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Tumor Regression Grades: Can They Influence Rectal Cancer Therapy Decision Tree?

Tumor Regression Grades: Can They Influence Rectal Cancer Therapy Decision Tree? Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2013, Article ID 572149, 8 pages http://dx.doi.org/10.1155/2013/572149 Clinical Study Tumor Regression Grades: Can They Influence Rectal Cancer Therapy Decision Tree? 1 1 1 2 Marisa D. Santos, Cristina Silva, Anabela Rocha, Eduarda Matos, 1 3,4 Carlos Nogueira, and Carlos Lopes Digestive Surgery Service, Department of Surgery, Hospital de Santo Anto´nio, Largo Professor Abel Salazar, 4099-003 Porto, Portugal Department of Community Health, Instituto de Cien ˆ cias Biomed ´ icas Abel Salazar, Rua Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal Pathological Anatomy Service, Department of Pathology, Hospital de Santo Anto´nio, Largo Professor Abel Salazar, 4099-003 Porto, Portugal ˆ ´ Department of Pathology and Molecular Immunology, Instituto de Ciencias Biomedicas Abel Salazar, Rua Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal Correspondence should be addressed to Marisa D. Santos; marisadsantos@gmail.com Received 30 April 2013; Revised 17 August 2013; Accepted 17 August 2013 Academic Editor: Frank A. Frizelle Copyright © 2013 Marisa D. Santos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Evaluating impact of tumor regression grade in prognosis of patients with locally advanced rectal cancer (LARC). Materials and Methods. We identified from our colorectal cancer database 168 patients with LARC who received neoadjuvant therapy followed by complete mesorectum excision surgery between 2003 and 2011: 157 received 5-FU-based chemoradiation (CRT) and 11 short course RT. We excluded 29 patients, the remaining 139 were reassessed for disease recurrence and survival; the slides of surgical specimens were reviewed and classified according to Mandard tumor regression grades (TRG). We compared patients with good response (Mandard TRG1 or TRG2) versus patients with bad response (Mandard TRG3, TRG4, or TRG5). Outcomes evaluated were 5-year overall survival (OS), disease-free survival (DFS), local, distant and mixed recurrence. Results.Meanage was 64.2 years, and median followup was 56 months. No statistically significant survival difference was found when comparing patients with Mandard TRG1 versus Mandard TRG2 (𝑝=.77 ). Mandard good responders (TRG1 + 2) have significantly better OS and DFS than Mandard bad responders (TRG3 + 4 + 5) (OS𝑝 = .013 ;DFS𝑝 = .007 ). Conclusions. Mandard good responders had a favorable prognosis. Tumor response (TRG) to neoadjuvant chemoradiation should be taken into account when defining the optimal adjuvant chemotherapy regimen for patients with LARC. 1. Introduction insufficient to maintain levels of locoregional recurrence between 4 and 6% [7, 8]. Colorectal cancer is the third most common cancer in Neoadjuvant CRT allows a reduction of regional recur- developed countries. It ranks second in Portugal, and it is rences, and when there is a complete pathological response estimated that each year more than 7,000 new cases arise with (ypCR), an increase in survival is verified [ 9]. 8 Portuguese patients with colorectal cancer dying per day, eTh rate of response is better in neoadjuvant CRT com- on average [1, 2]. Surgery remains the primary therapeutic paredwithlongcourseRTandpossiblyabsentinshortcourse tool in the treatment of rectal cancer, and with the advent RT with immediate surgery. In fact, the maximal response of mesorectum complete excision (TME) in cancers of the of the radiation occurs only several weeks after its end [ 10]. middle and lower rectum, it was possible to reduce the locoregional recurrence [3–6]. However, concerning locally For that reason, surgery has been delayed until 8–12 weeks following neoadjuvant CRT [11–13]. advanced rectal cancer (LARC), this approach has proved 2 International Journal of Surgical Oncology The use of neoadjuvant CRT can lead to tumor shrinkage, Table 1: Mandard TRG system. increases the likelihood of performing a sphincter preserving TRG1 No viable cancer cells, complete response surgery, and in the surgical specimen increases circumfer- TRG2 Single cells or small groups of cancer cells ential and distal margins, with reduction of lymphatic and TRG3 Residual cancer outgrown by b fi rosis vascular invasion [14–19]. TGR4 Significant b fi rosis outgrown by cancer However,thetypeandremissionratetoneoadjuvantCRT remain considerably variable. While some patients may not TRG5 No fibrosis with extensive residual cancer respond, other patients experience downstaging, and 15–25% have surgical specimens without any viable tumor cells, a condition referred to as pathologic complete response (ypCR) The neoadjuvant CRT protocol included a total irradia- [20, 21]. tion of 50.4 Gy in 28 fractions and 5-fluorouracil by infusion Complete pathological response leads to excellent locore- pump. gional management as it provides an increase in survival for Radical surgery consisted mainly of sphincter saving stage I values, that is, 90% at 5 years [22–26]. Based on these rectal resection (SSRE) or abdominoperineal resection (APR) data,there arecenters that in case of aypCRadvocateapolicy with TME. In the operative procedure selection, we consid- of “wait and see” reserving surgical resection only for cases of ered the distance of the lesion to the anus, the comorbidities “tumor escape.” The published results of these centers refer to of the patient, and the condition of the anal sphincter. survival rates equal to or greater than those achieved in ypCR Operated patients were subjected to adjuvant chemother- patients with resection [27–30]. apy protocol for 6 months performed preferably with 5- While there are substantial data regarding the relation- u fl orouracil (5-FU) or a combination of 5-FU and oxaliplat- ship between ypCR and improved oncologic outcomes, the inum. prognostic significance of “near complete” response to CRT Standard pathologic tumor staging of the resected spec- has not been extensively evaluated [31]. eTh refore, the aim of imen was performed in accordance with the guidelines of this study was to verify if the association of ypCR with near the American Joint Committee on Cancer. Circumferential complete response (good responders) maintains a similar resection margin (CRM) was scored as positive when cancer prognostic of ypCR alone in patients with LARC. cells were within 1 mm of the margin. Evidence of ypCR was To quantify the response to neoadjuvant CRT, different defined as absence of viable adenocarcinoma in the surgical systems can be used which are particularly important in specimen or the presence of lakes of mucus without tumor situations where the pathological response is not complete. cells. The histology of all surgical specimens was reviewed Most of them have 5 grades, allowing the creation of groups and confirmed by an independent element and was classified according to the response [20, 32, 33]. based on Mandard tumor regression grade system (Table 1). This study evaluates the degree of tumor regression We divided our patient population based on TRG Man- according to Mandard classification in patients with LARC dard into two groups: good responders den fi ed as Man- who underwent neoadjuvant CRT followed by surgical resec- dard TRG1/TRG2 and bad responders defined as Mandard tion with TME. TRG3/4/5. eTh two groups were used to evaluate outcome results. Disease recurrence was evaluated according to location: 2. Material and Methods locoregional (LR), systemic (DR), or mixed. A single-institution database was queried for consecutive None of the patients were lost from followup. patients with LARC and biopsy-proven rectal adenocarci- All surviving patients were observed in our query in the noma who underwent neoadjuvant CRT followed by elective last three months. radical surgery with TME with curative intent between January1,2003and December 31,2011. Admission criteria were patients with rectal cancers 2.1. Statistical Analysis. Survival time was defined as the interval between the beginning of neoadjuvant therapy and located less than 12 cm tumor distance from anal verge and the date of the last observation. clinical stage T2N+ M0 or cT3/4 N0/+M0. Oncologic outcomes were evaluated for 5-year overall Exclusion criteria were patients with other diagnosed survival (OS), 5-year disease-free survival (DFS), overall neoplasia, short course RT, yp stage IV, R1/R2 surgery, and recurrence (OR), local recurrence (LR), and distant recur- death during 60 days postoperatively. rence (DR). All patients receiving neoadjuvant CRT were operated Survival curves were performed using the Kaplan-Meier with an average of 8 weeks aeft r the end of radiotherapy method and compared by log rank test. andwereincludedinthisanalysis. eTh patients receiving Mandard groups (good/bad) were compared in relation short-course radiation were excluded since when immediate to age, sex, tumor distance from anal verge, clinical stage, surgery is carried out, no downstaging occurs. surgical procedure performed, and pathological stage (yp- Staging assessment included rigid proctoscopy, total colonoscopy, chest, abdominal and pelvic CT scan, endo- stage) using Student’s t-test and the𝑋 . For survival analysis, rectal ultrasound (ERUS), pelvic magnetic resonance image the independent variables Mandard TRG, ypN-stage, the (MRI) (since 2008), and carcinoembryonic antigen serum ypT-stage, and tumor distance from anal verge were analyzed levels. using Cox’s proportional hazard (method forward stepwise). International Journal of Surgical Oncology 3 Table 2: Results—clinical parameters. Table 3: Results—pathological parameters and clinical long term outcome. Variables Variables Sex Postoperative stage Male 87 (62.6%) 0 25 (18%) Female 52 (37.4%) I 19 (13.7%) Age II 53 (38.2%) Mean (range) 64.2 (32–82) III 42 (30.2%) Tumor distance from anal verge TRG Mandard 139 >6 cm 68 (48.9%) Good response (1 or 2) 70 (50.4%) ≤6 cm 71 (51.1%) Bad response (3, 4, or 5) 69 (49.6%) Clinical stage Overall recurrence disease 26 (18.7%) II 76 (54.7%) Local 4 (2.9%) III 63 (45.3%) Distant 20 (14.4%) Neoadjuvant therapy Local and distant 2 (1.4%) CRT 139 Five years overall survival (os) 72.3% (se = 4.2%) Surgical procedure Five years disease survival (DFS) 72.1% (se = 4.1%) SSRR (sphincter saving rectal resection) 88 (63.3%) APR (abdominoperineal resection) 46 Other (rectal resection without anastomose) 5 eTh two groups of patients (good response Mandard Perioperative complications versus bad response Mandard) are statistically comparable Morbidity 35 (25.1%) in respecttoage (𝑝 = .12 ), sex (𝑝 = .52 ), clinical stage Abdominal or pelvic abscess 11 (𝑝=.11 ), and surgical procedures performed (𝑝=.13 )with Anastomose leak 2 the exception of tumor distance from anal verge (𝑝=.009 ), Reoperation 5 ypN-stage (ypN0/ypN+) (𝑝 = .001 ), and ypT-stage (ypT0- Readmission 2 2/ypT3-4) (𝑝<.001 )(Table 4). Was considered statistically significant 𝑝 < .05 .IBM SPSS 3.3. Disease Recurrence Statistics version 20 was used. 3.3.1. Pelvic Recurrence. Four patients (2.9%) had isolated pelvic recurrence. Considering only the group of patients 3. Results with a good response, pelvic recurrence appeared in 1 of 70 The database query returned 168 patients. We excluded 29 (1.4%) 45 months aer ft surgery; TRG1 ( Table 3). patients: 11 subjected to short course RT, 11 patients with free radial margin≤1 mm (R1 surgery), 3 patients yp stage IV, and 3.3.2. Distant Recurrence. Distant recurrence without pelvic four deaths in 60 days postoperatively. recurrence appeared in 20 of 139 patients (14.4%). If we con- sider only patients with a good response, distant recurrence 3.1. Operative Procedure. The surgery performed in 139 appeared in six of 70 (8.5%) patients (1/25 TRG1 and 5/45 patients was a sphincter saving rectal resection, with anas- TRG2). For patients who had a complete pathologic response, tomosis (with or without protective ileostomy) in 88 patients distant recurrence emerged in one patient (brain metastasis (63.3%). Abdominal-perineal resection was performed in 46 25 months aer ft surgery). patients, and vfi e patients were subjected to proctectomy with definitive stoma. 3.3.3. Mixed Recurrence. Two patients (1.4%) had pelvic The morbidity of the series was 25.11% ( Table 2). and distant disease. Both were classified as bad responders according to Mandard classification. 3.2. Pathology. Stage distribution is shown in Table 3.The average number of dissected lymph nodes in surgical spec- imen was 8.2 (range 0–22). 3.4. Survival. The mean followup was 56 months (range 6– Response to neoadjuvant therapy is characterized in 125). Five years overall survival (OS) and vfi e years disease- Table 3. free (DFS) survival were 72.3% and 71.2%, respectively Classification of TRG according to Mandard system (Table 3). allowed us to define two groups as previously mentioned: To the different subsets, survival at 5 years was matched TRG1+2 and TRG3+4+5. (Table 5). We veriefi d a good response to neoadjuvant CRT in 70 eTh survival of patients who showed a good response on patients (ypCR in 25−17.9%)andabadresponsein69patients Mandard TGR was significantly higher than the patients with (49.6%). poorer responses in 5-year overall survival (OS) and 5-year 4 International Journal of Surgical Oncology Table 4: Comparison between TRG and demographic and clinic variables. TRG1 + TRG2 TRG3 + TRG4 + TRG5 𝑝 value Variables Sex 42 (60%) 45 (65.2%) Male 28 (40%) 24 (34.7%) Female Age Mean (range) 63.1 66.1 .12 Tumor distance from anal verge 27 (38.5%) 41 (59.4%) >6cm ≤6cm 43 (61.4%) 28 (40.5%) Clinical stage 43 (61.4%) 33 (47.8%) II III 27 (38.5%) 36 (52.1%) Surgical procedure SSRR (sphincter saving rectal resection) 40 (57.1%) 48 (69.5%) 30 (42.8%) 21 (30.4%) APR (abdominoperineal resection) + other (rectal resection without anastomose) Pathological N-stage 61 (87.1%) 36 (52.1%) ypN0 9 (12.8%) 33 (47.8%) ypN+ Pathological T-stage 42 (60%) 7 (10.1%) ypT0− 2 <.001 28 (40%) 62 (89.9%) ypT3 + 4 Table 5: Results—TRG and clinical long term outcome. Univariable analysis followup: mean—56 months (range: 6–125). CRT (𝑛=139 ) Five years overall survival Mandard good response (TRG1 + 2) 80.8% (se = 5.3%) 𝑝=.013 Mandard bad response (TRG3+ 4 + 5) 63.4% (se = 6.4%) Five years overall survival ypCR (Mandard TRG1) 80.4% (se = 8.9%) 𝑝=.77 Mandard partial response (TRG2) 81.0% (se = 6.7%) Five years DFS Mandard good response (TRG1 + 2) 81.7% (se = 5.1%) 𝑝=.007 Mandard bad response (TRG3 + 4 + 5) 61.7% (se = 6.3%) Five years DFS ypCR (Mandard TRG1) 80.1% (se = 9.1%) 𝑝=.71 Mandard partial response (TRG2) 82.8% (se = 6.1%) Se: standard error. Log rank test. disease-free survival (𝑝 = .013 and .007, resp.) as we can 4. Discussion observe in Table 4 and Figures 1 and 2. The aim of neoadjuvant CRT in LARC is cytoreduction In this series, no statistically signica fi nt survival dieff r- and downstaging of the tumor, but the tumor response to ence was found when comparing patients with complete neoadjuvant CRT is variable. Only when response is good, (ypCR or Mandard TRG1) and partial pathological response sphincterpreservationratemay increase andreducethe pos- (Mandard TRG2) (OS𝑝=.77 ;DFS𝑝=.71 )(Table 5). itiveradialmarginand thepositivelymph node in resected Overallsurvival(OS)and DFSinpatientswithgood specimen (aspects related to rectal cancer prognosis) [17– Mandard response were significantly better than those with 19, 34, 35]. Prognosis impact of tumor response assessment a bad response aer ft we enter in the Cox model the following by TRG is still controversial. Published data are inconclusive variables: the ypN-stage (ypN0/ypN+), the ypT-stage, and the distance from anal verge (Table 6). [21, 36–42]. Despite uncertain clinical utility of TRG, recently International Journal of Surgical Oncology 5 Table 6: Survival in patients TRG (1 + 2) versus TRG (3 + 4 + 1,0 5) controlling ypN-stage (ypN0/ypN+), ypT-stage, and the distance from anal verge multivariable analysis. Hazard ratio (95% confidence interval) 𝑝 value 0,8 OS 0.46 (0.24–0.86) .016 DFS 0.43 (0.23–0.81) .007 0,6 1,0 0,4 0,8 0,2 0,6 0,0 0,4 0 12 24 36 48 60 72 84 96 108 120 Months TRG Mandard 0,2 Bad response Bad response-censored Good response Good response-censored Figure 2: Five years disease-free survival comparison of the two 0,0 groups Mandard. 0 12 24 36 48 60 72 84 96 108 120 Months of two subgroups of patients with dieff rent impact in terms of TRG Mandard survival. Bad response Bad response-censored We had a complete pathological response in 25 patients Good response Good response-censored out of 139 patients (TRG1). A good response, defined as Figure 1: Five years overall survival comparison of the two groups Mandard 1 and 2 classicfi ations, was present in 70 of 139 Mandard. (50.4%) patients (Table 3). eTh se percentages are consistent with the available literature [35, 36]. In our series, we did not find a significant survival published 7th edition of TNM Staging Manual recommends difference comparing TRG1 with TRG2 (OS 𝑝=.77 ;DFS evaluation of TRG after chemoradiation of rectal cancer as a 𝑝 = .71 ). When we consider TRG1+ TRG2 versus the routine procedure [43]. remaining TRG (3+4+5), we obtain significant different Tumor regression grades evaluate tumor response to survival values (𝑝=.013 ). This aspect justiefi d our patients neoadjuvant treatment, mainly in CRT. er Th e are several division in two different groups: good responders (TRG 1+2) tumorregressionsystems trying to quantify theresponseto and bad responders (TRG3+4+5). This type of Mandard CRT and ultimately to have a prognostic value [20, 33, 38]. A TRG division was already used by other authors [19, 36, 40]. common, largely accepted, standardized, and validated TRG While there are substantial data regarding the rela- system does not exist, so the published systems vary in the tionship between ypCR and improved oncologic outcomes, definition of categories, interfering with studies results. the prognostic significance of near complete response to Mandard TRG was proved effective identifying sub- neoadjuvant CRT has not been extensively evaluated. In groups with different responses. In our studies, we applied most studies, only the presence of a pathological complete Mandard system, which essentially counts the number of response is correlated to better long outcome and survival residual tumor cells (Table 1). TRG1 identifies a complete improvement [48]. response (ypCR). Beddy et al. [38] used Mandard TRG and observed eTh association of tumor response and prognosis has better DFS in the combined group of patients having either been previously reported. Previous reports have focused on complete response or near complete response (TRG0+TRG1) specicTo fi r Ndownstaging andincludedintheir analysis compared with the remaining patients. Dhadda et al. [49] pCR [44–46]. Other authors have emphasized the value of applied Mandard system, and the results obtained suggested tumor regression grade, which could more accurately reflect improved DFS and OS after preoperative CRT in TRG2 tumor response at a cellular level [32, 33, 47]. In our series, the application of the Mandard system allowed identification versus TRG3 in the Cox regression analysis. 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Tumor Regression Grades: Can They Influence Rectal Cancer Therapy Decision Tree?

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Hindawi Publishing Corporation
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Copyright © 2013 Marisa D. Santos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2013/572149
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Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2013, Article ID 572149, 8 pages http://dx.doi.org/10.1155/2013/572149 Clinical Study Tumor Regression Grades: Can They Influence Rectal Cancer Therapy Decision Tree? 1 1 1 2 Marisa D. Santos, Cristina Silva, Anabela Rocha, Eduarda Matos, 1 3,4 Carlos Nogueira, and Carlos Lopes Digestive Surgery Service, Department of Surgery, Hospital de Santo Anto´nio, Largo Professor Abel Salazar, 4099-003 Porto, Portugal Department of Community Health, Instituto de Cien ˆ cias Biomed ´ icas Abel Salazar, Rua Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal Pathological Anatomy Service, Department of Pathology, Hospital de Santo Anto´nio, Largo Professor Abel Salazar, 4099-003 Porto, Portugal ˆ ´ Department of Pathology and Molecular Immunology, Instituto de Ciencias Biomedicas Abel Salazar, Rua Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal Correspondence should be addressed to Marisa D. Santos; marisadsantos@gmail.com Received 30 April 2013; Revised 17 August 2013; Accepted 17 August 2013 Academic Editor: Frank A. Frizelle Copyright © 2013 Marisa D. Santos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Evaluating impact of tumor regression grade in prognosis of patients with locally advanced rectal cancer (LARC). Materials and Methods. We identified from our colorectal cancer database 168 patients with LARC who received neoadjuvant therapy followed by complete mesorectum excision surgery between 2003 and 2011: 157 received 5-FU-based chemoradiation (CRT) and 11 short course RT. We excluded 29 patients, the remaining 139 were reassessed for disease recurrence and survival; the slides of surgical specimens were reviewed and classified according to Mandard tumor regression grades (TRG). We compared patients with good response (Mandard TRG1 or TRG2) versus patients with bad response (Mandard TRG3, TRG4, or TRG5). Outcomes evaluated were 5-year overall survival (OS), disease-free survival (DFS), local, distant and mixed recurrence. Results.Meanage was 64.2 years, and median followup was 56 months. No statistically significant survival difference was found when comparing patients with Mandard TRG1 versus Mandard TRG2 (𝑝=.77 ). Mandard good responders (TRG1 + 2) have significantly better OS and DFS than Mandard bad responders (TRG3 + 4 + 5) (OS𝑝 = .013 ;DFS𝑝 = .007 ). Conclusions. Mandard good responders had a favorable prognosis. Tumor response (TRG) to neoadjuvant chemoradiation should be taken into account when defining the optimal adjuvant chemotherapy regimen for patients with LARC. 1. Introduction insufficient to maintain levels of locoregional recurrence between 4 and 6% [7, 8]. Colorectal cancer is the third most common cancer in Neoadjuvant CRT allows a reduction of regional recur- developed countries. It ranks second in Portugal, and it is rences, and when there is a complete pathological response estimated that each year more than 7,000 new cases arise with (ypCR), an increase in survival is verified [ 9]. 8 Portuguese patients with colorectal cancer dying per day, eTh rate of response is better in neoadjuvant CRT com- on average [1, 2]. Surgery remains the primary therapeutic paredwithlongcourseRTandpossiblyabsentinshortcourse tool in the treatment of rectal cancer, and with the advent RT with immediate surgery. In fact, the maximal response of mesorectum complete excision (TME) in cancers of the of the radiation occurs only several weeks after its end [ 10]. middle and lower rectum, it was possible to reduce the locoregional recurrence [3–6]. However, concerning locally For that reason, surgery has been delayed until 8–12 weeks following neoadjuvant CRT [11–13]. advanced rectal cancer (LARC), this approach has proved 2 International Journal of Surgical Oncology The use of neoadjuvant CRT can lead to tumor shrinkage, Table 1: Mandard TRG system. increases the likelihood of performing a sphincter preserving TRG1 No viable cancer cells, complete response surgery, and in the surgical specimen increases circumfer- TRG2 Single cells or small groups of cancer cells ential and distal margins, with reduction of lymphatic and TRG3 Residual cancer outgrown by b fi rosis vascular invasion [14–19]. TGR4 Significant b fi rosis outgrown by cancer However,thetypeandremissionratetoneoadjuvantCRT remain considerably variable. While some patients may not TRG5 No fibrosis with extensive residual cancer respond, other patients experience downstaging, and 15–25% have surgical specimens without any viable tumor cells, a condition referred to as pathologic complete response (ypCR) The neoadjuvant CRT protocol included a total irradia- [20, 21]. tion of 50.4 Gy in 28 fractions and 5-fluorouracil by infusion Complete pathological response leads to excellent locore- pump. gional management as it provides an increase in survival for Radical surgery consisted mainly of sphincter saving stage I values, that is, 90% at 5 years [22–26]. Based on these rectal resection (SSRE) or abdominoperineal resection (APR) data,there arecenters that in case of aypCRadvocateapolicy with TME. In the operative procedure selection, we consid- of “wait and see” reserving surgical resection only for cases of ered the distance of the lesion to the anus, the comorbidities “tumor escape.” The published results of these centers refer to of the patient, and the condition of the anal sphincter. survival rates equal to or greater than those achieved in ypCR Operated patients were subjected to adjuvant chemother- patients with resection [27–30]. apy protocol for 6 months performed preferably with 5- While there are substantial data regarding the relation- u fl orouracil (5-FU) or a combination of 5-FU and oxaliplat- ship between ypCR and improved oncologic outcomes, the inum. prognostic significance of “near complete” response to CRT Standard pathologic tumor staging of the resected spec- has not been extensively evaluated [31]. eTh refore, the aim of imen was performed in accordance with the guidelines of this study was to verify if the association of ypCR with near the American Joint Committee on Cancer. Circumferential complete response (good responders) maintains a similar resection margin (CRM) was scored as positive when cancer prognostic of ypCR alone in patients with LARC. cells were within 1 mm of the margin. Evidence of ypCR was To quantify the response to neoadjuvant CRT, different defined as absence of viable adenocarcinoma in the surgical systems can be used which are particularly important in specimen or the presence of lakes of mucus without tumor situations where the pathological response is not complete. cells. The histology of all surgical specimens was reviewed Most of them have 5 grades, allowing the creation of groups and confirmed by an independent element and was classified according to the response [20, 32, 33]. based on Mandard tumor regression grade system (Table 1). This study evaluates the degree of tumor regression We divided our patient population based on TRG Man- according to Mandard classification in patients with LARC dard into two groups: good responders den fi ed as Man- who underwent neoadjuvant CRT followed by surgical resec- dard TRG1/TRG2 and bad responders defined as Mandard tion with TME. TRG3/4/5. eTh two groups were used to evaluate outcome results. Disease recurrence was evaluated according to location: 2. Material and Methods locoregional (LR), systemic (DR), or mixed. A single-institution database was queried for consecutive None of the patients were lost from followup. patients with LARC and biopsy-proven rectal adenocarci- All surviving patients were observed in our query in the noma who underwent neoadjuvant CRT followed by elective last three months. radical surgery with TME with curative intent between January1,2003and December 31,2011. Admission criteria were patients with rectal cancers 2.1. Statistical Analysis. Survival time was defined as the interval between the beginning of neoadjuvant therapy and located less than 12 cm tumor distance from anal verge and the date of the last observation. clinical stage T2N+ M0 or cT3/4 N0/+M0. Oncologic outcomes were evaluated for 5-year overall Exclusion criteria were patients with other diagnosed survival (OS), 5-year disease-free survival (DFS), overall neoplasia, short course RT, yp stage IV, R1/R2 surgery, and recurrence (OR), local recurrence (LR), and distant recur- death during 60 days postoperatively. rence (DR). All patients receiving neoadjuvant CRT were operated Survival curves were performed using the Kaplan-Meier with an average of 8 weeks aeft r the end of radiotherapy method and compared by log rank test. andwereincludedinthisanalysis. eTh patients receiving Mandard groups (good/bad) were compared in relation short-course radiation were excluded since when immediate to age, sex, tumor distance from anal verge, clinical stage, surgery is carried out, no downstaging occurs. surgical procedure performed, and pathological stage (yp- Staging assessment included rigid proctoscopy, total colonoscopy, chest, abdominal and pelvic CT scan, endo- stage) using Student’s t-test and the𝑋 . For survival analysis, rectal ultrasound (ERUS), pelvic magnetic resonance image the independent variables Mandard TRG, ypN-stage, the (MRI) (since 2008), and carcinoembryonic antigen serum ypT-stage, and tumor distance from anal verge were analyzed levels. using Cox’s proportional hazard (method forward stepwise). International Journal of Surgical Oncology 3 Table 2: Results—clinical parameters. Table 3: Results—pathological parameters and clinical long term outcome. Variables Variables Sex Postoperative stage Male 87 (62.6%) 0 25 (18%) Female 52 (37.4%) I 19 (13.7%) Age II 53 (38.2%) Mean (range) 64.2 (32–82) III 42 (30.2%) Tumor distance from anal verge TRG Mandard 139 >6 cm 68 (48.9%) Good response (1 or 2) 70 (50.4%) ≤6 cm 71 (51.1%) Bad response (3, 4, or 5) 69 (49.6%) Clinical stage Overall recurrence disease 26 (18.7%) II 76 (54.7%) Local 4 (2.9%) III 63 (45.3%) Distant 20 (14.4%) Neoadjuvant therapy Local and distant 2 (1.4%) CRT 139 Five years overall survival (os) 72.3% (se = 4.2%) Surgical procedure Five years disease survival (DFS) 72.1% (se = 4.1%) SSRR (sphincter saving rectal resection) 88 (63.3%) APR (abdominoperineal resection) 46 Other (rectal resection without anastomose) 5 eTh two groups of patients (good response Mandard Perioperative complications versus bad response Mandard) are statistically comparable Morbidity 35 (25.1%) in respecttoage (𝑝 = .12 ), sex (𝑝 = .52 ), clinical stage Abdominal or pelvic abscess 11 (𝑝=.11 ), and surgical procedures performed (𝑝=.13 )with Anastomose leak 2 the exception of tumor distance from anal verge (𝑝=.009 ), Reoperation 5 ypN-stage (ypN0/ypN+) (𝑝 = .001 ), and ypT-stage (ypT0- Readmission 2 2/ypT3-4) (𝑝<.001 )(Table 4). Was considered statistically significant 𝑝 < .05 .IBM SPSS 3.3. Disease Recurrence Statistics version 20 was used. 3.3.1. Pelvic Recurrence. Four patients (2.9%) had isolated pelvic recurrence. Considering only the group of patients 3. Results with a good response, pelvic recurrence appeared in 1 of 70 The database query returned 168 patients. We excluded 29 (1.4%) 45 months aer ft surgery; TRG1 ( Table 3). patients: 11 subjected to short course RT, 11 patients with free radial margin≤1 mm (R1 surgery), 3 patients yp stage IV, and 3.3.2. Distant Recurrence. Distant recurrence without pelvic four deaths in 60 days postoperatively. recurrence appeared in 20 of 139 patients (14.4%). If we con- sider only patients with a good response, distant recurrence 3.1. Operative Procedure. The surgery performed in 139 appeared in six of 70 (8.5%) patients (1/25 TRG1 and 5/45 patients was a sphincter saving rectal resection, with anas- TRG2). For patients who had a complete pathologic response, tomosis (with or without protective ileostomy) in 88 patients distant recurrence emerged in one patient (brain metastasis (63.3%). Abdominal-perineal resection was performed in 46 25 months aer ft surgery). patients, and vfi e patients were subjected to proctectomy with definitive stoma. 3.3.3. Mixed Recurrence. Two patients (1.4%) had pelvic The morbidity of the series was 25.11% ( Table 2). and distant disease. Both were classified as bad responders according to Mandard classification. 3.2. Pathology. Stage distribution is shown in Table 3.The average number of dissected lymph nodes in surgical spec- imen was 8.2 (range 0–22). 3.4. Survival. The mean followup was 56 months (range 6– Response to neoadjuvant therapy is characterized in 125). Five years overall survival (OS) and vfi e years disease- Table 3. free (DFS) survival were 72.3% and 71.2%, respectively Classification of TRG according to Mandard system (Table 3). allowed us to define two groups as previously mentioned: To the different subsets, survival at 5 years was matched TRG1+2 and TRG3+4+5. (Table 5). We veriefi d a good response to neoadjuvant CRT in 70 eTh survival of patients who showed a good response on patients (ypCR in 25−17.9%)andabadresponsein69patients Mandard TGR was significantly higher than the patients with (49.6%). poorer responses in 5-year overall survival (OS) and 5-year 4 International Journal of Surgical Oncology Table 4: Comparison between TRG and demographic and clinic variables. TRG1 + TRG2 TRG3 + TRG4 + TRG5 𝑝 value Variables Sex 42 (60%) 45 (65.2%) Male 28 (40%) 24 (34.7%) Female Age Mean (range) 63.1 66.1 .12 Tumor distance from anal verge 27 (38.5%) 41 (59.4%) >6cm ≤6cm 43 (61.4%) 28 (40.5%) Clinical stage 43 (61.4%) 33 (47.8%) II III 27 (38.5%) 36 (52.1%) Surgical procedure SSRR (sphincter saving rectal resection) 40 (57.1%) 48 (69.5%) 30 (42.8%) 21 (30.4%) APR (abdominoperineal resection) + other (rectal resection without anastomose) Pathological N-stage 61 (87.1%) 36 (52.1%) ypN0 9 (12.8%) 33 (47.8%) ypN+ Pathological T-stage 42 (60%) 7 (10.1%) ypT0− 2 <.001 28 (40%) 62 (89.9%) ypT3 + 4 Table 5: Results—TRG and clinical long term outcome. Univariable analysis followup: mean—56 months (range: 6–125). CRT (𝑛=139 ) Five years overall survival Mandard good response (TRG1 + 2) 80.8% (se = 5.3%) 𝑝=.013 Mandard bad response (TRG3+ 4 + 5) 63.4% (se = 6.4%) Five years overall survival ypCR (Mandard TRG1) 80.4% (se = 8.9%) 𝑝=.77 Mandard partial response (TRG2) 81.0% (se = 6.7%) Five years DFS Mandard good response (TRG1 + 2) 81.7% (se = 5.1%) 𝑝=.007 Mandard bad response (TRG3 + 4 + 5) 61.7% (se = 6.3%) Five years DFS ypCR (Mandard TRG1) 80.1% (se = 9.1%) 𝑝=.71 Mandard partial response (TRG2) 82.8% (se = 6.1%) Se: standard error. Log rank test. disease-free survival (𝑝 = .013 and .007, resp.) as we can 4. Discussion observe in Table 4 and Figures 1 and 2. The aim of neoadjuvant CRT in LARC is cytoreduction In this series, no statistically signica fi nt survival dieff r- and downstaging of the tumor, but the tumor response to ence was found when comparing patients with complete neoadjuvant CRT is variable. Only when response is good, (ypCR or Mandard TRG1) and partial pathological response sphincterpreservationratemay increase andreducethe pos- (Mandard TRG2) (OS𝑝=.77 ;DFS𝑝=.71 )(Table 5). itiveradialmarginand thepositivelymph node in resected Overallsurvival(OS)and DFSinpatientswithgood specimen (aspects related to rectal cancer prognosis) [17– Mandard response were significantly better than those with 19, 34, 35]. Prognosis impact of tumor response assessment a bad response aer ft we enter in the Cox model the following by TRG is still controversial. Published data are inconclusive variables: the ypN-stage (ypN0/ypN+), the ypT-stage, and the distance from anal verge (Table 6). [21, 36–42]. Despite uncertain clinical utility of TRG, recently International Journal of Surgical Oncology 5 Table 6: Survival in patients TRG (1 + 2) versus TRG (3 + 4 + 1,0 5) controlling ypN-stage (ypN0/ypN+), ypT-stage, and the distance from anal verge multivariable analysis. Hazard ratio (95% confidence interval) 𝑝 value 0,8 OS 0.46 (0.24–0.86) .016 DFS 0.43 (0.23–0.81) .007 0,6 1,0 0,4 0,8 0,2 0,6 0,0 0,4 0 12 24 36 48 60 72 84 96 108 120 Months TRG Mandard 0,2 Bad response Bad response-censored Good response Good response-censored Figure 2: Five years disease-free survival comparison of the two 0,0 groups Mandard. 0 12 24 36 48 60 72 84 96 108 120 Months of two subgroups of patients with dieff rent impact in terms of TRG Mandard survival. Bad response Bad response-censored We had a complete pathological response in 25 patients Good response Good response-censored out of 139 patients (TRG1). A good response, defined as Figure 1: Five years overall survival comparison of the two groups Mandard 1 and 2 classicfi ations, was present in 70 of 139 Mandard. (50.4%) patients (Table 3). eTh se percentages are consistent with the available literature [35, 36]. In our series, we did not find a significant survival published 7th edition of TNM Staging Manual recommends difference comparing TRG1 with TRG2 (OS 𝑝=.77 ;DFS evaluation of TRG after chemoradiation of rectal cancer as a 𝑝 = .71 ). When we consider TRG1+ TRG2 versus the routine procedure [43]. remaining TRG (3+4+5), we obtain significant different Tumor regression grades evaluate tumor response to survival values (𝑝=.013 ). This aspect justiefi d our patients neoadjuvant treatment, mainly in CRT. er Th e are several division in two different groups: good responders (TRG 1+2) tumorregressionsystems trying to quantify theresponseto and bad responders (TRG3+4+5). This type of Mandard CRT and ultimately to have a prognostic value [20, 33, 38]. A TRG division was already used by other authors [19, 36, 40]. common, largely accepted, standardized, and validated TRG While there are substantial data regarding the rela- system does not exist, so the published systems vary in the tionship between ypCR and improved oncologic outcomes, definition of categories, interfering with studies results. the prognostic significance of near complete response to Mandard TRG was proved effective identifying sub- neoadjuvant CRT has not been extensively evaluated. In groups with different responses. In our studies, we applied most studies, only the presence of a pathological complete Mandard system, which essentially counts the number of response is correlated to better long outcome and survival residual tumor cells (Table 1). TRG1 identifies a complete improvement [48]. response (ypCR). Beddy et al. [38] used Mandard TRG and observed eTh association of tumor response and prognosis has better DFS in the combined group of patients having either been previously reported. Previous reports have focused on complete response or near complete response (TRG0+TRG1) specicTo fi r Ndownstaging andincludedintheir analysis compared with the remaining patients. Dhadda et al. [49] pCR [44–46]. Other authors have emphasized the value of applied Mandard system, and the results obtained suggested tumor regression grade, which could more accurately reflect improved DFS and OS after preoperative CRT in TRG2 tumor response at a cellular level [32, 33, 47]. In our series, the application of the Mandard system allowed identification versus TRG3 in the Cox regression analysis. Others series Cumulative overall survival Cum disease-free survival 6 International Journal of Surgical Oncology with different TGR system and multivariate analyses failed to approach is indicated for the patients who undergo preoper- demonstrate the prognostic value of TRG for DFS [21, 50]. ative chemoradiation and TME surgery with Mandard bad In most studies, the pathologic T category and the nodal response (TRG3+4+5). status after neoadjuvant CRT still remain the most important independent prognostic factors for DFS [21, 51]. References eTh reason for these different results of the literature can be related to several differences in number of patients of [1] M. H. Abreu, F. C. Poc¸as, R. Rocha, and J. 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