Clinicopathological factors predict residual lymph node metastasis in locally advanced rectal cancer with ypT0-2 after neoadjuvant chemoradiotherapy.

PURPOSE: Residual lymph node metastases (RLNM) remained a great concern in the implementation of organ-preserving strategies and led to poor prognosis in locally advanced rectal cancer (LARC). In this study, we aimed to identify the clinicopathological factors correlated with RLNM in LARC patients with ypT0-2 after neoadjuvant chemoradiotherapy (NCRT). METHODS: We retrospectively analyzed 417 patients histologically diagnosed middle-low LARC after NCRT and total mesorectal excision (TME), whose pathological staging was ypT0-2. All patients received pelvic magnetic resonance imaging (MRI) before NCRT. The radiation doses were 50-50.6 Gy for the planning gross tumor volume and 41.8-45 Gy for the planning target volume, respectively. A nomogram for predicting RLNM was constructed using a binary logistic regression. Nomogram performance was assessed by receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA) and clinical impact curve (CIC). RESULTS: After surgery, 191 patients (45.8%) were ypT0, 43 patients (10.3%) were ypT1 and 183 patients (43.9%) were ypT2, and a total of 49 patients (11.8%) were found the presence of RLNM. Multivariable analyses identified MRI-defined mesorectal fascia (MRF)-positive, high-grade histopathology at biopsy, advanced ypT-category, and the presence of perineural invasion (PNI) as the predictive factors. The nomogram, incorporating all these predictors, showed good discrimination and calibration efficacy, with the areas under the ROC curve of 0.690 (95% CI: 0.610-0.771). Both DCA and CIC demonstrated that this nomogram has good clinical usefulness. CONCLUSION: The nomogram model can predict RLNM in patients with ypT0-2 tumors. It can help select suitable patients for performing organ-preserving strategies after NCRT.

lncRNA SNHG1 promotes the progression of hepatocellular carcinoma by regulating the miR-7-5p/IGF2BP2 axis.

Long noncoding RNA small nucleolar RNA host gene 1 (lncRNA SNHG1) plays a crucial role in the occurrence and progression of various tumors. This study investigates the function of lncRNA SNHG1 in hepatocellular carcinoma (HCC). We discovered that lncRNA SNHG1 is significantly upregulated in HCC and markedly enhances cell proliferation, migration, and invasion, while simultaneously suppressing apoptosis in HCC cells. Furthermore, lncRNA SNHG1 was found to downregulate miR-7-5p expression. Overexpression of lncRNA SNHG1 counteracted the suppression of HCC cell migration, proliferation, and invasion caused by miR-7-5p mimics, and reversed the miR-7-5p mimics' enhancement of apoptosis in HCC cells. Additionally, miR-7-5p was shown to negatively regulate IGF2BP2, with the silencing of IGF2BP2 diminishing the abilities of HCC cells to proliferate, migrate, and invade, and increasing their propensity for apoptosis. Overexpression of lncRNA SNHG1 negated these effects. Thus, lncRNA SNHG1 fosters HCC progression by upregulating IGF2BP2 expression through targeting miR-7-5p.

The ypT may better predict the efficacy of neoadjuvant chemoradiotherapy than tumor regression grade in locally advanced rectal cancer patients diagnosed ypT1-4N0.

PURPOSE: This study aimed to assess the impact of ypT stage and tumor regression grade (TRG) on the long-term prognosis of patients with locally advanced rectal cancer (LARC) stage ypT1-4N0 after neoadjuvant chemoradiotherapy (NCRT). METHODS: We retrospectively analyzed 585 patients with histologically diagnosed middle-low LARC (cT3-4 or cN + by pelvic MRI) from 2014 to 2019. All patients underwent NCRT, followed by total mesorectal excision. Disease-free survival (DFS) rates were compared among patients with different ypT stages and TRGs by Kaplan-Meier survival analysis. The chi-square test was used to analyze the relationship between clinicopathological or therapeutic factors and ypT stage. RESULTS: The median follow-up was 35.8 months (range 2.8-71.8 months). The 3-year DFS was 79.5%. A better 3-year DFS was achieved in patients with a pathologic complete response (94.0% vs. 74.3%, p < 0.001) and those in the ypT0-2 (86.5% vs. 66.6%, p < 0.001), ypN0 (85.0% vs. 60.2%, p < 0.001), and TRG0 + 1 (83.1% vs. 73.0%, p = 0.004) subgroups. A total of 309 patients (52.8%) achieved stage ypT1-4N0 after surgery. Among these patients, the ypT1-2N0 subgroup achieved a significantly higher 3-year DFS than the ypT3-4N0 subgroup (85.4% vs. 72.8%, p = 0.018); in contrast, the 3-year DFS did not significantly differ between the TRG1 and TRG2 + 3 subgroups (79.9% vs. 81.1%, p = 0.833). In the ypT1-2N0 or ypT3-4N0 subgroup, different TRG had no significant effect on failure patterns. CONCLUSIONS: For LARC patients with a ypT1-4N0 status after NCRT, ypT stage may be a more effective predictor of long-term prognosis than TRG.

4D-MRI assisted stereotactic body radiation therapy for unresectable colorectal cancer liver metastases.

This study evaluated the feasibilities and outcomes following four-dimensional magnetic resonance imaging (4D-MRI) assisted stereotactic body radiation therapy (SBRT) for unresectable colorectal liver metastases (CRLMs). From March 2018 to January 2022, we identified 76 unresectable CRLMs patients with 123 lesions who received 4D-MRI guided SBRT in our institution. 4D-MRI simulation with or without abdominal compression was conducted for all patients. The prescription dose was 50-65 Gy in 5-12 fractions. The image quality of computed tomography (CT) and MRI were compared using the Clarity Score. Clinical outcomes and toxicity profiles were evaluated. 4D-MRI improved the image quality compared with CT images (mean Clarity Score: 1.67 vs 2.88, P < 0.001). The abdominal compression reduced motions in cranial-caudal direction (P = 0.03) with two phase T2 weighted images assessing tumor motion. The median follow-up time was 12.5 months. For 98 lesions assessed for best response, the complete response, partial response and stable disease rate were 57.1 %, 30.6 % and 12.2 %, respectively. The local control (LC) rate at 1 year was 97.3 %. 46.1 % of patients experienced grade 1-2 toxicities and only 2.6 % patients experienced grade 3 hematologic toxicities. The 4D-MRI technique allowed accurate target delineation and motion tracking in unresectable CRLMs patients. Favorable LC rate and mild toxicities were achieved. This study provided evidence for using 4D-MRI assisted SBRT as an alternative treatment in unresectable CRLMs.

KRAS status predicted by pretreatment MRI radiomics was associated with lung metastasis in locally advanced rectal cancer patients.

BACKGROUND: Mutated KRAS may indicate an invasive nature and predict prognosis in locally advanced rectal cancer (LARC). We aimed to establish a radiomic model using pretreatment T2W MRIs to predict KRAS status and explore the association between the KRAS status or model predictions and lung metastasis. METHODS: In this retrospective multicentre study, LARC patients from two institutions between January 2012 and January 2019 were randomly divided into training and testing cohorts. Least absolute shrinkage and selection operator (LASSO) regression and the support vector machine (SVM) classifier were utilized to select significant radiomic features and establish a prediction model, which was validated by radiomic score distribution and decision curve analysis. The association between the model stratification and lung metastasis was investigated by Cox regression and Kaplan‒Meier survival analysis; the results were compared by the log-rank test. RESULTS: Overall, 103 patients were enrolled (73 and 30 in the training and testing cohorts, respectively). The median follow-up was 38.1 months (interquartile range: 26.9, 49.4). The radiomic model had an area under the curve (AUC) of 0.983 in the training cohort and 0.814 in the testing cohort. Using a cut-off of 0.679 defined by the receiver operating characteristic (ROC) curve, patients with a high radiomic score (RS) had a higher risk for lung metastasis (HR 3.565, 95% CI 1.337, 9.505, p = 0.011), showing similar predictive performances for the mutant and wild-type KRAS groups (HR 3.225, 95% CI 1.249, 8.323, p = 0.016, IDI: 1.08%, p = 0.687; NRI 2.23%, p = 0.766). CONCLUSIONS: We established and validated a radiomic model for predicting KRAS status in LARC. Patients with high RS experienced more lung metastases. The model could noninvasively detect KRAS status and may help individualize clinical decision-making.

Towards deep-learning (DL) based fully automated target delineation for rectal cancer neoadjuvant radiotherapy using a divide-and-conquer strategy: a study with multicenter blind and randomized validation.

PURPOSE: Manual clinical target volume (CTV) and gross tumor volume (GTV) delineation for rectal cancer neoadjuvant radiotherapy is pivotal but labor-intensive. This study aims to propose a deep learning (DL)-based workflow towards fully automated clinical target volume (CTV) and gross tumor volume (GTV) delineation for rectal cancer neoadjuvant radiotherapy. MATERIALS & METHODS: We retrospectively included 141 patients with Stage II-III mid-low rectal cancer and randomly grouped them into training (n = 121) and testing (n = 20) cohorts. We adopted a divide-and-conquer strategy to address CTV and GTV segmentation using two separate DL models with DpuUnet as backend-one model for CTV segmentation in the CT domain, and the other for GTV in the MRI domain. The workflow was validated using a three-level multicenter-involved blind and randomized evaluation scheme. Dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (95HD) metrics were calculated in Level 1, four-grade expert scoring was performed in Level 2, and head-to-head Turing test in Level 3. RESULTS: For the DL-based CTV contours over the testing cohort, the DSC and 95HD (mean ± SD) were 0.85 ± 0.06 and 7.75 ± 6.42 mm respectively, and 96.4% cases achieved clinical viable scores (≥ 2). The positive rate in the Turing test was 52.3%. For GTV, the DSC and 95HD were 0.87 ± 0.07 and 4.07 ± 1.67 mm respectively, and 100% of the DL-based contours achieved clinical viable scores (≥ 2). The positive rate in the Turing test was 52.0%. CONCLUSION: The proposed DL-based workflow exhibited promising accuracy and excellent clinical viability towards automated CTV and GTV delineation for rectal cancer neoadjuvant radiotherapy.

Quantitative assessment of adaptive radiotherapy for prostate cancer using deep learning: Bladder dose as a decision criterion.

BACKGROUND: Adaptive radiotherapy (ART) can incorporate anatomical variations in a reoptimized treatment plan for fractionated radiotherapy. An automatic solution to objectively determine whether ART should be performed immediately after the daily image acquisition is highly desirable. PURPOSE: We investigate a quantitative criterion for whether ART should be performed in prostate cancer radiotherapy by synthesizing pseudo-CT (sCT) images and evaluating dosimetric impact on treatment planning using deep learning approaches. METHOD AND MATERIALS: Planning CT (pCT) and daily cone-beam CT (CBCT) data sets of 74 patients are used to train (60 patients) and evaluate (14 patients) a cycle adversarial generative network (CycleGAN) that performs the task of synthesizing high-quality sCT from daily CBCT. Automatic delineation (AD) of the bladder is performed on the sCT using the U-net. The combination of sCT and AD allows us to perform dose calculations based on the up-to-date bladder anatomy to determine whether the original treatment plan (ori-plan) is still applicable. For positive cases that the patients' anatomical changes and the associated dose calculations warrant re-planning, we made rapid plan revisions (re-plan) based on the ori-plan. RESULTS: The mean absolute error within the region-of-interests (i.e., body, bladder, fat, muscle) between the sCT and pCT are 41.2, 25.1, 26.5, and 29.0HU, respectively. Taking the calculated results of pCT doses as the standard, for PTV, the gamma passing rates of sCT doses at 1 mm/1%, 2 mm/2% are 87.92%, 98.78%, respectively. The Dice coefficients of the AD-contours are 0.93 on pCT and 0.91 on sCT. According to the result of dose calculation, we found when the bladder volume underwent a substantial change (79.7%), the bladder dose is still within the safe limit, suggesting it is insufficient to solely use the bladder volume change as a criterion to determine whether adaptive treatment needs to be done. After AD-contours of the bladder using sCT, there are two cases whose bladder dose D mean > 4000 cGy ${{\mathrm{D}}}_{{\mathrm{mean}}} > 4000{\mathrm{\ cGy}}$ . For the two cases, we perform re-planning to reduce the bladder dose to D mean = 3841 cGy ${{\mathrm{D}}}_{{\mathrm{mean}}} = 3841{\mathrm{\ cGy}}$ , D mean = 3580 cGy ${{\mathrm{D}}}_{{\mathrm{mean}}} = 3580{\mathrm{\ cGy\ }}$ under the condition that the PTV meets the prescribed dose. CONCLUSION: We provide a dose accurate adaptive workflow for prostate cancer patients by using deep learning approaches, and implement ART that adapts to bladder dose. Of note, the specific replanning criterion for whether ART needs to be performed can adapt to different centers' choices based on their experience and daily observations.

Prognostic impact of sarcopenia in patients with locally advanced adenocarcinoma of the esophagogastric junction treated with neoadjuvant chemoradiotherapy.

Background: Few studies have evaluated the significance of sarcopenia in predicting the outcomes of patients with adenocarcinoma of the esophagogastric junction (AEG), especially those who received neoadjuvant chemoradiotherapy (NCRT). We aimed to identify the sarcopenic status and its impact on the outcomes of patients with locally advanced AEG who received NCRT followed by radical surgery or systemic therapy. Materials and methods: Patients with T3-4N+M0 AEG with accessible abdominal computed tomography (CT) before and after NCRT were retrospectively analyzed. Body composition parameters, particularly the skeletal muscle index (SMI), were assessed using a CT-based method, and sarcopenia was defined using a predetermined SMI cutoff value. Survival analysis was conducted using the Kaplan-Meier method. A Cox proportional hazards regression model was used to identify independent prognostic factors. Receiver operating characteristic curve analysis was carried out, and the area under the curve (AUC) was calculated to test the prognostic accuracy of different factors. Results: A total of 63 patients were enrolled, 65.1 and 79.4% of whom developed pre- and post-NCRT sarcopenia, respectively. Patients with pre-NCRT sarcopenia had lower radical surgery rates (70.7 vs. 95.5%, p = 0.047) than those without sarcopenia; however, sarcopenic status did not affect other short-term outcomes, including treatment-related toxicity and efficacy. Pre-NCRT sarcopenia was identified as an independent predictive factor for poor overall survival (OS) [adjusted hazard ratio (HR), 6.053; p = 0.002] and progression-free survival (PFS) (adjusted HR, 2.873; p = 0.031). Compared with nutritional indices such as the Nutritional Risk Screening 2002, weight loss during NCRT, and post-NCRT sarcopenia, pre-NCRT sarcopenia was regarded as the best predictive index for the 5-year OS (AUC = 0.735) and PFS rates (AUC = 0.770). Conclusion: Pre-NCRT sarcopenia may be an independent predictive factor for OS and PFS rates in patients with locally advanced AEG receiving multimodal treatment.

MRI-based radiomics to predict neoadjuvant chemoradiotherapy outcomes in locally advanced rectal cancer: A multicenter study.

Background and purpose: Predicting tumour response would be useful for selecting patients with locally advanced rectal cancer (LARC) for organ preservation strategies. We aimed to develop and validate a prediction model for T downstaging (ypT0-2) in LARC patients after neoadjuvant chemoradiotherapy and to identify those who may benefit from consolidation chemotherapy. Materials and methods: cT3-4 LARC patients at three tertiary medical centers from January 2012 to January 2019 were retrospectively included, while a prospective cohort was recruited from June 2021 to March 2022. Eight filter (principal component analysis, least absolute shrinkage and selection operator, partial least-squares discriminant analysis, random forest)-classifier (support vector machine, logistic regression) models were established to select radiomic features. A nomogram combining radiomics and significant clinical features was developed and validated by calibration curve and decision curve analysis. Interaction test was conducted to investigate the consolidation chemotherapy benefits. Results: A total of 634 patients were included (426 in training cohort, 174 in testing cohort and 34 in prospective cohort). A radiomic prediction model using partial least-squares discriminant analysis and a support vector machine showed the best performance (AUC: 0.832 [training]; 0.763 [testing]). A nomogram combining radiomics and clinical features showed significantly better prognostic performance (AUC: 0.842 [training]; 0.809 [testing]) than the radiomic model. The model was also tested in the prospective cohort with AUC 0.727. High-probability group (score > 81.82) may have potential benefits from ≥ 4 cycles consolidation chemotherapy (OR: 4.173, 95 % CI: 0.953-18.276, p = 0.058, pinteraction = 0.021). Conclusion: We identified and validated a model based on multicenter pre-treatment radiomics to predict ypT0-2 in cT3-4 LARC patients, which may facilitate individualised treatment decision-making for organ-preservation strategies and consolidation chemotherapy.

Gut microbiota-mediated nucleotide synthesis attenuates the response to neoadjuvant chemoradiotherapy in rectal cancer.

Preoperative neoadjuvant chemoradiotherapy (nCRT) is a standard treatment for locally advanced rectal cancer (LARC) patients, yet little is known about the mediators underlying the heterogeneous patient response. In this longitudinal study, we performed 16S rRNA sequencing on 353 fecal specimens and find reduced microbial diversity after nCRT. Multi-omics data integration reveals that Bacteroides vulgatus-mediated nucleotide biosynthesis associates with nCRT resistance in LARC patients, and nonresponsive tumors are characterized by the upregulation of genes related to DNA repair and nucleoside transport. Nucleosides supplementation or B. vulgatus gavage protects cancer cells from the 5-fluorouracil or irradiation treatment. An analysis of 2,205 serum samples from 735 patients suggests that uric acid is a potential prognosis marker for LARC patients receiving nCRT. Our data unravel the role of intestinal microbiota-mediated nucleotide biosynthesis in the response of rectal tumors to nCRT, and highlight the importance of deciphering the cross-talk between cancer cells and gut microorganisms during cancer therapies.

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

Background: 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. Methods: 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. Results: 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 (ß = -0.062, P =0.030), BM-V10ab (ß = -0.065, P =0.030) and BM-V15ab (ß = -0.064, P =0.042). Conclusion: 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.

Dentate line invasion as a predictive factor of poor distant relapse-free survival in locally advanced lower rectal cancer with anal sphincter involvement.

BACKGROUND: While an important surgical landmark of the dentate line has been established for locally advanced lower rectal cancer (LALRC), the prognostic significance of dentate line invasion (DLI) has not been well defined. This study aimed to explore the impact of DLI on prognosis in LALRC patients with anal sphincter involvement after neoadjuvant chemoradiotherapy followed by surgery. METHODS: We analyzed 210 LALRC patients and classified them into DLI group (n = 45) or non-DLI group (n = 165). The exact role of DLI in survival and failure patterns was assessed before and after propensity-score matching(PSM). Finally, 50 patients were matched. RESULTS: Before matching, patients in the DLI group had poorer 5-year distant relapse-free survival (DRFS) (P < 0.001), disease-free survival (DFS) (P < 0.001), and overall survival (OS) (P = 0.022) than those in the non-DLI group, with the exception of local recurrence-free survival (LRFS) (P = 0.114). After PSM, the 5-year DRFS, DFS, OS, and LRFS were 51.7% vs. 79.8%(P = 0.026), 51.7% vs. 79.8%(P = 0.029), 71.6% vs. 85.4%(P = 0.126), and 85.7% vs. 92.0%(P = 0.253), respectively, between the two groups. DLI was also an independent prognostic factor for poor DRFS with (Hazard ratio [HR] 3.843, P = 0.020) or without matching (HR 2.567, P = 0.001). The DLI group exhibited a higher rate of distant metastasis before (44.4% vs. 19.4%, P < 0.001) and after matching (48.0% vs. 20.0%, P = 0.037) and similar rates of locoregional recurrence before (13.3% vs.7.9%, P = 0.729) and after matching (16.0% vs.12.0%, P = 1.000). CONCLUSIONS: DLI may portend worse DRFS and distant metastasis in LALRC patients with anal sphincter involvement, and this may be an important variable to guide clinicians.

Phase 2 Evaluation of Neoadjuvant Intensity-Modulated Radiotherapy in Centrally Located Hepatocellular Carcinoma: A Nonrandomized Controlled Trial.

Importance: Centrally located hepatocellular carcinoma (HCC) is a special type of HCC whose outcome is unsatisfactory when treated with surgery alone. No standard adjuvant or neoadjuvant treatment for this disease has been established that improves clinical outcomes. Objective: To evaluate the effectiveness and safety of adding neoadjuvant intensity-modulated radiotherapy (IMRT) before surgery in patients with centrally located HCC. Design, Setting, and Participants: This phase 2, single-center, single-group prospective nonrandomized controlled trial was conducted between December 16, 2014, and January 29, 2019, at the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences in Beijing, China. The last follow-up was on July 30, 2021. Patients with centrally located HCC who underwent neoadjuvant IMRT and surgery were included in the analysis. Interventions: Neoadjuvant IMRT followed by hepatectomy. Main Outcomes and Measures: The primary end point was 5-year overall survival (OS). The secondary end points were tumor response to IMRT, 5-year disease-free survival (DFS), and treatment-related adverse events. Results: Thirty-eight patients (mean [SD] age, 55.6 [9.3] years; 35 male [92.1%] individuals) completed the prescribed neoadjuvant IMRT without interruption. Radiographic tumor response to IMRT before surgery included partial response (16 [42.1%]) and stable disease (22 [57.9%]). Thirteen patients (34.2%) achieved major pathological response, of which 5 (13.2%) achieved pathologic complete response. With a median follow-up of 45.8 months, the median OS was not reached, and the OS rates were 94.6% at 1 year, 75.4% at 3 years, and 69.1% at 5 years. The median DFS was 45.8 months, and DFS rates were 70.3% at 1 year, 54.1% at 3 years, and 41.0% at 5 years. Radiotherapy-related grade 3 adverse events were observed in 3 patients (7.9%). Nineteen operative complications developed in 13 patients (34.2%), including grade I to II complications in 12 patients (31.6%) and grade IIIa complication in 1 patient (2.6%). No grade IIIb or higher operative complications were observed. Conclusions and Relevance: Results of this trial suggest that neoadjuvant IMRT plus surgery is effective and well-tolerated in patients with centrally located HCC. These data may inform a future randomized clinical trial of this new treatment strategy. Trial Registration: ClinicalTrials.gov Identifier: NCT02580929.

Consolidation chemotherapy with capecitabine after neoadjuvant chemoradiotherapy in high-risk patients with locally advanced rectal cancer: Propensity score study.

BACKGROUND: The effects of consolidation chemotherapy (CC) in neoadjuvant therapy in locally advanced rectal cancer (LARC) have been explored. However, the optimal neoadjuvant chemoradiotherapy (NCRT) and surgery interval, regimen, and cycles of chemotherapy remains unclear. AIM: To evaluate the effects of one to two cycles of CC with capecitabine on high-risk patients with LARC without extending NCRT and surgery interval. METHODS: We retrospectively evaluated high-risk patients with LARC, who were defined as having at least one of the following factors by magnetic resonance imaging: depth of invasion beyond the muscularis propria of more than 5 mm (cT3c-cT3d), T4, meso-rectal fascia or extramural vascular invasion positive, and treatment date between January 2015 and July 2019 in our center. Patients were divided into the CC and non-CC group according to whether they received CC (capecitabine 1000 mg/m2 twice daily from days 1 to 14 every 21 d) after NCRT. Propensity score matching (PSM) and inverse probability of treatment weight (IPTW) were used to balance the differences between the two groups. The main outcome was the complete response (CR) rate. RESULTS: A total of 265 patients were enrolled: 136 patients in the CC group and 129 patients in the non-CC group. The median interval was 70 d (range, 37-168). The CR rate was 24.3% and 16.3% (P = 0.107) in the CC and non-CC groups' original samples, respectively. After PSM and IPTW, the CR rate in the CC group was higher than that in non-CC group (27.6% vs 16.2%, P = 0.045; 25.9% vs 16.3%, P = 0.045). The median follow-up was 39.8 mo (range, 2.9-74.8), and there were no differences in 3-year non-regrowth disease-free survival nor overall survival in the original samples (73.2% vs 71.9%, P = 0.913; 92.3% vs 86.7%, P = 0.294), PSM (73.2% vs 73.5%, P = 0.865; 92.5% vs 89.3%, P = 0.612), and IPTW (73.8% vs 72.1%, P = 0.913; 92.4% vs 87.4%, P = 0.294). There was also no difference in grade 2 or higher acute toxicity during neoadjuvant therapy in the two groups (49.3% vs 53.5%, P = 0.492). CONCLUSION: One to two cycles of CC with capecitabine after NCRT was safe and increased the CR rate in high-risk LARC but failed to improve the long-term outcomes.

Phase 1 trial of apatinib combined with intensity-modulated radiotherapy in unresectable hepatocellular carcinoma.

BACKGROUND: To investigate the maximum tolerated dose (MTD) of apatinib delivered during and after intensity-modulated radiotherapy (IMRT) for unresectable hepatocellular carcinoma (HCC). METHODS: Patients with unresectable HCC who were not eligible for radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), or residual/ recurrent after the prior local treatment were enrolled. Patients were scheduled to be treated with IMRT at 50-60 Gy/25-30 fractions. Oral apatinib tablets were administered concurrently with IMRT and continued thereafter. We used a 3 + 3 dose-escalation design, with three dose levels of apatinib (250, 500, and 750 mg). Grade 3 or more severe adverse events (AEs) were defined as dose-limiting toxicities (DLTs). The treatment response was calculated using the Modified Response Evaluation Criteria in Solid Tumours. RESULTS: Nine patients with Barcelona Clinic Liver Cancer Stage C were included. One patient withdrew from the apatinib 250 mg group and another patient was added. No DLTs occurred in the apatinib 250 mg group. Five patients were included in the apatinib 500 mg group, and 2 cases of DLT (grade 3 leukopenia) were found among them. Dose escalation was terminated and the MTD was determined to be 250 mg. Common grade 1-2 AEs included fatigue, hypertension, dizziness, bone marrow suppression, and hyperbilirubinemia. The median follow-up time for all patients was 16.0 months. Three patients achieved complete response and another three achieved partial response. The objective response rate was 6/9 (66.7%), and the disease control rate was 9/9 (100%). Three patients relapsed out of the radiation field. The median progression-free survival was 17.0 months, and the median overall survival was 16.7 months. CONCLUSIONS: When combined with IMRT, apatinib 250 mg daily was recommended for a phase 2 study of unresectable HCC. The antitumor activity of the combination treatment was encouraging. The safety and efficacy of apatinib combined with IMRT for unresectable HCC should be further investigated in future studies. TRIAL REGISTRATION: Registration No. ChiCTR1800018309 . Registered 11 September 2018. Retrospectively registered, https://www.chictr.org.cn/showproj.aspx?proj=30461 .

Improving the accuracy and consistency of clinical target volume delineation for rectal cancer by an education program.

BACKGROUND: Accurate target volume delineation is the premise for the implementation of precise radiotherapy. Inadequate target volume delineation may diminish tumor control or increase toxicity. Although several clinical target volume (CTV) delineation guidelines for rectal cancer have been published in recent years, significant interobserver variation (IOV) in CTV delineation still exists among radiation oncologists. However, proper education may serve as a bridge that connects complex guidelines with clinical practice. AIM: To examine whether an education program could improve the accuracy and consistency of preoperative radiotherapy CTV delineation for rectal cancer. METHODS: The study consisted of a baseline target volume delineation, a 150-min education intervention, and a follow-up evaluation. A 42-year-old man diagnosed with stage IIIC (T3N2bM0) rectal adenocarcinoma was selected for target volume delineation. CTVs obtained before and after the program were compared. Dice similarity coefficient (DSC), inclusiveness index (IncI), conformal index (CI), and relative volume difference [ΔV (%)] were analyzed to quantitatively evaluate the disparities between the participants' delineation and the standard CTV. Maximum volume ratio (MVR) and coefficient of variation (CV) were calculated to assess the IOV. Qualitative analysis included four common controversies in CTV delineation concerning the upper boundary of the target volume, external iliac area, groin area, and ischiorectal fossa. RESULTS: Of the 18 radiation oncologists from 10 provinces in China, 13 completed two sets of CTVs. In quantitative analysis, the average CTV volume decreased from 809.82 cm3 to 705.21 cm3 (P = 0.001) after the education program. Regarding the indices for geometric comparison, the mean DSC, IncI, and CI increased significantly, while ΔV (%) decreased remarkably, indicating improved agreement between participants' delineation and the standard CTV. Moreover, an 11.80% reduction in MVR and 18.19% reduction in CV were noted, demonstrating a smaller IOV in delineation after the education program. Regarding qualitative analysis, the greatest variations in baseline were observed at the external iliac area and ischiorectal fossa; 61.54% (8/13) and 53.85% (7/13) of the participants unnecessarily delineated the external iliac area and the ischiorectal fossa, respectively. However, the education program reduced these variations. CONCLUSION: Wide variations in CTV delineation for rectal cancer are present among radiation oncologists in mainland China. A well-structured education program could improve delineation accuracy and reduce IOVs.

Initial clinical experience of surface guided stereotactic radiation therapy with open-face mask immobilization for improving setup accuracy: a retrospective study.

PURPOSE: To propose a specific surface guided stereotactic radiotherapy (SRT) treatment procedure with open-face mask immobilization and evaluate the initial clinical experience in improving setup accuracy. METHODS AND MATERIALS: The treatment records of 48 SRT patients with head lesions were retrospectively analyzed. For each patient, head immobilization was achieved with a double-shell open-face mask. The anterior shell was left open to expose the forehead, nose, eyes and cheekbones. The exposed facial area was used as region-of-interest for surface tracking by AlignRT (VisionRT Inc, UK). The posterior shell provided a sturdy and personalized headrest. Patient initial setup was guided by 6DoF real-time deltas (RTD) using the reference surface obtained from the skin contour delineated on the planning CT images. The endpoint of initial setup was 1 mm in translational RTD and 1 degree in rotational RTD. CBCT guidance was performed to derive the initial setup errors, and couch shifts for setup correction were applied prior to treatment delivery. CBCT couch shifts, AlignRT RTD values, repositioning rate and setup time were analyzed. RESULTS: The absolute values of median (maximal) CBCT couch shifts were 0.4 (1.3) mm in VRT, 0.1 (2.5) mm in LNG, 0.2 (1.6) mm in LAT, 0.1(1.2) degree in YAW, 0.2 (1.4) degree in PITCH and 0.1(1.3) degree in ROLL. The couch shifts and AlignRT RTD values exhibited highly agreement except in VRT and PITCH (p value < 0.01), of which the differences were as small as negligible. We did not find any case of patient repositioning that was due to out-of-tolerance setup errors, i.e., 3 mm and 2 degree. The surface guided setup time ranged from 52 to 174 s, and the mean and median time was 97.72 s and 94 s respectively. CONCLUSIONS: The proposed surface guided SRT procedure with open-face mask immobilization is a step forward in improving patient comfort and positioning accuracy in the same process. Minimized initial setup errors and repositioning rate had been achieved with reasonably efficiency for routine clinical practice.

Hyperfractionation versus Conventional Fractionation of Preoperative Intensity-Modulated Radiotherapy with Oral Capecitabine in Locally Advanced Mid-Low Rectal Cancer: A Propensity Score Matching Study.

Purpose: In theory, the hyperfractionated radiotherapy can enhance biological effect dose against tumor and alleviate normal tissue toxicity. This study is to assess the efficacy and safety of preoperative hyperfractionated intensity-modulated radiotherapy (IMRT) with oral capecitabine in patients with locally advanced rectal cancer (LARC). Methods: We retrospectively screened patients with LARC from January 2015 to June 2016. Patients that received hyperfractionated IMRT or conventional fractionated IMRT were eligible in the hyperfractionation (HF) group or conventional fractionation (CF) group, respectively. The primary outcome was the complete response rate. Secondary outcomes included toxicity, postoperative complications, anus-reservation operation rate, local recurrence and distant metastases rate, overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Results: 335 patients were included in the analysis. The complete response rate for the hyperfractionated and conventional fractionated IMRT was 20.41% vs. 23.47% (P = 0.583). The anus-reservation operation rate was 68.37% vs. 65.31% (P = 0.649). There were no cases of grade 4 toxicity during radiotherapy; the rate of grade 3 toxicity and postoperative complications was both comparable between groups. However, in the CF group, more patients had a second operation due to complications (0.0% vs. 5.68%, P = 0.011). The cumulative local regional recurrence and distant metastases rates of the HF group and CF group were 5.10% vs. 9.18% (P = 0.267) and 22.45% vs. 24.49% (P = 0.736), respectively. The 5-year OS, CSS, and DFS in the HF group and CF group were 86.45% vs. 73.30% (P = 0.503), 87.34% vs. 75.23% (P = 0.634), and 70.80% vs. 68.11% (P = 0.891), respectively. Conclusions: The preoperative hyperfractionated IMRT with oral capecitabine, with an acceptable toxicity and favorable response and survival, could reduce the rate of secondary surgery.

MRI radiomics independent of clinical baseline characteristics and neoadjuvant treatment modalities predicts response to neoadjuvant therapy in rectal cancer.

BACKGROUND: To analyse the performance of multicentre pre-treatment MRI-based radiomics (MBR) signatures combined with clinical baseline characteristics and neoadjuvant treatment modalities to predict complete response to neoadjuvant (chemo)radiotherapy in locally advanced rectal cancer (LARC). METHODS: Baseline MRI and clinical characteristics with neoadjuvant treatment modalities at four centres were collected. Decision tree, support vector machine and five-fold cross-validation were applied for two non-imaging and three radiomics-based models' development and validation. RESULTS: We finally included 674 patients. Pre-treatment CEA, T stage, and histologic grade were selected to generate two non-imaging models: C model (clinical baseline characteristics alone) and CT model (clinical baseline characteristics combining neoadjuvant treatment modalities). The prediction performance of both non-imaging models were poor. The MBR signatures comprising 30 selected radiomics features, the MBR signatures combining clinical baseline characteristics (CMBR), and the CMBR incorporating neoadjuvant treatment modalities (CTMBR) all showed good discrimination with mean AUCs of 0.7835, 0.7871 and 0.7916 in validation sets, respectively. The three radiomics-based models had insignificant discrimination in performance. CONCLUSIONS: The performance of the radiomics-based models were superior to the non-imaging models. MBR signatures seemed to reflect LARC's true nature more accurately than clinical parameters and helped identify patients who can undergo organ preservation strategies.

Establishment of prognostic models for adenocarcinoma of oesophagogastric junction patients with neoadjuvant chemoradiotherapy: a real-world study.

BACKGROUND: Multimodal therapies based on surgical resection have been recommended for the treatment of adenocarcinoma of the oesophagogastric junction (AEG). We aimed to evaluate prognostic factors in AEG patients receiving neoadjuvant chemoradiotherapy and to build predictive models. METHODS: T3 - T4N + M0 AEG patients with resectable Siewert type II/III tumours were enrolled in this study. All patients underwent neoadjuvant chemoradiation, followed by radical surgery or systemic therapy according to clinical response. Survival analysis was performed using the Kaplan-Meier method; multivariate analysis using the Cox proportional hazards method was also conducted. The Harrell concordance index (C-index) was used to test the prognostic value of models involving prognostic factors, and consistency between actual and predicted survival rates was evaluated by calibration curves. RESULTS: From February 2009 to February 2018, 79 patients were treated with neoadjuvant chemoradiotherapy; 60 patients of them underwent radical surgery. The R0 resection rate was 98.3%, and 46.7% of patients achieved a major pathologic response (MPR), namely, a residual tumour issue less than 10%. The 5-year overall survival (OS) rate was 63%, and the 5-year progression-free survival (PFS) rate was 48%. The incidence of grade 3 complications was 21.5%, and no grade 4 complications were reported. According to the results of univariate and multivariate analyses, we included the neutrophil-lymphocyte ratio (NLR), prognostic nutrition index (PNI), eosinophilic granulocyte (EOS) and postoperative pathologic stage in nomogram analysis to establish prediction models for OS and PFS; the C-index of each model was 0.814 and 0.722, respectively. Both the C-index and calibration curves generated to validate consistency between the actual and predicted survival indicated that the models were well calibrated and of good predictive value. CONCLUSIONS: AEG patients achieved favourable downstaging and pathologic response after neoadjuvant chemoradiation, with acceptable adverse effects. Inflammation-based and nutrition-related factors and postoperative pathologic stage had a significant influence on OS and PFS, and the predictive value was verified through prognostic models.