI = 1.00-1.78, P = .05) and OS (pooled HR = 1.49, 95% CI = 1.31-1.70, P < .001). MSI adjustment enhanced the effect of the mutations on outcome in the MSI-adjusted subgroup for both the KRAS mutation (pooled HR for DFS = 1.43, 95% CI = 1.15-1.79, P = .001; and pooled HR for OS = 1.33, 95% CI = 1.03-1.71, P = .03) and the BRAF mutation (pooled HR for DFS = 1.59, 95% CI = 1.22-2.07, P = .001; and pooled HR for OS = 1.67, 95% CI = 1.37-2.04, P < .001). The interaction between BRAF and MSI adjustment was statistically significant for DFS (P interaction = 0.02). This interaction was even more pronounced in the DFS/OS multivariate meta-analysis.

Both KRAS and BRAF mutations were statistically significantly associated with both DFS and OS, with the mutation effect being enhanced by MSI adjustment. Effective adjuvant treatment for microsatellite stable BRAF or KRAS-mutated colon cancer represents an unmet clinical need and exploring the use of recently available BRAF and KRAS inhibitors in this setting would be highly desirable.

Disease-free survival (DFS) with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival (OS) with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence in patients who received adjuvant FOLFOX. Hence, reevaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed.

Individual patient data from 9 randomized studies conducted between 1998 and 2009 were included; 3 trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (RWLS2) and Copula bivariate (RCopula2) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation.

Data from a total of 18 396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (T1-3 and N1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high or deficient mismatch repair tumors. Trial-level correlation between 3-year DFS and 5-year OS remained strong (RWLS2 = 0.82, 95% CI = 0.67 to 0.98; RCopula2 = 0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results.

Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

Neoadjuvant chemotherapy without radiation (NAC) shows favorable outcomes for locally advanced rectal cancer (LARC), however, the optimal regimen has not been determined yet. This study aimed to compare the efficacy and safety of oxaliplatin, irinotecan, folinic acid, and 5-fluorouracil (mFOLFOXIRI) with capecitabine/S-1 and oxaliplatin (XELOX/SOX) in rectal cancer patients.

We retrospectively examined patients with LARC who received mFOLFOXIRI or XELOX/SOX as NAC.

Between January 2015 and July 2019, 49 patients received mFOLFOXIRI and 37 patients received XELOX/SOX. The pathological response rates (over two-thirds affected tumor area) were 36.7% and 40.5% in the mFOLFOXIRI and XELOX/SOX groups, respectively. Grade 3/4 neutropenia was experienced by 45.0% of the patients in the mFOLFOXIRI group and 8.0% in the XEOX/SOX group.

Although pathological responses were comparable between two groups, mFOLFOXIRI tended to be more toxic compared to XELOX/SOX as NAC for LARC.

In resected colonic liver metastasis (CLM), randomized studies of oxaliplatin-based chemotherapy have demonstrated improvements in disease-free survival (DFS), but not overall survival (OS). Additionally, oxaliplatin regimens have not been compared to non-oxaliplatin chemotherapy. Despite limited evidence, perioperative chemotherapy is often used in the management of CLM. The primary aim of this study was to assess the impact of oxaliplatin chemotherapy regimens on OS in patients who have undergone resection of CLM in a real-world setting.

Patients who underwent resection of CLM in the provinces of Alberta and British Columbia, Canada, were identified from 1996 to 2016. Perioperative (pre- and/or post-) systemic therapy was categorized as oxaliplatin or non-oxaliplatin-based chemotherapy or no chemotherapy. The primary and secondary outcomes were OS and DFS, respectively.

We identified 511 patients who underwent R0 resection of CLM. A significant difference in median OS was identified among the oxaliplatin, non-oxaliplatin, and no-chemotherapy groups of 100, 60, and 59 months, respectively (P = .009). In multivariate analysis, patients who received oxaliplatin regimens had a lower risk of death (hazard ratio, 0.68; 95% confidence interval, 0.51-0.92; P = .012), whereas the non-oxaliplatin chemotherapy group did not (hazard ratio, 0.88; 95% confidence interval, 0.65-1.20; P = .422) compared with no chemotherapy.

In this multicenter, retrospective, population-based study, perioperative oxaliplatin-based chemotherapy was associated with improved OS in conjunction with R0 resection of CLM. Further studies should evaluate the optimal duration and sequencing of perioperative chemotherapy in relation to curative-intent surgical resection of CLM.

In many health systems, access to off-label drug use is controlled through reimbursement restrictions by health insurers, especially for expensive cancer drugs.

To determine whether evidence from randomized clinical trials is associated with reimbursement decisions for requested off-label use of anticancer drugs in the Swiss health system.

This cross-sectional study used reimbursement requests from routinely collected health records of 5809 patients with drug treatment for cancer between January 2015 and July 2018 in 3 major cancer centers, covering cancer care of approximately 5% of the Swiss population, to identify off-label drug use. For each off-label use indication with 3 or more requests, randomized clinical trial evidence on treatment benefits was systematically identified for overall survival (OS) or progression-free survival (PFS). Data were analyzed from August 2018 to December 2020.

Available randomized clinical trial evidence on benefits for OS or PFS for requested off-label use indications.

The main outcome was the association between evidence for treatment benefit (expressed as improved OS or PFS) and reimbursement in multivariable regression models.

Among 3046 patients with cancer, 695 off-label use reimbursement requests in 303 different indications were made for 598 patients (median [interquartile range] age, 64 [53-73] years; 420 [60%] men). Off-label use was intended as first-line treatment in 311 requests (45%). Reimbursement was accepted in 446 requests (64%). For 71 indications, including 431 requests for 376 patients, there were 3 or more requests. Of these, 246 requests (57%) had no supporting evidence for OS or PFS benefit. Reimbursement was granted in 162 of 246 requests without supporting evidence (66%). Of 117 requests supported by OS benefit, 79 (67%) were reimbursed, and of 68 requests supported by PFS benefit alone, 54 (79%) were reimbursed. Evidence of OS benefit from randomized clinical trials was not associated with a higher chance of reimbursement (odds ratio, 0.76, 95% CI, 0.45-1.27).

These findings suggest that in a health care system enabling access to off-label use, it was frequently intended as a first-line treatment in cancer care. Availability of randomized clinical trial evidence showing survival benefit was not associated with reimbursement decisions for off-label anticancer drug treatment in Switzerland. A transparent process with criteria considering clinical evidence is needed for evidence-based reimbursement decisions to ensure fair access to cancer treatments.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While there have been significant developments in the treatments for patients with metastatic CRC in recent years, improving outcomes in the adjuvant setting has been more challenging. Recent technological advances in circulating tumour DNA (ctDNA) assay with the ability to detect minimal residual disease (MRD) after curative intent surgery will fundamentally change how we assess recurrence risk and conduct adjuvant trials. Studies in non-metastatic CRC have now demonstrated the prognostic impact of ctDNA analysis after curative intent surgery over and above current standard of care clinicopathological criteria. This ability of ctDNA analysis to stratify patients into low- and very-high-risk groups provides a window of opportunity to personalise adjuvant treatment where escalation/de-escalation of adjuvant systemic therapy could potentially increase cure rates and also reduce treatment-related physical and financial toxicity. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. This real-time assessment of treatment benefit could be used as a surrogate endpoint for adjuvant novel drug development. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer.

Micrometastatic disease that is present at the time of surgery is responsible for the overwhelming majority of deaths in patients with what is otherwise perceived to be local and regional colon cancer. The goal of perioperative therapy is to eliminate microscopic residual disease that would otherwise be left behind following surgery. A secondary goal specific to neoadjuvant (preoperative) therapy is to downstage tumors deemed potentially not amenable to an R0 resection on the basis of a suspected T4b primary (locally invading into a surrounding structure). In this landmark series paper, we review the current standard for perioperative therapy in patients with colon cancer.

5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2-1.0%.

Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.

In patients with stage III colon cancer (CC), adjuvant chemotherapy with the combination of oxapliplatin to a fluoropyrimidine (FOLFOX or CAPOX) is a standard of care. The duration of treatment can be reduced from 6 months to 3 months, depending on the regimen, for patients at low risk of recurrence, without loss of effectiveness and allowing a significant reduction in the risk of cumulative sensitive neuropathy. However, our capacity to identify patients that do really need this doublet adjuvant treatment remains limited. In fact, only 30% at the most will actually benefit from this adjuvant treatment, 50% of them being already cured by the surgery and 20% of them experiencing disease recurrence despite the adjuvant treatment. Thus, it is necessary to be able to better predict individually for each patient the risk of recurrence and the need for adjuvant chemotherapy together with the need of new treatment approaches for specific subgroups. Many biomarkers have been described with their own prognostic weight, without leading to any change in clinical practices for now. In this review, we will first discuss the recommendations for adjuvant chemotherapy, and then the different biomarkers described and the future perspectives for the management of stage III CC.

In colon cancer, primary surgery followed by postoperative chemotherapy represents the standard of care. In rectal cancer, the standard of care is preoperative radiotherapy or chemoradiation, which significantly reduces local recurrence but has no impact on subsequent metastatic disease or overall survival. The administration of neoadjuvant chemotherapy (NACT) before surgery can increase the chance of a curative resection and improves long-term outcomes in patients with liver metastases. Hence, NACT is being explored in both primary rectal and colon cancers as an alternative strategy to shrink the tumor, facilitate a curative resection, and simultaneously counter the risk of metastases. Yet, this lack of clarity regarding the precise aims of NACT (downstaging, maximizing response, or improving survival) is hindering progress. The appropriate cytotoxic agents, the optimal regimen, the number of cycles, or duration of NACT prior to surgery or in the postoperative setting remains undefined. Several potential strategies for integrating NACT are discussed with their advantages and disadvantages.

Click here to listen to the Podcast BACKGROUND: Form 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Hitherto only few trials with curative intent have been field tested using form 1. We aimed to evaluate the applicability of the scale and to assess the reasonableness of the generated scores in early colon cancer, in order to identify shortcomings that may be rectified in future amendments.

Adjuvant studies were identified in PubMed, Food and Drug Administration and European Medicines Agency registration sites, as well as ESMO and National Comprehensive Cancer Network guidelines. Studies meeting inclusion criteria were graded using form 1 of the ESMO-MCBS V.1.1 and field tested by ESMO Colorectal Cancer Faculty. Shortcomings of the scale were identified and evaluated.

Eighteen of 57 trials and 7 out of 14 meta-analyses identified met criteria for ESMO-MCBS V.1.1 grading. In stage III colon cancer, randomised clinical trials and meta-analyses of modulated 5-fluorouracil (5-FU) based chemotherapy versus surgery scored ESMO-MCBS grade A and randomised controlled trials (RCTs) and meta-analyses comprising oxaliplatin added to this 5-FU backbone showed a more modest additional overall survival benefit (grade A and B). For stage II colon cancer, the findings are less consistent. The fluoropyrimidine trials in stage II were graded 'no evaluable benefit' but the most recent meta-analysis demonstrated a 5.4% survival advantage after 8 years follow-up (grade A). RCTs and a meta-analysis adding oxaliplatin demonstrated no added benefit. Exploratory toxicity evaluation and annotation was problematic given inconsistent toxicity reporting and limited results of late toxicity. Field testers (n=37) reviewed the scores, 25 confirmed their reasonableness, 12 found them mostly reasonable. Moreover, they identified the inability of crediting improved convenience in non-inferiority trials as a shortcoming.

Form 1 of the ESMO-MCBS V.1.1 provided very reasonable grading for adjuvant colon cancer studies.

Colon cancer continues to be one of the leading causes of mortality and morbidity throughout the world despite the availability of reliable screening tools and effective therapies. The majority of patients with colon cancer are diagnosed at an early stage (stages I to III), which provides an opportunity for cure. The current treatment paradigm of early stage colon cancer consists of surgery followed by adjuvant chemotherapy in a select group of patients, which is directed at the eradication of minimal residual disease to achieve a cure. Surgery alone is curative for the vast majority of colon cancer patients. Currently, surgery and adjuvant chemotherapy can achieve long term survival in about two-thirds of colon cancer patients with nodal involvement. Adjuvant chemotherapy is recommended for all patients with stage III colon cancer, while the benefit in stage II patients is not unequivocally established despite several large clinical trials. Contemporary research in early stage colon cancer is focused on minimally invasive surgical techniques, strategies to limit treatment-related toxicities, precise patient selection for adjuvant therapy, utilization of molecular and clinicopathologic information to personalize therapy and exploration of new therapies exploiting the evolving knowledge of tumor biology. In this review, we will discuss the current standard treatment, evolving treatment paradigms, and the emerging biomarkers, that will likely help improve patient selection and personalization of therapy leading to superior outcomes.

The treatment of colon cancer has had numerous recent advances, in terms of surgical approach, adjuvant therapies, and more. In this review, the authors examine randomized clinical trials comparing open surgery to laparoscopic surgery (including total mesocolic excision), and also examine the role of robotic surgery. Novel surgical techniques including the no-touch technique, side-to-side anastomosis, suture technique, complete mesocolic excision (CME) with central vascular ligation (CVL), and natural orifice transluminal endoscopic surgery (NOTES) are outlined. The role of placing endoscopic self-expandable metal stents (SEMS) for colonic obstruction is compared and contrasted with the surgical approach, and the effect that the anti-VEGF inhibitor bevacizumab may have on this side effect profile is further explored. The role of the resection of the primary tumor in the setting of metastatic disease is examined with respect to survival benefit. Pathways of perioperative care which can accelerate post-surgical recovery, including enhanced recovery after surgery (ERAS) are examined. The role of adjuvant chemotherapy in patients with high-risk stage II and patients with stage III disease is examined, along with the role on circulating tumor DNA (ctDNA) as well as with the biologic targeted agents cetuximab and bevacizumab. Lastly, the authors detail the postoperative surveillance schedules after surgical resection with respect to survival outcomes.