Total Neoadjuvant Therapy of SCRT+CAPOX vs SCRT+CAPOXIRI for Locally Advanced Rectal Cancer (ENSEMBLE)
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ABSTRACT:
DISEASE(S): Rectal Neoplasms,Colorectal Neoplasms,Locally Advanced Rectal Cancer
PROVIDER: 2068 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Neoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC. We analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LARC cohorts, including a LARC patient RNA sequencing (RNA-seq) dataset from our cohort and GSE15781 and GSE94104 datasets. Gene ontology analysis showed that preoperative CRT significantly enriched the immune response in LARC tissues. Moreover, gene set enrichment analysis revealed six significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways associated with downregulated genes, including mismatch repair (MMR) genes, in LARC tissues after CRT in all three cohorts. Radiation also induced apoptosis and downregulated various MMR system-related genes in three colorectal cancer cells. One patient with LARC showed a change in microsatellite instability (MSI) status after CRT, as demonstrated by the loss of MMR protein and PCR for MSI. Moreover, CRT significantly increased tumor mutational burden in LARC tissues. CIBERSORT analysis revealed that the proportions of M2 macrophages and CD8 T cells were significantly increased after CRT in both the RNA-seq dataset and GSE94104. Notably, preoperative CRT increased various immune biomarker scores, such as the interferon-γ signature, the cytolytic activity and the immune signature. Taken together, our findings demonstrated that neoadjuvant CRT modulated the immune-related characteristics of LARC, suggesting that neoadjuvant CRT may enhance the responsiveness of LARC to immunotherapy.
2023-05-31 | GSE233517 | GEO
Project description:OBJECTIVE:The aim of this prospective, single-arm phase II trial was to confirm the safety and efficacy of neoadjuvant chemotherapy (NAC) using oxaliplatin plus capecitabine (CapOX) for patients with operable locally advanced colon cancer (CC). METHODS:Patients with computed tomography-defined T4 or lymph node-positive CCs were enrolled. After radiological staging, patients were treated with at least 2 cycles of NAC consisting of 130 mg/m2 oxaliplatin on d 1, plus 1,000 mg/m2 capecitabine twice daily for 14 d every 3 weeks, followed by surgery, and then with the rest cycles of adjuvant chemotherapy. Radiological response was evaluated after 2 cycles of NAC. Tumor response, treatment toxicity, and surgical complications were recorded. The pathological response to therapy was evaluated according to the tumor regression grade (TRG) score. The primary endpoint was pathologic tumor response. This trial is registered in ClinicalTrials.gov (No: NCT02415829). RESULTS:Forty-seven patients were enrolled in the study. Forty-two patients completed the planned treatments. The total radiological response rate was 68% (32/47), including complete and partial response rates of 2% (1/47) and 66% (31/47), respectively. Stable disease was observed in 32% (15/47) and progressive disease was observed in none. Complete pathologic response, major regression, and at least moderate regression were achieved in 1 (2%), 2 (4%), and 29 (62%) patients, respectively. Four patients developed grade 3 treatment toxicities. One patient with wound infection occurred after operation (1/47, 2%). There was no treatment-related death. CONCLUSIONS:Our results suggest that NAC with CapOX is an effective and safe treatment option for patients with locally advanced CCs.
| S-EPMC5242445 | biostudies-literature
Project description:ImportanceTreatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases.ObjectiveTo compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC.Design, setting, and participantsA retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified.ExposuresOf the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT).Main outcomes and measuresTreatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK.ResultsOf the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort.Conclusions and relevanceOur findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.
| S-EPMC5885165 | biostudies-literature
Project description:Multimodality treatment is a standard of care for LARC, but the optimal sequencing of the treatment modalities remains unclear. Several randomized clinical trials (RCTs) compared total neoadjuvant treatment (TNT) vs. standard neoadjuvant chemoradiotherapy (CRT) with inconsistent results. A systematic review and meta-analysis was performed to evaluate the efficacy of TNT in terms of complete pathological response (pCR) rate, disease-free and overall survival vs. standard CRT in LARC. A systematic search was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and meeting abstracts up to May 2020. RCTs comparing CRT vs. TNT followed by surgery in LARC were eligible for the study. Study selection and data extraction were done following PRISMA guidelines by two independent reviewers. The Mantel-Haenzel method was used to obtain a fixed-effects model of pooled odds or hazard ratios for the main outcomes. Eight RCTs, including 2301 patients, met the eligibility criteria. TNT significantly improved pCR rate (OR = 1.99, 95% confidence interval (CI) 1.59-2.49; p < 0.001), 3-year disease-free-survival (DFS) (HR = 0.82, 95%CI 0.71-0.95; p = 0.01) and 3-year overall survival (OS) (hazard ratio (HR) = 0.81, p = 0.04). Grade 3-4 adverse events were not significantly different in both strategies (OR = 1.58; p = 0.14). An improved pCR rate was documented regardless of the type of radiotherapy administered (long vs. short fractionation schedules). No significant heterogeneity was found. The results of this meta-analysis show that TNT improves pCR and survival rates vs. standard preoperative CRT in patients with LARC. TNT may become a new standard of care in LARC, although longer follow-up is needed to properly assess its long-term impact on survival.
| S-EPMC7762140 | biostudies-literature
Project description:For the past several decades, disease-related outcomes, particularly local recurrence rate, in patients with locally advanced rectal cancer have significantly improved as a result of advancement of surgical technique and implementation of neoadjuvant chemoradiation. However, distant metastasis remains unresolved, being a significant cause of cancer death. To focus on micrometastases early in the course of multimodal treatment, delivering systemic chemotherapy in the neoadjuvant setting is emerging. Also, driven by patient demand and interest in preserving quality of life, upfront chemotherapy prior to surgery serves as a strategy for organ preservation in the management of rectal cancer. Herein, currently available literature on different methods and strategies of the multimodal approach is critically appraised.
| S-EPMC6635691 | biostudies-literature
Project description:BACKGROUND:The optimal treatment for locally advanced esophageal squamous cell carcinoma remains unclear. We compared the clinical outcomes of neoadjuvant concurrent chemoradiotherapy (CCRT) followed by esophagectomy [the surgery group] and CCRT without surgery [the CCRT group] in patients with squamous cell carcinoma from an Asian population. METHODS:Eligible patients diagnosed from 2008 to 2015 were identified through the Taiwan Cancer Registry. To balance observable potential confounders, we constructed a 1:1 propensity score-matched cohort [surgery vs CCRT]. We compared the hazard ratios between the surgery and CCRT groups for death using a robust variance estimator. We also evaluated the outcomes of patients for freedom from local regional recurrence (FFLRR) and esophageal cancer-specific survival (ECSS). Extensive supplementary analyses were performed to examine the robustness of our findings. RESULTS:Our study population included 298 patients balanced with respect to the observed covariables. The hazard ratio of death was 0.56 [95% confidence interval 0.42~0.75] when surgery was compared to CCRT. The results remained significant in the FFLRR and ECSS outcomes. In the supplementary analyses, our results also remained significant when additional covariables were taken into consideration or when the definition of the index date was changed. CONCLUSIONS:When compared to definitive CCRT, neoadjuvant CCRT followed by esophagectomy was associated with improved overall survival for locally advanced esophageal squamous cell carcinoma. However, given the nonrandomized nature of the study and the sensitivity to potentially unmeasured confounders, our results should be interpreted cautiously.
| S-EPMC6046100 | biostudies-literature
Project description:Background:There is recent interest in treating locally advanced rectal cancer (LARC) patients with total neoadjuvant therapy (TNT). However, whether TNT is associated with improved overall survival (OS) remains unknown. This study compares outcomes following TNT and following neoadjuvant chemoradiation therapy (nCRT) in patients with LARC, clinically defined cT3/4 or node positive disease, using the National Cancer Database. Methods:LARC patients diagnosed between 2004-2015 were included. TNT was defined as multi-agent chemotherapy given at least 2 months before RT followed by pre-operative chemoradiation therapy and definitive surgery without adjuvant chemotherapy. nCRT was defined as pre-operative RT and chemotherapy started within 2 weeks from each other followed by definitive surgery with or without adjuvant chemotherapy. Kaplan-Meier curve with logrank test and multivariable Cox proportional hazards regression modelling were used to analyse the primary endpoint of overall survival (OS). Multivariable logistic regression modelling was used for secondary outcomes to determine if TNT is associated with pathological complete response (pCR), defined as ypT0N0, and negative circumferential resection margin (CRM). Findings:Data from 372 TNT patients and 707 nCRT patients were analysed after a 2:1 propensity matching with replacement. Kaplan-Meier curve showed that OS with TNT was comparable to that with nCRT (p = 0•16). The 5-year OS rates for TNT and nCRT were 73•6% vs. 78•5% (p = 0•20). Multivariable Cox proportional hazards regression modelling confirmed no difference in OS between TNT and nCRT (HR = 1•21, p = 0•25). With TNT, 16•9% patients achieved pCR, whereas 13•1% patients achieved pCR with nCRT (p = 0•12). TNT was not found to be significantly associated with pCR (OR = 1•36, p = 0•13) or negative CRM (OR = 1•77, p = 0•19) in multivariable logistic regression modelling. Interpretation:With results from current clinical trials pending, our data suggested that TNT and nCRT resulted in similar survival, while TNT led to higher pCR and CRM negative rate, albeit not statistically significant.
| S-EPMC6890979 | biostudies-literature
Project description:BackgroundTotal neoadjuvant therapy (TNT) is a novel approach for locally advanced rectal cancer (LARC), which attempts to deliver both systemic chemotherapy and neoadjuvant chemoradiotherapy prior to surgery. However, its efficacy and safety remain controversial in randomized controlled trials (RCTs). We conducted this meta-analysis to assess such concerns.Materials and methodsHead-to-head phase II/III RCTs were searched in Embase, PubMed, Web of Science, and the Cochrane Library, as well as other sources. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were disease-free survival (DFS), overall survival (OS), local recurrence-free survival, distant metastasis-free survival, and the R0 resection rate.ResultsEight phase II/III RCTs involving 2,196 patients with LARC were assessed. The primary analysis demonstrated a statistically significant improvement in the pCR rate for TNT treatment (odds ratio, 1.77; 95% confidence interval [CI], 1.28-2.45; p = .0005). TNT treatment also showed improvements in DFS and OS outcomes compared with standard chemoradiotherapy (hazard ratio [HR], 0.83; 95% CI, 0.72-0.96; p = .03 and HR, 0.88; 95% CI, 0.74-1.05; p = .15). In addition, TNT treatment showed significant efficacy in reducing the risk of distant metastasis (HR, 0.81; 95% CI, 0.68-0.95; p = .012).ConclusionThe overall pCR rate may be improved with TNT compared with standard treatment. The TNT strategy may also improve DFS and OS and reduce the risk of distant metastasis.Implications for practiceLocally advanced rectal cancer (LARC) is a relatively common disease, with a poor prognosis because of its high metastatic potential. The role of total neoadjuvant therapy (TNT) has always been controversial. This meta-analysis found that TNT in LARC is associated with a significant improvement in overall pathologic complete response rate, disease-free survival, overall survival, and distant metastasis-free survival compared with standard treatment. TNT is a promising strategy for LARC, especially for patients who have little desire for surgery.
| S-EPMC8417863 | biostudies-literature
Project description:BackgroundBreast cancer is one of the most common challenges for women's health. Until now, neoadjuvant chemotherapy is a standard approach in locally advanced breast cancer (LABC), as it increases the probability of breast-conserving surgery (BCS). This study aimed to compare the survival rate in neoadjuvant and adjuvant groups to suggest a better treatment strategy for locally advanced breast cancer.MethodsThe study was conducted between 2009 and 2019 on 845 LABC patients at the Cancer Research Center of Shahid Beheshti University of Medical Sciences in Iran. All patients with LABC at stages 3A, 3B, and two were evaluated for treatment with adjuvants (n = 520 female patients) and neoadjuvant (n = 320 female patients) treatment strategies. Patients were followed up for at least 120 months. The Kaplan-Meier method calculated the survival rate using SPSS version 23 software.ResultThe 5 and 10 years survival rates of neoadjuvant and adjuvant groups were 87 ± 0.04, 80 ± 0.07% and 87 ± 0.02, 83 ± 0.03%, respectively. Statistical analysis results with the mentioned treatment strategies did not show any significant difference in overall survival.ConclusionThe result of this study on LABC patients demonstrated that compared to surgery first following adjuvant chemotherapy, the neoadjuvant chemotherapy has several benefits, including downstaging and more BCS, with no statistically significant difference in the overall survival rate of the patients.
| S-EPMC9758373 | biostudies-literature
Project description:The current standard of care for locally advanced rectal cancer (LARC) includes preoperative chemoradiation, followed by total mesorectal excision and adjuvant chemotherapy. This multimodality treatment improves local control but is associated with low compliance rates without clear beneficial effects on overall survival (OS) and distant metastasis. In this retrospective study, the charts of patients diagnosed with cT3/4 or cT2-node-positive rectal cancer between January 2011 and June 2019 were reviewed. The chemoradiation therapy (CRT) group received a long course of CRT with capecitabine followed by surgery and adjuvant chemotherapy. The total neoadjuvant therapy (TNT) group received 6 cycles mFOLFOX and a short course of radiation therapy followed by surgery. A total of 81 patients were included, among which 55 (67.9%) received CRT and 26 (32.1%) received TNT. In the CRT group, 15 (27.3%) patients achieved pathologic complete response (pCR) compared with 10 (38.5%) in the TNT group (P=0.22). A total of 19 (35.8%) cases in the CRT group downstaged to pT0N0 or pT1N0 compared with 11 (42.3%) in the TNT group (P=0.33). The 2-year disease-free survival (DFS) rate was 81.0% in the TNT group and 84.0% in the CRT group (P=0.15). Out of 55 patients in the CRT group, 30 patients received adjuvant chemotherapy, 22 (40.0% of CRT cases) of which completed a full course. All 26 patients in the TNT group received neoadjuvant chemotherapy, where 22 (84.6%) patients took a full course (P<0.001). In conclusion, the present study revealed that patients treated with TNT were more compliant to chemotherapy than those treated with CRT. A numerically higher pCR rate, and nodal and tumor downstaging were noted in the TNT group without significance. No difference was noted in the 2-year DFS. Longer follow-up is required.
| S-EPMC8408679 | biostudies-literature