Although limited trials have demonstrated the feasibility of rectal-preserving approaches in clinical T1-3N0 adenocarcinoma, local excision after neoadjuvant therapy has been associated with high rates of morbidity. We hypothesized that this strategy would be comparable to the standard, total mesorectal excision. The aim of this study was to describe trends of early-stage rectal cancer management.

cT1-3N0 rectal cancers in the National Cancer Database (2006-2018) were grouped into 5 treatments: total mesorectal excision, total neoadjuvant therapy + local excision, neoadjuvant chemoradiotherapy + local excision, total neoadjuvant therapy + total mesorectal excision, and neoadjuvant chemoradiotherapy + total mesorectal excision. Morbidity was defined as a combination of readmissions and 30- and 90-day mortality.

We identified 22,793 patients. Neoadjuvant chemoradiotherapy + local excision had the highest proportion of patients ≥70 years (41%) and those with comorbidities (Charlson-Deyo score ≥2, 9%). Median stay was 1 day for local excision and 5 days for total mesorectal excision. Overall composite morbidity was 9%, which, after adjustment, was not statistically different between local excision and total mesorectal excision (odds ratio = 0.45, 95% confidence interval: 0.17-1.19). Among local excision patients, 56% had pathologic complete response, 33% were pStage I, and 12% pStage II-III. In multivariable analysis, all strategies had similar overall survival compared with total mesorectal excision, except for neoadjuvant chemoradiotherapy + local excision, which was associated with worse prognosis (hazard ratio = 1.57, 95% confidence interval: 1.21-2.03).

Although infrequent, neoadjuvant chemoradiotherapy/total neoadjuvant therapy + local excision were associated with high rates of tumor downstaging, suggesting that rectal-preserving strategies are feasible. However, 1 in 8 patients had more advanced disease, which may have compromised future total mesorectal excision planes. Together with the similar morbidity and relatively worse prognosis of neoadjuvant chemoradiotherapy + local excision, these observations should prompt careful patient selection for this approach, while cautioning against its widespread use.

To determine how outcomes of lateral lymph node dissection for rectal cancer have changed over time.

This retrospective study included patients with rectal cancer without distant metastasis who underwent total mesorectal excision and lateral lymph node dissection at our institution between 1975 and 2020. We examined the association of surgical time period with relapse-free and overall survival. Multivariable analyses were performed using Cox proportional hazards regression models.

Among a total of 992 patients, 386 underwent surgery in 1975-2000, 296 in 2001-2010, and 310 in 2011-2020. Overall, 924 patients (93%) underwent surgery without preoperative therapy. The respective 5-year relapse-free survival rates were 64.2%, 64.2%, and 68.2% (P = .314), and the 5-year overall survival rates were 72.3%, 84.0%, and 89.3% (P < .001). Overall survival could be stratified by surgical time period, especially stage III (P < .001). In patients with lateral lymph node metastasis, the 5-year overall survival rate was 43.5% in 1975-2000, 61.1% in 2001-2010, and 71.1% in 2011-2020 (P = .003). Multivariable analysis revealed significant differences in overall survival between 2011-2020 and 1975-2000 (hazard ratio, 2.81; P < .001) and between 2011-2020 and 2001-2010 (hazard ratio, 1.59; P = .040), but not in relapse-free survival.

The impact of lateral lymph node dissection on rectal cancer treatment may not have changed in 45 years, given the lack of difference in relapse-free survival. Treatment outcomes after recurrence may have improved. The prognosis remains poor for lateral lymph node metastasis, highlighting the need for further development of multimodality treatments.

Non-adherence in advanced rectal cancer therapy is common and severely impairs clinical outcomes. Although behavioral research suggests emotional factors influence adherence, limited evidence links pretreatment emotional distress (PED) to treatment adherence in rectal cancer patients.

This post hoc analysis of a phase 3 randomized clinical trial was conducted from June 9, 2010, to February 15, 2015, involving 219 patients (assigned to receive neoadjuvant therapy with fluorouracil plus radiotherapy [group A, 67 patients], modified fluorouracil, leucovorin, and oxaliplatin [mFOLFOX6] plus radiotherapy [group B, 66 patients], or mFOLFOX6 alone [group C, 86 patients] followed by TME resection and postoperative adjuvant chemotherapy) with locally advanced rectal cancer from the main center. The PED of patients was measured through the emotional dimension items in the Quality of Life Questionnaire-Core Questionnaire (QLQ-C30). The primary outcome was adherence to therapy, with non-adherence defined as patients in groups A and B receiving fewer than ten cycles of chemotherapy or less than 37 Gy of radiotherapy, and patients in group C receiving fewer than ten cycles of chemotherapy. Multivariable logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for adherence by PED levels. Additionally, the structural equation model (SEM) was utilized to analyze the impact pathways of PED on adherence.

Among the 219 patients (142 men; mean age, 53.4 years) who completed the QLQ-C30 scale, 27.8% (61/219) demonstrated non-adherence to the treatment regimen. Multivariable analyses showed that each 1-point increase in PED score raised non-adherence risk by 4.37 times (OR: 4.37, 95% CI: 1.92-9.96, P < 0.001). The SEM analysis revealed that PED score was positively correlated with the risk of non-adherence (standardized regression coefficients [β] = 0.25, 95% CI: 0.11 to 0.28), while economic burden was positively correlated with PED (β = 0.17, 95% CI: 0.11 to 0.28), and could indirectly affect adherence through PED (β = 0.04, 95% CI: 0.01 to 0.09).

Higher levels of pretreatment emotional distress were associated with an increased risk of treatment non-adherence, thereby highlighting the potential significance of addressing emotional distress in cancer management.

ClinicalTrials.gov identifier: NCT01211210.

In a multicenter phase 2 trial the sequence of chemoradiotherapy (CRT) followed by consolidation chemotherapy (CT) prior to total mesorectal excision demonstrated higher pathological complete response rates than induction CT before CRT. Here, we present findings on quality of life (QoL).

Patients with rectal carcinoma (cT3-4 cN0-2) were randomly assigned to group A (CT+CRT; N=156) or group B (CRT+CT; N=150). This is a secondary QoL analysis (EORTC QLQ-C30+CR29, Wexner) before and during treatment and of disease-free patients during follow-up.

gov identifier: XXXX.

At baseline, completed questionnaires were available for 86% (N=134/156; group A) and 89% (N=133/150; group B) of participants, with availability decreasing to 73% versus 64% at 1 year, 61% versus 59% at 2 years, and 51% versus 47% at 3 years. Global health status remained stable in both groups (range 0-100) with baseline scores of 65.2 (mean, SD=21.5; N=133; group A) and 64.7 (SD=23.2; N=131; group B) and with scores of 67.6 (SD=18.4; N=52) and 65.4 (SD=22.2; N=46), respectively, at 3 years. No statistically or clinically relevant differences were observed between groups in any QoL scale upon treatment completion or during follow-up. Both groups experienced declines in role functioning, body image, male impotence, and stool incontinence (Wexner), which did not fully recover over the follow-up period. Rectal blood/mucus discharge and anxiety improved during treatment.

QoL did not differ between the two total neoadjuvant treatment sequences. QoL domains with long lasting deterioration may serve as endpoints in future studies focused on organ preservation.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effectiveness and safety of total neoadjuvant therapy versus standard therapy in individuals with locally advanced rectal cancer.

The aim of the study is to assess whether transcatheter rectal arterial chemoembolization (TRACE) with oxaliplatin could increase the pathologic complete response (pCR) rate of locally advanced rectal cancer (LARC) and improve survival outcomes, while minimizing adverse events compared to preoperative chemoradiotherapy (CRT) alone.

Eligible LARC patients who received TRACE with oxaliplatin plus chemoradiotherapy (the NATRACE-CRT group) or preoperative CRT alone (the NA-CRT group) were retrospectively selected from the database of our institution. Pathological results, treatment-related adverse events and survival in the two groups were compared.

A total of 236 patients were enrolled. The pCR rates were 18.38 % in the NATRACE-CRT group and 14.00 % in the NA-CRT group, with a non-significant difference of 4.38 % (P = 0.473). The median follow-up time was 42 months. The 5-year DFS (75.7 % vs. 73.2 %; P = 0.879) and OS (73.4 % vs. 70.3 %; P = 0.855) rates were comparable between the NATRACE-CRT group and the NA-CRT group. However, the NATRACE-CRT group had significantly fewer patients achieving TRG3 compared to the NA-CRT group (16.18 % vs. 35.00 %; P = 0.001). Furthermore, TRG3 patients in the NATRACE-CRT group exhibited significantly longer OS compared to those in the NA-CRT group (5-year OS: 88.9 % vs 59.5 %; P = 0.016).

TRACE with oxaliplatin demonstrates potential in improving treatment response and prognosis of LARC patients with chemoradiotherapy resistance.

Over the past few decades, considerable progress has been made in the treatment of rectal cancer, leading to a reduction in local recurrence rates and an improvement in prognosis. The current German S3 guideline on colorectal cancer recommends neoadjuvant therapy for UICC stage II and III tumours of the middle and lower rectum. Primary surgery is still recommended for UICC I tumours, although exceptions are being discussed for certain subgroups, such as cT1/2 tumours with questionable nodal involvement. Current trials are focusing on multimodality treatment concepts, in particular total neoadjuvant therapy (TNT), which has been examined in several phase II and phase III trials. Therapies with selective omission of neoadjuvant radiotherapy and organ-preserving approaches are also being investigated. This review provides a comprehensive overview of the current evidence on neoadjuvant treatment of rectal cancer, highlights new multimodal treatment approaches, and discusses future challenges and opportunities to optimise treatment according to stage and to provide patients with the best possible individualised treatment.

This article summarizes the French intergroup guidelines regarding rectal adenocarcinoma (RA) management published in September 2023, available on the French Society of Gastroenterology website.

This work was supervised by French medical and surgical societies involved in RA management. Recommendations were rated from A to C according to the literature until September 2023.

Based on the pretreatment work-up, RA treatment was divided into four groups. T1N0 can be treated by endoscopic or surgical excision alone if there is no risk factor for lymph node involvement. For T2N0, radical surgery with total mesorectal excision is recommended, but rectal conservation is possible for small tumors (<4cm) after complete/subcomplete response following chemoradiotherapy. For T12N+ or T3+any N, total neoadjuvant treatment (TNT) followed by radical surgery is the gold standard, but rectal conservation is possible for small tumors after complete/subcomplete response following TNT. T3N2 or T+any N are an indication for TNT followed by radical surgery. Immunotherapy shows promise for dMMR/MSI RA. For metastatic tumors, recommendations are based on less robust evidence and chemotherapy plays a major role.

These guidelines aim at providing a personalized therapeutic strategy and are constantly being optimized. Each case should be discussed by a multidisciplinary team.

The purpose of this study was to assess and compare the clinical effectiveness of capecitabine monotherapy and that of capecitabine combined with oxaliplatin as neoadjuvant chemoradiotherapy during preoperative radiotherapy in the management of low and middle rectal cancer. A retrospective cohort study was performed. Medical data were collected from individuals with locally progressing low and middle rectal cancer admitted to a regional hospital in China. Two groups of patients were formed for different chemoradiotherapy regimens: the oxaliplatin group and the capecitabine monotherapy group. Within the oxaliplatin group, the CAPEOX regimen was applied for 2 rounds during radiotherapy, intravenous infusion of oxaliplatin was administered 1 day prior to radiotherapy. In the capecitabine monotherapy group, capecitabine was implemented once daily during radiotherapy, and no medication was taken without radiotherapy. A total of 260 patients were included in the study. When oxaliplatin is administered concurrently with preoperative radiation therapy for patients with locally progressing low and middle rectal cancer, the pathologic complete remission rate can be considerably increased without appreciably increasing adverse effects or impairing postoperative recovery. On the other hand, the long-term effectiveness against metastasis and/or recurrence showed no discernible benefit.

We present 10-year results of the phase Ⅲ FOWARC trial, which evaluated the efficacy of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) with or without radiation compared with fluorouracil with radiation in patients with locally advanced rectal cancer. A total of 495 patients age 18-75 years with stage Ⅱ-Ⅲ rectal cancer were randomly assigned to three treatment arms: fluorouracil plus radiotherapy, mFOLFOX6 plus radiotherapy, or mFOLFOX6 alone, followed by surgery and adjuvant chemotherapy. With a median follow-up of 10 years, the 10-year disease-free survival (DFS) rates were 52.5%, 62.6%, and 60.5%, respectively (P = .56). The 10-year locoregional recurrence (LR) rates were 10.8%, 8.0%, and 9.6% (P = .57), and the 10-year overall survival (OS) rates were 65.9%, 72.3%, and 73.4% (P = .90). Subgroup analysis identified ypTNM stage as a significant prognostic factor for DFS, LR, and OS (P < .0001, P < .006, P < .0001, respectively). Patients achieving pathologic complete response had 10-year DFS, LR, and OS rates of 84.3%, 3.0%, and 92.4%, respectively. No significant difference was observed in long-term survival outcome between mFOLFOX6 with and without radiation and fluorouracil plus radiation. These results demonstrate that neoadjuvant mFOLFOX6 chemotherapy can be considered as a therapeutic option in LARC.

Preoperative radiotherapy of rectal cancer has been a hot topic of research in recent years with the introduction of total neoadjuvant therapies and immunotherapeutic agents. We utilized bibliometrics and visualization analysis to examine studies in this field, aiming to identify current hotspots and research trends.

We searched the Web of Science database for all publications related to preoperative radiotherapy of rectal cancer in the past 10 years. Using bibliometric analysis software, such as VOSviewer, CiteSpace and R-studio, we extracted and analyzed the data, summarizing the publication output of countries, institutions, authors, and journals in this field, and analyzing their relationships. We also summarized the keywords, burst words, and most cited articles, and analyzed the relationships among them.

We found 794 publications in the field, sourced from 217 journals or books, involving 5,805 authors from various organizations and countries. Through bibliometric analysis, we observed a growing trend in the number of publications in preoperative radiotherapy of rectal cancer over the past 10 years. China, United States and Italy were the top countries in terms of publication output. Sun Yat-sen University, Fujian University, and Fudan University were the top three medical centers in terms of publication output, while Leiden University from Netherlands led globally in terms of citation impact. Professor Zhen Zhang, Sanjun Cai, and Ji Zhu were the top three authors with the highest publication output. The most highly cited journals in this field includes "The Lancet Oncology," "J Clinical Oncology," and "Annals of Oncology." Journals such as "Radiotherapy and Oncology," "Frontiers in Oncology," and "BMC Cancer" have the highest number of articles published. Based on the analysis of keywords and burst words, we found that "preoperative chemoradiation" and "oral capecitabine" were the research hotspots before 2016, while the focus shifted to "short-course radiotherapy" and "long-term outcomes" after 2017. Currently, the most frequently cited publications mainly summarize multicenter clinical studies and total neoadjuvant treatment models and immunotherapy.

Research on preoperative radiotherapy of rectal cancer is increasing year by year, and attracting attention from high-cited journals such as "The Lancet Oncology," "JCO," and "Annals of Oncology." Based on current data, the total neoadjuvant treatment models and radiation combined with immunotherapy are the research trends.

Low anterior resection (LAR) and abdominoperineal resection (APR) are the two main surgical procedures after preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. APR is associated with poorer prognosis; however existing data do not consider intensified CRT (5-Fluorouracil (5-FU)/Oxaliplatin + radiation) protocols. Clinicopathological data of patients treated with APR and LAR from the CAO/ARO/AIO-04 trial were analysed in terms of prognostic parameters and quality of life (QoL). Based on higher response rate after intensified CRT, subgroup analyses were performed. Data from n = 1173 patients were assessed. APR after preoperative CRT was associated with a significantly worse overall survival (p = 0.0056), disease-free survival (p < 0.0001) and local recurrence rate (p = 0.0047). Clinicopathological data including clinical T stage (p < 0.000001), grading (p = 0.0038), postoperative lymph node (LN) positivity (p = 0.013), and number of positive LN (p = 0.0049) significantly differed between procedures and showed higher values in APR patients. The quality of total mesorectal excision (TME) was significantly better (p < 0.0001) and complete resection rates were higher (p = 0.0022) in LAR compared to APR patients. Subgroup analyses showed worse LR rates in APR patients after standard CRT (5-FU mono and radiation) but not after intensified CRT. After 3 years, role functioning (p = 0.019) and physical functioning (p = 0.001) had a slightly poorer outcome in APR patients. The poorer prognosis of patients undergoing APR for locally advanced rectal cancer may be explained by clinicopathological characteristics. Intensified CRT may compensate for the higher risk of LR after APR in patients with worse TME quality. QoL in APR patients was comparable to LAR patients.

Previous research has demonstrated that after neoadjuvant therapy for rectal cancer, the sensitivity of magnetic resonance complete response (mrCR) for detecting pathologic complete response (pCR) in the surgical specimen ranges from 74 to 94%. Patient and provider interest in nonoperative management of rectal cancer that responds favorably to neoadjuvant therapy has grown, necessitating stronger evidence for how well radiographic complete response truly predicts pCR. We sought to determine the current association between mrCR and pCR in locally advanced rectal cancer.

We conducted a retrospective cohort study of patients with rectal adenocarcinoma who underwent neoadjuvant chemoradiation followed by index proctectomy at a single academic referral center from January 2012 to December 2021. Our primary outcomes were mrCR, defined as the absence of residual disease on restaging MRI, and pCR, defined as the absence of residual adenocarcinoma in surgical pathology specimens.

Among 523 eligible patients, 157 met the inclusion criteria (38.9% females; 51.0% nonwhite; mean [SD] age, 58.6 [13.2] years). Overall, 8.9% of patients had mrCR and 7.0% had pCR. The sensitivity and positive predictive value of mrCR were 36.4% (95% CI: 10.9 to 69.2) and 28.6% (95% CI: 8.4 to 58.1). Our findings were qualitatively unchanged when only patients in the last 5 years of the study period were included. Study limitations include that neoadjuvant therapy regimens were not standardized and patients who were offered and elected to undergo nonoperative management were not included.

The value of mrCR in predicting pathologic response following neoadjuvant therapy in locally advanced rectal cancer is low, and mrCR should be interpreted with caution when counseling patients about nonoperative management. Early, frequent surveillance is critical in patients who elect nonoperative management after mrCR.

MRI plays a critical role in the local staging, restaging, surveillance, and risk stratification of patients, ensuring they receive the most tailored therapy. As such, radiologists must be familiar not only with the key MRI findings that influence management decisions but also with the appropriate MRI protocols and structured reporting. Given the complexity of selecting the optimal therapy for each patient-which often requires multidisciplinary discussions-radiologists should be well-versed in relevant treatment strategies and surgical terms, understanding their significance in guiding patient care. In this manuscript, we review the most common treatment options for managing patients with rectal adenocarcinoma, emphasizing key MRI principles and protocol characteristics for accurate staging. We also highlight important anatomical landmarks and essential factors to be described during baseline assessment. Additionally, we discuss crucial information for restaging and surveillance.

Rectal cancer (RC) presents significant challenges in diagnosis and treatment, with increasing incidence among younger populations. Treatment approaches, particularly for locally advanced rectal cancer (LARC), have evolved, notably with the introduction of total neoadjuvant therapy (TNT). TNT combines neoadjuvant chemotherapy and chemoradiotherapy before surgery, improving overall survival and reducing both metastasis and local recurrence rates compared to traditional methods, while enabling more patients to complete the full oncological treatment. Clinical trials, such as RAPIDO, OPRA, and PRODIGE 23, have demonstrated the effectiveness of TNT in tumor downstaging and complete pathological responses, offering better outcomes for patients; however, debates persist regarding the role of neoadjuvant radiotherapy, with novel strategies exploring its omission in specific cases to reduce toxicity and enhance quality of life. In addition, organ preservation strategies, such as the watch-and-wait (WW) approach, have emerged as viable options for patients with a complete response to neoadjuvant therapy. Future directions point towards personalized treatment plans incorporating radiogenomics and the integration of artificial intelligence into diagnostics to optimize patient outcomes. This review aims to synthesize current treatment strategies and ongoing advancements in rectal cancer management, providing insights into potential future innovations.

Rectal cancer accounts for over 35% of the worldwide colorectal cancer burden representing a distinctive subset of cancers from those arising in the colon. Colorectal cancers exhibit a continuum of traits that differ with their location in the large intestine. Due to anatomical and molecular differences, rectal cancer is treated differently from colon cancer, with neoadjuvant chemoradiotherapy playing a pivotal role in the control of the locally advanced disease. However, radioresistance remains a major obstacle often correlated with poor prognosis. Multifunctional nanomedicines offer a promising approach to improve radiotherapy response rates, as well as to increase the intratumoral concentration of chemotherapeutic agents, such as 5-Fluorouracil. Here, we revise the main molecular differences between rectal and colon tumors, exploring the complex orchestration beyond rectal cancer radioresistance and the most promising nanomedicines reported in the literature to improve neoadjuvant therapy response rates.

Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) and selective use of adjuvant chemotherapy is currently considered the standard of care for locally advanced rectal cancer (LARC). Despite this, the concept of organ preservation is gradually challenging this approach. The management of complete clinical remission (cCR) lacks international consensus, leading scholars to develop their own perspectives based on well-designed studies and long-term data from large multicenter cohorts. To ensure appropriate treatment, this review focuses on the choice of neoadjuvant therapy, criteria for defining cCR, and treatment strategies for patients who achieve cCR after neoadjuvant therapy. By providing guidance on the accurate management of LARC patients after cCR, this review aims to prevent over- or under-treatment.

Owing to multimodal treatment and complex surgery, locally advanced rectal cancer (LARC) exerts a large healthcare burden. Watch and wait (W&W) may be cost saving by removing the need for surgery and inpatient care. This systematic review seeks to identify the economic impact of W&W, compared with standard care, in patients achieving a complete clinical response (cCR) following neoadjuvant therapy for LARC.

The PubMed, OVID Medline, OVID Embase, and Cochrane CENTRAL databases were systematically searched from inception to 26 April 2024. All economic evaluations (EEs) that compared W&W with standard care were included. Reporting and methodological quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS), BMJ and Philips checklists. Narrative synthesis was performed. Primary and secondary outcomes were (incremental) cost-effectiveness ratios and the net financial cost.

Of 1548 studies identified, 27 were assessed for full-text eligibility and 12 studies from eight countries (2016-2024) were included. Seven cost-effectiveness analyses (complete EEs) and five cost analyses (partial EEs) utilized model-based (n = 7) or trial-based (n = 5) analytics with significant variations in methodological design and reporting quality. W&W showed consistent cost effectiveness (n = 7) and cost saving (n = 12) compared with surgery from third-party payer and patient perspectives. Critical parameters identified by uncertainty analysis were rates of local and distant recurrence in W&W, salvage surgery, perioperative mortality and utilities assigned to W&W and surgery.

Despite heterogenous methodological design and reporting quality, W&W is likely to be cost effective and cost saving compared with standard care following cCR in LARC. Clinical Trials Registration PROSPERO CRD42024513874.

To compare the value of tumor stroma ratio (TSR) and radiomic signature from baseline MRI for stratifying the risk of distant metastases (DM) in patients with locally advanced rectal cancer (LARC).

Data from 302 patients with LARC who underwent neoadjuvant chemoradiotherapy and total mesorectal excision in our hospital between 2015 and 2018 were retrospectively reviewed, and the patients were randomly allocated into the training and validation cohorts in a ratio of 7:3. Patients were followed-up for more than 3 years postoperatively with metachronous DM as the endpoint. Independent risk factors for DM-free survival (DMFS) were analyzed using Cox regression. The TSR of endoscopic biopsy specimens was scored automatically. Totally 1229 radiomic features of each tumor were extracted from baseline MRI, and the Radscore was calculated.

The median follow-up time was 54.3 (51.6-57.1) months, and the 3-year DMFS was 83.8%. The best cutoff value of the TSR to distinguish a patient's DM risk was 0.477 (Sen=70.8%, Sep=78%, P <0.001). Increased TSR (HR=3.072, P =0.006) and Radscore (HR=719.231, P =0.023), advanced MR-evaluated T stage (HR=2.660, P =0.023) and ypN (HR=2.362, P =0.028) stage were independent risk factors for DMFS. The area under the curve of the combined model was significantly higher than that of the radiomic model ( P =0.013) but without a significant advantage over the TSR model ( P =0.086).

TSR of colonoscopic biopsies can independently stratify DM risk in patients with LARC. The TSR model is the most convenient and efficient method for DM risk stratification in LARC.

Neoadjuvant chemoradiotherapy (NCRT) is a standard treatment option for locally advanced rectal cancer. However, there is still conflicting data about the genetic landscape and potential dynamics during and after NCRT. This study evaluated oncogenic driver mutations before NCRT and investigated corresponding resection samples after treatment.

In 17 patients the pre-therapeutic biopsy and in ten cases the related resection specimen were investigated by next-generation sequencing using a dedicated cancer panel (708 genes). Oncogenic driver mutations and tumor mutational burden (TMB) were compared pre- and post NCRT to evaluate stability of the genomic landscape. TMB and frequently detected driver mutations were correlated with outcome parameters.

In our corresponding tumor samples before and after NCRT 95.2 % of the oncogenic driver mutations could be found in both specimens whereas one ATM and one RYR1 mutation were not detectable after NCRT. TMB decreased in all patients after neoadjuvant treatment. KRAS ± TP53 mutations and TMB ≥ 5 were associated with impaired outcome.

Most oncogenic driver mutations investigated persisted after neoadjuvant treatment. At the same time, we did not observe ascending TMB after treatment but decline. Thus, NCRT does not seem to induce a relevant number of new driver mutations or mutational burden. Genetic profiling implies the potential to support tumor-informed approaches and outcome estimation in future.

Locally advanced recurrent rectal cancer (RRC) requires a multimodal approach. Intraoperative high-dose-rate brachytherapy (HDR-BT) may reduce the risk of local recurrence. However, the optimal therapeutic regimen remains unclear. The aim of this retrospective monocentric study was to evaluate the toxicity of HDR-BT after resection of RRC.

Between 2018 and 2022, 17 patients with RRC received resection and HDR-BT. HDR-BT was delivered alone or as an anticipated boost with a median dose of 13 Gy (range 10-13 Gy) using an 192iridium microSelectron HDR remote afterloader (Elekta AB, Stockholm, Sweden). All participants were followed for assessment of acute and late adverse events using the Common Terminology Criteria for Adverse Events version 5.0 and the modified Late Effects in Normal Tissues criteria (subjective, objective, management, and analytic; LENT-SOMA) at 3‑ to 6‑month intervals.

A total of 17 patients were treated by HDR-BT with median dose of 13 Gy (range 10-13 Gy). Most patients (47%) had an RRC tumor stage of cT3‑4 N0. At the time of RRC diagnosis, 7 patients (41.2%) had visceral metastases (hepatic, pulmonary, or peritoneal) in the sense of oligometastatic disease. The median interval between primary tumor resection and diagnosis of RRC was 17 months (range 1-65 months). In addition to HDR-BT, 2 patients received long-course chemoradiotherapy (CRT; up to 50.4 Gy in 1.8-Gy fractions) and 2 patients received short-course CRT up to 36 Gy in 2‑Gy fractions. For concomitant CRT, all patients received 5‑fluorouracil (5-FU) or capecitabine. Median follow-up was 13 months (range 1-54). The most common acute grade 1-2 toxicities were pain in 7 patients (41.2%), wound healing disorder in 3 patients (17.6%), and lymphedema in 2 patients (11.8%). Chronic toxicities were similar: grade 1-2 pain in 7 patients (41.2%), wound healing disorder in 3 patients (17.6%), and incontinence in 2 patients (11.8%). No patient experienced a grade ≥3 event.

Reirradiation using HDR-BT is well tolerated with low toxicity. An individualized multimodality approach using HDR-BT in the oligometastatic setting should be evaluated in prospective multi-institutional studies.

Background Rectal cancer, accounting for a significant proportion of colorectal malignancies, presents unique challenges in treatment. Surgery remains the primary curative approach, but recurrence rates post-surgery poses challenges. While neoadjuvant chemoradiation has improved outcomes, the role of adjuvant chemotherapy is still debated. Herein, we aimed to clarify the efficacy of adjuvant chemotherapy in patients with confirmed pathological stage II rectal cancer. Methods In this retrospective single-center study, we investigated the role of adjuvant chemotherapy in 173 patients with biopsy-proven stage II rectal adenocarcinoma. Participants received neoadjuvant chemoradiation followed by open TME surgery, with or without adjuvant chemotherapy. The study was conducted at Sina Hospital between January 2014 and 2019, and analyzed overall survival (OS) and disease-free survival (DFS) outcomes. Propensity score matching (PSM) was used to adjust for potential confounders. Survival outcomes were assessed using Cox proportional hazards models, and sensitivity analysis was conducted using doubly robust estimation. Results Before matching, 173 patients showed significantly improved overall survival (HR:0.33, 95%C:0.22-0.50, p < 0.001) and disease-free survival (HR:0.41, 95%CI:0.28-0.61, p < 0.001) with adjuvant chemotherapy. Age ≥ 70 years was associated with poorer overall survival (HR:1.76, 95%CI:1.08-2.88, p = 0.02). After matching, in 100 patients (50 with chemotherapy, 50 without), adjuvant chemotherapy remained significantly beneficial for both overall and disease-free survival (p < 0.001), while age ≥ 70 years continued to negatively impact overall survival. Conclusion Our findings suggest that adjuvant chemotherapy provides benefits in terms of OS and DFS in stage II rectal cancer following neoadjuvant chemoradiation and TME surgery. Further prospective studies are warranted to confirm these results and optimize treatment strategies.

Current approaches for locally advanced rectal cancer (LARC) typically recommend neoadjuvant chemoradiotherapy (nCRT) with 5-fluorouracil (5FU) or its oral analogs followed by surgery as the standard of care. However, the question of whether intensifying concurrent chemotherapy by adding oxaliplatin to the 5FU-based backbone can yield better outcomes remains unresolved. This study aimed to investigate the benefits of incorporating oxaliplatin into fluoropyrimidine-based chemoradiotherapy (CRT) to increase locoregional control and survival.

Among 290 patients with LARC admitted to the Iran Cancer Institute's radiation oncology department between January 2008 and December 2019, 29 received CAPEOX (capecitabine 625 mg/m²/bid on RT days and weekly oxaliplatin 50 mg/m²), whereas 293 received capecitabine (825 mg/m² twice daily or rarely 5FU in the first 4 days and last week of radiotherapy (RT)). Variables potentially affecting treatment outcomes were used for propensity score matching. Kaplan‒Meier and log-rank tests were employed for overall survival (OS) and disease-free survival (DFS) analyses and were adjusted with propensity score matching.

Data from 29 patients who received CAPEOX and 216 patients who received capecitabine were analyzed after propensity score matching without replacement. After propensity score matching, in the multivariate analysis, CAPEOX significantly increased the likelihood of achieving a pathologic complete response (pCR) by 4.38 times (CI: 1.90-10.08, p value < 0.001). However, CAPEOX did not demonstrate any statistically significant predictive value for DFS (P = 0.500) or OS (P = 0.449).

The addition of oxaliplatin resulted in a significantly higher rate of pCR without any translation into long-term survival outcomes.

This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: Primary objectives To identify and estimate the prognostic value of molecular biomarkers as predictors of pathological complete response to neoadjuvant chemoradiotherapy in people with locally advanced rectal cancer. summarises the review question in population, index prognostic factor, comparator prognostic factor(s), outcome, timing, and setting (PICOTS) format. [Table: see text] [Figure: see text] Secondary objectives To explore the following biomarker measurement, treatment, and study design factors as possible sources of heterogeneity in the association between the prognostic factor and pathological response: type of assay/measurement method, biomarker positivity criteria or cut-off point, chemotherapy regimen, and radiotherapy regimen.

The optimal treatment of ypT1 rectal cancer after neoadjuvant chemoradiotherapy (nCRT) remains controversial. This study aimed to determine whether local excision is non-inferior to radical surgery and whether adjuvant chemotherapy (ACT) would improve survival in patients with ypT1 rectal cancer after nCRT.

We enrolled 1212 and 91 patients with ypT1 rectal cancer underwent nCRT followed by radical surgery from the SEER database (2004-2018) and the Zhejiang Cancer Hospital (ZJCH) (2010-2022), respectively. Another 62 patients underwent LE were also identified from SEER registries. Propensity score matching was performed to balance baseline characteristics between patients in different treatment groups.

Regional nodal metastasis was histopathologically detected in 257 patients (20.7%) within the SEER cohort, showing a significant association with poor cancer-specific survival (CSS) and overall survival (OS). Consistent findings were also observed in the ZJCH cohort. After 1:1 propensity score matching (60 pairs), no significant differences were observed between the extended resection and local excision groups in CSS (hazard ratio [HR] 0.88, P = 0.785) and OS (HR 0.81, P = 0.450). Patients with regional nodal metastases were more likely to receive ACT, while no apparent survival benefit was observed with additional ACT after PSM adjusting (187 pairs). Notwithstanding, for individuals younger than 50 years, ACT might provide a survival benefit in CSS (HR 0.25, P = 0.033) and OS (HR 0.30, P = 0.022).

Although patients with ypT1 rectal cancer have a non-negligible risk for nodal metastasis, oncologic outcomes of local excision following nCRT seem to be comparable to radical surgery. ACT could not effectively improve prognosis in patients with ypT1 tumors, except for those younger than 50 years of age.

In locally advanced rectal cancer, the prediction of tumor response during and after neoadjuvant treatment remains challenging. In terms of organ preservation, adaptive radiotherapy, and intensified (total) neoadjuvant therapies, biomarkers are desirable for patient stratification.

In 16 patients, weekly blood samples (n = 86) to detect cell-free tumor DNA (ctDNA) during long-course neoadjuvant chemoradiotherapy were analyzed. Data were correlated with initial tumor volumes, MRI response in week 2 and 5 of radiotherapy as well as with pathologic tumor response after resection and outcome parameters.

Most patients showed decreasing ctDNA during the course of radiochemotherapy. However, we found heterogenous dynamics of ctDNA and could identify three groups: (1) decline (2) no clear decline and/or late shedding (3) persistence of ctDNA. In seven patients we could detect significant amounts of ctDNA in week 5 or week 6 of treatment. In our pilot cohort, we did not find significant correlations of ctDNA dynamics with pathologic response or outcome parameters. However, patients with distinct decline of ctDNA had larger tumor volumes prior to treatment, and MRI imaging in week 2 and 5 revealed bigger absolute decrease of tumor volumes. If significant levels of ctDNA were found in week 5 and / or 6, patients showed less absolute tumor volume decrease in week 2 and 5.

Weekly measurement of ctDNA during radiochemotherapy is feasible and might represent a promising biomarker. Bigger initial primary tumors showed different ctDNA shedding profiles compared with smaller primary tumors and correlations of ctDNA dynamics with early imaging response were found.

To evaluate the feasibility and safety of total neoadjuvant therapy with long-course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer.

This prospective, multicenter, single-arm, phase II trial was conducted at 10 centers. The eligibility criteria included age ≥20 y, locally advanced rectal cancer within 12 cm of the anal verge, and cT3-4N0M or TanyN+M0 at diagnosis, enabling curative resection. The protocol treatment was capecitabine (1650 mg/m2/day)-based long-course chemoradiotherapy (50.4 Gy/28 fractions) and consolidation chemotherapy (CAPOX, four courses) followed by total mesorectal excision. Nonoperative management was allowed if a clinical complete response was achieved. The primary endpoint was the pathologic complete response rate.

Among 28 enrolled patients (19 men, 9 women; median age, 69.5 [41-79] y), the long-course chemoradiotherapy and consolidation chemotherapy completion rates were 100% and 96.4%, respectively. The clinical responses included clinical complete response, (35.7%, 10/28), near-complete response (28.6%, 8/28), and incomplete response (32.1%, 9/28). Total mesorectal excision and nonoperative management were performed in 21 and six patients, respectively. The final analysis included 21 patients. Five patients (23.8% [90% confidence interval 11.8%-41.8%]) achieved pathologic complete response, while 10 of 28 patients (35.7%) achieved a pathological complete response or a sustained clinical complete response. No treatment-related deaths occurred. Grade ≥3 adverse events included diarrhea (7.1%) and leukopenia (7.1%).

ENSEMBLE-2 demonstrated comparable pathologic complete response rates and well-tolerated safety of total neoadjuvant therapy with long-course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer.

Objectives: Additional adjuvant treatment in patients with rectal cancer with limited response to neoadjuvant treatment to mitigate their higher risk of treatment failure remains controversial. Methods: This is a post hoc analysis of a cohort study of 3 randomized phase 2 or 3 trials (CAO/ARO/AIO-94, -04, and -12 trial) that included 1948 patients with locally advanced rectal adenocarcinoma. After excluding patients with missing information, 1788 patients (1254 men and 524 women; median age: 62.6 years, age range: 19-84 years) were eligible. We analyzed the extent of tumor response and its association with the incidence of treatment failure after different neoadjuvant treatment approaches. Results: Tumor response was significantly enhanced with more intensive neoadjuvant treatment. After a median follow-up of 55 months for the entire cohort (IQR: 37 months-62 months), the incidence of treatment failure (TF) stratified by tumor response or post-neoadjuvant pathological outcome was not significantly affected by the intensity of neoadjuvant treatment, whereas the ypTNM stage was significantly associated with the risk of treatment failure. Conclusions: In this cohort study, we provide evidence that limited or no response to intensified neoadjuvant treatment protocols is not likely to be more strongly associated with an extensive risk of TF after 5-FU CRT+/- adjuvant chemotherapy.

Objective: The optimal management of rectal cancer remains a subject of ongoing research. This meta-analysis of individual patient data assessed the benefit of chemoradiotherapy (fluorouracil-based) in local advanced rectal cancer: disease-free survival and overall survival. Methods: We pooled the data of 6145 patients from 24 studies of rectal cancer who received neoadjuvant radiotherapy with concomitant fluorouracil or capecitabine and surgery. The PRISMA 2020 abstract checklist was followed. Individual participant survival was reconstructed with an algorithm from published Kaplan-Meier curves. Results: The median OS was not reached; the mean survival time was 135.4 months (127.9-141.5). The median DFS was 176.9 months, and the mean disease-free survival time was 122.6 months (111.7-131.9). Conclusions: We provided a benchmark for future studies on rectal cancer treatment. The present results can be used in decision-making for locally advanced rectal cancer patients.

Patients with locally advanced rectal cancer and persistent lymph node metastases (PLNM) after neoadjuvant treatment are at high risk of developing locoregional and distant metastasis, yet optimal postsurgical treatment of these patients is limited.

To analyze the association of PLNM with pretreatment clinical parameters, intensity of neoadjuvant treatment, and long-term oncological outcomes.

This cohort study is a post-hoc analysis of 3 randomized clinical trials (Surgical Oncology Working Group of Germany [CAO], Radiological Oncology Working Group of Germany [ARO], and Working Group for Internal Oncology in the German Cancer Society [AIO]) conducted in Germany in 1994, 2004, and 2012 that included 1948 patients with locally advanced rectal cancer recruited between February 1995 and January 2018. Statistical analysis was conducted between September 2023 and February 2024.

Receiving preoperative fluorouracil-based chemoradiotherapy (CRT, comprising the preoperative group of CAO/ARO/AIO-94 and the control group of CAO/ARO/AIO-04), fluorouracil-based CRT plus oxaliplatin (experimental group of CAO/ARO/AIO-04), or total neoadjuvant treatment (TNT) with fluorouracil-based CRT plus oxaliplatin with induction or consolidation leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin chemotherapy within the CAO/ARO/AIO-12 trial.

The associations of PLNM with clinical parameters, intensity of neoadjuvant treatment, and cumulative incidences of LR, DM, and overall survival were assessed.

A total of 1888 patients (1333 male participants [70.6%]; median [range] age, 62 [19-84] years) with locally advanced rectal adenocarcinoma (clinical tumor stage 3 to 4 and/or clinically node-positive) treated within 3 consecutive clinical trials were analyzed. A total of 522 (29%) experienced PLNM; 378 had lymph node stage (ypN) 1 (20%) after neoadjuvant treatment (ypN) 1 (20%), and 174 had ypN2 (9%). Age, clinical T-stage, N-stage, grading, carcinoembryonic antigen levels, and time interval from completion of CRT to surgery were significantly associated with PLNM, whereas sex and tumor location were not. The percentage of patients with ypN2 stage was almost halved after TNT (18 of 293 patients [6%]) compared with patients treated with fluorouracil-based CRT (114 of 1009 patients [11.3%]; χ26 = 16.693; P = .01). After a median (IQR) follow-up of 54 (37-62) months, 5-year overall survival was 86.1% (95% CI, 83.9%-88.4%) for ypN0, 74.0% (95% CI, 83.9%-88.4%) for ypN1, and 43% for ypN2 (95% CI, 35.4%-52.2%) (P < .001). The 5-year cumulative incidences of locoregional and distant metastases were, respectively, 3% (95% CI, 2.1%-4.2%) and 20% (95% CI, 18%-23%) for ypN0, 6% (95% CI, 3.4%-8.8%) and 40% (95% CI, 34%-46%) for ypN1, and 19% (95% CI, 13%-26%) and 72% (95% CI, 63%-79%) for ypN2 (both P < .001).

In this cohort study, PLNM unmasked an unfavorable phenotype of rectal cancer at high risk for treatment failure. More aggressive adjuvant treatment might be considered; however, risk-adapted surveillance strategies and early recurrence-directed surgery, if feasible, are important strategies in this group of patients with CRT- and/or chemotherapy-resistant disease.

Although oxaliplatin (OXA) is widely used in the frontline treatment of colorectal cancer (CRC), CRC recurrence is commonly observed due to OXA resistance. OXA resistance is associated with a number of factors, including abnormal regulation of pyroptosis. It is therefore important to elucidate the abnormal regulatory mechanism underlying pyroptosis. Here, we identified that the circular RNA circPDIA3 played an important role in chemoresistance in CRC. CircPDIA3 could induce chemoresistance in CRC by inhibiting pyroptosis both in vitro and in vivo. Mechanistically, RIP, RNA pull-down and co-IP assays revealed that circPDIA3 directly bonded to the GSDME-C domain, subsequently enhanced the autoinhibitory effect of the GSDME-C domain through blocking the GSDME-C domain palmitoylation by ZDHHC3 and ZDHHC17, thereby restraining pyroptosis. Additionally, it was found that the circPDIA3/miR-449a/XBP1 positive feedback loop increased the expression of circPDIA3 to induce chemoresistance. Furthermore, our clinical data and patient-derived tumor xenograft (PDX) models supported the positive association of circPDIA3 with development of chemoresistance in CRC patients. Taken together, our findings demonstrated that circPDIA3 could promote chemoresistance by amplifying the autoinhibitory effect of the GSDME-C domain through inhibition of the GSDME-C domain palmitoylation in CRC. This study provides novel insights into the mechanism of circRNA in regulating pyroptosis and providing a potential therapeutic target for reversing chemoresistance of CRC.