Histological tumour response to pre‐operative combined modality therapy in locally advanced rectal cancer

Abstract

BACKGROUND: Pre-operative combined modality therapy (CMT) is used in locally advanced rectal cancer. Its use affects the clinicopathological staging based on the resected specimen. Assessment of the tumour response in the resected specimen may provide prognostic information. This study was undertaken to determine the histological response to pre-operative chemoradiation and to assess the interobserver reliability of a newly developed tumour response grading system for rectal cancer. METHODS: Pre-operative biopsy specimens and the resected specimens of 21 patients with low rectal cancer were assessed. The patients underwent pre-operative CMT consisting of radiotherapy (45 Gy) with 5-FU either as a continuous infusion or as a bolus intravenous infusion with leucovorin. After four to six weeks tumour response was assessed by comparing pre-operative transrectal ultrasound (TRUS) findings (uT1-4, uN0-1) with postoperative histopathological assessment (pT1-4, pN0-1) using UICC TNM characteristics. Tumour response was defined as a decrease in T status. The histological response to CMT was based on the tumour regression grade (TRG) and ranged from fibrosis extending through the rectal wall with no residual cancer (TRG 1), to no evidence of tumour response (TRG 5). Inter-observer reliability was assessed using weighted and unweighted kappa statistics. RESULTS: Local downstaging was demonstrated in 11/21 (52%) of patients. Three of 21 patients had a TRG 1 response. Thirteen of 21 (62%) patients had TRG 1-3 responses to CMT. There was no significant correlation between local downstaging and TRG. The interobserver correlation coefficient for assessment of TRG was 0.88 (unweighted kappa). CONCLUSIONS: Local downstaging by pre-operative CMT can be demonstrated if pre-operative TRUS staging is compared to standard pathology staging in patients with rectal cancer. Local downstaging is not directly related to histologic response as assessed by TRG. Inter-observer reporting of tumour regression grade (TRG) is reliable.

Usefulness of two independent histopathological classifications of tumor regression in patients with rectal cancer submitted to hyperfractionated pre-operative radiotherapy

“…Ultrasound-histopathological tumor regression parameter, "T-downstaging" represents a simple marker of rectal cancer radiosensitivity both in patients submitted to shortterm preoperative radiotherapy [11,18,19,44,45] as well as in patients with surgery delayed by 1 to 8 wk following irra diation [17,20,21,23,[25][26][27][28][34][35][36]39,[46][47][48][49] . Reports have been published showing the prognostic value of "T-downstaging" for overall survival [17,28,34] , cancer-specific survival [48] , recurrence-free survival [48] , disease-free survival [25,28] , local recurrence risk [26,34,48] , and the risk of distant metastases [48] .…”

“…This finding may prove to be of significance during planning of surgical treatment. The percentage of patients with "T-downstaging" in the group submitted to long-term radiotherapy and radiochemotherapy ranged from 23/88 (26.0%) to 15/20 (75.0%) [14,17,[20][21][22][23][24]27,[34][35][36]39,[46][47][48][49]51,52] . Among patients submitted to short-term preoperative radiotherapy "T-downstaging" ranged between 10/28 (35.7%) and 44/104 (43%) [11,14,18,19] .…”

“…The value of ypT parameter equal or higher than uT indicates lack of tumor regression [11,14,[17][18][19][20][21] . This parameter may also be applied to the regression of metastatic regional lymph nodes in rectal cancer, "N-downstaging" [17,20,[22][23][24][25][26] .…”

“…Tumor regression grade (TRG) is a semi-quantitative parameter describing a relative proportion of residual tumor and stromal fibrosis. It is regarded a useful parameter for the assessment of histopathological changes in tumor following neoadjuvant therapy [14,18,19,21,22,29,[34][35][36][37][38] . There are five grades of cancer response to treatment in TRG staging, ranging from TRG 1-no residual cancer cells in the intestinal wall, replaced by fibrous tissue, through TRG 2-presence of occasional residual cancer cells, scattered in fibrous stroma, TRG 3-fibrosis dominating over residual cancer, TRG 4-residual cancer outgrowing fibrosis, to TRG 5-no tumor response or regression, no fibrosis with extensive residual cancer [29] .…”

“…Reports on the relationship between "T-downstaging" or ypT and TRG are not numerous, and are with regard to preoperative longterm radiotherapy and chemoradiotherapy [21,22,35,36] . The relationship between TRG and the probability of lymph nodes involvement has been described in detail only in patients with rectal cancer submitted to long-term radiochemotherapy [22,41] .…”