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.

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.

It is estimated that 60% of new rectal cancer cases will be diagnosed in patients ≥ 65 years old. The geriatric patient is heterogeneous and underrepresented in clinical trials, and oncologic therapies are often tailored with little evidence. We describe a cohort of patients diagnosed with locally advanced rectal cancer in geriatric and non-geriatric patients.

Retrospective and descriptive analysis of 137 patients, 44 (32.1%) ≥ 75 years old and 93 (67.9%) ≤ 75 years old, with diagnosis of locally advanced rectal cancer. All patients received neoadjuvant chemoradiotherapy (nCRT), followed by total mesorectal excision (TME) and adjuvant chemotherapy.

Mean age was 79.5 for ≥ 75 years and 62.7 for ≤ 75 years, tumor location was: upper rectum (16.1% and 11.3%), middle rectum (60.2% and 47.7%) and lower rectum (23.7% and 41%), using the Eastern Cooperative Oncology Group (ECOG) 0: 74.1% and 81.8%, ECOG 1: 25.9% and 18.2%. Pathological complete response was 21.5% and 22.7%, partial response, 57% and 59% and no response, 21.5% and 18.3%, respectively. Tumor shrinkage in both groups after neoadjuvant treatment was 34.5% and 35.46%. Local recurrence was 2.2% and 3.2% and distance recurrence, 11.3% and 8.6%, respectively.

The study shows similar outcomes in both groups following radical treatment, with similar rates of pathological complete response. However, it has notable limitations, including a small sample size and the absence of a comprehensive geriatric assessment. To enhance these findings, future research should involve larger patient cohorts with comparative analysis and clinical trials specifically focused on the geriatric population.

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.

A disproportionate incidence's increase of rectal cancer in patients younger than 50 years of age. The ESMO and NCCN recommendations are not age-specific and the literature is poor and conflicting. We decided to examine patients with rectal cancer treated in our centre in the last 15 years with curative neoadjuvant radiochemotherapy comparing outcomes in the two groups under and over 55 years old.

788 rectal cancer patients were enrolled in this monocentric retrospective observational study (523 =>55 years and 265 < 55). All patients received neoadjuvant chemoradiation treatment. R statistical software v.4.1.3 was used for the entire analysis. The outcomes were death, local recurrence, and new distant metastases. Survival analysis was performed using the Kaplan-Meier method and the Log-rank was used to compare the two groups.

All patients were classified in different risk groups, according to the ESMO 2017 rectal cancer clinical practice guidelines. 88 % of patients under 55 years old at the diagnosis belonged to the bad or advanced risk groups with an equal division. In patients over 55 years old, there was a clear dominance of the advanced risk class (62 % of the total). In multivariate analysis, OS and DFS decrease with increasing age and ESMO risk group. The other variables in multivariate were not significant. For Both OS, DFS and MFS, the curves separated significantly at 55 years of age, with a prevalence of metastasis development in the older group.

Elderly patients have a prevalence of advanced disease. Younger patients seem having a better OS at 3 and 5 years. ESMO risk group and age were the only variables affecting OS and DFS. Young patients have better MFS and DFS at 2 and 5 years than patients older than 55 years. The addition of oxaliplatin to fluoropyrimidine-based neoadjuvant chemotherapy resulted not significant in both groups.

With the results of several recently published clinical trials, this guideline focused update provides evidence-based recommendations for the indications and dose-fractionation regimens for neoadjuvant radiation therapy (RT), optimal sequencing of RT and systemic therapy in the context of total neoadjuvant therapy (TNT), and considerations for selective omission of RT and surgery for rectal cancer.

The American Society for Radiation Oncology convened a multidisciplinary task force to update 3 key questions that focused on the role of RT for patients with operable rectal cancer. The key questions addressed (1) indications for neoadjuvant RT, (2) selection of neoadjuvant regimens, and (3) indications for consideration of a nonoperative management (NOM) or local excision approach after definitive/preoperative chemoradiation. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for quality of evidence grading and strength of recommendation.

For patients with stage II-III rectal cancer, neoadjuvant RT was strongly recommended; however, among patients deemed at lower risk of locoregional recurrence, consideration of omission of neoadjuvant RT was conditionally recommended in favor of neoadjuvant chemotherapy with a favorable treatment response or upfront surgery. For patients with T3-T4 and node-positive rectal cancer undergoing neoadjuvant RT, a TNT approach was strongly recommended. Among patients with higher risk of locoregional recurrence, TNT with chemotherapy before or after long-course chemoradiation was strongly recommended, whereas TNT with short-course RT followed by chemotherapy was conditionally recommended. For patients with rectal cancer for whom NOM is a priority, concurrent chemoradiation followed by consolidation chemotherapy was strongly recommended. Selection of RT dose-fractionation regimen, sequencing of therapies, and consideration of NOM should be determined by multidisciplinary consensus and based on disease extent, disease location, patient preferences, and quality of life considerations.

The task force proposed recommendations to inform best clinical practices on the use of RT for rectal cancer with strong emphasis on multidisciplinary care. Future studies should focus on further addressing optimal treatment regimens to allow for more personalized recommendations based on individual risk stratification and patient priorities regarding quality of life.

To investigate whether MRI risk factors can be used to predict clinical outcomes and whether MRI risk assessment can be used to select stage II-III rectal cancer patients who may benefit from neoadjuvant chemoradiotherapy (nCRT).

A total of 947 rectal cancer patients who underwent total mesorectal excision (TME) were retrospectively recruited. An MRI scoring system was established using the cumulative score of three risk factors (mesorectal fascia involvement, extramural venous invasion, and tumour deposits). Patients with mrT3c-T4 stage, N2 stage, or any risk factors were considered MRI high-risk cases of rectal cancer. Cox regression analysis was used to identify independent risk factors for overall survival (OS) and disease-free survival (DFS). Kaplan-Meier curves were generated to show the benefits of nCRT after propensity score matching (PSM).

OS and DFS were more favourable in the MRI low-risk group than in the MRI high-risk group, and the MRI scoring system facilitated prognostic stratification in stage II-III rectal cancer patients. NCRT significantly improved 3-year OS (89.1 % versus 78.8 %, p = 0.001) and 3-year DFS (73.4 % versus 68.0 %, p = 0.030) in the MRI high-risk group. After PSM, OS and DFS were improved in the MRI high-risk group with an MRI score of 1 (OS: HR = 0.432 [95 % CI: 0.214-0.871], p = 0.019; DFS: HR = 0.477 [95 % CI: 0.275-0.825], p = 0.008) and an MRI score of 2 (OS: HR = 0.276 [95 % CI: 0.130-0.586], p = 0.001; DFS: HR = 0.358 [95 % CI: 0.182-0.705], p = 0.003), whereas MRI low-risk patients did not obtain any survival benefit from nCRT.

MRI-defined high-risk patients with MRI scores of 1 or 2 may benefit from nCRT. Baseline MRI should be given more consideration in nCRT decision-making.

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.

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 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.

Objectives: Despite optimal local control obtained with neoadjuvant chemoradiotherapy (CRT), data on overall survival (OS) and disease-free survival (DFS) of local advanced rectal cancer patients are still equivocal. This meta-analysis aimed to estimate the pathological complete response (pCR), regression rate, DFS, and OS probabilities of rectal cancer patients treated with a second chemotherapy drug added to fluoropyrimidine and long-term radiotherapy. Methods: Computerized bibliographic searches of MEDLINE, PUBMED, Web of Science and the Cochrane Central Register of Controlled Trials databases (1970-2023) were supplemented with hand searches of reference lists. Studies were included if they were randomised controlled trials (RCTs) comparing intensified chemotherapy with CRT to preoperative CRT and if they had patients with resectable, histologically proven rectal adenocarcinoma without metastases. Results: Eighteen RCTs (7695 patients) were analysed. Data on population, intervention, and outcomes were extracted from each RCT, following the intention-to-treat method, by three independent observers and combined using the DerSimonian and Laird methods. A chemotherapy with two drug and long-term radiotherapy CRT, compared to preoperative CRT (fluoropyrimidine and long-term radiotherapy), significantly increases the rate of pathological complete response (OR 1.37 (95% CI, 1.16-1.63) p = 0.0003) and the regression rate (OR 1.57 (95% CI, 1.16-2.14) p < 0.00001). Furthermore, it increases DFS (HR 0.87 (95% CI, 0.79 to 0.95) p = 0.002 and OS HR 0.84 (95% CI, 0.74 to 0.95) p = 0.007). The risk of severe adverse events (≥G3) is increased OR 1.96 (95% CI 1.35-2.85), p = 0.0005. Conclusions: In patients with resectable rectal cancer, intensified chemotherapy can reduce by 13% the risk of disease progression and by 16% the risk of death.

Lateral node metastasis confers a poor prognosis in rectal cancer. Several multidisciplinary treatments have been proposed with favorable outcomes. However, appropriate neoadjuvant/adjuvant treatments or follow-up plans based on information about the probable recurrence site have not been specified. We aimed to clarify the distinctive features of recurrence patterns for lateral node-positive low rectal cancer according to the lateral and mesorectal lymph node status.

We retrospectively analyzed 508 patients with stage III low rectal cancer who underwent lateral node dissection. We investigated the impact of lateral and mesorectal lymph node status on site-specific recurrence rates and patient survival.

Analyses for relapse-free survival revealed the prognostic impact of lateral node positivity in stage III low rectal cancer (p < 0.0001). Lateral node-positive patients exhibited higher risk of overall recurrence, local recurrence, and recurrence in extra-regional nodes than lateral node-negative patients (p < 0.0001, p = 0.001, and p < 0.0001, respectively). However, lateral node positivity was not statistically associated with a hematogenous recurrence rate. In lateral node-positive patients, both tumor-node-metastasis (TNM)-N status and number of lateral nodes involved were revealed as significant prognostic factors (p < 0.0001, both). In addition, the number of lateral nodes involved could be a discriminatory indicator of probabilities of local recurrence and recurrence in extra-regional nodes (p = 0.02, and p < 0.0001, respectively).

Lateral node-positive low rectal cancer exhibits higher local recurrence and extra-regional node recurrence rates that correlate with the number of lateral nodes involved.

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.

Rectal cancer shows specific characteristics in terms of pattern of recurrence, which occurs commonly at both local and distant sites. The standard of care for locally advanced rectal cancer (LARC) including neoadjuvant chemoradiotherapy, followed by surgery based on the total mesorectal excision principles leads to a reduction in the rates of local recurrences to 6-7% at 5 years. However, the outcomes among those with high-risk lesions remain unsatisfactory. On the contrary, neoadjuvant chemoradiotherapy results in long-term morbidities among those with low-risk lesions. Furthermore, the overall survival benefit of neoadjuvant therapy is still a subject to be debated, except for patients with complete or near-complete response to neoadjuvant therapy. Total neoadjuvant therapy (TNT) is a new paradigm of management of high-risk rectal cancer that includes early administration of the most effective systemic therapy either before or after neoadjuvant radiotherapy with or without chemotherapy prior to surgery with or without adjuvant chemotherapy. TNT potentially improves disease-free survival, even though whether it can prolong survival has been debatable. Recently, neoadjuvant chemotherapy only has been proved to be non-inferior to neoadjuvant chemoradiotherapy in patients with low-risk lesions. This review intends to review the current evidences of neoadjuvant therapy and propose a more customized paradigm of management of LARC.

Improvement in oncological survival for rectal cancer increases attention to anorectal dysfunction. Diagnostic questionnaires can evaluate quality of life but are subjective and dependent on patients' compliance. Anorectal manometry can objectively assess the continence mechanism and identify functional sphincter weakness and rectal compliance. Neoadjuvant chemoradiotherapy is presumed to affect anorectal function. We aim to assess anorectal function in rectal cancer patients who undergo total mesorectal excision, with or without neoadjuvant chemoradiation, using anorectal manometry measurements.

MEDLINE, Embase, and Cochrane databases were searched for studies comparing perioperative anorectal manometry between neoadjuvant chemoradiation and upfront surgery for rectal cancers. Primary outcomes were resting pressure, squeeze pressure, sensory threshold volume and maximal tolerable volume.

Eight studies were included in the systematic review, of which seven were included for metanalysis. 155 patients (45.3%) had neoadjuvant chemoradiation before definitive surgery, and 187 (54.6%) underwent upfront surgery. Most patients were male (238 vs. 118). The standardized mean difference of mean resting pressure, mean and maximum squeeze pressure, maximum resting pressure, sensory threshold volume, and maximal tolerable volume favored the upfront surgery group but without statistical significance.

Currently available evidence on anorectal manometry protocols failed to show any statistically significant differences in functional outcomes between neoadjuvant chemoradiation and upfront surgery. Further large-scale prospective studies with standardized neoadjuvant chemoradiation and anorectal manometry protocols are needed to validate these findings.

In locally advanced rectal cancer, neoadjuvant treatment has evolved from no preoperative treatment to the addition of radiation and systemic therapy and ultimately total neoadjuvant therapy. Total neoadjuvant therapy is the completion of preoperative radiation or chemoradiation and chemotherapy before surgery in order to maximize tumor response and improve survival outcomes. This review summarizes the literature of the neoadjuvant approaches related to locally advanced rectal cancer and highlights the nuances of selecting the appropriate treatment.

The optimal management of T3N0 rectal cancer is an area of active debate that has withstood multiple decades of research. In this comprehensive review, we delve into the many nuances that come with treating T3N0 rectal cancer, particularly examining the role and evolution of radiation therapy. We review both the historical paradigms and latest advances in treatment and highlight the significance of precise preoperative staging. As the field continues to evolve, this review highlights a shift toward more tailored treatments, considering both patient goals and the desire for optimal oncologic outcomes. In the current era, clinical decision-making for T3N0 rectal cancer requires a patient-centric approach that balances effective therapy while minimizing undue side effects.

Treatment of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiotherapy plus total mesorectal excision and adjuvant chemotherapy. However, total neoadjuvant therapy (TNT) protocols (ie, preoperative chemotherapy in addition to radiotherapy) may allow better adherence and early treatment of distant micrometastases and may increase pathological complete response (pCR) rates.

To assess the efficacy and tolerability of TNT protocols for LARC.

MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science Core Collection electronic databases and ClinicalTrials.gov for unpublished studies were searched from inception to March 2, 2024.

Randomized clinical trials including adults with LARC who underwent rectal resection as a final treatment were included. Studies including nonoperative treatment (watch-and-wait strategy), treatments other than rectal resection, immunotherapy, or antiangiogenic agents were excluded. Among the initially identified studies, 2.9% met the selection criteria.

Two authors independently screened the records and extracted data. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant pairwise and network meta-analyses with a random-effects model were performed in a frequentist framework, and the certainty of evidence was assessed according to the confidence in network meta-analysis approach.

The primary outcome was pCR, defined as the absence of residual tumor at pathological assessment after surgery. Secondary outcomes included tolerability, toxic effects, perioperative outcomes, and long-term survival.

Of 925 records identified, 27 randomized clinical trials, including 13 413 adults aged 18 years or older (median age, 60.0 years [range, 42.0-63.5 years]; 67.2% male) contributed to the primary network meta-analysis. With regard to pCR, long-course chemoradiotherapy (L-CRT) plus consolidation chemotherapy (relative risk [RR], 1.96; 95% CI, 1.25-3.06), short-course radiotherapy (S-RT) plus consolidation chemotherapy (RR, 1.76; 95% CI, 1.34-2.30), and induction chemotherapy plus L-CRT (RR, 1.57; 95% CI, 1.09-2.25) outperformed standard L-CRT with single-agent fluoropyrimidine-based chemotherapy. Considering 3-year disease-free survival, S-RT plus consolidation chemotherapy (RR, 1.08; 95% CI, 1.01-1.14) and induction chemotherapy plus L-CRT (RR, 1.12; 95% CI, 1.01-1.24) outperformed L-CRT, in spite of an increased 5-year locoregional recurrence rate of S-RT plus consolidation chemotherapy (RR, 1.65; 95% CI, 1.03-2.63).

In this systematic review and network meta-analysis, 3 TNT protocols were identified to outperform the current standard of care in terms of pCR rates, with good tolerability and optimal postoperative outcomes, suggesting they should be recognized as first-line treatments.

Despite therapeutic advancements, disease-free survival and overall survival of patients with locally advanced rectal cancer have not improved in most trials as a result of distant metastases. For treatment decision-making, both long-term oncologic outcomes and impact on quality-of-life indices should be considered (for example, bowel function). Total neoadjuvant therapy (TNT), comprised of chemotherapy and radiotherapy or chemoradiotherapy, is now a standard treatment approach in patients with features of high-risk disease to prevent local recurrence and distant metastases. In selected patients who have a clinical complete response, subsequent surgery might be avoided through non-operative management, but patients who do not respond to TNT have a poor prognosis. Refined molecular characterization might help to predict which patients would benefit from TNT and non-operative management. Specifically, integrated analysis of spatiotemporal multi-omics using artificial intelligence and machine learning is promising. Three prospective trials of TNT and non-operative management in Japan, the USA and Germany are collaborating to better understand drivers of response to TNT. Here, we address the future direction for TNT.

Long-course neoadjuvant chemoradiotherapy (NCRT), followed by surgery after an interval of 6-8 weeks, represents standard of care for patients with locally advanced rectal cancer (LARC). Increasing this interval may improve rates of complete pathological response (pCR) and tumour downstaging. We performed a meta-analysis comparing standard (SI, within 8 weeks) versus longer (LI, after 8 weeks) interval from NCRT to surgery.

PubMed, Embase, and Cochrane databases were searched up to 31 August 2022. Randomized controlled trials (RCTs) comparing SI with LI after NCRT for LARC were included. The primary endpoint was pCR rate. Secondary endpoints included rates of R0 resection, circumferential resection margin positivity (+CRM), TME completeness, lymph node yield (LNY), operative duration, tumour downstaging (TD), sphincter preservation, mortality, postoperative complications, surgical site infection (SSI) and anastomotic leak (AL). Random effects models were used to calculate pooled effect size estimates.

Four RCTs encompassing 867 patients were included. There were 539 males (62.1%). LI was associated with a higher pCR rate (OR 0.61, 95%CI ​= ​0.39-0.95, p ​= ​0.03), and more TD (OR 0.60, 95%CI ​= ​0.37-0.97, p ​= ​0.04) compared to SI. However, there was no difference in rates of R0 resection (p ​= ​0.87), +CRM (p ​= ​0.66), sphincter preservation (p ​= ​0.26), incomplete TME (p ​= ​0.49), LNY (p ​= ​0.55), SSI (p ​= ​0.33), AL (p ​= ​0.20), operative duration (p ​= ​0.07), mortality (p ​= ​0.89) or any surgical complication (p ​= ​0.91).

A LI to surgery after NCRT for LARC increases pCR and TD rates. Local recurrence or survival were not assessed due to unavailable data. We recommend deferring TME until after an interval of 8 weeks following completion of NCRT.

A major advance has been made in the management of rectal cancer, with the emergence in 2021 of total neoadjuvant treatment. The main publications from the RAPIDO and PRODIGE-23 trials reported a significant improvement in progression-free survival and the pathological complete response rate. The aim of this review is to synthesize recent data on neoadjuvant treatment of rectal cancer, to explain the long-term results of the RAPIDO and PRODIGE-23 trials, and to put them into perspective, considering current advances in de-escalation strategies. The update of the 5-year survival data from the RAPIDO trial highlights an increased risk of loco-regional relapse, with 11.7% of relapses in the experimental group and 8.1% in the control group, while the update of the PRODIGE-23 trial confirms the benefits of this treatment regimen, with a significant improvement in overall survival. In addition, the results of the OPRA and PROPSPECT trials confirm the benefit of total neoadjuvant treatment with induction chemotherapy, as well as the possibility of surgical de-escalation in the OPRA trial and radiotherapy in the PROSPECT trial. The challenge for the future is to identify patients who require total neoadjuvant treatment with the aim of curative surgery to obtain a cure without local or distant relapse, and those for whom therapeutic de-escalation can be envisaged.

The treatment of locally advanced rectal cancer (LARC) is a challenging situation for radiation oncologists and colorectal surgeons. Most current approaches recommend neoadjuvant fluorouracil or capecitabine-based chemoradiotherapy followed by surgery as a standard of care. Intensification of concurrent chemotherapy by adding oxaliplatin to fluorouracil or capecitabine backbone to get better outcomes is the matter that has remained unresolved. In this review, we searched Medline and Google Scholar databases and selected 28 prospective phase II and III clinical trials that addressed this question. We discussed the potential advantages and drawbacks of incorporating oxaliplatin into concurrent chemoradiation therapy. We tried to define whether adding oxaliplatin to concurrent chemoradiation with excellent performance and high-risk features benefits some subpopulations. The available literature suggests that by adding oxaliplatin there are some benefits in enhancing response to neoadjuvant chemoradiotherapy, however, without any translated improvements in long-term outcomes including overall and disease-free survival.

Local and metastatic recurrence are primary concerns following the treatment of locally advanced rectal cancer (LARC). Chemoradiation (CRT) can reduce the local recurrence rates and has subsequently moved to the neoadjuvant setting from the adjuvant setting. Pathological complete response (pCR) rates have also been noted to be greater in patients treated with neoadjuvant CRT prior to surgery. The standard approach to treating LARC would often involve CRT followed by surgery and optional adjuvant chemotherapy and remained the treatment paradigm for almost two decades. However, patients were often unable to complete adjuvant chemotherapy due to a decreased tolerance of chemotherapy following surgery, which led to upfront treatment with both CRT and chemotherapy, and total neoadjuvant therapy, or TNT, was created. The efficacy outcomes of local recurrence, disease-free survival, and pCR have improved in patients receiving TNT compared to the standard approach. Additionally, more recent data suggest a possible improvement in overall survival as well. Patients with a complete clinical response following TNT have the opportunity for watch-and-wait surveillance, allowing some patients to undergo organ preservation. Here, we discuss the clinical trials and studies that led to the adoption of TNT as the standard of care for LARC, with the possibility of watch-and-wait surveillance for patients achieving complete responses. We also review the possibility of overtreating some patients with LARC.

Randomised controlled trials (RCTs) continue to provide the best evidence for treatment options, but the quality of reporting in RCTs and the completeness rate of reporting of surgical outcomes and complication data vary widely. The aim of this study was to measure the quality of reporting of the surgical outcome and complication data in RCTs of rectal cancer treatment and whether this quality has changed over time.

Eligible articles with the keywords ("rectal cancer" OR "rectal carcinoma") AND ("radiation" OR "radiotherapy") that were RCTs and published in the English, German, Polish, or Italian language were identified by reviewing all abstracts published from 1982 through 2022. Two authors independently screened and analysed all studies. The quality of the surgical outcome and complication data was assessed based on fourteen criteria, and the quality of RCTs was evaluated based on a modified Jadad scale. The primary outcome was the quality of reporting in RCTs and the completeness rate of reporting of surgical results and complication data.

A total of 340 articles reporting multimodal therapy outcomes for 143,576 rectal cancer patients were analysed. A total of 7 articles (2%) met all 14 reporting criteria, 13 met 13 criteria, 27 met from 11 to 12 criteria, 36 met from 9 to 10 criteria, 76 met from 7 to 8 criteria, and most articles met fewer than 7 criteria (mean 5.5 criteria). Commonly underreported criteria included complication severity (15% of articles), macroscopic integrity of mesorectal excision (17% of articles), length of stay (18% of articles), number of lymph nodes (21% of articles), distance between the tumour and circumferential resection margin (CRM) (26% of articles), surgical radicality according to the site of the primary tumour (R0 vs. R1 + R2) (29% of articles), and CRM status (38% of articles).

Inconsistent surgical outcome and complication data reporting in multimodal rectal cancer treatment RCTs is standard. Standardised reporting of clinical and oncological outcomes should be established to facilitate comparing studies and results of related research topics.

Current management of locally advanced rectal cancer achieves high cure rates, distant metastatic spread being the main cause of patients' death. Total neoadjuvant therapy (TNT) employs (chemo)radiotherapy and combined chemotherapy prior to surgery to improve the treatment outcomes. TNT has been shown to reduce significantly distant metastases, increase disease-free survival by 5 - 10% in 3 years, and finally also overall survival (≈ 5% in 7 years). It proved to double the rate of pathologic complete responses, making it an attractive strategy for non-operative management to avoid permanent colostomy in patients with distal tumors. In addition, it endorses adherence to the therapy due to better tolerance and, potentially, shortens its overall duration. A number of questions related to TNT remain currently unresolved including the indications, preferred radiotherapy and chemotherapy regimens, their sequence, timing of surgery, and role of adjuvant therapy. A stratified approach may be the optimal way to go.

There are various preoperative treatments that are useful for controlling local or distant metastases in lower rectal cancer. For planning perioperative management, preoperative stratification of optimal treatment strategies for each case is required. However, a stratification method has not yet been established. Therefore, we attempted to predict the prognosis of lower rectal cancer using preoperative magnetic resonance imaging (MRI) with artificial intelligence (AI).

This study included 54 patients [male:female ratio was 37:17, median age 70 years (range 49-107 years)] with lower rectal cancer who could be curatively resected without preoperative treatment at Tokyo Medical University Hospital from January 2010 to February 2017. In total, 878 preoperative T2 MRIs were analyzed. The primary endpoint was the presence or absence of recurrence, which was evaluated using the area under the receiver operating characteristic curve. The secondary endpoint was recurrence-free survival (RFS), which was evaluated using the Kaplan-Meier curve of the predicted recurrence (AI stage 1) and predicted recurrence-free (AI stage 0) groups.

For recurrence prediction, the area under the curve (AUC) values for learning and test cases were 0.748 and 0.757, respectively. For prediction of recurrence in each case, the AUC values were 0.740 and 0.875, respectively. The 5-year RFS rates, according to the postoperative pathologic stage for all patients, were 100%, 64%, and 50% for stages 1, 2, and 3, respectively (p = 0.107). The 5-year RFS rates for AI stages 0 and 1 were 97% and 10%, respectively (p < 0.001 significant difference).

We developed a prognostic model using AI and preoperative MRI images of patients with lower rectal cancer who had not undergone preoperative treatment, and the model could be useful in comparison with pathological classification.

Total neoadjuvant therapy (TNT) is a novel treatment strategy that is an alternative to preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). However, an optimal protocol for TNT has not yet been established. The present study will be an open-label, single-arm, single-center trial to develop a new protocol.

Thirty LARC patients at high risk of distant metastasis will receive CRT consisting of long-course radiation, concurrent with tegafur/uracil, oral leucovorin, irinotecan (TEGAFIRI), followed by mFOLFOX-6 or CAPOX before undergoing surgery.

Since previous findings showed a high percentage of grade 3-4 adverse events with the TEGAFIRI regimen for CRT and TNT, the primary outcome of this study will be safety and feasibility. Our regimen for CRT consists of the biweekly administration of irinotecan for good patient compliance. The novel combination approach of this treatment may improve the long-term outcomes of LARC.

Japan Registry of Clinical Trials jRCTs031210660.

Standard treatment of locally advanced rectal cancer (LARC) was neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Patients treated with neoadjuvant chemotherapy were more likely to show higher tumor regression. The objective of this trial was to increase complete clinical rate (cCR) for LARC patients by optimizing tumor response, using TNT regimen as compared to conventional chemoradiotherapy. TESS, a prospective, open-label, multicenter, single-arm, phase 2 study, is underway.

Main inclusion criteria include cT3-4aNany or cT1-4aN+ rectal adenocarcinoma aged 18-70y; Eastern Cooperative Oncology Group (ECOG) performance 0-1; location ≤5 cm from anal verge. Ninety-eight patients will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplatin) before, during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease-free survival; locoregional recurrence-free survival; acute toxicity; surgical complications; long-term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment.

The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.

Many consider the standard of care for locally advanced rectal cancer (LARC) to be preoperative chemoradiotherapy, radical surgery involving a total mesorectal excision, and post-operative adjuvant chemotherapy based on the pathology of the specimen. The poor impact on distant control is a major limitation of this strategy, with metastasis rates remaining in the 25-35% range and recovery after radical surgery leading to reluctance with prescription and inconsistent patient compliance with adjuvant chemotherapy. A second limitation is the low rate of pathologic complete response (pCR) (around 10-15%) despite multiple efforts to potentiate preoperative chemoradiation regimens, which in turn means it is less effective at achieving non-operative management (NOM). Total neoadjuvant treatment (TNT) is a pragmatic approach to solving these problems by introducing systemic chemotherapy at an early timepoint. Enthusiasm for delivering TNT for patients with LARC is increasing in light of the results of published randomized phase III trials, which show a doubling of the pCR rate and a significant reduction in the risk of subsequent metastases. However, there has been no demonstrated improvement in quality of life or overall survival. A plethora of potential chemotherapy schedules are available around the radiotherapy component, which include preoperative induction or consolidation with a range of options (FOLFOXIRI, FOLFOX, or CAPEOX,) and a varying duration of 6-18 weeks, prior to long course chemoradiation (LCCRT) or consolidation NACT following short-course preoperative radiation therapy (SCPRT) using 5 × 5 Gy or LCCRT using 45-60 Gy, respectively. The need to maintain optimal local control is a further important factor, and preliminary data appear to indicate that the RT schedule remains a crucial issue, especially in more advanced tumors, i.e., mesorectal fascia (MRF) invasion. Thus, there is no consensus as to the optimum combination, sequence, or duration of TNT. The selection of patients most likely to benefit is challenging, as clear-cut criteria to individuate patients benefiting from TNT are lacking. In this narrative review, we examine if there are any necessary or sufficient criteria for the use of TNT. We explore potential selection for the individual and their concerns with a generalized use of this strategy.

Over the last two decades, the standard treatment for locally advanced rectal cancer (LARC) has been neoadjuvant chemoradiotherapy plus total mesorectal excision followed by adjuvant chemotherapy. Total neoadjuvant treatment (TNT) and immunotherapy are two major issues in the treatment of LARC. In the two latest phase III randomized controlled trials (RAPIDO and PRODIGE23), the TNT approach achieved higher rates of pathologic complete response and distant metastasis-free survival than conventional chemoradiotherapy. Phase I/II clinical trials have reported promising response rates to neoadjuvant (chemo)-radiotherapy combined with immunotherapy. Accordingly, the treatment paradigm for LARC is shifting toward methods that increase the oncologic outcomes and organ preservation rate. However, despite the progress of these combined modality treatment strategies for LARC, the radiotherapy details in clinical trials have not changed significantly. To guide future radiotherapy for LARC with clinical and radiobiological evidence, this study reviewed recent neoadjuvant clinical trials evaluating TNT and immunotherapy from a radiation oncologist's perspective.

This study aimed to evaluate the benefit of additional administration of oxaliplatin during fluorouracil-based neoadjuvant radiochemotherapy (nRCT) in terms of pathologic complete remission (pCR), disease-free survival (DFS), and overall survival (OS) in patients with advanced rectal cancer. Between 2006 and 2021, 669 patients (pts) were diagnosed with locally advanced rectal cancer, of whom a total of 414 pts with nRCT were identified and included in the study. A total of 283 pts were treated by nRCT using concurrent chemotherapy with fluorouracil or capecitabine; 131 pts were treated using a combination of fluorouracil or capecitabine and oxaliplatin. Propensity score matching analyses (PSM) with 114 pts in each group were used to balance the patients' characteristics. OS, DFS, pCR-rate, and potential prognostic factors were compared between the two groups. The median follow-up time was 59.5 weeks in the fluorouracil-group and 43 weeks in the fluorouracil/oxaliplatin group (p = 0.003). After PSM, the pCR-rate (including sustained clinical complete remission) was 27% (31/114 pts) in the fluorouracil/oxaliplatin group and 16% (18/114 pts) in the fluorouracil-group (p = 0.033). There was no difference between these two groups for both 10-year OS and DFS neither before nor after PSM, respectively (OS: 72.6% vs. 55.4%, p = 0.066, and 67.8% vs. 55.1%, p = 0.703, and DFS: 44.8% vs. 46.8%, p = 0.134, and 44.7% vs. 42.3%, p = 0.184). Multivariate analysis identified regression grading according to Dworak grade 4 (HR: 0.659; CI: 0.471-0.921; p = 0.015) and age over 60 years (HR: 2.231; CI: 1.245-4.001; p = 0.007) as independent predictors for OS. In conclusion, the addition of oxaliplatin to fluorouracil during nRCT significantly improved pCR-rate without having an impact on survival.

The purpose of this phase II trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, to preoperative chemoradiotherapy (CRT) with capecitabine confers a clinical benefit to patients with locally advanced rectal cancer (LARC).

Patients with LARC (defined by clinical stage T3/4 and/or lymph node positivity) received preoperative radiation (45-50.4 Gy in 25-28 daily fractions) with concomitant capecitabine (825 mg/m2 twice per day) and simvastatin (80 mg, daily). Curative surgery was planned 4-8 weeks after completion of the CRT regimen. The primary endpoint was pathologic complete response (pCR). The secondary endpoints included sphincter-sparing surgery, R0 resection, disease-free survival, overall survival, the pattern of failure, and toxicity.

Between October 2014 and July 2017, 61 patients were enrolled; 53 patients completed CRT regimen and underwent total mesorectal excision. The pCR rate was 18.9% (n=10) by per-protocol analysis. Sphincter-sparing surgery was performed in 51 patients (96.2%). R0 resection was achieved in 51 patients (96.2%). One patient experienced grade 3 liver enzyme elevation. No patient experienced additional toxicity caused by simvastatin.

The combination of 80 mg simvastatin with CRT and capecitabine did not improve pCR in patients with LARC, although it did not increase toxicity.

The standard treatment regimen of preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) is still controversial. The purpose of this study was to analyze the efficacy and safety of preoperative intensive CRT in our institution.

A retrospective data collection and analysis of 181 LARC patients receiving oxaliplatin (85%) of standard doses in capecitabine-based preoperative CRT and two additional cycle of neoadjuvant chemotherapy between the end of concurrent CRT and surgery.

The compliance of the preoperative CRT was satisfactory with 99.4%patients completed radiotherapy and 97.19%patients completed all 2 cycles of concurrent chemotherapy. Except for 20 patients diagnosed clinical complete remission (cCR) managed according to watch and wait strategy, 160 patients received R0 radical surgery. The pathological complete response (pCR) rate was 23.75% (38/160) and tumor regression grade (TRG) 0/1 was 40% (72/180). In terms of tumor downstaging, 89 (55.63%) had T downstaging while 115 (71.88%) had N downstaging. The 1-overall survival (OS),2-OS,3-OS and 5-OS were 98.7%, 96.5%, 91.4% and 81.5%, respectively. The total rate of sphincter preservation was 86.25% (138/160) and the rate of patients with low rectal cancer was 73.0% (54/74) without affecting local control rates and survival rates. Both acute adverse reactions to preoperative CRT and postoperative complications were tolerable and controllable.

In this retrospective study, preoperative intensive CRT of patients with LARC achieved satisfied disease control and survival outcomes and well acquired the sphincter retention rate in recent years in our institution. On the basis of these findings, a Phase III study to definitively test the intensified preoperative CRT strategy is warranted.

Addition of perioperative multi-agent chemotherapy to the treatment strategy for locally advanced rectal cancer (LARC) may be a promising option. We conducted a phase II study to evaluate the safety and efficacy of capecitabine combined with oxaliplatin and irinotecan (XELOXIRI) as triplet neoadjuvant chemotherapy in patients with LARC.

Patients received neoadjuvant irinotecan and oxaliplatin and capecitabine and then underwent total mesorectal excision. The primary study endpoint was the pathological complete response (pCR) rate.

Between June 2013 and December 2016, 55 patients were enrolled in the study. Forty-two (77.8%) of 54 completed the study protocol. The pCR rate was 7.7% (95% CI 3.0% to 18.2%). The 3-year local recurrence rate was 3.9%, the 3-year disease-free survival (DFS) rate was 77.3, and the 3-year overall survival rate was 96.0%.

XELOXIRI neoadjuvant chemotherapy appears to be feasible and efficacious for patients with LARC. Although neoadjuvant XELOXIRI alone did not yield our expected pCR rate, the local recurrence rate, 3-year DFS, and measures of safety met current standards.

Few studies fairly compared anorectal function and prognostic outcomes between patients undergoing abdominoperineal resection (APR) and anorectal-function-saving operations (ASO) under the equivalent conditions. By contrast, surgeons used to be somewhat hesitant to conduct total intersphincteric resection (T-ISR) as maximal ASO, due to its technical complexity and potential anorectal dysfunction.

Propensity-score matched cohorts undergoing robot-assisted R0 surgery [T-ISR vs APR vs partial-subtotal ISR (PS-ISR)/lower anterior resection (LAR)] for rectal cancer (n = 1361) were included. Operative outcomes, recurrence, and disease-free/overall survival (DFS/OS) were analyzed. Anorectal function was evaluated based on fecal incontinence score and high-resolution manometry between the T-ISR and other ASO groups.

Few differences were detected between the T-ISR and APR groups. More patients undergoing APR had T4 stage disease, while the lowest tumor margin was the same in both groups (mean, 1.5 cm from anal verge). Prognostic outcomes did not differ between the T-ISR and APR groups, including local (5.1% vs 7.7%, p = 1) or systemic (15.4% vs 25.6%, p = 0.401) recurrence, and 5-year DFS (78.7% vs 61.5%, p = 0.1) and OS (89% vs 82.1%, p = 0.434) rates, nor were there differences between the T-ISR and PS-ISR/LAR groups. The PS-ISR group generally showed less anorectal dysfunction than the T-ISR group, but maximal tolerance volume did not differ between these two groups and was within the range for the healthy population.

T-ISR can replace most traditional APR, except for advanced T4 disease with aggressive infiltration into the levator-sphincters, and can provide tolerable anorectal dysfunction.

Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for patients with locally advanced rectal cancer (LARC). Therapeutic efficacy of nCRT is significantly affected by treatment-induced diarrhea and hematologic toxicities. Metabolic alternations in cancer therapy are key determinants to therapeutic toxicities and responses, but exploration in large-scale clinical studies remains limited. Here, we analyze 743 serum samples from 165 LARC patients recruited in a phase III clinical study using untargeted metabolomics and identify responsive metabolic traits over the course of nCRT. Pre-therapeutic serum metabolites successfully predict the chances of diarrhea and hematologic toxicities during nCRT. Particularly, levels of acyl carnitines are linked to sex disparity in nCRT-induced diarrhea. Finally, we show that differences in phenylalanine metabolism and essential amino acid metabolism may underlie distinct therapeutic responses of nCRT. This study illustrates the metabolic dynamics over the course of nCRT and provides potential to guide personalized nCRT treatment using responsive metabolic traits.