Preoperative Chemoradiotherapy Research Articles

Downstaging after preoperative chemoradiation for locally advanced rectal cancer is associated with better survival than pathologic stage 0–1 disease treated with upfront surgery

Background and objectivesIt is unknown how patients with locally advanced rectal cancer with significant response to preoperative radiotherapy/chemoradiotherapy fare relative to patients with true pathologic 0–1 disease undergoing upfront surgery. We aimed to determine whether survival is improved in locally advanced rectal cancer downstaged to pathologic stage 0–1 disease compared to true pathologic stage 0–1 tumors.MethodsA retrospective review of the National Cancer Database between 2004 and 2016 was conducted. Three groups were identified: (1) clinical stage 2–3 disease downstaged to pathologic stage 0–1 disease after radiotherapy, (2) clinical stage 2–3 disease not downstaged after radiotherapy, and (3) true pathologic 0–1 tumors undergoing upfront surgery. The primary endpoint was overall survival and was compared using Kaplan–Meier and multivariate Cox regression analyses.ResultsThe study population consisted of 59,884 patients. Of the 40,130 patients with locally advanced rectal cancer treated with preoperative radiation, 12,670 (31.5%) had significant downstaging (group 1), while 27,460 (68.4%) had no significant downstaging (group 2). A total of 19,754 had pathologic 0–1 disease treated with upfront resection (group 3). On Kaplan–Meier analysis, downstaged patients had significantly better overall survival compared to both non-downstaged and true pathologic stage 0–1 patients (median 156 vs. 99 and 136 months, respectively, p < 0.001). On multivariate analysis, downstaged patients had significantly better survival (HR 0.88, p < 0.001) compared to true pathologic 0–1 patients.ConclusionsLocally advanced rectal cancer downstaged after preoperative radiotherapy has significantly better survival compared to true pathologic stage 0–1 disease treated with upfront surgery. Response to chemoradiotherapy likely identifies a subset of patients with a particularly good prognosis.

Primary Surgery Followed by Selective Chemoradiotherapy Versus Preoperative Chemoradiotherapy Followed by Surgery for Locally Advanced Rectal Cancer: A Randomized Clinical Trial

The aim of this work was to determine whether locally advanced rectal cancer (LARC) with negative mesorectal fascia (MRF) predicted by magnetic resonance imaging (MRI) can be excluded from preoperative radiation therapy treatment. This multicenter, open-label, non-inferiority, randomized clinical trial enrolled patients with LARC within 6 to 12 cm from the anal verge and with negative MRI-predicted MRF. Participants were randomized to the intervention group (primary surgery, in which the patients with positive pathologic [CRM] circumferential margins were subjected to chemoradiotherapy [CRT] and those with negative CRM underwent adjuvant chemotherapy according to pathologic staging) or the control group (preoperative CRT, in which all patients underwent subsequent surgery and adjuvant chemotherapy). The primary endpoint was 3-year disease-free survival (DFS). A total of 275 patients were randomly assigned to the intervention (n = 140) and control (n = 135) groups, in which 33.57% and 28.15% patients were at clinical T4 stage and 85.92% and 80.45% patients were at "bad" or "ugly" risk in the intervention and control groups, respectively. There were 2 patients (1.52%) and 1 patient (0.77%) with positive CRM in the intervention and control groups, respectively (P > .05). The non-adherence rates for the intervention and control groups were 3.6% and 23.7%, respectively. After a median follow-up of 34.6 months (IQR, 18.2-45.7), 43 patients had positive events (28 patients and 15 patients in the intervention and control groups, respectively). There were 6 patients (4.4%) with local recurrence in the intervention group and none in the control group, which led to the termination of the trial. The 3-year DFS rate was 81.82% in the intervention group (95% CI, 78.18%-85.46%) and 85.37% in the control group (95% CI, 81.75%-88.99%), with a difference of -3.55% (95% CI, -3.71% to -3.39%; hazard ratio, 1.76; 95% CI, 0.94-3.30). In the per-protocol data set, the difference between 3-year DFS rates was -5.44% (95% CI, -5.63% to -5.25%; hazard ratio, 2.02; 95% CI, 1.01-4.06). Based on the outcomes of this trial, in patients with LARC and MRI-negative MRF, primary surgery could negatively influence their DFS rates. Therefore, primary surgery was an inferior strategy compared with preoperative CRT followed by surgery and cannot be recommended for patients with LARC.

Does CT overestimate extra-pancreatic perineural invasion in patients with pancreatic ductal adenocarcinoma following neoadjuvant chemoradiation therapy?

To evaluate the diagnostic performance of CT in the assessment of extra-pancreatic perineural invasion (EPNI) in patients with pancreatic ductal adenocarcinoma (PDAC). This retrospective study included 123 patients (66 men; median age, 66 years) with PDAC who underwent radical surgery and pancreatic protocol CT for assessing surgical resectability between September 2011 and March 2019. Among the 123 patients, 97 patients had received neoadjuvant chemoradiation therapy (CRT). Two radiologists reviewed the CT images for evidence of EPNI using a 5-point scale (5 = definitely present, 4 = probably present, 3 = equivocally present, 2 = probably absent, and 1 = definitely absent). Diagnostic performance for assessing EPNI was evaluated with receiver operating characteristic (ROC) curve analysis. The sensitivity, specificity, and area under the ROC curve for assessing EPNI were 98%, 30%, and 0.62 in all patients; 97%, 22%, and 0.59 in patients with neoadjuvant CRT; and 100%, 100%, and 1.00 in patients without neoadjuvant CRT, respectively. False-positive assessment of EPNI occurred in 23% of patients (n = 28/123), and 100% of these (n = 28/28) had received neoadjuvant CRT. There was moderate to substantial agreement between the readers (ĸ = 0.49-0.62). Pancreatic protocol CT has better diagnostic performance for determination of EPNI in treatment naïve patients with PDAC and overestimation of EPNI is likely in patients who have received preoperative CRT. Pancreatic protocol CT has better diagnostic performance for the detection of EPNI in treatment naïve patients compared to patients receiving neoadjuvant CRT.

Is ypTNM staging a comparable predictor as pTNM staging for survival in non-metastatic rectal cancer after preoperative chemoradiation therapy?

Background: The pTNM staging system is widely recognized as the most effective prognostic indicator for cancer. The latest update of this staging system introduced a new pathological staging system (ypTNM) for patients receiving neoadjuvant chemoradiotherapy (NACRT). However, whether the prognostic value of the ypTNM staging system for rectal cancer is similar to that of the pTNM staging system remains unclear. This study was conducted to compare the ypTNM and pTNM staging systems in terms of their prognostic value for patients with nonmetastatic rectal cancer undergoing proctectomy. Material and Methods: This study was conducted at a large teaching hospital. Between January 2014 and December 2022, 542 patients with rectal cancer were analyzed (median follow-up period, 60 months; range, 6-105 months). Of them, 258 and 284 were included in the pTNM and ypTNM groups, respectively. Inverse probability of treatment weighting (IPTW) was performed to account for the effects of confounders. Cox proportional-hazards regression was performed for the between-group comparison of overall survival (OS). Results: The crude model revealed that OS was similar between the two groups (p = 0.607). After performing IPTW, we found that patients with the same ypTNM- and pTNM-classified stages had similar overall survival (hazard ratio = 1.15; 95% CI = 0.76-1.73; p = 0.5074). Conclusions: For patients with rectal cancer who have received preoperative NACRT, the prognostic value of ypTNM staging appears to be similar to that of pTNM staging, mostly because of the downstaging effect of neoadjuvant chemoradiotherapy.

Occurrence and Prognosis of Mixed Subtype Adenocarcinoma and Adeno-Squamous Carcinoma in Esophageal Cancer.

Purpose: To gain a deeper understanding of the incidence and survival rates of rare esophageal mixed adenoacanthoma (EAM) and esophageal mixed adeno-squamous carcinoma (EASC) to promote a more comprehensive understanding of these two subtypes. Background: EAM and EASC are rare subtypes of esophageal cancer with limited literature available. Extensive research has been conducted on the clinical and pathological characteristics of gastric and colorectal mixed adenoacanthomas, but there is relatively little literature on esophageal mixed adenoacanthomas. Therefore, this study aims to investigate the incidence and survival rates of these two subtypes in depth. Methods: Patients diagnosed with EAM and EASC between 2000 and 2019 were selected from the SEER database for the study. Joinpoint software was used to calculate the incidence rates of esophageal AM and ASC patients, and differences in cancer overall survival (OS) and cancer-specific survival (CSS) based on Kaplan-Meier curves were compared. Multivariate Cox regression analysis was employed to identify independent prognostic factors for OS and CSS, and a prognostic model was established and validated for accuracy. Results: The study found that the incidence of EAM increased until 2014, followed by a decline, while the incidence of EASC decreased until 2017, followed by an increase. Both of these subtypes were more common in male patients and those over the age of 65. For EAM patients, preoperative chemoradiotherapy was associated with better survival rates, while for EASC patients, preoperative radiotherapy combined with adjuvant chemotherapy improved survival. Finally, we constructed nomograms for predicting the overall survival of EAM and EASC patients by incorporating identified risk factors, which demonstrated good sensitivity and specificity. Conclusion: EAM and EASC are rare subtypes of esophageal cancer, and an in-depth exploration of their incidence and survival rates provides valuable data and insights for understanding these rare esophageal cancer subtypes. This information can assist clinical decision-making for healthcare professionals.

Robotic Versus Laparoscopic Abdominoperineal Resection for Locally Advanced Rectal Cancer Following Preoperative Chemoradiotherapy.

The usefulness of robotic surgery compared to laparoscopic surgery for rectal cancer has been reported; however, few reports exist on robotic abdominoperineal resection (APR). The aim of this study was to compare the outcomes of robotic and laparoscopic surgery to determine their usefulness in patients with locally advanced rectal cancer who had undergone preoperative chemoradiotherapy (CRT). This retrospective study included 43 patients with locally advanced rectal cancer who underwent preoperative CRT and robotic (22 patients) or laparoscopic APR (21 patients) between December 2012 and September 2022. We examined the short- and long-term outcomes in the robotic and laparoscopic groups. The median follow-up durations were 36 and 48 months for the robotic and laparoscopic groups, respectively. No significant differences in operative time, intraoperative blood loss, or overall complication rates were observed. However, the incidence of organ/space surgical site infection (SSI) was significantly lower in the robotic surgery group than in the laparoscopic group (9.1% vs. 38.1%, p=0.034) and the 3-year overall survival rate was significantly higher in the robotic surgery group than in the laparoscopic group (95% vs. 67%, p=0.029). Robotic APR was associated with a significantly lower rate of organ/space SSIs than the laparoscopic approach, indicating the usefulness of the robotic approach.

Systemic Inflammatory Response Following Preoperative Chemoradiotherapy Can Affect Oncologic Outcomes in MSI-H/dMMR Rectal Cancer.

Systemic inflammatory response (SIR) is a crucial determinant of disease progression and survival in patients with colorectal cancer. This study investigated the prognostic relevance of changes in the platelet count on survival and the predictive value of changes in the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) on the pathological tumor response to preoperative chemoradiotherapy (CRT) in patients with microsatellite instability-high (MSI-H) rectal cancer. From 2011 to 2022, data of 46 consecutive patients with MSI-H rectal cancer who were treated with preoperative CRT followed by curative surgery at Kyungpook National University Chilgok Hospital (Daegu, South Korea) were retrospectively analyzed. A 235 cut-off value was used to define whether PLR was high or low. Any change in the PLR or NLR was calculated on the basis of subtracting the pre-CRT PLR or NLR from the post-CRT values. Both pre-CRT and post-CRT values of the NLR and PLR were not significantly associated with clinical outcomes. Simple logistic regression analysis showed that a change in the PLR following CRT was not significantly associated with survival outcomes; however, patients who maintained a high change in the PLR following CRT showed significantly better pathologic T-stage. No statistically significant association was noted between changes in the platelet count and clinical outcomes of patients. The results suggested that changes in the PLR following CRT are associated with pathologic T-stage of the group. However, the SIR markers showed no prognostic values on the survival outcomes of the patients with MSI-H/mismatch repair-deficient (dMMR) locally advanced rectal cancer (LARC).

Prospect, the end of the reign of preoperative chemoradiotherapy in locally advanced rectal cancer

Prospect, the end of the reign of preoperative chemoradiotherapy in locally advanced rectal cancer

Clinical and pathological parameters predicting pathologic complete response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Objective The aim of this study is to identify possible clinical predictors of complete response after neoadjuvant treatment in locally advanced rectal cancer (LARC) patients. Background Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision and postoperative adjuvant chemotherapy for LARC is the standard of care with a local recurrence rate of only 5–10%. On the other hand, various people react differently to neoadjuvant CRT. Neoadjuvant CRT is well received by the majority of patients, with a pathologic complete response (pCR) occurring in 10–30% of cases. Predicting the response to neoadjuvant CRT is crucial from a clinical standpoint, since patients with pCR have a better prognosis and may require a different treatment plan than patients without pCR. As a result, predicting pCR following neoadjuvant CRT for rectal cancer continues to be extremely useful for treating physicians. To identify the clinical and pathological variables linked to a full response to preoperative CRT for rectal cancer, we assessed a group of patients with pCR in this study. Patients and methods The study included 153 patients with LARC that were enrolled in the study based on specific inclusion and exclusion criteria. Patients were treated by standard neoadjuvant therapy. Surgical resection was planned for 6–8 weeks after the completion of neoadjuvant CRT, irrespective of the response to CRT. Pathological examination was performed to assess pathological response in the resected specimen. pCR was defined as the absence of viable tumor cells in the surgical specimen, including lymph nodes. Results After neoadjuvant chemoradiation, the pCR rate for rectal cancer patients was 20.8%; patients were split into pCR and non-pCR groups. Age, sex, BMI, performance score, tumor stage, tumor differentiation, tumor location, and surgical method were all evenly distributed across the two groups. The results of the multivariate analysis showed that pretreatment lymph node status, tumor size, and a carcinoembryonic antigen level of less than or equal to 5 ng/ml were independent risk factors of an elevated likelihood of pCR, as was an interval of more than or equal to 8 weeks between the completion of chemoradiation and treatment. Conclusion The pCR in rectal cancer following neoadjuvant chemoradiation is predicted by pretreatment carcinoembryonic antigen level of less than or equal to 5 ng/ml, an interval of more than or equal to 8 weeks between the end of chemoradiation and surgical resection, tumor size greater than 5 cm, and pretreatment lymph node status. By utilizing these predictive variables, we are able to forecast patients’ outcomes and create flexible treatment plans. In certain, very specific situations, a wait-and-see policy might be appropriate.

How Can We Improve the Tumor Response to Preoperative Chemoradiotherapy for Locally Advanced Rectal Cancer?

How Can We Improve the Tumor Response to Preoperative Chemoradiotherapy for Locally Advanced Rectal Cancer?

Role of Radical Surgery Following Preoperative Chemoradiotherapy in Octogenarians With Rectal Cancer: A SEER Analysis.

There has been a growing trend toward a watch-and-wait strategy to avoid surgery. This study evaluated the prognostic outcomes of nonoperative management following chemoradiotherapy (CRT) in the very old patients with rectal cancer. Using the Surveillance, Epidemiology, and End Results database, we conducted a retrospective analysis of octogenarians (age ≥80 years) with stage II-III rectal cancer who received neoadjuvant CRT with or without radical surgery between 2005 and 2016. Long-term survival outcomes of the two treatment strategies were compared. Propensity-matched cohorts were identified and analyzed for CRT followed by radical surgery vs. CRT alone (n=782). The 7-year rates of overall survival (OS) and disease-specific survival (DSS) of the two groups were 43% vs. 11% and 57% vs. 26%, respectively (p<0.001 for both comparisons). Radical surgery after CRT was the strongest prognostic factor associated with improved OS and DSS [hazard ratio (HR)=2.66 and 95% confidence interval (CI)=2.15-3.28 for OS; HR=2.50 and 95%CI=1.94-3.24 for DSS]. Based on the time-course hazard rate function plots of disease-specific mortality, short-term and late risk increments were observed in patients who underwent nonoperative management. This study highlights the importance of an active treatment strategy with radical surgery even in the highest age population with rectal cancer. Omitting surgery may not generally be considered safe when it is considered solely on chronological age. Further research is needed to identify the appropriate indications for nonoperative management.

Nomogram for predicting pathologic complete response following preoperative chemoradiotherapy in patients with esophageal squamous cell carcinoma.

In patients with esophageal squamous cell carcinoma (ESCC), accurately predicting a pathologic complete response (pCR) to preoperative chemoradiotherapy (PCRT) has the potential to enable an active surveillance strategy without esophagectomy. We aimed to establish a reliable multiparameter nomogram model that combines tumor characteristics, imaging modalities, and hematologic markers to predict pCR in patients with ESCC who underwent PCRT and esophagectomy. We retrospectively reviewed the medical records of 457 patients with ESCC who received PCRT followed by esophagectomy between January 2005 and October 2020. The nomogram model was developed using logistic regression analysis with a training cohort and externally validated with a validation cohort. In the training and validation cohorts, 44.2% (126/285) and 48.3% (83/172) of patients, respectively, achieved pCR after PCRT. The 5-year rates of overall survival, progression-free survival, and freedom from local progression in the training cohort were 51.6%, 48.5%, and 77.6%, respectively. The parameters included in the nomogram were histologic grade, clinical N stage, maximum standardized uptake value on positron emission tomography, and post-PCRT biopsy. Hematologic markers were significantly associated with survival outcomes but not with pCR. The area under the receiver operating characteristic curve of the nomogram was 0.717, 0.704, and 0.707 for the training cohort, internal validation cohort, and external validation cohort, respectively. Our nomogram model based on four parameters obtained from standard clinical practice demonstrated good performance in both the training and validation cohorts and could be useful to aid clinical decision-making to determine whether surgery or active surveillance strategy should be pursued.

Prognostic Value of Tumor Volume, Tumor Volume Reduction Rate and Magnetic Resonance Tumor Regression Grade in Rectal Cancer.

Background and Objectives: Rectal cancer poses significant treatment challenges, especially in advanced stages. Radiologic assessment, particularly with MRI, is critical for surgeons and oncologists to understand tumor dynamics and tailor treatment strategies to improve patient outcomes. The purpose of this study was to correlate MRI-based tumor volumetric and tumor regression grade analysis in patients with advanced rectal cancer, assessing the impact of preoperative chemotherapy (CT) alone or chemoradiotherapy (CRT) on surgical technique choices. Materials and Methods: Between 2015 and 2022, a prospective study was enrolled, including a cohort of 89 patients diagnosed with rectal cancer at stage II or III. The participants were divided into two distinct therapy groups, ensuring an equal distribution with a ratio of 1:1. The initial group was treated with the contemporary preoperative chemotherapy protocol FOLFOX4. In contrast, the alternative group received conventional preoperative chemoradiotherapy. Before surgery, each patient underwent a rectal MRI scan at 1.5 T, including T2-weighted and diffusion-weighted imaging (DWI) sequences. Results: The CT group showed a 36.52% tumor volume reduction rate (TVRR), and the CRT group showed 54.87%, with varying magnetic resonance and pathological tumor regression grades (mrTRG and pTRG). Analysis revealed a significant interaction between mrTRG and tumor volumetrics (volume and VRR) in both groups, especially CRT, underscoring the complexity of tumor response. Both treatment groups had similar initial tumor volumes, with CRT displaying a higher TVRR, particularly in higher pathological TRG (3/4) cases. This interaction and the strong correlation between mrTRG and pTRG suggest mrTRG's role as a non-invasive predictor for treatment response, highlighting the need for personalized treatment plans. Conclusions: Rectal tumor volume, volume reduction rate, and mrTRG are not just abstract measures; they are concrete indicators that have a direct and practical impact on surgical decision-making, planning, and prognosis, ultimately influencing the quality of care and life expectancy of patients with rectal cancer.

Essential anatomy for lateral lymph node dissection.

In Western countries, the gold-standard therapeutic strategy for rectal cancer is preoperative chemoradiotherapy (CRT) following total mesorectal excision (TME), without lateral lymph node dissection (LLND). However, preoperative CRT has recently been reported to be insufficient to control lateral lymph node recurrence in cases of enlarged lateral lymph nodes before CRT, and LLND is considered necessary in such cases. We performed a literature review on aspects of pelvic anatomy associated with rectal surgery and LLND, and then combined this information with our experience and knowledge of pelvic anatomy. In this review, drawing upon research using a 3-dimensional anatomical model and actual operative views, we aimed to clarify the essential anatomy for LLND. The LLND procedure was developed in Asian countries and can now be safely performed in terms of functional preservation. Nonetheless, the longer operative time, hemorrhage, and higher complication rates with TME accompanied by LLND than with TME alone indicate that LLND is still a challenging procedure. Laparoscopic or robotic LLND has been shown to be useful and is widely performed; however, without a sufficient understanding of anatomical landmarks, misrecognition of vessels and nerves often occurs. To perform safe and accurate LLND, understanding the landmarks of LLND is essential.

Evolution of therapy for locally advanced rectal cancer

AbstractRectal cancer is a prevalent disease worldwide. The standard treatment of locally advanced rectal cancer (LARC) is preoperative chemoradiotherapy followed by surgery and adjuvant systemic chemotherapy. Studies have been done to determine the best sequence of treatments to improve survival, cure rate and long term toxicity profile. In this paper, we will review the literature regarding the evolution of LARC treatment.

Preoperative Intensified Chemoradiation with Intensity-Modulated Radiotherapy and Simultaneous Integrated Boost Combined with Capecitabine in Locally Advanced Rectal Cancer: Long-Term Outcomes of a Real-Life Multicenter Study

Background: Despite the feasibility and promising activity data on intensity-modulated RT and simultaneous integrated boost (IMRT-SIB) dose escalation in preoperative chemoradiation (CRT) for locally advanced rectal cancer (LARC), few data are currently available on long-term outcomes. Patients and Methods: A cohort of 288 LARC patients with cT3-T4, cN0-2, cM0 treated with IMRT-SIB and capecitabine from March 2013 to December 2019, followed by a total mesorectal excision (TME) or an organ-preserving strategy, was collected from a prospective database of 10 Italian institutions. A dose of 45 Gy in 25 fractions was prescribed to the tumor and elective nodes, while the SIB dose was prescribed according to the clinical practice of each institution on the gross tumor volume (GTV). Concurrent capecitabine was administered at a dose of 825 mg/m2 twice daily, 7 days a week. The primary objective of the study was to evaluate long-term outcomes in terms of local control (LC), progression-free survival (PFS) and overall survival (OS). The secondary objective was to confirm the previously reported feasibility, safety and efficacy (pCR, TRG1-2 and downstaging rates) of the treatment in a larger patient population. Results: All patients received a dose of 45 Gy to the tumor and elective nodes, while the SIB dose ranged from 52.5 Gy to 57.5 Gy (median 55 Gy). Acute gastrointestinal and hematologic toxicity rates of grade 3–4 were 5.7% and 1.8%, respectively. At preoperative restaging, 36 patients (12.5%) with complete or major clinical responses (cCR or mCR) were offered an organ-preserving approach with local excision (29 patients) or a watch and wait strategy (7 patients). The complete pathologic response rate (pCR) in radically operated patients was 25.8%. In addition, 4 TME patients had pT0N1 and 19 LE patients had pT0Nx, corresponding to an overall pT0 rate of 31.3%. Of the 36 patients selected for organ preservation, 7 (19.5%) required the completion of TME due to unfavorable pathologic features after LE or tumor regrowth during W-W resulting in long-term rectal preservation in 29 of 288 (10.1%) of the total patient population. Major postoperative complications occurred in 14.2% of all operated patients. At a median follow-up of 50 months, the 5-year PFS and OS rates were 72.3% (95% CI: 66.3–77.4) and 85.9% (95% CI: 80.2–90.1), respectively. The 5-year local recurrence (LR) rate was 9.2% (95% CI: 6.0–13.2), while the distant metastasis (DM) rate was 21.3% (95% CI: 16.5–26.5). The DM rate was 24.5% in the high-risk subset compared to 16.2% in the low-intermediate risk group (p = 0.062) with similar LR rates (10% and 8%, respectively). On multivariable analysis, cT4 and TRG3–5 were significantly associated with worse PFS, OS and metastasis-free survival. Conclusions: Preoperative IMRT-SIB with the moderate dose intensification of 52.5–57.5 Gy (median 55 Gy) and the full dose of concurrent capecitabine confirmed to be feasible and effective in our real-life clinical practice. Organ preservation was shown to be feasible in carefully selected, responsive patients. The favorable long-term survival rates highlight the efficacy of this intensified treatment program. The incorporation of IMRT-SIB with a more effective systemic therapy component in high-risk patients could represent a new area of investigational interest.

Abstract B065: Enhancing the therapeutic gain of proton radiotherapy in Locally Advanced Rectal Cancer (LARC) through manipulation of WSB1, ATM, and β-Catenin/c-Myc pathway Ubiquitination

Abstract Just 20% of patients with LARC attain a complete response to preoperative chemoradiotherapy which portends an excellent prognosis and opportunity to preserve the rectum through nonoperative surveillance. Moreover, normal tissue radiation toxicity can lead to significant morbidity, and becomes an even more important consideration in non-operative approaches where irradiated tissue is not resected. The geometry of conventional proton beams is already being used clinically to spare patient’s normal tissue, but the biology of entrance (ENT) vs. Bragg Peak (BP) protons has yet to be fully exploited to enhance tumor efficacy. Protons, unlike conventional x-ray radiation, spare normal tissue by lacking an exit dose - but they also exhibit a Bragg Peak (BP), which causes more complex DNA damage and is more biologically effective. ATM is critical in the repair of double strand DNA breaks (DSBs) and our lab has demonstrated that inhibitors of ATM (iATM) preferentially radiosensitize BP protons in CRC (Fig. 1A). Overactivation of the Wnt/β-catenin pathway via loss of function of APC is the most common genetic mutation in colorectal cancer (75-80%) and β-catenin over-expression negatively correlates with prognosis. WSB1 has been discovered by our lab to regulate ATM ubiquitination and degradation, it decreases metastates-free survival in CRC, and also forms a positive feedback loop with β-catenin and c-Myc that drives oncogenic progression. It is unknown if this upregulation of WSB1 promotes ATM degredation in LARC specifically, and a deubiquitinase (DUB) for ATM (which would counter WSB1) has yet to be identified. We preformed a comprehensive database search (UbiBrowser 2.0) for the most likely predicted DUBs for ATM (Fig. 1B), several of which have been identified as regulators of β-catenin/c-Myc, DSB repair pathways, and correlated with poor prognosis in CRC. We have also performed a screen of DUBs predicted to interact with ATM, and have preliminary evidence suggesting USP14 as the worlds first identified DUB of ATM (Fig 1C). USP14 expression is upregulated in CRC compared to surrounding normal tissue, promotes radioresistance, and promotes Wnt/β-catenin signalling. Higher USP14 expression in CRC is associated with liver and lymph node metastases and worse overall survival. USP14 regulates β-catenin by deubiquitinating K63-linked polyubiquitin chains of Dvl, and several small molecule inhibitors of USP14 have been identified. Our lab has preliminary data demonstrating USP14 is preferentially activated after BP proton irradiation (Fig. 1D), suggesting ATM may be necessary for repair of complex DSBs. While more work will be necessary to confirm these findings, many of the other predicted DUBs of ATM have overlapping functions regulating DSB repair and/or β-catenin/c-Myc signalling. We hypothesize that targeting ATM ubiquitination will open a therapeutic window in LARC by disrupting β-catenin/c-Myc signalling and selectively radiosensitizing BP protons. Citation Format: Sonja Dragojevic, Cameron M. Callaghan. Enhancing the therapeutic gain of proton radiotherapy in Locally Advanced Rectal Cancer (LARC) through manipulation of WSB1, ATM, and β-Catenin/c-Myc pathway Ubiquitination [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B065.

Comparison of the efficacy and safety of single-port versus multi-port robotic total mesorectal excision for rectal cancer: A propensity score-matched analysis

BackgroundIt is unknown whether the da Vinci single-port system performs similarly to the previous multi-port system during complicated procedures, such as rectal cancer surgery. Therefore, we compared the short-term clinical outcomes of single-port and multi-port robotic total mesorectal excision for the treatment of rectal cancer. MethodsThis retrospective study reviewed 128 patients who underwent robotic total mesorectal excision between July 2020 and June 2022, of whom 84 (42 each: single-port versus multi-port) were included in the propensity score-matched cohort. Perioperative and pathologic outcomes were compared between groups. ResultsMedian tumor height was similar between groups (single-port versus multi-port, 5.9 ± 2.1 vs 5.6 ± 1.8 cm, P = .719). Preoperative chemoradiotherapy was performed equally. The total operative time was less (160.0 ± 42.2 minutes vs 199.6 ± 78.6 minutes, P = .005), the total length of incision was shorter (4.0 ±0.3 vs 5.4 ± 0.7 cm, P = .003), postoperative hospital stay was shorter (6.2 ±1.7 vs 7.2 ±2.8 days, P = .050), and C-reactive protein levels on postoperative day 3 trended to be lower (7.3 ± 4.7 vs 8.9 ± 5.6 mg/L, P = .096) in the single-port group, compared with the multi-port group. Postoperative complications did not differ between groups (single-port versus multi-port, 11.9% vs 16.6%, P = .864). Anastomotic leakage occurred in 1 and 2 patients in the single-port and multi-port groups, respectively. The circumferential resection margins were positive in 1 patient in the multi-port group. ConclusionThe perioperative outcomes of single-port robotic total mesorectal excision were comparable to those of multi-port robotic TME. The single-port robot can be considered a surgical option for treating rectal cancer.

Combination of Multiple MRI Parameters Related to Signal Intensity and Volume for Predicting Response to Neoadjuvant Chemoradiotherapy by Patients with Locally Advanced Rectal Cancer.

MRI of patients with locally advanced rectal cancer (LARC) can predict the pathological complete response (pCR) to preoperative chemoradiation therapy (CRT). Our purpose was to use MRI results to evaluate the diagnostic value of combined changes in signal intensity (SI) and volume (V) of patients with LARC for predicting pCR to CRT. This retrospective study on 100 patients with LARC analyzed clinical and imaging data that were collected from March, 2018, to March, 2020. Before and after CRT, T2-weighted (T2W), apparent diffusion coefficient (ADC), and contrast-enhanced T1-weighted (ceT1W) data were analyzed. Percent changes of V (%#916;V) and relative SI ratio (%#916;SIR) on different sequences were calculated. After CRT, patients had pathological confirmation as pCR or non-pCR. Data were analyzed using nonparametric tests and receiver operating characteristic (ROC) analysis. There were 34 pCR and 66 non-pCR patients. Except for ADC-%#916;SIR, the combined parameters and single parameters had a greater decrease in the pCR group. The combination of ADC-%#916;V and T2W-%#916;SIR had the greatest diagnostic value (AUC=0.85,cutoff=0.23%) and the combination of ADC-%ΔV% and #916;SIR had the best accuracy (89%, cutoff=44.11%). Except for T2W-%#916;V and T2W-%#916;SIR, the different sequences had moderate differences in diagnostic performance. The diagnostic performance of combined parameters or single parameters on ADC and T2W was significantly better than those on ceT1W (p#916;60;0.01). All sequences except ADC-%#916;SIR provided reliable predictions of pCR, although ceT1W data had limited usefulness.</p>.

Resection of anorectal fistula cancer associated with Crohn’s disease after preoperative chemoradiotherapy: a case report

BackgroundAnorectal fistula cancer is often diagnosed in an advanced state, and radical resection is difficult when invasion of the pelvic wall is observed. In addition, there is currently no clear evidence for perioperative treatment of locally advanced cases. We report a case of anorectal fistula cancer with widespread infiltration diagnosed during the course of Crohn’s disease, which was curatively resected after preoperative chemoradiotherapy.Case presentationA 49-year-old man who had been diagnosed with Crohn’s disease (ileocolonic type) at the age of 25 and was found to have an anorectal fistula and perianal abscess at the age of 44 was referred to our department with complaints of abdominal pain and diarrhea. Computed tomography (CT) showed anal stenosis due to a pelvic mass. Pathological analysis of a biopsy taken under general anesthesia indicated mucinous carcinoma. Magnetic resonance imaging (MRI) revealed infiltration into the prostate, seminal vesicles, levator ani muscle, and left internal obturator muscle, and the patient was diagnosed with cT4N0M0 cStage IIIB anorectal fistula cancer (UICC TNM classification 8th edition). After performing a laparoscopic sigmoid colostomy, chemoradiation therapy (capecitabine + oxaliplatin, 50.4 Gy/28fr) was initiated. The patient then underwent laparoscopic total pelvic exenteration, colonic conduit diversion, extensive perineal resection, and reconstruction using bilateral gluteus maximus flaps and a right rectus abdominis musculocutaneous flap. The pathological diagnosis was mucinous adenocarcinoma, pT4, and all margins were negative. No recurrence was evident 6 months after the operation without adjuvant chemotherapy.ConclusionWe described a case of curative resection after preoperative chemoradiotherapy for anorectal fistula cancer with extensive invasion that was diagnosed during the course of Crohn’s disease.An accumulation of cases is needed to determine the usefulness of preoperative chemoradiation therapy for local control of anorectal fistula cancer associated with Crohn’s disease.