Osteonecrosis of the jaw after radiation followed by bevacizumab.

Osteonecrosis of the jaw is a recognized complication associated with bevacizumab. Here, we present a patient with squamous cell carcinoma of the tonsil who experienced minimal skin fibrosis following intensity-modulated radiation therapy. Subsequently, the patient developed rectal adenocarcinoma and encountered osteonecrosis of the jaw after receiving two cycles of bevacizumab. Close monitoring, accompanied by thorough examination to detect early signs of osteonecrosis of the jaw, should be considered for patients who have undergone radiation therapy in the head and neck region and are receiving bevacizumab or other medications known to be associated with osteonecrosis of the jaw.

An International Expert-Based Consensus on the Definition of a Clinical Near-Complete Response After Neoadjuvant (Chemo)radiotherapy for Rectal Cancer.

BACKGROUND: A variety of definitions for a clinical near-complete response after neoadjuvant (chemo) radiotherapy for rectal cancer are currently used. This variety leads to inconsistency in clinical practice, long-term outcome, and trial enrollment. OBJECTIVE: The aim of this study was to reach expert-based consensus on the definition of a clinical near-complete response after (chemo) radiotherapy. DESIGN: A modified Delphi process, including a systematic review, 3 surveys, and 2 meetings, was performed with an international expert panel consisting of 7 surgeons and 4 radiologists. The surveys consisted of individual features, statements, and feature combinations (endoscopy, T2-weighted MRI, and diffusion-weighted MRI). SETTING: The modified Delphi process was performed in an online setting; all 3 surveys were completed online by the expert panel, and both meetings were hosted online. MAIN OUTCOME MEASURES: The main outcome was to reach consensus (80% or more agreement). RESULTS: The expert panel reached consensus on a 3-tier categorization of the near-complete response category based on the likelihood of the response to evolve into a clinical complete response after a longer waiting interval. The panelists agreed that a near-complete response is a temporary entity only to be used in the first 6 months after (chemo)radiotherapy. Furthermore, consensus was reached that the lymph node status should be considered when deciding on a near-complete response and that biopsies are not always needed when a near-complete response is found. No consensus was reached on whether primary staging characteristics have to be taken into account when deciding on a near-complete response. LIMITATIONS: This 3-tier subcategorization is expert-based; therefore, there is no supporting evidence for this subcategorization. Also, it is unclear whether this subcategorization can be generalized into clinical practice. CONCLUSIONS: Consensus was reached on the use of a 3-tier categorization of a near-complete response, which can be helpful in daily practice as guidance for treatment and to inform patients with a near-complete response on the likelihood of successful organ preservation. See Video Abstract. UN CONSENSO INTERNACIONAL BASADO EN EXPERTOS ACERCA DE LA DEFINICIN DE UNA RESPUESTA CLNICA CASI COMPLETA DESPUS DE QUIMIORADIOTERAPIA NEOADYUVANTE CONTRA EL CNCER DE RECTO: ANTECEDENTES:Actualmente, se utilizan una variedad de definiciones para una respuesta clínica casi completa después de quimioradioterapia neoadyuvante contra el cáncer de recto. Esta variedad resulta en inconsistencia en la práctica clínica, los resultados a largo plazo y la inscripción en ensayos.OBJETIVO:El objetivo de este estudio fue llegar a un consenso de expertos sobre la definición de una respuesta clínica casi completa después de quimioradioterapia.DISEÑO:Se realizó un proceso Delphi modificado que incluyó una revisión sistemática, 3 encuestas y 2 reuniones con un panel internacional de expertos compuesto por siete cirujanos y 4 radiólogos. Las encuestas consistieron en características individuales, declaraciones y combinaciones de características (endoscopía, T2W-MRI y DWI).AJUSTE:El proceso Delphi modificado se realizó en un entorno en línea; el panel de expertos completó las tres encuestas en línea y ambas reuniones se realizaron en línea.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue llegar a un consenso (≥80% de acuerdo).RESULTADOS:El panel de expertos llegó a un consenso sobre una categorización de tres niveles de la categoría de respuesta casi completa basada en la probabilidad de que la respuesta evolucione hacia una respuesta clínica completa después de un intervalo de espera más largo. Los panelistas coincidieron en que una respuesta casi completa es una entidad temporal que sólo debe utilizarse en los primeros 6 meses después de la quimioradioterapia. Además, se llegó a un consenso en que se debe considerar el estado de los nódulos linfáticos al decidir sobre una respuesta casi completa y que no siempre se necesitan biopsias cuando se encuentra una respuesta casi completa. No se llegó a un consenso sobre si se deben tener en cuenta las características primarias de estadificación al decidir una respuesta casi completa.LIMITACIONES:Esta subcategorización de 3 niveles está basada en expertos; por lo tanto, no hay evidencia que respalde esta subcategorización. Además, no está claro si esta subcategorización puede generalizarse a la práctica clínica.CONCLUSIONES:Se alcanzó consenso sobre el uso de una categorización de 3 niveles de una respuesta casi completa que puede ser útil en la práctica diaria como guía para el tratamiento y para informar a los pacientes con una respuesta casi completa sobre la probabilidad de una preservación exitosa del órgano. (Traducción - Dr. Aurian Garcia Gonzalez).

The efficacy and safety of short-course radiotherapy followed by sequential chemotherapy and Cadonilimab for locally advanced rectal cancer: a protocol of a phase II study.

BACKGROUND: For patients with locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT), namely, intensifying preoperative treatment through the integration of radiotherapy and systemic chemotherapy before surgery, was commonly recommended as the standard treatment. However, the risk of distant metastasis at 3 years remained higher than 20%, and the complete response (CR) rate was less than 30%. Several clinical trials had suggested a higher complete response rate when combining single-agent immunotherapy with short-course radiotherapy (SCRT). The CheckMate 142 study had shown encouraging outcomes of dual immunotherapy and seemingly comparable toxicity for CRC compared with single-agent immunotherapy in historical results. Therefore, dual immunotherapy might be more feasible in conjunction with the TNT paradigm of SCRT. We performed a phase II study to investigate whether the addition of a dual immune checkpoint inhibitor bispecific antibody, Cadonilimab, to SCRT combined with chemotherapy might further increase the clinical benefit and prognosis for LARC patients. METHODS: This single-arm, multicenter, prospective, phase II study included patients with pathologically confirmed cT3-T4N0 or cT2-4N + rectal adenocarcinoma with an ECOG performance score of 0 or 1. Bispecific antibody immunotherapy was added to SCRT combined with chemotherapy. Patients enrolled would be treated with SCRT (25 Gy in five fractions over 1 week) for the pelvic cavity, followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX and Cadonilimab. The primary endpoint was the CR rate, which was the ratio of the pathological CR rate plus the clinical CR rate. The secondary endpoints included local-regional control, distant metastasis, disease-free survival, overall survival, toxicity profile, quality of life and functional outcome of the rectum. To detect an increase in the complete remission rate from 21.8% to 40% with 80% power, 50 patients were needed. DISCUSSION: This study would provide evidence on the efficacy and safety of SCRT plus bispecific antibody immunotherapy combined with chemotherapy as neoadjuvant therapy for patients with LARC, which might be used as a candidate potential therapy in the future. TRIAL REGISTRATION: This phase II trial was prospectively registered at ClinicalTrials.gov, under the identifier NCT05794750.

Surgical management of rectal cancer with synchronous treatment of prostate cancer.

PURPOSE: To assess the safety and efficacy of synchronous treatments for rectal (RC) and prostate (PC) cancers. METHODS: Single-center retrospective study (2007-2021) of patients treated with neoadjuvant radiotherapy (RT) and total mesorectal excision (TME) for RC with synchronous PC treatment. The endpoints were 30-day postoperative severe complications, R0 resection rates, 3-year disease-free survival (DFS) and 3-year overall survival (OS). RESULTS: Among the 16 patients, 15 (93.7%) received neoadjuvant pelvic RT (40-50.4 Gray) followed by either transperineal high dose rate prostate brachytherapy (62.5%), prostate external RT boost (25.0%), or androgen deprivation therapy (ADT) alone (6.3%). One (6.3%) patient received neoadjuvant rectal brachytherapy and ADT. Pelvic RT was combined with chemotherapy in 87.5% of cases. TME was performed in all patients with low anterior resection (87.5%) or abdominoperineal resection (12.5%), primarily using minimally invasive surgery (87.5%). The R0 resection rate was 93.8%. Six (37.5%) patients experienced 30-day Clavien-Dindo grade IIIb complications, including one (7.1%) anastomotic leak. After a median follow-up of 39.0 months, 63.6% of diverting ileostomies were reversed. Three-year DFS from RC was 71.4% (CI 40.2-88.3) and 3-year OS was 84.4% (CI 95% 50.4-95.9). No PC recurrence or death occurred. CONCLUSIONS: Synchronous management of RC and PC with pelvic RT followed by curative prostate RT doses and TME showed acceptable morbidity and oncologic results. Prostate brachytherapy, the most commonly used treatment modality, allowed avoidance of prostatectomy and additional external RT to the rectum. PC should not limit the curative intent of RC, as all recurrences were from rectal origin.

PDCD4-induced oxidative stress through FGR/NF-κB axis in rectal cancer radiotherapy-induced AKI.

This study aimed to investigate the molecular mechanism of the effect of PDCD4 on radiotherapy-induced acute kidney injury (AKI) in rectal cancer through the regulation of FGR/NF-κB signaling. Differentially expressed genes were identified using Gene Expression Omnibus (GEO) datasets (GSE90627 for rectal cancer and GSE145085 for AKI) and R software. The human renal tubular epithelial cell line, HK-2, was used to establish an in vitro model of radiotherapy-induced AKI. RT-qPCR and western blotting were used to detect gene and protein expression levels, respectively. Cell proliferation and apoptosis were assessed using the CCK-8 assay and flow cytometry, respectively. The malondialdehyde and superoxide dismutase levels in the cell culture supernatants were determined. Additionally, an in vivo AKI model was established using BALB/c mice, and kidney tissue morphology, expression of the renal injury molecule KIM-1, apoptosis of renal tubular cells, and TAS and TOS in serum were evaluated. Bioinformatics analysis revealed the upregulated expression of PDCD4 in AKI. In vitro experiments demonstrated that PDCD4 induced apoptosis in renal tubular cells by promoting FGR expression, which activated the NF-κB signaling pathway and triggered an oxidative stress response. In vivo animal experiments confirmed that PDCD4 promoted oxidative stress response and radiotherapy-induced AKI through the activation of the FGR/NF-κB signaling pathway. Silencing PDCD4 attenuated radiotherapy-induced AKI. Our findings suggest that PDCD4 may induce radiotherapy-induced AKI in rectal cancer by promoting FGR expression, activating the NF-κB signaling pathway, and triggering an oxidative stress response.

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

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

Proton beam reirradiation for locally recurrent rectal cancer patients with prior pelvic irradiation.

The aim of the present study was to report the feasibility of proton beam reirradiation for patients with locally recurrent rectal cancer (LRRC) with prior pelvic irradiation. The study population included patients who were treated with proton beam therapy (PBT) for LRRC between 2008 and December 2019 in our institution. Those who had a history of distant metastases of LRRC, with or without treatment, before reirradiation, were excluded. Overall survival (OS), progression-free survival (PFS) and local control (LC) were estimated using the Kaplan-Meier method. Ten patients were included in the present study. The median follow-up period was 28.7 months, and the median total dose of prior radiotherapy (RT) was 50 Gy (range, 30 Gy-74.8 Gy). The median time from prior RT to reirradiation was 31.5 months (range, 8.1-96.6 months), and the median reirradiation dose was 72 Gy (relative biological effectiveness) (range, 56-77 Gy). The 1-year/2-year OS, PFS and LC rates were 100%/60.0%, 20.0%/10.0% and 70.0%/58.3%, respectively, with a median survival time of 26.0 months. Seven patients developed a Grade 1 acute radiation dermatitis, and no Grade ≥ 2 acute toxicity was recorded. Grade ≥ 3 late toxicity was recorded in only one patient, who had developed a colostomy due to radiation-related intestinal bleeding. Reirradiation using PBT for LRRC patients who had previously undergone pelvic irradiation was feasible. However, the indications for PBT reirradiation for LRRC patients need to be considered carefully due to the risk of severe late GI toxicity.

Novel radiation and targeted therapy combinations for improving rectal cancer outcomes.

Neoadjuvant radiotherapy (RT) is commonly used as standard treatment for rectal cancer. However, response rates are variable and survival outcomes remain poor, highlighting the need to develop new therapeutic strategies. Research is focused on identifying novel methods for sensitising rectal tumours to RT to enhance responses and improve patient outcomes. This can be achieved through harnessing tumour promoting effects of radiation or preventing development of radio-resistance in cancer cells. Many of the approaches being investigated involve targeting the recently published new dimensions of cancer hallmarks. This review article will discuss key radiation and targeted therapy combination strategies being investigated in the rectal cancer setting, with a focus on exploitation of mechanisms which target the hallmarks of cancer.

Radiomics-enhanced early regression index for predicting treatment response in rectal cancer: a multi-institutional 0.35 T MRI-guided radiotherapy study.

PURPOSE: The accurate prediction of treatment response in locally advanced rectal cancer (LARC) patients undergoing MRI-guided radiotherapy (MRIgRT) is essential for optimising treatment strategies. This multi-institutional study aimed to investigate the potential of radiomics in enhancing the predictive power of a known radiobiological parameter (Early Regression Index, ERITCP) to evaluate treatment response in LARC patients treated with MRIgRT. METHODS: Patients from three international sites were included and divided into training and validation sets. 0.35 T T2*/T1-weighted MR images were acquired during simulation and at each treatment fraction. The biologically effective dose (BED) conversion was used to account for different radiotherapy schemes: gross tumour volume was delineated on the MR images corresponding to specific BED levels and radiomic features were then extracted. Multiple logistic regression models were calculated, combining ERITCP with other radiomic features. The predictive performance of the different models was evaluated on both training and validation sets by calculating the receiver operating characteristic (ROC) curves. RESULTS: A total of 91 patients was enrolled: 58 were used as training, 33 as validation. Overall, pCR was observed in 25 cases. The model showing the highest performance was obtained combining ERITCP at BED = 26 Gy with a radiomic feature (10th percentile of grey level histogram, 10GLH) calculated at BED = 40 Gy. The area under ROC curve (AUC) of this combined model was 0.98 for training set and 0.92 for validation set, significantly higher (p = 0.04) than the AUC value obtained using ERITCP alone (0.94 in training and 0.89 in validation set). CONCLUSION: The integration of the radiomic analysis with ERITCP improves the pCR prediction in LARC patients, offering more precise predictive models to further personalise 0.35 T MRIgRT treatments of LARC patients.

Evaluation of treatment outcomes and tolerability in older patients with rectal cancer treated with radiotherapy accompanied by the G-8 geriatric score: TROD13-003 multicenter study.

INTRODUCTION: The choice of treatment for rectal cancer often differs in older and younger patients, with the rate of radiotherapy use lower among older adults. In our daily practice, when evaluating a frail older patient with rectal cancer, we usually choose to give less treatment. This may be due to concern that the patient will not be able to tolerate radiotherapy. The Geriatric 8 score (G8GS) is a guide to evaluating treatment tolerability as it relates to frailty in older adults with cancer. The aim of this study was to evaluate treatment outcomes and tolerability in older patients with rectal cancer treated with radiotherapy (RT) accompanied by G8GS. MATERIALS AND METHODS: Patients aged 65 and older with stage I-III rectal adenocarcinoma who were treated with RT and had a G8 evaluation were included in this multicenter retrospective study. Prognostic factors related to G8GS were calculated using Chi-square and logistic regression tests and survival rates were calculated by the Kaplan-Meier test using the SPSS v24.0 software. All p-values ≤0.05 were considered statistically significant. RESULTS: A total of 699 patients from 16 national institutions were evaluated. The median age was 72 years (range 65-96), and the median follow-up was 43 (range 1-190) months. Four hundred and fifty patients (64%) were categorized as frail with G8GS ≤14 points. Frail patients had higher ages (p = 0.001) and more comorbidities (p = 0.001). Ability to receive concomitant and/or adjuvant chemotherapy rates were significantly higher in fit patients (p = 0.002 and p = 0.001, respectively). No significant difference was observed in terms of grade 3-4 early and late toxicity for both groups. Cancer-related death was higher (p = 0.003), and 5- and 8-year survival rates were significantly lower (p = 0.001), in the frail group. Age and being frail were significantly associated with survival. DISCUSSION: Radiotherapy is a tolerable and effective treatment option for older adults with rectal cancer even with low G8GS. Being in the frail group according to G8GS and having multiple comorbidities was negatively associated with survival. Addressing the medical needs of frail patients through a comprehensive geriatric assessment prior to radiotherapy may improve G8GS, allowing for standard treatment and increased survival rates.

Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy - A review.

Rectal cancer accounts for the second highest cancer-related mortality, which is predominant in Western civilizations. The treatment for rectal cancers includes surgery, radiotherapy, chemotherapy, and immunotherapy. Radiotherapy, specifically external beam radiation therapy, is the most common way to treat rectal cancer because radiation not only limits cancer progression but also significantly reduces the risk of local recurrence. However, therapeutic radiation-induced radioresistance to rectal cancer cells and toxicity to normal tissues are major drawbacks. Therefore, understanding the mechanistic basis of developing radioresistance during and after radiation therapy would provide crucial insight to improve clinical outcomes of radiation therapy for rectal cancer patients. Studies by various groups have shown that radiotherapy-mediated changes in the tumor microenvironment play a crucial role in developing radioresistance. Therapeutic radiation-induced hypoxia and functional alterations in the stromal cells, specifically tumor-associated macrophage (TAM) and cancer-associated fibroblasts (CAF), play a crucial role in developing radioresistance. In addition, signaling pathways, such as - the PI3K/AKT pathway, Wnt/ß-catenin signaling, and the hippo pathway, modulate the radiation responsiveness of cancer cells. Different radiosensitizers, such as small molecules, microRNA, nanomaterials, and natural and chemical sensitizers, are being used to increase the effectiveness of radiotherapy. This review highlights the mechanism responsible for developing radioresistance of rectal cancer following radiotherapy and potential strategies to enhance the effectiveness of radiotherapy for better management of rectal cancer.

Low energy contact X-ray brachytherapy for treatment of rectal cancer: a health technology appraisal by Health Technology Wales.

AIM: Health Technology Wales sought to evaluate the clinical and cost-effectiveness of contact X-ray brachytherapy (CXB) for early-stage rectal cancer. METHODS: Relevant studies were identified through systematic searches of MEDLINE, Embase, Cochrane Library and Scopus. A cost-utility model was developed to estimate the cost-effectiveness of CXB in National Health Service Wales, using results of the Organ Preservation in Early Rectal Adenocarcinoma (OPERA) trial. Patient perspectives were obtained through the Papillon Patient Support group and All-Wales Cancer Network. RESULTS: The OPERA randomized controlled trial showed that CXB improved complete response and organ preservation rates compared with external-beam boost for people with T2-3b, N0-1, M0 rectal cancer who are fit for surgery. Managing more of this population non-operatively after CXB was estimated to provide 0.2 quality-adjusted life years at an additional cost of £887 per person. CXB was cost effective compared with external-beam boost at a cost of £4463 per quality-adjusted life year gained. This conclusion did not change in scenario analysis and CXB was cost effective in 91% of probabilistic sensitivity analyses. Patients valued receiving clear information on all available options to support their individual treatment choices. The detrimental impact of a stoma on quality of life led some patients to reject the idea that surgery was their only option. CONCLUSION: This evidence review and cost-utility analysis indicates that CXB is likely to be clinically and cost effective, as part of a watch and wait strategy for adults fit for surgery. Wider access to CXB is supported by patient testimonies.

ST6GAL1 is associated with poor response to chemoradiation in rectal cancer.

INTRODUCTION: Colorectal cancer is the third most common cause of cancer death. Rectal cancer makes up a third of all colorectal cases. Treatment for locally advanced rectal cancer includes chemoradiation followed by surgery. We have previously identified ST6GAL1 as a cause of resistance to chemoradiation in vitro and hypothesized that it would be correlated with poor response in human derived models and human tissues. METHODS: Five organoid models were created from primary human rectal cancers and ST6GAL1 was knocked down via lentivirus transduction in one model. ST6GAL1 and Cleaved Caspase-3 (CC3) were assessed after chemoradiation via immunostaining. A tissue microarray (TMA) was created from twenty-six patients who underwent chemoradiation and had pre- and post-treatment specimens of rectal adenocarcinoma available at our institution. Immunohistochemistry was performed for ST6GAL1 and percent positive cancer cell staining was assessed and correlation with pathological grade of response was measured. RESULTS: Organoid models were treated with chemoradiation and both ST6GAL1 mRNA and protein significantly increased after treatment. The organoid model targeted with ST6GAL1 knockdown was found to have increased CC3 after treatment. In the tissue microarray, 42 percent of patient samples had an increase in percent tumor cell staining for ST6GAL1 after treatment. Post-treatment percent staining was associated with a worse grade of treatment response (p = 0.01) and increased staining post-treatment compared to pre-treatment was also associated with a worse response (p = 0.01). CONCLUSION: ST6GAL1 is associated with resistance to treatment in human rectal cancer and knockdown in an organoid model abrogated resistance to apoptosis caused by chemoradiation.

Pre-existing subclones determine radioresistance in rectal cancer organoids.

More than half of all patients with cancer receive radiation therapy, but resistance is commonly observed. Currently, it is unknown whether resistance to radiation therapy is acquired or inherently present. Here, we employed organoids derived from rectal cancer and single-cell whole-genome sequencing to investigate the long-term evolution of subclones in response to radiation. Comparing single-cell whole-genome karyotypes between in-vitro-unirradiated and -irradiated organoids revealed three patterns of subclonal evolution: (1) subclonal persistence, (2) subclonal extinction, and (3) subclonal expansion. Organoids in which subclonal shifts occurred (i.e., expansion or extinction) became more resistant to radiation. Although radioresistant subclones did not share recurrent copy-number alterations that could explain their radioresistance, resistance was associated with reduced chromosomal instability, an association that was also observed in 529 human cancer cell lines. These data suggest that resistance to radiation is inherently present and associated with reduced chromosomal instability.

Automatic end-to-end VMAT treatment planning for rectal cancers.

BACKGROUND: The treatment planning process from segmentation to producing a deliverable plan is time-consuming and labor-intensive. Existing solutions automate the segmentation and planning processes individually. The feasibility of combining auto-segmentation and auto-planning for volumetric modulated arc therapy (VMAT) for rectal cancers in an end-to-end process is not clear. PURPOSE: To create and clinically evaluate a complete end-to-end process for auto-segmentation and auto-planning of VMAT for rectal cancer requiring only the gross tumor volume contour and a CT scan as inputs. METHODS: Patient scans and data were retrospectively selected from our institutional records for patients treated for malignant neoplasm of the rectum. We trained, validated, and tested deep learning auto-segmentation models using nnU-Net architecture for clinical target volume (CTV), bowel bag, large bowel, small bowel, total bowel, femurs, bladder, bone marrow, and female and male genitalia. For the CTV, we identified 174 patients with clinically drawn CTVs. We used data for 18 patients for all structures other than the CTV. The structures were contoured under the guidance of and reviewed by a gastrointestinal (GI) radiation oncologist. The predicted results for CTV in 35 patients and organs at risk (OAR) in six patients were scored by the GI radiation oncologist using a five-point Likert scale. For auto-planning, a RapidPlan knowledge-based planning solution was modeled for VMAT delivery with a prescription of 25 Gy in five fractions. The model was trained and tested on 20 and 34 patients, respectively. The resulting plans were scored by two GI radiation oncologists using a five-point Likert scale. Finally, the end-to-end pipeline was evaluated on 16 patients, and the resulting plans were scored by two GI radiation oncologists. RESULTS: In 31 of 35 patients, CTV contours were clinically acceptable without necessary modifications. The CTV achieved a Dice similarity coefficient of 0.85 (±0.05) and 95% Hausdorff distance of 15.25 (±5.59) mm. All OAR contours were clinically acceptable without edits, except for large and small bowel which were challenging to differentiate. However, contours for total, large, and small bowel were clinically acceptable. The two physicians accepted 100% and 91% of the auto-plans. For the end-to-end pipeline, the two physicians accepted 88% and 62% of the auto-plans. CONCLUSIONS: This study demonstrated that the VMAT treatment planning technique for rectal cancer can be automated to generate clinically acceptable and safe plans with minimal human interventions.