Beneficiaries of radical surgery among clinical complete responders to neoadjuvant chemoradiotherapy in rectal cancer.
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ABSTRACT:
SUBMITTER: Zhang S
PROVIDER: S-EPMC8409289 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer, but less than half of patients have a clinical complete response to this treatment. To define the molecular features that are associated with response to neoadjuvant therapy, we generated and collected genomic and transcriptomic data from 712 cancers prior to treatment from our own data and from publicly available data. We found that patients with a complete response have decreased risk of local recurrence and future metastasis. We identified multiple differences in DNA mutations and transcripts between complete and incomplete responders. Complete responder tumors have a higher tumor mutation burden and many more significant co-occurring mutations than the incomplete responder tumors. In addition, mutations in DNA repair genes (across multiple mechanisms of repair) were enriched in complete responders and they also had lower expression of these genes indicating that defective DNA repair is associated with complete response to nCRT. Using logistic regression, we identified three significant predictors of complete response: tumor size, mutations within specific network genes, and the existence of three or more concurrent mutations. In tumors that do not completely respond to nCRT, abnormal cell-cell interaction and increased cancer associated fibroblasts were associated with recurrence. Additionally,gene expression analysis identified a subset of immune hot tumors with worse outcomes and upregulation of immune checkpoint proteins. Overall, our study provides a comprehensive understanding of the molecular features associated with response to nCRT and the molecular differences in non-responder tumors that later reoccur. This knowledge may provide critical insight into the development of precision therapy for rectal cancer.
2024-08-09 | GSE242786 | GEO
Project description:BackgroundAddition of oxaliplatin to capecitabine remains controversial for locally advanced rectal cancer (LARC). And cumulative oxaliplatin dose (COD) varied among clinical trials showing different therapeutic effects of this regimen. The objective of this study was to explore how COD affected tumor metastasis and patient survival.MethodsTotally 388 patients diagnosed with stage cII-III rectal cancer and treated with neoadjuvant chemoradiotherapy followed by radical surgery plus adjuvant chemotherapy were consecutively enrolled into this study and retrospectively reviewed. After grouping by total chemotherapy cycle (TCC), influences of COD on adverse effects and patients' survivals were analyzed in each group. Univariate and multivariate survival analyses were performed through Kaplan-Meier approach and COX proportional hazards model, respectively. Age, gender, anemia, differentiation, carcinoembryonic antigen, carbohydrate antigen 19-9, pretreatment clinical stage and postsurgical pathologic stage were used as covariates.ResultsCOD <?460?mg/m2 emerged as an independent predictor of poorer overall, metastasis-free and disease-free survivals, in patients treated with TCC???7. The hazard ratios were 1.972, 1.763 and 1.637 (P values were 0.021, 0.028 and 0.041), respectively. But it was note-worthy that COD ?460?mg/m2 increased incidence of acute toxicities from 38.4 to 70.8% (P?<?0.001). And in patients treated with TCC???8, COD failed to be a prognosticator.ConclusionsFor LARC patients treated with insufficient TCC (? 7), oxaliplatin of ?460?mg/m2 might be needed to improve survival, though it might resulted in more acute toxicities.
| S-EPMC7268650 | biostudies-literature
Project description:Background:Inflammatory response and nutritional status are associated with cancer development and progression. The purpose of this study was to explore whether the preoperative fibrinogen-albumin ratio index (FARI) is related to prognosis and chemoradiotherapy outcome of radical surgery after neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced rectal cancer (LARC). Methods:In total, 123 patients with LARC who underwent radical surgery after NCRT between June 2012 and December 2018 were collected in this study. Time-dependent receiver operating characteristic (ROC) curve analysis was made to evaluate the ability of the markers for forecasting prognosis. The correlation between FARI and clinicopathological parameters was analyzed. The Kaplan-Meier survival analysis, univariate and multivariate analysis based on Cox proportional hazards models, and subgroup analysis were performed to evaluate overall survival (OS) and disease-free survival (DFS). A nomogram was constructed to evaluate the predictive role of FARI in DFS. Results:The ROC curve analysis showed that the ability of FARI on DFS prediction was superior to those of other inflammatory markers and carcinoembryonic antigen (CEA) (P<0.05). Based on the Youden's index, the optimal cut-off value of FARI was 8.8%. High FARI patients (>8.8%) showed a poor response to NCRT and a decreased DFS rate (P<0.05). In addition, multivariate analysis revealed that FARI (HR=3.098, P=0.033), neutrophil-to-lymphocyte ratio (NLR), and postoperative T stage were independent prognostic factors for DFS in TNM stage III LARC patients. However, FARI failed to distinguish patients with poor OS. Harrell's concordance index (C-index) of the nomogram containing FARI (0.807) was obviously higher than that without it (0.732) among LARC patients who underwent radical surgery after NCRT. Moreover, multivariate analysis revealed FARI (OR=3.044, P=0.012) as an independent predictor for response to NCRT. Conclusion:Among LARC patients who underwent radical surgery after NCRT, preoperative FARI is an independent prognostic factor for DFS and an independent predictor for response to NCRT.
| S-EPMC7505706 | biostudies-literature
Project description:ObjectiveTo evaluate the predictive value of the apparent diffusion coefficient (ADC) for pathologic complete response (pCR) to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal cancer.MethodsA total of 265 patients with rectal adenocarcinoma, whole Diffusion-Weighted MRI (DWI-MRI) images, clinically stage II to III (cT3-4 and/or cN+) and treated with NCRT followed by TME were screened. Fifty patients with pCR and another 50 patients without pCR with similar clinical charcacters and treatment regimens were selected for statistical analysis. All the patients' pre-CRT and post-CRT average ADC values were calculated from the coefficient maps created by DWI-MRI and recorded independently. The difference in the ADC values between the pCR and non-pCR was analyzed by the Mann-Whitney U test. The cut-off ADC value of the receiver operating characteristic (ROC) curve with pCR was then established.ResultsThe mean pre- and post-ADC values in all patients, and in pCR patients and non-pCR patients were 0.879±0.06 and 1.383±0.11, 0.859±0.04 and 1.440±0.10, 0.899±0.07 and 1.325±0.09 (×10(-3) mm(2)/s), respectively. The difference between the pre- and post-ADC values in all patients, pCR patients, and non-pCR patients were considered to be statistically significant. The pre-ADC value was significantly lower in the pCR patients than in the non-pCR patients (p = 0.003), whereas the post-ADC values were significantly higher in the pCR patients than in the non-pCR patients. The percentage increase of the ADC value (?ADC%) in the pCR and non-pCR patients were 68% and 48% respectively (p<0.001). The ROC curves of the cut-off value of the pre-CRT patient ADC value was 0.866×10(-3) mm(2)/s. The AUC, sensitivity, specificity, PPV, NPV, and accuracy of diagnosing pCR were 0.670 (95% CI 0.563-0.777), 0.600, 0.640, 60%, 60%, and 60%, respectively. The cut-off value of ?ADC% was 58%. The corresponding AUC, sensitivity, specificity, PPV, NPV, and accuracy of diagnosing pCR were 0.856 (95% CI 0.783-0.930), 0.800, 0.760, 76.9%, 79.2%, and 78%, respectively.ConclusionsDWI-MRI technology can be efficient for predicting pCR for LARC after NCRT. Although the mean pre-CRT ADC value and the ?ADC% are moderate predictors for pCR, the latter would be more accurate.
| S-EPMC4839695 | biostudies-literature
Project description:Therapeutic strategies for patients with locally advanced rectal cancer (LARC) who are achieving a pathological complete response (pCR) after neoadjuvant radio-chemotherapy (neoCRT) are being increasingly investigated. Recent trials challenge the current standard therapy of total mesorectal excision (TME). For some patients, the treatment strategy of "watch-and-wait" seems a preferable procedure. The key factor in determining individual treatment strategies following neoCRT is the precise evaluation of the tumor response. Contrast-enhanced computer tomography (ceCT) has proven its ability to discriminate benign and malign lesions in multiple cancers. In this study, we retrospectively analyzed the ceCT based density of LARC in 30 patients, undergoing neoCRT followed by TME. We compared the tumors´ pre- and post-neoCRT density and correlated the results to the amount of residual vital tumor cells in the resected tissue. Overall, the density decreased after neoCRT, with the highest decrease in patients achieving pCR. Densitometry demonstrated a specificity of 88% and sensitivity of 68% in predicting pCR. Thus, we claim that ceCT based densitometry is a useful tool in identifying patients with LARC who may benefit from a "watch-and-wait" strategy and suggest further prospective studies.
| S-EPMC8202275 | biostudies-literature
Project description:There is increasing interest in nonoperative management (NOM) for rectal cancer with complete clinical response (cCR) after neoadjuvant chemoradiation (nCRT).The aim of this systematic review was to summarize the available data on NOM, with the intention of formulating standardized protocols on which to base future investigations.A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. A highly sensitive literature search identified all relevant studies published between January 2004 and December 2016. Data extraction and quality assessment was performed independently by two authors, and resolved by consensus with a third reviewer.In total, 15 studies, including 920 patients, met the inclusion criteria; 575 (62.5%) of these patients underwent NOM after cCR, with the remaining patients forming a surgical control group. The weighted mean follow-up was 39.4 (12.7) months in the NOM group and 39.8 (5.1) months in the surgery group. The pooled regrowth rate in the NOM group was 21.3% at a mean of 15.6 (7.0) months. Surgical salvage was possible and was undertaken in 93.2% of these patients. Overall survival in the NOM group was 91.7%, while disease-free survival was 82.7%. For the comparison proctectomy group, pooled rates of local recurrence, overall survival, and disease-free survival were 8.4, 92.4, and 87.5%, respectively.NOM may be a feasible option for surgically eligible rectal cancer patients with cCR after nCRT. Before such a strategy can be widely implemented, further prospective data are required with standardized definitions, diagnostic criteria, and management protocols, with an emphasis on shared patient-provider decision making and patient-centered outcomes.
| S-EPMC6106774 | biostudies-literature
Project description:Following standard neoadjuvant chemoradiotherapy and total mesorectal excision, some patients with locally advanced rectal cancer achieve good response (pathological T0-2N0), while others show nonresponse (pathological T3-4N0 or node-positive). To date, the clinicopathological predictors of good response and the necessity of adjuvant chemotherapy treatment (ACT) in good responders remain unclear. In this retrospective study, clinicopathological characteristics were surveyed to investigate the correlation with good response; furthermore, a propensity score matching (PSM) model was designed to balance the confounding factors between good responders treated with ACT or observation. A total of 2255 patients were enrolled, including 1069 good responders and 1186 nonresponders. The results of the survival analysis showed a good response predicted a better 3-year prognosis (p < 0.001). The logistic regression analysis showed less advanced T and N stages (T3 vs. T4; N0 vs. N1-2), more neoadjuvant chemotherapy (nCT) cycles (≥4 vs. 1-3), and delayed surgery (≥8 weeks vs. <8 weeks) were independent predictors of a good response (p < 0.05). Especially, patients treated with both more nCT cycles and a delay in surgery included the greatest number of good responders (p < 0.001). For good responders, after PSM (1:3), 235 observation cases were matched to 705 ACT cases. As compared with observation, ACT had no greater impact on prognosis analysis (p > 0.05). In conclusion, more cycles of nCT and a delay in surgery predicted a better response, and the delivery of ACT might be omitted in good responders.
| S-EPMC8290248 | biostudies-literature
Project description:BackgroundNeoadjuvant chemoradiation therapy (CRT) has been widely implemented in the treatment of rectal cancer patients, but optimal timing of surgery after neoadjuvant therapy is unclear. The purpose of this study was to evaluate the effects of prolonged intervals between long-course CRT and surgery in rectal cancer patients.MethodsData on all rectal cancer patients diagnosed between 2006 and 2011 were retrieved from the population-based Netherlands Cancer Registry; the main outcome parameters were pathologic complete response (pCR) and overall survival (OS). Outcomes were reported separately for patients with early tumors (ETs; N = 217) and locally advanced rectal cancer (LARC; N = 1073). Patients were divided into 2-week interval groups according to treatment interval, ranging from 5-6 to 13-14 weeks. Kaplan-Meier curves, and logistic regression and Cox regression models were used for data analysis.ResultsNo significant difference in pCR rate was observed for ET patients according to treatment interval. Compared with a treatment interval of 7-8 weeks, pCR rates in LARC patients were higher after 9-10 weeks (18.4 %; odds ratio [OR] 1.56, 95 % CI 1.03-2.37) and 11-12 weeks of treatment interval (20.8 %; OR 1.94, 95 % CI 1.15-3.26). Treatment interval did not influence OS in ET or LARC patients.ConclusionsTreatment intervals of 9-12 weeks between surgery and CRT seem to improve the chances of pCR in LARC patients, without an effect on OS. The length of treatment interval did not affect outcomes in patients with ET. The ongoing search for minimally invasive surgery drives the need for exploration of factors that improve pathologic response.
| S-EPMC5009153 | biostudies-literature
Project description:BackgroundThe watch-and-wait strategy offers a non-invasive therapeutic alternative for rectal cancer patients who have achieved a clinical complete response (cCR) after chemoradiotherapy. This study aimed to investigate the long-term clinical outcomes of this strategy in comparation to surgical resection.MethodsStage II/III rectal adenocarcinoma patients who received neoadjuvant chemoradiotherapy and achieved a cCR were selected from the databases of three centers. cCR was evaluated by findings from digital rectal examination, colonoscopy, and radiographic images. Patients in whom the watch-and-wait strategy was adopted were matched with patients who underwent radical resection through 1:1 propensity score matching analyses. Survival was calculated and compared in the two groups using the Kaplan-Meier method with the log rank test.ResultsA total of 117 patients in whom the watch-and-wait strategy was adopted were matched with 354 patients who underwent radical resection. After matching, there were 94 patients in each group, and no significant differences in term of age, sex, T stage, N stage or tumor location were observed between the two groups. The median follow-up time was 38.2 months. Patients in whom the watch-and-wait strategy was adopted exhibited a higher rate of local recurrences (14.9% vs. 1.1%), but most (85.7%) were salvageable. Three-year non-regrowth local recurrence-free survival was comparable between the two groups (98% vs. 98%, P = 0.506), but the watch-and-wait group presented an obvious advantage in terms of sphincter preservation, especially in patients with a tumor located within 3 cm of the anal verge (89.7% vs. 41.2%, P < 0.001). Three-year distant metastasis-free survival (88% in the watch-and-wait group vs. 89% in the surgical group, P = 0.874), 3-year disease-specific survival (99% vs. 96%, P = 0.643) and overall survival (99% vs. 96%, P = 0.905) were also comparable between the two groups, although a higher rate (35.7%) of distant metastases was observed in patients who exhibited local regrowth in the watch-and-wait group.ConclusionThe watch-and-wait strategy was safe, with similar survival outcomes but a superior sphincter preservation rate as compared to surgery in rectal cancer patients achieving a cCR after neoadjuvant chemoradiotherapy, and could be offered as a promising conservative alternative to invasive radical surgery.
| S-EPMC7816381 | biostudies-literature
Project description:Background and purposePatients with rectal cancer could avoid major surgery if they achieve clinical complete response (cCR) post neoadjuvant treatment. Therefore, prediction of treatment outcomes before treatment has become necessary to select the best neo-adjuvant treatment option. This study investigates clinical and radiomics variables' ability to predict cCR in patients pre chemoradiotherapy.Materials and methodsUsing the OnCoRe database, we recruited a matched cohort of 304 patients (152 with cCR; 152 without cCR) deriving training (N = 200) and validation (N = 104) sets. We collected pre-treatment MR (magnetic resonance) images, demographics and blood parameters (haemoglobin, neutrophil, lymphocyte, alkaline phosphate and albumin). We segmented the gross tumour volume on T2 Weighted MR Images and extracted 1430 stable radiomics features per patient. We used principal component analysis (PCA) and receiver operating characteristic area under the curve (ROC AUC) to reduce dimensionality and evaluate the models produced.ResultsUsing Logistic regression analysis, PCA-derived combined model (radiomics plus clinical variables) gave a ROC AUC of 0.76 (95% CI: 0.69-0.83) in the training set and 0.68 (95% CI 0.57-0.79) in the validation set. The clinical only model achieved an AUC of 0.73 (95% CI 0.66-0.80) and 0.62 (95% CI 0.51-0.74) in the training and validation set, respectively. The radiomics model had an AUC of 0.68 (95% CI 0.61-0.75) and 0.66 (95% CI 0.56-0.77) in the training and validation sets.ConclusionThe predictive characteristics of both clinical and radiomics variables for clinical complete response remain modest but radiomics predictability is improved with addition of clinical variables.
| S-EPMC9253904 | biostudies-literature