Neoadjuvant Chemoradiotherapy For Rectal Cancer Research Articles

Updated analysis of a prospective, randomized, controlled trial on the impact on clinical outcomes of fish oil supplementation during neoadjuvant chemoradiation for rectal cancer.

e15594 Background: The intake of nutritional supplements, such as fish oil, can modulate the inflammatory response and thus interfere with therapeutic results. Methods: Patients clinically staged as T3,4 and / or N + rectal adenocarcinoma were randomized 1:1 to receive oral ingestion four capsules, totaling 4g of concentrated fish oil (each gram of fish oil concentrate contained 1448 mg of Eicosapentaenoic acid (EPA) + 964 mg of docosahexaenoic acid (DHA)) throughout neoadjuvant conventional chemoradiation (intervention group – IG) or chemoradiation without supplement (control group – CG). All patients were operated about 8 weeks after chemoradiation. Correlation of inflammatory response - Glasgow Prognostic Score (GPS) with disease-free survival (DFS) was the primary outcome; measurements were collected at 4 moments: M1: at diagnosis; M2: at the end of chemoradiation; M3: at 4 weeks after end of chemoradiotherapy; and M4: preoperatively. Results: From January, 2015 and July, 2017, a total of 111 patients with cT3, 4 and / or N (+) rectal adenocarcinoma were accrued and randomized; 105 were randomized (IG: 51 and CG: 54). Mean age were 60 years, ranging from 30-86 years. There was no difference between groups in M1. In M2 and M3 there were differences between the IG and the CG in systemic inflammatory response measured by GPS (M2: p = 0.001; M3: p = 0.027). After neoadjuvant therapy, 49 patients in the CG and 46 patients in the IG were submitted to surgery; complete pathological response (pCR) was present in 15 patients in the CG and in 10 patients in the IG; there was no association of pCR and fish oil supplementation (P = 0.34). Median follow-up time was 45 months (range: 2-72). With a median follow up time of 24 months, DFS was shorter in patients with KPS < 90% (47.0% vs 80.1%, P = 0.01), high risk (T4 or N+) rectal cancer (67.4% vs 89.7%, P = 0.01) and patients who did not achieve pCR after neoadjuvant CRT (65.5% vs 95.8%, P = 0.003). Also, shorter DFS was observed in patients with GPS 1 or 2 in M2 (69.1% vs 76.7%, p = 0.01) and M4 (38.9% vs 75.3%, p = 0.04) compared to patients with GPS 0 (reduced inflammatory response). In multivariate analysis, patients with high risk rectal cancer and GPS 1 or 2 in M2 had 3.07 and 2.11-fold greater risk of disease relapse; patients who achieved pCR had 84% reduction risk of DFS. KPS and GPS in M4 were not independent prognostic biomarkers for DFS. Conclusions: The oil fish supplementation during neoadjuvant chemoradiotherapy for rectal cancer was able to reduce the systemic inflammation syndrome (GPS = 0) associated with cancer. This reduction during treatment, especially in the preoperative moment was associated with better DFS. Thus, this intervention proposed in our study, as it is easily accessible and low cost, may be a viable strategy in this population and this finding should be better evaluate in future trials. Clinical trial information: NCT02534389.

Consensus recommendation (from the 11th conference of the European federation for colorectal cancer): Adjuvant chemotherapy after neoadjuvant chemoradiotherapy for rectal cancer and TME surgery

Chemoradio therapy followed by total mesorectal excision is the standard of care for rectal cancer. Although locoregional recurrence and survival have improved, distant recurrence has not. Adjuvant chemotherapy might prevent distant metastases, however, its use for patients with rectal cancer treated with preoperative radiochemotherapy and surgery is largely debated. Available data do not support its routine use in these settings, unlike in colon cancer where adjuvant therapy role is well established. According to ESMO Guidelines, adjuvant chemotherapy after preoperative radiochemo therapy with postoperative histology stage III and high-risk stage II can be considered (level of evidence is lower than in colon cancer). These consensus recommendations have been developed based on the review of current evidence and expert opinions, and are expected to assist in selecting subgroups of patients that could benefit from adjuvant chemotherapy after neoadjuvant radio chemotherapy and TME surgery and choosing chemotherapeutic agent in different post-operative scenarios.

Clinical prediction model of pathological response following neoadjuvant chemoradiotherapy for rectal cancer

Patients with pathologic complete response (pCR) achievement can consider local excision or “watch and wait” strategy instead of a radical surgery. This study analyzed the predictive factors of pCR in rectal cancer patients who underwent radical operation after neoadjuvant chemoradiotherapy (nCRT). This study also analyzed the recurrence patterns in patients who achieved pCR and the oncologic outcomes and prognostic factors by ypStage. Between 2000 and 2013, 1,089 consecutive rectal cancer patients who underwent radical resection after nCRT were analyzed. These patients were classified into two groups according to pCR. The clinicopathologic and oncologic outcomes were analyzed and compared between the two groups. Multivariate analysis was conducted on factors related to pCR. The proportion of patients achieving pCR was 18.2% (n = 198). The pCR group demonstrated earlier clinical T and N stages, smaller tumor size, better differentiation, and a lower percentage of circumferential resection margin (CRM) involvement than did the non-pCR group. The prognostic factors associated with poorer disease-free survival were high preoperative carcinoembryonic antigen levels, non-pCR, poor histology, lymphatic/perineural invasion, and involvement of CRM. Multivariate analysis revealed that clinical node negativity, tumor size < 4 cm, and well differentiation were significant independent clinical predictors for achieving pCR. Patients with pCR displayed better long-term outcomes than those with non-pCR. The pCR-prediction model, based on predictive factors, is potentially useful for prognosis and for prescribing a treatment strategy in patients with advanced rectal cancer who need nCRT.

PO-1318 MRI based radiomics as imaging biomarker for response to Neoadjuvant Chemoradiation in Rectal Cancer

PO-1318 MRI based radiomics as imaging biomarker for response to Neoadjuvant Chemoradiation in Rectal Cancer

Magnetic Resonance Image under the Low-Rank Matrix Denoising Algorithm in Evaluating the Efficacy of Neoadjuvant Chemo-Radiotherapy for Rectal Cancer

This study was to explore the application value of magnetic resonance imaging (MRI) images obtained by low-rank matrix recovery algorithm (LRMR algorithm) in evaluating the curative effect of rectal cancer patients receiving the neoadjuvant chemo-radiotherapy (nCRT). In this study, an image denoising model was designed based on the LRMR algorithm, the original low-rank data matrix was recovered from the error, and the low-rank matrix was restored by solving the optimal kernel norm, so as to effectively separate the image data information and the interference noise. In addition, the model was applied to 60 patients with rectal cancer who received nCRT to extract the texture parameters and lesion-related data from the MRI images. The results showed that the MRI images optimized by LRMR algorithm were clearer than the original images, contained less excess noise, and had improved imaging accuracy and image quality. The results of typical cases suggested that the front of the rectal wall membrane of a patient in the T-downstage group was not smooth before treatment, the internal angiography was blurred, and the wall membrane was thickened, but the wall membrane became thinner after treatment, the highest position was reduced from 1.46 cm to 0.38 cm, the average value of the apparent diffusion coefficient (ADC) increased from 0.732 × 10−3 mm2/s to 1.196 × 10−3 mm2/s, and the lesion tissue was thicker. It was found that the height, length, and ADC of the lesion after the nCRT showed statistically great difference in contrast to the values before the treatment P &lt; 0.05 . Such results indicated that the nCRT showed obvious effects in the clinical treatment of rectal cancer. In short, the LRMR algorithm could remove the interference noise in the MRI image, and from the information about rectal cancer tumor lesions extracted from that, the height value and length value of tumor lesions in patients given neoadjuvant chemo-radiotherapy were reduced compared with those before treatment, and the apparent diffusion coefficient value was increased, indicating that neoadjuvant chemo-radiotherapy has a significant effect in the clinical treatment of rectal cancer.

Local Excision-Better Than All (TME) or Nothing (Watch and Wait) in Complete Clinical Response Following Neoadjuvant Chemoradiation for Rectal Cancer?

Local Excision-Better Than All (TME) or Nothing (Watch and Wait) in Complete Clinical Response Following Neoadjuvant Chemoradiation for Rectal Cancer?

External Validation of a Radiomics Model for the Prediction of Complete Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer.

Simple SummaryIn locally advanced rectal cancer (LARC), a minority of patients presents a pathological complete response (pCR) after neoadjuvant chemoradiotherapy (CRT). In this sub-population, organ preservation could be proposed without compromising overall survival. Using a robust neural network based statistical approach, correction of imbalanced data and inter-center variability, a radiomics-based model was externally validated with a balanced accuracy of 85.5%. This model efficiently predicted the patients with a pCR in an external cohort and could be used to select the patients eligible for organ preservation.Objective: Our objective was to develop a radiomics model based on magnetic resonance imaging (MRI) and contrast-enhanced computed tomography (CE-CT) to predict pathological complete response (pCR) to neoadjuvant treatment in locally advanced rectal cancer (LARC). Material: All patients treated for a LARC with neoadjuvant CRT and subsequent surgery in two separate institutions between 2012 and 2019 were considered. Both pre-CRT pelvic MRI and CE-CT were mandatory for inclusion. The tumor was manually segmented on the T2-weighted and diffusion axial MRI sequences and on CE-CT. In total, 88 radiomic parameters were extracted from each sequence using the Miras© software, with a total of 822 features by patient. The cohort was split into training (Institution 1) and testing (Institution 2) sets. The ComBat and Synthetic Minority Over-sampling Technique (SMOTE) approaches were used to account for inter-institution heterogeneity and imbalanced data, respectively. We selected the most predictive characteristics using Spearman’s rank correlation and the Area Under the ROC Curve (AUC). Five pCR prediction models (clinical, radiomics before and after ComBat, and combined before and after ComBat) were then developed on the training set with a neural network approach and a bootstrap internal validation (n = 1000 replications). A cut-off maximizing the model’s performance was defined on the training set. Each model was then evaluated on the testing set using sensitivity, specificity, balanced accuracy (Bacc) with the predefined cut-off. Results: Out of the 124 included patients, 14 had pCR (11.3%). After ComBat harmonization, the radiomic and the combined models obtained a Bacc of 68.2% and 85.5%, respectively, while the clinical model and the pre-ComBat combined achieved respective Baccs of 60.0% and 75.5%. Conclusions: After correction of inter-site variability and imbalanced data, addition of radiomic features enhances the prediction of pCR after neoadjuvant CRT in LARC.

Inhibition of DNA-PK may improve response to neoadjuvant chemoradiotherapy in rectal cancer.

Treatment of locally advanced rectal cancer includes chemoradiation and surgery, but patient response to treatment is variable. Patients who have a complete response have improved outcomes; therefore, there is a critical need to identify mechanisms of resistance to circumvent them. DNA-PK is involved in the repair of DNA double-strand breaks caused by radiation, which we found to be increased in rectal cancer after treatment. We hypothesized that inhibiting this complex with a DNA-PK inhibitor, Peposertib (M3814), would improve treatment response.We assessed pDNA-PK in a rectal cancer cell line and mouse model utilizing western blotting, viability assays, γH2AX staining, and treatment response. The three treatment groups were: standard of care (SOC) (5-fluorouracil (5FU) with radiation), M3814 with radiation, and M3814 with SOC.SOC treatment of rectal cancer cells increased pDNA-PK protein and increased γH2AX foci, but this was abrogated by the addition of M3814. Mice with CT26 tumors treated with M3814 with SOC did not differ in average tumor size but individual tumor response varied. The clinical complete response rate improved significantly with the addition of M3814 but pathological complete response did not. We investigated alterations in DNA repair and found that Kap1 and pATM are increased after M3814 addition suggesting this may mediate resistance.When the DNA-PK inhibitor, M3814, is combined with SOC treatment, response improved in some rectal cancer models but an increase in other repair mechanisms likely diminishes the effect. A clinical trial is ongoing to further explore the role of DNA-PK inhibition in rectal cancer treatment.

Selecting Candidates for Organ-Preserving Strategies After Neoadjuvant Chemoradiotherapy for Rectal Cancer: Development and Validation of a Model Integrating MRI Radiomics and Pathomics.

Histopathologic evaluation after surgery is the gold standard to evaluate treatment response to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). However, it cannot be used to guide organ-preserving strategies due to poor timeliness. To develop and validate a multiscale model incorporating radiomics and pathomics features for predicting pathological good response (pGR) of down-staging to stage ypT0-1N0 after nCRT. Retrospective. A total of 153 patients (median age, 55 years; 109 men; 107 training group; 46 validation group) with clinicopathologically confirmed LARC. A 3.0-T; fast spin echo T2 -weighted and single-shot EPI diffusion-weighted images. The differences in clinicoradiological variables between pGR and non-pGR groups were assessed. Pretreatment and posttreatment radiomics signatures, and pathomics signature were constructed. A multiscale pGR prediction model was established. The predictive performance of the model was evaluated and compared to that of the clinicoradiological model. The χ2 test, Fisher's exact test, t-test, the minimum redundancy maximum relevance algorithm, the least absolute shrinkage and selection operator logistic regression algorithm, regression analysis, receiver operating characteristic curve (ROC) analysis, Delong method. P < 0.05 indicated a significant difference. Pretreatment radiomics signature (odds ratio [OR]=2.53; 95% CI: 1.58-4.66), posttreatment radiomics signature (OR=9.59; 95% CI: 3.04-41.46), and pathomics signature (OR=3.14; 95% CI: 1.40-8.31) were independent factors for predicting pGR. The multiscale model presented good predictive performance with areas under the curve (AUC) of 0.93 (95% CI: 0.88-0.98) and 0.90 (95% CI: 0.78-1.00) in the training and validation groups, those were significantly higher than that of the clinicoradiological model with AUCs of 0.69 (95% CI: 0.55-0.82) and 0.68 (95% CI: 0.46-0.91) in both groups. A model incorporating radiomics and pathomics features effectively predicted pGR after nCRT in patients with LARC. 3 TECHNICAL EFFICACY: Stage 4.

The impact of mistletoe extract on tumor regression in neoadjuvant chemoradiotherapy for rectal cancer

Background: Mistletoe extract, which is usually used as a complementary agent for cancer patients, has an anticancer effect on various malignancies. The present study aimed to evaluate the impact of mistletoe extract (Abnoba Viscum Q®) on tumor responses to neoadjuvant chemoradiotherapy (NCRT) for locally advanced rectal cancer.

Tumor-Infiltrating PD-1+ Immune Cell Density is Associated with Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer

BackgroundElevated tumor-infiltrating T-cell density is associated with favorable outcomes in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). Here, we evaluated the significance of programmed cell death 1 (PD-1)-positive cells, regulatory T cells, and macrophages in response to CRT and prognosis. Patients and MethodsWe assessed CD8+, PD-1+, FOXP3+, CD68+, and CD163+ intratumoral and stromal cell densities by immunohistochemistry using pre-treatment biopsies from 275 patients with rectal cancer treated with neoadjuvant CRT. We determined the impact of these measurements on response to CRT and survival. Response to CRT was determined by tumor regression grade (TRG) of surgical specimens, with good responders defined as TRG3-4. ResultsIntratumoral CD8+ and PD-1+ cell densities were significantly higher in good responders than in poor responders, whereas stromal CD68+ cell density was significantly lower in good responders as compared with poor responders. The multivariable analysis revealed high intratumoral CD8+ and PD-1+ cell densities to be independently associated with good responders (CD8: odds ratio [OR], 2.27; 95% confidence interval [CI], 1.21 – 4.34, P = .010; PD-1: OR, 1.97; 95%CI, 1.03 – 3.84, P = .039), and improved recurrence-free survival (CD8: hazard ratio [HR], 0.56; 95%CI, 0.32 – 0.98, P = .044; PD-1: HR, 0.37; 95%CI, 0.19 – 0.71, P = .002). Only high intratumoral CD8+ cell density was associated with improved overall survival (P = .022). ConclusionPre-treatment high intratumoral PD-1+ and CD8+ cell densities were independently associated with good response to CRT and improved recurrence-free survival, with high intratumoral CD8+ cell density additionally associated with improved overall survival. These values may serve as predictive and prognostic biomarkers in rectal cancer.

Using Multi-Scale Convolutional Neural Network Based on Multi-Instance Learning to Predict the Efficacy of Neoadjuvant Chemoradiotherapy for Rectal Cancer.

Background: At present, radical total mesorectal excision after neoadjuvant chemoradiotherapy is crucial for locally advanced rectal cancer. Therefore, the use of histopathological images analysis technology to predict the efficacy of neoadjuvant chemoradiotherapy for rectal cancer is of great significance for the subsequent treatment of patients. Methods: In this study, we propose a new pathological images analysis method based on multi-instance learning to predict the efficacy of neoadjuvant chemoradiotherapy for rectal cancer. Specifically, we proposed a gated attention normalization mechanism based on the multilayer perceptron, which accelerates the convergence of stochastic gradient descent optimization and can speed up the training process. We also proposed a bilinear attention multi-scale feature fusion mechanism, which organically fuses the global features of the larger receptive fields and the detailed features of the smaller receptive fields and alleviates the problem of pathological images context information loss caused by block sampling. At the same time, we also designed a weighted loss function to alleviate the problem of imbalance between cancerous instances and normal instances. Results: We evaluated our method on a locally advanced rectal cancer dataset containing 150 whole slide images. In addition, to verify our method’s generalization performance, we also tested on two publicly available datasets, Camelyon16 and MSKCC. The results show that the AUC values of our method on the Camelyon16 and MSKCC datasets reach 0.9337 and 0.9091, respectively. Conclusion: Our method has outstanding performance and advantages in predicting the efficacy of neoadjuvant chemoradiotherapy for rectal cancer. Clinical and Translational Impact Statement—This study aims to predict the efficacy of neoadjuvant chemoradiotherapy for rectal cancer to assist clinicians quickly diagnose and formulate personalized treatment plans for patients.

Predicting response to neoadjuvant chemoradiotherapy in rectal cancer: from biomarkers to tumor models.

Colorectal cancer (CRC) is a major contributor to cancer-associated morbidity worldwide and over one-third of CRC is located in the rectum. Neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection is commonly applied to treat locally advanced rectal cancer (LARC). In this review, we summarize current and novel concepts of neoadjuvant therapy for LARC such as total neoadjuvant therapy and describe how these developments impact treatment response. Moreover, as response to nCRT is highly divergent in rectal cancers, we discuss the role of potential predictive biomarkers. We review recent advances in biomarker discovery, from a clinical as well as a histopathological and molecular perspective. Furthermore, the role of emerging predictive biomarkers derived from the tumor environment such as immune cell composition and gut microbiome is presented. Finally, we describe how different tumor models such as patient-derived cancer organoids are used to identify novel predictive biomarkers for chemoradiotherapy (CRT) in rectal cancer.

Association between microsatellite instability and tumor response to neoadjuvant chemoradiotherapy for rectal cancer

PurposeThe relationship between microsatellite instability (MSI) and tumor response after neoadjuvant chemoradiotherapy (nCRT) in rectal cancer remains unclear. The present study aimed to evaluate the association between MSI and tumor response to nCRT in rectal cancer treatment.MethodsPatients with rectal cancer from 2 tertiary hospitals who underwent nCRT, followed by radical surgery, were included. The microsatellite status was determined using a PCR-based Bethesda panel. Tumors with a Dworak’s tumor regression grade of 3 or 4 were considered to have a good response. Predictive factors for a good response to nCRT were analyzed.ResultsOf the 1,401 patients included, 910 (65.0%) had MSI results and 1.5% (14 of 910) showed MSI-H. Among all the patients, 519 (37.0%) showed a good response to nCRT. A univariate analysis showed that MSI-H tended to be negatively associated with a good response to nCRT, but no statistical significance was observed (7.1% vs. 24.1%, P = 0.208). Multivariate analysis showed that well-differentiated tumors were the only predictive factor for good response to nCRT (odds ratio [OR], 2.241; 95% confidence interval [CI], 1.492–3.364; P < 0.001). MSI status tended to be associated with the response to nCRT (OR, 0.215; 95% CI, 0.027–1.681; P = 0.143).ConclusionMSI-H was not associated with response to nCRT in patients with rectal cancer.

Physical activity programmes for patients undergoing neo-adjuvant chemoradiotherapy for rectal cancer: A systematic review and meta-analysis.

Background:Patients diagnosed with localized rectal cancer should undergo Neoadjuvant Radio-Chemotherapy (NACRT) followed, a few weeks later, by surgical resection. NACRT is known to cause significant decline in the physical and psychological health of patients. This literature review aims to summarize the effects of a prehabilitation programme during and/or after NACRT but before surgery.Methods:Articles included in this review have been selected by two independent researchers on Pubmed, Google Scholar, and Cochrane databases with the following terms: “Rectal Cancer AND Physical Activity” and “Exercise AND Rectal Cancer.”Results:We obtained 560 articles. We selected 12 of these, representing 7 series but only one randomized study, constituting 153 patients in total. Most studies included have considerable variation in their prehabilitation programmes, in terms of supervision, training content, frequency, intensity, duration, and temporality, in regard to NACRT and surgery. Implementing a prehabilitation programme during NACRT seems feasible and safe, with adherence ranging from 58% to 100%. VO2max (maximal oxygen consumption during incremental exercise) was improved in three of the studies during the prehabilitation programme. No significant difference in the step count, 6-minute-walk test, or quality of life was seen.Conclusions:Prehabilitation programmes during NACRT for localized rectal cancer patients are safe and feasible; however, due to considerable variation in the prehabilitation programmes and their small size, impact on fitness, quality of life, and surgical outcome are unknown. Larger randomized studies are needed.

Factors Predicting Pathological Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer: The Experience of a Single Institution with 269 Patients (STONE-01).

Simple SummaryNeoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision is currently the standard of care for locally advanced rectal cancer (LARC). This retrospective cohort study evaluated the pathological response after CRT in relation to treatment factors and patient and disease factors in order to find useful indicators to further improve the efficacy of CRT and create tailored therapeutic approaches. To date, the optimal timing for surgery after CRT has not been established. In literature, there are controversial results regarding the risk of higher surgical morbidity and perioperative complications due to delayed surgery. In our study carried out on 269 consecutive LARC patients, among the items analyzed, an interval time from CRT to surgery of >8 weeks was the only independent significant factor for pCR and downstaging.Aims: The aim of this study was to define a potential benefit of pathological complete response rate (pCR) and downstaging rate after neoadjuvant chemoradiotherapy (CRT) in relation to treatment and patient factors in locally advanced rectal cancer. Methods: We performed a retrospective cohort study. Patients were divided according to chemotherapy regimens concurrent to radiotherapy (1-drug vs. 2-drug) and according to the time interval between the end of CRT and surgery (≤8 weeks vs. >8 weeks), as well as in relation to specific relevant clinical factors. Logistic regression was used to estimate the independent factors for pCR and downstaging. Results: 269 patients were eligible for this study. Overall, pCR and downstaging rates were 26% and 75.4%, respectively. Univariate analysis showed that female gender (p = 0.01) and time to surgery >8 weeks (p = 0.04) were associated with pCR; age > 70 years (p = 0.05) and time to surgery >8 weeks (p = 0.002) were correlated to downstaging. At multivariate analysis, interval time to surgery of >8 weeks was the only independent factor for both pCR and downstaging (p = 0.02; OR: 0.5, CI: 0.27–0.93 and p = 0.003; OR: 0.42, CI: 0.24–0.75, respectively). Conclusions: This study indicates that, in our population, an interval time to surgery of >8 weeks is an independent significant factor for pCR and downstaging. Further prospective studies are needed to define the best interval time.

Cost-Effectiveness of TME Alone vs. Neoadjuvant Chemoradiotherapy for Stage II and III Rectal Cancer

<h3>Purpose/Objective(s)</h3> The role of neoadjuvant chemoradiotherapy in rectal cancer is rapidly evolving. Neoadjuvant chemoradiotherapy (nCRT) reduces the risk of local recurrence in rectal cancer patients, but is associated with increased adverse events, costs, and prolonged treatment time. Pre-operative risk stratification of patients into low- and high-risk categories for local recurrence may identify populations that benefit from nCRT, despite these additional costs. Although total mesorectal excision (TME) alone and nCRT with TME (nCRT/TME) are both in clinical practice, no cost-effectiveness analysis comparing these two treatment approaches in rectal cancer has been published. We sought to determine the cost-effectiveness of primary TME versus nCRT with TME for patients with rectal cancer. <h3>Materials/Methods</h3> We developed a Markov model to simulate the 3-year outcomes of 1 million hypothetical patients as treated on the OCUM trial (NCT 325649) with histologically confirmed invasive carcinoma of the rectum (cT2 to cT4, mC0) with distal tumor margin less than 16 cm from the anal verge undergoing either primary TME or nCRT followed by TME. To calculate the incremental cost-effectiveness ratios, we used utilities and probabilities from the literature and costs from Medicare fee schedules and the Healthcare Bluebook. We discounted utilities and costs at 3% annually. Willingness to pay (WTP) was defined at ICER of $100 000 or less per quality-adjusted life-year (QALY). 1-way sensitivity analyses were performed varying selective model inputs to account for uncertainty. Probabilistic sensitivity analysis (PSA) was conducted. <h3>Results</h3> TME was the dominant strategy compared with nCRT and TME (incremental cost-effectiveness ratio, -$158,201.86/QALY). TME and nCRT/TME were associated with costs of $32,518 and $70,583 and QALYs of 1.91 and 1.67, respectively. TME remained the dominant strategy across all 1-way sensitivity analyses in cost, utility states, and probabilities with the exception of the utilities of the health states post-TME and post-nCRT/TME. When the utility of TME treatment fell below 0.4, nCRT/TME became the dominant strategy. Conversely, when the utility of nCRT/TME treatment rose above 0.69 (.1 above the baseline TME utility), nCRT/TME became the dominant strategy. PSA with 1,000,000 samples revealed TME was the cost-effective strategy in 67.4% of trials. <h3>Conclusion</h3> In patients with rectal cancer, TME was the cost-effective strategy compared with nCRT/TME. TME remained the cost-effective strategy across a range of tested variations in cost, probabilities, and utilities but was sensitive to the utility of TME and nCRT/TME. The results of this study contribute to the growing body of literature decreasing usage of nCRT/TME for patients with rectal cancer, particularly if they have low risk of local recurrence.

Organoids as a Robust Preclinical Model for Precision Medicine in Colorectal Cancer: A Systematic Review.

Patients with locally advanced or metastatic colorectal cancer (CRC) display heterogeneous responses to standard-of-care therapy. Robust preclinical models of malignancy in the form of patient-derived tumor organoids (PDTOs) have recently come to the fore in tailoring patient care to a personalized medicine level. This study aimed to review the literature systematically regarding PTDOs and gauge their impact on precision medicine in the management of CRC. A PRISMA-compliant systematic review of the MEDLINE, EMBASE, Web of Science, and Cochrane Library databases was performed. The results were categorized based on the primary objective of the individual studies as follows: organoid use in predicting effective hyperthermic intraperitoneal chemotherapy (HIPEC), systemic chemotherapy in CRC, or neoadjuvant chemoradiotherapy in rectal cancer. The literature search found 200 publications, 16 of which met the inclusion criteria. Organoid models of primary and metastatic CRC have been increasingly used to assess clinical responses to standard therapy. Marked heterogeneity exists, matching the responses observed in clinical practice with ex vivo drug and radiation screening. Repeated correlation between organoid and patient sensitivity to forms of HIPEC, systemic chemotherapy, and chemoradiotherapy has been observed. Patient-derived tumor organoids are the latest tool in predictive translational research. Current organoid-based studies in precision medicine have shown their great potential for predicting the clinical response of patients to CRC therapy. Larger-scale, prospective data are required to fully support this exciting avenue in cancer care.

Pretreatment Neutrophil-to-Lymphocyte Ratio Associated with Tumor Recurrence and Survival in Patients Achieving a Pathological Complete Response Following Neoadjuvant Chemoradiotherapy for Rectal Cancer.

Simple SummaryPatients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiotherapy have been associated with excellent long-term prognosis. However, approximately 9% to 12% of patients with a pathological complete response have been reported to experience tumor recurrence and thereby experience poor outcomes. Identifying predictors of recurrence in patients with a pathological complete response is crucial for precise medicine. The neutrophil-to-lymphocyte ratio is a widely available biomarker of systemic inflammation and affects colorectal prognosis. The study aimed to assess the association between neutrophil-to-lymphocyte ratio and oncological outcomes in rectal cancer patients exhibiting a pCR. We found that a pretreatment high neutrophil-to-lymphocyte ratio (≥3.2) was an independent predictor of reduced overall survival and disease-free survival in patients with locally advanced rectal cancer who achieved a pathological complete response to neoadjuvant chemoradiotherapy. Our findings demonstrate that the neutrophil-to-lymphocyte ratio helps identify patients with a pathological complete response who are at high risk of tumor relapse and might facilitate patient selection for precise medicine.The clinical influence of the neutrophil-to-lymphocyte ratio (NLR) in predicting outcomes in patients with locally advanced rectal cancer (LARC) who achieve a pathological complete response (pCR) to neoadjuvant chemoradiotherapy (NACRT) has seldom been investigated. We retrospectively recruited 102 patients with LARC who achieved a pCR to NACRT and the association of NLR status with survival and tumor recurrence in the patients was analyzed. Thirteen patients (12.7%) developed tumor recurrence. A high NLR (≥3.2) was significantly associated with tumor recurrence (p = 0.039). The 5-year OS rates in patients with a low NLR and patients with a high NLR were 95.1% and 77.7%, respectively (p = 0.014); the 5-year DFS rates in patients with low NLR and patients with a high NLR were 90.6% and 71.3%, respectively (p = 0.031). The Cox proportional hazards model indicated that an NLR of ≥3.2 was an independent poor prognostic factor for DFS (hazard ratio [HR] = 3.12, 95% confidence interval [CI] = 1.06–9.46, p = 0.048) and OS (HR = 6.96, 95% CI = 1.53–35.51, p = 0.013). A pretreatment high NLR (≥3.2) was a promising predictor of reduced OS and DFS in patients with LARC who achieved a pCR to NACRT.

Concurrent use of statins and neoadjuvant chemoradiotherapy for rectal cancer: a systematic review and meta-analysis.

Statins are used primarily in patients with cardiovascular disease. More recently, they have demonstrated benefit in oncology patients. In vitro models have shown decreased rectal tumor cell viability in cells receiving chemoradiation and statin therapy. In vivo models have been less clear. This study aims to elucidate the impact of concurrent use of statins on the efficacy of neoadjuvant therapy for rectal cancer. Search of Medline, EMBASE, and CENTRAL was performed. Articles were included if they reported complete pathological response (pCR), long-term oncologic outcomes, or chemoradiotherapy-induced toxicity in patients with rectal cancer receiving concurrent statin and neoadjuvant therapy. A pairwise meta-analyses was performed using inverse variance random effects. From 1564 citations, six studies with 726 patients on statin therapy (24.5% female, age: 63.6years) and 1863 patients not on statin therapy (35.6% female, age: 60.9years) were included. There was no significant difference in pCR rate between patients on statin therapy and patients not on statin therapy (RR 1.23, 95%CI 0.98-1.54, p = 0.08). Similarly, no difference existed between groups in long-term oncologic outcomes (5-year overall survival: RR 1.03, 95%CI 0.86-1.24, p = 0.75; 5-year disease-free survival: RR 1.04, 95%CI 0.85-1.26, p = 0.73). Chemoradiotherapy-induced toxicities were similar between groups. The concurrent use of statin and neoadjuvant therapy did not significantly impact short- or long-term oncologic outcomes in patients with rectal cancer. Yet, despite pooling of data, this study remained inadequately powered. Larger, prospective studies are required to further elucidate the impact of statins on patients undergoing neoadjuvant therapy for rectal cancer.