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Malignant small bowel obstruction (mSBO) is a common consequence of advanced malignancies. Surgical consultation is common, however data on the outcomes following an operation are lacking. We investigated a specific operative approach-intestinal bypass-to determine the outcomes associated with this intervention.Patients with a preoperative diagnosis of mSBO who underwent intestinal bypass between 2015 and 2021 were included. Isolated colonic obstruction was excluded as was gastric outlet obstruction. Perioperative and postoperative outcomes were measured, including complications, overall survival, return to oral intake, and return to intended oncologic therapy. Patients were additionally grouped as to whether the operation was performed as elective or as inpatient.Overall, 55 patients were identified, with a mean age of 61.2 ± 14 years. The most common primary malignancy was colorectal cancer (65.5%) and 80% of patients had a preoperative diagnosis of metastatic disease. Small bowel to colon was the most common bypass procedure (51%). Severe complications occurred in 25.5% of patients with three in-hospital mortalities (5.5%). Survival rates at 30, 90, and 180 days were 91%, 80%, and 62%, respectively. The majority of patients were discharged to home (85.5%) and were tolerating an oral diet (74.6%). Twenty-seven patients (49.1%) returned to some form of oncologic treatment.Patients with mSBO face a potentially terminal condition. In this study, approximately 75% of patients who underwent intestinal bypass were able to regain the ability to eat, and 49% returned to oncologic therapy. Although retrospective, these data suggest the approach is efficacious for palliation of this difficult sequela of advanced cancer.

Homologous recombination mutations (HRM) have led to increased responses to platinum chemotherapy in pancreatic cancer. However, HRMs' role in nonpancreatic gastrointestinal (GI) cancers remains to be determined. Our objective was to evaluate the prognostic and predictive role of core (BRCA1, BRCA2, PALB2) and noncore HRM in nonpancreatic GI cancers receiving platinum therapy.This study performed at Moffitt Cancer Center included metastatic nonpancreatic GI cancer patients treated with platinum therapy. All patients had either a core or noncore HRM, determined by next generation sequencing. Response rates, median progression-free survival (PFS), and median overall survival (OS) were determined and compared between core versus noncore HRM patients.In the study, 69 patients with one or more HRM were included: 63.8% were male, 87.0% were Caucasian, and 47.9% had colorectal cancer. Twenty-one (30.4%) patients had a core HRM and 48 (69.6%) had a noncore HRM. Among evaluable patients (n=64), there was no significant difference in objective response: 20.0% with core HRM versus 22.7% with noncore HRM responded to platinum therapy (P=0.53). Median PFS was 10.4 months versus 7.1 months for core HRM versus noncore HRM, respectively (P=0.039). Median OS was 68.9 months versus 24.3 months (P=0.026) for core HRM versus noncore HRM, respectively.Our study demonstrated response of core and noncore HRM to platinum therapy in metastatic nonpancreatic GI malignancies, suggesting benefit in both groups. Core HRM patients had significantly increased median OS and median PFS compared with those with noncore HRM, suggesting potential prognostic and predictive significance. Larger prospective studies are needed to confirm our findings.

Background Mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) is a unique disease entity with growing interest given the rise of young-onset CRC. Given its heterogeneous behavior and potential for highly effective treatment outcomes, we sought to identify the clinical and molecular features that offer prognostic value for MMR-D CRC. Materials/Methods This was a retrospective cohort study of patients with metastatic CRC with MMR-D or microsatellite instability in a real-world database. Overall survival (OS) was determined by the date of metastatic disease to date of death with stratification made based on factors including BRAF and RAS mutation status, age, and MMR protein loss type. Results There were 1101 patients in the study. Patients with BRAF mutations had worse OS compared with patients with wild-type BRAF with a median survival of 18.9 months versus 33.2 months (hazard ratio [HR] 1.52, 95% confidence interval [CI]: 1.25-1.86, P < .001). Patients with age >50 were found to have decreased OS versus age ≤50 with a median survival of 21.4 months versus 38.7 months (HR 1.66, 95% CI: 1.33-2.07, P < .001). BRAF mutations and age >50 remained significant predictors of OS in multivariate analysis. Conclusion BRAF mutations and age >50 are associated with worse survival outcomes for patients with MMR-D mCRC. RAS mutations and specific MMR alterations are not associated with survival outcomes.

Differential tumor response to therapy is partially attributed to tumor heterogeneity. Additional efforts are needed to identify tumor heterogeneity parameters in response to therapy that is easily applicable in clinical practice. We aimed to describe tumor response-speed heterogeneity and evaluate its prognostic value in patients with metastatic colorectal cancer.Individual patient data from Amgen (NCT00364013) and Sanofi (NCT00305188; NCT00272051) trials were retrieved from Project Data Sphere. Patients in the Amgen 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) arm were used to establish response-speed heterogeneity. Its prognostic value was subsequently validated in the Sanofi FOLFOX arms and the Amgen panitumumab+FOLFOX arm. Kaplan-Meier method and Cox proportional hazards models were used for survival analyses.Patients with high response-speed heterogeneity in the Amgen FOLFOX cohort had significantly shorter (P0.001) median progression-free survival (PFS) of 7.27 months (95% CI, 6.12-7.96 mo) and overall survival (OS) of 16.0 months (95% CI, 13.8-18.2 mo) than patients with low response-speed heterogeneity with median PFS of 9.41 months (95% CI, 8.75-10.89 mo) and OS of 22.4 months (95% CI, 20.1-26.7 mo), respectively. Tumor response-speed heterogeneity was a poor prognostic factor of shorter PFS (hazard ratio, 4.17; 95% CI, 2.49-6.99; P0.001) and shorter OS (hazard ratio, 2.57; 95% CI, 1.64-4.01; P0.001), after adjustment for other common prognostic factors. Comparable findings were found in the external validation cohorts.Tumor response-speed heterogeneity to first-line chemotherapy was a novel prognostic factor associated with early disease progression and shorter survival in patients with metastatic colorectal cancer.

The benefit of adjuvant chemotherapy (AC) is unclear in stage II (cT3-T4 N0) rectal adenocarcinoma (RAC) after neoadjuvant chemoradiation (NCRT) and total mesorectal excision (TME). We aim to identify pathologic factors that influence overall survival (OS) and stratify patients into risk profiles to assess the AC benefit within each profile.The National Cancer Database for rectal cancer was utilized to identify patients with stage II RAC who completed NCRT and TME. Cox multivariable analysis was used to identify pathologic predictors of 5-year OS, which were then used to construct a nomogram and stratify patients into low-, intermediate-, and high-risk subgroups. Propensity score matching was applied for the receipt of AC within each risk stratum, and Kaplan-Meier analysis was used to measure 5-year OS.We identified 3570 patients who met the inclusion criteria. Inadequate lymphadenectomy (12), poor differentiation, involved distal margin, involved circumferential margin, perineural invasion, and absence of T-downstaging after NCRT were identified as unfavorable predictors of 5-year OS and were used to construct the nomogram. Kaplan-Meier analysis of the matched patients demonstrated the absolute 5-year survival benefits for each risk stratum as follows: 4% for low-risk patients (hazard ratio (HR) = 0.869; [0.651-1.021]; P = .062), 26% for intermediate-risk patients (HR, 0.249; [0.133-0.468]; P.001), and 10% in high-risk patients (HR = 0.633 [0.427-0.940]; P = .024).The survival benefit of AC for clinical stage II RAC following NCRT and TME is most pronounced among intermediate- and high-risk patients as determined by our nomogram. Risk-adaptive AC may be appropriate for selected patients by integrating standard reported pathologic elements into the treatment plan.

BACKGROUND: MMR proficient (pMMR) colorectal cancer (CRC) is usually unresponsive to immunotherapy. Recent data suggest that ibrutinib may enhance the anti-tumour activity of anti-PD-1 immunotherapy. In this study, we evaluated the safety and efficacy of ibrutinib plus pembrolizumab in refractory metastatic CRC. METHODS: This was a phase 1/2 study in patients with refractory metastatic pMMR CRC. The primary endpoints for phases 1 and 2 were maximum tolerated dose (MTD) and disease control rate, respectively. The secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 40 patients were enrolled. No dose-limiting toxicity was observed, and MTD was not identified. The highest tested dose of ibrutinib, 560 mg once daily, was combined with a fixed dose of pembrolizumab 200 mg every 3 weeks for the phase 2 portion. The most common grade 3/4 treatment-related adverse events were anaemia (21%), fatigue (8%) and elevated alkaline phosphatase (8%). Among 31 evaluable patients, 8 (26%) achieved stable disease, and no objective response was observed. The median PFS and OS were 1.4 and 6.6 months, respectively. CONCLUSION: Ibrutinib 560 mg daily plus pembrolizumab 200 mg every 3 weeks appears to be well tolerated with limited anti-cancer activity in metastatic CRC. CLINICALTRIALS.GOV IDENTIFIER: NCT03332498.

PurposeDifferential tumor response to therapy is partially attributed to tumor heterogeneity. Additional efforts are needed to identify tumor heterogeneity parameters in response to therapy that are easily applicable in clinical practice. We aimed to describe tumor response-speed heterogeneity and evaluate its prognostic value in patients with metastatic colorectal cancer (mCRC).Patients and MethodsIndividual patient data from Amgen (NCT00364013) and Sanofi (NCT00305188; NCT00272051) trials were retrieved from Project Data Sphere. Patients in the Amgen 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) arm were used to establish response-speed heterogeneity. Its prognostic value was subsequently validated in the Sanofi FOLFOX arms and the Amgen panitumumab + FOLFOX arm. Kaplan-Meier method and Cox proportional hazards models were used for survival analyses.ResultsPatients with high response-speed heterogeneity in the Amgen FOLFOX cohort had significantly shorter (PPPConclusionTumor response-speed heterogeneity to first-line chemotherapy was a novel prognostic factor associated with early disease progression and shorter survival in patients with mCRC.Implications for PracticeRoutine clinical decision making heavily relies on radiographic assessment of disease response to therapy. For patients with heterogeneous tumors, the degree and kinetics of individual tumor response to the same therapy can sometimes be vastly different. We explored a novel quantitative parameter to describe response-speed heterogeneity by utilizing individual patient data from previous clinical trials. This parameter was an independent prognostic factor associated with early disease progression and shorter survival. Complementary to existing molecular and radiographic tumor heterogeneity parameters, it may help practicing oncologists describe tumor response disparity and serve as a new prognostic factor for patients with mCRC.

Background: The purpose of this study was to characterize pre-treatment non-contrast computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography (PET) based radiomics signatures predictive of pathological response and clinical outcomes in rectal cancer patients treated with neoadjuvant chemoradiotherapy (NACRT). Material and methods: An exploratory analysis was performed using pre-treatment non-contrast CT and PET imaging dataset. The association of tumor regression grade (TRG) and neoadjuvant rectal (NAR) score with pre-treatment CT and PET features was assessed using machine learning algorithms. Three separate predictive models were built for composite features from CT + PET. Results: The patterns of pathological response were TRG 0 (n = 13; 19.7%), 1 (n = 34; 51.5%), 2 (n = 16; 24.2%), and 3 (n = 3; 4.5%). There were 20 (30.3%) patients with low, 22 (33.3%) with intermediate and 24 (36.4%) with high NAR scores. Three separate predictive models were built for composite features from CT + PET and analyzed separately for clinical endpoints. Composite features with α = 0.2 resulted in the best predictive power using logistic regression. For pathological response prediction, the signature resulted in 88.1% accuracy in predicting TRG 0 vs. TRG 1–3; 91% accuracy in predicting TRG 0–1 vs. TRG 2–3. For the surrogate of DFS and OS, it resulted in 67.7% accuracy in predicting low vs. intermediate vs. high NAR scores. Conclusion: The pre-treatment composite radiomics signatures were highly predictive of pathological response in rectal cancer treated with NACRT. A larger cohort is warranted for further validation.

A nonoperative management strategy, or Watch-and-Wait, following neoadjuvant therapies of locally advanced rectal adenocarcinoma is increasingly considered for select patients. Yet, standardized tumor response assessment to best select and surveil suitable patients remains an unmet clinical challenge. Endoscopic and MRI currently provide the most reliable tumor response estimations. However, resources illustrating variable tumor responses to neoadjuvant therapies remain limited. This pictorial review aims to provide detailed and annotated examples of common endoscopic and MRI findings of rectal cancer treatment response, while also emphasizing their respective diagnostic shortcomings and consequently, the necessity for a multidisciplinary approach to optimally manage these patients.

The impact of adjuvant chemotherapy (AT) on resected colon adenocarcinoma based on histologic subtype is poorly defined and extrapolated from patients with advanced disease. We evaluated the receipt and effect of AT on overall survival stratified by histologic subtype—mucinous, non-mucinous, and signet ring adenocarcinomas. A retrospective cohort study from 2004 to 2015 was conducted using the National Cancer Database. Patients with colon adenocarcinoma who underwent curative resection with pathologic stage III were included. Appendiceal and rectal tumors were excluded. The predictor variable was histologic subtype, and outcome variables were overall survival and receipt of AT. Absolute survival was increased for mucinous, non-mucinous, and signet ring tumors with receipt of AT (88.1, 108.9, and 38.1 months, respectively). In multivariable analysis, there was no difference in overall survival for mucinous patients relative to non-mucinous patients. In subgroup analysis, a modest survival advantage for non-mucinous patients relative to the mucinous patients was observed (HR, 0.92; 95% CI, 0.89–0.95). In multivariable modeling, non-mucinous and signet ring adenocarcinoma had decreased odds of receipt of AT relative to mucinous adenocarcinoma patients. Histologic subtype is an important prognostic factor for overall survival for stage III colon adenocarcinoma. Although the magnitude of the benefit of AT may vary in stage III curatively resected patients, it has a substantial survival benefit across all histologic subtypes. Based on these observations, there is no indication that patients with stage III mucinous adenocarcinoma of the colon should not receive AT. All patients with resected stage III colon cancer should be referred for AT regardless of histologic subtype.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is offered to select patients with peritoneal metastases. In instances of recurrence/progression, a repeat CRS/HIPEC may be considered. The perioperative morbidity and the potential oncologic benefits are not well described. We performed a retrospective analysis of a multiinstitutional database to assess the perioperative outcomes following repeat CRS/HIPEC (repeat). Kaplan–Meier and Cox estimates were used to assess survival. In the entire cohort, 2157 patients were analyzed, with 158 (7.3%) in the repeat cohort. The rate of complete cytoreduction was 89.8% versus 83.0% in initial versus repeat groups. The overall incidence of major complications was similar (26.3% vs. 30.7%); however, reoperation was more common in the repeat group. Perioperative outcomes such as length of stay and nonhome discharge were not significantly different. For the entire cohort, 5-year overall survival (OS) was 56.0% in the initial group and 59.5% in the repeat group. In patients with only appendiceal cancer, we observed a 5-year OS of 64.0% in the initial group compared with 67.3% in the repeat cohort. For patients with appendiceal cancer who developed a recurrence/progression, median OS was 36 months in the no repeat operation group compared with 73 months for those that did. Multivariable regression demonstrated that completeness of cytoreduction and tumor grade were associated with OS, but repeat operation was not. Repeat CRS/HIPEC is not associated with prohibitive risk. Survival is possibly improved, and therefore, repeat operation should be considered in selected patients with recurrent or progressive disease.

In contrast to mismatch repair deficient (dMMR) colorectal cancer (CRC), mismatch repair proficient (pMMR) CRC is usually unresponsive to anti-PD-1 immunotherapy. Recent preclinical data suggest that regorafenib may enhance the antitumor activity of anti-PD-1 immunotherapy. However, the safety and efficacy of regorafenib plus nivolumab have not been established in patients with refractory metastatic pMMR CRC. This study aimed to evaluate the safety and efficacy of regorafenib plus nivolumab in metastatic pMMR metastatic CRC.This was a phase I/Ib study with standard 3 + 3 design plus dose expansion of the maximum tolerated dose (MTD) in patients with refractory metastatic pMMR CRC. Patients were treated with regorafenib combined with nivolumab. The primary end-points were dose-limiting toxicity (DLT) and MTD. The secondary end-points were objective response rate, safety and overall survival (OS).A total of 52 patients were enrolled, and 51 patients received at least one dose of treatment. Three patients experienced DLT (all grade 3 rash). MTD was regorafenib 80 mg and nivolumab 240 mg every 2 weeks. Most common grade 3/4 treatment-related adverse events were hypertension (16%), rash (10%) and anaemia (6%). Among 40 evaluable patients, four (10%) achieved partial response, including one unconfirmed response, 21 (53%) achieved stable disease, and disease control rate was 63%. The median progression-free survival and OS were 4.3 and 11.1 months, respectively.Regorafenib plus nivolumab appears to be well tolerated with limited anticancer activity in metastatic pMMR CRC.ClinicalTrials.gov identifier: NCT03712943.

188 Background: Our previous phase I/Ib study revealed modest clinical efficacy of rego/nivo in refractory MSS-CRC, implying benefits in selected populations. This has prompted us to investigate predictive biomarkers. Methods: Pre-treatment tumor samples from the previous phase Ib rego/nivo study were obtained and assessed for mRNA sequencing (RNAseq). Response-associated transcripts were identified using DESeq2 method and annotated using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Results: A total of 19 pretreatment tumor samples were analyzed including 14 patients (pts) with disease control (DC) (2 partial response and 12 stable disease) and 5 pts with progression disease (PD). We observed significant upregulation of 89 genes including SFTPB ( P

228 Background: We previously conducted a phase I/Ib study with regorafenib and nivolumab in patients with refractory metastatic mismatch repair proficient (pMMR) colorectal cancer (CRC). This study aimed to investigate the biomarkers that predict the treatment response. Methods: Out of the 51 patients who received regorafenib and nivolumab, 22 archival pretreatment tumor samples were subjected to the Xerna TME Panel, a machine learning-based RNA-sequencing biomarker assay and were classified into one of four TME biomarker subtypes: Angiogenesis (A), Immune Active (IA), Immune Desert (ID), or Immune Suppressed (IS). Potential predictive biomarkers including the TME subtypes, KRAS (wild type vs mutant), PD-L1 (negative vs. positive, samples with > 1% tumor cells for PD-L1 were considered positive), CD8 expression (low vs. high), and Treg cells (low vs. high) in tumor microenvironment were evaluated for correlation with overall survival (OS), progression free survival (PFS) and disease control rate (DCR, defined as complete response + partial response + stable disease). Results: Among the 22 patients, 16 (72.7%) had liver metastasis and 15 (68.2%) had lung metastasis. KRAS mutation was found in 16 (68.2%) patients. 11/21 (52.4%) were positive for PD-L1. 12 (54.5%) had high CD8 expression, whereas 9/21 (42.9%) had high Treg cells in tumor microenvironment. Ten (45.5%) patients were classified as biomarker-positive (IA + IS subtypes) and 12 (54.5%) were biomarker-negative (A + ID) based on Xerna TME panel. Two (9.1%) patients achieved partial response, 12 (54.5%) had stable disease, and five (22.7%) developed progressive disease. The median PFS was 5.6 months and median OS was 13.1 months. No significant correlation was observed between RAS mutation (p = 0.664, p = 0.609), PD-L1 expression (p = 0.287, p = 0.173), CD8 (p = 0.152, p = 0.456) and PFS or OS. Low Treg was found to be associated with prolonged PFS (median: 9.8 vs. 1.9 months, p = 0.011) but not OS (p = 0.280). Similarly, only low Treg level was related with DCR (83.3% vs. 33.3%, p = 0.032). While not reaching statistical significance, Xerna TME biomarker-positive patients showed trends for higher median PFS (7.9 months vs. 4.1 months, p = 0.254), median OS (15.75 months vs. 11.9 months, p = 0.378), and higher DCR (70% vs. 58%, p = 0.675) compared to biomarker-negative patients. Additionally, the two patients with partial responses were Xerna TME biomarker-positive. Conclusions: Our study demonstrated that low Treg in tumor microenvironment is correlated with better prognosis in patients with refractory metastatic pMMR CRC who were treated with regorafenib plus nivolumab. Xerna TME panel analysis of these patients also showed trends for predictive clinical benefit. Prospective and larger cohort studies are needed to better define predictive biomarkers for this combination in the future.

The standard of care for locally advanced rectal cancer (clinical T3/4N0 or T any N+) has evolved from upfront surgery followed by postoperative adjuvant therapy to a paradigm delivering neoadjuvant chemoradiation (CRT). More recently, the sequence of therapies has been re-examined, delivering all treatment (CRT and chemotherapy) in a total neoadjuvant approach. Subgroups of patients with locally advanced or earlier stage disease may achieve a clinical complete response (cCR), allowing highly selected patients to defer or avoid major pelvic surgery, managed by a rectal-preserving non-operative management (NOM) strategy. In rare instances, early and severe toxicity may occur during CRT which can be associated with genetic alterations that disrupt DNA damage response pathways. In this case report, we highlight the clinical course of a patient with T2N0 rectal cancer who declined APR and subsequently experienced early toxicity during treatment, ultimately discovered to be a carrier for Fanconi anemia after broad panel testing for hereditary cancer. Summary Acute toxicities secondary to pelvic radiotherapy are common, however, most are not treatment-limiting. In rare instances, radiotherapy can induce acute and severe toxicities which may be attributed to genetic alterations. Pathogenic genetic variants in DNA damage response genes can be associated with radiation-induced toxicity. Herein, we describe a patient with rectal cancer receiving pelvic irradiation with significant early toxicity subsequently confirmed to have a heterozygous Fanconi anemia mutation in the FANCD2 gene.

Background The impact of socioeconomic status (SES) has been described for screening and accessing treatment for colon cancer. However, little is known about the “downstream” effect in patients who receive guideline‐concordant treatment. This study assessed the impact of SES on cancer‐specific survival (CSS) and overall survival (OS) for stage III colon cancer patients. Methods The SEER Census Tract‐Level SES Dataset from 2004 to 2015 was used to identify stage III colon adenocarcinoma patients who received curative‐intent surgery and adjuvant chemotherapy. The predictor variable was census tract SES. SES was analyzed as quintiles. The outcome variables were OR and CSS. Statistical analysis included chi square tests for association, Kaplan–Meier, Cox, Fine and Gray regression for survival analysis. Results In total, 27,222 patients met inclusion criteria. Lower SES was associated with younger age, Black or Hispanic race/ethnicity, Medicaid/uninsured, higher T stage, and lower grade tumors. CSS at the 25th percentile was 54 months for the lowest SES quintile and 80 for the highest. Median OS was 113 months for the lowest SES quintile and not reached for highest. The 5‐year CSS rate was 72.4% for the lowest SES quintile compared to 78.9% in the highest (p, This is the first study to evaluate CSS and OS in a national cohort of stage III colon cancer patients using a granular, standardized measure of SES. We showed that despite receipt of guideline‐based treatment, socioeconomic status is associated with disparities in overall and cancer specific survival. These findings suggest opportunities to improve colon cancer outcomes farther down the cancer care continuum.

Simple Summary The use of multi-gene testing platforms to individualize treatment is rapidly expanding into routine oncology practice. UGT1A1, which encodes for the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme, is commonly included on multi-gene molecular testing assays. UGT1A1 polymorphisms may influence drug-induced toxicities of numerous medications used in oncology. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is sparse and can differ depending on the referenced resource. We summarize the literature describing associations between UGT1A1 polymorphisms and toxicity risk with irinotecan, belinostat, pazopanib, and nilotinib. Resources that provide recommendations for UGT1A1-guided drug prescribing are reviewed, and considerations for implementation into patient care are provided. Abstract Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.

The impact of adjuvant chemotherapy (AT) on resected colon adenocarcinoma based on histologic subtype is poorly defined and extrapolated from patients with advanced disease. We evaluated the receipt and effect of AT on overall survival stratified by histologic subtype-mucinous, non-mucinous, and signet ring adenocarcinomas.A retrospective cohort study from 2004 to 2015 was conducted using the National Cancer Database. Patients with colon adenocarcinoma who underwent curative resection with pathologic stage III were included. Appendiceal and rectal tumors were excluded. The predictor variable was histologic subtype, and outcome variables were overall survival and receipt of AT.Absolute survival was increased for mucinous, non-mucinous, and signet ring tumors with receipt of AT (88.1, 108.9, and 38.1 months, respectively). In multivariable analysis, there was no difference in overall survival for mucinous patients relative to non-mucinous patients. In subgroup analysis, a modest survival advantage for non-mucinous patients relative to the mucinous patients was observed (HR, 0.92; 95% CI, 0.89-0.95). In multivariable modeling, non-mucinous and signet ring adenocarcinoma had decreased odds of receipt of AT relative to mucinous adenocarcinoma patients.Histologic subtype is an important prognostic factor for overall survival for stage III colon adenocarcinoma. Although the magnitude of the benefit of AT may vary in stage III curatively resected patients, it has a substantial survival benefit across all histologic subtypes. Based on these observations, there is no indication that patients with stage III mucinous adenocarcinoma of the colon should not receive AT. All patients with resected stage III colon cancer should be referred for AT regardless of histologic subtype.

Aim: Genomic-based risk stratification to personalize radiation dose in rectal cancer. Patients & methods: We modeled genomic-based radiation dose response using the previously validated radiosensitivity index (RSI) and the clinically actionable genomic-adjusted radiation dose. Results: RSI of rectal cancer ranged from 0.19 to 0.81 in a bimodal distribution. A pathologic complete response rate of 21% was achieved in tumors with an RSI

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

This review examines the pathophysiological features of microsatellite instability (MSI) high colorectal cancer and discusses recent clinical studies of immune checkpoint inhibitors for MSI high colorectal cancer. Emerging clinical data demonstrated durable clinical activity and safety of PD-1 blockade agents in diverse cancers, and PD-1 blockade agents have led to a paradigm shift in the cancer therapy. Although initial clinical data showed disappointing result of anti-PD-1 therapy in unselected metastatic colorectal cancer, recent data demonstrated promising results with significant anticancer activity of PD-1 blockade in colorectal cancers with microsatellite instability which have highly immunogenic tumor microenvironment. Anti-PD-1 therapy demonstrated durable clinical activity and safety, and it has changed the landscape of cancer therapy in MSI high colorectal cancer. Further studies with better understanding of tumor microenvironment will improve clinical outcomes of colorectal cancer.

663 Background: GI malignancies continue to be a major cause of cancer related deaths, despite advances in therapy options. In pancreatic cancer, the presence of homologous recombination mutations (HRM) has been shown to confer increased sensitivity to platinum chemotherapy. However, the role of HRM mutations in other GI cancers remains to be determined. The focus of this study is to evaluate the prognostic nature of core and noncore HRM in nonpancreatic GI cancers. Additionally, we aim to understand the predictive nature of these mutations related to platinum exposure. Methods: This was a retrospective review of patients at Moffitt Cancer Center with a primary stage IV nonpancreatic GI cancer treated with platinum therapy. All patients had next generation sequencing and were in the Clinical Genomics Action Committee database between 1/1/2013 and 11/1/2020. All patients had either a core HRM (BRCA1, BRCA2, PALB2) or noncore HRM (such as ATM, ATR, BARD1, BRIP1, FANCA, NBN, and RAD51). Patients were grouped into core HRM vs. noncore HRM. Response was stratified between responders (complete response and partial response) vs. non responders (stable disease and progressive disease), based on RECIST criteria. Progression free survival and overall survival were estimated using Kaplan-Meier method, and the log-rank test was used to assess the difference in progression free survival (PFS) and overall survival (OS) by HRM status and type of platinum therapy used. Results: There were 72 patients included in the study: the majority of patients were male (65.3%) and Caucasian (87.5%). Twenty-one (29.2%) patients had a core HRM and 51 (70.8%) had a noncore HRM. There was no significant difference in response rate between patients with core HRM and patients with noncore HRM for evaluable patients (n = 66): 20.0% of patients with core HRM vs. 21.7% of patients with noncore HRM demonstrated a response to platinum therapy (p = 0.41). An improved OS was noted for patients with core HRM vs. those with noncore HRM at 68.9 vs. 24.3 months (p = 0.019). An improved PFS was also seen in patients with core HRM at 10.4 months vs. 6.3 months with noncore HRM (p = 0.027). There was no difference in PFS based on type of platinum therapy used (oxaliplatin vs. carboplatin vs. cisplatin), while an improved OS was noted for patients treated with oxaliplatin vs. carboplatin vs. cisplatin at 43.1 vs. 28.2 vs. 16.0 months (p = 0.011). Conclusions: Our study demonstrated that in stage IV nonpancreatic GI malignancies treated with platinum therapy, patients with core HRM had a greater OS and PFS compared to those with noncore HRM, suggesting a potential prognostic and predictive role of these mutations. Further studies are needed to confirm our findings.

174 Background: Colorectal cancer (CRC), while one of the most common cancer diagnoses, can behave heterogeneously based on molecular characteristics. A subset of patients (pts) with CRC are characterized with mismatch repair deficiency (MMR-d), these pts exhibit encouraging responses to immunotherapy. The predictive nature of various factors, such as BRAF status, age, and MMR-D protein loss type, have been investigated in pts with MMR-d CRC. However, the prognostic role of these factors has not been well established. The purpose of this study was to identify characteristics that influence survival in MMR-d mCRC. Methods: This study evaluated pts with MMR-d mCRC in the Flatiron database. Overall survival (OS) was determined from date of diagnosis of stage IV disease to date of death and stratified based on age greater than or less than 50 years, BRAF mutation status, RAS mutation status, and type of MMR gene loss. For statistical analysis, the Chi-Square test was implemented to determine the prognostic significance of clinical and molecular features. Univariate and multivariate analyses were determined through the Cox regression model. Results: There were 1,101 pts in the study. The majority of pts were older than 50 (79.7%), Caucasian (75%), and had ECOG 0-1 (83.4%). Among the 803 pts with known BRAF status, 44.3% (n=356) had BRAF V600E mutation and 55.7% (n=447) were BRAF wildtype. Pts with BRAF V600E mutation had OS of 18.9 months vs. 33.2 months for pts with wild type BRAF (HR 1.52, 95% CI: 1.25-1.86, p

Background US health care is increasingly defined by over expenditure and inefficiency. Optimizing patient follow-up is critical, especially in cancers treated with high control rates. To optimize patient care, this study assessed time to disease recurrence or toxicity in patients with anal carcinoma. Materials and methods In total, 140 patients with biopsy-proven, nonmetastatic anal carcinoma, treated with chemoradiation utilizing intensity-modulated radiation therapy, were identified from our institutional database. This retrospective study evaluated local recurrence (LR), distant metastasis (DM), overall survival (OS), and late ≥grade 3 toxicity (LG3T). Patients were followed posttreatment every 3 months for 2 years, every 6 months in years 3 to 5, then yearly thereafter per NCCN recommendations. Results The median age and follow-up was 58 years and 27 months, respectively. Patients were categorized into high (n=61; 44%) and low (n=77; 55%) risk groups based on stage. The 2-year LC, DMFS, and OS were 93%, 94%, and 89% and 5-year LC, DMFS, OS were 92%, 87%, and 85%, respectively. Overall, there were 29 events (9 LR, 11 DM, and 9 LG3T), with 62% of events occurring within year 1 and 79% within 2 years. Stratified by event type, at 2 years 89% of LR, 64% of DM, and 89% LG3T were identified. At the remaining follow-up points, the event incidence rate was 1.3%. Conclusion With the majority of recurrences/toxicities occurring within the first 2 years, a reduction in follow-up during years 3 to 5 may provide adequate surveillance. Revisions of the current recommendations could maximize resources while improving patient quality of life.

Introduction Innovative biomarkers to predict treatment response in rectal cancer would be helpful in optimizing personalized treatment approaches. In this study, we aimed to develop and validate a CT-based radiomic imaging biomarker to predict pathological response. Methods We used two independent cohorts of rectal cancer patients to develop and validate a CT-based radiomic imaging biomarker predictive of treatment response. A total of 91 rectal cancer cases treated from 2009 to 2018 were assessed for the tumour regression grade (TRG) (0 = pathological complete response, pCR; 1 = moderate response; 2 = partial response; 3 = poor response). Exploratory analysis was performed by combining pre-treatment non-contrast CT images and patterns of TRG. The models built from the training cohort were further assessed using the independent validation cohort. Results The patterns of pathological response in training and validation groups were TRG 0 (n = 14, 23.3%; n = 6, 19.4%), 1 (n = 31, 51.7%; n = 15, 48.4%), 2 (n = 12, 20.0%; n = 7, 22.6%) and 3 (n = 3, 5.0%; n = 3, 9.7%), respectively. Separate predictive models were built and analysed from CT features for pathological response. For pathological response prediction, the model including 8 radiomic features by random forest method resulted in 83.9% accuracy in predicting TRG 0 vs TRG 1-3 in validation. Conclusion The pre-treatment CT-based radiomic signatures were developed and validated in two independent cohorts. This imaging biomarker provided a promising way to predict pCR and select patients for non-operative management.

7 Background: Panitumumab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) and is a standard therapy in KRAS/NRAS/BRAF WT mCRC. Preclinical data shows that anti-EGFR therapy causes a tumor-specific adaptive immune response and immunogenic apoptosis, with functional adaptive immunity required to mediate efficacy. However, resistance to anti-EGFR antibody therapy inevitably develops and is associated with increased expression of CTLA-4 and PD-L1. We hypothesized that addition of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) to panitumumab will increase response rate in patients with KRAS/NRAS/BRAF WT MSS mCRC. Methods: LCCC1632 was a multicenter, single-arm, Simon’s two stage phase II clinical trial with a pre-specified safety run-in of panitumumab, ipilimumab, and nivolumab in KRAS/NRAS/BRAF WT, MSS mCRC (NCT03442569). Eligible patients must have received 1-2 prior lines of therapy and no prior anti-EGFR or immune checkpoint inhibitor therapy. Subjects received ipilimumab 1 mg/kg IV q6wk, nivolumab 240 mg IV q2wk, and panitumumab 6 mg/kg IV q2wk until progression, toxicity, or patient withdrawal. The primary endpoint was response rate at 12 weeks per RECIST 1.1, and key secondary endpoints included progression-free survival and duration of response. Results: A total of 56 subjects were enrolled 3/2018-6/2020. This included the 6-subject safety run-in, with 0/6 dose-limiting toxicities in first 12 weeks. The first stage of the Simon’s two-stage clinical trial (n=32) had sufficient response rate to merit full enrollment. There were 7 unevaluable subjects for the primary endpoint of 12-week response rate. Among 49 evaluable subjects, 12-week response rate was 35% (95% CI 21-48; n=17 responses). Twenty subjects had at least an unconfirmed response at any time. Median PFS was 5.7 months (95% CI 5.5-7.9). There was one treatment-related grade 5 adverse event of myocarditis. The most common treatment-related grade 3-4 AEs included lipase increased (9%), amylase increased (7%), ALT increased (5%), AST increased (5%), diarrhea (5%), hypophosphatemia (5%), and maculopapular rash (5%). Conclusions: The combination of panitumumab, ipilimumab, and nivolumab demonstrated evidence of activity and met its prespecified primary endpoint of 12-wk response rate criteria to merit further study. The PFS in this single-arm study compares favorably to expected PFS for anti-EGFR monotherapy in RAS wild-type patients, and results suggest activity of immune checkpoint inhibitors combined with anti-EGFR therapy in MSS mCRC. Clinical trial information: NCT03442569.

Purpose: Targeting dual/multiple angiogenesis receptor has been shown to augment tumor response. Lenvatinib, a multikinase inhibitor aimed towards FGFR/ PDGFR/ KIT/RET has shown potent antitumor activity in preclinical models. This study aims to understand the effectiveness and safety of lenvatinib and capecitabine combined with radiation in patients with locally advanced rectal cancer (LARC). Methods: Patients with MRI or endoscopic ultrasound confirmed stage II or stage III rectal cancer were enrolled in 3 cohorts. All cohorts received standard dose 850 mg/m2 PO BID of capecitabine and external beam radiation (180 cGY) on day 1-5 weekly for 5 ½ to 6 weeks. Oral lenvatinib was administered in dose escalation manner in 3 cohorts of 3 patients per dose level (DL), with an expansion cohort at the MTD [cohort 1:14 mg daily; cohort 2: 20 mg daily; cohort 3:24 mg daily]. At the MTD dose, 10 additional patients were added to further evaluate safety and efficacy. Results: Twenty patients were enrolled and received at least 1 dose of study drug. One patient was deemed not eligible due to having stage IV disease at the time of diagnosis and is only reviewed for toxicity. 3/19 patients had stage II and 16/19 had stage III cancer at time of enrollment. 73.6% (14/19) patients enrolled were male and 26.4% (5/19) were female. The median age was 55 years (42,73). There was no noted dose limited toxicity at maximum tolerated dose (24 mg) of lenvatinib. There were no grade 4 adverse events. The most common grade 3 toxicities were hypertension observed in 15% (3/20) and lymphopenia in 15% (3/20) patients. Other grade 3 toxicities included rectal pain, hyponatremia, lymphopenia, leukocytosis and transaminitis, each noted in 5% (1/20) patients respectively. 19 patients underwent surgery in 6-10 weeks following completion of dual-targeted therapy and radiation. Median time to surgery was 62 days. There were no peri-operative adverse events. 14/19 patients underwent low anterior resection and 5 have had abdominoperineal resection. 7/19 (36.8%) showed complete pathological response (cPR), and downstaging were seen in 73.7% of the patients (14/19). The mean neoadjuvant rectal cancer score (NAR) was 10.4 and median NAR was 8.43. Conclusion: The combination of lenvatinib and capecitabine plus radiation shows encouraging safety and efficacy results. Larger randomized study is warranted to verify our findings. Citation Format: Ankita Tandon, Jessica M. Frakes, Rutika Mehta, Sarah Hoffe, Iman Imanirad, Maria E. Martinez Jimenez, Julian Sanchez, Mokenge Malafa, Seth Felder, Sophie Dessureault, Richard D. Kim. Final result of lenvatinib and capecitabine in combination with external beam radiation in treatment of locally advanced rectal cancer: Phase I clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4293.

7032 Background: Socioeconomic status (SES) has been associated with worse outcomes in stage III colon cancer. However, these studies have used large geographic areas (zip codes or counties) as a proxy for SES which may bias results. To overcome this challenge, we used a national database with census-tract level SES to assess the impact on cancer-specific (CSS) and overall survival (OS). Methods: Using the SEER Census-Tract Dataset from 2004-2015, we identified 8th edition AJCC stage III colon adenocarcinoma patients who underwent curative-intent surgery and initiated adjuvant chemotherapy. The predictor variable was census-tract level SES, consisting of 7 variables such as income, housing, and education. SES was analyzed as quartiles. Statistical analysis included chi square tests for association and Kaplan-Meier and Cox regression for survival analysis. Results: We identified 27,222 patients who met inclusion criteria. Lower SES was associated with younger age, Black or Hispanic race/ethnicity, Medicaid or uninsured status, higher T stage, th percentile CSS time was 54 months for the lowest SES (LSES) quartile and 80 months for the highest (HSES). Median OS was 113 months for LSES and not reached for HSES. The 5-year CSS rate was 72.4% for the LSES quartile compared to 78.9% in the HSES (p

125 Background: Neoadjuvant chemo-radiation is a standard of care for locally advanced rectal cancer. Patients with pathologic complete response (pCR) have improved outcomes with less local and systemic failure. Dual targeting with platelet derived growth factor (PDGF) and vascular endothelial growth factor receptor (VEGFR) in combination with radiation can escalate tumor response with radiation. Lenvatinib is an oral multi-kinase inhibitor and had shown potent anti-tumor activity in xenograft models cultured with human colorectal cancer (CRC) lines. Methods: Patients with stage II or III rectal cancer, confirmed by endoscopic ultrasound or MRI, were recruited in 3 cohorts of 3 patients per dose level, with an expansion cohort at the MTD. Lenvatinib oral daily dose started at 14 mg (cohort 1) and was escalated to 20 mg (cohort 2) followed by 24 mg (cohort 3). In this 3+3 design, patients received dose escalation of lenvatinib with standard doses of capecitabine (850 mg/m2 PO BID) concurrent with external beam radiation on days 1-5 weekly for 28 treatments. Following completion patients underwent surgery in 6-10 weeks. Results: Twenty patients with median age of 55 were enrolled in 3 cohorts (1 patient was ineligible). There were no dose limiting toxicity at the maximum tested dose of lenvatinib (24 mg). Two patients are still awaiting surgery. 12 patients have undergone low anterior resection and 5 patients have had abdominoperineal resection. Therefore, out of 17 patients, 29.4% (5/17) showed pCR, and downstaging was observed in 71% of the patients (12/17). The mean neoadjuvant rectal cancer score (NAR) was 11.4 and median NAR was 8.43. Six patients had grade 3 adverse events (AEs) (1 rectal pain,1 transaminitis, 2 lymphopenia, 1 HTN, 1 with both leukocytosis and hyponatremia). No grade 4 AEs were noted. Most common AEs were hypertension, rectal pain, nausea, diarrhea, fatigue and dermatitis. No peri operative complications were observed. Conclusions: The study shows that the combination of lenvatinib and capecitabine with radiation is well tolerated in locally advanced rectal cancer with promising mean NAR score. The encouraging results will need to be validated in a randomized study. Clinical trial information: NCT02935309.

TPS4149 Background: Patients with advanced gastric cancer experience a 5 year survival rate 2 twice daily. Each cycle length will be 28 days. The primary endpoint is 6 month OS and secondary endpoints are safety, objective response rate and PFS. Fifteen patients will be enrolled in the first stage. If ≥ 7 of the 15 are alive at 6 months, an additional 10 patients will be enrolled in the second phase. Enrollment is currently ongoing. Clinical trial information: NCT03686488.

The myelodysplastic syndromes (MDS) are often diagnosed in outpatient clinics and may be under-reported to state cancer registries, which predominantly rely on hospital records and laboratory reports. We used a new method of cancer case capture to determine the rate of missed cases and estimate a more accurate incidence of MDS. Using a unique keyword algorithm, we queried all electronic pathology (E-path) reports sent to the state of Florida cancer registry in 2006 to identify potential MDS cases. A stratified, random sample of E-path reports was then reviewed to confirm diagnosis and assign MDS subtype. Characteristics were compared between captured and uncaptured MDS cases. 7111 E-path reports with MDS keyword hits were identified, of which only 18% linked to a registered MDS case, 47% linked to a different cancer, and 34% did not link with any record. Case review of a stratified, random sampling of 285 individuals led to the discovery that uncaptured cases made up 37.7% of the total true MDS cases in 2006. It is estimated that the true incidence of MDS is 5.3 individuals out of 100,000, compared to previous reports of 3.3 out of 100,000. Uncaptured MDS cases were younger and more likely to have information in the pathology report facilitating MDS subtype assignment. Only two-thirds of true MDS cases are captured in Florida using current case-finding mechanisms. Application of a keyword search strategy to identify cases among E-path reports is a feasible technique to improve MDS case ascertainment.

Thrombotic thrombocytopenic purpura (TTP) is a heterogeneous disease primarily characterized by thrombocytopenia and microangiopathic hemolytic anemia. Therapeutic plasma exchange has dramatically improved mortality, allowing for emergence of refractory, relapsing, and atypical presentations. In this article, we describe four cases of TTP presenting with minimal schistocytes, mild elevation of lactate dehydrogenase, and symptoms suggestive of macrovascular arterial involvement. With increasing reports of less common presentations of TTP, clinicians should consider this diagnosis in cases of unexplained arterial thrombosis, thrombocytopenia, or hemolytic anemia. Testing for a disintegrin and metalloprotease with thrombospondin Type 1 motif, Member 13 ADAMTS13 activity was extremely useful to help confirm the diagnosis in our series of patients. J. Clin. Apheresis, 2012. © 2012 Wiley Periodicals, Inc.

689 Background: U.S. health care is increasingly defined by over expenditure and inefficiency. Optimizing patient follow-up is critical especially in cancers treated with high control rates. The objective of this study was to assess time to disease recurrence or toxicity in a cohort of patients with anal carcinoma in order to optimize patient care. Methods: 140 patients diagnosed with biopsy-proven, non-metastatic anal carcinoma, treated with chemoradiation utilizing IMRT, were identified from an institutional database at our high volume center. After IRB approval, a retrospective study was conducted that evaluated local recurrence (LR), distant metastasis (DM), overall survival (OS), and late ≥ grade three toxicity (LG3T) based on National Cancer Institute Common Terminology for Adverse Events version 4. Patients were followed post-treatment every three months for two years, every six months in years 3-5 then yearly thereafter with imaging per National Comprehensive Cancer Network recommendations. Results: Median age and follow up is 58 years and 27 months, respectively. Patients were staged based on AJCC 8th edition and 24 patients were stage I (17%), 55 stage II (39%) and 61 stage III (44%). The median radiation dose was 54 Gy (range: 40-62.5), and 11% of patients required a radiation break. The two year LC, DMFS, and OS were 93%, 94% and 89% and 5-year LC, DMFS, OS were 92%, 87% and 85% respectively. In total, there were 29 disease or treatment related events: LR occurred in nine patients, DM in 11 patients, and LG3T in nine patients. Overall, 62% of events occurred within year one and 77 % within two years. Stratified by event type, at two years 79% of LR, 64% of DM and 89% LG3T were identified. At the remaining follow-up points after 2 years there was an event incidence rate of 1.4%. Conclusions: The majority of recurrences/toxicities in patients diagnosed with non-metastatic anal carcinoma after chemoradiation occur within the first year, with 77% of any event occurring before year two. The data from individual time points suggest a reduction in follow-up during years 3-5 may provide adequate surveillance. Considering revisions of the current follow-up recommendations could maximize health care resources while also improving patient quality of life.

694 Background: Despite routine use of neoadjuvant chemoradiation, patients with advanced rectal tumors experience significant rates of treatment failure and recurrence. Radiation resistance is a particular problem. Dual targeting of PDGF and VEGFR (Vascular endothelial cell growth factor receptor) in combination with radiation can enhance tumor response. Lenvatinib inhibits the kinase activities of VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET and in vivo results show that it effectively delays the growth of human colorectal xenografts. Methods: This is a phase I clinical trial of lenvatinib in combination with capecitabine administered with radiation. Patients with stage II or III rectal cancer confirmed by endoscopic ultrasound or MRI were eligible for the study. In this 3+3 phase I study with 3 cohorts, patients were treated with escalating doses of lenvatinib administered in combination with standard doses of capecitabine (850 mg/m2 PO BID D1-5 weekly for 5 ½ to 6 weeks) and external beam radiation therapy (180 cGY on D1-5 weekly for 5 ½ to 6 weeks). Patients underwent surgery 6-10 weeks after neoadjuvant therapy. Results: Nine patients have been enrolled in the 3 cohorts with the median age of 51 years. Lenvatinib dosing started at 14 mg PO daily (cohort 1) and was safely escalated to 20 mg PO daily (cohort 2) followed by 24 mg PO daily (cohort 3). There were no DLTs at the maximum tested dose of lenvantinib (24 mg). 5 patients have undergone low anterior resection and 4 have had abdominoperineal resection. The pathological complete response (pCR) rate was 33.33%, and downstaging was observed in 100% of patients. Median neoadjuvant rectal cancer score (NAR) was 8.7. Three pts had grade 3 events (2 hypertension (HTN), 1 lymphopenia) without any grade 4 events. Most common AEs were HTN and fatigue. No perioperative complications were observed. Tissues for all pts have been collected for planned correlative studies. Conclusions: This study shows that the combination of lenvatinib with capecitabine, and EBRT is well tolerated. NAR score and downstaging rates are encouraging. Currently we are enrolling 10 additional pts at the maximum tested dose of lenvatinib to further evaluate efficacy and safety. Clinical trial information: NCT02935309.

687 Background: Sarcopenia has been identified as a negative prognostic factor in several gastrointestinal malignancies. We sought to evaluate whether total psoas area (TPA) was predictive of grade ≥ 3 toxicity, recurrence and overall survival in patients with rectal carcinoma who received tri-modality therapy. Methods: After IRB approval, a retrospective analysis of 112 patients with biopsy-proven rectal cancer treated with neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy was performed. The L4 vertebra was identified on pre-treatment axial CT and the bilateral psoas muscles were manually contoured to determine the skeletal muscle index, which was normalized by height. Sarcopenia was defined as TPA less than the median of the cohort. (< 1463 mm3/m). Acute toxicity was defined as within 3 months of radiation based on Common Terminology Criteria for Adverse Events version 4. Chi-square was used to assess differences between groups. Time to event analysis was estimated by Kaplan-Meier methods followed by log rank comparison. Predictor variables for outcomes were assessed with Cox regression. Results: Median follow-up was 31 months. Female gender was strongly associated with being sarcopenic (P < 0.001) otherwise no other differences in clinical or treatment characteristics were found. 20 patients (17.8%) developed recurrence (95% distant). Patients with sarcopenia had a decreased risk of recurrence (P = 0.048) as well as a longer time to recurrence from radiation (50 vs. 21.4 months, P = 0.006) and surgery (47.2 vs. 17.9 months, P = 0.006). Gender was not associated with risk of recurrence (p = 0.131). On multivariable analysis, absence of sarcopenia was predictive of time to recurrence following radiation (HR 4.7, 95% CI: 1.2-18.8; P = 0.03). The presence of sarcopenia was not associated with overall survival (P = 0.12) or grade ≥ 3 acute toxicity (P = 0.242). Conclusions: In our cohort, patients with sarcopenia appear to have better tumor control when compared to patients without sarcopenia independent of gender, suggesting this may be a predictor of treatment response. However, sarcopenia was not associated with overall survival or probability of having grade ≥ 3 acute toxicity.

573 Background: Given the lack of biomarkers to predict a pathologic complete response (pCR) after neoadjuvant chemoradiation (NACRT) for rectal cancer, selection for non-operative management (NOM) mandates complete clinical response. We have previously developed/validated a model to assess genomic-based tumor radiosensitivity: the radiosensitivity index (RSI), which formulates a clinically actionable model to calculate genomic-adjusted radiation dose (GARD). We determined the profiles of RSI and GARD for rectal cancer and correlated these findings with the pathologic response patterns. Methods: One hundred seventeen rectal cancer patients treated from 2009 to 2018 with NACRT were assessed for the tumor regression grade (TRG) (0 = pCR; 1 = moderate response; 2 = partial response; 3 = poor response). RSI was analyzed in an independent tissue cohort of 113 resected rectal cancer samples. GARD was derived as described before, which shows a high GARD value indicated a superior therapeutic effect of radiation. Results: Median follow-up from completion of NACRT was 26 months. The primary tumor stages were 7% T2, 84% T3, and 9% T4. The majority of patients (82%) received concurrent 5-FU or Capecitabine and (83%) received RT dose of 50.4 Gy (range 45-56 Gy). Median time from end of NACRT to surgery was 61 days (range 36-105 days). The patterns of pathological response were TRG 0 (n = 24; 21%), 1 (n = 62; 53%), 2 (n = 25; 21%), and 3 (n = 6; 5%), suggesting heterogeneous sensitivity to treatment with similar tumor stage and treatment regimens. The median RSI for the tissue cohort was 0.46 (range 0.19-0.81) with 37% of the samples considered radiosensitive based on prior data. GARD values ranged from 5.17 to 41.79 (median 19.24), suggesting heterogeneous RT therapeutic effects. Conclusions: The findings from the clinical cohort were consistent with the tissue cohort showing significant heterogeneity in the individual tumor radiosensitivity and GARD-based RT therapeutic effects. With the development of GARD-based prospective trials, we anticipate more biology-based customized RT dosing which could optimize patient selection for NOM and individualize the most appropriate dose for each patient.

Antiangiogenic therapy has shown promise in the treatment of patients with renal cell carcinoma (RCC). Two classes of antiangiogenic drugs, the anti-vascular endothelial growth factor antibody bevacizumab and the tyrosine kinase inhibitors sorafenib, sunitinib and pazopanib, have shown efficacy in patients with RCC and are approved by the US Food and Drug Administration for treatment of this cancer. In practice, the clinical benefit of antiangiogenic drugs in RCC has been heterogeneous, and in patients who do respond, benefits are modest and/or short-lived. To improve efficacy, combination targeted therapy has been attempted, but with either very limited additional efficacy or nontolerable toxicities. Recent advances in the molecular understanding of tumor angiogenesis and mechanism of resistance, along with the rapid development of targeted drug discovery, have made it possible to further explore novel combination therapy for RCC.

Disease remission in patients with myelodysplastic syndromes can be achieved with azanucleosides, which act as pyrimidine analogs and hypomethylating agents. However, despite treatment with azanucleoside induction, patients with myelodysplastic syndromes nearly always relapse. Allogeneic hematopoietic cell transplantation (HCT) can be curative, but it is risky. Given that azanucleosides affect human leukocyte antigen expression and lymphocyte reactivity, we conducted a retrospective study to define the impact of pre-HCT azanucleoside therapy on post-HCT donor chimerism. Patients receiving azanucleoside induction therapy achieved rapid and high levels of donor chimerism post-transplant. Lineage analysis also found rapid donor chimerism of lymphocyte and granulocyte subsets. These data indicate the feasibility of pretransplant azanucleoside therapy in patients who subsequently receive an HCT.