Neoadjuvant Rectal Score Research Articles

Total Neoadjuvant Therapy Versus Standard Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer: A Comparison of Short- and Long-term Oncologic Outcomes.

To evaluate the impact of neoadjuvant multi-agent systemic chemotherapy and radiation (TNT) vs neoadjuvant single-agent chemoradiation (nCRT) and multi-agent adjuvant chemotherapy on overall survival (OS), tumor downstaging, and circumferential resection margin (CRM) status in patients with locally advanced rectal cancer. Outside of clinical trials and small institutional reports, there is a paucity of data regarding the short and long-term oncologic impact of TNT as compared to nCRT. Adult patients with stage II-III rectal adenocarcinoma were identified in the National Cancer Database [2006-2015]. Out of 8,548 patients, 36% received TNT and 64% nCRT. In the cohort, 13% had a pCR and 20% a neoadjuvant rectal (NAR) score <8. In multivariable analysis, as compared to nCRT, TNT demonstrated numerically higher pCR rates ( P = 0.05) but had similar incidence of positive CRM ( P = 0.11). Similar results were observed with NAR scores <8 as the primary endpoint. After adjusting for confounders, OS was comparable between the 2 groups. Additional factors independently associated with lower OS included male gender, uninsured status, low income status, high comorbidity score, poorly differentiated tumors, abdominoperineal resection, and positive surgical margins (all P <0.01). In separate models, both pCR and a NAR score <8 were associated with improved OS. In this national cohort, TNT was not associated with better survival and/or CRM negative status in comparison with nCRT, despite numerically higher downstaging rates. Further refinement of patient selection and treatment regimens are needed to establish effective neoadjuvant platforms to improve outcomes of patients with rectal cancer.

PO-1265 Neoadjuvant rectal and Clavien-Dindo scores in Locally Advanced Rectal Cancer

PO-1265 Neoadjuvant rectal and Clavien-Dindo scores in Locally Advanced Rectal Cancer

The impact of neoadjuvant concurrent chemoradiation on exosomal markers (CD63 and CD9) expression and their prognostic significance in patients with rectal adenocarcinoma.

Introduction: Exosomes have pivotal roles in cancer development. The impact of neoadjuvant concurrent chemoradiation (NCCR) on exosomal markers (CD63 and CD9) expression and their prognostic significance in patients with rectal adenocarcinoma are yet to be explored.Materials and Methods: Between 2015 and 2018, 33 patients had rectal adenocarcinoma treated with NCCR and had pre-NCCR biopsy and post-NCCR resected rectum. CD63 and CD9 expression was assessed by immunohistochemistry (IHC). The short-term surrogate endpoint neoadjuvant rectal (NAR) score was used for assessment of prognostic significance. Un-Paired t-test was used for statistical analysis.Results: The mean tumor CD63 and CD9 scores in pre-NCCR biopsy vs. post-NCCR resected rectum were 106 vs. 165 (P = 0.0022) and 136 vs. 215 (P < 0.0001) respectively. The mean tumor CD63 and CD9 scores respectively in pre-NCCR biopsy was 99 and 130 in patients with low-intermediate NAR score compared to 117 and 144 in patients with high NAR score (P = 0.4934) (P = 0.5519). The mean tumor CD63 and CD9 scores respectively in post-NCCR resected rectum was 155 and 205 in patients with low-intermediate NAR score compared to 180 and 230 in patients with high NAR score (P = 0.3793) (P = 0.2837).Conclusions: The expression of the exosomal markers (CD63 and CD9) increased in patients with rectal adenocarcinoma after treatment with NCCR. The exosomal markers (CD63 and CD9) may have a prognostic significance. There was a trend for higher CD63 and CD9 expression in patients with high NAR score compared with low-intermediate NAR scores. The lack of statistical significance is likely due to the small sample size.

P-265 Neoadjuvant radiotherapy for locally advanced rectal cancer during the first wave of COVID19 pandemic: Guy’s cancer cohort experience

The Covid-19 pandemic is a healthcare emergency with a significant impact on cancer services provision. In March 2020, our institution adopted the ESMO expert consensus guidelines for radiotherapy management of rectal cancer during the pandemic. Here we present short-term oncological outcomes of this approach compared to the same period in 2018. Patients who underwent neoadjuvant (chemo) radiotherapy for rectal cancer between 1st March 2020 and 31 May 2020 were identified from a research ethics committee (REC)-approved research database for cancer patients (Guy’s Cancer Cohort). Patient demographics and treatment characteristics were extracted and compared with a control cohort treated in the same period in 2018. The definition of local response was based on identification of downstaging on re-staging Magnetic Resonance Imaging (MRI) post neoadjuvant treatment (mrT3c/d-4 to mrT0-2 and mrT2 to mrT0-1) and classified in a binary format (response vs no response). In addition, in patients who underwent total mesorectal excision (TME), neoadjuvant rectal (NAR) score was calculated, as described previously, and classified into low (<8), intermediate (>=8<=16) and high (>16). The frequency of MRI and pathological response was compared using non-parametric Fisher exact test. Thirty patients were treated in the three-month period in 2020 as compared with 21 in 2018 (43% increase). No statistically significant differences were observed in baseline tumour characteristics. The use of neoadjuvant short-course radiotherapy (SCRT) treatment increased significantly from 19% of cases in 2018 to 50% during the pandemic, which was reflected in reduced radiotherapy-related hospital footfall (median 15 appointments in 2020 vs 25 appointments in 2018). While the use of concomitant fluoropyrimidines was lower (47 vs 71%), the use of induction chemotherapy was higher (30 vs 19%) in 2020 compared to 2018, which may reflect more prevalent use of total neoadjuvant treatment. There was no difference in the proportion of MRI responders between cohorts (52% in 2020 vs 38% in 2018). In patients who underwent TME, there was no difference in the proportion of R1 resection (0 in 2020 vs 9% in 2018), median NAR scores (8 (1-30) in 2020 v 15 (range 4-50) in 2018) or NAR score categories (22% good responders, 64% intermediate and 14% non-responders during Covid-19 vs 9% good responders, 55% intermediate and 36% non-responders in 2018). Changes in radiotherapy treatment of rectal cancer during Covid-19 pandemic, including more frequent use of SCRT (often in combination with neoadjuvant chemotherapy), did not seem to have negatively impacted short-term oncological outcomes, as measured by MRI downstaging rates and NAR scores following TME. The effect of the pandemic on medium and long-term oncological outcomes is still awaited.

P-54 Higher muscle mass is associated with better response to concurrent neoadjuvant chemoradiotherapy in rectal cancer patients

Sarcopenia (low muscle mass) is an emerging syndrome associated with poor outcome in cancer patients. We investigated the relationship between skeletal muscle index (SMI), psoas muscle index (PMI), and neoadjuvant rectal score (NAR) in a group of patients with locally advanced rectal adenocarcinoma, treated with neoadjuvant concurrent chemoradiotherapy (nCCRT) with capecitabine and surgery.

Abstract 349: Association of DNA damage response capacity with neoadjuvant chemoradiation response in locally advanced rectal cancer

Abstract Background: Locally advanced rectal cancer (RC) cases are ~60% of newly diagnosed RCs, with neoadjuvant chemoradiation therapy (nCRT) followed by surgery as the standard of care. While nCRT is highly toxic, it is also beneficial. Recent prospective trials reported that up to 59% locally advanced RC cases exhibit complete clinical response, suggesting these patients as ideal candidates for organ preservation. However, currently there is no biomarker to predict who will or will not benefit from nCRT. The goal of this study was to establish a predictive biomarker for benefit from nCRT, based on the hypothesis that inherent DNA damage response (DDR) capacity contributes to nCRT response in RC. Methods: To gain insight into inherent DDR capacity, we profiled primary peripheral blood lymphocytes (pPBLs) from RC patients by quantitative immunofluorescence, Luminex-multianalyte assay, and pPBL DNA whole exome sequencing (WES). RC patients analyzed were segregated by neoadjuvant rectal (NAR) score: NAR&amp;lt;1, complete responders (CRs), n=21; NAR&amp;gt;14, poor responders (PoRs), n=21; 1&amp;lt;NAR&amp;lt;14, partial responders (PRs), n=12. Conditional inference trees were used to establish optimal cut points for the nCRT response outcomes data. Single nucleotide variants from WES data were annotated and analyzed for variation in genes involved in DDR, and associated pathways. The variants were annotated as predicted-pathogenic based on the consensus of four variant effect prediction programs. Results: pPBLs from CRs showed significantly elevated γH2AX foci (a hallmark of double strand breaks) vs. PoRs (P&amp;lt;0.001, Kruskal-Wallis test). Multianalyte DDR panel testing revealed significantly increased expression or activation of 6 DDR proteins (ATR, MDM2, phosphorylated H2AXS139 (γ), p53S15, Chk1S345, and Chk2T68) in pPBLs from CRs versus PoRs (p&amp;lt;0.01, logistic regression model) and significantly increased protein levels of 4 DDR proteins (ATR, MDM2, p53S15, Chk2T68) in pPBLs from CRs vs. pPBLs from PRs (p&amp;lt;0.05, logistic regression model). We generated a combined DDR Score which positively and significantly correlated with CR vs. PoR (P&amp;lt;0.001, ordinal logistic regression model). From the combined DDR score, using mean score &amp;gt;0.082 as a cutpoint, we could include 90% patients with a CR. Finally, WES analysis of pPBL DNA from 15 CRs and 15 PoRs revealed that CRs were enriched in predicted-pathogenic variants in base excision repair genes vs. PoRs (p&amp;lt;0.01, q&amp;lt;0.025, FDR). Conclusion and future work: Overall, our data suggests inherent DDR capacity testing may predict the magnitude of benefit from nCRT and assist in patient selection for treatment. Validation in a larger RC patient population is needed to confirm these findings. Biological studies testing the impact of the identified variants in base excision repair on inherent DDR capacity are warranted. Citation Format: Elena V. Demidova, Randy W. Lesh, Vladimir Avkshtol, Margret B. Einarson, Erica A. Golemis, Sanjeevani Arora, Joshua E. Meyer. Association of DNA damage response capacity with neoadjuvant chemoradiation response in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 349.

The concept and use of the neoadjuvant rectal score as a composite endpoint in rectal cancer.

There is no universally accepted instrument to use as a validated surrogate endpoint for overall survival in phase 2 and phase 3 multimodal rectal cancer trials using chemoradiotherapy. Efforts are hampered by the inaccuracy of clinical TNM staging, the variability of indications for neoadjuvant treatment, and diverse definitions of tumour regression grade. Pathological complete response is commonly used, but fails to capture information from the majority of patients. The neoadjuvant rectal score categorises response and downstaging from the entire trial population to identify whether or not a novel treatment group in a chemoradiation trial is superior by predicting overall survival outcomes. Additionally, the neoadjuvant rectal score assesses the difference between initial clinical and pathological T stage and the presence or absence of nodal involvement after treatment. The neoadjuvant rectal score has been conceptually, but incompletely, statistically validated by two independent trial datasets. However, a fundamental weakness of the score is that no preoperative phase 3 trials in locally advanced rectal cancer in the past 20 years have provided a significant benefit in overall survival to statistically validate the neoadjuvant rectal score as a surrogate endpoint for overall survival. We review the robustness, practical value, applicability, generalisability, advantages, and disadvantages of the neoadjuvant rectal score as a surrogate endpoint for overall survival and recommend how this score could be improved and be acceptable as a standard endpoint in studies investigating neoadjuvant chemotherapy and chemoradiation in patients with rectal cancer.

Vascular calcification and response to neoadjuvant therapy in locally advanced rectal cancer: an exploratory study

PurposePatients with locally advanced rectal cancer (LARC) may experience a clinical complete response (cCR) to neoadjuvant chemoradiotherapy (NACRT) and opt for non-operative management. Pathological factors that relate to NACRT response have been well described. Host factors associated with response, however, are poorly defined. Calcification of the aortoiliac (AC) vessels supplying the rectum may influence treatment response.MethodsPatients with LARC having NACRT prior to curative surgery at Glasgow Royal Infirmary (GRI) and St Mark’s hospital (SMH) between 2008 and 2016 were identified. AC was scored on pre-treatment CT imaging. NACRT response was assessed using pathologic complete response (pCR) rates, tumour regression grades (TRGs), the NeoAdjuvant Rectal score and T-/N-downstaging. Associations were assessed using Chi-squared, Mantel–Haenszel and Fisher’s exact tests.ResultsOf 231 patients from GRI, 79 (34%) underwent NACRT for LARC. Most were male (58%), aged over 65 (51%) with mid- to upper rectal tumours (56%) and clinical T3/4 (95%), node-positive (77%) disease. pCR occurred in 10 patients (13%). Trends were noted between higher clinical T stage and poor response by Royal College of Pathologist’s TRG (p = 0.021) and tumour height > 5 cm and poor response by Mandard TRG (0.068). In the SMH cohort, 49 of 333 (15%) patients underwent NACRT; 8 (16%) developed a pCR. AC was not associated with NACRT response in either cohort.ConclusionsAC was not associated with NACRT response in this cohort. Larger contemporary cohorts are required to better assess host determinants of NACRT response and develop predictive models to improve patient selection.

Pretreatment CT and PET radiomics predicting rectal cancer patients in response to neoadjuvant chemoradiotherapy.

The purpose of this study was to characterize pre-treatment non-contrast computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (PET) based radiomics signatures predictive of pathological response and clinical outcomes in rectal cancer patients treated with neoadjuvant chemoradiotherapy (NACR T). 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. 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. The pre-treatment composite radiomics signatures were highly predictive of pathological response in rectal cancer treated with NACR T. A larger cohort is warranted for further validation.

Neoadjuvant rectal (NAR) score: Value evaluating the efficacy of neoadjuvant therapy and prognostic significance after surgery?

IntroductionThe Neoadjuvant rectal (NAR) score is a new surrogate endpoint to be used in clinical trials for early determination of treatment response to different preoperative therapies. The aim is to further validate the NAR-score, primarily developed using chemoradiotherapy (CRT) with a delay to surgery 6–8 weeks, and explore its value using other schedules. Materials and MethodsThe study included all 9978 patients diagnosed with non-metastasized RC in 2007–2015 that had undergone surgery and was registered in the Swedish Colorectal Cancer Registry. The patients of interest had either short-course radiotherapy (scRT)/CRT + delayed surgery, long-course radiotherapy (RT) + delayed surgery, (C)RT + additional chemotherapy, primary surgery, or scRT + immediate surgery. The scRT/CRT + delayed surgery groups were further divided based on time to surgery. ResultsMean NAR-score differed significantly (p < 0.0001) between different treatments. (C)RT + additional chemotherapy had the lowest mean score of 16.3 and CRT + delayed surgery had 17.7. There was a significant difference (p < 0.05) in overall survival (OS) and time to recurrence (TTR) of patients with a Low NAR-score (<8) compared to those with a High score (>16) for both CRT- and scRT, with a stronger correlation for CRT-patients. C-index for the NAR-score model (0.623) was not superior to when only pathological T- and N-stage was used (0.646). ConclusionsThe NAR-score is prognostic, but it is not better than pT- and pN-stage. However, the NAR-score can still discriminate between two treatments that have different cell killing effect and may still be of value in clinical trials as an easier method than pT- and N-stage.

Prognostic and Predictive Value of NAR Score in Gastric Cancer.

Neoadjuvant treatment is a widely accepted approach for locally advanced rectum cancer. Efforts to explore a surrogate endpoint for clinical trials revealed a new prognostic scoring system which is named as neoadjuvant rectal score (NAR) in patients who received neoadjuvant treatment for rectal cancer. 88 patients who met inclusion criteria were included in the study. The optimal cutoff value of the NAR score was 17.6 with 71% sensitivity and 63% specificity. Patients with NAR score > 17.6 (n: 48, 54%) were defined as the high-risk group and those with NAR score ≤ 17.6 (n: 40, 56%) as the low-risk group. Survival analysis according to the NAR score group (low-risk vs high-risk) revealed that there was a statistically significant difference between groups regarding OS and DFS. The median OS for high-risk patients was 27.3months (95% CI, 15.0-39.6); it was 76.6months (47.3-106.0) for low-risk patients (p < 0.0001). The median DFS was 15.1months (11.8-18.4) for high-risk patients; it was 44.3months (95% CI, 4.1-84.6) in the low-risk group (p = 0.002). As a result, we interpreted our findings as supporting data about the utility of NAR score not only as a surrogate endpoint for the clinical trial of rectal cancer but also as a prognostic marker in patients with gastric cancer who received neoadjuvant treatment.

Impact of KRAS status on tumor response and survival after neoadjuvant treatment of locally advanced rectal cancer.

Mutation of the KRAS oncogene (mKRAS) in colorectal cancer has been associated with aggressive tumor biology, resistance to epidermal growth factor inhibitors, anddecreased overall survival (OS). The aim of the current study was to analyze the association of mKRAS with pathologic complete response (pCR) and neoadjuvant rectal (NAR) score, and its impact on the survival of patients with locally advanced rectal cancer who were managed with multimodality therapy. The National Cancer Database was queried for stage II-III rectal cancer patients with a known KRAS status who underwent neoadjuvant chemoradiation therapy (nCRT) and proctectomy between 2004 and 2015. In total, 1886 patients were identified; 12% had pCR and 36% had mKRAS. Patients with mKRAS were more likely to have advanced pathologic T stage, tumor deposits, perineural invasion, and elevated carcinoembryonic antigen levels (all p ≤ .05). After adjustment for available confounders, mKRAS status was not associated with pCR or NAR score. In multivariable analysis, patients with pCR and lower NAR score had better OS, whereas mKRAS was independently associated with a worse prognosis. In this cohort of locally advanced rectal cancer patients who underwent proctectomy after nCRT, mKRAS was not associated with lower pCR rates or NAR scores;however,these patients experienced worse survival.

Predictive significance of cancer related-inflammatory markers in locally advanced rectal cancer.

BACKGROUNDLocally advanced rectal cancer is treated using neoadjuvant chemoradiation (nCRT), followed by total mesorectal excision (TME). Tumor regression and pathological post-treatment stage are prognostic for oncological outcomes. There is a significant correlation between markers representing cancer-related inflammation, including high neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte (MLR) and unfavorable oncological outcomes. However, the predictive role of these markers on the effect of chemoradiation is unknown.AIMTo evaluate the predictive roles of NLR, MLR, and PLR in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiation.METHODSPatients (n = 111) with locally advanced rectal cancer who underwent nCRT followed by TME at the Minimally Invasive Surgery Unit, Siriraj Hospital between 2012 and 2018 were retrospectively analyzed. The associations between post-treatment pathological stages, neoadjuvant rectal (NAR) score and the pretreatment ratios of markers of inflammation (NLR, MLR, and PLR) were analyzed.RESULTSClinical stages determined using computed tomography, magnetic resonance imaging, or both were T4 (n = 16), T3 (n = 94), and T2 (n = 1). The NAR scores were categorized as high (score > 16) in 23.4%, intermediate (score 8-16) in 41.4%, and low (score < 8) in 35.2%. The mean values of the NLR, PLR, and MLR correlated with pathological tumor staging (ypT) and the NAR score. The values of NLR, PLR and MLR were higher in patients with advanced pathological stage and high NAR scores, but not statistically significant.CONCLUSIONIn patients with locally advanced rectal cancer, pretreatment NLR, MLR and PLR are higher in those with advanced pathological stage but the differences are not significantly different.

Prognostic Significance of Neoadjuvant Rectal Scores in Preoperative Short-Course Radiotherapy and Long-Course Concurrent Chemoradiotherapy for Patients with Locally Advanced Rectal Cancer.

This study aimed to investigate the prognostic factors and the utility of the neoadjuvant rectal (NAR) score for patients who have locally advanced rectal cancer (LARC) treated with preoperative short-course radiotherapy (SRT) or long-course concurrent chemoradiotherapy (CRT). Of 314 consecutive stage 2 or 3 rectal cancer patients enrolled from January 2006 to December 2017, 205 underwent preoperative SRT (2500cGy/5 fractions), and 109 underwent preoperative CRT (4200-5080cGy/21-28 fractions) after total mesorectal excision (TME). The study calculated NAR scores using the following equation: [5 pN - 3(cT - pT) + 12]2/9.61. The multivariate analysis showed that age above 65years, pT4, pN2, NAR scores higher than 16, and distance from anal verges (< 8cm) were significant prognostic factors for overall survival (OS), whereas, pN2, NAR scores lower than 16, and distance from anal verges (< 8cm) were significant prognostic factors for disease-free survival (DFS) and distant metastasis (DM). The patients with an NAR score higher than 16, had a 5-year OS rate of 67.6%, a DFS rate of 56.9%, a locoregional recurrence (LRR) rate of 7.7%, and a DM rate of 35% compared with corresponding rates of 87.6%, 76.7%, 5.4%, and 7.2% for the patients with an NAR score of 16 or lower (p < 0.001 for OS, < 0.001 for DFS, 0.25 for LRR, and < 0.001 for DM). For patients who undergo SRT or CRT for LARC, a higher NAR score is associated with worse OS and DFS and higher DM rates at 5years. The NAR score could be used as a short-term surrogate end point after neoadjuvant therapy for LARC.

Abstract 4293: Final result of lenvatinib and capecitabine in combination with external beam radiation in treatment of locally advanced rectal cancer: Phase I clinical trial

Abstract 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.

Radiomics of MRI for pretreatment prediction of pathologic complete response, tumor regression grade, and neoadjuvant rectal score in patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation: an international multicenter study.

To investigate whether pretreatment MRI-based radiomics of locally advanced rectal cancer (LARC) and/or the surrounding mesorectal compartment (MC) can predict pathologic complete response (pCR), neoadjuvant rectal (NAR) score, and tumor regression grade (TRG). One hundred thirty-two consecutive patients with LARC who underwent neoadjuvant chemoradiation and total mesorectal excision (TME) were retrospectively collected from 2 centers in the USA and Italy. The primary tumor and surrounding MC were segmented on the best available T2-weighted sequence (axial, coronal, or sagittal). Three thousand one hundred ninety radiomic features were extracted using a python package. The most salient radiomic features as well as MRI parameter and clinical-based features were selected using recursive feature elimination. A logistic regression classifier was built to distinguish between any 2 binned categories in the considered endpoints: pCR, NAR, and TRG. Repeated k-fold validation was performed and AUCs calculated. There were 24, 87, and 21 T4, T3, and T2 LARCs, respectively (median age 63years, 32 to 86). For NAR and TRG, the best classification performance was obtained using both the tumor and MC segmentations. The AUCs for classifying NAR 0 versus 2, pCR, and TRG 0/1 versus 2/3 were 0.66 (95% CI, 0.60-0.71), 0.80 (95% CI, 0.74-0.85), and 0.80 (95% CI, 0.77-0.82), respectively. Radiomics of pretreatment MRIs can predict pCR, TRG, and NAR score in patients with LARC undergoing neoadjuvant treatment and TME with moderate accuracy despite extremely heterogenous image data. Both the tumor and MC contain important prognostic information. • Machine learning of rectal cancer on images from the pretreatment MRI can predict important patient outcomes with moderate accuracy. • The tumor and the tissue around it both contain important prognostic information.

SO-37 Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stability and microsatellite instability-high, locally advanced rectal cancer (EPOC 1504)

Chemoradiotherapy (CRT) followed by radical surgery is the standard therapy for patients with locally advanced rectal cancer (LARC). Sequential use of an anti-PD-1 antibody after radiation demonstrates synergistic effects in in vivo models, and an anti-PD-1 antibody is effective in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer. We studied nivolumab and radical surgery following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. phase I investigated the feasibility of 240 mg q2 weeks x 5 cycles of nivolumab and radical surgery after the quality-assured CRT. In phase II, the efficacies and safeties for both patients with microsatellite stable (MSS) (cohort A1) and MSI-H (cohort A2) LARC were evaluated. In cohort A-1, the primary endpoint was a centrally confirmed pathological complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR=10% and 30% was 37 patients, with a 1-sided alpha of 5% and power of 90%. In Cohort A-2, 5 patients were included in an exploratory manner. Sequential use of nivolumab 240 mg q2 weeks x 5 cycles and radical surgery were well tolerated. From Jan/2017 to Oct/2019, a targeted number of patients was included and assessed. In cohort A-1, 30% (11/37; 90% CI 18-44%) of pCR (AJCC grade 0) rate and 38% (14/37) of major pathological response (MPR) (AJCC grade 0+1) rate were observed. Clinical CR was observed in one additional patient (3%) refusing surgery after nivolumab. The median neoadjuvant rectal (NAR) score was 8.4 (range: 0.0-50.4). pCR rates of 60% (6/10) and 19% (5/27) were seen in patients with tumor cells with PD-L1 ≥1% and < 1% immunohistochemistry staining, respectively (p=0.038, Fisher exact test), performed on biopsy samples taken pre-CRT. pCR rates of 62% (8/13) and 10% (1/10) were seen in 23 patients with pre-CRT tumor samples analyzable by flow cytometry, according to CD8+ T cell /effector regulatory T cell (CD8/eTreg) ratios ≥2 and < 2, respectively (p=0.029, Fisher exact test). In cohort A-2, 60% (3/5) of pCR rate and 0.9 (range: 0.9-20.4) of median NAR score were observed. As of Jan/2020, only 2 patients (1 local and 1 metastatic) in cohort A-1 and none in cohort A-2 recurred. Immune-related severe adverse events were observed in 3 patients (grade 3 myasthenia, grade 3 interstitial nephritis, and grade 2 peripheral motor neuropathy); all fully recovered and received radical surgery. During the follow-up period, one additional patient with grade 2 colitis was observed. No treatment-related deaths were observed. Promising pCR rates of 30% and 60%, with mild toxicities, were shown in MSS and MSI-H LARC patients treated with nivolumab plus radical surgery after CRT, suggesting that it is a candidate therapy for the future non-surgical approach.

Usefulness of Restaging Pelvis Magnetic Resonance Imaging After Neoadjuvant Concurrent Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer

IntroductionIn patients with locally advanced rectal cancer, restaging pelvis magnetic resonance imaging (MRI) after neoadjuvant concurrent chemoradiotherapy is recommended despite its limited accuracy in predicting pathologic T (ypT) and N (ypN) stage. Neoadjuvant rectal (NAR) score is a novel short-term surrogate endpoint for disease-free survival (DFS) and overall survival (OS). We tested the agreement between restaging MRI T (yT) and N (yN) with ypT and ypN stages, respectively, and explored the prognostic significance of restaging MRI NAR (mNAR) score. Patients and MethodsBetween 2014 and 2018, 43 patients with locally advanced rectal cancer completed neoadjuvant concurrent chemoradiotherapy, had a restaging MRI, and underwent surgery. Weighted kappa was used to test the agreement between yT and yN with ypT and ypN, respectively. A kappa value of less than 0.5 was deemed unacceptable. Paired t test was used to compare NAR and mNAR mean scores. Survival was estimated by Kaplan-Meier curves. ResultsRestaging MRI could not predict ypT stage (slight agreement, κ = 0.111) or ypN stage (fair agreement, κ = 0.278). The mean mNAR score was higher than the mean NAR score (20 vs. 16, P = .0079). The median DFS for patients with low-intermediate NAR and high NAR was not reached vs. 30 months (P = .0063). The median OS for patients with low-intermediate NAR and high NAR was not reached vs. 40 months (P = .0056). There was a trend for longer DFS and OS in patients with low-intermediate mNAR scores (not reached in both groups, P = .058) compared to patients with high mNAR scores (not reached in both groups, P = .15). ConclusionRestaging MRI could not predict ypT and ypN stage. The mean mNAR score was higher than the mean NAR score. There was a trend for longer DFS and OS in patients with low-intermediate mNAR scores compared to patients with high mNAR scores.

A phase 1 trial of the safety, tolerability and biological effects of intravenous Enadenotucirev, a novel oncolytic virus, in combination with chemoradiotherapy in locally advanced rectal cancer (CEDAR)

BackgroundChemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously. Pre-clinical evidence of synergy with radiation warrants further clinical testing and assessment of safety with radiation.MethodsEligibility include histology confirmed locally advanced rectal cancer that require chemoradiation. The trial will use a Time-to-Event Continual Reassessment Model-based (TiTE-CRM) approach using toxicity and efficacy as co-primary endpoints to recommend the optimal dose and treatment schedule 30 patients will be recruited. Secondary endpoints include pathological complete response the neoadjuvant rectal score. A translational program will be based on a mandatory biopsy during the second week of treatment for ‘proof-of-concept’ and exploration of mechanism. The trial opened to recruitment in July 2019, at an expected rate of 1 per month for up to 4 years.DiscussionChemoradiation with Enadenotucirev as a radiosensitiser in locally Advanced Rectal cancer (CEDAR) is a prospective multicentre study testing a new paradigm in radiosensitization in rectal cancer. The unique ability of EnAd to selectively infect tumour cells following intravenous delivery is an exciting opportunity with a clear translational goal. The novel statistical design will make efficient use of both toxicity and efficacy data to inform subsequent studies.Trial registrationClinicalTrial.gov, NCT03916510. Registered 16th April 2019.

Relationship of lymphopenia to overall survival and progression-free survival in rectal cancer patients receiving neoadjuvant chemoradiation.

39 Background: Pelvic radiation and myelosuppressive chemotherapy can lead to lymphopenia during the course of preoperative chemoradiation when treating rectal cancer. Lymphopenia during chemoradiation has been associated with higher risks of recurrence in other cancers, possibly due to decreased immunosurveillance. The effect in rectal cancer is not well described. We hypothesize that high-grade lymphopenia is associated with worse progression-free survival (PFS) and overall survival (OS) in rectal cancer patients undergoing preoperative chemoradiation. Methods: All patients treated at our institution with neoadjuvant chemoradiation between 2013 and 2019 were reviewed (n = 99). The study was limited to patients with Stage II – IV (AJCC 8th edition) rectal adenocarcinoma. Patients were excluded if they had prior systemic therapy (n = 13) or if lymphocyte data was unavailable (n = 30). Lymphopenia which arose during or within 30 days of completion of chemoradiation was graded by the CTCAE v.4.0. Neoadjuvant Rectal (NAR) scores, indicators of pathologic response, were calculated for each surgical patient. Kaplan-Meier analysis was used to calculate PFS and OS. Two-tailed t-tests (a=0.05) were used to detect differences between subgroups. Results: Fifty-six patients met inclusion criteria. Grade 2 (G2) or higher lymphopenia occurred in 43 (76.8%) patients (G2 = 22, G3 = 20, G4 = 1). In patients with G2 vs G3-4 lymphopenia, there were no differences in baseline, treatment, or demographic characteristics. The median PFS for these patients was 20.0 months. Patients with G3-4 lymphopenia had significantly worse 2-year PFS compared to those with G2 lymphopenia (83.3% vs 59.3% p = 0.03). The two-year OS did not differ between groups (100% vs 60.3%, p = 0.10). Lymphocyte nadir did not correlate with pathologic response, as measured by the NAR score (r = -0.28, p = 0.07). Conclusions: In this study, G3-4 lymphopenia was associated with worse PFS in rectal cancer patients treated with neoadjuvant chemoradiation, despite a small sample size. The prognostic implications of lymphopenia in rectal cancer should be confirmed in larger cohorts and the underlying mechanisms explored.