Chemoradiotherapy For Rectal Cancer Research Articles

Dynamics of cell-free tumor DNA correlate with early MRI response during chemoradiotherapy in rectal cancer

BackgroundIn locally advanced rectal cancer, the prediction of tumor response during and after neoadjuvant treatment remains challenging. In terms of organ preservation, adaptive radiotherapy, and intensified (total) neoadjuvant therapies, biomarkers are desirable for patient stratification.MethodsIn 16 patients, weekly blood samples (n = 86) to detect cell-free tumor DNA (ctDNA) during long-course neoadjuvant chemoradiotherapy were analyzed. Data were correlated with initial tumor volumes, MRI response in week 2 and 5 of radiotherapy as well as with pathologic tumor response after resection and outcome parameters.ResultsMost patients showed decreasing ctDNA during the course of radiochemotherapy. However, we found heterogenous dynamics of ctDNA and could identify three groups: (1) decline (2) no clear decline and/or late shedding (3) persistence of ctDNA. In seven patients we could detect significant amounts of ctDNA in week 5 or week 6 of treatment. In our pilot cohort, we did not find significant correlations of ctDNA dynamics with pathologic response or outcome parameters. However, patients with distinct decline of ctDNA had larger tumor volumes prior to treatment, and MRI imaging in week 2 and 5 revealed bigger absolute decrease of tumor volumes. If significant levels of ctDNA were found in week 5 and / or 6, patients showed less absolute tumor volume decrease in week 2 and 5.ConclusionsWeekly measurement of ctDNA during radiochemotherapy is feasible and might represent a promising biomarker. Bigger initial primary tumors showed different ctDNA shedding profiles compared with smaller primary tumors and correlations of ctDNA dynamics with early imaging response were found.

Association of Collagen Changes in Distal Anastomotic Margin and Anastomotic Stenosis after Neoadjuvant Chemoradiotherapy for Rectal Cancer.

Neoadjuvant chemoradiotherapy (nCRT) for rectal cancer can lead to structural changes in collagen in the tumor microenvironment and increase the risk of postoperative anastomotic stenosis (AS). However, the quantitative relationship between AS and collagen has not been defined. This study is to quantitatively analyze the collagen features in rectal cancer and explore the relationship between the changes of collagen and postoperative anastomotic stenosis after nCRT. This is a retrospective study. A total of 371 patients with rectal cancer were included. Collagen features in the resection margin of rectal cancer anastomosis was extracted by multiphoton imaging. The least absolute shrinkage operator logistic regression was performed to select features related to AS and the collagen score (CS) was constructed. Area under the receiver operating curve (AUROC) and decision curve analysis were performed to evaluate the discrimination and clinical benefit of the nomogram. The probability of AS was 23% in the training cohort and 15.9% in the validation cohort. In the training cohort, the distance between tumor and resection margin, anastomotic leakage and CS were independent risk factors for postoperative AS in univariate and multivariate analyses. A nomogram was constructed based on these results. The prediction nomogram showed good discrimination (AUROC 0.864; 95% CI 0.776 to 0.952) and was validated in the validation cohort (AUROC 0.918; 95% CI 0.851 to 0.985). CS is an independent risk factor for AS in rectal cancer after nCRT. The predictive model based on CS can predict the occurrence of postoperative AS.

Physical activity at diagnosis is associated with tumor downstaging after neoadjuvant chemoradiotherapy in patients with rectal cancer

BackgroundPatients with rectal cancer are often treated with neoadjuvant chemoradiotherapy, followed by a waiting period and surgical resection. Good or complete response to neoadjuvant chemoradiotherapy might enable organ preservation, which highlights the need to increase response rates. Pre-clinical studies suggest that physical activity during neoadjuvant chemoradiotherapy may improve tumor downstaging. PurposeTo investigate whether physical activity and physical functioning of patients with rectal cancer at diagnosis are associated with tumor downstaging after neoadjuvant chemoradiotherapy. Materials and methodsPatients were included if they participated in the Dutch Prospective ColoRectal Cancer Cohort, a nationwide cohort providing an infrastructure for scientific research, and received neoadjuvant chemoradiotherapy for rectal cancer. Tumor downstaging was dichotomized into good/complete or moderate/poor downstaging. Physical activity (total physical activity, moderate-to-vigorous physical activity (MVPA), and Dutch physical activity guideline adherence) and physical functioning were assessed using questionnaires. Logistic regression analyses were performed to examine associations of physical activity and physical functioning with tumor downstaging, adjusted for relevant confounders. Results268 patients (aged 62 ± 11 years, 33 % female) with rectal cancer were included. Patients with moderate (OR = 2.07; 95%CI = 1.07 – 4.07; p = 0.03) or high (OR = 2.05; 95%CI = 1.05 – 4.07; p = 0.04) levels of MVPA were more likely to have good/complete tumor downstaging than patients with low levels. No significant associations with tumor downstaging were found for total physical activity, Dutch physical activity guideline adherence, and physical functioning. ConclusionsWe found augmented tumor downstaging in patients with rectal cancer with moderate or high levels of self-reported MVPA before the start of neoadjuvant chemoradiotherapy compared to patients with low levels.

169 Nutritional Support During Preoperative Chemoradiotherapy for Rectal Cancer Prevents Significant Weight Loss

169 Nutritional Support During Preoperative Chemoradiotherapy for Rectal Cancer Prevents Significant Weight Loss

Machine learning in predicting pathological complete response to neoadjuvant chemoradiotherapy in rectal cancer using MRI: a systematic review and meta-analysis.

To evaluate the performance of machine learning models in predicting pathological complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) in patients with rectal cancer using magnetic resonance imaging. We searched PubMed, Embase, Cochrane Library, and Web of Science for studies published before March 2024. The Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) was used to assess the methodological quality of the included studies, random-effects models were used to calculate sensitivity and specificity, I2 values were used for heterogeneity measurements, and subgroup analyses were carried out to detect potential sources of heterogeneity. A total of 1699 patients from 24 studies were included. For machine learning models in predicting pCR to nCRT, the meta-analysis calculated a pooled area under the curve (AUC) of 0.91 (95% CI, 0.88-0.93), pooled sensitivity of 0.83 (95% CI, 0.74-0.89), and pooled specificity of 0.86 (95% CI, 0.80-0.91). We investigated 6 studies that mainly contributed to heterogeneity. After performing meta-analysis again excluding these 6 studies, the heterogeneity was significantly reduced. In subgroup analysis, the pooled AUC of the deep-learning model was 0.93 and 0.89 for the traditional statistical model; the pooled AUC of studies that used diffusion-weighted imaging (DWI) was 0.90 and 0.92 in studies that did not use DWI; the pooled AUC of studies conducted in China was 0.93, and was 0.83 in studies conducted in other countries. This systematic study showed that machine learning has promising potential in predicting pCR to nCRT in patients with locally advanced rectal cancer. Compared to traditional machine learning models, although deep-learning-based studies are less predominant and more heterogeneous, they are able to obtain higher AUC. Compared to traditional machine learning models, deep-learning-based studies are able to obtain higher AUC, although they are less predominant and more heterogeneous. Together with clinical information, machine learning-based models may bring us closer towards precision medicine.

Acute Toxicities and Treatment tolerance of Neoadjuvant Chemoradiation in Rectal Cancer: A Tertiary Cancer Centre Analysis

Aims: To assess acute toxicities and treatment tolerance in patients of carcinoma rectum of NACTRT at a tertiary care centre of North-East India. Materials and Methods: A total of 50 patients of histologically proven Rectal Adenocarcinoma recruited from July 2022 to May 2023 were included in the study. All patients were planned for either NACTRT (n=44) or Total Neoadjuvant Treatment (TNT)(n=6) followed by assessment for surgery. A total dose of 50.4Gy/28# was planned with concurrent oral chemotherapy with T. Capecitabine at a dose of 825 mg/m2 twice daily. Acute toxicities were assessed using RTOG grading criteria. Patients’ toxicity assessment was done weekly with clinical examination and laboratory parameters. Patients were also assessed at the end of RT and 4 weeks post completion of NACTRT. Results: All patients could complete the prescribed dose of EBRT (50.4Gy/28#) over a period of 6 weeks. On toxicity assessment, Grade-I dermatitis was seen in 14 patients (56%), Grade-II in 14 patients (54%), Grade-III in 2 patients (7.6%). In lower gastrointestinal toxicities, Grade-I diarrhea occurred for 4 patients (50%), Grade-II diarrhea in 3 patients (37.5%) and Grade III diarrhea in 1 patient (7.6%). Grade-I genitourinary toxicity was observed in 4 patients (8%). Hematological toxicities were seen for 40 patients of which Grade-I, Grade-II, Grade-III Anemia were seen in 10 (38.4%), 14 (54%), 2 (7.6%) patients respectively. Grade 1 and Grade 2 leucopenia were seen in 4 (57%) and 3 (43%) patients respectively. Deranged LFT was seen for 7 patients (15%), out of whom dose modifications were required for 5 patients (10%). Treatment was put on hold for 3 patients (6%) for 3 days due to grade 3 toxicities. Conclusion: NACTRT in rectal cancer patients was associated with acceptable toxicities and treatment tolerance. Modern EBRT techniques like IMRT should be evaluated in an effort to further reduce the radiation related toxicities.

Outcome of surgery after total neoadjuvant treatment in comparison to standard chemoradiotherapy of rectal cancer: a meta-analysis

Outcome of surgery after total neoadjuvant treatment in comparison to standard chemoradiotherapy of rectal cancer: a meta-analysis

1793: The role of concomitant boost in chemoradiation for rectal cancer; a randomized clinical trial

1793: The role of concomitant boost in chemoradiation for rectal cancer; a randomized clinical trial

Rectal Cancer Survival for Residual Carcinoma In Situ Versus Pathologic Complete Response After Neoadjuvant Therapy.

Pathologic complete response after neoadjuvant chemoradiotherapy for rectal cancer is associated with improved survival. It is unclear whether residual carcinoma in situ portends a similar outcome. To compare the survival of patients with locally advanced rectal cancer who received neoadjuvant therapy and achieved pathologic carcinoma in situ versus pathologic complete response. Retrospective cohort study. National public database. A total of 4594 patients in the National Cancer Database from 2006 to 2016 with locally advanced rectal cancer who received neoadjuvant therapy, underwent surgery, and had node-negative ypTis or ypT0 on final pathology were included. Of these, 4321 patients (94.1%) had ypT0 and 273 (5.9%) had ypTis on final pathology. Overall survival. The median age was 60 years, and 1822 patients (39.7%) were women. On initial staging, 54.5% (n = 2503) had stage II disease and 45.5% (n = 2091) had stage III disease. The ypTis group had decreased overall survival compared to the ypT0 group (HR 1.42; 95% CI, 1.04-1.95; p = 0.028). Other factors associated with decreased overall survival were older age at diagnosis, increasing Charlson-Deyo score, and poorly differentiated tumor grade. Variables associated with improved survival were female sex, private insurance, and receipt of both neoadjuvant and adjuvant chemotherapy. For the total cohort, there was no difference in survival between clinical stage II and stage III. Standard therapy versus total neoadjuvant therapy could not be abstracted. Overall survival was defined as the time from surgery to death from any cause or last contact, allowing for some erroneously misclassified deaths. ypTis is associated with worse overall survival than ypT0 for patients with locally advanced rectal cancer who receive neoadjuvant chemoradiotherapy followed by surgery. For this cohort, clinical stage was not a significant predictor of survival. Prospective trials comparing survival for these pathologic outcomes are needed. See Video Abstract . ANTECEDENTESLa respuesta patológica completa después de la quimiorradioterapia neoadyuvante para el cáncer de recto se asocia con una mayor supervivencia. No está claro si el carcinoma residual in situ presagia un resultado similar.OBJETIVOComparar la supervivencia de pacientes con cáncer de recto localmente avanzado que recibieron terapia neoadyuvante y lograron un carcinoma patológico in situ versus una respuesta patológica completa.DISEÑOEstudio de cohorte retrospectivo.ESCENARIOBase de datos pública nacional.PACIENTESSe incluyeron 4,594 pacientes de la Base de Datos Nacional de Cáncer de 2006 a 2016 con cáncer de recto localmente avanzado que recibieron terapia neoadyuvante, fueron sometidos a cirugía y tuvieron ganglios negativos, ypTis o ypT0 en el reporte patológico final. 4.321 (94,1%) tuvieron ypT0 y 273 (5,9%) tuvieron ypTis en el reporte final.PRINCIPALES MEDIDAS DE RESULTADOSupervivencia general.RESULTADOSLa mediana de edad fue de 60 años. 1.822 pacientes (39,7%) fueron mujeres. El 54,5% (n = 2.503) tuvo la enfermedad en estadio II y el 45,5% (n = 2.091) tuvo la enfermedad en estadio III según la estadificación inicial. El grupo ypTis tuvo una supervivencia general reducida en comparación con el grupo ypT0 (HR 1,42, IC 95 % 1,04-1,95, p = 0,028). Otros factores asociados con una menor supervivencia general fueron una edad más avanzada al momento del diagnóstico, un aumento de la puntuación de Charlson-Deyo y un grado tumoral poco diferenciado. Las variables asociadas con una mejor supervivencia fueron el sexo femenino, el seguro privado y la recepción de quimioterapia neoadyuvante y adyuvante. Para la cohorte total, no hubo diferencias en la supervivencia entre el estadio clínico 2 y el estadio 3.LIMITACIONESNo se pudo resumir el tratamiento estándar versus el tratamiento neoadyuvante total. La supervivencia general se definió como el tiempo transcurrido desde la cirugía hasta la muerte por cualquier causa o último contacto, lo que permite algunas muertes erróneamente clasificadas.CONCLUSIONESypTis se asocia con una peor supervivencia general que ypT0 en pacientes con cáncer de recto localmente avanzado que reciben quimiorradioterapia neoadyuvante seguida de cirugía. Para esta cohorte, el estadio clínico no fue un predictor significativo de supervivencia. Se necesitan ensayos prospectivos que comparen la supervivencia de estos resultados patológicos. ( Traducción-Dr Osvaldo Gauto ).

ST6GAL1 is associated with poor response to chemoradiation in rectal cancer

IntroductionColorectal 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. MethodsFive 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. ResultsOrganoid 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). ConclusionST6GAL1 is associated with resistance to treatment in human rectal cancer and knockdown in an organoid model abrogated resistance to apoptosis caused by chemoradiation.

Paradigm shift in the indication for neoadjuvant radiochemotherapy in rectal cancer: a clear mesorectal fascia (MRF) on MRI is crucial!

Paradigm shift in the indication for neoadjuvant radiochemotherapy in rectal cancer: a clear mesorectal fascia (MRF) on MRI is crucial!

An immune-related gene prognostic prediction risk model for neoadjuvant chemoradiotherapy in rectal cancer using artificial intelligence.

This study aimed to establish and validate a prognostic model based on immune-related genes (IRGPM) for predicting disease-free survival (DFS) in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy, and to elucidate the immune profiles associated with different prognostic outcomes. Transcriptomic and clinical data were sourced from the Gene Expression Omnibus (GEO) database and the West China Hospital database. We focused on genes from the RNA immune-oncology panel. The elastic net approach was employed to pinpoint immune-related genes significantly impacting DFS. We developed the IRGPM for rectal cancer using the random forest technique. Based on the IRGPM, we calculated prognostic risk scores to categorize patients into high-risk and low-risk groups. Comparative analysis of immune characteristics between these groups was conducted. In this study, 407 LARC samples were analyzed. The elastic net identified a signature of 20 immune-related genes, forming the basis of the IRGPM. Kaplan-Meier survival analysis revealed a lower 5-year DFS in the high-risk group compared to the low-risk group. The receiver operating characteristic (ROC) curve affirmed the model's robust predictive capability. Validation of the model was performed in the GSE190826 cohort and our institution's cohort. Gene expression differences between high-risk and low-risk groups predominantly related to cytokine-cytokine receptor interactions. Notably, the low-risk group exhibited higher immune scores. Further analysis indicated a greater presence of activated B cells, activated CD8 T cells, central memory CD8 T cells, macrophages, T follicular helper cells, and type 2 helper cells in the low-risk group. Additionally, immune checkpoint analysis revealed elevated PDCD1 expression in the low-risk group. The IRGPM, developed through random forest and elastic net methodologies, demonstrates potential in distinguishing DFS among LARC patients receiving standard treatment. Notably, the low-risk group, as defined by the IRGPM, showed enhanced activation of adaptive immune responses within the tumor microenvironment.

Retrospective cohort study for thrombocytopenia during concurrent chemoradiotherapy for rectal cancer.

The aim of this article was to establish the clinical prognostic models and identify the predictive radiation dosimetric parameters for thrombocytopenia during concurrent chemoradiotherapy for rectal cancer. In this retrospective cohort study, patients with rectal adenocarcinoma undergoing concurrent long-term chemoradiotherapy were included. The primary outcome of interest was grade 2 or higher (2+) thrombocytopenia (platelet(PLT) count <75,000/μL). Secondary outcomes included: grade 1 or higher thrombocytopenia (PLT count<100,000/μL) and the PLT count during chemoradiotherapy and its nadir. The risk prediction model was developed by logistic regression to identify clinical predictors of 2+ thrombocytopenia. Univariate linear regression models were used to test correlations between radiation dosimetric parameters and the absolute PLT count at nadirs. This retrospective cohort comprised 238 patients. Fifty-four (22.6%) patients developed thrombocytopenia during concurrent chemoradiotherapy, while 15 (6.3%) patients developed 2+ thrombocytopenia. Four independently associated risk factors, including age, Alb level, PLT count, and chemotherapy regimen, were included in the final model and used to form a 2+ thrombocytopenia probability estimation nomogram. The C-index was 0.87 (95% CI: 0.78-0.96). The calibration plot showed a moderate agreement, and the Brier score was 0.047 (95% CI: 0.025-0.070). The total absolute volume of bone marrow irradiated by 5 Gy, 10 Gy and 15 Gy of radiation (BM-V5ab, BM-V10ab, BM-V15ab), calculated by the volume of bone marrow multiplied by the corresponding Vx, were identified as new predictors. The nadir of PLT was found to be negatively correlated with BM-V5ab (β = -0.062, P =0.030), BM-V10ab (β = -0.065, P =0.030) and BM-V15ab (β = -0.064, P =0.042). The occurrence of 2+ thrombocytopenia during concurrent chemoradiotherapy for rectal cancer can be predicted by the patient's baseline status and chemoradiotherapy regimen, and low dose irradiation of bone marrow can affect the level of platelets during the treatment.

Interpretation of Complete Tumor Response on MRI Following Chemoradiotherapy of Rectal Cancer: Inter-Reader Agreement and Associated Factors in Multi-Center Clinical Practice.

To measure inter-reader agreement and identify associated factors in interpreting complete response (CR) on magnetic resonance imaging (MRI) following chemoradiotherapy (CRT) for rectal cancer. This retrospective study involved 10 readers from seven hospitals with experience of 80-10210 cases, and 149 patients who underwent surgery after CRT for rectal cancer. Using MRI-based tumor regression grading (mrTRG) and methods employed in daily practice, the readers independently assessed mrTRG, CR on T2-weighted images (T2WI) denoted as mrCRT2W, and CR on all images including diffusion-weighted images (DWI) denoted as mrCRoverall. The readers described their interpretation patterns and how they utilized DWI. Inter-reader agreement was measured using multi-rater kappa, and associated factors were analyzed using multivariable regression. Correlation between sensitivity and specificity of each reader was analyzed using Spearman coefficient. The mrCRT2W and mrCRoverall rates varied widely among the readers, ranging 18.8%-40.3% and 18.1%-34.9%, respectively. Nine readers used DWI as a supplement sequence, which modified interpretations on T2WI in 2.7% of cases (36/1341 [149 patients × 9 readers]) and mostly (33/36) changed mrCRT2W to non-mrCRoverall. The kappa values for mrTRG, mrCRT2W, and mrCRoverall were 0.56 (95% confidence interval: 0.49, 0.62), 0.55 (0.52, 0.57), and 0.54 (0.51, 0.57), respectively. No use of rectal gel, larger initial tumor size, and higher initial cT stage exhibited significant association with a higher inter-reader agreement for assessing mrCRoverall (P ≤ 0.042). Strong negative correlations were observed between the sensitivity and specificity of individual readers (coefficient, -0.718 to -0.963; P ≤ 0.019). Inter-reader agreement was moderate for assessing CR on post-CRT MRI. Readers' varying standards on MRI interpretation (i.e., threshold effect), along with the use of rectal gel, initial tumor size, and initial cT stage, were significant factors associated with inter-reader agreement.

Abstract PR013: Association of a polymorphic variant in JMJD1C with response to chemoradiotherapy in rectal cancer and head and neck cancer: Implications for a diverse population

Abstract Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer (LARC). Although nCRT has improved outcomes for many patients, ~70-80% of patients show poor or no response, and CRT is toxic. No biomarker exists that can predict which patients may benefit from nCRT. CRT efficacy arises from unrepaired double-strand breaks (DSBs). Recent work has suggested that dynamic changes in lysine modification of chromatin regulate DSB repair. This study investigated the association of germline single nucleotide polymorphisms (SNPs) in lysine-modifying genes with DSB repair and CRT outcomes in LARC. The LARC patients (n=84) were segregated into poor (PoR) and complete (CR) responders using the Neoadjuvant Rectal score. Blood DNA was sequenced to identified SNPs, matched LARC patient-derived cells were tested for sensitivity to DNA damage, and results correlated. Significant SNP-response correlations were confirmed in an independent cohort of CRT-treated head and neck squamous cell carcinoma (HNSCC) patients who had received chemoradiation (n=90). The HNSCC patients were segregated into 3 groups based on response: disease-free (n=30), recurrent disease (n=28), and never-disease free (n=32). Isogenic HNSCC lines with either the wildtype (WT) or SNP were generated using CRISPR/Cas9 technology, and bulk RNA sequencing and immunofluorescence-based studies were performed to assess pathways affected. LARC CRs were significantly enriched versus PoRs for a germline SNP in the lysine H3K9 demethylase, JMJD1C, resulting in a missense variant (discovery (n=30, p&amp;lt;0.00001), validation (n=54, p=0.001); Fisher’s Exact). In the HNSCC cohort, the JMJD1C SNP was significantly associated with no recurrence (p=0.0003, Fisher’s Exact). LARC patient-derived cell lines carrying the SNP were significantly more sensitive to DSB damage versus those carrying the WT (n=12, p&amp;lt;0.001, Mann-Whitney). Cells bearing the SNP were significantly enriched for altered mRNA levels of genes associated with DNA repair compared with WT cells (q-value&amp;lt;0.05). On irradiation, the SNP cells showed robust activation of DSB repair (γH2AX, BRCA1 foci, JMJD1C nuclear localization) versus the WT cells. Finally, analysis of the JMJD1C SNP frequency in large population datasets found that while it was abundant in European Americans (EAs), it is relatively rare in African Americans (AAs) (EA= 0.3139 vs. AA=0.072; gnomAD population). This study provides novel insight into a SNP in a lysine-modifying gene affecting DSB repair that may serve as a predictive biomarker for CRT response in 2 different cancer types. Our data suggest that host genetics impact DSB repair and warrant further investigation to better understand disparities in response to CRT. Future research will further explore the racial/ethnic disparities in tumor recurrence and confirm results in in vitro and in vivo models of cancer, and in large patient datasets. Citation Format: Adria Hasan, Elena Demidova, Philip Czyzewicz, Shreya Shah, Karthik Devarajan, Thomas J. Galloway, Margret B. Einarson, Barbara Burtness, Erica A. Golemis, Joshua E. Meyer, Sanjeevani Arora. Association of a polymorphic variant in JMJD1C with response to chemoradiotherapy in rectal cancer and head and neck cancer: Implications for a diverse population [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr PR013.

Prediction of Neoadjuvant Chemoradiotherapy Response in Rectal Cancer Patients Using Harmonized Radiomics of Multcenter 18F-FDG-PET Image

We developed machine and deep learning models to predict chemoradiotherapy in rectal cancer using 18F-FDG PET images and harmonized image features extracted from 18F-FDG PET/CT images. Patients diagnosed with pathologic T-stage III rectal cancer with a tumor size &gt; 2 cm were treated with neoadjuvant chemoradiotherapy. Patients with rectal cancer were divided into an internal dataset (n = 116) and an external dataset obtained from a separate institution (n = 40), which were used in the model. AUC was calculated to select image features associated with radiochemotherapy response. In the external test, the machine-learning signature extracted from 18F-FDG PET image features achieved the highest accuracy and AUC value of 0.875 and 0.896. The harmonized first-order radiomics model had a higher efficiency with accuracy and an AUC of 0.771 than the second-order model in the external test. The deep learning model using the balanced dataset showed an accuracy of 0.867 in the internal test but an accuracy of 0.557 in the external test. Deep-learning models using 18F-FDG PET images must be harmonized to demonstrate reproducibility with external data. Harmonized 18F-FDG PET image features as an element of machine learning could help predict chemoradiotherapy responses in external tests with reproducibility.

Radiomics of skeletal muscle helps to predict gastrointestinal toxicity in locally advanced rectal cancer patients receiving neoadjuvant chemoradiotherapy

BackgroundThe skeletal muscle index (SMI) can serve as a surrogate for a patient’s nutritional status, which is associated with treatment toxicity. This study aims to investigate the potential of baseline skeletal muscle radiomics features to predict gastrointestinal toxicity of neoadjuvant chemoradiotherapy for rectal cancer. MethodsA total of 214 rectal cancer patients (115, 49 and 50 in the training, internal and external validation set, respectively) who underwent neoadjuvant pelvic radiotherapy with capecitabine and irinotecan were retrospectively identified. The skeletal muscle at the level of the third lumber vertebra was contoured, and the radiomics features were extracted from computed tomography scans. In the training set, the least absolute shrinkage and selection operator (LASSO) regression algorithm was applied to select features that were most significantly associated with grade 3–4 gastrointestinal toxicity (diarrhea, nausea, vomiting and proctitis). The predictive performance and clinical utility were estimated using the area under the receiver operator characteristic curve (AUC), F1-score and decision curve analysis (DCA). ResultsNine features, including the SMI and eight radiomics features, were associated with grade 3–4 gastrointestinal toxicity and included in the logistic regression. This combined predictive model, which incorporated the SMI and radiomics features, showed better discrimination than the SMI alone, with an AUC of 0.856 (95 % CI: 0.782–0.929) in the training cohort, 0.812 (95 % CI: 0.667–0.956) in the internal validation cohort and 0.745 (95 % CI: 0.600–0.890) in the external validation cohort. DCA further verified the clinical utility of the combined predictive model. ConclusionRadiomics features of skeletal muscle were significantly associated with gastrointestinal toxicity. The predictive model incorporating the SMI and radiomics features exhibits favorable discrimination and may be highly informative for clinical decision-makings.

The "Watch and Wait" Method After Chemoradiotherapy for Rectal Cancer Requiring Abdominoperineal Resection.

The present study examined the therapeutic effects of preoperative neoadjuvant chemoradiation therapy (NACRT) and predictive factors for complete clinical remission, compared the prognosis and costs of abdominoperineal resection (APR) and the "watch and wait" method (WW), and evaluated the usefulness of WW.In our department, patients with stage II-III lower rectal cancer requiring APR receive NACRT. NACRT was performed as a preoperative treatment (52Gy + S-1: 80-120mg/day × 25days). Eight weeks after the completion of NACRT, rectal examination, endoscopic, computed tomography, and magnetic resonance imaging findings were evaluated to assess its therapeutic effects. APR was indicated for patients in whom endoscopic findings suggested a residual tumor in which a deep ulcer or marginal swelling remained or lymph node metastasis. However, WW was selected for patients who refused APR after informed consent was obtained. In the APR and WW groups, 5- and 20-year treatment costs after CRT were calculated using the Medical Fee Points of Japan in 2020.No significant differences were observed in 3-year disease-free survival rates for either parameter between the two groups. Regarding expenses, treatment costs were lower in the WW group than in the APR group.Organ preservation using active surveillance with CRT for rectal cancer requiring APR is feasible with the achievement of endoluminal complete remission.

Relationships between Microbiome and Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer

Gut microbiome is known to be involved in antitumor immunotherapy and chemotherapy responses; however, few research has focused on the role of gut microbiome in the setting of concurrent chemoradiotherapy (CCRT). In this study, we investigated the tumor microbiome dynamics in patients undergoing neoadjuvant CCRT for locally advanced rectal cancer and sought to determine whether the diversity and composition of microbiome affect treatment response. A total of 103 samples from 26 patients with locally advanced rectal cancer were collected and 16S ribosomal RNA amplicon sequencing was performed. All patients underwent neoadjuvant CCRT followed by surgical resection between 2008 and 2016. Samples were obtained from both tumor and normal rectal tissue at pre- and post-CCRT. According to the American Joint Committee on Cancer tumor regression grading (TRG) system, patients were divided into responders (TRG 0, 1) and non-responders (TRG 2, 3). We performed diversity, taxonomy, and network analyses to compare responders and non-responders. Then, we established the Bayesian network model to predict treatment response in patients with rectal cancer. Overall, we detected 1260 microbial genera from 287 families, 132 orders, 56 classes, and 32 phyla in the bacteria kingdom. Between tumor and normal rectal tissues, there was no difference in microbial diversity and composition. On the other hand, there was a significant decrease in diversity and compositional alterations when comparing pre- and post-CCRT samples (all p<0.001). Ten patients (38.5%) were classified as responders and 16 patients (61.5%) were classified as non-responders. In both groups, CCRT significantly reduced microbial diversity and altered their composition, but it was more pronounced in non-responders. In taxonomic analysis of pre-CCRT samples, butyrate-producing bacteria were differentially enriched in responders. Meanwhile, in post-CCRT samples, opportunistic pathogen were overrepresented in non-responders. The network analysis revealed that butyrate-producing bacteria had strong interactions in responders, whereas opportunistic pathogen demonstrated strong interactions in non-responders (Pearson's coefficient>0.5). Finally, five microbes were selected as the optimal set for the response prediction model, which yielded an area under the curve value of 82.33%. CCRT significantly changed the diversity and composition of microbiome, especially in non-responders. Several microbes might be related with treatment response. These findings highlight the potential of microbiome to play an important role as a biomarker in patients with rectal cancer. (NCT02533271).

Combination of irinotecan silicasome nanoparticles with radiation therapy sensitizes immunotherapy by modulating the activation of the cGAS/STING pathway for colorectal cancer

Our previous clinical trial (Identifier: NCT02605265) revealed that addition of irinotecan (IRIN) to neoadjuvant chemoradiotherapy for rectal cancer could improve the curative effect. However, the adverse effects caused by IRIN limited the wide application of IRIN chemoradiotherapy. This study aimed to explore the mechanism under the synergistic effects of IRIN plus radiation therapy in colorectal cancer (CRC) cells and optimization of IRIN delivery via a silicasome nanocarrier in vivo. Our results revealed that compared with single IRIN or radiation treatment, IRIN combined with radiation therapy remarkably activated the intracellular cGAS/STING pathway, and promoted the expression levels of major histocompatibility complex class I (MHC-I) and programmed death ligand 1 (PD-L1). Further, a silicasome (mesoporous silica nanoparticle coated with lipid bilayer) nanocarrier was utilized to improve the delivery of IRIN with enhanced efficacy and reduced side effects. In the MC38 CRC syngeneic tumor model, IRIN silicasome combined with radiation therapy demonstrated a greater antitumor efficacy than free IRIN plus radiation therapy. Flow cytometry showed the increased number of CD4+ T cells, CD8+ T cells, and dendritic cells (DCs) in tumor in the IRIN silicasome plus radiation group. The immunofluorescence staining further confirmed the activated immune microenvironment with the elevated interferon-γ (IFN-γ) deposition. Besides, the antitumor effect of IRIN silicasome plus radiation therapy was synergistically enhanced by anti-PD-1 immunotherapy. These findings indicated that the combination of IRIN silicasome with radiation therapy could sensitize immunotherapy by manipulating the cGAS/STING pathway serving as a new strategy for CRC treatment.