Primary Tumor Response to Preoperative Chemoradiation With or Without Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Results of the STAR-01 Randomized Phase III Trial

2011 ◽  
Vol 29 (20) ◽  
pp. 2773-2780 ◽  
Author(s):  
Carlo Aschele ◽  
Luca Cionini ◽  
Sara Lonardi ◽  
Carmine Pinto ◽  
Stefano Cordio ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Primary Tumor ◽  
Tumor Response ◽  
Locally Advanced ◽  
Muscularis Propria ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Phase Iii ◽  
Preoperative Treatment ◽  
The Impact

Purpose To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Patients and Methods Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m2/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m2 weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here. Results Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014). Conclusion Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.

Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial

2009 ◽  
Vol 27 (18_suppl) ◽  
pp. CRA4008-CRA4008 ◽  
Author(s):  
C. Aschele ◽  
C. Pinto ◽  
S. Cordio ◽  
G. Rosati ◽  
A. Tagliagambe ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Tumor Response ◽  
Anal Verge ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Pathologic Response ◽  
Phase Iii ◽  
Local Tumor ◽  
Phase Iii Trial

CRA4008 Background: Oxaliplatin (OXA) enhances the efficacy of FU-based chemotherapy in colon cancer. This randomized phase III trial investigated the effect of adding OXA to preoperative (preop) FU-based pelvic chemoradiation (CRT) in patients (pts) with locally-advanced rectal cancer. Methods: Eligibility required a resectable, biopsy-proven rectal adenocarcinoma within 12 cm from the anal verge with radiological evidence of perirectal fat or lymphnode involvement. Randomization was between infused FU (225 mg/msq/day) concomitant to external-beam pelvic radiation (50.4 Gy in 28 daily fractions) (arm A) or the same regimen + weekly OXA (60 mg/msq × 6) (Arm B). Surgery was scheduled 6–8 weeks after completing CRT. Overall survival was the primary endpoint. A protocol-planned analysis of local tumor response to preop treatment (secondary end-point) is the object of this report. Results: 747 pts from 41 Italian centers were randomized between 12/2003 and 8/2008 (arm A/B: 379/368). Pretreatment characteristics in arm A/B: median age 63/62 years; male:female 2:1; median distance from anal verge 6 cm; T4 16/14%, N+ 63/65%. Overall grade 3–4 toxicity rates on treated pts (mainly diarrhoea) were 8% and 24% (arm A/B, p<0.001). 96/90% of pts (arm A/B) received > 90% of the planned RT. 82% of Arm B pts had > 5 oxa courses. 358/342 pts (arm A/B) had surgery at a median of 52/53 days from the end of CRT, 14 pts in each arm were not operated (progression 8, death 5, other/unknown 15) and surgery data are not yet available for 19 pts. Pathologic response data analyzed on the randomized population are reported in the table . Conclusions: The addition of weekly OXA to standard FU-based preop CRT significantly increases toxicity without affecting local tumor response. The reduced pathologic M+ rate suggests a potential effect on distant micrometastases. Longer follow-up is needed to assess the impact on efficacy endpoints. [Table: see text] No significant financial relationships to disclose.

A multicenter randomized phase III trial of capecitabine with or without irinotecan driven by UGT1A1 in neoadjuvant chemoradiation of locally advanced rectal cancer (CinClare).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3510-3510 ◽  
Author(s):  
Zhen Zhang ◽  
Xinchen Sun ◽  
Anwen Liu ◽  
Yuan Zhu ◽  
Yaqun Zhu ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Phase Iii ◽  
Preoperative Treatment ◽  
Pelvic Radiation ◽  
Irinotecan Dose ◽  
Ugt1a1 Genotype

3510 Background: Our phase I/II study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant CRT and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Methods: We underwent a prospective, randomized, open-label, multicenter, phase 3 trial in China from Nov.2015 to Dec.2017. Eligible patients with clinical stage T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to two arms. The approach in control arm (Arm A, n = 180) was pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT. The experimental arm (Arm B, n = 180) was pelvic radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. Results: Surgery was performed in 86.5% and 88.2% of patients in two groups, with 38.9% and 30.5% of patients got abdominoperineal resection respectively. The pCR rate was 17.5% in Arm A and 33.8% in Arm B (P = 0.001). Four and 6 patients maintained a complete clinical response status at least 12 months and were marked as cCR. The CR rate, including pCR and cCR, was 17.4% in Arm A and 33.1% in Arm B (P = 0.001). The most common grade 3-4 adverse events during preoperative treatment were leucopenia (3.4% vs. 25.3%), neutropenia (1.7% vs. 19.7%) and diarrhea (1.7% vs. 13.5%) in two arms. The overall rate of surgical complications were not significantly different between arms (11.0% vs. 14.6%). Conclusions: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. This treatment can be as an option for ‘watch and wait’ approach. Clinical trial information: NCT02605265.

scholarly journals Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer

2021 ◽  
Vol 9 (3) ◽  
pp. e001610
Author(s):  
Incheol Seo ◽  
Hye Won Lee ◽  
Sang Jun Byun ◽  
Jee Young Park ◽  
Hyeonji Min ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Enrichment Analysis ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Neoadjuvant Chemoradiation ◽  
Cytolytic Activity ◽  
Gene Set Enrichment Analysis ◽  
Preoperative Treatment ◽  
Rna Seq

BackgroundNeoadjuvant 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.MethodsWe 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.ResultsGene 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.ConclusionsTaken 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.

scholarly journals Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2071
Author(s):  
Jihane Boustani ◽  
Valentin Derangère ◽  
Aurélie Bertaut ◽  
Olivier Adotevi ◽  
Véronique Morgand ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Tumor Regression Grade ◽  
The Impact

In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data from biopsies and surgical specimens in 74 patients. The main objective was to evaluate the impact of neoadjuvant RT and fractionation on PD-L1 expression. Secondary objectives were to study the relation between PD-L1 expression and tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and CD8 TILs infiltration. Median rates of cells expressing PD-L1 pre- and post-RT were 0.15 (range, 0–17) and 0.5 (range, 0–27.5), respectively (p = 0.0005). There was no effect of RT fractionation on PD-L1+ cell rates. We found no relation between CD8+ TILs infiltration and PD-L1 expression and no difference between high-PD-L1 or low-PD-L1 expression and TRG. High-to-high PD-L1 expression profile had none significant higher OS and PFS compared to all other groups (p = 0.06). Median OS and PFS were higher in biopsies with >0.08 PD-L1+ cells. High-to-high PD-L1 profile and ypT0-2 were significantly associated with higher OS and PFS. This study did not show the differential induction of PD-L1 expression according to fractionation.

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