The National Accreditation Program for Rectal Cancer (NAPRC) was established in 2017 to decrease rectal cancer treatment variation and improve oncologic outcomes. Initiating curative intent treatment <60 days of first evaluation is one NAPRC standard. We evaluated whether oncologic outcomes improved with timely treatment and factors associated with its receipt.

Using the NCDB, we identified stage I to III rectal cancer patients treated from 2004 to 2020 treated with curative-intent surgery. Patients were stratified into 2 cohorts (timely [<60 d], delayed [≥60 d]) for survival analysis and exploration of variables associated with timely treatment.

We included 117,459 patients with a median age of 61 years (interquartile range: 52 to 70 y). Most patients were male (61.1%), White (86.2%), Charlson 0 (77.1%) with stage II (33.5%) or III (44.3%) cancer treated with chemoradiation (58.1%), or surgery (27.0%) first. Timely treatment was associated with improved overall survival (OS; median OS: 153.26 vs. 128.59 m). Patients in the highest income bracket (odds ratio [OR] 1.30) with stage II (OR: 1.27) or III (OR: 1.50) cancer receiving neoadjuvant chemotherapy (OR: 2.24) or chemoradiation (OR: 1.73) as the first treatment received more timely treatment. Patients with Charlson ≥2 (OR: 0.83) of Black (OR: 0.56) or Hispanic (OR: 0.73) race received more delayed treatment (all P <0.01).

Timely rectal cancer treatment is associated with improved survival. Socioeconomic disparities limit timely treatment with attendant worse survival, supporting national homogenization of care. As multimodal care for rectal cancer becomes increasingly complex, timely treatment remains paramount.

Total neoadjuvant therapy has been shown to increase pathological complete response and disease-free survival in patients with locally advanced rectal cancer after total mesorectal excision (TME). We hypothesised that total neoadjuvant therapy could maximise the number of patients attaining a clinical complete response who could then be instead referred to organ preservation with watch and wait.

This open-label, multicentre, single-arm, phase 2 study (CAO/ARO/AIO-16) was conducted at four centres across Germany. Patients aged 18 years or older with histologically confirmed cT1-2N1-2 or cT3a-dN0/N1-2 rectal adenocarcinoma up to 12 cm from the anal verge and without distant metastases received chemoradiotherapy. Radiotherapy was administered in daily fractions of 1·8 Gy, 5 days per week, starting at day 1 and ending at day 38, for a total of 28 fractions and total dose of 50·4 Gy. Concomitant fluorouracil (250 mg/m2 per day as a continuous venous infusion from day 1 to day 14 and day 22 to day 35) and oxaliplatin (50 mg/m2 intravenously on days 1, 8, 22, and 29) were administered. Chemoradiotherapy was followed by three cycles of consolidation FOLFOX (fluorouracil [2400 mg/m2 over 46 h by continuous venous infusion], oxaliplatin [100 mg/m2 intravenously as a 2-h infusion], and leucovorin [400 mg/m2 intravenously as a 2-h infusion]) starting on days 57, 71, and 85. Response assessment was scheduled on day 106 after the start of total neoadjuvant therapy and included digital rectal examination, rectoscopy, and pelvic MRI. In case of a clinical complete response, patients were scheduled for a watch and wait surveillance protocol. Patients with a near clinical complete response on day 106 were offered a second assessment on day 196. In case of conversion to a clinical complete response on this repeated assessment, the same watch and wait surveillance protocol was initiated. Alternatively, local excision was considered on day 196 if technically feasible. In all other cases, immediate TME surgery was recommended. The primary endpoint was the clinical complete response rate on day 106 or 196 assessed in patients who started chemoradiotherapy (intention-to-treat population). Toxicity was also assessed in this patient population. The study was registered with ClinicalTrials.gov (NCT03561142) and is complete.

Between June 1, 2018, and Oct 7, 2020, we enrolled 93 patients, of whom 91 (mean age 61 years [SD 10]; 61 [67%] men and 30 [33%] women) started chemoradiotherapy, 88 started consolidation chemotherapy, and 88 had a response assessment on day 106. At this first assessment, 13 (15%) patients were classified as having a clinical complete response and were assigned to watch and wait, 33 (38%) met criteria for a near clinical complete response and were scheduled for reassessment, and 42 (48%) had a poor response and were referred for immediate TME. At the second assessment, on day 196, 21 (64%) of 33 patients converted to a clinical complete response, two underwent local excision with a pathological complete response (and were also assigned to watch and wait), and ten had TME. Therefore, for the primary endpoint, 34 (37%) of the initial 91 patients attained a clinical complete response after total neoadjuvant therapy. Overall, 33 (36%) of 91 patients developed grade 3 or 4 toxicity during total neoadjuvant therapy. 17 (19%) patients developed grade 3 toxicity during chemoradiotherapy, with no grade 4-5 toxicity occurring at this treatment stage. The most frequently reported grade 3 toxicities during chemoradiotherapy were diarrhoea in nine (10%) patients and infections in six (7%). During consolidation chemotherapy, 17 (19%) of 88 patients had grade 3 toxicities, the most common of which were leucopenia (in seven [8%] patients) and neutropenia (in seven [8%]). One (1%) patient had grade 4 neutropenia and one patient died of COVID-19-associated pneumonia. Grade 3 and grade 4 adverse events during follow-up were recorded in 19 (21%) of 91 patients.

Upfront chemoradiotherapy and three cycles of consolidation FOLFOX result in a high rate of clinical complete response with an acceptable toxicity profile. Total neoadjuvant therapy combined with a watch and wait approach after a clinical complete response can be considered for patients with locally advanced rectal cancer seeking an alternative to TME surgery.

Medical Faculty Tübingen.

As patients with rectal cancer with clinical complete response (cCR) after neoadjuvant therapy may be safely spared Total Mesorectal Excision (TME), strategies to maximize cCR are needed.

We conducted a single-arm phase II study to determine whether dose-escalated short-course radiotherapy (25 Gy/5 fractions + 5 Gy/1 fraction boost) followed by eight cycles of FOLFOXIRI increased cCR rates among adult patients with > T2N0M0 or low T2N0 rectal cancer.

Between 2020 and 2023, we enrolled 37 patients, of whom 27 (73 %) had at least one high-risk feature (cT4, extramural vascular invasion [EMVI], N2, threatened circumferential resection margin, positive lateral node). At primary endpoint assessment, nine (24 %) patients had cCR on both endoscopy and MRI, and pursued organ preservation (OP). Fourteen (38 %) patients had cCR only on endoscopy, nine of whom pursued OP. Of the 18 patients who pursued OP, nine had local regrowth at two years from radiotherapy start, with two-year TME-free survival of 26 %. Baseline factors significantly associated with not achieving OP included age < 50 years and T4 disease. At mid-treatment restaging, patients who achieved OP were significantly less likely to have persistent node positivity, EMVI, and endoscopically visible tumor. Grade 3+ adverse events at least possibly attributed to chemotherapy and radiotherapy occured in 51% and 43% of patients, respectively.

Short-course radiotherapy with a boost followed by FOLFIXIRI results in OP in one-quarter of patients with high-risk rectal cancer, with poorer response among younger patients and T4 disease. Mid-treatment response may help guide timely decision-making regarding treatment.

To evaluate the feasibility and utility of an LET-optimized proton treatment planning algorithm in locally advanced rectal cancer and to assess whether the degree of LET-optimization achieved in clinical plans improves efficacy and toxicity in preclinical models.

A series of five rectal cancer patients treated with standard 25 fraction clinical proton plans were re-planned using an LET-optimization treatment planning algorithm and evaluated for dosimetric endpoints. LET-optimized plans were generated using an algorithm which iteratively increases the weights of higher LET spots in GTV and lower LET in OARs. Murine and in vitro preclinical models of tumor efficacy and normal tissue toxicity were evaluated using comparable LETd range to that achieved in clinical LET-optimized plans.

LET-optimized proton plans increased dose-averaged LET (LETd) in the GTV and LET-weighted dose in the GTV, and CTV5625cGy V100% coverage. At the same time, LET-optimization also decreased mean LET-weighted dose to bladder and small bowel, as well as small bowel V30Gy(cc) compared to standard proton plans. Optimizing the LETd to a volume of GTV-3 mm further increased LETd compared to total GTV. LET-optimization in preclinical models increased tumor efficacy in colorectal cancer cell lines in vitro and decreased small bowel radiation enteropathy in murine models of normal tissue toxicity.

LET-optimized proton plans increased LETd in gross tumor while maintaining or improving target coverage and OAR sparing, with acceptable plan robustness. Preclinical models demonstrated that comparable LET-optimization may increase tumor efficacy and decrease normal tissue toxicity in rectal cancer.

In the last decade, the role of radiotherapy in rectal cancer has changed significantly with the introduction of total neoadjuvant therapy (TNT) and nonoperative management (NOM). For the setting of irradiation field in rectal cancer, the pararectal, lateral lymph nodes, and those along the inferior mesenteric artery (IMA) are most important. In total mesorectal excision (TME), the root of the IMA is dissected. In the atlas of pelvic irradiation for rectal cancer, the setting of the upper margin of the mesorectum varies from atlas to atlas, and no atlas sets the upper margin of the mesorectum to the root of the IMA. In particular, there is no consensus on the definition of anatomical boundaries regarding the lymph nodes along the superior rectal artery (SRA). The upper margin of the irradiation field in clinical trials of preoperative radiotherapy and TNT is generally set at the level of the internal and external iliac artery branches, L5/S1, or S2/S3. However, it is not necessary to include the entire mesorectum to the root of the IMA in patients undergoing preoperative radiotherapy plus TME. Conversely, for patients receiving NOM, the irradiation field may have to include the mesorectum to the IMA root, though the incidence of lymph node metastasis and gastrointestinal adverse events merits consideration. It is increasingly important to determine the extent of clinical target volume around the SRA region and the setting of the upper margin of the irradiation field after formulating the treatment policy together with the surgeons and medical oncologists.

Total neoadjuvant therapy (TNT) has become the standard of care in locally advanced rectal cancer, but its economic impact is unclear. This study compares the cost of TNT with conventional neoadjuvant therapy (CNT), consisting of either short-course radiotherapy or long-course chemoradiotherapy, within a universally funded public healthcare system.

A trial-based costing analysis was conducted from a third-party payer's perspective with a 2-year time horizon, following CHEERS guidelines. Consecutive patients with rectal cancer treated with neoadjuvant therapy from 2014 to 2023 were extracted from a multi-institutional database. Inpatient, outpatient, imaging and pathology resource costs were extracted and adjusted to 2024 AUD with a 5% discount rate. Primary outcomes were overall cost per cohort and mean per patient cost. Secondary outcomes were overall and mean cost per cost category. Sensitivity analysis explored the influence of discount rates and inflation methods.

Of 115 eligible patients, 60 (52.2%) received CNT and 55 (47.8%) received TNT. Overall treatment costs for the cohorts were $8 429 710.66 (CNT) and $6 992 616.67 (TNT), with mean per patient costs of $140 495.18 (CNT) and $127 138.48 (TNT). Overall per patient costs were $13 356.70 (9.51%) lower for TNT patients, mainly driven by lower mean inpatient costs ($78 523.53 vs. $96 843.08, 18.9%). TNT increased outpatient ($43 001.18 vs. $39 376.12, 9.21%), imaging ($4179.13 vs. $2973.61, 40.5%) and pathology ($1434.65 vs. $1302.38, 10.1%) costs. The results were robust to sensitivity analysis.

TNT is less costly than CNT within a universally funded public healthcare system, primarily due to reduced inpatient costs associated with higher rates of organ preservation.

Chemoradiotherapy plus total mesorectal excision has been established as the standard treatment for locally advanced rectal cancer (LARC) and can achieve satisfactory local control. However, systemic control of LARC, especially in patients with risk factors for poor prognosis, is still of concern. As application of total neoadjuvant therapy (TNT) has been proposed as a potential solution, a clearer risk stratification of LARC to guide individual treatment is needed. Combination therapy such as targeted therapy or immunotherapy can be used to increase treatment intensity for high-risk LARC. In this review, we evaluate recent trials of several treatment modalities, specifically focusing on intensified TNT regimens for high-risk LARC with the goal of summarizing optimal clinical strategies and future study designs.

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 Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

Rectal cancer poses a significant global health burden. Conventional neoadjuvant chemoradiotherapy (nCRT) demonstrates limited efficacy in achieving disease-free survival (DFS) and organ preservation. Total neoadjuvant therapy (TNT), an emerging paradigm integrating systemic chemotherapy with radiotherapy, aims to address these limitations.

To evaluate the short- and long-term oncological outcomes and organ preservation feasibility of TNT in high-risk locally advanced rectal cancer (LARC) patients.

A retrospective study was conducted to analyze the short-term and long-term results after total nCRT.

This retrospective study involved 110 rectal cancer patients with high-risk features treated at the Fudan University Shanghai Cancer Center from 2008 to 2022. Patients underwent comprehensive staging and received nCRT followed by either total mesorectal excision (TME) or a watch and wait (W&W) strategy. The regimen included concurrent chemoradiotherapy with 50 Gy/25 fractions and at least six cycles of induction or consolidation chemotherapy. Both short-term and long-term outcomes were collected and analyzed.

Among the LARC patients, 73.6% were stage III, and 47.3% opted for the W&W strategy. The combined rate of clinical complete response or confirmed pathological complete response (pCR) reached 49.1%. During follow-up, 10% of patients experienced local regrowth. The 3-year DFS and overall survival (OS) rates were 75.7% and 92.4%, respectively. The W&W strategy could achieve superior outcomes than patients without pCR in DFS (p = 0.021) and OS (p = 0.006).

TNT demonstrates durable survival outcomes and facilitates organ preservation in over 50% of high-risk LARC patients. Intensive surveillance is critical for the early detection of local regrowth.

Our study is retrospective in nature, rather than a prospective clinical trial. Therefore, registration was not conducted, and the Clinical Trial Number is not applicable.

BackgroundNonoperative management in patients with rectal cancer with complete response to radiation therapy and chemotherapy is of increasing interest. Most of the data on nonoperative management have centered around patients treated with long-course chemoradiotherapy. The ability of short-course radiation-based treatment courses to achieve durable complete responses with sustained organ preservation is less defined. This study updates our institution's long-term experience with nonoperative management following upfront short-course radiation therapy and sequential/consolidation chemotherapy.MethodsWe retrospectively reviewed patients with nonmetastatic rectal cancer treated with sequential short-course radiation therapy and chemotherapy who reached complete response and were subsequently followed with nonoperative management. We report on disease control outcomes, including rates of regrowth and results of salvage surgery. We investigated characteristics associated with local tumor regrowth.ResultsOur study included 52 patients. The 2-year freedom from local regrowth for the entire cohort was 75%. Notably, patients with high-risk disease characteristics at diagnosis exhibited a trend toward a higher rate of local tumor regrowth. No patient with sustained clinical complete response developed metastatic disease. Of the twelve patients undergoing surgical salvage for regrowth of disease, ten were resected with complete/near-complete total mesorectal surgical specimens with negative margins.ConclusionsThe optimal approach to achieving sustained organ preservation through the use of radiation therapy and chemotherapy is not well defined. Our findings show the viability of neoadjuvant therapy incorporating short-course radiation therapy to achieve durable complete responses.

Background/Objectives: With recent advancements in rectal cancer management leading to longer patient survival, the impact of various treatment approaches on patients' quality of life (QOL) becomes an important focus of attention. While QOL studies exist for watch-and-wait after (chemo)radiation with/without local excision, data on health-related QOL (HRQOL) outcomes after contact X-ray brachytherapy (CXB) remain limited. This study evaluated functional and HRQOL outcomes in rectal cancer patients undergoing CXB and (chemo)radiation over one year. Methods: This prospective observational study (enrolment January-October 2023) with one-year follow-up assessed functional and HRQOL outcomes after CXB and (chemo)radiation using EORTC-QLQ-CR29, HADS, and EQ-5D-3L questionnaires. Longitudinal analyses were conducted using linear mixed-effects models, incorporating both fixed and random effects, following data processing based on relevant scoring manuals. Results: QOL was assessed in 53 patients who attended our centre for CXB for various clinical indications, with 51, 47, and 42 remaining at the end of treatment, 6-month, and 12-month follow-ups, respectively. Overall, symptom and functional scores from EORTC-QLQ-CR29 remained stable throughout the follow-up period. Significant improvements were observed in abdominal pain, flatulence, urinary frequency, and body weight at 12 months. HADS and EQ-5D-3L scores remained stable, while EQ-VAS scores showed improvement, indicating a good overall quality of life following CXB treatment. Conclusions: CXB treatment combined with (chemo)radiation maintained stable HRQOL, with some improvements in symptoms and QOL noted during the subsequent year. These findings will help rectal cancer patients understand the benefits and limitations of CXB as a treatment option.

There is increasing adoption of nonoperative management of rectal cancer; however, the extent to which trainees are proficient in nonoperative management is unclear. The aim of this work was to describe the exposure of recent colorectal resident graduates to nonoperative management, their comfort level in assessing clinical responses and their comfort in performing rectal cancer surgeries.

This was an online survey of Accreditation Council for Graduate Medical Education-certified colorectal surgery residency graduates of training programmes in 2020, 2021 and 2022 utilizing their respective WhatsApp class chat groups. Data on resident comfort in assessing complete or near complete clinical response as part of nonoperative management, adoption in practice and perceived effects on rectal cancer operative experience were collected.

Forty five graduates responded, with 83.3% exposed to nonoperative management in training. Eighty five per cent utilize nonoperative management in their own practices and 37.1% felt it had a negative impact on preparing them for rectal cancer surgeries. While 82.4% felt comfortable assessing a complete clinical response, only 61.8% felt comfortable assessing a near complete response. Residents who perceived a positive effect on their training felt more comfortable assessing a complete or near complete response.

Most recent graduates were exposed to nonoperative management in training and utilize it in practice, although many did not feel comfortable assessing a near complete response. A significant portion felt it had a negative impact on their experience and quantity of rectal cancer surgeries. This suggests a need to improve colorectal resident education in nonoperative management of rectal cancer while simultaneously preserving surgical experience for trainees.

The effect of neoadjuvant chemotherapy and chemoradiotherapy in patients with locally advanced rectal cancer, at increased risk of failing current treatment regimens, is unknown. This study compared the complete response rate and long-term survival of these patients treated with or without neoadjuvant chemotherapy prior to chemoradiotherapy.

Patients with high-risk locally advanced rectal cancer, who were surgically treated or entered a watch and wait approach after neoadjuvant chemoradiotherapy with or without neoadjuvant chemotherapy in Erasmus Medical Centre or Catharina Hospital between 2016 and 2020, were retrospectively identified. High-risk was defined as the presence of tumour invasion into the mesorectal fascia, grade 4 extramural venous invasion, enlarged lateral lymph nodes, or tumour deposits. The primary endpoint was complete response rate, which was defined as a histopathological complete response or a sustained (during 12 months) clinical complete response. Long-term oncological outcomes were evaluated based on Kaplan-Meier and Cox regression survival analyses.

The neoadjuvant chemotherapy group consisted of 64 patients, of whom 61 (95.3 %) were treated with chemotherapy prior to chemoradiotherapy, the chemoradiotherapy group of 194 patients. The complete response rates were 25.0 % and 9.8 %, respectively (P = 0.002). The estimated 3-year overall survival was 92.2 % in the neoadjuvant chemotherapy group versus 66.9 % in the chemoradiotherapy group.

Excellent oncological outcomes were observed in patients with high-risk locally advanced rectal cancer selected during a multidisciplinary team (MDT) meeting for neoadjuvant chemotherapy and chemoradiotherapy. The actual difference with patients treated with chemoradiotherapy alone should be investigated in prospective trials. Pretreatment referral to expert MDTs is encouraged.

Prospective data comparing watch-and-wait (WW) to mandatory total mesorectal excision (TME) in patients with locally advanced rectal cancer (LARC) remain limited, as randomized control trials assessing these two treatment approaches are considered impractical. This pooled analysis of the CAO/ARO/AIO-12 and OPRA trials analyzes survival outcomes among LARC patients managed with either a selective WW or mandatory TME strategy following total neoadjuvant therapy (TNT).

The CAO/ARO/AIO-12 and OPRA trials were multicenter, phase II trials that randomized patients with stage II/III rectal cancer to receive either induction or consolidation chemotherapy as part of TNT. All patients in the CAO/ARO/AIO-12 trial underwent TME within 6 weeks of completing TNT. The OPRA trial allowed patients with a complete or near-complete response to enter WW while those with an incomplete response proceeded to TME. The primary endpoint of the present pooled analysis was disease-free survival (DFS). Secondary endpoints included distant recurrence-free survival (DRFS), local recurrence-free survival (LRFS) and overall survival (OS).

This pooled analysis included 628 patients (n = 304 CAO/ARO/AIO-12; n = 324 OPRA). Median follow-up was 3.6 [interquartile range (IQR) 1.13] years and 5.1 (IQR 2.2) years, respectively. Patients in the CAO/ARO/AIO-12 trial were more likely to have cT3/4 and cN-positive disease while patients in the OPRA trial had tumors closer to the anal verge. Compliance to TNT and rates of grade 3+ adverse events were similar between studies. There were no differences in DFS, DRFS, LRFS or OS based on treatment strategy or TNT treatment arm.

This pooled analysis demonstrated equivalent oncologic outcomes between patients treated with mandatory TME and selective WW strategies following TNT. These results strengthen available evidence indicating that WW is a safe treatment option for patients with an excellent response to neoadjuvant therapy.

Among patients with rectal cancer who achieve a complete clinical response (cCR) after neoadjuvant therapy and undergo nonoperative management (NOM), a subset experience tumor regrowth and require salvage surgery. We sought to identify clinicopathologic factors associated with tumor regrowth to assist in patient selection for NOM.

Patients treated for rectal cancer at a single National Cancer Institute (NCI)-designated Comprehensive Cancer Center in whom NOM was pursued based on cCR or near-cCR were identified. Patients were stratified based on whether they developed tumor regrowth during follow-up. Tumor and treatment details were compared to identify factors affecting regrowth-free survival (RFS).

Among 125 patients, 26 (20.8%) experienced local regrowth and 8 (6.4%) experienced distant metastasis at a median follow-up of 35 months. Extramural vascular invasion (EMVI) and clinically positive pelvic sidewall lymph nodes (PSW) were associated with worse RFS (hazard ratio [HR] 2.48, 95% confidence interval [CI] 1.08-5.72, p = 0.03; HR 2.77, 95% CI 1.16-6.61, p = 0.002). Among 107 patients eligible for post hoc endoscopic evaluation, those with cCR (n = 80) at first endoscopic re-evaluation had trended towards higher RFS than those with near-cCR (n = 27; HR 2.12, 95% CI 0.95-4.75, p = 0.07), with a significant difference in patients without regrowth at 1 year (HR 5.58, 95% CI 1.23-25.32, p = 0.03).

Rectal cancer patients with high-risk magnetic resonance imaging (MRI) features, namely EMVI and positive PSW nodes, are more likely to experience tumor regrowth despite an excellent clinical response. Patients with a near-complete endoscopic response may also be at higher risk of later regrowth. The decision to attempt NOM should be carefully weighed against the increased risk of tumor regrowth.

The incidence of colorectal cancer (CRC) has been rising in recent years, with a concurrent increase in early-stage rectal cancer (ESRC) cases. This study aimed to investigate risk factors and developed nomograms to predict overall survival (OS) and cancer-specific survival (CSS) in ESRC patients in order to improve clinical outcomes across diverse patient subgroups.

Risk factors were investigated in ESRC patients by analyzing data from the Surveillance, Epidemiology, and End Results (SEER) database. We developed and validated nomograms to predict OS and CSS after dividing patients into two risk groups. Then we assessed the potential benefits of various therapies across subgroups after propensity score-matching (PSM).

T stage, tumor grade, age, carcinoembryonic antigen (CEA) levels, tumor size, and surgical options emerged as independent risk factors through univariate and multivariate Cox regression analyses, contributing to the OS nomogram; while for CSS, the identified risk factors were tumor grade, age, elevated CEA levels and surgical options. The Concordance-index of the nomogram surpassed that of the American Joint Committee on Cancer (AJCC) 7th staging system, with values of 0.69 (C-index, 0.64-0.74) in the training set and 0.65 (C-index, 0.62-0.68) in the testing set. The receiver operating characteristic (ROC) analysis revealed area under the curve (AUC) values of 0.70, 0.70, and 0.67 for 1-, 3-, and 5-year OS in the development cohort, with comparable results in the validation cohort. Calibration plots demonstrated strong alignment between predicted and observed outcomes. Decision curve analysis (DCA) confirmed the nomogram's superior clinical utility relative to the AJCC 7th staging system, with similar findings for CSS. Kaplan-Meier curves illustrated significant differences in OS and CSS between low- and high-risk groups. Notably, radiation and chemotherapy conferred no benefit, while low-risk patients, especially younger individuals, may benefit from local resection.

This study presents a comprehensive prognostic analysis of patients with ESRC and developed predictive nomograms for OS and CSS. Subgroup analyses highlight the potential benefits of local resection in younger patients with low risk.

We examined whether QuantCRC, a digital pathology segmentation algorithm, on pretherapy rectal cancer biopsies is associated with pathologic complete response (pCR) to neoadjuvant therapy, recurrence-free survival (RFS), and transcriptomic spatial profiling. QuantCRC was evaluated in an observational cohort of 288 pretherapy biopsies and a separate validation cohort of 37 pretherapy biopsies of rectal adenocarcinoma from patients undergoing neoadjuvant therapy. Associations between QuantCRC features and clinical outcomes, pCR, and RFS were analyzed using multivariable logistic regression and Cox proportional hazards modeling, respectively. QuantCRC variables were also correlated with transcriptomic digital spatial profiling of 37 pretreatment biopsies of cT3N+ rectal cancer. QuantCRC-derived lymphocytes per square millimeter of tumor epithelium (tumor-infiltrating lymphocytes [TILs]) was significantly associated with pCR (multivariate odds ratio, 1.05; 95% CI, 1.02-1.10; P = .038). QuantCRC-derived TILs were significantly higher in pretherapy biopsies with pCR (91.3 vs 55.9 lymphocytes/mm2; P = .004). The validation cohort confirmed that only QuantCRC-derived TILs in pretherapy biopsies of rectal cancer were significantly associated with complete response to neoadjuvant therapy. QuantCRC %high tumor grade was independently associated with worse RFS (multivariate hazards ratio, 1.27; 95% CI, 1.09-1.47; P = .002). Patients with ≥10.1% high tumor grade identified by QuantCRC had significantly reduced RFS (5-year RFS 69% vs 83%, log-rank P = .007). Transcriptomic profiling identified high interleukin (IL)-6/JAK/STAT3 signaling within immune cells to be associated with worse RFS (adjusted P = .01). Tumors with low IL-6/JAK/STAT3 expression within immune cells had significantly higher TILs compared with tumors with high expression (median, 152 vs 97 TILs/mm2; P = .039). Biopsy-adapted QuantCRC in pretherapy rectal cancer may be helpful in identifying patients who achieve pCR and are at risk for recurrence.

Among patients with mismatch repair-deficient (dMMR), locally advanced rectal cancer, neoadjuvant checkpoint blockade eliminated the need for surgery in a high proportion of patients. Whether this approach can be extended to all early-stage dMMR solid tumors, regardless of tumor site, is unknown.

We conducted a phase 2 study in which patients with stage I, II, or III dMMR solid tumors that were amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, for 6 months. The response to treatment was assessed in two cohorts: patients in cohort 1 had dMMR, locally advanced rectal cancer, and patients in cohort 2 had dMMR nonrectal solid tumors. Patients with a clinical complete response could elect to proceed with nonoperative management; those with residual disease were to undergo resection. In this analysis, the primary end point, assessed in cohort 1, was a sustained clinical complete response at 12 months. Recurrence-free survival and safety were evaluated.

A total of 117 patients were included in the analysis. In cohort 1, all 49 patients who completed treatment had a clinical complete response and elected to proceed with nonoperative management. A total of 37 patients had a sustained clinical complete response at 12 months, a finding that met the criterion for efficacy. In cohort 2, a total of 35 of 54 patients who completed treatment had a clinical complete response, and 33 elected to proceed with nonoperative management. Among the 103 patients who completed treatment across both cohorts, 84 had a clinical complete response, and 82 did not undergo surgery. Among the 117 total patients, recurrence-free survival at 2 years was 92% (95% confidence interval, 86 to 99); the median follow-up for recurrence was 20.0 months (range, 0 to 60.8). The majority of patients (95%) had reversible, grade 1 or 2 adverse events (60%) or had no adverse events (35%). The option for curative resection was not compromised during or after treatment in any of the patients.

Among patients with early-stage dMMR solid tumors that were amenable to curative-intent surgery, neoadjuvant PD-1 blockade led to organ preservation in a high proportion of patients. (Funded by Swim Across America and others; ClinicalTrials.gov number, NCT04165772.).

Objective.To quantify interfraction shape and positional variations of primary tumor volumes for rectal cancer patients receiving long course radiotherapy by comparing two quantification strategies: a center-of-mass (COM) method and a surface-based metric that captures local deformations.Approach.This study utilized repeat MRI scans before and during radiotherapy (RT) for rectal cancer to investigate the positional variation of the primary gross tumor volume (GTVp). Sixteen patients underwent six MRI exams, with the initial three before the RT course and the subsequent three at one, two, and four weeks into the RT course. GTVp's were delineated on 3D T2-weighted MRIs, and positional variation analyzed using both COM and point-based surface displacements against the initial scan. Surface displacements were quantified using a bidirectional local distance measure, analyzing 3D displacement vectors. Additionally, the study examined local right-left (RL) and anterior-posterior (AP) surface variations relative to tumor height in the rectum by mapping baseline GTVp volumes onto a reference rectum structure.Main results.Systematic error for COM measurements were 1.7, 1.3 and 2.0 mm for AP, RL, and cranial-caudal (CC) direction, respectively. Random errors were 2.1, 1.2 and 2.2 mm, while the GM errors were -0.3, 0.5 and -0.3 mm for AP, RL, and CC directions, respectively. An increase in systematic and random errors were observed when comparing 95th percentile surface displacements to the COM measurements, indicating local displacements which the COM did not detect. Additionally, a general tendency for higher-located tumors to experience larger left-right and AP surface variations were seen when evaluating the 95th percentile.Significance.COM-based analysis might underestimate local deformations. Consequently, surface-based methods might provide more robust estimations of systematic, random and group mean errors for planning target volume-margin calculation. The surface variations tend to increase for tumors located in the upper part of the rectum.

The management of locally advanced rectal cancer (LARC) has seen much development over recent decades. Neoadjuvant radiotherapy combined with high-quality total mesorectal excision saw improvements in locoregional control. With the advent of several key trials, neoadjuvant therapy for LARC has seen a shift toward total neoadjuvant therapy, with corresponding improvements in tumor response and survival outcomes. The collective pool of evidence has allowed for increasingly personalized treatment of LARC, with organ-preservation now an option for many. The aims of the review are to summarize the evolution of neoadjuvant therapy for LARC, highlight key studies informing contemporary best practices, navigate the complexity of options available, and present areas of ongoing development.

This network meta-analysis examined the efficacy of different types of neoadjuvant therapy (NAT) for rectal cancer in improving clinical and pathologic outcomes.

PRISMA-compliant systematic review of PubMed and Scopus including only randomized clinical trials comparing two or more NAT regimens for rectal cancer. A network meta-analysis was undertaken for the main outcomes, including pathological complete response (pCR), disease downstaging, R0 resection, permanent stoma, and major adverse effects. Risk of bias was assessed using the ROB-2 tool.

19 randomized controlled trials incorporating 7037 patients (62 % males) were included in the analysis. Compared to standard neoadjuvant chemoradiation (NCRT), consolidation total neoadjuvant therapy (TNT) (OR: 1.82, 95 % CI: 1.46-2.27; p < 0.001) and induction TNT (OR: 1.72, 95 % CI: 1.31-2.26; p < 0.001) had higher odds of achieving pCR. Induction TNT was also significantly associated with higher odds of major adverse effects than was NCRT (OR: 3.14, 95 % CI: 2.50-3.94; p < 0.0001). Compared to NCRT, long course chemotherapy significantly increased the odds of R0 resection (OR: 1.42, 95 % CI: 1.13-1.78; p = 0.002), while consolidation TNT significantly increased organ preservation rates (OR: 2.82, 95 % CI: 1.58-5.05; p < 0.001). Short course radiotherapy doubled the odds of positive circumferential resection margins (CRM) compared to NCRT (OR: 1.99, 95 % CI: 1.11-3.55; p = 0.02).

Consolidation and induction TNT were superior in achieving better pathological outcomes in rectal cancer, offering significant benefits over standard NCRT. However, they were associated with a higher risk of adverse effects. Conversely, short course radiotherapy was linked to higher rates of positive CRM.

Concurrent chemo-radiotherapy is standard of care for locally advanced cancer patients. While radiotherapy and immuno-oncology have advanced precision oncology, chemotherapies in the chemo-radiotherapy paradigm remain non-targeted cytotoxins. Antibody drug conjugates offer an opportunity for targeted radiosensitization that stimulates immune responses while protecting normal tissues. Here, we discuss the rationale for combining antibody drug conjugates, radiotherapy and immunotherapies and opportunities for clinical translation to advance towards targeted chemo-radio-immunotherapy precision cancer care.

To assess the reliability of rectal MRI radiomic features across reader expertise level, image segmentation technique, and timing of rectal MRI.

This retrospective single-institutional study included consecutive patients with rectal adenocarcinoma who underwent total neoadjuvant therapy from January 2018 to June 2018. Baseline and restaging rectal MRI T2-weighted images were segmented independently by six radiologists (two fellows, two non-rectal radiologists, and two rectal radiologists). Four segmentation strategies were used and varied by image segmentation technique and timing of rectal MRI: (a) baseline volume of interest (VOI), (b) baseline region of interest (ROI), (c) restaging VOI, and (d) restaging ROI. Inter-reader agreement on each extracted radiomic feature was evaluated using the intra-class correlation coefficient (ICC).

Among 24 patients (16 men; median age, 56 years [interquartile range: 49-62]), 1,595 radiomic features were extracted. Baseline VOI segmentation achieved the highest inter-reader agreement rate, with 68 % (1,079/1,595) of radiomic features having an ICC > 0.7. Restaging ROI segmentation achieved the worst inter-reader agreement rate, with only 26 % (415/1,595) of radiomic features having an ICC > 0.7. First-order statistics and Gray Level Co-occurrence Matrix (GLCM) feature subgroups showed high inter-reader agreement rates, and the application of 'Square Root' and 'LOG Sigma' filters resulted in improved inter-reader agreement rates relative to original images. The expertise level of radiologists performing the segmentations did not affect the distribution of inter-agreement rates according to image segmentation technique or timing of rectal MRI.

Radiomic features were more reliable when extracted from baseline (vs. restaging) rectal MRIs and using 3D volume of interest (vs. 2D region of interest) segmentation, independent of the expertise level of the radiologists performing the segmentation.

Radiomic studies on rectal MRI employ various segmentation strategies and few assess their impact on reproducibility. Establishing the optimal segmentation method enhances radiomics model generalizability, potentially bridging the gap in clinical translation and improving clinical management of patients.

An increasing number of patients with rectal cancer who respond well to neoadjuvant chemoradiotherapy (nCRT) are being considered for organ preservation programs. However, due to the lack of high-level evidence, the survival outcomes of the organ preservation programs are still full of controversy and uncertainty.

To assess the effects of total mesorectal excision (TME) surgery, watch-and-wait (W&W), and local excision (LE) on long-term outcomes after nCRT, we searched PubMed, Embase, and Web of Science for articles published between 1 January 2010, and 31 December 2023.

We found 7029 pieces of literature, of which 26 studies met the inclusion criteria, and recruited 2778 participants in the network meta-analysis. Risk of bias assessment showed that most included studies had a low risk of bias. Low-certainty evidence suggests that the TME group was significantly superior to all other interventions for the 2-year local regrowth rate. (W&W group [OR, 0.20; 95% CI, 0.12-0.35], LE group compared with TME group [3.00; 1.60-5.80]). There was no significant difference in the 2-year local regrowth rate between W&W and LE group (OR, 0.60; 95% CI, 0.32-1.20). There was high to moderate certainty evidence that at 3 years, the W&W group had a significant advantage in overall survival compared with the TME group (OR, 0.37; 95% CI, 0.09-0.95). After 5 years, no significant difference in overall survival was found between the 3 treatment modalities.

We concluded that TME achieved the most significant reduction in 2-year local regrowth rates. However, the W&W strategy and LE demonstrated noninferiority to TME in long-term survival outcomes.

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.

The role of FDG-PET in the restaging rectal cancer following neoadjuvant therapy (NAT) is not clear. We compared the accuracy of FDG-PET and MRI in the assessment of rectal cancer response to NAT.

Data of patients treated between January 2015 and September 2022 were captured from a rectal tumor registry. Restaging FDG-PET and MRI were evaluated for the presence of viable tumor. Imaging was compared to the reference standard of pathological results for patients that underwent surgery, and sustained clinical complete response for patients that entered watch and wait. Sensitivity was defined as correctly identifying patients with a complete response.

Eighty-two patients met the inclusion criteria. Of these, 60 patients underwent restaging MRI and 54 underwent restaging FDG-PET. Thirty-two were evaluated by both modalities. Mean age and distance from anal verge were 59.9 ± 12.7 years and 5.9 ± 3.2 cm. Baseline staging was cT1-2, cT3 and cT4 for 7 (8.5%), 62 (75.6%) and 13 (15.9%) of the patients, respectively. Baseline nodal staging was cN0 and cN + for 32 (39%) and 50 (61%) of the patients, respectively. All patients were treated with radiation with the majority 73 (89%) receiving chemoradiotherapy. There were 17 patients (21%) that had a pathological or sustained clinical complete response. All baseline characteristics were not meaningfully different between groups. MRI was more accurate than FDG-PET in all parameters including sensitivity, specificity, positive and negative predictive value and overall accuracy.

MRI outperforms FDG-PET in the identification of complete response in rectal cancer patients after NAT.

Organ preservation through a watch-and-wait (W&W) strategy has become a viable option for select rectal cancer patients with clinical complete responses (cCR) to total neoadjuvant therapy (TNT). This approach limits the morbidity associated with multimodal treatment. However, the optimal treatment strategy and predictors of treatment response are still unresolved. Rectal cancer incidence is rising, particularly in developing countries, and the disease is a major public health concern in Chile. Prior to the no operation after short-course radiotherapy followed by consolidation chemotherapy in locally advanced rectal cancer (NOAHS-ARC) trial, TNT-based treatments and W&W programs had not been implemented in Chile.

This single-arm, multicenter, phase II prospective trial, conducted in Santiago, Chile, will enroll patients with stage II/III rectal adenocarcinoma. Treatment involves induction short-course radiotherapy (25 Gy in 5 fractions) followed by consolidation chemotherapy (FOLFOX × 9 or CAPOX × 6 cycles). The response will be assessed 4-8 weeks after chemotherapy completion. Patients achieving cCR will be offered W&W, while those with incomplete responses will undergo total mesorectal excision. The primary endpoint is the rate of complete tumor response, combining pathologic complete responses (pCR) and sustained cCR (> 1 year), compared to a matched cohort treated with neoadjuvant chemoradiation alone. The trial aims to recruit 48 patients, assuming a combined pCR/sustained cCR rate of 12%. Quality of life measures will be assessed, and a biorepository of tissue and plasma samples will be established for future research, alongside serial endoscopic and MRI images.

NOAHS-ARC seeks to advance organ preservation strategies in rectal cancer while pioneering TNT and W&W protocols in Chile. The study will also focus on functional outcomes and provide valuable data for improving patient care both locally and globally.

ClinicalTrials.gov identifier NCT04864067. Registered on April 28, 2021.

The Eastern Canadian Gastrointestinal Cancer Consensus Conference was an annual meeting that was held in St. John's, Newfoundland and Labrador, from 26 to 28 September 2024. This included experts in medical oncology, radiation oncology, surgical oncology, nuclear medicine, and general practitioners in oncology (GPO) from across the eastern Canadian provinces who are involved in the management of patients with gastrointestinal malignancies. This consensus statement generated by the conference addresses multiple topics, including the management of localized rectal cancer, liver-limited colorectal cancer, systemic therapy for advanced biliary tract cancers, radioligand therapy for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), systemic therapy for pancreatic and midgut well-differentiated NETs, and systemic therapy for HER2-positive gastroesophageal cancers.

In recent years, new therapeutic approaches have emerged in addition to classical neoadjuvant (chemo)radiotherapy for the treatment of locally advanced rectal cancer (LARC): total neoadjuvant treatment, non-operative management, and radiotherapy-free strategy. While the introduction of these approaches in a relatively short timeframe has quickly increased our therapeutic armamentarium, on the other hand it has complicated the decision-making process regarding the choice of the most appropriate treatment strategy for each patient with LARC. Therefore, a tool to interpret the evidence from clinical trials and to translate them into daily practice is highly demanded. In the present review, we address how these new developments are changing the multimodal treatment of LARC and offer an algorithm to integrate them into clinical practice.

The combination of capecitabine and oxaliplatin (CAPOX) is commonly used in patients with localized colorectal cancer (CRC) receiving curative-intent treatment. Our study aimed to assess the real-world tolerability of CAPOX in a single-institution cohort of patients with localized CRC.

This is a single-institution retrospective study that included patients with localized CRC receiving neoadjuvant or adjuvant CAPOX. The primary end point was completion rate of intended number (obtained by chart review) of CAPOX cycles irrespective of dose levels. Secondary outcome measures included the rate of grade ≥3 adverse events, hospital admission rate, and dose reductions.

The study included 153 patients with a median age of 61 years; 49% were female and 78.4% had stage III CRC. The proportion of patients (95% CI) who completed all planned CAPOX cycles was 44.4% (36 to 52) in the entire cohort and 34.6% (23 to 45) among female patients. Independent variables associated with treatment completion in multivariable analysis were race, sex, and intended number of cycles. Notably, the therapy completion rates (95% CI) were 55% (43 to 66) and 33% (20 to 45) in patients intended to receive four and eight cycles of CAPOX, respectively. The rate of grade ≥3 adverse events and hospitalization because of CAPOX-related toxicity were 30.7% (95% CI, 23 to 38) and 17.6% (95% CI, 11 to 23), respectively.

This study highlights that a substantial number of patients with localized CRC undergoing curative-intent treatment with CAPOX do not complete the planned cycles of chemotherapy because of toxicity. These findings underscore the need for careful patient selection and appropriate supportive care to optimize the therapeutic benefit of CAPOX in this setting.

Rectal cancer patients display heterogeneous responses to neoadjuvant treatment-including the intensive total neoadjuvant therapy (TNT)-and reliable biomarkers are lacking to guide which tumors will benefit most from these regimens. Here, we profiled DNA methylation in tumor tissue and matched patient-derived organoids (PDOs) from 18 rectal cancer cases (50 total samples), leveraging the Illumina MethylationEPIC array and quality control filters that retained 771,964 CpG sites. Analyses used linear models (for tissue-only or PDO-only) and a joint linear mixed-effects approach (accounting for patient-level random effects) to identify significant CpGs associated with log-transformed FOLFOX IC50. We found that PDOs faithfully recapitulate patient-tumor methylation patterns (Spearman's correlation >0.95 among replicate organoids), and the joint model uncovered 745 CpGs tied to FOLFOX sensitivity, many of which were missed in tissue-only analyses. Differentially methylated regions reinforced that broader epigenetic blocks near TSS or enhancer regions may modulate chemo-resistance, while pathway enrichment pinpointed focal adhesion, ECM-receptor interaction, calcium signaling, and folate metabolism as key processes. A methylation risk score derived from these CpGs significantly predicted progression-free survival in an independent colorectal cancer cohort (p=0.019), outperforming single-sample-based signatures. These findings suggest that combining methylation profiles from both tumors and PDOs can expose robust epigenetic drivers of therapy response, aiding the development of clinically actionable biomarkers for rectal cancer TNT.