Molecular profiles of response to neoadjuvant chemoradiotherapy in oesophageal cancers to develop personalized treatment strategies.
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ABSTRACT:
SUBMITTER: de Klerk LK
PROVIDER: S-EPMC8024738 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPatients with a pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) for oesophageal cancer may benefit from non-surgical management. The aim of this study was to determine the diagnostic performance of visual response assessment of the primary tumour after nCRT on T2-weighted (T2W) and diffusion-weighted (DW) MRI.MethodsPatients with locally advanced oesophageal cancer who underwent T2W- and DW-MRI (1·5 T) before and after nCRT in two hospitals, between July 2013 and September 2017, were included in this prospective study. Three radiologists evaluated T2W images retrospectively using a five-point score for the assessment of residual tumour in a blinded manner and immediately rescored after adding DW-MRI. Histopathology of the resection specimen was used as the reference standard; ypT0 represented a pCR. Sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC) and interobserver agreement were calculated.ResultsTwelve of 51 patients (24 per cent) had a pCR. The sensitivity and specificity of T2W-MRI for detection of residual tumour ranged from 90 to 100 and 8 to 25 per cent respectively. Respective values for T2W + DW-MRI were 90-97 and 42-50 per cent. AUCs for the three readers were 0·65, 0·66 and 0·68 on T2W-MRI, and 0·71, 0·70 and 0·70 on T2W + DW-MRI (P = 0·441, P = 0·611 and P = 0·828 for readers 1, 2 and 3 respectively). The κ value for interobserver agreement improved from 0·24-0·55 on T2W-MRI to 0·55-0·71 with DW-MRI.ConclusionPreoperative assessment of residual tumour on MRI after nCRT for oesophageal cancer is feasible with high sensitivity, reflecting a low chance of missing residual tumour. However, the specificity was low; this results in overstaging of complete responders as having residual tumour and, consequently, overtreatment.
| S-EPMC6594024 | biostudies-literature
Project description:BackgroundConditional survival accounts for the time already survived after surgery and may be of additional informative value. The aim was to assess conditional survival in patients with oesophageal cancer and to create a nomogram predicting the conditional probability of survival after oesophagectomy.MethodsThis retrospective study included consecutive patients with oesophageal cancer who received neoadjuvant chemoradiation followed by oesophagectomy between January 2004 and 2019. Conditional survival was defined as the probability of surviving y years after already surviving for x years. The formula used for conditional survival (CS) was: CS(x|y) = S(x + y) /S(x) , where S(x) represents overall survival at x years. Cox proportional hazards models were used to evaluate predictors of overall survival. A nomogram was constructed to predict 5-year survival directly after surgery and given survival for 1, 2, 3 and 4 years after surgery.ResultsSome 660 patients were included. Median overall survival was 44·4 (95 per cent c.i. 37·0 to 51·8) months. The probability of achieving 5-year overall survival after resection increased from 45 per cent directly after surgery to 54, 65, 79 and 88 per cent given 1, 2, 3 and 4 years already survived respectively. Cardiac co-morbidity, cN category, ypT category, ypN category, chyle leakage and pulmonary complications were independent predictors of survival. The nomogram predicted 5-year survival using these predictors and number of years already survived.ConclusionThe probability of achieving 5-year overall survival after oesophagectomy for cancer increases with each additional year survived. The proposed nomogram predicts survival in patients after oesophagectomy, taking the years already survived into account.
| S-EPMC7317937 | biostudies-literature
Project description:BackgroundThe literature lacks robust evidence comparing definitive chemoradiotherapy (dCRT) with neoadjuvant chemoradiotherapy and surgery (nCRS) for oesophageal squamous cell carcinoma (ESCC). This study aimed to compare long-term survival of these approaches in patients with ESCC.MethodsA systematic review performed according to PRISMA guidelines included studies identified from PubMed, Scopus, and Cochrane CENTRAL databases up to July 2021 comparing outcomes between dCRT and nCRS for ESCC. The main outcome measure was overall survival (OS), secondary outcome was disease-free survival (DFS). A meta-analysis was conducted using random-effects modelling to determine pooled adjusted multivariable hazard ratios (HRs).ResultsTen studies including 14 092 patients were included, of which 30 per cent received nCRS. Three studies were randomized clinical trials (RCTs) and the remainder were retrospective cohort studies. dCRT and nCRS regimens were reported in six studies and surgical quality control was reported in two studies. Outcomes for OS and DFS were reported in eight and three studies respectively. Following meta-analysis, nCRS demonstrated significantly longer OS (HR 0.68, 95 per cent c.i. 0.54 to 0.87, P < 0.001) and DFS (HR 0.50, 95 per cent c.i. 0.36 to 0.70, P < 0.001) compared with dCRT.ConclusionNeoadjuvant chemoradiotherapy followed by oesophagectomy correlated with improved survival compared with definitive chemoradiation in the treatment of ESCC; however, there is a lack of literature on RCTs.
| S-EPMC9728519 | biostudies-literature
Project description:To use gene expression profiles to predict response to neoadjuvant chemoradiotherapy in oesophageal cancer patients.
2008-02-08 | E-MEXP-426 | biostudies-arrayexpress
Project description:BackgroundExcessive skeletal muscle loss during neoadjuvant concurrent chemoradiotherapy (NACRT) is significantly related to survival outcomes of oesophageal cancer. However, the conventional method for measuring skeletal muscle mass requires computed tomography (CT) images, and the calculation process is labour-intensive. In this study, we built machine-learning models to predict excessive skeletal muscle loss, using only body mass index data and blood laboratory test results.MethodsWe randomly split the data of 232 male patients treated with NACRT for oesophageal cancer into the training (70%) and test (30%) sets for 1000 iterations. The naive random over sampling method was applied to each training set to adjust for class imbalance, and we used seven different machine-learning algorithms to predict excessive skeletal muscle loss. We used five input variables, namely, relative change percentage in body mass index, albumin, prognostic nutritional index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio over 50 days. According to our previous study results, which used the maximal χ2 method, 10.0% decrease of skeletal muscle index over 50 days was determined as the cut-off value to define the excessive skeletal muscle loss.ResultsThe five input variables were significantly different between the excessive and the non-excessive muscle loss group (all P < 0.001). None of the clinicopathologic variables differed significantly between the two groups. The ensemble model of logistic regression and support vector classifier showed the highest area under the curve value among all the other models [area under the curve = 0.808, 95% confidence interval (CI): 0.708-0.894]. The sensitivity and specificity of the ensemble model were 73.7% (95% CI: 52.6%-89.5%) and 74.5% (95% CI: 62.7%-86.3%), respectively.ConclusionsMachine learning model using the ensemble of logistic regression and support vector classifier most effectively predicted the excessive muscle loss following NACRT in patients with oesophageal cancer. This model can easily screen the patients with excessive muscle loss who need an active intervention or timely care following NACRT.
| S-EPMC8517349 | biostudies-literature
Project description:Oesophageal adenocarcinoma (OAC) is the sixth most common cause of cancer deaths worldwide, and the 5-year survival rate for patients diagnosed with the disease is approximately 17%. The standard of care for locally advanced disease is neoadjuvant chemotherapy or, more commonly, combined neoadjuvant chemoradiation therapy (neo-CRT) prior to surgery. Unfortunately, ~60-70% of patients will fail to respond to neo-CRT. Therefore, the identification of biomarkers indicative of patient response to treatment has significant clinical implications in the stratification of patient treatment. Furthermore, understanding the molecular mechanisms underpinning tumour response and resistance to neo-CRT will contribute towards the identification of novel therapeutic targets for enhancing OAC sensitivity to CRT. MicroRNAs (miRNA/miR) function to regulate gene and protein expression and play a causal role in cancer development and progression. MiRNAs have also been identified as modulators of key cellular pathways associated with resistance to CRT. Here, to identify miRNAs associated with resistance to CRT, pre-treatment diagnostic biopsy specimens from patients with OAC were analysed using miRNA-profiling arrays. In pre-treatment biopsies miR-330-5p was the most downregulated miRNA in patients who subsequently failed to respond to neo-CRT. The role of miR-330 as a potential modulator of tumour response and sensitivity to CRT in OAC was further investigated in vitro. Through vector-based overexpression the E2F1/p-AKT survival pathway, as previously described, was confirmed as a target of miR-330 regulation. However, miR-330-mediated alterations to the E2F1/p-AKT pathway were insufficient to significantly alter cellular sensitivity to chemotherapy (cisplatin and 5-flurouracil). In contrast, silencing of miR-330-5p enhanced, albeit subtly, cellular resistance to clinically relevant doses of radiation. This study highlights the need for further investigation into the potential of miR-330-5p as a predictive biomarker of patient sensitivity to neo-CRT and as a novel therapeutic target for manipulating cellular sensitivity to neo-CRT in patients with OAC.
| S-EPMC4519309 | biostudies-literature
Project description:Standard use of neoadjuvant chemoradiotherapy, total mesorectal excision, and postoperative adjuvant chemotherapy in locally advanced rectal cancer has tremendously improved oncologic outcomes over the past several decades. However, these improvements come with costs of significant morbidity and poor quality of life. Along with developments in imaging techniques, clinical experience and evidence have identified a certain subgroup of patients that have exceptionally good clinical outcomes while preserving quality of life. Driven by patient demand and interest in preserving quality of life, numerous organ preservation treatment strategies for managing rectal cancer are rapidly evolving. Herein, the flow of research in organ preservation strategies and counter arguments are discussed.
| S-EPMC6529751 | biostudies-literature
Project description:Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer.This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided ? 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy.If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care.
| S-EPMC5801846 | biostudies-literature
Project description:BackgroundNeoadjuvant therapy plus oesophagectomy has been accepted as the standard treatment for patients with potentially curable locally advanced oesophageal cancer. No completed randomized controlled trial (RCT) has directly compared neoadjuvant chemotherapy and neoadjuvant chemoradiation in patients with oesophageal squamous cell carcinoma (ESCC). The aim of the current RCT is to investigate the impact of neoadjuvant chemotherapy plus surgery and neoadjuvant chemoradiotherapy plus surgery on overall survival for patients with resectable locally advanced ESCC.MethodsThis open label, single-centre, phase III RCT randomized patients (cT2-T4aN + M0 and cT3-4aN0M0) in a 1:1 fashion to receive either the CROSS regimen (paclitaxel 50 mg/m2; carboplatin (area under the curve = 2), q1w, 5 cycles; and concurrent radiotherapy, 41.4 Gy/23 F, over 5 weeks) or neoadjuvant chemotherapy (paclitaxel 175 mg/m2; and cisplatin 75 mg/m2, q21d, 2 cycles). Assuming a 12% 5-year overall survival difference in favour of the CROSS regimen, 80% power with a two-sided alpha level of 0.05 and a 5% dropout each year for an estimated 3 years enrolment, the power calculation requires 456 patients to be recruited (228 in each group). The primary endpoint is 5-year overall survival, with a minimum 5-year follow-up. The secondary endpoints include 5-year disease-free survival, toxicity, pathological complete response rate, postoperative complications, postoperative mortality and quality of life. A biobank of pre-treatment and resected tumour tissue will be built for translational research in the future.DiscussionThis RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.Trial registrationNCT04138212, date of registration: October 24, 2019.
| S-EPMC7158003 | biostudies-literature
Project description:Long-term survival in oesophageal squamous cell carcinoma (ESCC) is related with pathological response after neoadjuvant chemoradiotherapy (NCRT) followed by surgery. However, effective biomarkers to predict the pathologic response are still lacking. Therefore, a systematic analysis focusing on genes associated with the efficacy of chemoradiotherapy in ESCC will provide valuable insights into the regulation of molecular processes. By screening publications deposited in PubMed, we collected genes associated with the efficacy of chemoradiotherapy. A specific subnetwork was constructed using the Steiner minimum tree algorithm. Survival analysis in Kaplan-Meier Plotter online resources was performed to explore the relationship between gene mRNA expression and the prognosis of patients with ESCC. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemical staining (IHC) were used to evaluate the expression of key genes in cell lines and human samples. The areas under the receiver operating characteristic (ROC) curves (AUCs) were used to describe performance and accuracy. Transwell assays assessed cell migration, and cell viability was detected using the Cytotoxicity Assay. Finally, we identified 101 genes associated with efficacy of chemoradiotherapy. Additionally, specific molecular networks included some potential related genes, such as CUL3, MUC13, MMS22L, MME, UBC, VAPA, CYP1B1, and UGDH. The MMS22L mRNA expression level showed the most significant association with the ESCC patient outcome (p < 0.01). Furthermore, MMS22L was downregulated at both the mRNA (p < 0.001) and protein levels in tumour tissues compared with that in normal tissues. Lymph node metastasis was significantly associated with low MMS22L expression (p < 0.01). MMS22L levels were inversely correlated with the NCRT response in ESCC (p < 0.01). The resulting area under the ROC curve was 0.847 (95% CI: 0.7232 to 0.9703; p < 0.01). In conclusion, low expression of MMS22L is associated with poor response to NCRT, worse survival, lymph node metastasis, and enhanced migration of tumour cells in ESCC.
| S-EPMC8514954 | biostudies-literature