Keywords:
Rectal neoplasms - Neoadjuvant therapy - Antineoplastic agents - Radiotherapy
Descritores:
Neoplasias retais - Terapia neoadjuvante - Agentes antineoplásicos - Radioterapia
INTRODUCTION
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.
MATERIAL AND METHODS
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.
Statistical analysis
Demographic data, tumor data, chemotherapy and radiotherapy treatments performed,
CPR rate, tumor recurrence rate and treatment toxicities were presented through descriptive
statistics. The sample size was by convenience, according to the patients treated
in the historical cohort. Comparative analyzes were performed using the methods: Kaplan
Meier, Pearson's chi-square or Fischer's exact and the Cox regression method. A p-value of ≥0.05 was considered statistically significant.
RESULTS
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].
Table 1
Demografic and clinical-pathologic data
|
Total of patients
|
156
|
|
Male (%)
|
101 (64)
|
|
Median age (years)
|
65 (37-85)
|
|
Low rectum (0-5 cm) (%)
|
78 (49)
|
|
Middle rectum (6-10) (%)
|
74 (47)
|
|
High rectum (11-15) (%)
|
4 (2)
|
|
MRI at staging (%)
|
6 (3,8)
|
|
Well differentiated (%)
|
9 (5,7)
|
|
Moderate differentiated (%)
|
141 (89)
|
|
Poor differentiated (%)
|
6 (3,8)
|
|
cT2 (%)
|
6 (3,8)
|
|
cT3 (%)
|
138 (8,7)
|
|
cT4 (%)
|
12(7,6)
|
|
cN0 (%)
|
40 (25,4)
|
|
cN positive (%)
|
116 (74,6)
|
|
Treatment between 2006-2010 (%)
|
40 (25,4)
|
|
Treatment between 2011-2014 (%)
|
60 (38,2)
|
|
Treatment between 2015-2018 (%)
|
57 (36,3
|
|
Neo 5FU bolus (%)
|
118 (75,1)
|
|
Neo Capecitabine (%)
|
30 (19,1)
|
|
Neo 5FU infusional (%)
|
9 (5)
|
|
Perfomed adjuvant chemotherapy
|
109 (69,4)
|
|
Radiotherapy dose of 50 Gy (%)
|
101 (64)
|
|
Radiotherapy dose of 45 Gy (%)
|
26 (16,5)
|
|
Completed planned RDT
|
117 (74,5)
|
|
Disease progression (%)
|
42 (26,7)
|
|
Systemic progression (%)
|
32 (20)
|
|
Local progression (%)
|
10 (6,4)
|
|
Grade ¾ adverse efects (%)
|
34 (21,6)
|
Table 2
Surgical and histopathological
|
Total of patients
|
156
|
|
ypT0
|
23 (14,6)
|
|
ypT1
|
11 (7)
|
|
ypT2
|
38 (24,2)
|
|
ypT3
|
73 (46,5)
|
|
ypT4
|
12 (7,6)
|
|
ypN0
|
122 (77,7)
|
|
ypN1
|
22 (14
|
|
ypN2
|
13 (8,3)
|
|
TRG 0 (%)
|
20 (12,8)
|
|
TRG 1 (%)
|
32 (20,3)
|
|
TRG 2 (%)
|
63 (40)
|
|
TRG 3 (%)
|
41 (26)
|
|
Resected lymph nodes (median)
|
15 (0-64)
|
|
Positive margin
|
12 (7)
|
|
Median time to surgery ( days)
|
63(25-629)
|
|
Median time to surgery ( weeks)
|
9 (3,5- 89)
|
|
Sphincter- sparing surgery (%)
|
89 (56,6)
|
|
Surgery - sphincter sparing of low rectum (%)
|
27 (34,1)
|
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]).
Figure 1 Kaplan Meier curve of disease free survival
Analysis of tumor regression grade
The comparison between patients who had no tumor regression after CRT (TRG 3) versus
those who had a response (TRG 0, 1 and 2) showed increased risk of progression with
RR 3.14 (95%CI: 1.7-5.8) p<0.0001 ([Figure 3]) and increased risk of death with RR of 4.52 (95%CI: 1.66-12.2, p<0.003) ([Figure 3 - Supplemental]).
Figure 2 Comparison of disease-free survival according to TRG
Figure 3 Comparison of disease-free survival according to the presence or absence of tumor
regression
Analyzing the outcomes according to the tumor regression grade, the observed 5-year
DFS rate in the TRG 0, 1, 2, and 3 were: 94.7%, 84.9%, 67.3%, and 44%, respectively;
p<0.0001 ([Figure 2]). The overall survival rate at 5-year was: 100%, 88.3%, 91.9% and 74.2%, respectively;
p<0.009 ([Figure 4 - Supplemental]).
Analyzing patients with paired pathological staging and different tumor regression
grade
We performed a subgroup analysis with 50 patients with pathological stage T3N0. In
this group 15 had TRG grade 3 and 35 had TRG grade 1 or 2. We observed a better prognosis
for patient with TRG 1 + 2 versus TRG 3. The 5-year SLP rate was 77.5% versus 55.7%
([Figure 4]). This trend is also seen in ypT3 and ypN1 patients ([Figure 9]).
Figure 4 Comparison of disease-free survival in patients with ypT3ypN0 with or without tumor
regression.
Analysis of pathological staging
The DFS analysis according to the different subgroups of tumor pathological staging
(T) and lymph node (N) showed a significant difference between the groups.
The groups ypT3 and ypT4 showed an increased risk of progression compared with the
group with ypT0, with RR of 8.9 (95%CI: 1.2-66.3, p<0.03) and 22.7 (95%CI: 2.8-182, p<0.003), respectively. ([Figure 5 - Supplemental]). The OS analysis showed worsening of survival for the ypT4 group ([Figure 6 - Supplemental]).
The comparison was between different pathological lymph node staging, N1 and N2. Comparing
the DFS in patients N1 versus N0, we observed RR 2.32 (95%CI: 1.0-5.2, p<0.041) in detriment of N1 patients and between N2 vs N0, RR 8.3 (95%CI: 3.9-17.8,
p<0.001) in detriment of N2 ([Figure 7 - Supplemental]). The analysis of OS shows worse survival in N2 patients, with RR of 1.9; however,
without reaching a statistical difference ([Figure 8 - Supplemental]).
Multivariate analysis correlating pathological staging, tumor regression and progression-free
survival ([Table 3])
A multivariate analysis was made comparing different variables and correlating to
DFS. This analysis showed that the variables correlated to a worst DFS with a statistical
significance difference were: ypN2 and the absence of tumor regression (TRG 3) ([Table 3]).
Table 3
Multivariate analysis correlating pathological staging and TRG 3 to disease-free survival
|
RR
|
IC 95.0%
|
P
|
|
ypT
|
|
|
|
.244
|
|
ypT(1)
|
3.203
|
0.289
|
35547
|
.343
|
|
ypT(2)
|
3.059
|
0.356
|
25.628
|
.303
|
|
ypT(3)
|
4843
|
0.621
|
37.771
|
.132
|
|
ypT(4)
|
8.430
|
0.982
|
72.839
|
.052
|
|
ypN
|
|
|
|
.001
|
|
ypN (1)
|
1.845
|
0.807
|
4.221
|
.147
|
|
ypN (2)
|
4.861
|
2.180
|
10.840
|
.000
|
|
absence of tumor regression
|
1.956
|
1.017
|
3.764
|
.044
|
Analysis of the interval between neoadjuvant treatment and surgery
The median time from the end of the CRT to surgery was 9 weeks. Analyzing this interval,
the highest rates of pCR were accomplished in weeks 8, 9, 11, and 12 ([Figure 10 - Supplemental]).
We compared different intervals between the CRT to surgery: less than 8 weeks, between
8-12 weeks and above 12 weeks ([Figure 5]). The rate of CPR was 4.3%, 18.6% and 7.1%, respectively. The difference between
4.3 and 18.6% was statistically significant. Analyzing the TRG 3 in the same periods,
the rates were 32.6%, 18.6%, 57.1%, respectively ([Figure 12 - Supplemental]). The difference between 18.6% and 57.1% had a statistically significant difference
([Figures 11] and [12 - Supplemental]). Analyzing only the period after 12 weeks, the median time for surgery for this
group was 15 weeks and only one patient was operated with more than 6 months of interval.
Figure 5 Comparison of the complete tumor response rate between different intervals between
chemoradiotherapy and surgery.
DISCUSSION
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 45Gy[4] 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.
CONCLUSION
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.
SUPPLEMENTARY FIGURES
Figure 1 Supplemental - Kaplan meier curve of overall survival
Figure 2 Supplemental - Kaplan meier curve of metastasis-free-survival
Figure 3 Supplemental. Comparison of overall surival according to the presence or absence
of tumor regression
Figure 4 Supplemental - Comparison of overall survival according to TRG
Figure 5 Supplemental - comparison of disease-free survival according to ypT
Figure 6 Supplemental - Comparison of overall survival according to ypT
Figure 7 Supplemental - Comparison of disease-free survival according to ypN
Figure 8 Supplemental - Comparison of overall survival according to ypN
Figure 9 Supplemental - Comparison of disease-free survival in patients with ypT3ypN1 with
or without tumor regression
Figure 10 Supplemental - Rate of pathological complete response according to the interval in
weeks between chemo-radiotherapy and surgery
Figure 11 Supplemental - Rate of TRG 3 according to the interval in weeks between chemo-radiotherapy
and surgery
Figure 12 Supplemental - Comparison of the TRG 3 rate between different intervals between chemo
- radiotherapy and surgery
Bibliographical Record
Jeziel Basso, Daniel de Carvalho Damin, Luis Fernando Moreira, Marta Nassif Pereira
Lima, Sergio Jobim de Azevedo , Rodrigo Perez Pereira . Preoperatory treatment of
adenocarcinoma of the rectum: historical analysis and correlation between tumor regression
grade and the outcomes. Brazilian Journal of Oncology 2022; 18: e-20220265.
DOI: 10.5935/2526-8732.20220265
