Updates in Surgery (2021) 73:1795–1803 https://doi.org/10.1007/s13304-021-01044-0 ORIGINAL ARTICLE Contemporary snapshot of tumor regression grade (TRG) distribution in locally advanced rectal cancer: a cross sectional multicentric experience Paola Germani1,2 · Francesca Di Candido3 · Daniel Léonard4 · Dajana Cuicchi5 · Ugo Elmore6 · Marco Ettore Allaix7 · Vittoria Pia Barbieri8 · Laura D’Allens9 · Seraina Faes10 · Marika Milani11 · Damiano Caputo12 · Carmen Martinez13 · Jan Grosek14 · Valerio Caracino15 · Niki Christou16 · Sapho X. Roodbeen17 · Umberto Bracale18 · Aurelia Wildeboer19 · Antonella Usai20 · Michele Benedetti21 · Alessandro Balani23 · Giuseppe Piccinni22 · Marco Catarci21 · Paolo Millo20 · Nicole Bouvy19 · Francesco Corcione24 · Roel Hompes17 · Frédéric Ris16 · Massimo Basti15 · Ales Tomazic14 · Eduardo Targarona13 · Alessandro Coppola12 · Andrea Pietrabissa11 · Dieter Hahnloser10 · Michel Adamina9 · Massimo Viola8 · Mario Morino7 · Riccardo Rosati6 · Gilberto Poggioli5 · Alex Kartheuser4 · Antonino Spinelli3 · Nicolò de Manzini1,2 on behalf of the TRG Snapshot Study Group Received: 28 December 2020 / Accepted: 25 March 2021 / Published online: 5 April 2021 © The Author(s) 2021 Abstract Pre-operative chemoradiotherapy (CRT) followed by surgical resection is still the standard treatment for locally advanced low rectal cancer. Nowadays new strategies are emerging to treat patients with a complete response to pre-operative treat- ment, rendering the optimal management still controversial and under debate. The primary aim of this study was to obtain a snapshot of tumor regression grade (TRG) distribution after standard CRT. Second, we aimed to identify a correlation between clinical tumor stage (cT) and TRG, and to define the accuracy of magnetic resonance imaging (MRI) in the restaging setting. Between January 2017 and June 2019, a cross sectional multicentric study was performed in 22 referral centers of colon-rectal surgery including all patients with cT3-4Nx/cTxN1-2 rectal cancer who underwent pre-operative CRT. Shap- iro–Wilk test was used for continuous data. Categorical variables were compared with Chi-squared test or Fisher’s exact test, where appropriate. Accuracy of restaging MRI in the identification of pathologic complete response (pCR) was determined evaluating the correspondence with the histopathological examination of surgical specimens. In the present study, 689 patients were enrolled. Complete tumor regression rate was 16.9%. The “watch and wait” strategy was applied in 4.3% of TRG4 patients. A clinical correlation between more advanced tumors and moderate to absent tumor regression was found (p = 0.03). Post-neoadjuvant MRI had low sensibility (55%) and high specificity (83%) with accuracy of 82.8% in identifying TRG4 and pCR. Our data provided a contemporary description of the effects of pre-operative CRT on a large pool of locally advanced low rectal cancer patients treated in different colon-rectal surgical centers. Keywords Rectal cancer · Pathologic complete response · Neoadjuvant therapy · Tumor regression grade Introduction Colorectal cancer represents the third most common cancer and the second cause of cancer-related mortality worldwide [1]. In about 35% of cases, patients present with rectal can- The members of the TRG Snapshot Study Group are listed in cer [2] and, in case of locally advanced low rectal lesions, Acknowledgements section. pre-operative chemoradiotherapy (CRT) followed by surgi- * Paola Germani cal resection with total mesorectal excision is currently the paolagermani1987@gmail.com standard treatment, reducing local recurrence from 25% to Extended author information available on the last page of the article 13 Vol.:(0123456789) 1796 Updates in Surgery (2021) 73:1795–1803 5–10% and significantly improving overall survival (OS) Methods [3–9]. Response to neoadjuvant CRT is evaluated on the surgi- Study design cal specimen by assessing the stage and tumor regression grade (TRG). Among the many TRG systems which aim to A cross sectional multicentric study was performed in 14 categorize the amount of regressive changes after CRT, the Italian and 8 European referral centers of colorectal surgery Dworak classification is one of the most commonly used for between January 2017 and June 2019. All the clinical and rectal cancer [10–12]. Response rate to pre-operative CRT pathological data were drawn together in a single anony- can be quite variable in the literature [10–12], with patholog- mous database. The manuscript adheres to the Strengthen- ical complete response (pCR) reported in 8–21% of patients ing the Reporting of Observational Studies in Epidemiology and partial responses reported in about 40% of patients [4, (STROBE) Statement [25]. 13–15]. Correct assessment of TRG, as well as thorough Inclusion criteria were: locally advanced rectal carcinoma evaluation of the tumor and nodal status (and, in case, of (cT3–cT4 and/or cN1–cN2 at diagnosis); neoadjuvant long- the metastatic status) on the surgical specimen (i.e. ypTNM) course CRT; surgical resection with curative intent or “watch [16], are of paramount importance to predict prognosis as and wait” strategy with either full-thickness or endoscopic long-term oncological outcomes are significantly better in biopsy. Patients were excluded in case of: stage IV at diag- patients with complete regression compared to those with nosis; neoadjuvant short-course radiotherapy (RT); neoadju- partial or absent regression [3, 4, 17–20]. vant chemotherapy (CT) without RT; lack of significant data According to these considerations, in 2004 Habr-Gama (i.e. pre-operative c-stage and/or yc-stage, histology, TRG, proposed the “watch and wait” strategy for patients with type of pre-operative regimen). clinical complete response (cCR), demonstrating that it was After being diagnosed with rectal cancer, all patients possible to avoid surgical resection and its related morbidity underwent a staging MRI. Primary tumor (T) and nodal and long-term sequelae without affecting OS and disease- involvement (N) were registered according to the Ameri- free survival (DFS) [21]. Nevertheless, more recent studies can Joint Committee on Cancer (AJCC), 7th edition [16]. have failed to reach the same results [22]. The main chal- Infiltration of the mesorectal fascia, and distance between lenge remains the correct identification of patients eligible primary tumor and mesorectal fascia were recorded. The for this approach. In fact, cCR does not always correspond to mesorectal fascia was considered infiltrated in case of tumor pCR, thus determining an increased risk of tumor regrowth distance ≤ 5 mm and non-infiltrated in case of tumor dis- in poorly selected patients [18, 20, 23], although salvage tance ≥ 6 mm. The same parameters were recorded in the surgery can still be performed without reduction in survival restaging setting, where available. [17, 18]. Consequently, current ESMO guidelines endorse a Different long-course CRT regimens were reported. After “watch and wait” strategy only for cCR cases that are poor pre-operative treatment, patients underwent surgical resec- surgical candidates, recommending at any rate that patients tion with curative intent. The “watch and wait” strategy was should be warned about the slightly increased risk of pelvic considered an option for patients with cCR, according to relapse and distant metastases [2]. Another topic of debate either surgeon’s or patient’s preference. Retrospective analy- is the fact that patients undergoing a “watch and wait” strat- sis of different surgeon’s attitudes was performed. egy demand a strict follow-up protocol, but no agreement All surgical specimens were classified according to the has been reached on the timing and type of evaluations (i.e. AJCC staging system, 7th edition [16]. Data about regres- clinical, endoscopic, and radiological) required [24]. sive changes after CRT, infiltration of the mesorectal fascia, As a matter of fact, the therapeutic approach to rectal and distance between primary tumor and mesorectal fascia cancer is constantly changing and defining the best treatment were recorded for all patients. Tumor regression grading was for each patient is currently one of the biggest challenges evaluated according to the Dworak classification [10]. in clinical oncology. The primary aim of this study was to obtain a snapshot of TRG distribution after standard CRT in some European referral centers of colorectal surgery. Sec- Statistical analysis ond, we aimed to identify a correlation between the clinical stage of the tumor (cT) and TRG, and to define the accuracy Continuous data were summarized by median and range of magnetic resonance imaging (MRI) in the restaging set- (minimum–maximum) and were tested for normality with ting. Finally, we aimed to present the current attitudes of the Shapiro–Wilk test. Post-hoc tests and pairwise com- colorectal surgeons towards cCR patients (i.e. surgery vs. parisons through Mann–Whitney test were conducted and conservative treatment). p value adjusted using Holm method. Categorical vari- ables were reported as absolute and relative frequencies 13 Updates in Surgery (2021) 73:1795–1803 1797 Fig. 1  Patients selection (percentages) and compared with Chi-Squared test or Fish- Table 1  Population distribution er’s exact test where appropriate. Centre Total number (%) The capability of restaging MRI at correctly identifying pCR patients was evaluated with sensibility, specificity, and Italy (14 centres) 442 (64.2%) accuracy. True positive results were considered in case of Switzerland (3 centres) 89 (12.9%) ycT0 patients at restaging MRI corresponding to TRG 4 Belgium (1 center) 72 (10.4%) specimens on histopathological examination. Netherlands (2 centres) 39 (5.7%) Statistical analysis was conducted with R version 3.5.0 Spain (1 center) 25 (3.6%) and STATA 14.2 (StataCorp, College Station, TX, USA). Slovenia (1 center) 22 (3.2%) All p values (p) were two-tailed and differences were con- Total (22 center) 689 sidered statistically significant when p < 0.05. Table 2  Pre-operative CRT regimens Chemotherapic agent No. (%) Results Capecitabine 474 (68.8%) A total of 848 patients from 22 European referral centers Folfox 32 (4.6%) of colorectal surgery were initially considered for the pre- 5-FU 30 (4.3%) sent study. Of these, 159 were excluded for the following Folfiri + panitumumab 2 (0.3%) reasons: 14 were metastatic, 14 were not locally advanced, Folfox + bevacizumab 2 (0.3%) 15 underwent only neoadjuvant chemotherapy (CT), 39 Folfoxiri 2 (0.3%) underwent short-course radiotherapy (RT), and 77 were Oxaliplatino 2 (0.3%) missing significant data (i.e. pre-operative c-Stage and/ 5-FU + levofolinile 1 (0.15%) or yc-Stage, histology, TRG, type of pre-operative regi- Docetaxel 1 (0.15%) men). Overall, 689 patients were included for final analysis Folfiri 1 (0.15%) (Fig. 1). Population distribution and type of long-course Folfirinox 1 (0.15%) CRT regimens are summarized in Tables 1 and 2. Atezolizumab 1 (0.15%) Capox + bevacizumab 1 (0.15%) Missing data 139 (20.2%) 13 1798 Updates in Surgery (2021) 73:1795–1803 Fig. 2  TRG distribution TRG distribution Data on the distance between the tumor and the mes- orectal fascia were available for 538 (78.1%) patients. Overall, TRG 0 was recorded in 21 (3%) patients, TRG Tumors close to or infiltrating the mesorectal fascia 1 in 124 (18%) patients, TRG 2 in 243 (35.3%) patients, (≤ 5 mm) were less likely to achieve TRG 4 response TRG 3 in 185 (26.8%) patients, and TRG 4 in 116 (16.9%) (p = 0.005). patients. Results are displayed in Fig. 2. Results are summarized in Figs. 3 and 4 and Tables 3 and 4. Surgeon’s attitude in case of TRG 4 patients Accuracy of restaging MRI A retrospective analysis of the therapeutic strategy in case of TRG 4 patients was performed. Overall, 111 (95.7%) Restaging MRI was performed in 607 (88.1%) patients. In 82 patients underwent surgical resection and 5 (4.3%) patients (11.9%) patients, it was omitted according to center protocol. underwent full-thickness biopsy as part of a “watch and All patients, in whom restaging MRI was omitted according wait” strategy. The reason behind the choice was reported to center protocol, underwent surgical resection, including in 42 cases and it was predominantly made by the surgeon TRG4 patients (i.e. 10 cases). (i.e. surgeon’s choice in 40 cases vs. patient’s choice in Overall, MRI showed a 55% sensibility, 83% specificity, two cases). and 82.8% accuracy for the correct identification of TRG 4 Among TRG 4 patients, despite complete tumor patients (p < 0.001). When analyzing the nodal status, MRI response (ypT0), a non-complete nodal response was showed similar results, with a 52% sensibility, 85% specific- observed in 11 (9.9%) cases on surgical specimen. ity, and 84.5% accuracy for correct identification of lymph node involvement (p < 0.001). Generally, MRI correctly identify ypT and ypN stages Association between TRG and clinical T‑stage (cT) in 49.8 and 66.2% of cases, respectively. Overestimation occurred in 41.3% of patients for T stage and 25.4% of Considering the clinical stage of the tumor at diagnosis patients for N stage, respectively. Underestimation occurred (i.e. cT), more advanced lesions were less likely to achieve in 8.9% of patients for T stage and in 8.4% of patients for N complete regression after neoadjuvant CRT. Indeed, TRG stage, respectively. 4 rate was 29.0% for cT1–cT2 tumors, 17.2% for cT3 tumors, and 11.6% for cT4 tumors, respectively (p = 0.09). Near-complete (i.e. TRG 3) and complete (i.e. TRG 4) regression significantly correlated with tumor size, as it was reported in 58.1% of cT1–cT2 tumors, 45.6% of cT3 tumors, and 30.4% of cT4 tumors (p = 0.003). 13 Updates in Surgery (2021) 73:1795–1803 1799 Fig. 3  Association between cT and TRG​ Fig. 4  Association between distance from mesorectal fascia and TRG​ Table 3  Association between cT and TRG​ TRG 0 TRG 1 TRG 2 TRG 3 TRG 4 Tot cT1-2 1 (3.2%) 4 (12.9%) 8 (25.8%) 9 (29.05%) 9 (29.05%) 31 p = 0.09 cT3 17 (3,1%) 94 (17.2%) 186 (34.1%) 155 (28.4%) 94 (17.2%) 546 cT4 3 (2.7%) 26 (23.2%) 49 (43.8%) 21 (18.7%) 13 (11.6%) 112 Tot 21 124 243 185 116 689 Poor responder (TRG0–2) Good responder (TRG3–4) Tot cT1–2 13 (41.9%) 18 (58.1%) 31 p = 0.003 cT3 297 (54.4%%) 249 (45.6%) 546 cT4 78 (69.6%) 34 (30.4%) 112 Tot 388 301 689 13 1800 Updates in Surgery (2021) 73:1795–1803 Table 4  Association between distance from mesorectal fascia and patients undergoing neoadjuvant treatment. In this study, TRG​ restaging MRI showed a low sensitivity (55%) but high TRG 0–3 TRG 4 Total specificity (83%) in the identification of ypT0 tumors, with an accuracy of 82.8%. Similar results were obtained for the Infiltrated 317 (87.6%) 45 (12.4%) 362 p = 0.005 nodal status and overall, restaging MRI correctly identified or ≤ 5 mm 49.8% of T stages and 66.2% of N stages, respectively. As ≥ 6 mm 138 (78.4%) 38 (21.6%) 176 reported by other studies, stage overestimation was more Total 455 83 538 common than stage underestimation. In 2014, Lee et al. [31] analyzed 150 patients with locally advanced rectal cancer undergoing post-CRT MRI and observed that pathologic T Discussion stage-matched restaging MRI findings in 64.7% of patients, with 24.0% of cases being over-staged. Similarly, patho- The present paper evaluated the factors associated with logic N stage-matched restaging MRI findings in 56.6% of tumor regression, analyzed the accuracy of restaging MRI, patients, with 36.0% of cases being over-staged. The authors and described real-life therapeutic strategies in case of com- concluded that restaging MRI has low accuracy for the pre- plete response to CRT among a sample of Italian and Euro- diction of pathologic T and N classifications in patients- pean surgeons. receiving pre-operative CRT. More recently, Cho et al. [34] Overall, our results are consistent with literature data. reported that magnetic resonance TRG (mrTRG) has a sen- Specifically, TRG 4 was recorded in 16.9% of patients. Of sibility of 37.9%, a specificity of 76.5%, and an accuracy these, the majority underwent surgical resection; whereas, of 66.3%, in the identification of ypT0 tumors. Further- a “watch and wait” strategy was performed only in 4.3% of more, Sclafani et al. [32] reported a low agreement between cases. This could be due to lack of standardized protocols, mrTRG and pTRG, although sensibility and specificity were but a major concern is certainly represented by the fact that high (74.4 and 62.8%, respectively). complete tumor regression does not always correspond to MRI accuracy in the assessment of TRG can be increased complete response in the lymph nodes. In the present series, by diffusion-weighted imaging (DWI). However, over-stag- 9.9% of TRG 4 patients presented residual nodal disease (i.e. ing and under-staging remains a problem, as the main limita- ypN+) at histological examination of the surgical specimen. tion of MRI lies in the difficulty at discriminating between This is consistent with literature data, reporting that up to residual tumor, fibrosis, edema, and inflammation. Moreo- 10% of ypT0 patients still present metastatic lymph nodes ver, small residual cells may not be seen on radiological at the time of surgery, thus determining an increased risk evaluation [33, 34]. Some authors believe that the addition of local recurrence and lower 5-year DFS and OS rates [20, of endoscopic ultrasound (EUS) imaging to MRI might 23, 26, 28]. increase the accuracy of post-treatment staging; however, a Tumor regression grade was also found to significantly satisfactory agreement has yet to be reached [33, 35]. In this correlate with clinical T stage and distance of the tumor setting, radiomic seems to be a promising technique. Pre- from the mesorectal fascia. According to our results, early liminary results, recently published by the MSKCC group, clinical T stages and tumors with a distance ≥ 6 mm from showed a better performance of radiomic in the identification the mesorectal fascia were more likely to achieve complete of a complete response compared to T2-weighted MRI and tumor regression (i.e. TRG 4). This is in accordance with DWI sequences [35], thus representing a significant potential the literature. Several studies have analyzed pCR predictive guidance in the individualization of the most appropriate factors and clinical T stage has been widely recognized as therapeutic approach for each patient [35–37]. a strong predictive factor of tumor response. Tan et al. [27] The present study had several limitations. First, it was ret- have recently reported that only 12% of cT4 patients achieve rospective and not fully representative of European surgical pCR compared to 21% of cT3, 23% of cT3, and 27% of cT1 attitudes in rectal cancers, although several referral centers patients, respectively (p < 0.001). Therefore, neoadjuvant were included in the analysis. Second, the study evaluated treatment may play a role also in early rectal cancers, and only some predictive factors of complete tumor response, specifically cT2N0 lesions. Recent studies comparing sur- such as clinical stage, neoadjuvant therapy, and distance gery alone versus CRT and local excision for cT2N0 patients of the tumor from the mesorectal fascia. However, other showed similar oncologic results [28–30]; however, further factors, including molecular pathways and tumoral mark- studies with longer follow-up periods and larger series are ers, may play a role as well. Third, the population was not required to draw definitive conclusions. homogeneous and included patients who underwent differ- A tailored therapeutic approach strongly relies on accu- ent schemes of chemotherapy, thus potentially influencing rate pre-operative imaging and MRI should be highly outcomes. effective in predicting the pathologic state of rectal cancer 13 Updates in Surgery (2021) 73:1795–1803 1801 Nevertheless, this is one of the first studies to offer some References sort of contemporary description of the effects of pre-oper- ative CRT on a large pool of locally advanced low rectal 1. (2018) https://​www.​uicc.​org/​news/​new-​global-​cancer-​data-​globo​ cancer patients treated in different Italian and European can-​2018 2. Glynne-Jones R, Wyrwicz L, Tiret E et al (2017) Rectal cancer: colorectal surgical centers. 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Lezoche G, Baldarelli M, Mario et al (2008) A prospective ran- domized study with a 5-year minimum follow-up evaluation of Authors and Affiliations Paola Germani1,2 · Francesca Di Candido3 · Daniel Léonard4 · Dajana Cuicchi5 · Ugo Elmore6 · Marco Ettore Allaix7 · Vittoria Pia Barbieri8 · Laura D’Allens9 · Seraina Faes10 · Marika Milani11 · Damiano Caputo12 · Carmen Martinez13 · Jan Grosek14 · Valerio Caracino15 · Niki Christou16 · Sapho X. Roodbeen17 · Umberto Bracale18 · Aurelia Wildeboer19 · Antonella Usai20 · Michele Benedetti21 · Alessandro Balani23 · Giuseppe Piccinni22 · Marco Catarci21 · Paolo Millo20 · Nicole Bouvy19 · Francesco Corcione24 · Roel Hompes17 · Frédéric Ris16 · Massimo Basti15 · Ales Tomazic14 · Eduardo Targarona13 · Alessandro Coppola12 · Andrea Pietrabissa11 · Dieter Hahnloser10 · Michel Adamina9 · Massimo Viola8 · Mario Morino7 · Riccardo Rosati6 · Gilberto Poggioli5 · Alex Kartheuser4 · Antonino Spinelli3 · Nicolò de Manzini1,2 on behalf of the TRG Snapshot Study Group 13 Updates in Surgery (2021) 73:1795–1803 1803 1 13 Department of Medical, Surgical and Health Sciences, Department of Medicine of the Autonomous University University of Trieste, Strada di Fiume 447, Trieste, Italy of Barcelona, Hospital de la Santa Creu i Sant Pau, 2 Barcelona, Spain Department of General Surgery, Academic Hospital 14 of Trieste, Strada di Fiume 447, Trieste, Italy Department of Abdominal Surgery, University Medical 3 Centre Ljubljana, Ljubljana, Slovenia Colon and Rectal Surgery Unit, Humanitas Research 15 Hospital, Milano, Italy Department of General Surgery UO III, Ospedale Santo 4 Spirito, Pescara, Italy Colorectal Surgery Unit, Saint‑Luc University Hospital, 16 Université Catholique de Louvain (UCL), Brussels, Belgium Division of Digestive Surgery, University Hospitals 5 of Geneva, Genève 1211, Switzerland Department of Medical and Surgical Sciences, Surgery 17 of the Alimentary Tract, Sant’Orsola Hospital, Alma Mater Department of Surgery, Amsterdam UMC, University Studiorum University of Bologna, Bologna, Italy of Amsterdam, Amsterdam, The Netherlands 6 18 Department of Gastrointestinal Surgery, San Raffaele Department of Advanced Biomedical Sciences, Federico II Scientific Institute, Vita e Salute University, Milano, Italy University, Naples, Italy 7 19 Department of Surgical Sciences, University of Torino, Department of Surgery, Maastricht University Medical Torino, Italy Centre, Maastricht, The Netherlands 8 20 Department of General Surgery, Cardinale Panico di Tricase Department of Surgery, General and Urgent Surgery Unit, Hospital, Lecce, Italy Regional Hospital “U. Parini”, Aosta, Italy 9 21 Department of Surgery, Cantonal Hospital Winterthur, General Surgery Unit, “C. E G. Mazzoni” Hospital, Winterthur, Switzerland Ascoli Piceno, Italy 10 22 Department of Visceral Surgery, Centre Hospitalier Department of General Surgery, Santa Maria Hospital GVM Universitaire Vaudois Lausanne, Lausanne University Care and Research, Bari, Italy Hospital, Lausanne, Switzerland 23 Department of Surgery, San Polo Hospital, Monfalcone, Italy 11 Department of Surgery, Fondazione IRCCS Policlinico San 24 Department of Public Health, Federico II University, Naples, Matteo, Pavia, Italy Italy 12 Department of General Surgery, University 25 Division of Radiology, University Hospitals of Geneva, Campus-Biomedico Roma, Roma, Italy Genève 1211, Switzerland 13