Preoperatory treatment of adenocarcinoma of the rectum: historical analysis and correlation between tumor regression grade and the outcomes

Colorectal neoplasia has a high prevalence and lethality. In Brazil, the incidence estimated for each year of the 2020-2022 triennium is 20,520 cases of colon and rectal cancer in men and 20,470 in women. In the South Region, it is the third most frequent tumor, with an estimated risk of 25.11 cases per 100 thousand people.1

The treatment of locally advanced rectal neoplasia is based on chemoradiotherapy (CRT) associated with surgery. The neoadjuvant treatment has a benefit in reducing local disease recurrence compared with adjuvant CRT.2 3 Pathological complete response (PCR) is a valid surrogate outcome for disease-free survival (DFS) and has important prognostic value.4-10 14 The presence of tumor regression in the pathological analysis was classified in tumor regression grade (TRG).11 One study estimated the 10-year DFS for patients with PCR, moderate response, and poor response to be 89.5%, 73.6%, and 63%, respectively.16

Although several different scoring systems for tumor regression have been advocated, the AJCC recommends the modified Ryan scheme, a four-point tumor regression score that provides good interobserver reproducibility and prognostic significance. This method was adopted by de College of Americans Pathologists.11 12

CRT can produce substantial tumor regression and approximately 15% will achieve PCR, reaching up to 40% in more favorable tumors. Whether the degree of response to neoadjuvant therapy should change, the subsequent treatment is subject to discussion.

Although the excellent prognosis of CPR, some evidence still suggests the benefit of adjuvant chemotherapy.13 The phase 2 ADORE study looked at FOLFOX escalation in patients who performed neoadjuvant treatment and had no response. The study showed benefit mainly if lymph nodes positive.15 Another subject of research is the strategy of delaying the interval between the end of CRT and the surgery, in addition to the classic interval of 6 to 8 weeks. This strategy aims to increase the rate of complete pathological response and possibly other outcomes.5

This study aims to evaluate the long-term results of treatment of locally advanced rectal neoplasia in the Hospital de Clínicas de Porto Alegre. We also aim to analyze the tumor regression grade as a prognostic factor and demonstrate relationships between variables that could be useful and generate hypotheses. Finally, we want to compare the interval between the end of the neoadjuvant treatment and surgery in weeks, seeking the time of higher pathological response rate.

A retrospective cohort of patients 18 years of age or older with locally advanced rectal adenocarcinoma treated at the clinical oncology and radiation oncology service of Hospital de Clínicas de Porto Alegre, between 2006 and 2018. The patients have been treated with neoadjuvant CRT and underwent tumor resection surgery. All of them must have had documentation of surgical pathology analyzed by our department of pathology. The chemotherapy protocols used in the neoadjuvant treatment included 5-flourouracil bolus, 5-floururoacil infusion, and capecitabine.

The tumor regression grade was formally reviewed in the pathology records and graduated by the investigators according to the AJCC classification, in grades from 0 to 3, with 0 - complete pathological response, 1 - the presence of minimal residual neoplastic focus, 2 - the presence of evident tumor regression but with evidently residual tumor and 3 - the absence of tumor regression.

We analyzed medical records and data on clinical history, analysis of imaging tests and surgical pathology as well as other factors relevant to the treatment of the rectal neoplasia. The TRG was correlated with overall survival and DFS. We documented the interval between the end of the CRT (the last day of radiotherapy) and surgery in weeks, correlating with the TRG, seeking the time of higher pathological response rate.

We accrued 156 patients who met the inclusion criteria, underwent CRT and surgery between 2006 and 2018. Most were men (65%), with a median age of 65 years. Most were of the inferior rectum (49%).

The clinical staging was T3 and N1 in 87% and 54.7%, respectively. The median number of lymph nodes resected was 15. The pathological staging was ypT3 and ypN0 in 46% and 77.7%, respectively. The rate of pathological complete response was 12.8%.

More than 80% of patients received dose of radiotherapy above 45Gy. Adjuvant chemotherapy was performed in 69.4% of the patients. However, in the remaining patients who weren't able to receive adjuvant treatment, 16.6% were lymph node positive. Sphincter-sparing surgery was performed in 56.6%. These data and other characteristics of the patients are shown in Table 1 and Table 2.

The median follow-up was 50.5 months. The overall survival (OS) rate at 5 years was 88% (Figure 1 - Supplemental). The 5-year disease-free survival rate (DFS) was 70.7%, similar to the 3-year (DFS) rate, which was 72.9% (Figure 1). The 5-year metastasis-free survival (MFS) rate was 75.2%, similar to the 3-year MFS rate, 77.6% (Figure 2 - Supplemental).

Our retrospective cohort during a period of 12 years showed an overall survival of 88% in 5 years. The recurrence rate was 26.7%, similar to that found in the main studies with this modality of treatment.2 3 The rate of local recurrence was identical to that found in the study published by Sauer et al. (2004)2 of 6%. The rate of pathologic complete response was 12.8%. The pathological (yP) stage in N, mostly N2 and the TRG 3 showed a significant difference in a worse prognosis for these patients in the multivariable analysis.

The TRG is an important prognostic factor. We were able to show a statistically significant difference in DFS according to the TRG. The difference in survival is large when comparing patients with response versus no response. It is also important to note that in our multivariate analysis, the factors related to a worse DFS with statistical significance were: TRG 3 and ypN2.

These findings are in consonance with the literature. In a study analyzing TRG as a prognostic factor, patients with CPR had an incidence rate of distant metastasis of 10.5%, while in those with poor regression it was 63%. The presence of lymph node metastasis and TRG were the only independent prognostic factors for the incidence of distant metastases and DFS.16 It is interesting that in our analysis, even comparing the same pathologic stage of patients, the presence of pathologic response against no response conferred a trend to better outcomes.

We compared the rate of pathologic response according to the interval between CRT and surgery. Surgery performed before 8 weeks and between 8-12 weeks, the PCR were 4.3 and 18.6%, and TRG 3 were 32.6% and 18.6%, respectively. This difference has statistical significance. This finding reinforces some data in the literature. A meta-analysis published in 2016 analyzed the strategy of delaying surgery beyond the classical 6 to 8. The probability of obtaining PCR, when waiting more than 6-8 weeks, was increased by 42%.5 A review of the Brazilian systematic published in 2019 sought to analyze the ideal time between neoadjuvant therapy and surgery. The analysis concludes that waiting longer than 8 weeks seems preferable, increasing the degree of tumor regression.17

A previous study was published looking for which factors have a greater influence on the CPR found that the use of 2 drugs, the use of infusional fluorouracil and a dose of radiotherapy higher than 45Gy4 were important. In our study, 74.5% of the patients were able to complete the desired full dose of radiotherapy. This aspect is important to explain the good results achieved in DFS and OS.

It is relevant to discuss that 16.8% of patients with positive pathologic lymph nodes could not be exposed to adjuvant chemotherapy. The strategy of adding more chemotherapy in the preoperative is established in gastric cancer, bladder cancer and others tumors. Nowadays, the total neoadjuvant treatment, which consists of adding cycles of chemotherapy in addition to preoperative CRT is becoming the new standard of care in selected patients.20 Two studies in this context, phase 3 were recently published: the RAPIDO and PRODIGE 23. The RAPIDO used a short course radiotherapy followed by CAPOX or FOLFOX-4 and surgery. The PRODIGE 23 protocol experimental protocol included FOLFIRINOX, chemoradiotherapy, surgery and adjuvant chemotherapy. Both studies achieved their primary outcomes. Both were able to increase the rate of CPR and reduced the rate of disease recurrence.18 19 The major strength of our study is to show the outcomes of a curable disease in a historical cohort at the Hospital de Clínicas de Porto Alegre, a public hospital. The treatment of rectal neoplasia is complex and involves a multidisciplinary team. Our data are according to the literature and show high overall survival. The main limitations of our study are that it is a retrospective cohort and our comparisons are of non-randomized groups.

The outcomes found are favorable, mainly because they are long-standing data from a public institution. The pathological tumor regression grade (TRG) is an important prognostic factor. The interval between the neoadjuvant treatment and surgery seems to influence the tumor regression grade, with the best results of surgery occurring between 8 and 12 weeks.