Advanced Rectal Adenocarcinoma Research Articles

Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial

The standard of care for the treatment of locally advanced rectal cancer results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free and metastatic-free survival with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival is reported here. The study design, participants, and primary endpoint disease-free survival (DFS) have been reported for this multicenter, randomized, open-label, phase 3 trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on MRI, and staged cT3/T4. Key secondary endpoints included overall survival (OS), metastasis-free survival (MFS), and local and metastatic recurrence rate. With a median follow-up of 82.2 months, the 7-year DFS were 67.6% (95% CI 60.7%-73.9%) and 62.5% (95% CI 55.6%-68.6%) (RMST difference 5.73 months; 95% CI 0.05-11.41; p=0.048) in the neoadjuvant chemotherapy and the standard of care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0%-84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8%-77.8%) in the standard of care group (RMST difference 6.1 months; 95% CI 0.93-11.37; p=0.021). The 7-year OS was 81.9% (95% CI 75.8%-86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7-81.2) in the standard of care group (RMST difference 4.37 months; 95% CI 0.35-8.38; p=0.033). The safety profile remained unchanged since the previous analysis. Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in locally advanced rectal cancer patients and should be considered as a one of the best options of care for these patients.

Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial.

The standard of care for the treatment of locally advanced rectal cancer results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free and metastatic-free survival with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival is reported here. The study design, participants, and primary endpoint disease-free survival (DFS) have been reported for this multicenter, randomized, open-label, phase 3 trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on MRI, and staged cT3/T4. Key secondary endpoints included overall survival (OS), metastasis-free survival (MFS), and local and metastatic recurrence rate. With a median follow-up of 82.2 months, the 7-year DFS were 67.6% (95% CI 60.7%-73.9%) and 62.5% (95% CI 55.6%-68.6%) (RMST difference 5.73 months; 95% CI 0.05-11.41; p=0.048) in the neoadjuvant chemotherapy and the standard of care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0%-84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8%-77.8%) in the standard of care group (RMST difference 6.1 months; 95% CI 0.93-11.37; p=0.021). The 7-year OS was 81.9% (95% CI 75.8%-86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7-81.2) in the standard of care group (RMST difference 4.37 months; 95% CI 0.35-8.38; p=0.033). The safety profile remained unchanged since the previous analysis. Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in locally advanced rectal cancer patients and should be considered as a one of the best options of care for these patients.

Efficacy of chemotherapy followed by chemoradiation versus initial chemoradiation as part of the total neoadjuvant therapy for patients with locally advanced rectal cancer: An NCDB analysis.

e15629 Background: Results from multiple trials lead to modern management for locally advanced rectal cancer, with total neoadjuvant therapy (TNT) followed by surgery. However, the best sequence of different treatment modalities is unclear. Methods: We used the National Cancer Database (NCDB) to identify patients with locally advanced rectal adenocarcinoma. We divided patients into different categories based on the timing of chemo and radiation therapy relative to surgery. We used chi-square and Wilcoxon rank test for unadjusted comparison. To compare treatment efficacy with initial chemotherapy to concurrent chemoradiation in downstaging (clinical to pathological stage), we used a linear mixed effect model (LME) with adjustments on age, sex, race, facility type, and year of diagnosis. Also, we evaluated the probability of having positive lymph nodes in the pathological specimen (N+) in the multivariable logistic regression model with adjustment on the clinical stage in addition to the previously mentioned variables. All analyses were done using R 4.6.2. Results: A total of 100509 patients were identified. Only 695 patients received six cycles of neoadjuvant chemotherapy before concurrent chemoradiation (TNT chemotherapy), and 8677 patients received upfront radiation therapy with neoadjuvant chemotherapy administered within 12 weeks of neoadjuvant radiation therapy (TNT radiation). Patients whose start date of chemotherapy or radiation after surgery were excluded. The median age of participants was 63 (IQR = 54-63), and 83% were white. Patients who had TNT chemotherapy were younger (56.4 VS 59.5, P-value < 0.01), had clinically and pathologically advanced stage (IIIB, IIIC) compared to TNT radiation (64%VS 37% and 33%VS 29%, P-value < 0.01). Patients who received TNT radiation had an upgrade in their pathological stage compared to their clinical stage by 0.67 points in the LME (P value < 0.01). In multivariable logistic regression. TNT chemotherapy had a 17% lower risk of (N+) with an OR of 0.83 (0.95 CI 0.59-1.16). However, it was not statistically significant. The two groups had no difference in OS, with a median OS of 137 months (0.95 CI 110 -NR) and 143 (0.95 CI 137-151), respectively. Conclusions: Upfront chemotherapy before starting chemoradiation could be associated with more significant downstaging. Future trials to validate our finding is warranted. [Table: see text] [Table: see text]

Evaluation of treatment response by multiparametric MR imaging in locally advanced rectal tumors following neoadjuvant chemotherapy.

To investigate the effectiveness of multiparametric MRI examination in determining tumor response after neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal tumors. 46 patients with locally advanced rectal adenocarcinoma were included and were divided into two groups as complete responders and nonresponders based on Mandard score. On MRI, relative T2w signal intensity and ADC values obtained before and after treatment and tumour volumes in dynamic contrast enhanced images (DCI) were used to determine complete response to treatment. There were no significant differences between mean ADC values obtained by single slice ADC and three circular ROI methods. There were significant differences between two groups in terms of Post-CRT ADC value, ΔADC and %ΔADC obtained by whole tumour volume ADC method (p < 0.05). There were significant differences between Pre-CRT and Post-CRT volume values. ΔV DCI and %ΔV DCI, ΔV ADC and T2w volume values were significantly lower in complete responders (p < 0.05). In multivariate analysis, sensitivity and specificity were calculated as 88.9% and 91.9% (AUC = 0.943) when Post-CRT mean ADC value and Post-CRT DCI volume values were used together, and sensitivity and specificity were calculated as 88.9% and 94.6% (AUC = 0.949) when ΔADC and Post-CRT DCI volume values were used together. Whole tumour volume mean ADC value is the most useful method to determine treatment response. Post-CRT DCI volume measurement stands out as the most useful method in assessing complete response alone. The highest diagnostic values are achieved when the post-CRT DCI volume is combined with the ADC change value of the whole tumor volume.

IFN-Type-I Response and Systemic Immunity in Rectal Adenocarcinoma Patients Treated with Conventional or Hypofractionated Neoadjuvant Radiotherapy.

The IFN-type-I pathway is involved in radiotherapy (RT)-mediated immune responses. Large RT fractions have been suggested to potently induce this pathway. Neoadjuvant hypofractionated short-course (scRT) and conventional long-course (lcRT) RT applied for the treatment of locally advanced rectal adenocarcinoma patients provides a unique model to address the immuno-stimulatory properties of RT on a systemic level. We prospectively analyzed the IFNβ plasma levels and lymphocyte counts (LCs) of rectal adenocarcinoma patients before and after treatment with scRT (n = 22) and lcRT (n = 40). Flow cytometry was conducted to assess the effects on lymphocytic subpopulations in a subset of 20 patients. A statistically significant increase in the post-RT IFNβ plasma levels was noted in patients undergoing scRT (p = 0.004). Improved pathological tumor regression was associated with elevated post-RT IFNβ levels (p = 0.003). Although all patients experienced substantial lymphopenia after treatment, the post-RT LC of patients treated with scRT were significantly higher compared to lcRT (p = 0.001). Patients undergoing scRT displayed significantly lower percentages of regulatory CD4+/CD25+ T-cells after therapy (p = 0.02). scRT enables effective stimulation of the IFN-type-I pathway on a systemic level and confers decreased lymphocytic cytotoxicity and limited regulatory T-cell activation compared to lcRT, supporting its increasing role in immuno-RT trials.

Machine Learning-Based Algorithms for Enhanced Prediction of Local Recurrence and Metastasis in Low Rectal Adenocarcinoma Using Imaging, Surgical, and Pathological Data.

(1) Background: Numerous variables could influence the risk of rectal cancer recurrence or metastasis, and machine learning (ML)-based algorithms can help us refine the risk stratification process of these patients and choose the best therapeutic approach. The aim of this study was to assess the predictive performance of 4 ML-based models for the prediction of local recurrence or distant metastasis in patients with locally advanced low rectal adenocarcinomas who underwent neoadjuvant chemoradiotherapy and surgical treatment; (2) Methods: Patients who were admitted at the first Oncologic Surgical Clinic from the Regional Institute of Oncology, Iasi, Romania were retrospectively included in this study between November 2019 and July 2023. Decision tree (DT), naïve Bayes (NB), support vector machine (SVM), and random forest (RF) were used to analyze imagistic, surgical, and pathological data retrieved from the medical files, and their predictive performance was assessed; (3) Results: The best predictive performance was achieved by RF when used to predict disease recurrence (accuracy: 90.85%) or distant metastasis (accuracy: 89.63%). RF was closely followed by SVM (accuracy for recurrence 87.8%; accuracy for metastasis: 87.2%) in terms of predictive performance. NB and DT achieved moderate predictive power for the evaluated outcomes; (4) Conclusions: Complex algorithms such as RF and SVM could be useful for improving the prediction of adverse oncological outcomes in patients with low rectal adenocarcinoma.

Prognostic Value of Immune Cells Subsets Within the Tumor Microenvironment in Patients With Rectal Adenocarcinoma.

One-third of newly diagnosed colorectal cancer cases are rectal cancers. Multimodal treatment regimens including surgery, radiotherapy, and chemotherapy improve local control and survival outcome and decrease tumor relapse for patients with rectal adenocarcinoma (READ). However, stratification of patients to predict their responses is urgently needed to improve therapeutic responses. Immunostainings of CD3+, CD8+, and CD45RO+ immune cell subsets within the tumor microenvironment were evaluated using immunohistochemistry in two hundred seventy-nine READ patients. In this study, we found that examination of the adaptive immune response by quantifying CD3+, CD8+, and CD45RO+ immune cell subsets, provides improved and independent prognostic value for patients with READ. Regardless of conventional clinical and pathologic parameters, the densities of T cell subsets were strongly related to a better prognosis in patients with READ. High density of intratumoral immune cells is associated with absence of nodal metastasis, lymphovascular invasion, and perineural invasion. Moreover, high tumor-infiltrating lymphocyte (TIL) subsets were associated with favorable survival outcome in patients with READ, especially high-risk patients with advanced READ. Immune cell subsets including CD3, CD8, and CD45RO within the tumor microenvironment were independent prognostic factors for patients with READ.

Comprehensive genomic profiling of advanced anal adenocarcinoma.

4 Background: Anal adenocarcinoma (anal AD) is a rare and aggressive gastrointestinal malignancy. Because of its rarity, no standard therapy is established and treatment strategy for advanced rectal adenocarcinoma (rectal AD) is extrapolated. Little is known for genetic alterations (GAs) and their therapeutic implications in advanced anal AD. We aim to investigate to clarify genomic profiles of advanced anal AD in comparison of advanced rectal AD. Methods: We retrospectively extracted data on patients with advanced anal AD and advanced rectal AD who underwent comprehensive genomic profiling (CGP) tests and were registered for the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. CGP tests were performed by NCC Oncopanel or FoundationOne CDx. We examined somatic GAs, microsatellite instability (MSI) status, and tumor mutation burden (TMB). TMB-high was defined as ≥10 mutations/Mb. Actionable GAs were counted if they were classified as “pathogenic/oncogenic” or “likely pathogenic/likely oncogenic” variants. Druggable GAs are actionable GAs with approved drugs for anal AD or other types of cancer or clinical trials showing efficacy for either anal AD or different types of cancer. Results: From June 2019 to April 2023, 45 patients with anal AD and 1915 patients with rectal AD were enrolled into the C-CAT database. In the anal AD group, most common actionable GAs were TP53 (89%), KRAS (51%), ERBB3 (22%), MYC (20%), SMAD4 (20%), and ERBB2 (11%). Compared with the rectal AD group, the anal AD group had a significantly higher frequency of actionable GAs in ERBB3 (22% vs. 2%, p &lt; 0.01), MYC (20% vs. 8%, p &lt; 0.01), and BRCA2 (7% vs. 1%, p &lt; 0.01), and a significantly lower frequency of actionable GAs in APC (7% vs. 85%, p &lt; 0.01). The proportion of MSI-high and TMB-high in the anal AD group and the rectal AD group were 0% vs. 0.2% (p = 0.79), and 7% vs. 5% (p = 0.54). Common druggable GAs in anal ADs included KRAS G12D mutation (22%), ERBB2 amplification (7%), BRCA2 mutation (7%), BRAF V600E mutation (2%). Compared with the rectal AD group, the anal AD group had a significantly higher frequency of druggable GAs in BRCA2 mutation (7% vs. 1%, p &lt; 0.01). Conclusions: The present study showed that anal AD had a different profile of GAs compared with advanced rectal AD. CGP tests are useful tool for identifying druggable GAs in advanced anal AD for expanding therapeutic opportunities.

The impact of multidisciplinary care for locally advanced rectal cancer referrals: A systems perspective.

85 Background: Locally advanced rectal cancer patients require multidisciplinary care for treatment planning. We sought to determine whether the order of surgical and radiation oncology consultation in relation to medical oncology consultation affects the time from cancer diagnosis to treatment initiation and the requirement for additional pre-treatment visits with medical oncology. Methods: We conducted a retrospective chart review of adult patients referred to The Ottawa Hospital with locally advanced rectal adenocarcinoma, seen in consultation by a surgical, radiation, and medical oncologist between January 2018 and December 2022. Results: Of 195 patients, the median time from diagnosis to treatment was 55 days (IQR: 45-68). Both surgical and radiation oncology consultation preceded medical oncology consultation in a minority of patients (72; 37%), and 48 (25%) patients required multidisciplinary cancer conference (MCC) discussion. However, the time from cancer diagnosis to treatment initiation was not significantly different between patients who were and were not seen by the surgeon and radiation oncologist prior to the medical oncologist (56 vs. 55 days respectively), nor if MCC discussions were or were not required (55 vs. 55 days). However, almost half of all patients (93; 48%) required an additional pre-treatment visit with their medical oncologist, and patients who saw both surgical and radiation oncology prior were significantly less likely to require additional pre-treatment visits with medical oncology (25% vs. 61%; p&lt;0.0001). Conclusions: The time from cancer diagnosis to treatment initiation was not significantly impacted by the order of specialist consultations with the multidisciplinary team, nor if patients required MCC discussion or additional pre-treatment visits with medical oncology. However additional pre-treatment visits with medical oncology were significantly more likely to occur when patients were seen by medical oncology prior to surgical and/or radiation oncology, representing a logistical and financial inefficiency in the system, and a potential area for process improvement. [Table: see text]

Overall Survival After Treatment Failure Among Patients With Rectal Cancer

Oncologic outcomes among patients with rectal cancer after developing local recurrence and/or distant metastases remain poorly studied. To analyze the trend of overall survival after treatment failure for patients with rectal cancer within three consecutive phase 2 or 3 trials of the German Rectal Cancer Study Group. This cohort study is a post hoc analysis of 3 randomized phase 2 or 3 trials (CAO/ARO/AIO-94, -04, and -12 trials, conducted in Germany) that included 1948 patients with locally advanced rectal adenocarcinoma. The CAO/ARO/AIO-94 trial recruited patients between February 1995 and September 2002, the CAO/ARO/AIO-04 trial recruited patients between July 2006 and February 2010, and the CAO/ARO/AIO-12 trial recruited patients between June 2015 and January 2018. Statistical analysis was conducted between September 2022 and March 2023. A total of 119 of 391 patients in the CAO/ARO/AIO-94 trial group A, 295 of 1236 patients in the CAO/ARO/AIO-04 trial, and 69 of 306 in the CAO/ARO/AIO-12 trial experienced treatment failure (R2 resection or local recurrence or distant metastases) and were included in further analyses. Characteristics of treatment failure and overall survival were assessed in all 3 trial cohorts. Of the 1948 patients treated in the 3 trials, 15 were excluded because of missing data. Of the remaining 1933 patients (median age, 62.5 years [range, 19-84 years]; 1363 men [71%] and 570 women [29%]) with locally advanced rectal adenocarcinoma (cT3 or 4 or cN+) treated within 3 consecutive clinical trials, 483 experienced treatment failure and were analyzed. After a median follow-up of 36 months (IQR, 24-51 months) for all patients, overall survival after treatment failure was significantly improved in the CAO/ARO/AIO-04 trial (at 3 years, 44% [IQR, 37%-51%]; hazard ratio [HR], 0.61 [95% CI, 0.47-0.79]) and further improved in the CAO/ARO/AIO-12 trial (at 3 years, 73% [IQR, 60%-87%]; HR, 0.32 [95% CI, 0.18-0.54]) compared with the CAO/ARO/AIO-94 trial (at 3 years, 30% [IQR, 22%-39%]) (both P < .001). Distant metastasis was the main reason for treatment failure throughout a 5-year follow-up (range, 67%-87%), and the relative risk for treatment failure was highest in the first 18 months in all 3 trials. ypTNM stage was significantly associated with the risk and time interval to treatment failure. Improvement in overall survival after treatment failure was independent of sex. This cohort study suggests that advancements in salvage strategies during the past decades have likely improved overall survival among patients with rectal cancer who experienced treatment failure.

Survival outcomes in locally advanced dMMR rectal cancer: surgery plus adjunctive treatment vs. surgery alone

BackgroundRecent studies have shown that deficient mismatch repair (dMMR) rectal cancer may be related to treatment resistance, resulting in a worse prognosis than proficient MMR (pMMR) rectal cancer. The purpose of this study was to explore whether surgery plus other treatments (radiotherapy and chemotherapy) can bring more benefits to these patients than surgery alone.MethodsA retrospective study of 168 patients with rectal adenocarcinoma who underwent total mesorectal excision was conducted using immunohistochemical methods to determine MMR status and a propensity score matching model to minimize potential confounding factors between subgroups of patients with different treatment regimens. Kaplan–Meier analysis, log-rank tests, and Cox regression models were used to assess overall survival (OS) and disease-free survival (DFS) in patient subgroups.ResultsOnly 6.9% (n = 168) of patients in the total cohort had dMMR rectal adenocarcinoma, and the most common cause of dMMR was a PMS2 deletion (103, 61.3%). The median DFS of the surgery alone group was 45.7 months (IQR, 40.9 to 77.8), and the median DFS of the surgery plus other treatment group was 43.9 months (IQR, 14.2 to 80.1). The surgery alone group was superior to the surgery plus other treatment group (HR, 0.16; 95% CI, 0.07 to 0.38; p = 0.005). There was no significant difference in OS (45.8 (IQR, 41.0 to 79.8) vs. 45.9 (IQR, 38.5 to 80.3)) between the two groups (HR, 0.57; 95% CI, 0.23 to 1.40; p = 0.263).ConclusionsFor patients with locally advanced dMMR rectal adenocarcinoma, compared with surgery alone, surgery plus other treatment options (radiotherapy and chemotherapy) do not grant long-term survival benefits but rather shorten DFS.

Outcomes of Watch and Wait Following Total Neoadjuvant Therapy for Rectal Cancer

To evaluate the outcomes of patients with locally advanced rectal cancer who achieved a clinical complete response (cCR) after total neoadjuvant therapy and enrolled in a prospective watch and wait (WW) database. Consecutive patients with locally advanced rectal cancer who achieved cCR following total neoadjuvant therapy (long-course chemoradiotherapy plus systemic chemotherapy) and were enrolled in our institutional WW surveillance protocol from 2014 through 2022 with the intention of organ preservation. Patients with lack of follow up according to our institutional protocol were excluded. Primary outcomes included local tumor regrowth and distant metastatic disease recurrence. Thirty-three consecutive patients (48% male; median age 61 [33-77] years) with the diagnosis of locally advanced rectal adenocarcinoma were managed by a multidisciplinary team. All patients had Eastern Cooperative Oncology Group Performance Status score of 0 or 1 at time of rectal cancer diagnosis. Location of tumor included upper rectum (18%), middle rectum (40%), and lower rectum (42%). On initial staging magnetic resonance imaging, 4 (12%) patients had evidence of extramural venous invasion, 6 (18%) had a threatened mesorectal margin, and 4 (12%) had anal sphincter or levator ani tumor involvement. A majority (61%) received chemotherapy followed by long-course chemoradiotherapy. Only one patient had an unplanned break during radiotherapy. Local tumor regrowth was diagnosed in 4 (12%) patients and all underwent successful salvage surgery without additional local failures at a median follow-up of 19 [12-48] months. Two of these four patients remain disease-free at a median follow-up time of 12.5 months. Mean time to local tumor regrowth as first site of cancer recurrence was 33.5 [18-46] months. Distant metastatic disease as the first site of recurrence occurred two patients (6%). Mean time to distant metastatic disease as first site of recurrence was 27 months. Only one mortality occurred in the entire group at a median follow-up of 49 [8-102] months. Organ preservation after total neoadjuvant therapy for locally advanced rectal cancer yields excellent outcomes with low local and distant relapse rates. Structured surveillance protocols and multidisciplinary care are essential for success.

The Association of Time Interval between Surgery and Neoadjuvant Chemoradiation Therapy with pCR and Overall Survival for Locally Advanced Rectal Adenocarcinoma

To determine the best time interval between neoadjuvant radiation therapy (RT) and surgery that is associated with the highest rate of complete pathological response (pCR) and evaluate its impact on overall survival (OS) for locally advanced rectal adenocarcinoma. We hypothesize that the longer interval the higher pCR and a higher pCR is associated with a higher OS. The National Cancer Database (NCDB) was used to extract data on patients diagnosed with stage II and III adenocarcinoma of the anus, rectum, or rectosigmoid between 2004-2019 and who had ≤ 24 weeks' time interval between neoadjuvant RT and surgery. Multivariable logistic regression analysis was used to determine factors associated with achieving pCR and odds ratios (OR) were reported as a measure of association between the covariates of interest and the outcome of achieving pCR. Multivariable Cox regression analysis was conducted to estimate hazard ratios (HR) and their associated 95% confidence intervals. The multivariable analyses were adjusted for age at diagnosis, sex, race, income, education, facility type, insurance status, comorbidity score, place of living, chemotherapy's sequence with surgery and RT, and year of diagnosis. Among 28,656 patients, 4,455 (15.6%) achieved pCR. In the multivariable logistic regression analysis, patients who received surgery between 5-8 weeks, 9-12 weeks, 13-16 weeks, 17-20 weeks, or 21-24 weeks after the completion of RT were more likely to achieve pCR compared to < = 4 weeks (ORs: 1.63, 2.16, 1.82, 1.73, 1.75, respectively, p<0.001 for all) with OR being the highest for the 9-12 weeks interval. In the multivariable Cox regression analysis, patients who achieved pCR had comparable OS regardless of when the surgery took place between < = 4 to 24 weeks after completing RT compared to < = 4 weeks after RT. Among patients who did not achieve pCR, OS was only similar if surgery was received between 5-8 weeks or 9-12 weeks after RT compared to < = 4 weeks after RT (HR: 0.90, p = 0.19 and HR: 1.02, p = 0.78 respectively). However, surgery between 13-16 weeks after RT, 71-20 weeks or 21-24 weeks after RT was associated with worse OS compared to < = 4 weeks after RT (HRs: 1.30, 1.67, 1.79, respectively, p<0.01). In the current study, we found that among patients who achieve pCR, OS does not depend on the time interval between the completion of RT and receipt of surgery, while among patients who do not achieve pCR, delaying surgery >12 weeks is associated with reduced OS. An interval of 9-12 weeks was the best optimal time as it was associated with the highest OR of achieving pCR and better OS compared to other interval times.

A Single-Institution Experience of Acute Neuropathic Lumbosacral Pain in Patients Treated with Short Course Hypofractionated Radiotherapy in Locally Advanced Rectal Cancer

There has been increased interest in the use of short course hypofractionated radiotherapy as part of a total neoadjuvant treatment (TNT) approach in the management of rectal cancer since publication of the RAPIDO trial. However, the literature on short course radiation for rectal cancer has not reported significant acute toxicities in the weeks immediately following the completion of treatment. Anecdotally, a subset of patients has experienced acute neuropathic pain characterized in a lumbosacral distribution. This study investigates acute lumbosacral toxicity for patients receiving hypofractionated short course radiation as part of their definitive treatment for rectal cancer. We retrospectively analyzed 75 patients with locally advanced rectal adenocarcinoma treated with hypofractionated short course radiation (25 Gy in 5 fractions) at our institution between 2016 and 2022. Acute toxicity caused by radiation was defined as that occurring from the start of radiation treatment to either 30 days post radiation completion, the start of chemotherapy, or date of surgery, whichever occurred first. Among 75 patients treated with hypofractionated short course preoperative radiation with definitive intent, we identified 10 patients (13.3%) who experienced significant lumbosacral neuropathic pain and initiated a report to their medical providers during the acute toxicity time frame. Commonly, this was described as an achy pain in the bilateral buttocks radiating down to the knees or posterior claves. Patients rated this pain between moderate to extreme and management included steroids after failure of improvement with conservative measures, gabapentin, and conservative treatment with NSAIDs and Tylenol. Average time to onset of acute lumbosacral neuropathic pain was 3.7 days (SD 2.05) from start of RT. We have identified a previously underappreciated acute toxicity of neuropathic lumbosacral pain in short course hypofractionated radiation therapy, which may be due to a lumbosacral plexus toxicity. Further analysis will seek to identify predictive factors such as comorbidities and dose to the lumbosacral plexus, and to determine whether there is a correlation between these observed acute toxicities and long-term outcomes.

Targeting Tri-Methyl-Histone H3 (Lys27) in Rectal Cancer: A Novel Strategy to Enhance Radiosensitivity and Predict Response to Neoadjuvant Therapy

Tri-Methyl-Histone H3 (Lys27) is a modification of histone H3 involved in gene regulation and chromatin organization. It plays a crucial role in cell response to ionizing radiation and affects DNA damage repair, with altered levels being linked to decreased radiation sensitivity. Our hypothesis is that high levels of Tri-Methyl-Histone H3 (Lys27) in rectal tumors can predict response to neoadjuvant chemoradiation, and targeting SETD2, the histone methyltransferase responsible for adding the tri-methyl group to Lys27 of histone H3, may enhance radiosensitivity in rectal cancer cells. Biopsy samples from 25 patients with locally advanced rectal adenocarcinoma (Stage II-III) were obtained for analysis. Immunohistochemistry (IHC) was used to evaluate Tri-Methyl-Histone H3 (Lys27) expression levels in the tumor biopsies. The staining intensity was scored semi-quantitatively. Samples with 100% positive staining were grouped as "Tri-Methyl-High," and all others were grouped as "Tri-Methyl-Low." Fisher's exact test was used to analyze the data to determine the correlation between Tri-Methyl-Histone H3 (Lys27) levels and response to neoadjuvant chemoradiation. The primary endpoint was either a sustained clinical complete response (cCR) at one year or a pathological complete response (pCR). To further understand the role of Tri-Methyl-Histone H3 (Lys27) in response to ionizing radiation (IR), clonogenic assays, γH2aX foci staining, and western blot analysis of DNA damage response proteins and histones were performed on two established human rectal cancer cell lines following either RNA inhibition (RNAi) or drug targeting of SETD2. Twenty-five patients with rectal cancer had pre-treatment biopsies analyzed for Tri-Methyl-Histone H3 (Lys27) levels, 11 were classified as Tri-Methyl-High and 14 as Tri-Methyl-Low. The groups were well balanced in terms of age, sex, clinical T/N stage, and neoadjuvant treatment approach. The overall combined complete response (cCR/pCR) rate was 36%, while the rate for Tri-Methyl-High patients was 9% (1/11) compared to 57% (8/14) in Tri-Methyl-Low patients (p = 0.03). After treating two colorectal cancer cell lines (SW837 and HCT116) with IR (5 Gy) in vitro, Tri-Methyl-Histone H3 (Lys27) levels increased 3-fold. SETD2 RNAi reduced Tri-Methyl-Histone H3 (Lys27) and increased cell death when combined with IR. In vitro treatment with a novel SETD2 inhibitor, EZM0414, led to a 2-fold increase in DNA damage following IR (5 Gy) as measured by γH2aX foci staining. EZM0414 treatment showed a 37% improvement in the dose enhancement ratio. Our study uncovers a new biomarker, Tri-Methyl-Histone H3 (Lys27), that could be used to predict response to neoadjuvant chemoradiation in rectal cancer patients. Our preclinical data indicates that targeting SETD2 to reduce Tri-Methyl-Histone H3 (Lys27) mediated DNA repair could improve the efficacy of radiation therapy for rectal cancer patients.

Mismatch Repair system protein deficiency as a resistance factor for locally advanced rectal adenocarcinoma patients receiving neoadjuvant chemo-radiotherapy.

Available data on Mismatch Repair system (MMR) deficiency are conflicting and derived from small studies. Our study aimed to evaluate the therapeutic implications of MMR status in patients with locally advanced rectal cancer (LARC). We retrospectively collected data from 318 patients affected by LARC treated in Italy at the Medical Oncology Units of the University Hospital of Cagliari, Istituto Nazionale dei Tumori Milan, and AOU Ospedali Riuniti Ancona. All patients underwent neoadjuvant chemoradiotherapy. The primary objective was major TRG while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). One hundred sixty patients (148 pMMR and 12 dMMR) were included in the exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in the validation cohort. A major TRG has been shown in 42.6% and 43.1% patients with pMMR in exploratory and validation cohort, respectively; while no major TRG have been shown in dMMR patients in both cohorts. Exploratory and validation cohorts showed a statistically significant higher mDFS in pMMR patients compared to dMMR: NR vs. 14 months and NR vs. 17 months, respectively. Our results indicated an association between dMMR and poor response to preoperative chemoradiotherapy and they represent a hypothesis-generating data for new neoadjuvant strategies.

Evaluation of the Response Rate to Neoadjuvant Chemoradiotherapy in Patients with Rectal Adenocarcinoma: A Retrospective Long-term Study in Two Terciary Reference Centers

Abstract Objectives To evaluate the complete response (CR) rate and surgeries performed in patients with rectal adenocarcinoma who underwent neoadjuvant therapy (NT) at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo and at Hospital São Paulo, in Ribeirão Preto, from January 2007 to December 2017. Methods We evaluated 166 medical records of patients with locally advanced rectal adenocarcinoma (T3, T4 or N + ) who underwent NT. The regimen consisted of performing conventional (2D) or conformational (three-dimensional-3D/ radiotherapy with modulated intensity – IMRT) at a dose of 45-50.4Gy associated with capecitabine 1650mg/m2 or 5-fluorouracil (5FU) and leucovorin (LV). The following variables were analyzed: gender, age, pretreatment stage, radiotherapy, CR index, local and distant recurrence rates. Surgical treatment and complications were also evaluated. Results The CR index was 28.3%. Patients treated with 3D/IMRT radiotherapy had a higher rate of CR (36.3% x 4.8%; p &lt; 0.001), higher rates of clinical follow-up (21% x 0%; p &lt; 0.001), lower surgery rates (79% x 100%; p &lt; 0.001), higher rates of transanal resection (37.1% x 9.5%; p = 0.001), lower rates of abdominal rectosigmoidectomy (25.8% x 50%; p = 0.007) and lower rates of abdominoperineal resection of the rectum (16.1% x 40.5%; p = 0.002), when compared to patients treated with 2D radiotherapy. Conclusion Modern radiotherapy techniques such as 3D conformal and IMRT, by offering greater adequacy and precision of treatment, could result in better local control and less toxicity in organs at risk, enabling organ preservation strategies and less invasive approaches in selected cases.

Improved Pathologic response to chemoradiation in MGMT methylated locally advanced rectal cancer.

With the growing interest in total neoadjuvant treatment for locally advanced rectal adenocarcinoma (LARC) there is an urgent unmet need to identify predictive markers of response to long-course neoadjuvant concurrent chemoradiotherapy (LCRT). O6-Methylguanine (O6-MG)-DNA-methyltransferase (MGMT) gene methylation has been associated in some malignancies with response to concurrent chemoradiotherapy. We attempted to find if pathologic response to LCRT was associated with MGMT promoter hypermethylation (MGMTh). Patients were identified with LARC, available pre-treatment biopsy specimens, and at least 1year of follow-up who received LCRT followed by surgical resection within 6months. Biopsies were tested for MGMTh using a Qiagen pyrosequencing kit (Catalog number 970061). The primary outcome of LCRT responsiveness was based on tumor regression grade (TRG), with grades of 0-1 considered to have excellent response and grades of 2-3 considered to be non-responders. Secondary outcomes included overall survival (OS) and recurrence free survival (RFS). Of 96 patients who met inclusion criteria, 76 had samples which produced reliable assay results. MGMTh corresponded with higher grade and age of the biopsy specimen. The percentage of responders to LCRT was higher amongst the MGMTh patients than the MGMTn patients (60.0% vs 27.5%, p value=0.0061). MGMTh was not significantly associated with improved OS (2-year OS of 96.0% vs 98.0%, p=0.8102) but there was a trend for improved RFS (2-year RFS of 87.6% vs 74.2%, p=0.0903). Significantly greater tumor regression following LCRT was seen in MGMTh LARC. Methylation status may help identify good candidates for close observation without surgery following LCRT.

Ventral incisional hernia and double parastomal hernia repair with retromuscular biosynthetic mesh using the SMART technique (Stapled Mesh Stoma Reinforcement Technique) after cancer-related pelvic exenteration

We report on the case of a 64-year-old man who underwent the SMART surgical technique using retromuscular biosynthetic mesh for parastomal hernia. This patient had a terminal colostomy and Bricker ileal conduit following pelvic exenteration for locally advanced low rectal adenocarcinoma. Since then, he had undergone a first median incisional hernia repair using intraperitoneal biosynthetic mesh, followed a year later by the onset of a symptomatic parastomal hernia at the stoma sites and next to the median laparotomy scar. It was thus decided to perform a double parastomal hernia repair using the SMART technique with retromuscular biosynthetic mesh.

Total Neoadjuvant Therapy (TNT) with Full Dose Concurrent Chemotherapy in Locally Advanced Rectal Adenocarcinoma Including Signet Ring and Mucinous Cancers.

Total neoadjuvant therapy (TNT) with pre-operative chemotherapy and chemoradiotherapy results in improved survival and is becoming the new standard of care in locally advanced rectal cancer (LARC). We describe our experience with TNT consisting of induction chemotherapy followed by chemoradiotherapy using full dose 5FU without oxaliplatin. Adults with biopsy-proven, newly diagnosed LARC with high-risk characteristics on pelvic MRI (T4a or T4b, extramural vascular invasion, N2, mesorectal fascia involvement, enlargement/tumor deposits on lateral lymph nodes) were included. The TNT protocol comprised of six biweekly courses of modified FOLFOX6 followed by pelvic RT with four concurrent cycles of biweekly 5-FU 2600mg/m2 + LV 200mg/m2 without oxaliplatin to complete 20 uninterrupted weeks of full dose 5FU. Surgery was planned 11-13weeks after completing chemoradiotherapy. Eighty-four LARC patients, including 26% with signet-ring cell carcinoma, with high-risk MRI characteristics were treated with the TNT protocol with a 96% completion rate. Significant (> grade 3) toxicities included neutropenia (23.8%), diarrhea (14.2%) anemia (10.7%), and two deaths. The median DFS at 2years was 22.5months with better survival noted for those who underwent surgery or had cCR (with NOM) compared to those who did not undergo surgery (due to progression, inadequate regression, or patient preference despite residual disease) -mDFS 27.7months versus 11.4months, p = < 0.0001 and mOS 29.2months versus 15months p = < 0.0001. The hybrid TNT regimen was administered without significant dose delays or interruptions. Toxicity was manageable but with two treatment-related deaths. Ability to undergo surgery after TNT predicted for improved DFS and OS.