Chemoradiotherapy For Rectal Cancer Research Articles

Results of phase II trial of intensified neoadjuvant treatment with interdigitating radiotherapy and chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid in patients with locally advanced rectal cancer (PROARCT trial)

Background and purposeThe chemotherapy exposure during chemoradiotherapy for rectal cancer is adequate for radiosensitization but suboptimal for treatment of distant micrometastasis. This study aimed to determine tolerability, dose intensity, response, and toxicity of a novel intensified neoadjuvant treatment approach. Materials and MethodsEligible patients were MRI-staged T3-4NxM0 rectal adenocarcinoma. Treatment consisted of FOLFOX chemotherapy given in weeks 1, 6, and 11 with pelvic radiotherapy (25.2 Gy in 3 weeks in 1.8 Gy/fraction with oxaliplatin and 5-FU continuous infusion) given in weeks 3–5, and weeks 8–10. Surgery was performed 4–6 weeks later. The primary endpoint was tolerability defined as the percentage of patients who were able to complete the planned treatment course. Survival rates were estimated using the Kaplan-Meier method. ResultsMedian age of the 40 patients was 61.5 years. Rectal MRI-stage was T3 in 88%. Overall, 95% completed the regimen. All patients received 50.4 Gy. Relative dose intensity (≥75%) was 92% and 98% for oxaliplatin and 5-FU, respectively. High grade toxicities included neutropenia (25% grade 3; 7.5% grade 4) and diarrhoea (10%). Pathologic CR rate was 20%. Median follow-up was 54 months. The 5-year overall survival, freedom from relapse, locoregional control, and freedom from distant metastasis of the cohort was 82%, 72%, 97% and 72%. ConclusionsDelivery of intensified neoadjuvant treatment with interdigitating chemotherapy and radiotherapy is feasible with no increase in acute perioperative complications. A larger prospective study is required to further evaluate the potential survival benefit of this design.

Complete Clinical Response after Chemoradiotherapy in Rectal Cancer: A Crossroad

Deiana, Enrica MD; Giuffrida, Dario MD; Mare, Marzia MD; Colarossi, Cristina MD; Memeo, Lorenzo MD; Di Mattia, Paolo MD; Carolina Picardo, Maria MD; De Zuanni, Marco MD; D'Agata, Costanza MD; Marino, Lorenza MD Author Information

Systemic inflammatory markers as predictors of response to chemoradiotherapy in rectal cancer

Systemic inflammatory markers as predictors of response to chemoradiotherapy in rectal cancer

Long-Term Results of a Prospective Phase 2 Study on Volume De-Escalation in Neoadjuvant Chemoradiotherapy of Rectal Cancer

PurposeIn the current study, we evaluated whether neoadjuvant chemoradiotherapy with reduced treatment volumes due to the exclusion of elective pelvic nodal irradiation is a feasible strategy for selected patients with locally advanced rectal cancer. Methods and MaterialsPatients with T2 low-lying/T3, N0-N1 rectal lesions without evidence of disease in the lateral lymph nodes were prospectively recruited. All patients underwent pretreatment testing, including computed tomography imaging of the chest, abdomen, and pelvis with intravenous contrast, pelvic magnetic resonance imaging with intravenous contrast, and 18-fluorodeoxyglucose positron emission/computed tomography. The clinical target volume included the primary tumor and the mesorectum with vascular supply containing the perirectal and presacral nodes, with the upper border at the S2/S3 interspace. The total radiation dose was 50.4 Gy, and fluoropyrimidine-based chemotherapy was associated concomitantly. The primary endpoint of the study was the reduction of gastrointestinal (GI) toxicity, and the secondary endpoints were pathologic complete response, local control, overall survival, and disease-free survival. ResultsFifty-two patients (30 men, 22 women) with a median age of 67 years (range, 45-85 years) were enrolled in the study. Acute grade 3 GI toxicity was 7.6%, and there were no cases of grade 4 toxicity. Three patients (5.7%) developed a local recurrence. No relapse occurred in the lateral lymph nodes. The local control rate at 5 years was 96.1%. With a median follow-up time of 72.9 months (range, 2.5-127.6 months), the 3- and 5-year overall survival rates were 89.4% and 87%, respectively. The 3- and 5-year disease-free survival rates were 82.4% and 82.4%, respectively. ConclusionsDe-escalation of radiation therapy target volume reduces GI side effects without compromising efficacy in patients with rectal cancer. These results cannot be clearly extended to high-risk disease and need further evaluation in future randomized trials.

Robotic lateral pelvic lymph node dissection after chemoradiation for rectal cancer: a Western perspective

There are limited outcome data for lateral pelvic lymph node dissection (LPLND) following neoadjuvant chemoradiotherapy (nCRT), particularly in the West. Our aim was to evaluate the short-term perioperative and oncological outcomes of robotic LPLND at a single cancer centre. A retrospective analysis of a prospective database of consecutive patients undergoing robotic LPLND for rectal cancer between November 2012 and February 2020 was performed. The main outcomes were short-term perioperative and oncological outcomes. Major morbidity was defined as Clavien-Dindo grade 3 or above. Forty patients underwent robotic LPLND during the study period. The mean age was 54 years (SD±15years) and 13 (31.0%) were female. The median body mass index was 28.6kg/m2 (IQR 25.5-32.6kg/m2 ). Neoadjuvant CRT was performed in all patients. Resection of the primary rectal cancer and concurrent LPLND occurred in 36 (90.0%) patients, whilst the remaining 4 (10.0%) patients had subsequent LPLND after prior rectal resection. The median operating time was 420min (IQR 313-540min), estimated blood loss was 150ml (IQR 55-200ml) and length of hospital stay was 4days (IQR 3-6days). The major morbidity rate was 10.0% (n=4). The median lymph node harvest from the LPLND was 6 (IQR 3-9) and 13 (32.5%) patients had one or more positive LPLNs. The median follow-up was 16months (IQR 5-33months), with 1 (2.5%) local central recurrence and 7 (17.5%) patients developing distant disease, resulting in 3 (7.5%) deaths. Robotic LPLND for rectal cancer can be performed in Western patients to completely resect extra-mesorectal LPLNs and is associated with acceptable perioperative morbidity.

Timing to achieve the highest rate of pCR after preoperative radiochemotherapy in rectal cancer: a pooled analysis of 3085 patients from 7 randomized trials

PurposeOptimal timing of surgery after neoadjuvant chemoradiotherapy (Nad-CRT) is still controversial in locally advanced rectal cancer (LARC). The primary goal of this study was to determine the best surgical interval (SI) to achieve the highest rate of pathological complete response (pCR) and secondly to evaluate the effect on survival outcomes according to the SI. Patients and methodsPatients data were extracted from the international randomized trials: Accord12/0405, EORTC22921, FFCD9203, CAO/ARO/AIO-94, CAO-ARO-AIO-04, INTERACT and TROG01.04. Inclusion criteria were: age≥ 18, cT3–T4 and cN0–2, no clinical evidence of distant metastasis at diagnosis, Nad-CRT followed by surgery.Pearson’s Chi-squared test with Yates’ continuity correction for categorical variables, the Mann–Whitney test for continuous variables, Mann–Kendall test, Kaplan–Meier curves with log-rank test, univariate and multivariate logistic regression model was used for data analysis. Results3085 patients met the inclusion criteria. Overall, the pCR rate was 14% at a median SI of 6 weeks (range 1–31). The cumulative pCR rate increased significantly when SI lengthened, with 95% of pCR events within 10 weeks from Nad-CRT.At univariate and multivariate logistic regression analysis, lengthening of SI (p< 0.01), radiotherapy dose (p< 0.01), and the addition of oxaliplatin to Nad-CRT (p< 0.01) had a favorable impact on pCR. Furthermore, lengthening of SI was not impact on local recurrences, distance metastases, and overall survival. ConclusionThis pooled analysis suggests that the best time to achieve pCR in LARC is at 10 weeks, considering that the lengthening of SI is not detrimental concerning survival outcomes.

Evaluation of Tissue and Circulating miR-21 as Potential Biomarker of Response to Chemoradiotherapy in Rectal Cancer.

Response to chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (RC) is quite variable and it is urgent to find predictive biomarkers of response. We investigated miR-21 as tissue and plasma biomarker of response to CRT in a prospective cohort of RC patients; The expression of miR-21 was analyzed in pre- and post-CRT rectal tissue and plasma in 37 patients with RC. Two groups were defined: Pathological responders (TRG 0, 1 and 2) and non-responders (TRG 3). The association between miR-21, clinical and oncological outcomes was assessed; miR-21 was upregulated in tumor tissue and we found increased odds of overexpression in pre-CRT tumor tissue (OR: 1.63; 95% CI: 0.40–6.63, p = 0.498) and pre-CRT plasma (OR: 1.79; 95% CI: 0.45–7.19, p = 0.414) of non-responders. The overall recurrence risk increased with miR-21 overexpression in pre-CRT tumor tissue (HR: 2.175, p = 0.37); Significantly higher miR-21 expression is observed in tumor tissue comparing with non-neoplastic. Increased odds of non-response is reported in patients expressing higher miR-21, although without statistical significance. This is one of the first studies on circulating miR-21 as a potential biomarker of response to CRT in RC patients.

Direct effectiveness of adding local hyperthermia to the scheme of neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Purpose of the study. Direct evaluation of the antitumor effectiveness of neoadjuvant chemoradiotherapy for rectal cancer using local electromagnetic hyperthermia. Materials and methods. The analysis of the direct results of treatment of patients with locally advanced rectal cancer in the clinic of the MRRC them. A.F.Tsyba is a branch of the Federal State Budgetary Institution Scientific Research Center for Radiology of the Ministry of Health of Russia from 2015 to 2018. The study included 2 groups of patients: the study group of 54 patients and the control group of 56 people. All patients underwent a comprehensive examination with the aim of staging and morphological verification of the tumor. Patients of the study group in the neoadjuvant mode received conventional radiation therapy with classical dose fractionation in ROD 2 Gy, up to SOD 50 Gy, for 5 weeks with CAPOX chemotherapy, and local electromagnetic hyperthermia on the Yacht 4 unit, in the amount of 6 sessions. Patients in the control group received neoadjuvant treatment in an absolutely identical manner, with the exception of local hyperthermia. After the end of neoadjuvant therapy after 8–10 weeks, a comprehensive examination was again performed to assess the response of the tumor and a decision was made to conduct surgical treatment. During the follow-up examination, the following parameters were evaluated: tumor regression according to clinical and radiological examination. After surgical treatment, a comprehensive evaluation of the removed drug was carried out, including an assessment of the degree of therapeutic tumor pathomorphism according to Lavnikova G. P. Results. When conducting a comparative analysis of the frequency of complete clinical regressions of the tumor in the thermo-chemoradiotherapy group, we more often recorded the full clinical response, 12 patients (22%), compared with the chemoradiotherapy group, 8 patients (14%). In terms of partial response and stabilization in the chemoradiotherapy group, partial regression was observed in 75% of patients, while in the thermochemioradiation group only in 52% of cases. Stabilization in the study and control groups was 14% and 6%, respectively. All patients of the study and control groups with partial tumor regression and stabilization underwent surgical treatment. As a result, the frequency of surgical operations in the control group was slightly higher than 48 (85.7%) versus 42 (77.7%) from the main group (p&gt;0.05). When analyzing the frequency of a complete pathomorphological response, we noted that in the thermochemo-radiation therapy group it was 34% versus 4% in the chemo-radiation therapy group. On the contrary, pathomorphism of the 1st degree was much more common in patients of the control group — 21% versus 2% in the study group. The differences in both cases are statistically highly significant (p&lt;0.001, χ2 15, χ27). Conclusion. The use of thermochemoradiotherapy with high statistical significance (p&lt;0.001) increases the frequency of complete pathomorphological response: 34% in the study group versus 4% in the chemoradiotherapy group.

The impact of sarcopenia on pathologic complete response following neoadjuvant chemoradiation in rectal cancer.

The role of sarcopenia in pathologic complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT) in non-metastatic locally advanced rectal cancer is currently unknown. The present study investigates the association between sarcopenia and post-nCRT pCR. The data of patients operated on following nCRT between January 2013 and January 2020 were collected retrospectively. Sarcopenia was diagnosed based on the calculation of the skeletal muscle index (SMI) from computed tomography carried out at the time of the initial diagnosis. A statistical analysis was then conducted for predictors of pCR. The study included 61 patients with an average age of 57.3 years, 28 of whom formed the non-sarcopenic group (NSG) and 33 the sarcopenic group (SG). Of the patients, 32.7% were at clinical stage 2, and 67.3% were at clinical stage 3. Pathologic data following a mesorectal excision revealed a pCR rate of 21.4% in the NSG compared with 3% in the SG, which was a statistically significant difference (p = 0.025). The TNM downstaging rate was higher in the NSG than in the SG, although the difference was not statistically significant (50% vs. 33.3%, p = 0.28). A univariate analysis revealed the factors affecting pCR to be non-sarcopenia (p = 0.025), age < 61 years (p = 0.004), interval to surgery ≥ 8 weeks (p = 0.029), and serum CEA < 2.5 ng/ml (p = 0.035). Sarcopenia was found to be a negative marker of pCR following nCRT in non-metastatic locally advanced rectal cancer.

Dual-energy CT parameters in correlation to MRI-based apparent diffusion coefficient: evaluation in rectal cancer after radiochemotherapy.

BackgroundRectal cancer (RC) is a frequent malignancy for which magnetic resonance imaging (MRI) is the most common and accurate imaging. Iodine concentration (IC) can be quantified with spectral dual-layer computed tomography CT (DL-CT), which could improve imaging of RC, especially for evaluation of response to radiochemotherapy (RCT).PurposeTo compare a DL-CT system to MRI as the non-invasive imaging gold standard for imaging of RC to evaluate the possibility of a response evaluation with DL-CT.Material and MethodsEleven patients who received DL-CT as well as MRI before and after RCT of RC were retrospectively included into this study. For each examination, a region of interest (ROI) was placed within the tumor. For MRI, the mean apparent diffusion coefficient (ADC) was assessed. For DL-CT, IC, z-effective, and Hounsfield Units (HU) were measured. IC, z-effective, and HU were normalized to the aorta. ADC was correlated to absolute and relative normalized IC, z-effective, and HU with Spearman’s ρ. Differences before and after treatment were tested with Wilcoxon signed-rank test.ResultsHU, IC, and Z-effective values in DL-CT images decreased significantly after RCT (P<0.01 for each comparison). The mean ADC increased significantly after RCT. Spearman’s ρ of the absolute IC difference and the absolute ADC (both before and after RCT) is high and significant (ρ = 0.73; P = 0.01), whereas the ρ-value for z-effective (ρ = 0.56) or HU (ρ = 0.45) to ADC was lower and non-significant.ConclusionResponse evaluation of RC after RCT could be possible with DL-CT via the measurement of IC.

Tumor-Infiltrating Lymphocytes in Biopsy Specimens Obtained 7 Days after Starting Chemoradiotherapy for Rectal Cancer Are Predictors of the Response to Chemoradiotherapy

Background: Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision surgery is a standard treatment for locally advanced rectal cancer (LARC). Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with tumor response; however, this remains to be established. We previously reported that histological changes on biopsy specimens obtained 7 days after starting nCRT are strong predictors of response to nCRT. Methods: The subjects were 208 patients with LARC who received nCRT. TILs on hematoxylin-eosin staining together with immunohistochemical staining of lymphocyte surface markers including CD3, CD4, CD8, and FoxP3 were performed both on the biopsy specimens before and 7 days after starting nCRT. Results: The proportions of patients with high densities of CD3+, CD4+, CD8+, and FoxP3+ cells 7 days after starting CRT were significantly lower than the respective values before starting nCRT (p < 0.0001, p < 0.0001, p = 0.0023, and p = 0.0046). In biopsy specimens obtained before treatment, high-density CD4+ cells and FOXP3+ cells were significantly associated with tumor shrinkage rate. High-density FOXP3+ cells were significantly associated with marked tumor regression. In biopsy specimens obtained 7 days after starting treatment, high-density CD4+ cells were significantly associated with marked tumor regression, tumor regression grade 1, and tumor shrinkage rate. High-density FoxP3+ cells were significantly associated with marked tumor regression and tumor shrinkage rate. Conclusions: In patients who received nCRT for LARC, the evaluations of immunohistochemical staining for CD4+ and FOXP3+ TILs were more intimately related to histological response to CRT and tumor shrinkage rates in biopsy specimens obtained 7 days after starting treatment than in biopsy specimens obtained before CRT.

Abstract 2014: Radiopathomics strategy combining multiparametric MRI with whole-slide image for pretreatment prediction of tumor regression grade to neoadjuvant chemoradiotherapy in rectal cancer

Abstract Backgrounds: Tumor regression grade (TRG) reflects the chemoradiosensitivity of rectal cancer patients undergone neoadjuvant treatment, and relates to distinct probabilities of cancer recurrence and survival. However, in clinical practice, it is significantly challenging to rely solely on radiographic or clinical diagnostic information to obtain a patient's pathological response pre-treatment for treatment optimization. The aim was combining both the tumor information of macroscopic radiological and microscopic pathological images to develop and validated a more accurate signature for pretreatment prediction of TRG to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) on a multicenter dataset. Materials and Methods: We prospectively enrolled 981 patients (303 in the primary cohort, 678 in three external validation cohort) with clinicopathologically confirmed LARC treated with nCRT followed by surgery between Aug 2007 and Nov 2017, and collected their pretreatment multi-parametric MRI (mp-MRI), whole-slide image (WSI) of biopsy specimen, and pathologic response according to AJCC TRG system as well as clinical outcomes. Briefly, an artificial intelligence model integrating quantitative imaging features of mp-MRI and WSI was proposed to predict each nCRT treated patient into a particular 4-category TRG. The signature from the model (hereafter Rp-Grade) was further assessed in three independent validation cohort. Results: Rp-Grade yielded an overall ACC of 87.76% and revealed significant improvement than signature generating from model with mp-MRI or WSI features alone in all validation cohorts (P&amp;lt;0.0.5) (Table). Performance of radiopathomics signature for predicting 4-category AJCC/CAP TRGMetrics (%) [95% CI]Validation Cohort1 (N=480)Validation Cohort2 (N=150)Validation Cohort3 (N=48)Accuracy87.76 [84.86-90.66]79.71 [72.52-84.9]81.24 [70.15-92.34]PPV (TRG=0)94.58 [90.48-98.69]93.52 [84.68-100.0]83.09 [61.19-100.0]PPV (TRG=1)92.02 [86.19-97.85]70.26 [56.42-84.1]70.26 [56.42-84.1]PPV (TRG=2)83.9 [79.6-88.19]74.24 [63.57-84.92]71.49 [52.04-90.94]PPV (TRG=3)-92.54 [78.21-100.0]-Sensitivity (TRG=0)96.49 [93.03-99.95]96.62 [89.92-100.0]91.3 [74.73-100.0]Sensitivity (TRG=1)96.49 [93.03-99.95]75.57 [61.75-89.4]63.39 [42.96-83.82]Sensitivity (TRG=2)97.16 [95.02-99.29]100.0 [100.0-100.0]100.0 [100.0 100.0]Sensitivity (TRG=3)-35.55 [19.99-51.12]-Note: The evaluation results were represented by ‘-' when the number of categories was insufficient in the independent cohort test. Conclusions: Combining the macroscopic radiological information of the whole tumor and microscopic pathological information of local lesions from biopsy, radiopathomics was a potential strategy for the pretreatment prediction of the TRG in patients with LARC who underwent nCRT. Citation Format: Lizhi Shao, Zhenyu Liu, Lili Feng, Xiaoying Lou, Zhenhui Li, Xiao-Yan Zhang, Xuezhi Zhou, Kai Sun, Da-Fu Zhang, Lin Wu, Guanyu Yang, Ying-Shi Sun, Ruihua Xu, Xiangbo Wan, Xinjuan Fan, Jie Tian. Radiopathomics strategy combining multiparametric MRI with whole-slide image for pretreatment prediction of tumor regression grade to neoadjuvant chemoradiotherapy in rectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2014.

Multiparametric MRI and Whole Slide Image-Based Pretreatment Prediction of Pathological Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer: A Multicenter Radiopathomic Study

BackgroundThe aim of this work is to combine radiological and pathological information of tumor to develop a signature for pretreatment prediction of discrepancies of pathological response at several centers and restage patients with locally advanced rectal cancer (LARC) for individualized treatment planning.Patients and MethodsA total of 981 consecutive patients with evaluation of response according to tumor regression grade (TRG) who received nCRT were retrospectively recruited from four hospitals (primary cohort and external validation cohort 1–3); both pretreatment multiparametric MRI (mp-MRI) and whole slide image (WSI) of biopsy specimens were available for each patient. Quantitative image features were extracted from mp-MRI and WSI and used to construct a radiopathomics signature (RPS) powered by an artificial-intelligence model. Models based on mp-MRI or WSI alone were also constructed for comparison.ResultsThe RPS showed overall accuracy of 79.66–87.66% in validation cohorts. The areas under the curve of RPS at specific response grades were 0.98 (TRG0), 0.93 (≤ TRG1), and 0.84 (≤ TRG2). RPS at each grade of pathological response revealed significant improvement compared with both signatures constructed without combining multiscale tumor information (P < 0.01). Moreover, RPS showed relevance to distinct probabilities of overall survival and disease-free survival in patients with LARC who underwent nCRT (P < 0.05).ConclusionsThe results of this study suggest that radiopathomics, combining both radiological information of the whole tumor and pathological information of local lesions from biopsy, could potentially predict discrepancies of pathological response prior to nCRT for better treatment planning.

Changes in Gut Microbiome Associated With Co-Occurring Symptoms Development During Chemo-Radiation for Rectal Cancer: A Proof of Concept Study.

To examine a) whether there are significant differences in the severity of symptoms of fatigue, sleep disturbance, or depression between patients with rectal cancer who develop co-occurring symptoms and those with no symptoms before and at the end of chemotherapy and radiation therapy (CRT); b) differences in gut microbial diversity between those with co-occurring symptoms and those with no symptoms; and c) whether before-treatment diversity measurements and taxa abundances can predict co-occurrence of symptoms. Stool samples and symptom ratings were collected from 31 patients with rectal cancer prior to and at the end of (24-28 treatments) CRT. Descriptive statistics were computed and the Mann-Whitney U test was performed for symptoms. Gut microbiome data were analyzed using R's vegan package software. Participants with co-occurring symptoms reported greater severity of fatigue at the end of CRT than those with no symptoms. Bacteroides and Blautia2 abundances differed between participants with co-occurring symptoms and those with no symptoms. Our random forest classification (unsupervised learning algorithm) predicted participants who developed co-occurring symptoms with 74% accuracy, using specific phylum, family, and genera abundances as predictors. Our preliminary results point to an association between the gut microbiota and co-occurring symptoms in rectal cancer patients and serves as a first step in potential identification of a microbiota-based classifier.

Application Value of Shear Wave Elastography in the Evaluation of Tumor Downstaging for Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiotherapy.

The aim of this study was to assess the application value of shear wave elastography in the evaluation of tumor downstaging for locally advanced rectal cancer after neoadjuvant chemoradiotherapy. A retrospective analysis was conducted using data from patients with locally advanced rectal cancer treated in our hospital who received endorectal ultrasound (ERUS) and shear wave elastographic examinations before and after chemoradiotherapy. The cases were grouped according to the postoperative pathologic tumor-staging scores. The lesions were divided into 2 groups: 1 showing and the other not showing tumor downstaging. The efficacy of ERUS in diagnosis of tumor downstaging was calculated. The differences in the mean and maximum values of the Young modulus of the lesions before and after chemoradiotherapy between the groups were calculated and compared. Receiver operating characteristic curves were constructed by using the differences in the 2 kinds of values of the Young modulus. The mean and maximum values of the Young modulus before and after chemoradiotherapy were significantly different (P < .05). The differences in the mean and maximum values of the Young modulus of rectal lesions between groups were statistically significant (P < .05). The results of the receiver operating characteristic curve showed that a difference in the mean value at 34.7 kPa was the optimal diagnostic threshold. Compared with ERUS, this standard showed a significant difference in diagnosis of tumor downstaging (P < .05). Shear wave elastography is an effective ultrasound elastographic technique to assist ERUS in evaluating lesions after chemoradiotherapy in rectal cancer. It can improve the diagnostic efficacy of tumor downstaging and provide effective imaging conclusions for clinical decision making.

Feasibility And Preliminary Efficacy Of High-intensity Interval Training During Neaodjuvant Chemoradiotherapy For Rectal Cancer

PURPOSE: To assess the feasibility, safety, and preliminary efficacy of a supervised high-intensity interval training (HIIT) program in rectal cancer patients undergoing 5-6 weeks of neoadjuvant chemoradiotherapy (NACRT). METHODS: Thirty-six rectal cancer patients scheduled to receive NACRT followed by surgery were randomized to either exercise training (n=18) or usual care (n=18) in the Exercise During and After Rectal Cancer Treatment (EXERT) Trial in Edmonton, Alberta. Patients in the exercise group were asked to complete 3 supervised HIIT sessions/week for the duration of NACRT. Feasibility was determined by eligibility rate, recruitment rate, follow-up rate and exercise adherence. Safety was assessed by tracking serious adverse events related to exercise. The primary efficacy outcome was cardiorespiratory fitness (VO2 peak) assessed immediately post-NACRT by a graded exercise test. Secondary efficacy outcomes included functional fitness assessed by the Senior’s Fitness Test. RESULTS: From June 2017 to August 2019, 205 rectal cancer patients were screened, 131 (64%) were eligible, and 36 (27%) were recruited. Follow-up fitness testing post-NACRT was completed in 75% (exercise n=14; control n=13). Reasons for missed fitness testing were medical issues. Median attendance for the supervised HIIT sessions during NACRT was 82%. No serious adverse events were observed, however, 2 patients in the exercise group experienced musculoskeletal events which resulted in 4 missed exercise sessions. Analyses of covariance showed no statistically significant or clinically meaningful difference between groups for the primary outcome of VO2 peak (adjusted between-group mean difference, 0.9 ml/kg/min; 95% CI, -1.6, 3.3; p = 0.47). The 8-foot up-and-go was significantly better in the exercise group post-NACRT (adjusted between group mean difference, -0.4 seconds; 95% CI, -0.7, 0.0, p = 0.031). No other significant group differences in functional fitness were observed. CONCLUSIONS: Supervised HIIT during NACRT for rectal cancer was feasible and safe. Further research is needed, however, to better understand the feasibility of completing fitness testing immediately following NACRT and whether HIIT can produce meaningful improvements in fitness in this challenging clinical setting.

Signet ring cell component in pretreatment biopsy predicts pathological response to preoperative chemoradiotherapy in rectal cancer.

Neoadjuvant therapy is routinely used in the management of locally advanced rectal cancer. This study aimed to evaluate the predictive value of pathological parameters in tumor response after treatment. We reviewed the hematoxylin-eosin slides from pretreatment biopsies of 150 rectal cancer patients who received preoperative chemoradiotherapy (PCRT) at Sun Yat-sen University Cancer Center between May 2013 and June 2016. Pathological and clinical parameters were both studied. The tumor response after chemoradiotherapy was evaluated using the tumor regression grade (TRG). Logistic regression was used to evaluate the relevance between these parameters and tumor response. Complete tumor response (TRG0 and pCR) to PCRT was identified in 40 (26.7%) patients. The pCR rate was 93.33% (14 of 15) in cases with signet ring cell component versus 19.26% (26 of 135) in those without signet ring cell component (p < 0.001). Four cases with signet ring cell component were evaluated as clinical complete response (cCR), all of whom also achieved pCR; in contrast, only 9 of 15 (60%) cCR cases without signet ring cell achieved pCR. Our data suggest that the signet ring cell component in pretreatment biopsies may be a potential predictor of tumor response to PCRT in rectal cancer. This suggests patients with clinical complete response are more suitable for a wait-and-watch approach.

Survival Benefit for Metformin Through Better Tumor Response by Neoadjuvant Concurrent Chemoradiotherapy in Rectal Cancer

Metformin may reduce cancer risk and mortality and improve radiotherapy responses in several malignancies. This study aimed to compare tumor responses and prognoses of metformin and nonmetformin groups of diabetic patients receiving neoadjuvant concurrent chemoradiotherapy for rectal cancer. This is a retrospective study. This study was conducted at a single institution in the Republic of Korea. Between January 2000 and November 2017, 104 patients with rectal cancer who were taking diabetes medication and treated with neoadjuvant concurrent chemoradiotherapy followed by radical surgery were reviewed. Patients were divided into those taking (n = 62) and not taking metformin (n = 42). Tumor responses, survival, and other outcomes were analyzed. Tumor response, rectal cancer-specific survival, and disease-free survival rates were measured. Tumor regression grade (p = 0.002), pathological complete response (p = 0.037), and N downstaging (p < 0.001) after neoadjuvant concurrent chemoradiotherapy were significantly higher in the metformin group than in the nonmetformin group. In analysis of cancer-specific mortality, metformin use, differentiation (well, moderate vs poor), pathological Union for International Cancer Control stage (3 vs 1-2), ypN stage (1-2 vs 0), and N downstaging (HR, 0.256 (95% CI, 0.082-0.794), p = 0.018; HR, 0.147 (95% CI, 0.031-0.697), p = 0.016; HR, 3.693 (95% CI, 1.283-10.635), p = 0.015; HR, 3.181 (95% CI, 1.155-8.759), p = 0.025, and HR, 0.175 (95% CI, 0.040-0.769), p = 0.021) were significant factors related to mortality in diabetic patients with rectal cancer. In addition, in the multivariate analysis of cancer recurrence, the interaction between metformin use and lymph node downstaging was a significant predictive factor (HR, 0.222 (95% CI, 0.077-0.639); p = 0.005). This was a small retrospective study conducted at a single institution. Metformin use was associated with better tumor responses and cancer-specific survival, as well as a lower risk of cancer recurrence, in patients with diabetes mellitus who had lymph node downstaging after neoadjuvant concurrent chemoradiotherapy in rectal cancer. See Video Abstract at http://links.lww.com/DCR/B185. BENEFICIO EN SUPERVIVENCIA CON METFORMINA A TRAVÉS DE UNA MEJOR RESPUESTA TUMORAL CON QUIMIORRADIOTERAPIA CONCURRENTE NEOADYUVANTE EN CÁNCER RECTAL: La metformina puede reducir el riesgo de cáncer y la mortalidad y mejorar las respuestas a la radioterapia en varios tumores malignos.Comparar las respuestas tumorales y los pronósticos de los grupos con metformina y sin metformina de pacientes diabéticos que reciben quimiorradioterapia concurrente neoadyuvante para cáncer de recto.Estudio retrospectivo.Institución única en la República de Corea.Se revisaron 104 pacientes entre enero de 2000 y noviembre de 2017, con cáncer rectal que tomaban medicamentos para diabetes y que fueron tratados con quimiorradioterapia concurrente neoadyuvante seguida de cirugía radical. Los pacientes se dividieron en aquellos que tomaban (n = 62) y los que no tomaban metformina (n = 42). Se analizaron las respuestas tumorales, la supervivencia y otros resultados.Se midieron las tasas de la respuesta tumoral, la supervivencia específica de cáncer rectal y de la supervivencia libre de enfermedad.El grado de regresión tumoral (p = 0.002), la remisión patológica completa (p = 0.037) y la reducción de la etapa N (p < 0.001) después de la quimiorradioterapia concurrente neoadyuvante fueron significativamente mayores en el grupo de metformina que en el grupo sin metformina. En el análisis de la mortalidad específica por cáncer, el uso de metformina, la diferenciación (bien, moderada vs pobre), el estadio patológico UICC (3 vs 1-2), el estadio ypN (1-2 vs 0) y la disminución de la etapa N (hazard ratios [intervalos de confianza 95%]: 0.256 [0.082-0.794], p = 0.018; 0.147 [0.031-0.697], p = 0.016; 3.693 [1.283-10.635], p = 0.015; 3.181 [1.155-8.759], p = 0.025 y 0.175 [0.040-0.769], p = 0.021, respectivamente) fueron factores significativos relacionados con la mortalidad en pacientes diabéticos con cáncer rectal. Adicionalmente, en el análisis multivariado de la recurrencia del cáncer, la interacción entre el uso de metformina y la disminución de la etapa ganglionar (N) fue un factor predictivo significativo (hazard ratios [intervalos de confianza del 95%]: 0.222 [0.077-0.639]; p = 0.005).Este fue un estudio retrospectivo pequeño realizado en un solo instituto.El uso de metformina se asoció con mejores respuestas tumorales y supervivencia específica de cáncer, así como un menor riesgo de recurrencia del cáncer, en pacientes con disminución de la etapa ganglionar (N) después de quimiorradioterapia concurrente neoadyuvante en pacientes con cáncer rectal y diabetes. Consulte Video Resumen en http://links.lww.com/DCR/B185. (Traducción-Dr. Jorge Silva Velazco).

Phase II trial of induction chemotherapy plus chemoradiotherapy with aspirin or placebo in high-risk rectal cancer (ICAR).

e16131 Background: Induction chemotherapy (IC) followed by chemoradiation (CRT) is an attractive approach in locally-advanced, high-risk rectal cancer. Additionally, aspirin has shown potential to lower recurrence rate in colorectal cancer, and improve outcomes alongside CRT in rectal cancer, with higher rate of tumor downstaging. Methods: Randomized, double-blind phase 2 trial to evaluate induction treatment with XELOX, followed by capecitabine-based chemoradiotherapy with aspirin or placebo in a high risk population selected by MRI. The aim of this study was to evaluate MRI response after total neoadjuvant treatment with aspirin or placebo. Results: Of the 25 pts who started treatment between January 2018 and March 2019, 4 pts did not complete (1 pt grade 5 diarrhea; 1pt treatment adherence). Median age was 55yo (32.9 - 73.6), 8 pts (32%) were women, and 80% had 3 or more high-risk criteria. 20 pts (80%) showed symptom improvement in the first cycle of IC. Of the 21 patients who finished treatment until interim analysis, 11 pts received aspirin (2 pts had MRI complete response (CR), 3 pts had minor/no response, and 3 pts had progression disease (PD)). 10 pts received placebo (4 MRI CR, 3 pts had minor/no response, and no PD). Conclusions: Aspirin added to chemoradiotherapy was safe but did not improve response to total neoadjuvant treatment. The study was closed due absence of benefit. Clinical trial information: NCT03170115 .

Napabucasin (BBI 608), a potent chemoradiosensitizer in rectal cancer.

The induction of reactive oxygen species (ROS) represents a viable strategy for enhancing the activity of radiotherapy. The authors hypothesized that napabucasin would increase ROS via its ability to inhibit NAD(P)H:quinone oxidoreductase 1 and potentiate the response to chemoradiotherapy in rectal cancer via distinct mechanisms. Proliferation studies, colony formation assays, and ROS levels were measured in HCT116 and HT29 cell lines treated with napabucasin, chemoradiation, or their combination. DNA damage (pγH2AX), activation of STAT, and downstream angiogenesis were evaluated in both untreated and treated cell lines. Finally, the effects of napabucasin, chemoradiotherapy, and their combination were assessed in vivo with subcutaneous mouse xenograft models. Napabucasin significantly potentiated the growth inhibition of chemoradiation in both cell lines. Napabucasin increased ROS generation. Inhibition of ROS by N-acetylcysteine decreased the growth inhibitory effect of napabucasin alone and in combination with chemoradiotherapy. Napabucasin significantly increased pγH2AX in comparison with chemoradiotherapy alone. Napabucasin reduced the levels of pSTAT3 and VEGF and inhibited angiogenesis through an ROS-mediated effect. Napabucasin significantly potentiated the inhibition of growth and blood vessel formation by chemoradiotherapy in mouse xenografts. Napabucasin is a radiosensitizer with a novel mechanism of action: increasing ROS production and inhibiting angiogenesis. Clinical trials testing the addition of napabucasin to chemoradiotherapy in rectal cancer are needed.