Pretreatment Transcriptional Profiling for Predicting Response to Neoadjuvant Chemoradiotherapy in Rectal Adenocarcinoma

3614 Background: The aim of this study was to evaluate the correlation among biomarkers, pathological response and clinical outcomes in patients (pts) with rectal cancer submitted to neoadjuvant chemoradiotherapy. Methods: Pts entering the study had rectal adenocarcinoma, uT3/4N-/+ or uT2N-/+ with inferior location. Chemotherapy consisted of oxaliplatin 60 mg/m2 weekly infusion IV for 6 times and 5-fluorouracil 225 mg/m2/die continuous infusion IV d 1–38. Radiotherapy was delivered up to a dose of 50.4 Gy in daily fractions of 1.8 Gy d 1–38. Rectal surgery with TME was performed 6–8 weeks after neoadjuvant treatment. Immunohistochemical determination of Ki67, p53, bcl2, TS, EGFR, MLH1 and MSH2 was performed in pretreatment biopsy and operative specimen. Results: Between March 2002 and May 2005, 32 pts had completed neoadjuvant therapy and surgery. Pt characteristics: 24 (75%) men and 8 (25%) women; median age 64 (33–80) years; stage uT2N-M0 3 (9.4%) pts, uT3N-M0 14 (43.8%), uT3N+M0 10 (31.2%), uT3NXM0 2 (6.2%), uT4N+M0 3 (9.4%). Surgery consisted of abdominal-perineal amputation in 12 (37.5%) and low-anterior resection in 17 (53.1%) pts, with negative circumferential resection margins in 86.2%. Laparoscopic local excision was performed in 3 (9.4%) pts. Pathological down-staging occurred in 18 (56.2%) pts, including 7 (21.9%) pT0N0, with sphincter preservation in 40%. Tumor Regression Grade (TRG) (according to Mandard) evaluation of operative specimen was: 7 TRG1, 11 TRG2, 11 TRG3 and 3 TRG4. Expression mean value in pretreatment biopsy and operative specimen was: Ki67 88.8% and 31.7%; p53 49.7% and 40.7%; TS 12.6% and 10.0%; MLH1 89.7% and 76.4%; MSH2 84.3% and 72.2%. The evaluation of biomarker profile in operative specimen of TRG2 pts vs TRG3–4 showed: Ki67 16.6% vs 46.2% (p=0.03); TS 4.5% vs 12.9% (ns); MSH2 82.3% vs 65.6% (ns); p53 52.3% vs 34.8% (ns). Median DFS was 19 (3–35) months. At a median follow-up of 22 (5–41) months, 100.0% of TRG1 pts, 90.9% of TRG2, 73.3% of TRG3–4 had no-evidence of disease relapse. Conclusions: These preliminary results suggest a correlation between Ki67 and pathological response in rectal cancer pts treated with neoadjuvant therapy. Moreover, DFS appears to be related to TRG. No significant financial relationships to disclose.

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Neoadjuvant chemoradiotherapy in rectal cancer patients (pt) with oxaliplatin (Ox) and capecitabine (Cp): Results of a phase II trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15101 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15101-e15101

Author(s):

J. Gasent Blesa ◽

V. Alberola Candel ◽

O. Juan ◽

M. Provencio Pulla ◽

V. Giner Marco ◽

...

Keyword(s):

Neoadjuvant Treatment ◽

Rectal Adenocarcinoma ◽

Neoadjuvant Chemoradiotherapy ◽

Preoperative Chemoradiotherapy ◽

Sphincter Preservation ◽

Pathological Result ◽

Complete Treatment ◽

Tumor Downstaging ◽

The Mean

e15101 Background: Between April 2006 and May 2008, 27 rectal adenocarcinoma pt were included (cT3: 25 pt, T4: 2 pt, N0: 11 Pt, N+: 16 pt), stages II-III, RMN staged, 14 male and 13 female. Mehtod: Neoadjuvant treatment was: Ox: 50 mg/m2 weekly, oral Cp: 825 mg/m2 tid the days of the Rt, and a Rt of 50.4 Gy. 9 pt had a lower third tumor, 9 middle, 9 upper. Surgery was planned 6–8 weeks after treatment´s end. 4 adjuvant chemotherapy cycles with Xelox were planned. Results: 7 pt had pCR (26%), 2 pt progression disease 18 pt tumor downstaging(dwst). Percentages of dwst were: T 85%, N 37%. Sphincter preservation (sp) was 81.9%, for tumors of the lower third sp was 44.4%. Presurgical (prsrg) RMN did not predict the pathological result in 21 pt. Main side effects: Dermatitis G1 in 21 pt, and G2 in 4 pt. Diarrhea 12 pt G1, 11 pt G2, and 4 pt G3. Hand and foot G1 5 Pt and G2 4 pt. Paresthesias G1 10 pt, G2 7 pt. Leucopenia 6 pt G1. 4 Pt did not complete treatment because of toxicity. Median Rt dose was 49.7 Gy (47.5–50.4 Gy).At a mean follow up of 22.5 months (7–31) 4 pt presented metastatic disease (15% ), none in the pCR group. Mean pre-neoadjuvant (preneo) CEA was 6.8 ng/ml (2.1–17.0). There was difference statistically significant when compared preneo CEA vs prsrg CEA: 2.72 ng/ml inferior with the second outcome (p<0.001). Mean prsurg CEA was 4.1 (0.1–12.0). In the subgroup with pCR the mean prsrg CEA was 1.1 (0.5–1.5), and in non-pCR it was 5.1 (0.1–12.0). Comparing the prsrg CEA between pCR and the non-pCR subgroups, the mean difference was 4.0 ng/ml greater in the non pCR. This difference was statistically significant (p=0.002, 95% CI: 1.68–6.3).We found a nadir of <5ng/ml as significantly associated with pCR (p=0.036). Conclusions: Preoperative chemoradiotherapy with Ox and Cp, is safe and well tolerated. Offers an interesting ratio of pCR, and of tumor downstaging. Prsrg CEA level and CEA nadir should be studied as predictors of pCR. It is possible that with more patients, the significant nadir level could be lower. We consider this combination and the CEA nadir interesting to be included in further studies. 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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Biomarkers of immunotherapy response in rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.593 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 593-593

Author(s):

Gurveen Kaur ◽

Pritam Tayshetye ◽

Prashant Mukesh Jani ◽

Ashten N Omstead ◽

Paul Renz ◽

...

Keyword(s):

Locally Advanced ◽

Neoadjuvant Treatment ◽

Rectal Adenocarcinoma ◽

Neoadjuvant Chemoradiotherapy ◽

Tumor Infiltrating Lymphocytes ◽

Distant Metastases ◽

Outcome Data ◽

Rt Pcr ◽

High Power Field ◽

Tissue Samples

593 Background: Immunotherapy (IO) in combination with chemoradiotherapy (CRT) in the neoadjuvant treatment for locally advanced rectal adenocarcinoma (RAC) is an area of active clinical research. There are no well-defined biomarkers in RAC predicting response to neoadjuvant therapy. Increase in tumor PD-L1 expression and tumor infiltrating lymphocytes (TIL) has been observed after neoadjuvant CRT which potentially enhances response to IO. We report herein expression of PD-L1 and CD8+ TIL and other biomarkers of immune activation including CXCL9, TIM3 (HAVCR2), IDO1, IFNG, IL17RE, LAG3 and OX40 (TNFRSF4) pre and post neoadjuvant CRT in RAC. Methods: We retrospectively evaluated 38 RAC patients from 2007-2016 treated with neoadjuvant CRT using 5FU based therapy. Pre and post CRT tissue samples were stained with VENTANA PD-L1 (SP263) rabbit monoclonal antibody to quantify PD-L1 expression. CD8+ TIL were recorded over one high power field (hpf) (40x objective) in the area of densest infiltrate. Additional biomarkers CXCL9, TIM3 (HAVCR2), IDO1, IFNG, IL17RE, LAG3 and OX40 (TNFRSF4) were assayed with RT-PCR. Independent sample and paired sample t-tests were used for statistical analysis of difference in biomarker expression. Relevant clinical endpoints including local relapse, distant metastases and survival were collected. Results: Median age was 60 years (range 32–87). Median follow up was 16.7 months (range 2.6-120.1). Median duration from completion of CRT to resection was 73 days (range 44–315). PD-L1 expression increased from 10% to 23% in pre-CRT versus post-CRT patients. CD8+ TIL increased in 30/39 (83%) patients with an average increase from 66.48 to 129.20 CD8+ TIL/hpf in the pre-CRT versus post-CRT setting. Using RT-PCR, a statistically significant increase in the expression of CXCL9, IFNG and OX40 (TNFRSF4) was found pre-CRT versus post-CRT using paired samples t-test. Conclusions: Neoadjuvant CRT for RAC increased PD-L1 expression and CD8+ TIL along with an increased expression of CXCL9, IFNG and OX40 (TNFRSF4). These data suggest a novel role for IO in neoadjuvant treatment of rectal cancer. Clinical outcome data on these patients will be presented.

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Chemoradiation-induced alteration of programmed death-ligand 1 and CD8+ tumor-infiltrating lymphocytes in rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.570 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 570-570

Author(s):

Marina Baretti ◽

Wei Fu ◽

Hao Wang ◽

Robert A Anders ◽

Nilofer Saba Azad ◽

...

Keyword(s):

Rectal Cancer ◽

Checkpoint Inhibitors ◽

Rectal Adenocarcinoma ◽

Neoadjuvant Chemoradiotherapy ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Stroma ◽

Immune Checkpoints ◽

Mucin Expression ◽

Significant Difference ◽

Potential Applicability

570 Background: DNA damage and subsequent neoantigen formation has been hypothesized as a mechanismfor radiotherapy and PD-1/PD-L1 pathway inhibition to synergize in an antitumor immune response. We investigated neoadjuvant chemoradiotherapy (nCRT)-induced changes in CD8+ tumor infiltrating lymphocyte, PD-L1 and mucin expression in rectal cancer patients as compared to patients who did not receive nCRT. Methods: Tumor samples were collected from rectal adenocarcinoma patients who had undergone resection between 2008-2014 with (n = 62) or without (n = 17) nCRT treatment. Tissue sections were stained with CD8 and PD-L1 antibodies for immunohistochemistry. Whole slides images were acquired at 20x magnification. The prevalence of positive CD8 stained cells was recorded in tumor, interface tumor side, interface background rectal side. Image analysis (HALO Indica Labs) was used to determine the density (# of cells/surface area analyzed) of CD8 expressing lymphocytes. The percentage of PD-L1 membranous expression was manually counted in tumor cells (TC), tumor stroma (TS) and invasive front (IF). Mucin expression was determined as the percentage of the mucin area in the whole tumor mass area. Results: PD-L1 expression on TCs was identified in 7.7 % (6/78) of specimens. All 6 cases had received nCRT (p = 0.33). 80% and 75.5% of the nCRT cases showed PD-L1 expression on TS and IF respectively, versus 20% (p = 0.55) and 24.5% (p = 0.56) in non-nCRT cases. The median densities of CD8+ infiltrating T lymphocytes in tumor, interface tumor side, interface background rectal side did not differ significantly between the two groups (p = 0.79, p = 0.47, p = 0.22). No nCRT-changes in mucin expression observed in the 28 evaluable cases (p = 0.25). Conclusions: nCRT exposure was associated with a non-significant difference in PD-L1 expression on TS and IF cells in patients with rectal adenocarcinoma as compared to non-nCRT case, possibly due to sample size limitations. Further mechanistic investigations and comprehensive analysis of other immune checkpoints are needed to understand nCRT-induced immunologic shift in rectal cancer and to expand the potential applicability of checkpoint inhibitors in this setting.

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133: Predictors of Nodal Response after Neoadjuvant Chemoradiotherapy for Rectal Adenocarcinoma; A Retrospective Study

Radiotherapy and Oncology ◽

10.1016/s0167-8140(16)33532-0 ◽

2016 ◽

Vol 120 ◽

pp. S50

Author(s):

Maged Nashed ◽

Zachary Raizman ◽

Gokulan Sivananthan ◽

Daniel Kroeker ◽

Pascal Lambert ◽

...

Keyword(s):

Retrospective Study ◽

Rectal Adenocarcinoma ◽

Neoadjuvant Chemoradiotherapy

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Restaging after neoadjuvant chemoradiotherapy for rectal adenocarcinoma: role of F18-FDG PET

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2004.08.005 ◽

2004 ◽

Vol 58 (8) ◽

pp. 451-457 ◽

Cited By ~ 44

Author(s):

Carlo Capirci ◽

Domenico Rubello ◽

Franca Chierichetti ◽

Giorgio Crepaldi ◽

Angelo Carpi ◽

...

Keyword(s):

Fdg Pet ◽

Rectal Adenocarcinoma ◽

Neoadjuvant Chemoradiotherapy

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Neoadjuvant concurrent chemoradiotherapy followed by transanal total mesorectal excision assisted by single-port laparoscopic surgery for low-lying rectal adenocarcinoma: a single center study

10.21203/rs.3.rs-34886/v2 ◽

2020 ◽

Author(s):

Yen-Jung Lu ◽

Chien-Hsin Chen ◽

En-Kwang Lin ◽

Szu-Yuan Wu

Keyword(s):

Laparoscopic Surgery ◽

Total Mesorectal Excision ◽

Single Port ◽

Rectal Adenocarcinoma ◽

Neoadjuvant Chemoradiotherapy ◽

Morbidity Rate ◽

Transanal Total Mesorectal Excision ◽

Distal Margin ◽

Mesorectal Excision ◽

The Mean

Abstract Purpose: To assess the feasibility and short-term outcomes of neoadjuvant chemoradiotherapy (CCRT) followed by transanal total mesorectal excision assisted by single-port laparoscopic surgery (TaTME-SPLS) for low-lying rectal adenocarcinoma.Methods and materials: A total of 23 patients with clinical stage II-III low-lying (from anal verge 0-8 cm) rectal adenocarcinoma who underwent neoadjuvant CCRT followed by TaTME-SPLS consecutively from December 2015 to December 2018, were enrolled into our study. Chi-squared testing and Student’s t testing were used to make parametric comparisons, and Fisher’s exact test or the Mann–Whitney U-test were used to make nonparametric comparisons.Results: Conversion rate in patients who underwent neoadjuvant CCRT followed by TaTME-SPLS was only 4%. The mean operation time was 366 minutes and the inter-sphincter resection (ISR) was done for 14 patients (60%). The mean number of lymph nodes harvested were 15. There was no surgical mortality, but the 30-day morbidity rate was 21% (5 patients were Clavien-Dindo I-II). Pathological complete response was 21.74% with 100% organ preservation and 100% clear distal margin after neoadjuvant CCRT followed by TaTME-SPLS. Conclusion: Neoadjuvant CCRT followed by TaTME-SPLS can be a safe and an effective sphincter-preserving procedure with acceptable morbidity rate for Asian patients with low-lying rectal adenocarcinoma.

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