Low-risk Stage Research Articles

Adjuvant Chemotherapy Duration and Disease-Free Survival in Low-Risk Stage III Colon Cancer with N1a-b and N1c Disease: Insights from a Single-Center Retrospective Analysis.

Tumor deposits (TDs) are known to have a poor prognosis independent of lymph node (LN) involvement and are considered equivalent to LN metastases in the latest staging system. In stage III colon cancer (CC), high-risk patients (pT4 or pN2) receive 6months of adjuvant chemotherapy, while low-risk patients (pT1-3 and N1) are recommended either 3 or 6months of CAPOX or 6months of FOLFOX therapy. However, the optimal chemotherapy duration for low-risk patients classified as pN1c remains unknown. The aim of this study is to investigate the impact of adjuvant chemotherapy duration (3months vs. 6months) on survival in patients with low-risk stage III CC either in pN1a-b and pN1c patient groups. We retrospectively analyzed patients with stage III CC who underwent surgery at a tertiary center between January 2014 and May 2024. Demographic and pathological data of patients were retrospectively collected. The primary outcome was disease-free survival (DFS). A total of 142 patients were included. Among the patients, 116 were pT1-3N1a-b and 26 were pT1-3N1c. Local (23.1% vs. 1.7%, P < 0.001) and overall (38.5% vs 14.6%, P = 0.011) recurrences were significantly higher in the pN1c group. Univariate and multivariate analyses revealed no significant impact of adjuvant chemotherapy duration on DFS in the pN1a-b group (P = 0.359), whereas in the pN1c group, 3-month chemotherapy resulted in significantly shorter DFS (P = 0.044) in univariate analysis. Our study indicates that shorter duration of adjuvant chemotherapy is associated with worse survival and 6-month chemotherapy is recommended for patients with pT1-3 and N1c disease.

Patients with T4N0 and T1‑3N1 colon cancer and a high preoperative carcinoembryonic antigen level benefit from adjuvant chemotherapy with oxaliplatin for 6 months.

A shorter duration of oxaliplatin adjuvant chemotherapy has recently emerged as a potential option for patients with high-risk stage II and low-risk stage III (T1-3N1) colon cancer (CC). The present study aimed to elucidate the risk factors for recurrence in these patient populations and to identify the appropriate indications for shortened treatment durations. The present study retrospectively analyzed 396 patients who underwent curative surgery for pathological T4N0 or stage III CC, followed by adjuvant chemotherapy, at two institutes. Overall, 234 patients with T4N0 and low-risk stage III CC were categorized into the low-risk group and 162 patients with high-risk stage III CC into the high-risk group. The 3-year relapse-free survival rate was significantly higher in the low-risk group than in the high-risk group. Multivariate Cox model analysis of the low-risk group revealed that high preoperative serum levels of carcinoembryonic antigen (CEA) and incomplete 6-month adjuvant chemotherapy with oxaliplatin were independent poor prognostic factors. The prognosis of patients in the low-risk group who had abnormal CEA levels and did not complete the 6-month adjuvant treatment with oxaliplatin was similar to that of patients in the high-risk group. However, the prognosis of patients in the low-risk group with high CEA levels improved with a 6-month adjuvant treatment with oxaliplatin to a similar level to that of all patients with low CEA levels in the low-risk group. In conclusion, the present study suggested that the duration of adjuvant chemotherapy with oxaliplatin should not be shortened in patients with high preoperative CEA levels, even in the low-risk group.

Radiotherapy alone vs radiotherapy with concurrent chemoradiotherapy in patients with low-risk nasopharyngeal carcinoma: Updated results from a multicenter, open-label, non-inferiority, randomized phase III trial.

142 Background: There is limited evidence for the role of concurrent chemotherapy with use of intensity-modulated radiation therapy (IMRT) in low-risk stage II/T3N0 Nasopharyngeal Carcinoma (NPC) patients. We previously reported comparable 3-year failure-free survival-free survival (FFS) using radiotherapy alone compared with concurrent chemoradiotherapy in the low-risk patients. Here, we present the 5-year overall survival (OS) analysis and additional analysis. Methods: This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes &lt;3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA &lt;4000 copies/mL), with enrollment between November 2015 and August 2020. This trial is registered with ClinicalTrials.gov, number NCT02633202. Results: In this randomized trial, patients were assigned to be treated IMRT alone (n=172) or with concurrent chemoradiotherapy (IMRT with cisplatin, n=169). With a median follow-up of 70.1 months, the IMRT-alone group had a similar 5-year overall survival (95.2% vs. 98.2%, hazard ratio, 2.27 [95%CI:0.70-7.40]; P=0.16), failure-free survival (86.2% vs. 88.4%, hazard ratio, 1.16 [95%CI:0.64-2.07]; p = 0.63). Hearing impairment (HI) data (assessed by The Hearing Handicap Inventory for Adult- Screening version (HHIA-S)) were collected from 86 patients in the IMRT-alone group and 81 patients in the concurrent chemoradiotherapy group. Among the patients, 45(26.9%) developed HI (IMRT-alone vs. CCRT: 20 [23.3%] vs. 25 [30.9%]), among which 36 (21.6%) had mind HI (IMRT-alone vs. CCRT: 15 [17.4%] vs. 21 [25.9%]). Conclusions: Radiotherapy alone provides comparable survival or disease control and less toxicity compared to CCRT in low-risk nasopharyngeal carcinoma. Clinical trial information: NCT02633202 .

Projected Impact of Nonpharmacologic Management of Stage 1 Hypertension Among Lower-Risk US Adults.

The 2017 American College of Cardiology/American Heart Association blood pressure guideline classified 31 million US adults as having stage 1 hypertension and recommended clinicians provide counseling on behavioral change to the low-risk portion of this group. However, nationwide reductions in cardiovascular disease (CVD) and associated health care expenditures achievable by nonpharmacologic therapy remain unquantified. We simulated interventions on a target population of US adults aged 35 to 64 years, identified from the 2015-2018 National Health and Nutrition Examination Survey, with low-risk stage 1 systolic hypertension: that is, untreated systolic blood pressure 130 to 139 mm Hg with diastolic BP <90 mm Hg; no history of CVD, diabetes, or chronic kidney disease; and a low 10-year risk of CVD. We used meta-analyses and trials to estimate the effects of population-level behavior modification on systolic blood pressure. We assessed the extent to which restricting intervention to those in regular contact with clinicians might prevent the delivery of nonpharmacologic therapy. Controlling systolic blood pressure to <130 mm Hg among the 8.8 million low-risk US adults with stage 1 hypertension could prevent 26 100 CVD events, avoid 2900 deaths, and save $1.7 billion in total direct health care costs over 10 years. Adoption of the Dietary Approaches to Stop Hypertension diet could prevent 28 000 CVD events. Other nonpharmacologic interventions could avert between 3800 and 19 500 CVD events. However, only 51% of men and 75% of women regularly interacted with clinicians for counseling opportunities. Among low-risk adults with stage 1 hypertension, substantial benefits to cardiovascular health could be achieved through public policy that promotes the adoption of nonpharmacologic therapy.

A multi-classifier system integrated by clinico-histology-genomic analysis for predicting recurrence of papillary renal cell carcinoma

Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I–III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy.

Impact of the IDEA Collaboration Study on Real-World Practice Patterns of Adjuvant Chemotherapy in Patients With Stage III Colon Cancer: A Population-Based Study.

The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration showed no significant clinical difference in outcomes in patients with stage III colon cancer (CC) treated with 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy (O-ACT). We aimed to assess change in real-world practice patterns before and after publication of the IDEA study. This retrospective cohort study included patients age ≥18 years with stage III CC diagnosed between January 1, 2012, and December 31, 2020. Eligible patients received >1 dose of ACT between March 20, 2012, and May 10, 2021 inclusive. They were categorized into pre-IDEA (diagnosed before March 31, 2018) and post-IDEA (diagnosed on or after April 1, 2018) groups. The primary outcome was the median duration and type of ACT and factors associated with a shorter duration. Secondary outcomes were 2-year overall survival (OS) and cancer-specific survival (CSS). In total, 740 patients were included (median age, 64 years, range, 27-90; 52.7% male). 48.8% had pT4 and/or pN2 disease. 77% received O-ACT. In the post-IDEA era, capecitabine plus oxaliplatin (CAPOX) ACT use increased (22.8%-50.7%, P < .001), and median duration of treatment was significantly shorter (2.7 v 4.8 months, P < .001). Factors associated with shorter O-ACT duration included diagnosis in the post-IDEA era (odds ratio, 2.08, P = .002), absence of pT4 and/or pN2 disease (hazard ratio [HR], 1.71, P = .01), and receipt of CAPOX (HR, 2.58, P < .001). Two-year OS and CSS were comparable between pre- and post-IDEA eras (OS 95% v 94%; CSS 96% v 96%). Our study shows that the results of the IDEA trial have been largely adopted in clinical practice with shorter duration of ACT in low-risk stage III CC.

P57 Clinical Outcomes of Low-Risk Stage II Colon Cancer Survivors Adhering to Guidelines: A Microsimulation Model

P57 Clinical Outcomes of Low-Risk Stage II Colon Cancer Survivors Adhering to Guidelines: A Microsimulation Model

21P The impact of adjuvant chemotherapy duration on progression-free survival in low-risk stage III colon cancer with N1a-b and N1c disease: A retrospective, single-center analysis

21P The impact of adjuvant chemotherapy duration on progression-free survival in low-risk stage III colon cancer with N1a-b and N1c disease: A retrospective, single-center analysis

ALYREF m5C RNA methylation reader predicts bladder cancer prognosis by regulating the tumor immune microenvironment.

5-Methylcytidine (m5C) methylation is a recently emerging epigenetic modification that is closely related to tumor proliferation, occurrence, and metastasis. This study aimed to investigate the clinicopathological characteristics and prognostic value of m5C regulators in bladder cancer (BLCA), and their correlation with the tumor immune microenvironment. Thirteen m5C RNA methylation regulators were analyzed using RNA-sequencing and corresponding clinical information obtained from the TCGA database. The Cluster Profiler package was used to analyze the gene ontology function of potential targets and enriched the Kyoto Encyclopedia of Genes and Genomes pathway. Kaplan-Meier survival analysis was used to compare survival differences using the log-rank test and univariate Cox proportional hazards regression. The correlation between signature prognostic m5C regulators and various immune cells was analyzed. Univariate and multivariate Cox regression analyses identified independence of the ALYREF gene signature. Nine out of the 13 m5C RNA methylation regulators were differentially expressed in BLCA and normal samples and were co-expressed. These 9 regulators were associated with clinicopathological tumor characteristics, particularly high or low tumor risk, pT or pTNM stage, and migration. Consensus clustering analysis divides the BLCA samples into 4 clusters. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment annotation and gene ontology function analysis identified 273 upregulated and 594 downregulated genes in BLCA. Notably, only ALYREF was significantly correlated with OS (P < .05). ALYREF exhibited significant infiltration levels in macrophage cells. Therefore, we constructed a nomogram for ALYREF as an independent prognostic factor. Additionally, we observed that both the mRNA and protein levels of ALYREF were upregulated, and immunofluorescence showed that ALYREF was mainly distributed in nuclear speckles. ALYREF overexpression was significantly associated with poor OS. Our findings demonstrated the potential of ALYREF to predict clinical prognostic risks in BLCA patients and regulate the tumor immune microenvironment. As such, ALYREF may serve as a novel prognostic indicator in BLCA patients.

Clinical, pathological, and adjuvant chemotherapy use differences among microsatellite unstable and microsatellite stable colon cancers

BackgroundColon cancers are categorized into mismatch repair deficient/microsatellite unstable (MSI-H) and mismatch repair proficient/microsatellite stable (MSS) cancers. This study aims to compare the disease characteristics and trends in the utilization of cancer therapies across different age groups and stages in these two groups. MethodsMSI-H and MSS colon adenocarcinomas from 2010 to 2016 were identified using the National Cancer Database. We compared patient and disease characteristics between the two groups and evaluated the use of adjuvant chemotherapy across age groups and cancer stages. Within MSI-H and MSS groups, we conducted a landmark analysis after propensity score matching for adjuvant chemotherapy versus no chemotherapy to determine its effect on survival. ResultsOf the 542,368 patients that met inclusion criteria, 120,751 (22%) had mismatch repair results available—out of these 96,928 (80%) had MSS colon cancers while 23,823 (19.7%) had MSI-H cancers. MSI-H disease had a bimodal age distribution (<40 years = 22%; ≥75 years = 26%) and was frequent among females (22%) and non-Hispanic Whites (20%). Among those < 65 years, 15% of low-risk stage 2 MSI-H patients and 40% of high-risk stage 2 MSI-H patients received adjuvant chemotherapy. More than two-thirds of stage 3 patients <65 years received adjuvant chemotherapy in both groups. After conducting propensity-score matching for age, gender, and co-morbidities, we found that adjuvant chemotherapy use had a trend towards lower overall survival (OS) in low-risk stage 2 MSI-H (HR = 1.8 [95% CI, 0.8–4.02]) and high-risk stage 2 MSI-H (HR = 1.42 [95% CI, 0.96–2.12]) groups. Adjuvant chemotherapy significantly improved OS in stage 3 colon cancer patients irrespective of microsatellite status or risk category of disease. ConclusionsMSI-H colon cancer had bimodal age distribution. Among stage 2 MSI-H patients <65 years, a notable proportion received adjuvant chemotherapy. Among MSI-H stage 2 patients, adjuvant chemotherapy use was associated with lower survival while it significantly improved survival for stage 3 patients, irrespective of MSI status.

MFOLFIRINOX versus mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancer - the FROST trial: study protocol for a multicenter, randomized controlled, phase II trial

BackgroundHigh-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.MethodsThis 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.DiscussionThe 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.Trial registrationClinicalTrials.gov NCT05179889, registered on 17 December 2021.

Unveiling the challenges of UTUC biopsies and cytology: insights from a global real-world practice study

PurposeDiagnostic ureteroscopy (dURS) is optional in the assessment of patients with upper tract urothelial carcinoma (UTUC) and provides the possibility of obtaining histology.MethodsTo evaluate endoscopic biopsy techniques and outcomes, we assessed data from patients from the CROES-UTUC registry. The registry includes multicenter prospective collected data on diagnosis and management of patients suspected having UTUC.ResultsWe assessed 2380 patients from 101 centers. dURS with biopsy was performed in 31.6% of patients. The quality of samples was sufficient for diagnosis in 83.5% of cases. There was no significant association between biopsy techniques and quality (p = 0.458). High-grade biopsy accurately predicted high-grade disease in 95.7% and high-risk stage disease in 86%. In ureteroscopic low-grade tumours, the prediction of subsequent low-grade disease was 66.9% and low-risk stage Ta-disease 35.8%. Ureteroscopic staging correctly predicted non-invasive Ta-disease and ≥ T1 disease in 48.9% and 47.9% of patients, respectively. Cytology outcomes did not provide additional value in predicting tumour grade.ConclusionBiopsy results adequately predict high-grade and high-risk disease, but approximately one-third of patients are under-staged. Two-thirds of patients with low-grade URS-biopsy have high-risk stage disease, highlighting the need for improved diagnostics to better assess patient risk and guide treatment decisions.Clinical trial registration: The study was registered at ClinicalTrials.gov (ClinicalTrials.gov NCT02281188; https://clinicaltrials.gov/ct2/show/NCT02281188).

Preoperative Strategies for Locally Advanced Colon Cancer.

Neoadjuvant 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.

Optimal duration of oxaliplatin-based adjuvant chemotherapy in patients with different risk factors for stage II-III colon cancer: a meta-analysis.

The duration of oxaliplatin-based chemotherapy in high-risk stage II, low-risk stage III, and high-risk stage III colon cancer (CC) patients is controversial. To reduce the risk of adverse events (AEs) without compromising efficacy while improving chemotherapy compliance is crucial. The authors searched Cochrane, Embase, Pubmed, and Web of Science databases for articles from inception to August 8, 2023, the main outcomes were disease-free survival, overall survival, chemotherapy completion rates, and AE frequency. Six randomized controlled trials (RCTs) involving 10332 patients were included. Disease-free survival analysis revealed that only the high-risk stage III CC patients experienced better results with the 6-month FOLFOX regimen when compared with the 3-month regimen [Hazard ratio (HR): 1.32, 95% CI: 1.15-1.51, P <0.0001). Overall survival (OS) analysis revealed that extending the use of FOLFOX and CAPEOX regimens did not provide survival benefits for stage III CC patients (HR: 1.16, 95% CI: 0.9-1.49, and HR: 0.89, 95% CI: 0.67-1.18, P =0.40). The completion rate of the 3-month oxaliplatin-based adjuvant chemotherapy regimen was significantly higher than that of the 6-month regimen [Relative risk (RR): 1.16, 95% CI: 1.06-1.27, P =0.002]. Moreover, the 3-month regimen had significantly lower AE rates than the 6-month regimen (RR: 0.62, 95% CI: 0.57-0.68, P <0.00001), with differences mainly concentrated in grade 3/4 neutropenia (RR: 0.70, 95% CI: 0.59-0.85, P =0.0002), peripheral sensory neuropathy at ≥grade 2 (RR: 0.45, 95% CI: 0.38-0.53, P <0.00001), and hand-foot syndrome at ≥grade 2 (RR: 0.36, 95% CI: 0.17-0.77, P =0.009). The 6-month FOLFOX regimen should only be recommended for high-risk stage III CC, while the 3-month regimen can be recommended for other stages. A 3-month CAPEOX regimen can be recommended for stage II-III CC.

Real-world adoption of 3 months of adjuvant oxaliplatin chemotherapy in patients with stage III colorectal cancer (CRC).

83 Background: Based on the IDEA analysis, 3 months (mos) of adjuvant chemotherapy (ACT) with CAPOX has emerged as an option for both low-risk and high-risk stage III CRC. This has resource utilization, cost and toxicity benefits (particularly less neurotoxicity) without compromising efficacy. This study examines the patterns of uptake of CAPOX vs FOLFOX and duration of ACT in a contemporary post-COVID real-world cohort of patients (pts) in the province of British Columbia (BC), Canada. Methods: The provincial pharmacy database was used to identify pts with resected stage III CRC who received adjuvant CAPOX or FOLFOX between January 2021 and December 2022. Pts with rectal cancer requiring neoadjuvant chemotherapy or radiotherapy were excluded. Demographic, tumor, and treatment information was collected. “High-risk features” were defined as pT4 or pN2 tumors. “Urban” setting was defined based on the population size of the regional health authority. Descriptive statistical analyses were performed to examine baseline characteristics and Fisher’s exact test was used to examine univariate associations. Results: 452 pts were included, of which 234 (52%) and 218 (48%) were planned to receive 3 and 6 mos of ACT respectively (see table). Within the 3 mos group, 226 (97%) received CAPOX. Within the 6 mos group, there was a 51%/49% split between CAPOX/FOLFOX. By univariate analysis, factors associated with 3 mos of CAPOX vs 6 mos of ACT were age &gt;70y (P=0.039), low/intermediate grade (P=0.005) and low-risk stage III disease (P&lt;0.0001). 29% of pts planned for 6 mos of oxaliplatin ACT had low-risk disease, with 52% of these receiving CAPOX. Conclusions: 3 mos of adjuvant CAPOX is an accepted option for nearly all pts with stage III disease with consequent less neurotoxicity and fewer treatment visits. Yet, in this contemporary cohort, use of 3 mos of adjuvant CAPOX remains low and is associated with older age and low-risk disease. 6 mos of oxaliplatin is still being offered to pts with low-risk disease. Exploration of patient preferences, real-world treatment and time toxicities, and resource costs may improve more widespread adoption of 3 mos of adjuvant CAPOX in stage III CRC. [Table: see text]

Development of an improved risk stratification scheme for stage II and III colorectal cancers through incorporation of the digital pathology biomarker QuantCRC.

162 Background: There is a need to improve current risk stratification of stage II and III colorectal cancer (CRC) to better inform risk of recurrence and guide adjuvant chemotherapy. The purpose of this study is to examine whether integration of QuantCRC, an AI-based digital pathology biomarker utilizing hematoxylin and eosin-stained slides, provides improved risk stratification over current American Society of Clinical Oncology (ASCO) guidelines. Methods: ASCO and QuantCRC-integrated risk schemes were applied to an observational cohort of 1,068 stage II and III CRCs. The stage II integrated scheme utilizes pT3 vs. pT4 and QuantCRC-derived risk groups. The stage III integrated scheme utilizes pT1-3 vs. pT4, pN1 vs. pN2, and QuantCRC-derived risk groups. Performance metrics included log-rank test, hazard ratios and Somers’ Dxy rank correlation. Results: Integration of QuantCRC provides improved risk stratification compared to the ASCO scheme for stage II and III CRC. The QuantCRC-integrated scheme placed more stage II tumors in the low-risk group compared to the ASCO scheme (69.3% vs. 60.4%) without decreased 3-year RFS. The QuantCRC-integrated scheme provided larger hazard ratios (HR) for both intermediate-risk (3.04, 95%CI 1.81-5.10, P=2.8x10-5) and high-risk (4.62, 95%CI 2.02-10.61, P=0.0003) groups compared to ASCO intermediate-risk (2.09, 95%CI 1.21-3.63, P=0.008) and high-risk (3.08, 95%CI 1.57-6.01, P=0.001) groups. The QuantCRC-integrated scheme for stage III tumors identified a small group of 80/518 (15.4%) CRCs at very high risk of recurrence with HR of 4.08 (95%CI 2.68-6.23, P=6.5x10-11) compared to a HR of 2.42 (95%CI 1.72-3.38, P=3.1x10-7) for 228/518 (44.0%) high-risk CRCs in the ASCO scheme. QuantCRC-integrated risk groups remained prognostic in stage III CRCs when stratified by presence or absence of any adjuvant chemotherapy. No difference in RFS were seen in QuantCRC-integrated low-risk and intermediate-risk stage III CRCs stratified by 3 vs. 6-months of oxaliplatin-based adjuvant chemotherapy suggesting that these two groups can be treated with 3-months of adjuvant therapy. Conclusions: Incorporation of QuantCRC into risk stratification provides a powerful predictor of RFS that has potential to guide subsequent treatment and surveillance.

MFOLFIRINOX versus mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancer (FROST trial): Study protocol for an open label, multicenter, randomized, phase II study.

TPS230 Background: Patients with high-risk stage III colon cancer have a significantly poorer prognosis than those with stage II or low-risk stage III colon cancer. Despite this distinction, most guidelines recommend similar adjuvant treatment approaches for all stages, and there is a dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis through more intensive adjuvant treatment. Given the proven efficacy of triplet chemotherapy in metastatic colorectal cancer, this study aims to assess the effectiveness and toxicity of modified 5-fluoropyrimidine (5-FU)/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) in comparison with the current standard of care—modified oxaliplatin and 5-FU (mFOLFOX-6)—as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer. Methods: This multicenter, randomized (1:1), open-label, phase II trial aims to compare the adjuvant treatment efficacy of mFOLFIRINOX and mFOLFOX-6 in patients with high-risk stage III colon cancer. The trial aimed to enroll 312 eligible patients aged between 20 and 70 years with an Eastern Cooperative Oncology Group performance status of 0-2, or between 70 and 75 years with an Eastern Cooperative Oncology Group performance status of 0. All patients underwent radical resection and were randomized into two arms: Arm A experimental arm, received 12 cycles of mFOLFIRINOX every 2 weeks, while arm B, the reference arm, received 12 cycles of mFOLFOX 6 every 2 weeks. The primary endpoint of this study was the 3-year disease-free survival, whereas the secondary endpoints included assessing the 3-year overall survival and treatment toxicity. Discussion: The Frost trial is expected to elucidate the safety and oncologic efficacy of mFOLFIRINOX compared to mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancers, and provide evidence about this treatment, and contribute to improve the prognoses ultimately. Clinical trial information: NCT05179889 .

A randomized controlled trial of CAPEOX vs observation in patients with early-stage colorectal cancer with positive MRD after curative surgery (CAREME).

TPS225 Background: Most patients (pts) with early-stage colorectal cancer (CRC) have a good prognosis, but some still relapse shortly after surgery. Effective methods to assess the risk of recurrence in these pts and guide adjuvant chemotherapy (ACT) decision-making are lacking. Increasing studies have shown that circulating tumor DNA (ctDNA) can detect minimal residual disease (MRD) and identify pts with a high risk of recurrence. ACT could improve survival of MRD-positive pts with stage Ⅱ CRC suggested by recent studies, whether it is appropriate for those with stage Ⅰ or clinically low-risk stage Ⅱ CRC remains unknown. Methods: CAREME is a multicenter randomized controlled clinical trial aimed at investigating the benefit of chemotherapy for MRD-positive pts with early-stage CRC. Pts with resected stage Ⅰ or Ⅱ CRC will be evaluated by oncologists. Those who did not receive neoadjuvant therapy and are deemed suitable for active surveillance (i.e., ACT is not needed) will undergo a postoperative ctDNA test using MinerVa MRD assay (a tumor-informed assay covering 769 cancer-related genes). Pts with mismatch repair-deficient tumors will be excluded and stage Ⅱ pts should have no traditional high-risk features according to clinical practice guidelines. Pts with positive ctDNA (N = 38) will be equally randomized into two groups: treatment group (Arm A) or surveillance group (Arm B). Arm A will receive 8 cycles of CAPEOX therapy while pts in Arm B will not receive any ACT; both groups will undergo ctDNA tests at 6 months after randomization and be followed up every 3 months. The primary endpoint is 18-month recurrence-free survival, and a key secondary endpoint is ctDNA clearance at 6 months after randomization. Tumor samples from the pts will be collected for MRD assay and exploratory research. Accrual started in February 2023. Support: Genecast Biotechnology Company. Clinical trial information: NCT05699746 .

Phase II results of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA) phase II/III study.

5 Background: For patients (pts) with colon cancer (CC), the detection of circulating tumor DNA (ctDNA) is associated with persistent disease after resection and outperforms traditional clinical and pathological features in prognosticating recurrence risk. We hypothesized that for pts with low-risk stage II CC, a positive ctDNA status after resection may identify those who benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts with resected stage II CC without traditional high risk features and whom the evaluating oncologist deems suitable for active surveillance (i.e., not needing adjuvant chemotherapy) were randomized 1:1 to two arms: standard-of-care/observation (Arm A), or ctDNA assay directed therapy (Arm B). Postoperative blood was analyzed for ctDNA with the Guardant LUNAR assay, covering CC-relevant mutations and CC-specific methylation profiling. Arm B pts with ctDNA detected were treated with 6 mos of adjuvant (CAPOX or FOLFOX) chemotherapy. Primary endpoint for the phase II study was clearance of ctDNA at the 6-mo timepoint. A 1-sided Fisher exact test was used to compare ctDNA clearance between Arm A and Arm B among the first 16 pts with ctDNA detected at baseline. If p&gt;.35, the study would be stopped for futility of ctDNA clearance but would otherwise continue to phase III if p≤.35. We present the results of the pre-planned phase II analysis. Results: 635 pts were randomized (Arm A: 318; Arm B: 317). One pt with ctDNA detected in Arm B declined protocol-directed chemotherapy but was included in the intention to treat analysis. Among the first 16 pts with ctDNA detected at baseline for the primary endpoint analysis, clearance of ctDNA after 6 mos was observed in 3/7 pts (43%, 95% CI 10-82%) in the control arm and in 1/9 pts (11%, 95% CI 0.3-48%) in the experimental arm after chemotherapy (p=.98). There were no unanticipated toxicities in those treated with chemotherapy. Conclusions: The phase II endpoint was not met and further enrollment has been halted based upon pre-specified study stopping rules utilizing the original assay. No improvement in ctDNA clearance was observed after 6 mos of chemotherapy for pts with ctDNA detected following resection of stage IIA CC. Future trials evaluating ctDNA as an integral biomarker for minimal residual disease determination must account for assay specificity in this pt population. Support: U10CA180868, -180822; UG1CA189867; Guardant Health. Clinical trial information: NCT04068103 .

Combining pathological risk factors and T, N staging to optimize the assessment for risk stratification and prognostication in low-risk stage III colon cancer

BackgroundThis study aimed to investigate the combined pathological risk factors (PRFs) to stratify low-risk (pT1-3N1) stage III colon cancer (CC), providing a basis for individualized treatment in the future.Patients and methodsPRFs for low-risk stage III CC were identified using COX model. Low-risk stage III CC was risk-grouped combining with PRFs, and survival analysis were performed using Kaplan–Meier. The Surveillance, Epidemiology, and End Results (SEER) databases was used for external validation.ResultsNine hundred sixty-two stage III CC patients were included with 634 (65.9%) as low risk and 328 (34.1%) as high risk. Poor differentiation (OS: P = 0.048; DFS: P = 0.011), perineural invasion (OS: P = 0.003; DFS: P < 0.001) and tumor deposits (OS: P = 0.012; DFS: P = 0.003) were identified as PRFs. The prognosis of low-risk CC combined with 2 PRFs (OS: HR = 3.871, 95%CI, 2.004–7.479, P < 0.001; DFS: HR = 3.479, 95%CI, 2.158–5.610, P < 0.001) or 3 PRFs (OS: HR = 5.915, 95%CI, 1.953–17.420, P = 0.002; DFS: HR = 5.915, 95%CI, 2.623–13.335, P < 0.001) was similar to that of high-risk CC (OS: HR = 3.927, 95%CI, 2.317–6.656, P < 0.001; DFS: HR = 4.132, 95%CI, 2.858–5.974, P < 0.001). In the SEER database, 18,547 CC patients were enrolled with 10,023 (54.0%) as low risk and 8524 (46.0%) as high risk. Low-risk CC combined with 2 PRFs (OS: HR = 1.857, 95%CI, 1.613–2.139, P < 0.001) was similar to that of high-risk CC without PRFs (HR = 1.876, 95%CI, 1.731–2.033, P < 0.001).ConclusionCombined PRFs improved the risk stratification of low-risk stage III CC, which could reduce the incidence of undertreatment and guide adjuvant chemotherapy.