Perspectives of the Use of Neoadjuvant Therapy in the Management of Locally Advanced and Locally Recurrent Colon Cancer: A Bi-National Survey of Colorectal Surgeons.

Opinion statementNeoadjuvant chemotherapy is safe for patients with locally advanced colon cancer (LACC). The FOxTROT trial demonstrated a reduction in residual and recurrent cancer at 2 years with neoadjuvant chemotherapy for patients with cT3-4 LACC. Preoperative chemotherapy should be avoided, if possible, for patients with dMMR LACC, as over 50% of dMMR cancers have no pathologic response. Early universal testing of MMR status is critical to selecting the appropriate neoadjuvant therapy. Concerns about CT staging of LACC have limited uptake of neoadjuvant chemotherapy, as approximately 25% of patients with cT3-T4 cancer on CT have low-risk stage II disease. Development of CT criteria for malignant nodes should reduce the risk of over-staging. A multidisciplinary approach is needed to identify patients for neoadjuvant therapy. Neoadjuvant immunotherapy is safe and results in dramatic pathologic responses in patients with dMMR LACC. Longer follow-up is needed to determine if the exceptionally high pathologic response rates observed will translate into long-term remission. Remarkably, neoadjuvant immunotherapy has been found to cause major pathologic responses in a subset of patients with pMMR LACC, indicating the potential to cure more patients with this common cancer. Patients with cT4 LACC, whether stage II or III, have a substantial risk of recurrence despite adjuvant fluoropyrimidine plus oxaliplatin chemotherapy. We recommend neoadjuvant systemic therapy for all patients with cT4b LACC (dMMR and pMMR). Features of T4b disease are routinely reported by radiology. We use three cycles of FOLFOX chemotherapy for patients with cT4b pMMR LACC, due to the high rate of compliance and improvement in residual and recurrent disease. Patients with cT4b dMMR LACC should receive neoadjuvant immunotherapy, if there are no contraindications. Clinical trials of neoadjuvant therapy for LACC are of great interest and should provide training for radiologists to identify eligible patients. Results are anticipated from multiple ongoing trials of neoadjuvant chemotherapy, immunotherapy, and targeted therapy for pMMR LACC and immunotherapy for dMMR LACC.

Neoadjuvant chemotherapy (NAC) has long been considered technically difficult in locally advanced colon cancer (LACC). However, the introduction of oxaliplatin-based regimens led to a growing interest in NAC for patients with LACC. Several cohort studies showed that NAC was safe and reduced the rate of incomplete resection in patients with LACC. This was followed by the pivotal phase III FOxTROT trials, which showed significant benefits of NAC in this population. However, in patients with deficient mismatch repair (dMMR), the response to a neoadjuvant fluoropyrimidine regimen may be poor, limiting the benefit of NAC in this subset of patients. Neoadjuvant immunotherapy is a potential alternative for NAC in LACC patients with dMMR. In this concise review, we present the published clinical evidence evaluating the efficacy and safety of NAC and/or neoadjuvant immunotherapy in patients with LACC. Overall, the evidence suggests that NAC can be associated with significant downstaging and tumor regression, which facilitate surgical resection. However, the impact of NAC on long-term survival is still under investigation. Despite the promising results of NAC in LACC, several concerns still exist that necessitate further evidence. On the other hand, LACC patients with dMMR can benefit from neoadjuvant immunotherapy; however, further trials are still needed to confirm its effectiveness, as well as biomarkers that can predict response.

Colorectal cancer is a leading cause of cancer-related morbidity and mortality worldwide, with more than 1.9 million new cases reported in 2020, and is associated with major survival challenges, particularly in patients with locally advanced colon cancer (LACC). LACC often involves T4 invasion or extensive nodal involvement and requires a multidisciplinary approach for management. Radical surgery followed by adjuvant chemotherapy remains the primary treatment strategy for LACC. However, achieving complete tumor resection (R0) is challenging because locally advanced colon tumors typically infiltrate adjacent organs or nodes. Advancements in LACC treatment have involved neoadjuvant chemotherapy (NACT), neoadjuvant chemoradiotherapy (NACRT), and neoadjuvant immunotherapy (NAIT). Studies such as FOxTROT and PRODIGE 22 have demonstrated that NACT, particularly with FOLFOX or CAPOX, can lead to major tumor downstaging, improved survival rates, and increased R0 resection rates. Predictive biomarkers, such as mismatch repair (MMR) status and T stage, are crucial in identifying candidates who may benefit from NACT. NACRT has demonstrated promise in enhancing tumor regression, particularly in patients with rectal cancer, underscoring its potential for use with LACC. NAIT, particularly for deficient MMR tumors, has emerged as a novel approach, with studies such as NICHE-2 and NICHE-3 reporting excellent pathologic responses and pathologic complete responses. Integrating these therapies can enhance the surgical and survival outcomes of patients with LACC, highlighting the importance of personalized treatment strategies based on tumor characteristics and response to neoadjuvant interventions. This review discusses the evolving landscape of LACC management, focusing on optimizing treatment approaches for improved patient outcomes.

Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for initially unresectable locally advanced colon cancer: short-term outcomes of an open-label, single-centre, randomised, controlled, phase 3 trial

Neoadjuvant Chemoradiotherapy Significantly Improved R0 Resection Rate in Unresectable Locally Advanced Colon Cancer: The Initial Analysis from the Randomized Controlled Phase 3 Trial

Neoadjuvant chemotherapy (NCT) for nonmetastatic colon cancer is not routinely used, and is currently only recommended as a treatment option for a subgroup of patients with T4b colon cancers in clinical guidelines. However, NCT may cause downstaging of the tumour, increase resectability, eradicate micrometastases and thereby improve long-term outcomes for patients with nonmetastatic colon cancer. The aim of this study was to investigate the short-term postoperative outcomes in a nationwide cohort of patients with locally advanced colon cancer (LACC) receiving NCT. Using the Danish Colorectal Cancer Group Database, data were retrieved on patients diagnosed with LACC (defined as clinical T3 with extramural tumour invasion >5mm or T4) and treated with resection with a curative intent between 2015 and 2019. Propensity score matching (PSM) in a 1:1 ratio was performed to compare short-term surgical and oncological outcomes in patients receiving NCT with patients operated on without receiving NCT. A total of 179 LACC patients were treated with NCT and 1131 were not. After PSM, 145 patients remained in each group. We found no significant differences in any short-term postoperative outcomes between the two groups. We found significant differences in favour of NCT regarding radicality and pathological N category [86% vs. 81% R0 (P=0.029) and 51% vs. 46% pN0 (P=0.017), respectively]. Neoadjuvant chemotherapy for LACC does not result in worse short-term postoperative outcomes and may increase the R0 rate as well as node-negative disease. Results on long-term benefits including survival are awaited from several ongoing randomized controlled trials.

Colon cancer is a leading cause of cancer-related mortality worldwide, with surgical resection followed by adjuvant chemotherapy being the traditional standard for localized disease. However, the emergence of neoadjuvant therapies has introduced new possibilities for improving outcomes in locally advanced colon cancer (LACC). Neoadjuvant chemotherapy has demonstrated promising results in tumor downstaging, improved resectability, and reduced recurrence rates, as highlighted in trials like FOxTROT (Fluoropyrimidine oxaliplatin and targeted receptor pre-operative therapy), OPTICAL (A phase III study to evaluate the 3-year disease-free survival in patients with locally advanced colon cancer receiving either perioperative or postoperative chemotherapy with FOLFOX or CAPOX regimens), and NeoCol (Neoadjuvant chemotherapy versus standard treatment in patients with locally advanced colon cancer). For deficient mismatch repair (dMMR) tumors, neoadjuvant immunotherapy, exemplified by the NICHE (Neoadjuvant immune checkpoint inhibition and novel IO combinations in early-stage colon cancer) trial, has shown good pathologic response rates. Despite these advancements, challenges such as disease progression during treatment, staging inaccuracies, and chemotherapy-related toxicities underscore the need for precise patient selection and monitoring. Immunotherapy offers significant potential for dMMR tumors, potentially leading to non-surgical management strategies, while neoadjuvant chemotherapy presents a viable option for MMR-proficient (pMMR) patients, improving long-term outcomes in select populations. As the landscape of LACC management evolves, this review emphasizes the importance of personalized treatment strategies informed by biomarkers such as MMR status to maximize therapeutic efficacy and minimize risks. Future directions include refining the role of neoadjuvant therapies in clinical practice, expanding the use of immunotherapy, and exploring innovative combinations of systemic and targeted approaches to enhance survival and quality of life in patients with LACC. This review examines the current evidence supporting neoadjuvant approaches in pMMR and dMMR colon cancer, emphasizing their potential benefits and challenges.

Background and Objectives: Increasing evidence supports the use of neoadjuvant chemotherapy (NAC) for locally advanced colon cancer (LACC). However, its effectiveness remains controversial. This study explored the safety and efficacy of NAC combined with laparoscopic radical colorectal cancer surgery and adjuvant chemotherapy (AC) for LACC. Materials and Methods: We retrospectively analyzed 444 patients diagnosed with LACC (cT4 or cT3, with ≥5 mm invasion beyond the muscularis propria) in our hospital between 2012 and 2015. Propensity score matching (PSM; 1:2) was performed to compare patients treated with NAC and those treated with adjuvant chemotherapy (AC). Results: Overall, 42 patients treated with NAC were compared with 402 patients who received only AC. After PSM, 42 patients in the NAC group were compared with 84 patients in the control group, with no significant differences in the baseline characteristics between groups. The pathological tumor sizes in the NAC group were significantly smaller than those in the AC group (3.1 ± 2.1 cm vs. 5.8 ± 2.5 cm). Patients in the NAC group had a significantly lower T stage than those in the AC group (p < 0.001). After neoadjuvant chemotherapy, a significant response was observed in four (9.6%) patients, with two (4.8%) showing a complete response. The 5-year overall survival rates (88.1% vs. 77.8%, p = 0.206) and 5-year disease-free survival rates (75.1% vs. 64.2%, p = 0.111) did not differ between the groups. However, the 5-year cumulative rate of distant recurrence was significantly lower in the NAC than in the AC group (9.6% vs. 29.9%, p = 0.022). Conclusions: NAC, combined with AC, could downstage primary tumors of LACC and seems safe and acceptable for patients with LACC, with a similar long-term survival between the two treatments.

Neoadjuvant chemotherapy (NAC) has emerged as a potential alternative to upfront surgery (US) followed by adjuvant chemotherapy in locally advanced colon cancer (LACC), offering benefits such as early micrometastases eradication and improved surgical outcomes. However, its efficacy and safety remain uncertain owing to conflicting evidence. A systematic review and meta-analysis was conducted evaluating randomized controlled trials (RCTs) comparing NAC with US with adjuvant chemotherapy for LACC. Primary outcomes were 5-year overall survival (OS) and disease-free survival (DFS). Secondary outcomes included positive surgical margin rates and anastomotic leak/abscess. Statistical analyses employed random-effects models, with trial sequential analysis (TSA) assessing the robustness of results. Eight RCTs with low risk of bias involving 3038 patients were included. NAC improved 5-year OS (81.4% versus 77.8%, hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.64-0.91, p = 0.0028) and DFS (79.2% versus 73.7%, HR 0.80, 95% CI 0.68-0.93, p = 0.0033), with low heterogeneity (I2 ≤ 4.4%). NAC significantly reduced positive margin rates (4.1% versus 6.3%, HR 0.49, p = 0.0011) without increasing anastomotic leak/abscess (p = 0.09). The leave-one-out and the TSA analyses confirmed the robustness of OS and DFS findings, with the cumulative Z-curve crossing both the conventional and trial sequential monitoring boundaries for benefit. The GRADE assessments indicated high quality of evidence for the primary outcomes. NAC offers superior OS, DFS, and surgical margin outcomes in LACC without heightened surgical risks, supporting its inclusion as a viable and safe treatment option.

e15171 Background: Locally advanced colon cancer (LACC) is a frequent presentation and has a high rate of recurrence. The aim of this study was to evaluate current population-based strategies in LACC patients, and to analyze patterns of recurrence. Methods: We conducted a retrospective review of all patients treated at a regional cancer agency with a diagnosis of LACC between 2005 and 2015 treated with curative intent resection. Inclusion criteria were adults with T4 colon cancer, 16 cm above the anal verge, with no evidence of distant metastases. Descriptive statistics were used to define the study population. Kaplan-Meier and Cox-proportional hazards modeling were used for survival analysis. Results: 1394 patients with LACC were reviewed. Median age was 69 [IQR 60-77] and 49.3% were female. Primary tumor location was right-sided in 57.1% of cases. Most tumors were T4a (69.4%) and 39.4% were node positive. A total of 35.4% had urgent/emergent surgery, 46.4% were at least partially obstructed, 22.0% were perforated and 1.9% had a diverting ostomy as an initial operation. En-bloc multi-visceral resection occurred in 23.5% of cases. Positive margins were present in 14.3%. Only 1.6% had neoadjuvant chemotherapy and 0.8% had neoadjuvant chemoradiation. Adjuvant chemotherapy was delivered in 59.8% and adjuvant chemoradiation in 2.8%. Median follow up was 37 months. During follow up 681 (48.9%) patients died and 584 (41.9%) patients developed recurrence. In the entire cohort, rates of recurrences were local-regional (14.7%) and distant metastatic (35.1%). Overall survival for the entire cohort was 63 months [95% CI 55.7-70.3] and recurrence-free survival was 61 months [95% CI 38.8-83.2]. Multivariate analysis identified age (HR 1.03, 95% CI [1.02-1.05] p &lt; 0.001), node negative status (HR 0.62, 95% CI [0.45-0.84] p = 0.002) and positive margin (HR 1.79, 95% CI [1.24-2.57] p = 0.002) as predictive of overall survival after adjusting for confounding factors. Predictive factors for recurrence-free survival were node negative status (HR 0.55, 95% CI [0.39-0.77] p &lt; 0.001) and positive margin (HR 1.51, 95% CI [1.02-2.23] p = 0.038). Conclusions: Recurrence after curative intent treatment for LACC is common. Recurrence and survival patterns are significantly influenced by tumor nodal status and margin positivity.

TPS3636 Background: The FOxTROT1 trial demonstrated a significant reduction in 2-year (yr) recurrence with 6 weeks (wks) of oxaliplatin and fluoropyrimidine (OxFp) NA chemotherapy (NAC) in patients (pts) with LACC, establishing NAC as a new therapeutic option. The ongoing FOxTROT platform will refine and personalize NA therapy in LACC. FOxTROT2 is testing NAC in older pts and those with frailty, who are poorly represented in clinical trials. FOxTROT3 is assessing intensified NAC with modified FOLFOXIRI (mFOLFOXIRI; 5-fluorouracil, oxaliplatin, irinotecan) in fit pts. The FOxTROT platform will also test targeted treatments with established safety and efficacy in defined molecular subgroups. FOxTROT4 is investigating the efficacy and safety of NA encorafenib and cetuximab in BRAF-mutant pMMR LACC. Other arms in setup are shown in Table. Methods: FOxTROT platform trials are international, multicenter, open-label, phase II/III RCTs. Pts with resectable, cT3-4 N0-2 M0, biopsy-proven colon adenocarcinoma are eligible for recruitment. Pts whose age or frailty precludes mFOLFOXIRI can be considered for FOxTROT2. Pts suitable for mFOLFOXIRI can be considered for FOxTROT3. BRAF-mutant pMMR pts can be considered for FOxTROT4. Pts are randomized 2:1 between intervention and control arms. FOxTROT2 randomizes between 6 wks OxFp NAC (choice of 100% or 80% dose) vs proceeding straight to surgery. Adjuvant chemotherapy (AC) is per physician choice. Primary outcome is 3-yr DFS. 759 pts will be recruited over 5 yrs. FOxTROT3: 6 wks mFOLFOXIRI NAC vs 6 wks OxFp NAC. All pts receive AC but physicians may de-escalate mFOLFOXIRI to OxFp. Hierarchical co-primary endpoints: tumor regression grade (TRG) (blinded central assessment) and 3-yr DFS. 873 pts over 5 yrs. FOxTROT4: 6 wks NA encorafenib and cetuximab vs 6 wks OxFp NAC. AC is per physician choice. Primary outcome: TRG. 45 pts over 3 yrs. Secondary outcomes include: histopathological endpoints, downstaging, minimal residual disease by ctDNA, safety, toxicity, OS, surgical outcomes and patient-reported outcomes; and DFS in FOxTROT4. The FOxTROT platform opened 7th Feb 2022, funded by Yorkshire Cancer Research. At submission, 50 pts had been randomized at 23 centers. Trial design and management is conducted in partnership with patient representatives. A program of translational and radiomics research is running in parallel. International recruitment in France and India will commence in 2023 with additional international partners joining from 2024. Clinical trial information: ISRCTN83842641 . [Table: see text]

To Explore the Efficacy and Safety of Neoadjuvant Chemoradiation Therapy in Locally Advanced Colon Cancer: A Systematic Review and Meta-analysis.

Pathological complete response after neoadjuvant chemotherapy with FOLFOX for locally advanced sigmoid colon cancer with diverticulitis: A case report

There is increasing evidence to support the use of neoadjuvant chemotherapy (NAC) in locally advanced colon cancer (LACC). However, its safety, efficacy and side effect profile is yet to be completely elucidated. This review aims to assess NAC regimens, duration, compare completion rates, intra-operative and post-operative complication profiles and oncological outcomes, in order to provide guidance for clinical practice and further research. PubMed, EMBASE and MEDLINE were searched for a systematic review of the literature from 2000 to 2020. Eight eligible studies were included, with a total of 1213 patients, 752 (62%) of whom received NAC. Of the eight studies analysed, two were randomised controlled trials comparing neoadjuvant chemotherapy followed by oncological resection to upfront surgery and adjuvant chemotherapy, three were prospective single-arm phase II trials analysing neoadjuvant chemotherapy followed by surgery only, one was a retrospective study comparing neoadjuvant chemotherapy followed by surgery versus surgery first followed by adjuvant chemotherapy and the remaining two were single-arm retrospective studies of neoadjuvant chemotherapy followed by surgery. All cases of LACC were determined and staged by computed tomography; majority of the studies defined LACC as T3 with extramural depth of 5 mm or more, T4 and/or nodal positivity. NAC administered was either folinic acid, fluorouracil and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (XELOX) with the exception of one study which utilised 5-fluorouracil and mitomycin. Most studies had NAC completion rates of above 83% with two notable exceptions being Zhou et al. and The Colorectal Cancer Chemotherapy Study Group of Japan who both recorded a completion rate of 52%. Time to surgery from completion of NAC ranged on average from 16 to 31 days. The anastomotic leak rate in the NAC group ranged from 0 to 4.5%, with no cases of postoperative mortality. The R0 resection rate in the NAC group was 96.1%. Meta-analysis of both RCTs included in this study showed that neoadjuvant chemotherapy increased the likelihood of a negative resection margin T3/4 advanced colon cancer (pooled relative risk of 0.47 with a 95% confidence interval) with no increase in adverse consequence of anastomotic leak, wound infection or return to theatre. Our systematic review and meta-analysis show that NAC is safe with an acceptable side effect profile in the management of LACC. The current data supports an oncological benefit for tumour downstaging and increased in R0 resection rate.

To predict cancer-specific survival, a refined nomogram model and brand-new risk-stratifying system were established to classify the risk levels of patients with early-onset locally advanced colon cancer (LACC). The clinical factors and survival outcomes of LACC cases from the SEER database from 2010 to 2019 were retrieved retrospectively. Early-onset and late-onset colon cancer were grouped according to the age (50 years old) at diagnosis. Differences between groups were compared to identify mutual significant variables. A multivariate Cox regression analysis was further performed and then constructed a nomogram. We compared it with the AJCC-TNM system. The external validation was performed for evaluation. Finally, a risk-stratifying system of patients with early-onset LACC was established. A total of 32,855 LACC patients were enrolled in, 4548 (13.84%) patients were included in the early-onset LACC group, and 28,307 (86.16%) patients were included in the late-onset LACC group. The external validation set included 228 early-onset LACC patients. Early-onset colon cancers had poorer prognosis (T4, N2, TNM stage III, CEA, tumor deposit, and nerve invasion), and a higher proportion received radiotherapy and systemic therapy (P<0.001). In the survival analysis, cancer-specific survival (CSS) was better in patients with early-onset LACC than in those with late-onset LACC (P <0.001). This nomogram constructed based on the results of COX analysis showed better accuracy in CSS prediction of early-onset LACC patients than AJCC-TNM system in the training set and external validation set (0.783 vs 0.728; 0.852 vs 0.773). We developed a novel nomogram model to predict CSS in patients with early-onset LACC it provided a reference in prognosis prediction and selection of individualized treatment, helping clinicians in decision-making.