Perineural Invasion is an Indication of Adjuvant Chemotherapy in Node Negative Colorectal cancer

Review question / Objective: Perineural invasion (PNI) is a possible route for metastatic spread in various cancer types, including colorectal cancer (CRC). PNI is linked to poor prognosis. For patients with lymph node positive colorectal cancer, a number of large-scale RCT studies have confirmed that they can benefit from chemotherapy, but there are still many controversies about whether colorectal patients with negative lymph nodes need adjuvant chemotherapy. At present, there is a general consensus that patients with stage II colorectal cancer who have risk factors such as PNI+ need chemotherapy. However, there are many recent literatures that show that patients with stage II colorectal cancer with nerve invasion risk factors can not prolong the OS and DFS of patients. At the same time, chemotherapy increases the toxicity, economic and mental burden of patients. Therefore, we hope to write this review to summarize the current research findings and provide some clinical guidance on whether patients with lymph node negative colon cancer who have perineural invasion should receive chemotherapy. Condition being studied: Patients with high-risk such as PNI+ stage II colon cancer (CC) are recommended to undergo adjuvant chemotherapy (ACT). However, whether such patients can benefit from ACT remains unclear. And recently studies shown that, ACT had no significant benefit among patients with PNI.

Prognostic Factors for Post-Recurrence Survival in Stage II and III Colorectal Carcinoma Patients

Background and objectives: This study aimed to evaluate prognostic factors for post-recurrence survival in local and locally advanced colorectal cancer patients. Materials and Methods: A total of 273 patients with stage III and high-risk stage II colorectal cancer were prospectively enrolled. All patients underwent operative treatment of the primary tumor and adjuvant fluorouracil-based chemotherapy. Results: Over the three-year period (2008–2010), a cohort of 273 patients with stage III and high-risk stage II colorectal cancer had been screened. During follow up, 105 (38.5%) patients had disease recurrence. Survival rates 1-, 3- and 5-year after recurrence were 53.9, 18.2 and 6.5%, respectively, and the median post-recurrence survival time was 13 months. Survival analysis showed that age at diagnosis (p < 0.01), gender (p < 0.05), elevated postoperative Ca19-9 (p < 0.01), tumor histology (adenocarcinoma vs. mucinous vs. signet ring tumors, p < 0.01) and tumor stage (II vs. III, p < 0.05) had a significant influence on post-recurrence survival. Recurrence interval and metastatic site were not related to survival following recurrence. Multivariate analysis showed that older age (HR 2.43), mucinous tumors (HR 1.51) and tumors expressing Ca19-9 at baseline (HR 3.51) were independently associated with survival following recurrence. Conclusions: Baseline patient and tumor characteristics largely predicted patient outcomes after disease recurrence. Recurrence intervals in local and locally advanced colorectal cancer were not found to be prognostic factors for post-recurrence survival. Older age, male gender, stage III and mucinous histology were poor prognostic factors after the disease had recurred. Stage II patients had remarkable post-recurrence survival compared to stage III patients.

Prognostic and predictive value of microsatellite instability status among patients with colorectal cancer

Objectives: Compare overall survival (OS) between microsatellite instability (MSI) high and MSI-stable and analyze the effect of chemotherapy on OS. Methods: National cancer database was queried for patients diagnosed with colorectal adenocarcinoma between 2010 and 2016. We evaluated the OS and the chemotherapy effect using Kaplan–Meier estimates and multivariate Cox regression analyses. Results: Total of 30,436 stage II patients and 30,302 stage III patients were included. In stage II with high-risk features and MSI-high, patients who received chemotherapy had better OS compared to patients who didn't receive chemotherapy. The same was found in stage II with no high-risk features and MSI-high group. Conclusion: Stage II colorectal cancer patients with high-risk features and MSI-high who received chemotherapy have better OS compared to patients who didn't receive chemotherapy.

The platelet to lymphocyte ratio is a potential inflammatory marker predicting the effects of adjuvant chemotherapy in patients with stage II colorectal cancer

Background The effects of adjuvant chemotherapy in patients with stage II colorectal cancer (CRC) has been in controversy for a long time. Our study aimed to find an effective inflammatory marker to predict the effects of chemotherapy. Methods Seven hundred eight stage II CRC patients in our institution were included. The subpopulation treatment effect pattern plot (STEPP) analysis was used to determine the optimal inflammatory marker and cut-off value. Propensity score matching (PSM) was performed to balance discrepancy between the chemotherapy and non-chemotherapy group. Survival analyses based on overall survival (OS) and cancer-specific survival (CSS) were performed with Kaplan-Meier methods with log-rank test and Cox proportional hazards regression. The restricted mean survival time (RMST) was used to measure treatment effect. Results The platelet to lymphocyte ratio (PLR) was chosen as the optimal marker with a cut-off value of 130 according to STEPP. In OS analysis, PLR was significantly associated with the effects of chemotherapy (interaction p = 0.027). In the low-PLR subgroup, the chemotherapy patients did not have a longer OS than the non-chemotherapy patients (HR: 0.983, 95% CI: 0.528–1.829). In the high-PLR subgroup, the chemotherapy patients had a significantly longer OS than the non-chemotherapy patients (HR: 0.371, 95% CI: 0.212–0.649). After PSM, PLR was still associated with the effects of chemotherapy. In CSS analysis, PLR was not significantly associated with the effects of chemotherapy (interaction p = 0.116). In the low-PLR subgroup, the chemotherapy patients did not have a longer CSS than the non-chemotherapy patients (HR: 1.016, 95% CI: 0.494–2.087). In the high-PLR subgroup, the chemotherapy patients had a longer CSS than the non-chemotherapy patients (HR: 0.371, 95% CI: 0.212–0.649). After PSM, PLR was not associated with the effects of chemotherapy. Conclusions PLR is an effective marker to predict the effects of chemotherapy in patients with stage II CRC.

JCOG1805 (PanDRa-BD study): A randomized controlled study of adjuvant chemotherapy for stage II colorectal cancer patients at high-risk of developing recurrence according to T-stage and three selected pathological factors (Pn, DR, and BD).

TPS3621 Background: Adjuvant chemotherapy for stage II colorectal cancer (CRC) still remains controversial. Although the NCCN and ESMO guidelines recommend adjuvant chemotherapy for patients with “high-risk features,” the survival benefit has not been confirmed. We reviewed the evidence levels for prognostic values of risk factors, because lack of their robustness is a major source of uncertainty regarding the optimal indication of adjuvant chemotherapy. Consequently, on top of the T-stage, three pathological factors—perineural invasion (Pn), tumor budding (BD), and desmoplastic reaction (DR)—were selected as robust risk factors of recurrence. Among the conventional factors, the prognostic value of Pn had been well validated in a multicenter study conducted by the Japanese Society for Cancer of the Colon and Rectum (JSCCR; Am J Surg Path 2013), but others were deemed suboptimal in terms of the prognostic value. BD and DR are novel tumor- and stroma-factors, respectively, associated with cancer microenvironment at the tumor front. According to the JSCCR and ITBCC 2016 criteria, tumors are graded as BD1, BD2, or BD3. The DR heterogeneity is categorized into Mature, Intermediate, and Immature patterns based on site-specific products of cancer-associated fibroblasts—keloid-like collagen and myxoid stroma. According to a recent prospective multicenter study, BD and DR characterization represent a higher level of prognostic value than other conventional factors (SACURA trial; J Clin Oncol 2019, Br J Cancer 2021). Based on the four selected risk factors, we can exclude the patient group with favorable prognosis (i.e., > 90% of 5-year RFS), which accounts for approximately 40% of the total population, resulting in enabling us to identify the concentrated population of high risk of developing recurrence. Methods: The Japan Clinical Oncology Group (JCOG) launched a randomized controlled phase III trial to evaluate the superiority of adjuvant chemotherapy in terms of relapse-free survival (RFS) over observation only in stage II CRC patients aged 20–80 years having one or more of the following risk factors: pathological T4, Pn, BD3, and non-Mature DR. Patients are randomised, in a 1:1:1 ratio, to [A] observation, [B] capecitabine monotherapy for 6 months, or [C] capecitabine and oxaliplatin (CAPOX) for 3 months. A total of 1680 patients will be accrued from 54 Japanese institutions assuming 3-year RFS with [A] to be 82% and expected 5% increase in 3-year RFS for [B] and [C] with one-sided alpha of 2.5% and power of 80% for each pair comparison. Patient enrollment was started in January 2020 and 170 patients have been enrolled until January 2021. This trial has been registered at Japan Registry of Clinical Trials as jRCTs031190186. Clinical trial information: jRCTs031190186.

Prognostic value of lymphovascular invasion in stage II colorectal cancer patients with an inadequate examination of lymph nodes

Background Lymphovascular invasion (LVI) is defined as the presence of cancer cells in lymphatics or blood vessels. This study aimed to evaluate the prognostic value of LVI in stage II colorectal cancer (CRC) patients with inadequate examination of lymph nodes (ELNs) and further combined LVI with the TNM staging system to determine the predictive efficacy for CRC prognosis. Adjuvant chemotherapy (ACT) was then evaluated for stage II CRC patients with LVI positivity (LVI+). Methods In order to avoid the effects of different ACT regimens, among 409 stage II patients, we chose 121 patients who received FOLFOX regimen and the 144 patients who did not receive ACT as the object of study. LVI was examined by hematoxylin-eosin (HE) staining. Kaplan-Meier analysis followed by a log-rank test was used to analyze survival rates. Univariate and multivariate analyses were performed using a Cox proportional hazards model. Harrell’s concordance index (C-index) was used to evaluate the accuracy of different systems in predicting prognosis. Results The LVI+ status was significantly associated with pT stage, degree of differentiation, tumor stage, serum CEA and CA19-9 levels, perineural invasion (PNI), tumor budding (TB), and KRAS status. The 5-year overall survival (OS) rate of stage II patients with < 12 ELNs and LVI+ was less than stage IIIA. Multivariate analyses showed that LVI, pT-stage, serum CEA and CA19-9 levels, PNI, TB, and KRAS status were significant prognostic factors for stage II patients with < 12 ELNs. The 8th TNM staging system combined with LVI showed a higher C-index than the 8th TNM staging system alone (C-index, 0.895 vs. 0.833). Among patients with LVI+, the ACT group had a significantly higher 5-year OS and 5-year disease-free survival (DFS) than the surgery alone (SA) group (5-year OS, 66.7% vs. 40.9%, P = 0.004; 5-year DFS, 64.1% vs. 36.3%, P = 0.002). Conclusions LVI is an independent prognostic risk factor for stage II CRC patients. Combining LVI with the 8th TNM staging system improved the predictive accuracy for CRC prognosis. ACT in stage II CRC patients with LVI+ is beneficial for survival.

Brief report: Lymph node morphology in stage II colorectal cancer

Background Colorectal cancer is one of the leading causes of cancer-associated morbidity and mortality worldwide. The local anti-tumour immune response is particularly important for patients with stage II where the tumour-draining lymph nodes have not yet succumbed to tumour spread. The lymph nodes allow for the expansion and release of B cell compartments such as primary follicles and germinal centres. A variation in this anti-tumour immune response may influence the observed clinical heterogeneity in stage II patients. Aim The aim of this study was to explore tumour-draining lymph node histomorphological changes and tumour pathological risk factors including the immunomodulatory microRNA-21 (miR-21) in a small cohort of stage II CRC. Methods A total of 23 stage II colorectal cancer patients were included. Tumour and normal mucosa samples were analysed for miR-21 expression levels and B-cell compartments were quantified from Haematoxylin and Eosin slides of lymph nodes. These measures were compared to clinicopathological risk factors such as perforation, bowel obstruction, T4 stage and high-grade. Results We observed greater Follicle density in patients with a lower tumour T stage and higher germinal centre density in patients with higher pre-operative carcinoembryonic antigen levels. Trends were also detected between tumours with deficiency in mismatch repair proteins, lymphatic invasion and both the density and size of B-cell compartments. Lastly, elevated tumour miR-21 was associated with decreased Follicle and germinal centre size. Conclusion Variation in B-cell compartments of tumour-draining lymph nodes is associated with clinicopathological risk factors in stage II CRC patients.

CT-Based Radiomics Signature: A Potential Biomarker for Predicting Postoperative Recurrence Risk in Stage II Colorectal Cancer

Objective: To evaluate whether a radiomics signature could improve stratification of postoperative risk and prediction of chemotherapy benefit in stage II colorectal cancer (CRC) patients.Material and Methods: This retrospective study enrolled 299 stage II CRC patients from January 2010 to December 2015. Based on preoperative portal venous-phase CT scans, radiomics features were generated and selected to build a radiomics score (Rad-score) using the Least Absolute Shrinkage and Selection Operator (LASSO) method. The minority group was balanced by the synthetic minority over-sampling technique (SMOTE). Predictive models were built with the Rad-score and clinicopathological factors, and the area under the curve (AUC) was used to evaluate their performance. A nomogram was also constructed for predicting 3-year disease-free survival (DFS). The performance of the nomogram was assessed with a concordance index (C-index) and calibration plots.Results: Overall, 114 features were selected to construct the Rad-score, which was significantly associated with the 3-year DFS. Multivariate analysis demonstrated that the Rad-score, CA724 level, mismatch repair status, and perineural invasion were independent predictors of recurrence. Results showed that the Rad-score can classify patients into high-risk and low-risk groups in the training cohort (AUC 0.886) and the validation cohort (AUC 0.874). On this basis, a nomogram that integrated the Rad-score and clinical variables demonstrated superior performance (AUC 0.954, 0.906) than the clinical model alone (AUC 0.765, 0.705) in the training and validation cohorts, respectively. The C-index of the nomogram was 0.872, and the performance was acceptable.Conclusion: Our radiomics-based model can reliably predict recurrence risk in stage II CRC patients and potentially provide complementary prognostic value to the traditional clinicopathological risk factors for better identification of patients who are most likely to benefit from adjuvant therapy. The proposed nomogram promises to be an effective tool for personalized postoperative surveillance for stage II CRC patients.