Predictive value of APAF-1 and COX-2 expression in pathologic complete response to neoadjuvant chemoradiotherapy for patients with locally advanced rectal adenocarcinoma

e11545 Background: Combined modality treatment is essential for acheiving optimal results in the management of locally advanced breast cancer (LABC). Neoadjuvant chemoradiotherapy is considered a promising approach for LABC. Pathologic complete response to neoadjuvant treatment for LABC predicts prolonged survival. Aim: To determine the rate of pathologic complete response (pCR) after neoadjuvant chemotherapy and radiotherapy for locally advanced breast cancer and to identify the predictors of pCR. Methods: Female patients with noninflammatory LABC received neo-adjuvant chemotherapy with concurrent radiotherapy, and then underwent mastectomy and axillary clearance. The pathologic response was analysed with respect to the baseline clinical factors and the receptor status on immunohistochemical studies of the initial biopsy specimen. Results: Of the 296 patients included in the study, 286 underwent mastectomy. Ninety-two (31 %) patients achieved a pCR. The significant predictor of a pCR was Oestrogen receptor negative status (p = 0.025), while progesterone receptor negative status (p=0.069 ), HER2 status (p= 0.62), age (p= 0.074), stage (p=0.6), grade (p=0.86), type of chemotherapy (p=0.37) and number of cycles of chemotherapy (p = 0.23) did not predict for pathologic response. Clinical complete response predicted for a pathologic complete response (p=0.0001). Conclusions: Neoadjuvant concurrent chemoradiotherapy results in good pathologic complete response rates in LABC. High pathologic compete response rates are achieved in patients with endocrine receptor negative disease, with neoadjuvant chemoradiotherapy, which might result in improved outcome in this high risk subset of patients. No significant financial relationships to disclose.

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Randomized multicenter phase III trial comparing two neoadjuvant chemoradiotherapy (CT-RT) regimens (RT45-Cap versus RT50-Capox) in patients (pts) with locally advanced rectal cancer (LARC): Results of the ACCORD 12/0405 PRODIGE 2

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.18_suppl.lba4007 ◽

2009 ◽

Vol 27 (18_suppl) ◽

pp. LBA4007-LBA4007 ◽

Cited By ~ 15

Author(s):

J. Gerard ◽

D. Azria ◽

S. Gourgou-Bourgade ◽

I. Martel-Laffay ◽

C. Hennequin ◽

...

Keyword(s):

Locally Advanced ◽

Rectal Adenocarcinoma ◽

Neoadjuvant Chemoradiotherapy ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Concurrent Chemotherapy ◽

Phase Iii ◽

Phase Iii Trial ◽

Total Mesorectum Excision

LBA4007 Background: Following the results of randomized trials FFCD 9203 and EORTC 2291, neoadjuvant CT-RT is considered standard treatment for LARC. The ACCORD 12/0405 PRODIGE 2 trial was initiated to optimize this regimen. Methods: Pts with T3 or resectable T4 N0–1-2 M0, rectal adenocarcinoma were randomized to arm A: concurrent RT 45Gy/25f/5 weeks (w) + capecitabine (800mg/m2/bid) or arm B: concurrent RT 50Gy/25f/5w + capecitabine (800mg/m2/bid/5/7days) + oxaliplatine 50mg/m2/w. Resection with Total Mesorectum Excision was scheduled 6 weeks after the end of CT-RT. Adjuvant chemotherapy was optional. 590 patients were needed to show an increase in the pathological complete response (Dworak) rate from 11% (arm A) to 20% (arm B). Circumferential positive rectal margin (CRM R1) was defined as the presence of residual cancer cells within 0 to 1 mm from the perirectal surface. Results: This trial closed in 07/2008 after randomization of 598 pts since 11/2005. Patients characteristics of 586 eligible pts were well balanced: male 66%, median age 61 years, 66% low rectum, 87% T3 stage. Data base was locked in March 2009. Results are reported in Table . Conclusions: The RT 50 capox regimen is compatible with surgery in 98% of cases with no increase in postoperative complication. In the RT 50 arm, there is a trend in favour of a higher rate of pathological complete sterilization and lower rate of positive CRM. These data could contribute to design a new standard preoperative regimen for LARC. 50 Gy/25 F/5 weeks combined with concurrent chemotherapy could be proposed as an efficient schedule. [Table: see text] No significant financial relationships to disclose.

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Positron emission tomography-computed tomography (PET-CT) for the assessment of pathologic response to neoadjuvant chemoradiotherapy in rectal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.537 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 537-537

Author(s):

Noman Ashraf ◽

Saqib Razzaque ◽

Ben C. Creelan ◽

Julio C. Chavez ◽

David Shibata ◽

...

Keyword(s):

Overall Survival ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Rectal Adenocarcinoma ◽

Neoadjuvant Chemoradiotherapy ◽

Standardized Uptake Value ◽

Neoadjuvant Chemoradiation ◽

Significant Trend ◽

Pet Ct

537 Background: Preoperative 5-fluorouracil and radiation (FU-XRT) has been demonstrated to improve recurrence-free survival in locally advanced rectal adenocarcinoma, however the role of interval PET-CT remains unclear. We performed a retrospective study with the primary objective of examining the association of change in standardized uptake value (SUV) by PET-CT after neoadjuvant chemoradiation and pathologic complete response (path CR) to survival. Methods: Data was extracted for cases at our institution between August 2006–August 2009, with last follow-up performed July 2012. Patients were included if (i) they had completed a full course of preoperative FU-XRT, followed by surgery with intent for R0 resection, and (ii) pre- and post- therapy PET-CT as well as pathologic reports were available for review. Data was compared by Fischer's exact and Wilcoxon rank-sum, and survival was analyzed using Kaplan-Meier method. Clinicopathologic data was compared by log-rank test and univariate Cox proportional hazards for relationship to overall survival (OS). Results: Of 128 total rectal cancer cases reviewed, 25 (19%) met inclusion criteria. Characteristics of 25 patients included: 13 female, age 57± 14 years (median ± SD). After 116 patient-years of follow-up, median OS was not reached; mean OS was 4.6 ± 0.9 years. Mean baseline pre-treatment PET SUV (18.5 ± 9.1) decreased after neoadjuvant FU-XRT (5.0 ± 4.3, p < 0.0001). Five achieved path CR. Presence of earlier stage was associated with non-significant trend towards improved chance of pathologic CR (RR 3.1, p = 0.07). A decrease in PET SUV by 80% or more was associated with improved odds of path CR (OR 25, 95% CI 1.2 - 513, p = 0.009), and was also associated with a non-significant trend towards improved OS (HR 0.19, 95% CI 0.01 - 2.7). Path CR was associated with a non-statistically significant trend to improved overall survival (HR 0.28, 95% CI 0.01 - 8.4). Conclusions: Reduction in PET-CT SUV after neoadjuvant chemoradiation may be a useful predictor of pathologic CR in rectal adenocarcinoma. These exploratory findings need to be validated in larger prospective studies.

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Phase Ib/II study of neoadjuvant chemoradiotherapy with CRLX101 and capecitabine for locally advanced rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15144 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15144-e15144 ◽

Cited By ~ 2

Author(s):

Andrew Wang ◽

Autumn Jackson McRee ◽

A. William Blackstock ◽

Bert H. O'Neil ◽

Dominic T. Moore ◽

...

Keyword(s):

Rectal Cancer ◽

Single Agent ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Neoadjuvant Chemoradiotherapy ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Phase Ib ◽

Grade 3

e15144 Background: There is strong interest in the development of novel agents to further improve the therapeutic ratio of neoadjuvant chemoradiotherapy for rectal cancer. CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload. The purpose of this Phase Ib/II study is to assess toxicity and to evaluate whether the addition of CRLX101 to chemoradiotherapy can improve pathologic complete response (pCR) for rectal cancer. Methods: This is a single-arm multicenter Phase Ib/II study examining the addition of CRLX101 to a standard capecitabine-based chemoradiotherapy regimen. Phase Ib employs a 3+3 dose escalation design with starting dose of 12 mg/m2 every other week (QOW). Dose level +1 was 15 mg/m2 (MTD for CRLX101 single agent QOW). Upon reaching MTD for QOW dosing, protocol was modified to evaluate QW CRLX101 dosing starting at 12 mg/m2 and 15 mg/m2as +1 level. Secondary endpoints included pCR and clinical outcome. Results: A total of 32 patients were enrolled on the trial. 26/32 had T3-4, 9/32 had N2 and 16/32 had N1 disease. For QOW dosing, 9 patients completed treatment without DLT and MTD was identified as 15 mg/m2 QOW. 14 patients were treated on the Phase II portion of the study at 15 mg/m2 QOW prior to the initiation of weekly dosing Phase Ib cohorts. For QW dosing, 0/3 patients experienced DLT at 12 mg/m2 and 1/6 patients experienced DLT at 15 mg/m2. The DLT was skin desquamation requiring treatment delay. QW MTD was identified as 15 mg/m2. Toxicities (all grade 3 except lymphopenia) that could possibly be attributed to CRLX101 are in Table 1. Full clinical and pathologic staging were available for 29/32 patients. Mean neoadjuvant rectal (NAR) score was 19 with standard deviation of 15. At the weekly MTD, 3/6 patients had pCR. Conclusions: CRLX101 weekly at 15 mg/m2+ standard capecitabine-based chemoradiotherapy appears to be well tolerated, with promising pCR rates that warrants further evaluation. A larger PhII trial should be considered with this regimen. Clinical trial information: NCT02010567. [Table: see text]

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Avoiding Unnecessary Major Rectal Cancer Surgery by Implementing Structural Restaging and a Watch-and-Wait Strategy After Neoadjuvant Radiochemotherapy

Annals of Surgical Oncology ◽

10.1245/s10434-020-09192-0 ◽

2020 ◽

Cited By ~ 1

Author(s):

J. F. Huisman ◽

I. J. H. Schoenaker ◽

R. M. Brohet ◽

O. Reerink ◽

H. van der Sluis ◽

...

Keyword(s):

Rectal Cancer ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Neoadjuvant Chemoradiotherapy ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Response Evaluation ◽

Watch And Wait ◽

Time To Event

Abstract Background Pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) is found in 15–20% of patients with locally advanced rectal cancer. A watch-and-wait (W&W) strategy has been introduced as an alternative strategy to avoid surgery for selected patients with a clinical complete response at multidisciplinary response evaluation. The primary aim of this study was to evaluate the efficacy of the multidisciplinary response evaluation by comparing the proportion of patients with pCR since the introduction of the structural response evaluation with the period before response evaluation. Methods This retrospective cohort study enrolled patients with locally advanced rectal cancer who underwent nCRT between January 2009 and May 2018, categorizing them into cohort A (period 2009–2015) and cohort B (period 2015–2018). The patients in cohort B underwent structural multidisciplinary response evaluation with the option of the W&W strategy. Proportion of pCR (ypT0N0), time-to-event (pCR) analysis, and stoma-free survival were evaluated in both cohorts. Results Of the 259 patients in the study, 21 (18.4%) in cohort A and in 8 (8.7%) in cohort B had pCR (p = 0.043). Time-to-event analysis demonstrated a significant pCR decline in cohort B (p < 0.001). The stoma-free patient rate was 24% higher in cohort B (p < 0.001). Conclusion Multidisciplinary clinical response evaluation after nCRT for locally advanced rectal cancer led to a significant decrease in unnecessary surgery for the patients with a complete response.

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Comprehensive Analysis of DNA Methylation and Prediction of Response to NeoadjuvantTherapy in Locally Advanced Rectal Cancer

Cancers ◽

10.3390/cancers12113079 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3079

Author(s):

Luisa Matos do Canto ◽

Mateus Camargo Barros-Filho ◽

Cláudia Aparecida Rainho ◽

Diogo Marinho ◽

Bruna Elisa Catin Kupper ◽

...

Keyword(s):

Dna Methylation ◽

Predictive Value ◽

External Validation ◽

Locally Advanced ◽

Rectal Adenocarcinoma ◽

Neoadjuvant Chemoradiotherapy ◽

Regulatory Elements ◽

Response To Therapy ◽

The Cancer Genome Atlas ◽

Predictive Tool

The treatment for locally advanced rectal carcinomas (LARC) is based on neoadjuvant chemoradiotherapy (nCRT) and surgery, which results in pathological complete response (pCR) in up to 30% of patients. Since epigenetic changes may influence response to therapy, we aimed to identify DNA methylation markers predictive of pCR in LARC patients treated with nCRT. We used high-throughput DNA methylation analysis of 32 treatment-naïve LARC biopsies and five normal rectal tissues to explore the predictive value of differentially methylated (DM) CpGs. External validation was carried out with The Cancer Genome Atlas-Rectal Adenocarcinoma (TCGA-READ 99 cases). A classifier based on three-CpGs DM (linked to OBSL1, GPR1, and INSIG1 genes) was able to discriminate pCR from incomplete responders with high sensitivity and specificity. The methylation levels of the selected CpGs confirmed the predictive value of our classifier in 77 LARCs evaluated by bisulfite pyrosequencing. Evaluation of external datasets (TCGA-READ, GSE81006, GSE75546, and GSE39958) reproduced our results. As the three CpGs were mapped near to regulatory elements, we performed an integrative analysis in regions associated with predicted cis-regulatory elements. A positive and inverse correlation between DNA methylation and gene expression was found in two CpGs. We propose a novel predictive tool based on three CpGs potentially useful for pretreatment screening of LARC patients and guide the selection of treatment modality.

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Circulating Biomarkers for Response Prediction of Rectal Cancer to Neoadjuvant Chemoradiotherapy

Current Medicinal Chemistry ◽

10.2174/0929867326666190507084839 ◽

2020 ◽

Vol 27 (25) ◽

pp. 4274-4294 ◽

Cited By ~ 1

Author(s):

Chiara Bedin ◽

Sara Crotti ◽

Edoardo D’Angelo ◽

Sara D’Aronco ◽

Salvatore Pucciarelli ◽

...

Keyword(s):

Rectal Cancer ◽

Clinical Benefit ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Treatment Protocol ◽

Predictive Biomarkers ◽

Complete Response ◽

Tumour Regression

: Rectal cancer response to neoadjuvant Chemoradiotherapy (pCRT) is highly variable. In fact, it has been estimated that only about 21 % of patients show pathologic Complete Response (pCR) after therapy, while in most of the patients a partial or incomplete tumour regression is observed. Consequently, patients with a priori chemoradioresistant tumour should not receive the treatment, which is associated with substantial adverse effects and does not guarantee any clinical benefit. For Locally Advanced Rectal Cancer Patients (LARC), a standardized neoadjuvant treatment protocol is applied, the identification and the usefulness of prognostic or predictive biomarkers can improve the antitumoural treatment strategy, modifying the sequence, dose, and combination of radiotherapy, chemotherapy and surgical resection. : For these reasons, a growing number of studies are actually focussed on the discovery and investigation of new predictive biomarkers of response to pCRT. In this review, we have selected the most recent literature (2012-2017) regarding the employment of blood-based biomarkers potentially predicting pCR in LARC patients and we have critically discussed them to highlight their real clinical benefit and the current limitations of the proposed methodological approaches.

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Multicenter, randomized phase II study of neoadjuvant pembrolizumab plus chemotherapy and chemoradiotherapy in esophageal adenocarcinoma (EAC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4005 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4005-4005

Author(s):

Manish A. Shah ◽

Khaldoun Almhanna ◽

Syma Iqbal ◽

Prashant Thakkar ◽

Bryan J. Schneider ◽

...

Keyword(s):

Gastroesophageal Junction ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Neoadjuvant Chemoradiotherapy ◽

Disease Free Survival ◽

Complete Response ◽

Type I ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Grade 3

4005 Background: Recent transformative studies in the treatment of EAC support adjuvant nivolumab for patients with residual disease following neoadjuvant chemoradiotherapy (CRT) (Checkmate 577) and pembrolizumab (P) with chemotherapy in untreated metastatic disease (Keynote 590). We hypothesized that pre-operative P combined with CRT can further improve outcomes in patients with locally advanced EAC. Methods: Patients with cT3-4Nx or T2N1 M0 EAC or gastroesophageal junction (GEJ) adenocarcinoma eligible for curative surgery were randomized (1:1) to receive either full-dose paclitaxel (T)/ carboplatin (C) or T/C + P induction therapy. All patients then received CRT with weekly T/C, RT 41.4Gy in 23 fractions, and P every 3 weeks. Following resection, patients received P for one year. The primary endpoint is rate of major pathologic response (MPR), defined as pathologic complete response or near complete response ( < 10% residual cancer), with 80% power and 0.1 one-sided significance level to detect the difference between a MPR proportion of 30% (historical control) and an alternative hypothesis of 47% (with preoperative P). Tissue was collected for tumor immune microenvironment (TIME) analysis including bulk and single cell RNA(scRNA) expression analysis, DNA sequencing, and flow cytometry. Results: From 8/4/17 to 10/26/20, 40 patients were enrolled: median age 68 [38-81], male 32, esophagus/GEJ type I (n = 16), GEJ II/III (n = 24). CRT was well tolerated, with no grade 3-4 adverse events attributed to P. Notable toxicity included grade 3-4 pneumonitis (13%), anastomotic leak (13%), infection (35%). In 31 evaluable patients to date, the MPR rate was 50.0% (95% CI, 32.7%-67.3%). 1-yr disease free survival was 100% for patients with MPR vs. 31.8% without MPR, p = 0.002. Esophageal/GEJ type I cancers had a significantly higher MPR rate when compared with GEJ type II/III (76.9% vs 37.5%, p = 0.03). scRNA seq on > 100,000 tumor cells revealed EAC/GEJ type I had higher infiltration of activated dendritic cells (p = 0.12), whereas GEJ tumors have significantly higher infiltration of activated B cells (p = 0.02). Conclusions: The addition of P to preoperative CRT for EAC is safe and associated with a significantly higher MPR rate compared to historical data. We found MPR to be significantly enriched in EAC/GEJ type I tumors compared with GEJ II/III, associated with important differences in the baseline tumor immune microenvironment. Clinical trial information: NCT02998268.

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