Total neoadjuvant therapy (TNT) is increasingly utilized for patients with locally advanced rectal cancer. Prior studies have suggested that markers of systemic inflammation at baseline may predict treatment outcomes for patients receiving neoadjuvant long-course chemoradiation (LC-CRT). However, this has not been evaluated in patients receiving TNT with short-course radiation (SC-RT). We evaluated the prognostic value of baseline neutrophil-to-lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) in rectal cancer patients receiving SC-TNT. Between 2010 and 2019, we identified 186 patients with rectal cancer who received SC-TNT at our institution. Of these, 141 patients had a pre-treatment complete blood counts available within 2 months prior to initiating therapy. All patients received neoadjuvant SC- RT 25 Gy/5 Fx to the pelvis followed by chemotherapy followed by delayed surgery +/- adjuvant chemotherapy based on pathologic features. Primary clinical outcomes of interest were pathologic complete response (pCR), loco-regional control (LRC), distant control (DC), disease-free survival (DFS), and overall survival (OS). Cox regression analysis was performed to determine potential associations between NLR, PLR, and MLR with clinical outcomes. NLR, PLR, and MLR were analyzed as both continuous and dichotomized variables. Multiple cutoff values were evaluated based on cohort mean, cohort median, and previously published values. Statistical analyses were performed using SPSS version 26. P <0.05 was considered statistically significant. The median baseline NLR was 2.5 (interquartile range 1.36). The median baseline PLR was 142.73 (interquartile range 82.11). The median baseline MLR was 2.56 (interquartile range 2.26). Median follow-up was 2.44 years (range 0.11 – 9.59 years). pCR was achieved in 34 patients (24.1%). Three-year actuarial LRC, DC, DFS, and OS were 93%, 84.2%, 78.9%, and 87.7%, respectively. NLR as a continuous variable was significantly associated with LRC, DFS, and OS on univariate analysis but not multivariate analysis. There was no other association found between NLR, PLR, or MLR with any other clinical outcomes of interest when analyzed as either continuous or dichotomous variables. In our SC-TNT cohort, baseline NLR, PLR, and MLR did not predict tumor response, oncologic outcomes, or overall survival in rectal cancer patients. Our data contrasts prior studies for LC-CRT, possibly due to differences in neutrophil or lymphocyte depletion with hypo-fractionated RT. Further studies are warranted to compare post-RT immune markers between LC-CRT and SC-RT. As hypo-fractionated RT use increases, identification and validation of biomarkers in rectal cancer patients undergoing neoadjuvant SCRT will become increasingly important.

Recent data show promise of short-course radiation (SCR) plus total neoadjuvant chemotherapy for rectal cancer. We evaluated the complete clinical response (cCR) rate and toxicity in patients who were treated with SCR followed by multi-agent chemotherapy (CH) and non-operative intent. From January 2018 to May 2019, 90 patients with newly diagnosed, non-metastatic rectal adenocarcinoma were treated with SCR-CH and non-operative intent at our institution. Patients received 25 Gy/5 fx to the pelvis with an optional primary boost to 30 Gy. Involved extra-mesorectal pelvic lymph nodes were boosted to 35 Gy. CH was initiated after RT. CR was assessed after CH by digital rectal examination, MRI pelvis, and endoscopy. Patients with a cCR were followed with these assessments every 3 months. Patients with a partial CR received surgery. Follow-up was calculated from CH completion. GI toxicity was graded per CTCAE v5. Of the 90 patients [median age 61 (range 25-91)], 86 (96%) had locally advanced disease (T3/4 or node positive) and median tumor size 4.6 cm (range 1.5-11 cm). The median distance from anal verge was 7 cm (range 0-13 cm). All patients completed prescribed RT. Five patients received CH ≤5 cycles due to poor tolerance. Among patients who completed CH ≥6 cycles, the initial cCR rate was 51% (43/85) overall and 49% (40/81) for patients with locally advanced disease. Median follow-up was 9.7 mos (range 0.7-21 mos) for living patients, and 44% (37/85) patients had continued cCR at last follow up. For patients with primaries ≤2 cm from anal verge, 6 (6/20, 30%) patients had an initial cCR and 5 (25%) patients had a continued cCR at last follow up. Among non-operative patients, 18 (49%) had no late GI toxicities and 0 had late G3/4 GI toxicities. In the 42 patients with a partial CR, 60% underwent low anterior resection, 29% underwent abdominoperineal resection, and 9.5% underwent transanal excision or proctectomy. Seven of 85 patients had local regrowth at a median of 8.5 mos (range 2.3-12 mos) after SCR-CH. Six cases occurred in non-operative patients requiring salvage surgery at a median of 6.0 (range 4.8-15) mos after completion of SCR-CH. Four (4/90, 4.4%) patients developed metastatic disease, all of whom had an initial partial CR and had undergone surgery. Our preliminary data show that SCR-CH can result in cCR and organ preservation in patients with locally advanced and/or low-lying rectal cancer with acceptable GI toxicity. Further follow-up is required to evaluate the durability of response and toxicity.Abstract 96; TablecT StageT212 (13%)T360 (67%)T418 (20%)cN StageN022 (24%)N127 (30%)N241 (46%)Group StageI5 (6%)II17 (19%)IIIA5 (6%)IIIB41 (45%)IIIC22 (24%)RT (Gy/fx)25/574 (82%)30/56 (7%)35/510 (11%)CH Cycles5 or fewer5 (6%)6-851 (56%)9-129 (10%)12 or more25 (28%)CH AgentsFOLFOX/mFOLFOX79 (88%)CAPOX7 (8%)Other4 (4%) Open table in a new tab

Recent data show promising results of short course radiation therapy followed by chemotherapy as total neoadjuvant therapy for rectal cancer (SC-TNT). The use of SC-TNT for organ preservation is unknown. We hypothesized that SC-TNT would result in a complete clinical response (cCR) rate of at least 20%. NORMAL-R is a phase I, prospective trial of SC-TNT for stage I-IIIB (cT1-3, N0-2, M0) lower rectal adenocarcinoma. All patients were candidates for TME. After closure of the OPERA study, the protocol was modified from stage I only to include stages II-III, and increased from 6 to 8 cycles of FOLFOX (or 5 cycles of CAPOX). Patients received 25 Gy / 5 fxs to the pelvis with a simultaneous integrated boost to 35 Gy for extra-mesorectal pelvic lymph nodes. FOLFOX or CAPOX was initiated 2-4 weeks after RT completion. Patients with cCR by MRI, endoscopy and digital rectal examination were followed with non-operative management with the latter assessments every 3 months. Patient reported symptoms were assessed by baseline, post-treatment and 1-year Functional Assessment of Cancer Therapy-Colorectal (FACT-C) assessments. An interim analysis after 10 patients was planned to ensure a cCR of at least 20%. Baseline and post-treatment FACT-C values were compared with Wilcoxon signed-rank test. The primary endpoint of the study is 1-year cCR. Between June 2016 and January 2019, 19 patients were treated on trial, with 17 patients accrued in the last 14 months after protocol amendment (11/2017). At the planned interim analysis of 10 patients, 9 patients were evaluable (one patient had an allergic reaction to chemotherapy and was excluded). Eight of nine (89%) evaluable patients had a cCR after SC-TNT. Of the patients included in the interim analysis, 4 patients received 8 cycles, and 6 patients received 6 or less cycles of FOLFOX. At a median follow-up 10.9 months, 88% have a persistent cCR. FACT-C for social/family, emotional, and functional wellbeing were not different post-treatment. As expected, FACT-C values for colorectal cancer subscale [24.5 (2.2) vs 19.5 (4.9), p=.019] and physical wellbeing [26.8 (1.5) vs 22.5 (3.2), p=.016] were decreased immediately post-treatment. Our preliminary data show that SC-TNT results in a high cCR and is well tolerated. Further follow-up is required to evaluate durability of response and toxicity. A phase II study is indicated to validate the clinical efficacy of SC-TNT.Abstract 1098; Table 1Baseline patient and tumor characteristics.Interim (n=10)Total (n=19)Age (years)59 (45-76)56 (38-76)SexFemale6 (60)8 (42)Male4 (40)11 (58)ECOG09 (90)15 (79)11 (10)4 (21)T stageT25 (50)6 (32)T35 (50)13 (68)N stageN07 (70)10 (53)N13 (30)7 (37)N20 (0)2 (11)Clinical StageI4 (40)5 (26)II3 (30)5 (26)III3 (30)9 (47)Distance from anal verge (cm)3.2 (1.7)4.4 (2.4)Size (cm)3.3 (0.9)4.4 (1.8)Data are median (range), number (%), or mean (SD). Some percentages do not add up to 100 because of rounding. ECOG = Eastern Cooperative Oncology Group. Open table in a new tab

Total Neoadjuvant Therapy (TNT), delivery of all chemotherapy and radiation prior to resection, has been suggested to improve outcomes for patients with locally advanced rectal cancer. The Neoadjuvant Rectal score (NAR) is a validated early predictor of outcome using a semi-continuous variable for downstaging between clinical and pathologic stage. This study compares NAR scores achieved by standard chemoradiation (CRT) and two TNT regimens utilizing different radiation approaches: neoadjuvant short course radiation followed by chemotherapy (SC-TNT) and induction chemotherapy followed by long course chemoradiation (LC-TNT). Patients undergoing neoadjuvant therapy for locally advanced rectal cancer at two US NCI-designated cancer centers were included for retrospective cohort analysis. Three different neoadjuvant regimens were evaluated: traditional CRT, which included 50-55 Gy / 25-28 fx with concurrent 5-FU or capecitabine; SC-TNT, comprised of 25Gy / 5 fx followed by FOLFOX/CAPOX chemotherapy; and LC-TNT, which had FOLFOX/CAPOX followed by standard chemoradiation. Patients then underwent total mesorectal excision or, in the setting of complete clinical response, nonoperative management. Primary outcome of NAR Score was calculated for each patient and categorized as "Low" (less than 8), "Intermediate" (8 – 16), or "High" (greater than 16). Nonoperatively managed patients with no evidence of recurrence at 12 months were classified as a complete pathologic response. Univariate analysis was performed with Kruskal-Wallace test; odds ratios of achieving NAR less than 8 were calculated. A total of 912 patients with locally advanced rectal cancer underwent neoadjuvant therapy at our centers from 2009 to 2017. 498 patients (55%) underwent chemoradiation, 318 (35%) received LC-TNT, and 96 (10%) were treated with SC-TNT. On univariate analysis, the LC-TNT cohort was significantly younger (38% under 50 years old versus 24% and 26%, respectively) and had more advanced disease (85% Stage III tumors compared to 69% and 72%, respectively) compared to the CRT or SC-TNT cohorts. Odds of achieving a "Low" NAR were significantly higher among SC-TNT (OR=1.95; 95%CI 1.24 – 3.07) and LC-TNT (OR=2.09; 95%CI 1.55 – 2.82) compared to CRT. However, direct comparison between SC-TNT and LC-TNT yielded no significant difference (Table 1). SC-TNT and LC-TNT both outperform traditional CRT but achieve similar tumor downstaging when directly compared in this large, multi-institutional cohort. These data highlight the need for a SC-TNT arm in prospective randomized studies evaluating rectal cancer downstaging and nonoperative management in the US.Abstract 130; Table 1NAR Score CategorynLow NAR n (%)Intermediate NAR n (%)High NAR n (%)CRT498131 (26)236 (48)131 (26)SC-TNT9639 (41)34 (35)23 (24)LC-TNT318136 (43)118 (37)64 (20)Odds Ratios of Achieving NAR<8Odds Ratio95% CISC-TNT vs. CRT1.951.243.07LC-TNT vs. CRT2.091.552.82LC-TNT vs. SC-TNT1.080.681.72 Open table in a new tab

PURPOSE:18F-fluorodeoxyglucose (FDG) positron emission tomography-(PET)/computed tomography (CT) imaging is used for staging and treatment planning of patients with anal cancer. Quantitative pre- and posttreatment metrics that are predictive of recurrence are unknown. We evaluated the association between pre- and posttreatment FDG-PET/CT parameters and outcomes for patients with squamous cell carcinoma of the anus (SCCA).METHODS AND MATERIALS:The records of 110 patients treated between 2003 and 2013 with definitive radiation therapy for SCCA were reviewed under an institutional review board-approved protocol. The median radiation therapy dose was 50.4 Gy (range, 35-60 Gy). Concurrent chemotherapy was administered for 109 of 110 patients and generally consisted of 5-fluorouracil and mitomycin C (n = 94). All patients underwent pretreatment FDG-PET/CT and 101 of 110 underwent posttreatment FDG-PET/CT 3 months after completion of radiation therapy. The maximum standard uptake value (SUVmax) was analyzed, in addition to multiple patient and treatment factors, by univariate and multivariate Cox regression for correlation with local recurrence (LR) and overall survival (OS).RESULTS:The median follow-up was 28.6 months. LR occurred in 1 of 15 (6.7%), 5 of 47 (10.6%), and 6 of 48 (12.5%) patients with stage I, II, and III disease, respectively. On univariate analysis, a significant association was observed between reduced LR and posttreatment SUVmax <6.1 (P = .0095) and between increased OS and posttreatment SUVmax <6.1 (P = .0086). On multivariate analysis, a significant association was observed between reduced LR and posttreatment SUVmax <6.1 (P = .0013) and the use of intensity modulated radiation therapy (P < .001). A significant multivariate association was observed between increased OS and posttreatment SUVmax <6.1 (P = .0373) and the use of 5-fluorouracil/mitomycin C chemotherapy (P = .001).CONCLUSION:Posttreatment SUVmax <6.1 is associated with reduced LR and increased OS after chemoradiation therapy for SCCA independent of T and N stage on multivariate analysis. Greater follow-up is required to confirm this association with late patterns of failure.

Purpose/Objective(s): RTOG 9811 reported relapse rates of 49% in locally advanced anal squamous cell carcinoma, following radical chemoradiation therapy (CRT).As the majority of patients relapse at the site of gross tumor, there may be a role for dose escalation to the primary tumor, however the dose-response relationship for anal cancer is not currently well known.Intensity modulated radiation therapy (IMRT) has been widely adopted; allowing delivery of a simultaneous integrated boost (SIB) to the gross tumor over the same number of fractions as the prophylactic dose to the uninvolved nodes.The use of SIB can reduce overall treatment time both by employing larger fraction sizes to the gross tumor and by causing fewer interruptions due to reduced toxicity.The aim is to fit a tumor control probability (TCP) model to the published outcome IMRT data.Materials/Methods: We performed a systematic review of PubMed and Embase databases to identify original papers published in English, from 2005 to the present which report the use of IMRT CRT including outcomes.Thirteen papers including a total of 625 patients were identified and predefined data fields collected; including number of patients (range 17 to 148) , median (54Gy) and range (45-67.6Gy) of doses delivered , fractionations used, overall treatment time (range 38-56 days) and local control at 2 to 3 years.A standard linear quadratic tumor control probability (TCP) model, which included repopulation, was fit by least squares minimization.Accelerated repopulation was assumed to commence after 20 days and contribute an additional 0.7 Gy per day; an a/b ratio of 14 was assumed, in keeping with published data for cervical cancer.Results: The fitted TCP curve demonstrated a dose response relationship with a Z 0.15.The estimated local control at EQD2a/b Z 14 50 Gy is 85% (95% confidence interval 57% to >100%).Calculations using an a/b of 10 demonstrated an a Z 0.14 therefore resulted in minimal difference.The adjustment for overall treatment time resulted in significant changes to the TCP curve (up to 10 Gy equivalent for prolonged or heavily interrupted schedules).In the IMRT series, specifically looking at locally advanced patients, the 3 year local control was 79%; relatively better than in RTOG 9811.The sigmoid nature of the TCP curve, suggests a 5 Gy EQD2 increase in dose, in locally advanced tumors may result in 10% improvement in local control.Conclusions: The published data are broadly consistent with a linear quadratic dose response model.The IMRT series appear to have better outcomes in locally advanced patients.IMRT based dose escalation using an SIB, in locally advanced anal cancer, should be further investigated in the context of clinical trials.