Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Dutch national guidelines for locally recurrent rectal cancer.

Due to improvements in treatment for primary rectal cancer, the incidence of LRRC has decreased. However, 6-12% of patients will still develop a local recurrence. Treatment of patients with LRRC can be challenging, because of complex and heterogeneous disease presentation and scarce - often low-grade - data steering clinical decisions. Previous consensus guidelines have provided some direction regarding diagnosis and treatment, but no comprehensive guidelines encompassing all aspects of the clinical management of patients with LRRC are available to date. The treatment of LRRC requires a multidisciplinary approach and overarching expertise in all domains. This broad expertise is often limited to specific expert centres, with dedicated multidisciplinary teams treating LRRC. A comprehensive, narrative literature review was performed and used to develop the Dutch National Guideline for management of LRRC, in an attempt to guide decision making for clinicians, regarding the complete clinical pathway from diagnosis to surgery.

Oncological outcomes after a pathological complete response following total neoadjuvant therapy or chemoradiotherapy for high-risk locally advanced rectal cancer in the RAPIDO trial.

BACKGROUND: A pathological complete response (pCR) following chemoradiation (CRT) or short-course radiotherapy (scRT) leads to a favourable prognosis in patients with rectal cancer. Total neo-adjuvant therapy (TNT) doubles the pCR rate, but it is unknown whether oncological outcomes remain favourable and whether the same characteristics are associated with pCR as after CRT. METHODS: Comparison between patients with pCR in the RAPIDO trial in the experimental [EXP] (scRT, chemotherapy, surgery, as TNT) and standard-of-care treatment [STD] (CRT, surgery, postoperative chemotherapy depending on hospital policy) groups. Primary and secondary outcomes were time-to-recurrence (TTR), overall survival (OS) and association between patient, tumour, and treatment characteristics and pCR. RESULTS: Among patients with a resection within six months after preoperative treatment, 120/423 (28%) [EXP] and 57/398 (14%) [STD] achieved a pCR. Following pCR, 5-year cumulative TTR and OS rates in the EXP and STD arms were 8% vs. 7% (hazard ratio 1.04, 95%CI 0.32-3.38) and 94% vs. 93% (hazard ratio 1.41, 95%CI 0.51-3.92), respectively. Besides the EXP treatment (odds ratio 2.70, 95%CI 1.83-3.97), pre-treatment carcinoembryonic antigen (CEA) <5, pre-treatment tumour size <40 mm and cT2 were associated with pCR. Distance from the anal verge was the only characteristic with a statistically significant difference in association with pCR between the EXP and STD treatment (Pinteraction=0.042). pCR rates did not increase with prolonged treatment time. CONCLUSIONS: The doubled pCR rate of TNT compared to CRT results in similar oncological outcomes. Characteristics associated with pCR are the EXP treatment, normal CEA, and small tumour size.

Prognostic significance of MRI-detected extramural venous invasion according to grade and response to neo-adjuvant treatment in locally advanced rectal cancer A national cohort study after radiologic training and reassessment.

BACKGROUND: Detection of grade 3-4 extra mural venous invasion (mrEMVI) on magnetic resonance imaging (MRI) is associated with an increased distant metastases (DM)-rate. This study aimed to determine the impact of different grades of mrEMVI and their disappearance after neoadjuvant therapy. METHODS: A Dutch national retrospective cross-sectional study was conducted, including patients who underwent resection for rectal cancer in 2016 from 60/69 hospitals performing rectal surgery. Patients with a cT3-4 tumour ≤8 cm from the anorectal junction were selected and their MRI-scans were reassessed by trained abdominal radiologists. Positive mrEMVI grades (3 and 4) were analyzed in regard to 4-year local recurrence (LR), DM, disease-free survival (DFS) and overall survival (OS). RESULTS: The 1213 included patients had a median follow-up of 48 months (IQR 30-54). Positive mrEMVI was present in 324 patients (27%); 161 had grade 3 and 163 had grade 4. A higher mrEMVI stage (grade 4 vs grade 3 vs no mrEMVI) increased LR-risk (21% vs 18% vs 7%, <0.001) and DM-risk (49% vs 30% vs 21%, p < 0.001) and decreased DFS (42% vs 55% vs 69%, p < 0.001) and OS (62% vs 76% vs 81%, p < 0.001), which remained independently associated in multivariable analysis. When mrEMVI had disappeared on restaging MRI, DM-rate was comparable to initial absence of mrEMVI (both 26%), whereas LR-rate remained high (22% vs 9%, p = 0.006). CONCLUSION: The negative oncological impact of mrEMVI on recurrence and survival rates was dependent on grading. Disappearance of mrEMVI on restaging MRI decreased the risk of DM, but not of LR.

Impact of the new rectal cancer definition on multimodality treatment and interhospital variability: Results from a nationwide cross-sectional study.

AIM: This study aimed to determine the consequences of the new definition of rectal cancer for decision-making in multidisciplinary team meetings (MDT). The new definition of rectal cancer, the lower border of the tumour is located below the sigmoid take-off (STO), was implemented in the Dutch guideline in 2019 after an international Delphi consensus meeting to reduce interhospital variations. METHOD: All patients with rectal cancer according to the local MDT, who underwent resection in 2016 in the Netherlands were eligible for this nationwide collaborative cross-sectional study. MRI-images were rereviewed, and the tumours were classified as above or on/below the STO. RESULTS: This study registered 3107 of the eligible 3178 patients (98%), of which 2784 patients had an evaluable MRI. In 314 patients, the tumour was located above the STO (11%), with interhospital variation between 0% and 36%. Based on TN-stage, 175 reclassified patients with colon cancer (6%) would have received different treatment (e.g., omitting neoadjuvant radiotherapy, candidate for adjuvant chemotherapy). Tumour location above the STO was independently associated with lower risk of 4-year locoregional recurrence (HR 0.529; p = 0.030) and higher 4-year overall survival (HR 0.732; p = 0.037) compared to location under the STO. CONCLUSION: By using the STO, 11% of the prior MDT-based diagnosis of rectal cancer were redefined as sigmoid cancer, with potential implications for multimodality treatment and prognostic value. Given the substantial interhospital variation in proportion of redefined cancers, the use of the STO will contribute to standardisation and comparability of outcomes in both daily practice and trial settings.

Value of Size and Malignant Features of Lateral Lymph Nodes in Risk Stratification at Lateral Local Recurrence of Rectal Cancer: A National Cohort Study.

BACKGROUND: Patients with rectal cancer who have enlarged lateral lymph nodes (LLNs) have an increased risk of lateral local recurrence (LLR). However, little is known about prognostic implications of malignant features (internal heterogeneity, irregular margins, loss of fatty hilum, and round shape) on MRI and number of enlarged LLNs, in addition to LLN size. METHODS: Of the 3,057 patients with rectal cancer included in this national, retrospective, cross-sectional cohort study, 284 with a cT3-4 tumor located ≤8 cm from the anorectal junction who received neoadjuvant treatment and who had visible LLNs on MRI were selected. Imaging was reassessed by trained radiologists. LLNs were categorized based on size. Influence of malignant features and the number of LLNs on LLR was investigated. RESULTS: Of 284 patients with at least 1 visible LLN, 122 (43%) had an enlarged node (≥7.0 mm) and 157 (55%) had malignant features. Of the 122 patients with enlarged nodes, 25 had multiple (≥2). In patients with a single enlarged node (n=97), a single malignant feature was associated with a 4-year LLR rate of 0% and multiple malignant features was associated with a rate of 17% (P=.060). In the group with multiple malignant features, their disappearance on restaging was associated with an LLR rate of 13% compared with an LLR rate of 20% for persistent malignant features (P=.532). The presence of intermediate-size LLNs (5.0-6.9 mm) with at least 1 malignant feature was associated with a 4-year LLR rate of 8%; the 4-year LLR rate was 13% when the malignant features persisted on restaging MRI (P=.409). Patients with multiple enlarged LLNs had a 4-year LLR rate of 28% compared with 11% for those with a single enlarged LLN (P=.059). CONCLUSIONS: The presence of multiple enlarged LLNs (≥7.0 mm), as well as multiple malignant features in an enlarged node contribute to the risk of developing an LLR. These radiologic features can be used for clinical decision-making regarding the potential benefit of LLN dissection.

Lymph node regression after neoadjuvant chemoradiotherapy in rectal cancer.

AIMS: Lymph node metastases (LNM) are one of the most important prognostic indicators in solid tumours and a major component of cancer staging. Neoadjuvant therapy might influence nodal status by induction of regression. Our aim is to determine the prevalence and role of regression of LNM on outcomes in patients with rectal cancer. METHODS AND RESULTS: Four independent study populations of rectal cancer patients treated with similar regimens of chemoradiotherapy were pooled together to obtain a total cohort of 469 patients. Post-treatment nodal status (ypN) and signs of tumour regression (Reg) were incorporated to form three-tiered (ypN- Reg+, ypN- Reg- and ypN+) and four-tiered (ypN- Reg+, ypN- Reg-, ypN+ Reg+ and ypN+ Reg-) classifications. In our cohort, 31% of patients presented with ypN+ rectal cancer. As expected, we found significantly worse overall survival (OS) in ypN+ patients compared to ypN- patients (P = 0.002). The percentage of ypN- patients with lymph nodes with complete regression was 20% in our cohort. While node-negative patients with and without regression had similar OS (P = 0.09), disease-free survival (DFS) was significantly better in node-negative patients with regression (P = 0.009). CONCLUSIONS: Regression in lymph nodes is frequent, and node-negative patients with evidence of lymph node regression have better DFS compared to node-negative patients without such evidence.

Prognostic Implications of Lateral Lymph Nodes in Rectal Cancer: A Population-Based Cross-sectional Study With Standardized Radiological Evaluation After Dedicated Training.

BACKGROUND: There is an ongoing discussion regarding the prognostic implications of the presence, short-axis diameter, and location of lateral lymph nodes. OBJECTIVE: To analyze lateral lymph node characteristics, the role of downsizing on restaging MRI, and associated local recurrence rates for patients with cT3-4 rectal cancer after MRI re-review and training. DESIGN: Retrospective population-based cross-sectional study. SETTINGS: This collaborative project was led by local investigators from surgery and radiology departments in 60 Dutch hospitals. PATIENTS: A total of 3057 patients underwent rectal cancer surgery in 2016: 1109 had a cT3-4 tumor located ≤8 cm from the anorectal junction, of whom 891 received neoadjuvant therapy. MAIN OUTCOME MEASURES: Local recurrence and (ipsi) lateral local recurrence rates. RESULTS: Re-review identified 314 patients (35%) with visible lateral lymph nodes. Of these, 30 patients had either only long-stretched obturator (n = 13) or external iliac (n = 17) nodes, and both did not lead to any lateral local recurrences. The presence of internal iliac/obturator lateral lymph nodes (n = 284) resulted in 4-year local recurrence and lateral local recurrence rates of 16.4% and 8.8%, respectively. Enlarged (≥7 mm) lateral lymph nodes (n = 122) resulted in higher 4-year local recurrence (20.8%, 13.1%, 0%; p <.001) and lateral local recurrence (14.7%, 4.4%, 0%; p < 0.001) rates compared to smaller and no lateral lymph nodes, respectively. Visible lateral lymph nodes (HR 1.8 [1.1-2.8]) and enlarged lateral lymph nodes (HR 1.9 [1.1-3.5]) were independently associated with local recurrence in multivariable analysis. Enlarged lateral lymph nodes with malignant features had higher 4-year lateral local recurrence rates of 17.0%. Downsizing had no impact on lateral local recurrence rates. Enlarged lateral lymph nodes were found to be associated with higher univariate 4-year distant metastasis rates (36.4% vs 24.4%; p = 0.021), but this was not significant in multivariable analyses (HR 1.3 [0.9-1.]) and did not worsen overall survival. LIMITATIONS: This study was limited by the retrospective design and total number of patients with lateral lymph nodes. CONCLUSIONS: The risk of lateral local recurrence due to (enlarged) lateral lymph nodes was confirmed, but without the prognostic impact of downsizing after neoadjuvant therapy. These results point toward the incorporation of primary lateral lymph node size into treatment planning. See Video Abstract. IMPLICACIONES PRONSTICAS DE LOS NDULOS LINFTICOS LATERALES EN EL CNCER DE RECTO UN ESTUDIO TRANSVERSAL DE BASE POBLACIONAL CON EVALUACIN RADIOLGICA ESTANDARIZADA DESPUS DE UN ENTRENAMIENTO ESPECFICO: ANTECEDENTES:Hay una discusión en curso acerca de las implicaciones pronósticas de la presencia, el diámetro del eje corto y la ubicación de los nódulos linfáticos laterales.OBJETIVO:Analizar las características de los nódulos linfáticos laterales, el rol de la reducción de tamaño en la IRM de reestratificación y las tasas de recurrencia local asociadas para pacientes con cáncer de recto cT3-4 después de una nueva revisión y entrenamiento de IRM.DISEÑO:Estudio transversal retrospectivo poblacional.CONFIGURACIÓN:Este proyecto colaborativo fue dirigido por investigadores locales de los departamentos de cirugía y radiología en 60 hospitales holandeses.PACIENTES:3057 pacientes fueron operados de cáncer de recto en 2016: 1109 tenían tumor cT3-4 ubicado a ≤8 cm de la unión anorrectal de los cuales 890 recibieron terapia neoadyuvante.INTERVENCIONES(S):Ninguna.PRINCIPALES MEDIDAS DE RESULTADO:recurrencia local y tasas de recurrencia local ipsilateral.RESULTADOS:Una nueva revisión identificó a 314 pacientes (35%) con nódulos linfáticos laterales visibles. 30 de estos pacientes tenían solo nódulos obturadores estirados (n = 13) o ilíacos externos (n = 17) y ambos no provocaron recurrencias locales laterales. La presencia de nódulos linfáticos laterales ilíacos internos/obturadores (n = 284) dio como resultado tasas de recurrencia local y recurrencia local lateral a los 4 años del 16.4% y el 8.8%, respectivamente. Los nódulos linfáticos laterales agrandados (≥7 mm) (n = 122) resultaron en una mayor recurrencia local a los 4 años (20.8%, 13.1%, 0%, p < 0.001) y recurrencia local lateral (14.7%, 4.4%, 0%, p < 0.001) en comparación con nódulos linfáticos más pequeños y sin nódulos linfáticos laterales, respectivamente. Los nódulos linfáticos laterales visibles (índice de riesgo 1,8 (1,1-2,8)) y los nódulos linfáticos laterales agrandados (índice de riesgo 1.9 (1.1-3.5)) se asociaron de forma independiente con la recurrencia local en el análisis multivariable. Los nódulos linfáticos laterales agrandados con características malignas tuvieron tasas de recurrencia local lateral a 4 años más altas del 17.0%. La reducción de tamaño no tuvo impacto en las tasas de recurrencia local lateral. Los nódulos linfáticos laterales agrandados se asociaron con tasas univariadas más altas de metástasis a distancia a los 4 años (36.4%, 24.4%, p = 0.021), pero no en el análisis multivariable (índice de riesgo 1.3 (0.9-1.8)), y no empeoró la supervivencia general.LIMITACIONES:Este estudio estuvo limitado por el diseño retrospectivo y el número total de pacientes con nódulos linfáticos laterales.CONCLUSIONES:Se confirmó el riesgo de recurrencia local lateral debido a los nódulos linfáticos laterales (agrandados), pero sin el impacto pronóstico de la reducción después de la terapia neoadyuvante. Estos resultados apuntan hacia la incorporación del tamaño del nódulo linfático lateral primario en la planificación del tratamiento. (Traducción-Dr. Aurian Garcia Gonzalez ).

Abandonment of Routine Radiotherapy for Nonlocally Advanced Rectal Cancer and Oncological Outcomes.

Importance: Neoadjuvant short-course radiotherapy was routinely applied for nonlocally advanced rectal cancer (cT1-3N0-1M0 with >1 mm distance to the mesorectal fascia) in the Netherlands following the Dutch total mesorectal excision trial. This policy has shifted toward selective application after guideline revision in 2014. Objective: To determine the association of decreased use of neoadjuvant radiotherapy with cancer-related outcomes and overall survival at a national level. Design, Setting, and Participants: This multicenter, population-based, nationwide cross-sectional cohort study analyzed Dutch patients with rectal cancer who were treated in 2011 with a 4-year follow-up. A similar study was performed in 2021, analyzing all patients that were surgically treated in 2016. From these cohorts, all patients with cT1-3N0-1M0 rectal cancer and radiologically unthreatened mesorectal fascia were included in the current study. The data of the 2011 cohort were collected between May and October 2015, and the data of the 2016 cohort were collected between October 2020 and November 2021. The data were analyzed between May and October 2022. Main Outcomes and Measures: The main outcomes were 4-year local recurrence and overall survival rates. Results: Among the 2011 and 2016 cohorts, 1199 (mean [SD] age, 68 [11] years; 430 women [36%]) of 2095 patients (57.2%) and 1576 (mean [SD] age, 68 [10] years; 547 women [35%]) of 3057 patients (51.6%) had cT1-3N0-1M0 rectal cancer and were included, with proportions of neoadjuvant radiotherapy of 87% (2011) and 37% (2016). Four-year local recurrence rates were 5.8% and 5.5%, respectively (P = .99). Compared with the 2011 cohort, 4-year overall survival was significantly higher in the 2016 cohort (79.6% vs 86.4%; P < .001), with lower non-cancer-related mortality (13.8% vs 6.3%; P < .001). Conclusions and Relevance: The results of this cross-sectional study suggest that an absolute 50% reduction in radiotherapy use for nonlocally advanced rectal cancer did not compromise cancer-related outcomes at a national level. Optimizing clinical staging and surgery following the Dutch total mesorectal excision trial has potentially enabled safe deintensification of treatment.

Optimisation of Organ Preservation treatment strategies in patients with rectal cancer with a good clinical response after neoadjuvant (chemo)radiotherapy: Additional contact X-ray brachytherapy versus eXtending the observation period and local excision (OPAXX) - protocol for two multicentre, parallel, single-arm, phase II studies.

INTRODUCTION: Standard treatment for patients with intermediate or locally advanced rectal cancer is (chemo)radiotherapy followed by total mesorectal excision (TME) surgery. In recent years, organ preservation aiming at improving quality of life has been explored. Patients with a complete clinical response to (chemo)radiotherapy can be managed safely with a watch-and-wait approach. However, the optimal organ-preserving treatment strategy for patients with a good, but not complete clinical response remains unclear. The aim of the OPAXX study is to determine the rate of organ preservation that can be achieved in patients with rectal cancer with a good clinical response after neoadjuvant (chemo)radiotherapy by additional local treatment options. METHODS AND ANALYSIS: The OPAXX study is a Dutch multicentre study that investigates the efficacy of two additional local treatments aiming at organ preservation in patients with a good, but not complete response to neoadjuvant treatment (ie near-complete response or a small residual tumour mass <3 cm). The sample size will be 168 patients in total. Patients will be randomised (1:1) between two parallel single-arm phase II studies: study arm 1 involves additional contact X-ray brachytherapy (an intraluminal radiation boost), while in study arm 2 the observation period is extended followed by a second response evaluation and optional transanal local excision. The primary endpoint of the study is the rate of successful organ preservation at 1 year following randomisation. Secondary endpoints include toxicity, morbidity, oncological and functional outcomes at 1 and 2 years of follow-up. Finally, an observational cohort study for patients who are not eligible for randomisation is conducted. ETHICS AND DISSEMINATION: The trial protocol has been approved by the medical ethics committee of the Netherlands Cancer Institute (METC20.1276/M20PAX). Informed consent will be obtained from all participants. The trial results will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05772923.

Results of a diagnostic imaging audit in a randomised clinical trial in rectal cancer highlight the importance of careful planning and quality control.

BACKGROUND: Magnetic resonance (MR) imaging is the modality used for baseline assessment of locally advanced rectal cancer (LARC) and restaging after neoadjuvant treatment. The overall audited quality of MR imaging in large multicentre trials on rectal cancer is so far not routinely reported. MATERIALS AND METHODS: We collected MR images obtained within the Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation (RAPIDO) trial and performed an audit of the technical features of image acquisition. The required MR sequences and slice thickness stated in the RAPIDO protocol were used as a reference. RESULTS: Out of 920 participants of the RAPIDO study, MR investigations of 668 and 623 patients in the baseline and restaging setting, respectively, were collected. Of these, 304/668 (45.5%) and 328/623 (52.6%) MR images, respectively, fulfilled the technical quality criteria. The main reason for non-compliance was exceeding slice thickness 238/668, 35.6% in the baseline setting and 162/623, 26.0% in the restaging setting. In 166/668, 24.9% and 168/623, 27.0% MR images in the baseline and restaging setting, respectively, one or more of the required pulse sequences were missing. CONCLUSION: Altogether, 49.0% of the MR images obtained within the RAPIDO trial fulfilled the image acquisition criteria required in the study protocol. High-quality MR imaging should be expected for the appropriate initial treatment and response evaluation of patients with LARC, and efforts should be made to maximise the quality of imaging in clinical trials and in clinical practice. CRITICAL RELEVANCE STATEMENT: This audit highlights the importance of adherence to MR image acquisition criteria for rectal cancer, both in multicentre trials and in daily clinical practice. High-resolution images allow correct staging, treatment stratification and evaluation of response to neoadjuvant treatment. KEY POINTS: - Complying to MR acquisition guidelines in multicentre trials is challenging. - Neglection on MR acquisition criteria leads to poor staging and treatment. - MR acquisition guidelines should be followed in trials and clinical practice. - Researchers should consider mandatory audits prior to study initiation.

Validated Pretreatment Prediction Models for Response to Neoadjuvant Therapy in Patients with Rectal Cancer: A Systematic Review and Critical Appraisal.

Pretreatment response prediction is crucial to select those patients with rectal cancer who will benefit from organ preservation strategies following (intensified) neoadjuvant therapy and to avoid unnecessary toxicity in those who will not. The combination of individual predictors in multivariable prediction models might improve predictive accuracy. The aim of this systematic review was to summarize and critically appraise validated pretreatment prediction models (other than radiomics-based models or image-based deep learning models) for response to neoadjuvant therapy in patients with rectal cancer and provide evidence-based recommendations for future research. MEDLINE via Ovid, Embase.com, and Scopus were searched for eligible studies published up to November 2022. A total of 5006 studies were screened and 16 were included for data extraction and risk of bias assessment using Prediction model Risk Of Bias Assessment Tool (PROBAST). All selected models were unique and grouped into five predictor categories: clinical, combined, genetics, metabolites, and pathology. Studies generally included patients with intermediate or advanced tumor stages who were treated with neoadjuvant chemoradiotherapy. Evaluated outcomes were pathological complete response and pathological tumor response. All studies were considered to have a high risk of bias and none of the models were externally validated in an independent study. Discriminative performances, estimated with the area under the curve (AUC), ranged per predictor category from 0.60 to 0.70 (clinical), 0.78 to 0.81 (combined), 0.66 to 0.91 (genetics), 0.54 to 0.80 (metabolites), and 0.71 to 0.91 (pathology). Model calibration outcomes were reported in five studies. Two collagen feature-based models showed the best predictive performance (AUCs 0.83-0.91 and good calibration). In conclusion, some pretreatment models for response prediction in rectal cancer show encouraging predictive potential but, given the high risk of bias in these studies, their value should be evaluated in future, well-designed studies.

New Opportunities for Minimizing Toxicity in Rectal Cancer Management.

Advances in multimodal management of locally advanced rectal cancer (LARC), consisting of preoperative chemotherapy and/or radiotherapy followed by surgery with or without adjuvant chemotherapy, have improved local disease control and patient survival but are associated with significant risk for acute and long-term morbidity. Recently published trials, evaluating treatment dose intensification via the addition of preoperative induction or consolidation chemotherapy (total neoadjuvant therapy [TNT]), have demonstrated improved tumor response rates while maintaining acceptable toxicity. In addition, TNT has led to an increased number of patients achieving a clinical complete response and thus eligible to pursue a nonoperative, organ-preserving, watch and wait approach, thereby avoiding toxicities associated with surgery, such as bowel dysfunction and stoma-related complications. Ongoing trials using immune checkpoint inhibitors in patients with mismatch repair-deficient tumors suggest that this subgroup of patients with LARC could potentially be treated with immunotherapy alone, sparing them the toxicity associated with preoperative treatment and surgery. However, the majority of rectal cancers are mismatch repair-proficient and less responsive to immune checkpoint inhibitors and require multimodal management. The synergy noted in preclinical studies between immunotherapy and radiotherapy on immunogenic tumor cell death has led to the design of ongoing clinical trials that explore the benefit of combining radiotherapy, chemotherapy, and immunotherapy (mainly of immune checkpoint inhibitors) and aim to increase the number of patients eligible for organ preservation.

Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR): protocol of a phase I dose-escalation trial.

INTRODUCTION: Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4-8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT. METHODS AND ANALYSIS: The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction. ETHICS AND DISSEMINATION: The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int).

Evaluation of National Surgical Practice for Lateral Lymph Nodes in Rectal Cancer in an Untrained Setting.

BACKGROUND: Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of surgical treatment for suspicious LLNs is lacking. This study evaluated the surgical treatment of LLNs in an untrained setting at a national level. METHODS: Patients who underwent additional LLN surgery were selected from a national cross-sectional cohort study regarding patients undergoing rectal cancer surgery in 69 Dutch hospitals in 2016. LLN surgery consisted of either 'node-picking' (the removal of an individual LLN) or 'partial regional node dissection' (PRND; an incomplete resection of the LLN area). For all patients with primarily enlarged (≥7 mm) LLNs, those undergoing rectal surgery with an additional LLN procedure were compared to those  undergoing only rectal resection. RESULTS: Out of 3057 patients, 64 underwent additional LLN surgery, with 4-year LR and LLR rates of 26% and 15%, respectively. Forty-eight patients (75%) had enlarged LLNs, with corresponding recurrence rates of 26% and 19%, respectively. Node-picking (n = 40) resulted in a 20% 4-year LLR, and a 14% LLR after PRND (n = 8; p = 0.677). Multivariable analysis of 158 patients with enlarged LLNs undergoing additional LLN surgery (n = 48) or rectal resection alone (n = 110) showed no significant association of LLN surgery with 4-year LR or LLR, but suggested higher recurrence risks after LLN surgery (LR: hazard ratio [HR] 1.5, 95% confidence interval [CI] 0.7-3.2, p = 0.264; LLR: HR 1.9, 95% CI 0.2-2.5, p = 0.874). CONCLUSION: Evaluation of Dutch practice in 2016 revealed that approximately one-third of patients with primarily enlarged LLNs underwent surgical treatment, mostly consisting of node-picking. Recurrence rates were not significantly affected by LLN surgery, but did suggest worse outcomes. Outcomes of LLN surgery after adequate training requires further research.

Coverage of Lateral Lymph Nodes in Rectal Cancer Patients with Routine Radiation Therapy Practice and Associated Locoregional Recurrence Rates.

PURPOSE: Involved internal iliac and obturator lateral lymph nodes (LLNs) are a known risk factor for the occurrence of ipsilateral local recurrences (LLR) in rectal cancer. This study examined coverage of LLNs with routine radiation therapy practice in the Netherlands and associated LLR rates. METHODS AND MATERIALS: Patients with a primary tumor ≤8 cm of the anorectal junction, cT3-4 stage, and at least 1 internal iliac or obturator LLN with short axis ≥5 mm who received neoadjuvant (chemo)radiation therapy, were selected from a national, cross-sectional study of patients with rectal cancer treated in the Netherlands in 2016. Magnetic resonance images and radiation therapy treatment plans were reviewed regarding segmented LLNs as gross tumor volume (GTV), location of LLNs within clinical target volume (CTV), and received proportion of the planned radiation therapy dose. RESULTS: A total of 223 out of 3057 patients with at least 1 LLN ≥5 mm were selected. Of those, 180 (80.7%) LLNs were inside the CTV, of which 60 (33.3%) were segmented as GTV. Overall, 202 LLNs (90.6%) received ≥95% of the planned dose. Four-year LLR rates were not significantly higher for LLNs situated outside the CTV compared with those inside (4.0% vs 12.5%, P = .092) or when receiving <95% versus ≥95% of the planned radiation therapy dose (7.1% vs 11.3%, P = .843), respectively. Two of 7 patients who received a dose escalation of 60 Gy developed an LLR (4-year LLR rate of 28.6%). CONCLUSIONS: This evaluation of routine radiation therapy practice showed that adequate coverage of LLNs was still associated with considerable 4-year LLR rates. Techniques resulting in better local control for patients with involved LLNs need to be explored further.

Risk and location of distant metastases in patients with locally advanced rectal cancer after total neoadjuvant treatment or chemoradiotherapy in the RAPIDO trial.

INTRODUCTION: Although optimising rectal cancer treatment has reduced local recurrence rates, many patients develop distant metastases (DM). The current study investigated whether a total neoadjuvant treatment strategy influences the development, location, and timing of metastases in patients diagnosed with high-risk locally advanced rectal cancer included in the Rectal cancer And Pre-operative Induction therapy followed by Dedicated Operation (RAPIDO) trial. MATERIAL AND METHODS: Patients were randomly assigned to short-course radiotherapy followed by 18 weeks of CAPOX or FOLFOX4 before surgery (EXP), or long-course chemoradiotherapy with optional postoperative chemotherapy (SC-G). Assessments for metastatic disease were performed pre- and post-treatment, during surgery, and 6, 12, 24, 36, and 60 months postoperatively. From randomisation, differences in the occurrence of DM and first site of metastasis were evaluated. RESULTS: In total, 462 patients were evaluated in the EXP and 450 patients in the SC-G groups. The cumulative probability of DM at 5 years after randomisation was 23% [95% CI 19-27] and 30% [95% CI 26-35] (HR 0.72 [95% CI 0.56-0.93]; P = 0.011) in the EXP and SC-G, respectively. The median time to DM was 1.4 (EXP) and 1.3 years (SC-G). After diagnosis of DM, median survival was 2.6 years [95% CI 2.0-3.1] in the EXP and 3.2 years [95% CI 2.3-4.1] in the SC-G groups (HR 1.39 [95% CI 1.01-1.92]; P = 0.04). First occurrence of DM was most often in the lungs (60/462 [13%] EXP and 55/450 [12%] SC-G) or the liver (40/462 [9%] EXP and 69/450 [15%] SC-G). A hospital policy of postoperative chemotherapy did not influence the development of DM. CONCLUSIONS: Compared to long-course chemoradiotherapy, total neoadjuvant treatment with short-course radiotherapy and chemotherapy significantly decreased the occurrence of metastases, particularly liver metastases.