263 Background: The total neoadjuvant therapy (TNT) paradigm for locally advanced rectal cancer (LARC) is evolving with intensification and de-escalation neoadjuvant therapies. Chemoradiation (CRT) followed by consolidation chemotherapy offers the highest rate of organ preservation. Circulating tumor DNA (ctDNA) response during TNT may serve as a biomarker that allows for therapy personalization to better select candidates for rectal organ preservation (Watch-and-Wait, WW). Methods: We enrolled patients with mismatch repair proficient LARC eligible for TNT on a prospective protocol (NCT05108428). Patients underwent CRT to 50.4 Gy with a mid-treatment evaluation (27 Gy) on a MRI-linac followed by 8 cycles of consolidation FOLFOX. A sequential MRI-guided adaptive radiotherapy boost to 59.4 Gy was delivered if rectal tumor volume reduced > 30% at 27 Gy. Standard restaging with diagnostic MRI and endoscopy occurred after TNT to evaluate organ preservation candidacy. ctDNA was obtained at diagnosis, mid-CRT (27 Gy), completion of TNT, and regular intervals in surveillance. ctDNA analysis was performed using a clinically validated, personalized, tumor-informed assay (Signatera, Natera, Inc.). Descriptive statistics for clinical response for mid-treatment assessment are reported. Additional clinical outcomes will be reported as follow up matures. Results: A total of 20 patients were enrolled (70% male, 70% cN+) with average age of 58 (range: 30-86) and 40% with threatened or involved radial margin. Average follow up is 12 months (range: 4-24 months) from date of completion of TNT. Average initial tumor volume was 26cc (range: 8.6cc- 66.8cc) with an average tumor reduction of 68.5% at 27 Gy. Volumetric change based on mid treatment MRI >30% did not predict WW eligibility (2 patients with <30% volumetric change maintains clinical complete responses). All patients demonstrated positive ctDNA at diagnosis (average 7.08 MTM/mL, range: 0.08 MTM/mL -77.96 MTM/mL). 25% of patients had elevated CEA at diagnosis. Conversion to negative ctDNA at mid-CRT occurred in 53% of patients. 57% of patients with a positive ctDNA at this timepoint underwent formal oncologic mesorectal excision with adenocarcinoma confirmed in the specimens. 25% of patients with negative ctDNA at this timepoint underwent a local excision, with no histologic invasive cancer in both specimens. We observed a 100% rectal organ preservation rate when early conversion to negative ctDNA at the 27 Gy of CRT timepoint. Conclusions: ctDNA clearance during CRT may be a good early predictor for patients that may be a candidate for a WW protocol. This biomarker may also guide consolidation therapy escalation (FOLFIRINOX) or de-escalation (chemotherapy omission) for select patients. Longer follow up is needed to correlate with clinical outcomes and future studies with more patients is needed. Clinical trial information: NCT05108428 .

Introduction Total pelvic exenteration (TPE) for clinical T4b colorectal cancer (CRC) is associated with significant morbidity. Short (0-30 days)- and intermediate (31-90 days)-term temporal analysis of complication onset is not well described, yet needed, to better counsel patients considering TPE. Methods A retrospective cohort study of consecutive patients with primary or recurrent clinical T4b pelvic CRC undergoing open TPE between 2014 and 2023 was conducted. Clinicopathologic variables were collected for each patient. Postoperative morbidity was classified according to the Clavien-Dindo (CD) grade system and stratified by time of onset within 90 days of surgery. Pearson’s Chi-square test, Fisher’s Exact test, and the Mann-Whitney U test were used to compare primary vs recurrent patient groups, and logistic regression assessed predictors of postoperative morbidity. Statistical analysis was performed using R with two-sided significance set at <0.05. Results Twenty-seven patients were identified of which 24 (88.9%) were male with a median age of 60.4 years (interquartile range [IQR]: 56.3-70.5). Seventeen (63.0%) patients had primary disease and 10 (37.0%) had recurrent CRC. Twenty-three (85.2%) patients experienced at least one complication within 90 days of surgery, but no mortality was observed. Ten (37.0%) patients experienced a CD ≥ 3 event, of which 40% took place beyond 30 days. The most common complication overall was anemia requiring transfusion, while the most common major complication was pelvic abscess. No clinicopathologic variables analyzed were predictive of major postoperative complication within 90 days of TPE. Conclusion TPE for clinical T4b CRC carries a high risk of postoperative morbidity in both the short- and intermediate-term after surgery, with a significant proportion of complications occurring after 30 days. Given the magnitude of operation, an extended recovery with high risk for complications is common. Although a single-center series, this annotated postoperative complication profile may assist patients and clinicians when reviewing informed consent for TPE.

e15675 Background: The incidence of early onset (EO) colorectal cancer is on the rise in the western world, with approximately 10% of all new cases diagnosed at or before the age of 50. We sought to characterize EO vs average onset (AO) colorectal cancer patients at a dedicated cancer center over a ten-year period. Methods: A retrospective review was performed of an institutional database that prospectively collects clinical and demographic data of all patients with colon or rectal (including rectosigmoid) cancers. Patients were then categorized by age range and their clinical characteristics recorded. Results: A total of 5,890 patients with colorectal cancer were identified between the years 2014 and 2023, with 1,316 (22.3%) diagnosed at or before age 50. Overall, median follow up duration was 1082.5 days (IQR 588-1916). Within the EO group, 800 (60.8%) had colon cancer and 516 (39.2%) had rectal cancer. Yearly rates of colorectal cancer in both EO and overall cancer groups, as well as the ratio of EO cases, remained stable within the study period. EO colorectal cancer was associated with lower overall mortality rate (37.5% vs 41.6%, p = 0.009), as well as lower histologic grade at diagnosis with fewer poorly differentiated (9.2% vs 11.1%) and undifferentiated tumors (2.1% vs 3.4%) when compared to AO group (p = 0.002). There were no differences in the rate of local (0.3% vs 0.5%), regional (0.5% vs 0.8%) or distant recurrences (5.6% vs 4.9%) in the EO and AO groups (p = 0.56). In the subset analysis between colon and rectal cancers, colon cancer was more common within the AO group as compared to EO group (64.3% vs.60.8%, p = 0.02). While there were no differences seen in overall mortality between the groups for colon cancer, rectal cancer had higher overall mortality in the AO group (39.7% vs 30.6%, p = 0.0002). Conclusions: EO colorectal cancer at or before the age 50 may confer lower mortality rate as well as lower histologic grade when compared to AO colorectal cancer patients. In the AO population as compared to the EO group, colon cancer appears to be more prevalent albeit with higher overall mortality rate for rectal cancers. We did not find any yearly difference in proportion of EO patients. Characteristics and outcomes of early onset versus average onset colorectal cancer. EO CRC (n=1,316) AO CRC (n=4,574) P-value Gender (n, %) 0.37 Male 691 (52.5) 2495 (54.5) Female 625 (47.5) 2079 (45.5) Primary sites (n, %) 0.02 Colon 800 (60.8) 2670 (64.3) Rectum 516 (39.2) 1904 (35.7) Grade (n, %) 0.002 Well differentiated 38 (8.0) 85 (3.8) Moderately differentiated 291 (61.1) 995 (56.7) Poorly differentiated 44 (9.2) 293 (11.6) Undifferentiated 10 (2.1) 65 (3.7) Recurrences (n, %) 0.56 Local 4 (0.3) 23 (0.5) Regional 6 (0.5) 37 (0.8) Distant 73 (5.6) 226 (4.9) Overall mortality (n, %) 494 (37.5) 1904 (41.6) 0.009 EO: early onset, AO: average onset, CRC: colorectal cancer.

Background and Objectives Rectal mucinous adenocarcinoma (MA) has poor response to neoadjuvant chemoradiation (NCR) and higher involved radial surgical margin rates than nonmucinous rectal adenocarcinoma (NMA). Methods The National Cancer Database (2010-2018) was queried for adult patients with clinical stage II and III rectal cancer. Patients with MA and NMA treated with NCR and total mesorectal excision (TME) were identified. We sought to evaluate differences in pathologic downstaging and completeness of resection between MA and NMA rectal adenocarcinoma. Results We identified 13 294 patients, 12 655 (95.2%) NMA and 639 (4.8%) MA. After 3:1 propensity score matching for pathologic outcomes, 1707 NMA and 569 MA patients were included. MA patients had more involved distal (2.1% vs. 1.1%, p = 0.047) and radial (29% vs. 15%, p < 0.001) margins, and less pathologic downstaging (49% vs. 55%, p = 0.015). Among MA patients, minimally invasive resection had higher distal (2.1% vs. 1.4%, p = 0.65) and radial margin involvement (35% vs. 26%, p = 0.09) compared to open resection. Incomplete resection rates were similar between low anterior and abdominoperineal resection. Conclusions TME of locally advanced rectal MA treated with NCR resulted in nearly double the involved radial surgical margins compared to NMA. Operative approach should be carefully considered. Extended or extra-mesorectal resection may reduce the risk of incomplete resection.

Although fungal infections causing intestinal perforation and necrosis are rare, they can be particularly dangerous in immunosuppressed patients, often leading to increased mortality rates and poor prognoses. Candida species are typically surface fungi, but in patients with compromised immune systems, they can invade the small intestine and cause angioinvasive infections. A case study involving a 30-year-old female with acute myeloid leukemia (AML) illustrates this phenomenon. The patient was presented with symptoms of abdominal pain, fever, diarrhea, recurrent episodes of intestinal necrosis, hematomas due to thrombocytopenia, and subsequent postoperative enterocutaneous fistulas. Extensive testing ruled out other possible causes of intestinal necrosis and enteritis, including Crohn’s and CMV diseases. Candida guilliermondi was ultimately identified in blood cultures from the periphery, peritoneal fluid, and intestinal biopsy of respected sections, indicating that it was responsible for intestinal invasion and necrosis. The patient was then treated with amphotericin B, cefepime, and metronidazole. This case highlights the potential severity of fungal infections in immunosuppressed patients, particularly Candida species, and the importance of prompt diagnosis and appropriate treatment.

Purpose/Objective(s) PET/CT is considered standard of care in initial staging for patients with anal squamous cell carcinoma (ASCC) and more frequently MRI has been used for initial disease evaluation and for radiotherapy (RT) treatment planning. The foundation of post-RT assessment is a physical examination with anoscopy; however, MRI is often considered for patients with locally advanced disease. There is limited data regarding the predictive value of routine PET and MRI imaging in the 6-month post-treatment window. We hypothesized that both PET/CT and MRI would improve accuracy of disease assessment in the post-treatment period. Materials/Methods This is an IRB approved, single-institution retrospective study of patients treated with definitive RT for ASCC from 2006 – 2023. If medically eligible, patients were treated per the Nigro protocol. Patients were included in this analysis if they underwent PET/CT with or without pelvic MRI within 6 months of completion of RT. PET standard uptake value max (SUVmax) of the primary site was recorded as a continuous variable. Patients who underwent MRI were codified as no evidence of disease (NED) with tumor regression grade (TRG) 1 or 2 and no measurable disease versus as residual disease (RD) with TRG 3 – 5 or the presence of any measurable viable tumor. Descriptive statistics and Mann-Whitney-U tests were performed in IBM statistical software. Results A total of 200 patients had a post-RT PET and were eligible for analysis. The majority were female (75.5%) with 46% (n = 92) staged as T3/T4 disease and 47% (n = 94) as clinically node positive at diagnosis and treated with a median RT dose to primary disease of 54 Gy. The crude local failure rate was 8.5% (n = 17) occurring at a median of 6.3 months from RT. A cohort of patients (n = 49) had both PET and MRI imaging at a median of 96 (range = 11 – 189) days from RT. The majority of this cohort (n = 31, 63%) were deemed as radiographic NED with the remainder RD. There were 4 local recurrences (8.2%) within this cohort at 3.1, 4.3, 10.8 and 23.4 months from RT. The post-treatment MRI demonstrated 50% sensitivity, 11% positive predictive value, 64% specificity and 94% negative predictive value. There was no significant difference in median post-treatment SUVmax in the total cohort for patients without or with local recurrence at 3.4 and 5.2, respectively (P = 0.061). Conclusion Due to the low prevalence of local failure after RT for ASCC, our results do not support the routine use of post-RT MRI in assessment of residual disease. However, in the setting of an equivocal physical exam there may be value with MRI with diffusion weighted imaging to clinical decision making.

Colorectal cancer, developing from malignant transformation of the distal gut epithelium, is the second leading cause of cancer death in the United States. We present a gentleman in his 60s who was diagnosed with colorectal cancer during a routine screening colonoscopy with no evidence of distant metastasis on subsequent staging with positron emission tomography and computed tomography (PET-CT). The outside rectal MR (magnetic resonance) imaging report localized a mass to the upper rectum. Review of the MRI at an institutional, Multidisciplinary Tumor Board designated the tumor as “rectosigmoid,” straddling the rectosigmoid junction at the level of the “sigmoid take-off” (STO) or alternatively at the level of the last sigmoid artery take-off (SAT) at the origin of the superior rectal artery. The anatomic differentiation between upper rectal and lower sigmoid colon cancers carries clinical importance which is highlighted in this case report and brief literature review. Optimal anatomic localization of colorectal cancers helps direct the clinical team to tailor an individualized patient care plan.

Supplementary Figures S1-S2 and Supplementary Tables S1-S3.

Background Malnutrition is under-recognized in cancer patients and can lead to poor treatment outcomes. We aim to develop an outpatient-focused score based on the Malnutrition Screening Tool (MST) to help identify colorectal cancer (CRC) profiles at high risk for malnutrition. Methods 506 CRC patients during initial outpatient oncology consultation at our tertiary referral outpatient oncology clinic completed the MST. Objective and subjective data were collected through chart review. Data gathered are as follows: demographics, anthropometrics, laboratory values, patient-reported symptoms, MST score, cancer history, performance status, socioeconomic status, and Charlson Comorbidity. Predictors of malnutrition were identified by logistic regression. Receiver operating curve (ROC), area under the curve (AUC), and our model’s predictability were determined. Results Significant predictors of malnutrition are as follows: younger age (20-39 vs >40 years) (P = .007), normal-to-low body mass index at presentation (P = .019), Eastern Cooperative Oncology Group classification 2-3 (P = .012), metastatic disease (P = .046), albumin <3.0 g/dL (P = .033), fatigue (P < .001), and change in stool/bowel habits (P = .002). In our derived malnutrition score, risk of malnutrition increased from 11% for score 0, to 100% for scores 9-10. Receiver operating curve showed AUC .745 (95% CI, .697-.793). Discussion An outpatient clinic-derived malnutrition score obtained from objective and patient-reported variables may facilitate identification of CRC patients at highest risk for malnutrition. Rapid identification and intervention in high-risk patients may improve treatment recovery, therapy tolerance, and quality of life. Our tool requires external validation before application in clinical practice.

AIM:Return to intended oncologic treatment (RIOT) is an important paradigm for surgically resected cancers requiring multimodal treatment. Benefits of minimally invasive colectomy (MIC) may allow earlier initiation of adjuvant chemotherapy (ACT) and have associated survival benefits. We sought to determine if operative approach affects RIOT timing in resected stage III colon cancer. METHODS:NCDB identified pathological stage III colon adenocarcinoma patients who underwent resection and received ACT. Propensity score matching and kernel density estimation compared operative approaches and conversion impact on intervals to RIOT. RESULTS:A total of 15,132 open colectomies (OC) versus 14,107 MIC were included. MIC patients had two-days shorter median length of stay (LOS) (4 vs. 6 days; p < 0.001), one-week shorter median time to RIOT (6 vs. 7 weeks; p = 0.015) comparing 12,867 matched pairs. There was no difference in time interval to RIOT between the LC versus RC, converted MIC vs. OC groups. MIC was a favourable predictor of earlier RIOT (HR 1.14 [1.07-1.22]; p < 0.001). CONCLUSION:MIC in stage III colon cancer is associated with a shorter time to RIOT when compared to OC. Since timely initiation of ACT may influence cancer outcome, MIC may be oncologically preferable. Prospective studies are needed to assess RIOT and survival outcomes in stage III colon cancer.

Local tumor response evaluation following neoadjuvant treatment(s) in rectal adenocarcinoma requires a multi-modality approach including physical and endoscopic evaluations, rectal protocoled MRI, and cross-sectional imaging. Clinical tumor response exists on a spectrum from complete clinical response (cCR), defined as the absence of clinical evidence of residual tumor, to near-complete response (nCR), which assumes a significant reduction in tumor burden but with increased uncertainty of residual microscopic disease, to incomplete clinical response (iCR), which incorporates all responses less than nCR that is not progressive disease. This article aims to review the clinical tools currently routinely available to evaluate treatment response and offers a potential management approach based on the extent of local tumor response.

Background: Tumor response to neoadjuvant therapy is heterogenous and prognostically important for locally advanced rectal adenocarcinoma (LARC) patients. Commonly applied response classification approaches including tumor regression grading (TRG) and TN downstaging can be discordant. The aim of this study is to compare the prognostic value of discordant tumor response measurement categorized according to the AJCC/CAP TRG schema and ypTN stage. Methods: This is a single-center retrospective review of 90 consecutive patients with stage II-III rectal cancer receiving neoadjuvant chemoradiation (nCRT), total mesorectal excision (TME) and adjuvant chemotherapy (ACT) between 2007 and 2018. Two pathologists re-examined each case to assign a consensus AJCC TRG. A Cox proportional hazards ratio model assessed the effect of patient, tumor, and treatment factors on disease-free survival (DFS). Results: Median follow-up after surgery was 46 months (95% CI: 41-50 months). Median age at diagnosis was 55 years (range: 27-80). Most patients were male (58%) and Caucasian (92%) with clinical stage III disease (68%). Seventy-three patients (81%) underwent low anterior resection (LAR), 17 (19%) underwent abdominoperineal resection (APR). The median interval from completion of nCRT to surgery was 62 days (IQR: 56-70 days). The 4-year OS, DFS, and LC was 92.4%, 74.4%, and 90.2%, respectively. In the multivariate analysis, ypTN downstaging was not prognostically significant; however, AJCC TRG score 3 (minimal tumor response to treatment) was strongly predictive for inferior DFS (3-year DFS 79% vs. 25%, P<0.001). Patients with TRG 3 had a significantly higher risk of both local (75% vs. 5%) and distant failure (75% vs. 19%). Conclusions: Minimal tumor response to neoadjuvant therapy, AJCC TRG 3, irrespective of ypTN downstaging, is a pattern of residual disease that is at highest risk for recurrence. Response categorization discrepancies may be partly explained by alternative patterns of residual disease, including tumor fragmentation, and may be best reflected by TRG. The optimal tumor response categorization method requires further study to best stratify patient risk and management.

Abstract Background Neoadjuvant chemoradiation with fluoropyrimidine followed by surgery and adjuvant chemotherapy has been the standard treatment of locally advanced stages II and III rectal cancer for many years. There is a high risk for disease recurrence; therefore, optimizing chemoradiation strategies remains an unmet need. Based on a few studies, there is evidence of the synergistic effect of VEGF/PDGFR blockade with radiation. Methods In this phase I, dose-escalation and dose-expansion study, we studied 3 different dose levels of lenvatinib in combination with capecitabine-based chemoradiation for locally advanced rectal cancer. Results A total of 20 patients were enrolled, and 19 were eligible for assessment of efficacy. The combination was well tolerated, with an MTD of 24 mg lenvatinib. The downstaging rate for the cohort and the pCR was 84.2% and 37.8%, respectively. Blood-based protein biomarkers TSP-2, VEGF-R3, and VEGF correlated with NAR score and were also differentially expressed between response categories. The NAR, or neoadjuvant rectal score, encompasses cT clinical tumor stage, pT pathological tumor stage, and pN pathological nodal stage and provides a continuous variable for evaluating clinical trial outcomes. Conclusion The combination of lenvatinib with capecitabine and radiation in locally advanced rectal cancer was found to be safe and tolerable, and potential blood-based biomarkers were identified. Clinical Trial Registration NCT02935309