What Is the Ideal Tumor Regression Grading System in Rectal Cancer Patients after Preoperative Chemoradiotherapy?

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Abstract

Purpose

Tumor regression grade (TRG) is predictive of therapeutic response in rectal cancer patients after chemoradiotherapy (CRT) followed by curative resection. However, various TRG systems have been suggested, with subjective categorization, resulting in interobserver variability. This study compared the prognostic validity of four different TRG systems in order to identify the most ideal TRG system.

Materials and Methods

This study included 933 patients who underwent preoperative CRT and curative resection. Primary tumors alone were graded according to the American Joint Committee on Cancer (AJCC), Dworak, and Ryan TRG systems, and both primary tumors and regional lymph nodes were graded according to a modified Dworak TRG system. The ability of each TRG system to predict recurrence-free survival (RFS) and overall survival (OS) was analyzed using chi-square and C statistics.

Results

All four TRG systems were significantly predictive of both RFS and OS (p < 0.001 each), however none was a better predictor of prognosis than ypStage. Among the four TRGs, the mDworak TRG system was a better predictor of RFS and OS than the AJCC, Dworak, and Ryan TRG systems, and both the chi-square and C statistics were higher for the former, although the differences were not statistically significant. The combination of ypStage and the modified Dworak TRG better predicted RFS and OS than ypStage alone.

Conclusion

The modified Dworak TRG system for evaluation of entire tumors including regional lymph nodes is a better predictor of survival than current TRG systems for evaluation of the primary tumor alone.

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Most cited references 20

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Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.

Claus Rödel, Torsten Liersch, Heinz Becker … (2012)

Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. German Cancer Aid (Deutsche Krebshilfe). Copyright © 2012 Elsevier Ltd. All rights reserved.

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The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer.

Vincenzo Valentini, Bruce Minsky, M Antonietta Gambacorta … (2005)

To examine the relationship between tumor regression grade (TRG) and outcomes in patients with rectal cancer treated with preoperative therapy. Specimens from 144 patients with cT3,4 rectal cancer who had received preoperative radiation +/- chemotherapy and had a minimum follow-up of 3 years were retrospectively reviewed. TRG, which involves examining the residual neoplastic cells and scoring the degree of both cytological changes, including nuclear pyknosis or necrosis and/or eosinophilia, as well as stromal changes, including fibrosis (either dense or edematous) with or without inflammatory infiltrate and giant-cell granulomatosis around ghost cells and keratin, was quantified in five grades according to the Mandard score (Cancer 1994;73:2680-2686). The greater the response, the lower the TRG score. The median follow-up was 72 months (range, 40-143 months). Of the 144 patients, 19% were TRG1, 12% were TRG2, 21% were TRG3, 46% were TRG4, and 1% were TRG5. To simplify the analysis, TRG was combined into two groups: TRG1-2 and TRG3-5. By univariate analysis, none of the pretreatment factors examined, including age, circumference, length, distance from the anorectal ring, pretreatment T and N stage, and INDpre (defined as the pretreatment reference index size based on digital rectal examination), had an impact on 5-year outcomes, including local control, metastases-free survival, disease-free survival, and overall survival. Postoperative parameters, including pathologic T stage (pT), pathologic N stage (pN), and TRG, did significantly influence 5-year outcomes. These included local failure: pT0-2: 5% vs. pT3-4: 19%, p = 0.007; pN0: 7% vs. pN1-3: 26%, p = 0.002; TRG1-2: 2% vs. TRG3-5: 17%, p = 0.013; metastasis-free survival: pT0-2: 86% vs. pT3-4: 62%, p = 0.005; pN-: 86% vs. pN*: 42%, p < 0.001; TRG1-2: 91% vs. TRG3-5: 66%, p = 0.004; disease-free survival: pT0-2: 83% vs. pT3-4: 54%, p = 0.001; pN0: 80% vs. pN1-3: 39%, p < 0.001; TRG1-2: 91% vs. TRG3-5: 58%, p < 0.001; and overall survival: pT0-2: 85% vs. pT3-4: 65%, p = 0.007; pN0: 86% vs. pN1-3: 45%, p < 0.001; TRG1-2: 89% vs. TRG3-5: 68%, p = 0.004. By multivariate analysis combining all pre- and posttreatment parameters, only pN (p < 0.001) and TRG (p = 0.005) significantly predicted disease-free survival. Furthermore, TRG predicted the incidence of pathologic nodal involvement (p < 0.0001). By univariate analysis, TRG is a predictor for local failure, metastases-free survival, and overall survival. By multivariate analysis, it predicts improved disease-free survival. Given the ability of TRG to predict those patients with N* disease, it may be helpful, in combination with other clinicopathologic factors, in selecting patients for a more conservative procedure, such as local excision rather than radical surgery, after preoperative therapy.

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Pathologic stage is most prognostic of disease-free survival in locally advanced rectal cancer patients after preoperative chemoradiation.

H Quah, Leonard Saltz, Martin R Weiser … (2008)

Preoperative chemoradiation is the standard treatment for locally advanced rectal cancer. However, it is uncertain whether pretreatment clinical stage, degree of response to neoadjuvant treatment, or pathologic stage is the most reliable predictor of outcome. This study compared various staging elements and treatment-related variables to identify which factors or combination of factors reliably prognosticates disease-free survival in rectal cancer patients receiving neoadjuvant combined modality therapy. From a prospectively maintained single institution database, 342 consecutive patients with locally advanced rectal cancer staged by endorectal ultrasound were identified. Patients underwent rectal resection 4 to 8 weeks after a 5.5-week course of pelvic radiotherapy/concurrent chemotherapy. The degree of tumor regression was histologically graded on each resected specimen using a previously reported response scale of 0% to 100%. Predictive models of disease-free survival were created utilizing available pretherapy and postoperative staging elements in addition to the degree of tumor regression noted histologically. Model accuracy was measured and compared by concordance index, with 95% confidence interval (CI). Stratifying patients by degree of tumor regression predicted outcome with a concordance index of 0.65 (95% CI, 0.59-0.71), which was significantly better than models using preoperative stage elements (concordance index of 0.54; 95% CI, 0.50-0.58). However, the model found to be most predictive of disease-free survival stratified patients by final pathologic T classification and N classification elements, with a concordance index of 0.75 (95% CI, 0.70-0.80). Tumor response to preoperative therapy is a strong predictor of disease-free survival. However, outcome is most accurately estimated by final pathologic stage, which is influenced by both preoperative stage and response to therapy. (Copyright) 2008 American Cancer Society.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Res Treat

Journal ID (iso-abbrev): Cancer Res Treat

Journal ID (publisher-id): CRT

Title: Cancer Research and Treatment : Official Journal of Korean Cancer Association

Publisher: Korean Cancer Association

ISSN (Print): 1598-2998

ISSN (Electronic): 2005-9256

Publication date (Print): July 2016

Publication date (Electronic): 22 October 2015

Volume: 48

Issue: 3

Pages: 998-1009

Affiliations

[1 ]Department of Pathology, Research Institute and Hospital, National Cancer Center, Goyang, Korea

[2 ]Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea

[3 ]Division of Colorectal Surgery, Department of Surgery, Seoul National University, Seoul, Korea

[4 ]Biometric Research Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea

Author notes

Correspondence: Hee Jin Chang, MD, PhD Department of Pathology, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel: 82-31-920-1741 Fax: 82-31-920-1369 E-mail: heejincmd@ 123456yahoo.com

[a]

Present address: Anatomic Pathology Reference Lab, Seegene Medical Foundation, Seoul, Korea

Article

Publisher ID: crt-2015-254

DOI: 10.4143/crt.2015.254

PMC ID: 4946373

PubMed ID: 26511803

SO-VID: 22b96cc8-9545-4c81-9560-41bbdb3fc476

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

What Is the Ideal Tumor Regression Grading System in Rectal Cancer Patients after Preoperative Chemoradiotherapy?

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Abstract

Purpose

Materials and Methods

Results

Conclusion

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Karger: Oncology

Most cited references 20

Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.

The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer.

Pathologic stage is most prognostic of disease-free survival in locally advanced rectal cancer patients after preoperative chemoradiation.

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