The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer

doi:10.1016/j.ijrobp.2004.11.017 CLINICAL INVESTIGATION Rectum THE RELATIONSHIP OF PATHOLOGIC TUMOR REGRESSION GRADE R Ra Un Ro E-m Int. J. Radiation Oncology Biol. Phys., Vol. 62, No. 3, pp. 752–760, 2005 Copyright © 2005 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/05/$–see front matter (TRG) AND OUTCOMES AFTER PREOPERATIVE THERAPY IN RECTAL CANCER FABIO MARIA VECCHIO, M.D.,* VINCENZO VALENTINI, M.D.,† BRUCE D. MINSKY, M.D.,‡ GILBERT D. A. PADULA, M.D.,‡ ENNAPADAM S. VENKATRAMAN, PH.D.,§ MARIO BALDUCCI, M.D.,† FRANCESCO MICCICHÈ, M.D.,† RICCARDO RICCI, M.D.,* ALESSIO GIUSEPPE MORGANTI, M.D.,† MARIA ANTONIETTA GAMBACORTA, M.D.,† FRANCESCA MAURIZI, M.D.,† AND CLAUDIO COCO, M.D.� Departments of *Pathology and �Surgery and †Division of Radiotherapy, Catholic University of the Sacred Heart, Rome, Italy; Departments of ‡Radiation Oncology and §Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY Purpose: To examine the relationship between tumor regression grade (TRG) and outcomes in patients with rectal cancer treated with preoperative therapy. Methods and Materials: Specimens from 144 patients with cT3,4 rectal cancer who had received preoperative radiation � chemotherapy and had a minimum follow-up of 3 years were retrospectively reviewed. TRG, which involves examining the residual neoplastic cells and scoring the degree of both cytological changes, including nuclear pyknosis or necrosis and/or eosinophilia, as well as stromal changes, including fibrosis (either dense or edematous) with or without inflammatory infiltrate and giant-cell granulomatosis around ghost cells and keratin, was quantified in five grades according to the Mandard score (Cancer 1994;73: 2680 –2686). The greater the response, the lower the TRG score. The median follow-up was 72 months (range, 40 –143 months). Results: Of the 144 patients, 19% were TRG1, 12% were TRG2, 21% were TRG3, 46% were TRG4, and 1% were TRG5. To simplify the analysis, TRG was combined into two groups: TRG1–2 and TRG3–5. By univariate analysis, none of the pretreatment factors examined, including age, circumference, length, distance from the anorectal ring, pretreatment T and N stage, and INDpre (defined as the pretreatment reference index size based on digital rectal examination), had an impact on 5-year outcomes, including local control, metastases-free survival, disease-free survival, and overall survival. Postoperative parameters, including pathologic T stage (pT), pathologic N stage (pN), and TRG, did significantly influence 5-year outcomes. These included local failure: pT0 –2: 5% vs. pT3– 4: 19%, p � 0.007; pN0: 7% vs. pN1–3: 26%, p � 0.002; TRG1–2: 2% vs. TRG3–5: 17%, p � 0.013; metastasis-free survival: pT0 –2: 86% vs. pT3– 4: 62%, p � 0.005; pN�: 86% vs. pN�: 42%, p < 0.001; TRG1–2: 91% vs. TRG3–5: 66%, p � 0.004; disease-free survival: pT0 –2: 83% vs. pT3– 4: 54%, p � 0.001; pN0: 80% vs. pN1–3: 39%, p < 0.001; TRG1–2: 91% vs. TRG3–5: 58%, p < 0.001; and overall survival: pT0 –2: 85% vs. pT3– 4: 65%, p � 0.007; pN0: 86% vs. pN1–3: 45%, p < 0.001; TRG1–2: 89% vs. TRG3–5: 68%, p � 0.004. By multivariate analysis combining all pre- and posttreatment parameters, only pN (p < 0.001) and TRG (p � 0.005) significantly predicted disease-free survival. Furthermore, TRG predicted the incidence of pathologic nodal involvement (p < 0.0001). Conclusions: By univariate analysis, TRG is a predictor for local failure, metastases-free survival, and overall survival. By multivariate analysis, it predicts improved disease-free survival. Given the ability of TRG to predict those patients with N� disease, it may be helpful, in combination with other clinicopathologic factors, in selecting patients for a more conservative procedure, such as local excision rather than radical surgery, after preoperative therapy. © 2005 Elsevier Inc. Neoadjuvant chemoradiation, Prognostic factors, Rectal neoplasms. eprint requests to: Vincenzo Valentini, M.D., Istituto di diologia, Università Cattolica del Sacro Cuore, Policlinico iversitario, “Agostino Gemelli,” Largo A. Gemelli, 8, 00168 These data were presented during the poster discussion session at the 44th Annual Meeting of ASTRO in New Orleans, LA, on October 6–10, 2002. ma, Italy. Tel: (�39) 6-30154376; Fax: (�39) 6-35511338; ail: [email protected] Received July 13, 2004, and in revised form Oct 28, 2004. Accepted for publication Nov 8, 2004. 752 In use cT res ab pre an loc (6 he an tiv res rec dis de ex on com be ing dis 5-y pre ch A tre che De Ro had pat rem low (n T eva (V pro ass hea Ph reg 37. age (5- Eli E inc tum eva firm acc ing Co loc 100 ser cle hea P CT ray Fo ativ T of fro defi (20 F pos inf Tr T seq 1. 2. 3. 4. 5. 6. O dio (20 Ra T me ilia late wa 753TRG in rectal cancer ● F. M. VECCHIO et al. INTRODUCTION the last several years, a number of studies examining the of preoperative chemoradiation (CMT) in patients with 3–4 rectal cancer have reported pathologic complete ponse rates (pCR) of 9–29%, as well as an increased ility to perform sphincter-sparing surgery (1–6). Many series report that patients who achieve a pCR after operative CMT, independent of their initial clinical T d N stage, have improved long-term outcomes, including al control, metastases-free survival, and overall survival –12). In patients who achieve less than a pCR, there is terogeneity in definitions and techniques of identifying d scoring the presence of residual tumor after preopera- e CMT. For example, stage pT3 has been defined as ponses ranging from gross disease remains in the peri- tal fat to those with a few foci of microscopic residual ease outside the bowel wall. Most series report that the gree of response is predictive of outcomes (6, 10). For ample, Wheeler et al. have suggested that patients with ly microscopic foci in the mesorectum had a better prognosis pared with patients with T3 (transmural) disease (13). The aim of this study is to evaluate the relationship tween the tumor regression grade (TRG) pathologic scor- system, which is based on the characteristics of the position of residual neoplastic cells in the specimen, and ear outcomes in patients with rectal cancer treated with operative radiation therapy with or without concomitant emotherapy. METHODS AND MATERIALS total of 216 patients with cT3–4 and/or N� rectal cancer were ated with preoperative radiation with or without concurrent motherapy between March 1990 and February 2000 in the partment of Radiation Oncology at the Catholic University, me, Italy. For this analysis, 144 patients were identified who a minimum follow-up of 3 years and the availability of the hologic specimen for the determination of TRG score. The aining 72 patients were excluded because of inadequate fol- -up (n � 5) or the lack of pathologic material for re-review � 67). he pathologic specimens were reviewed in serial section and luated to define the TRG by two independent pathologists .F.M., R.R.) who were not aware of the patient’s treatment tocol or outcome. In the rare cases of disagreement, the final essment was achieved by the same pathologists using a multi- d microscope. All patients were enrolled in previously reported ase I/II trials using a variety of preoperative radiation or CMT imens (4, 14–18). The radiation therapy doses ranged from 8 Gy to 50.4 Gy at 1.8 Gy/fraction, and the chemotherapeutic nt(s) used included one or more of the following: 5-fluorouracil FU), mitomycin C, cisplatin, oxaliplatin, and raltitrexed. gibility criteria and diagnostic workup ligibility criteria for all of the protocols were the same and luded the following: the most inferior aspect of the primary or’s being between 0 and 10 cm from the anorectal ring as luated by double-contrast barium enema, histologically con- 1 c ed adenocarcinoma, clinical stage T3–T4 and/or N1–N3, M0 ording to the 1992 American Joint Committee on Cancer stag- system (19), no prior radiation therapy to the pelvis, Eastern operative Oncology Group performance status of 0–2, granu- yte count greater than 3,000 per �L, platelet count greater than ,000 per �L, hemoglobin concentration greater than 10 dL, um creatinine value not greater than 1.5 mg/dL, creatinine arance �65 mL/min, no major intercurrent disease, adequate rt function, age �18 years, and informed consent. retreatment workup included digital rectal examination, pelvic scan, transrectal ultrasound, liver ultrasonography, chest X- , double-contrast barium enema, and proctoscopy with biopsy. ur to 5 weeks after the end of preoperative treatment, preoper- e restaging was performed. he clinical response was determined during a weekly meeting all specialists involved in the diagnostic investigation. Data m individual physicians’ examinations were compared, and the nitive combined staging and the tumor response were recorded ). In the event of a disagreement, majority consensus was used. or the cN stage, any visible nodes on CT scan were considered itive, and patients with nodes identified in the region of the erior mesenteric artery were considered N3. eatment schedules he patients were treated on one of six different preoperative uential protocols performed between 1990 and 2000. T3-FUMIR: 40 patients (28%) received bolus i.v. mitomycin C (10 mg/m2, Day 1) plus continuous infusion 5-FU (1,000 mg/m2, Days 1–4), combined with 37.8 Gy (14). T3-IORT: 23 patients (16%) received 37.8 Gy, and at surgery a 10 Gy intraoperative boost (IORT) was delivered to the presacral region with 6 MeV electrons (15). T3-PLAFUR: 41 patients (25%) were treated with a 1–4-h infusion of cisplatin (60 mg/m2, Days 1, 29) plus continuous infusion 5-FU (1,000 mg/m2, Days 1–4/5 and 29–32/33) and concurrent 45 Gy followed by a boost to 50.4 Gy (4). T3-TOMRT: 7 patients (5%) received raltitrexed (3 mg/m2 Days 1, 19, 38) plus concurrent 45 Gy followed by a boost to 50.4 Gy. At surgery, a 10 Gy IORT boost was delivered to the presacral region with 6 MeV electrons (16). T3-TOMOXRT: 9 patients (6%) received raltitrexed (3 mg/ m2) and dose escalation with oxaliplatin (60–85–110–130 mg/m2 Days 1, 19, 38) concurrent with 45 Gy followed by a boost to 50.4 Gy (17). T4-FUMIR: 24 patients (17%) received bolus i.v. mitomycin C (10 mg/m2, Day 1) plus continuous infusion 5-FU (1,000 mg/m2 Weeks 1, 5) concurrent with 45–48 Gy. At surgery, 4 patients received a 10 Gy IORT boost to the presacral region with 6 MeV electrons (18). verall, 23 patients (16%) were treated with preoperative ra- therapy alone, 121 (84%) with preoperative CMT, and 29 %) with postoperative adjuvant chemotherapy (Table 1). diation therapy techniques he clinical target volume 2 (CTV2) included the tumor, the sorectum, and the internal iliac nodes, with or without external c lymph nodes. A 4-field or 3-field technique was used. The ral border of anteroposterior-posteroanterior radiation fields s 1.5–2 cm outside the true bony pelvis; the inferior border was m above the anal verge in the tumors of the middle rectum and jus sup to we pos bon asp bor nod rec R tio tre acc Su S rad res wa wa der me ma rec Int A we IO the sco tro Po A pro rec me vor Fo P firs eac per em Th pat Ev T Or ina as inv of ini pos ava of T ( Tu T pat pat reg the log eos or cel the acc TR fi TR fi TR fi TR TR Sta T Ke abl tre con Ag M Ge M F cT T T T T T T T T T T T Tre P P A His A A M A 754 I. J. Radiation Oncology ● Biology ● Physics Volume 62, Number 3, 2005 t below the anal verge in the tumors of the lower rectum; the erior border was at least 2 cm above the tumor and not inferior the sacral promontory; corner blocks or multileaf collimators re used to exclude extrapelvic normal tissues. The lateral field terior border was a minimum of 1.5 cm behind the anterior y sacral margin and the anterior border at the most posterior ect of the symphysis pubis. In patients with T4 disease, this der was anterior to the symphysis pubis to include external iliac es. The clinical target volume 1 (CTV1) included the meso- tum corresponding to the tumor mass with 2-cm radial margins. adiation was delivered with a 10 MV linear accelerator. Frac- nation was at 180 cGy/day, 5 fractions per week. All fields were ated daily. The dose was prescribed to the axis intersection ording to ICRU 50/62 (21, 22). rgery urgery was performed 4 to 8 weeks after the completion of iation. The choice of the surgical procedure (abdominoperineal ection [APR], low anterior resection [LAR], or local excision) s at the surgeon’s discretion. Temporary colostomy after LAR s performed at the surgeon’s discretion. For patients who un- went an LAR or APR, the resection of whole mesorectum (total sorectal excision) was performed and inked distal and radial rgins were evaluated. For those undergoing an LAR, a distal tal margin of at least 2 cm was obtained. raoperative radiation therapy total of 34 patients with cT3 (n � 30) or cT4 (n � 4) disease re referred by a team of surgeons involved in a pilot study of RT (20). The IORT target was chosen according to the size of Table 1. Patient characteristics No. % e (years) edian (range) 64 (25–81) nder ale 96 66.6 emale 48 33.3 NM stage 2N0 1 0.7 2N1 3 2.1 2N2 1 0.7 3N0 23 15.9 3N1 52 36.1 3N2 38 26.3 3N3 3 2.1 4N0 1 0.7 4N1 6 4.1 4N2 13 9 4N3 3 2.1 atment reoperative radiotherapy alone 23 15.9 reoperative chemoradiation 121 84.1 djuvant chemotherapy 29 20.1 tologic classification denocarcinoma G1–G2 65 45 denocarcinoma G3 13 9 ucinous adenocarcinoma 2 1.4 denocarcinoma NOS 63 44.4 resected tumor and of the area thought to be at risk of micro- and pic residual disease. IORT was delivered using 6 MeV elec- ns, and the dose was 10 Gy. stoperative chemotherapy ll patients with stage cT4 (pretherapy), as well as those on tocols T3-TOMRT and T3-TOMOXRT with pN� (n � 29), eived postoperative chemotherapy as part of their primary treat- nt. The regimen was bolus 5-FU (400 mg/m2/day) and leuco- in (100 mg/m2 Days 1–5) monthly for 6 months (23). llow-up atients were seen in routine follow-up every 3 months for the t year, every 6 months for the next 2 years, and then yearly. At h follow-up visit, a digital examination and proctoscopy were formed. Liver ultrasound, chest X-ray, pelvic CT, and carcino- bryonic antigen were performed at 3–12-month intervals (20). e median follow-up was 72 months (range: 40–143 months). No ient was lost to follow-up. aluation of response he tumor response was assessed according to the World Health ganization score (24). Clinical response on digital rectal exam- tion was also evaluated using a reference index (IND) defined the product of the quarters of circumference of rectal wall olved (categorized 1 to 4) multiplied by the craniocaudal length the tumor in mm (4). This index was calculated at the time of tial diagnosis (INDpre) and 4 to 6 weeks after radiation (IND- t). INDpre was calculated in all patients, and INDpost was ilable in 97 patients. Downstaging was defined as any reduction stage comparing clinical T (cT) and N (cN) stage to pathologic pT) and N (pN) stage. mor regression grade umor regression grade (TRG) as reported by Mandard et al. in ients treated for esophageal cancer was used to assess the hologic tumor response after preoperative therapy (25). Tumor ression after preoperative therapy was assessed by examining residual neoplastic cells and scoring the degree of both cyto- ical changes, including nuclear pyknosis or necrosis and/or inophilia, and stromal changes, including fibrosis (either dense edematous) with or without inflammatory infiltrate and giant- l granulomatosis around ghost cells and keratin. On the basis of combination of these changes, tumor regression was classified ording to the five following grades (Fig. 1): G1: Complete response with absence of residual cancer and brosis extending through the wall. G2: Presence of residual cancer cells scattered through the brosis. G3: Increase in the number of residual cancer cells, with brosis predominant. G4: Residual cancer outgrowing fibrosis. G5: Absence of regressive changes. tistical analysis he distribution of ordered categories was analyzed by Gamma, ndall’s, and Stuart’s tau tests (26). When one categorical vari- e was dichotomous and the other ordered, the test for linear nd of proportions was used (27). Differences of p � 0.05 were sidered statistically significant. Local survival and disease-free overall survival were estimated according to the Kaplan-Meier act as haz con sur sig Pa mi log ye an ran inv res wa wa by wa dis an tan pa in an Re the an Tu ses co (49 ch po wi Su ap 82 plu Sp tie the un Do (17 pT 44 (2% pe 77 18 1 ( tw Ov (3% (42 we of pa Pa an pa fai loc loc dis (7% sit sur 87 Ou cu cT pa fai ye sur ye fac mo p sta dis sur wa 0.0 T TR TR 755TRG in rectal cancer ● F. M. VECCHIO et al. uarial method. Statistical significance of each observed variable a predictor of outcomes was analyzed by the Cox proportional ard model (28). The clinical end points evaluated were local trol, metastases-free survival, disease-free survival, and overall vival. Differences of p � 0.05 were considered statistically nificant. RESULTS tient characteristics (pretreatment) A total of 144 patients (96 male, 48 female) with a nimum follow-up of 3 years had TRG analysis of patho- ic specimen. The median age was 64 years (range, 25–81 ars). The tumor stage at initial (pretreatment) diagnosis d tumor grade are seen in Table 1. The median length of the tumor was 50 mm (SD, 17.6, ge, 10–150 mm). The number of quarters of rectal wall aded by the tumor were measured on CT scan images; the ults are as follows: 1 wall, 8 (6%); 2 walls, 69 (48%); 3 lls, 17 (12%); and 4 walls (circumferential), 50 (35%). IND s calculated as the product of number of quarters infiltrated the tumor and the length of the tumor. The median INDpre s 120 mm (SD, 92.9, range, 25–600 mm). The location of the tumor was defined by measuring the tance of the most inferior aspect of the tumor from the orectal ring as seen on barium enema. The median dis- ce was 40 mm (SD, 26.6; range, 12.5–120 mm). In 56 tients (39%) the tumor was located between 0 and 30 mm, 43 patients (30%) it was located between 30 and 50 mm, d in 45 patients (31%) it was more than 50 mm. sponse Four to 6 weeks after the completion of preoperative rapy, all patients were reevaluated with interval history d physical examination, CT scan, and barium enema. mor response comparing INDpre with INDpost was as- sed using World Health Organization criteria. The overall clinical response rate was 51%: 4% clinical mplete response and 47% partial response; the majority %) had a minor response that was classified as no ange. No patients developed disease progression. IND- st was available in 97 patients; it ranged from 10 to 280 th a median value of 40 (SD, 54.7). rgical procedures All patients underwent surgery after preoperative ther- y; the procedures included local excision: 2 (1%), LAR: (57%), LAR plus IORT: 11 (8%), APR: 29 (20%), APR s IORT: 18 (13%), and Hartmann procedure: 2 (1%). hincter-sparing surgery was performed in 66% of pa- nts. In the 56 patients in whom the most inferior aspect of tumor was 0–30 mm from the anorectal ring, 17 (30%) derwent sphincter-sparing surgery. wnstaging Posttreatment pathologic stages included pT0N0: 25 %), pT0N1: 2 (1%), pT1N0: 8 (6%), pT1N1: 1 (1%), A 2N0: 21 (15%), pT2N1: 3 (2%), pT2N2: 1 (1%), pT3N0: (31%), pT3N1: 15 (10%), pT3N2: 12 (8%), pT3N3: 3 ), pT4N0: 3 (2%), and pT4N1: 6 (4%). Overall, the rcentage of downstaging was 53% (77/144) for T stage % and 78% (93/119) for N stage. The tumor regression grade was TRG1: 27 (19%), TRG2: (13%), TRG3: 31 (22%), TRG4: 67 (47%), and TRG5: 1%). To simplify the analysis, TRG was combined into o groups, TRG1–2 and TRG3–5. The relationship between TRG and pN was analyzed. erall, 41 patients (28%) with TRG1–2 were pN0, and 4 ) with TRG1–2 were pN1–3. In contrast, 60 patients %) with TRG3–5 were pN0, and 39 (27%) with TRG3–5 re pN1–3, p � 0.0001 (Table 2). Therefore, 91% (41/45) patients with TRG1–2 were pN0, whereas 63% (60/95) of tients with TRG3–5 were pN0. tterns of failure and survival A total of 43 patients died: 34 deaths were due to tumor, d 9 were due to intercurrent disease. Of the remaining 101 tients, 53 are without evidence of disease. Patterns of lure in the remaining 48 patients include the following: al failure: 9 (7%), distant metastasis: 29 (20%), and both al failure and distant metastasie: 10 (7%). The sites of tant metastases were as follows: liver: 22 (15%), lung: 10 ), brain: 2 (1%), bone: 2 (1%), and other nonspecified es in 3 (2%). The 5-year local failure, metastasis-free vival, disease-free survival, and overall survival were %, 73%, 67%, and 74%, respectively. tcome according to pretreatment prognostic factors Univariate analysis of the impact of age, tumor cir- mference, length and distance from the anorectal ring, and cN stage, and INDpre is seen in Table 3. Younger tients had a significantly higher incidence of local lure (�50 years: 33%, 51–70 years: 9%, and �70 ars: 0%, p � 0.001) and lower 5-year disease-free vival (�50 years: 45%, 51–70 years: 71%, and �70 ars: 88%, p � 0.012). Tumor circumference and length were not prognostic tors. Overall 5-year survival was significantly lower for re distal tumors (�30 mm: 68% vs. 31–50 mm: 89%, � 0.029). However, there was no correlation with cT ge. Clinical nodal status significantly correlated with ease-free survival, metastasis-free survival, and overall vival. The 5-year disease-free survival by nodal status s cN0: 78%, cN1: 78%, cN2: 53%, and cN3: 50%, p � 49. The 5-year metastasis-free survival was cN0: 78%, Table 2. Correlation between TRG and pN (p � 0.0001) RG pN0 pN1–3 G1–2 41 (28%) 4 (3%) G3–5 60 (42%) 39 (27%) bbreviation: TRG � tumor regression grade. cN ov cN de (cN me fre (81 tw sur ind 0.0 0.0 an lym dis fro 0.0 dis lym Ou dis (pT Co IN fre (67 cre Th 19 vs. (pT sur Lik wi fai sis 5-y p � 45 the tiv TR Sim TR (p TR 5-y an TR (Fi TR TR dis 0.0 TR pre (p Ag Cir Le Dis cT cN p IN A pT pN TR IN A 756 I. J. Radiation Oncology ● Biology ● Physics Volume 62, Number 3, 2005 1: 87%, cN2: 56%, and cN3: 67%, p� 0.014. The 5-year erall survival was cN0: 87%, cN1: 78%, cN2: 66%, and 3: 50%, p � 0.029. The following 5-year outcomes creased with an increasing number of positive nodes 0–1 vs. cN2–3): local failure (9% vs. 17%, p � 0.316), tastasis-free survival (85% vs. 57%, p � 0.002), disease- e survival (78% vs. 53%, p� 0.005), and overall survival % vs. 65%, p � 0.003). There was no correlation be- een INDpre and the 5-year local failure, metastasis-free vival, disease-free survival, and overall survival. By multivariate analysis, the following variables were ependent factors for outcomes. Local failure: age (p � 06) and distance of tumor from the anorectal ring (p � 33); metastasis-free survival: distance of tumor from orectal ring (p � 0.003), length of the tumor (p � 0.015), ph node status (p � 0.045), and INDpre (p � 0.019); ease-free survival: age (p � 0.019), distance of tumor m the anorectal ring (p� 0.003), lymph node status (p� 40), and INDpre (p � 0.029); and overall survival: tance of tumor from the anorectal ring (p � 0.004) and ph node status (p � 0.016). tcomes according to posttreatment prognostic factors As seen in Table 4, by univariate analysis, except for the tance from the anorectal ring, all posttreatment factors , pN, INDpost, TRG) significantly predicted outcomes. mpared with patients with INDpost �30, those with Dpost �30 had a significant decrease in 5-year disease- e survival (64% vs. 76%, p� 0.025) and overall survival % vs. 86%, p � 0.043). There was a significant de- ase in favorable outcomes with increasing pT stage. is included 5-year local failure (pT0 –1: 4% vs. pT3– 4: %, p � 0.007), metastasis-free survival (pT0 –1: 86% Table 3. Univariate analysis of pretrea Local failure e p � 0.001 cumference NS ngth NS tance from the anorectal ring NS NS NS Dpre NS bbreviation: NS � nonsignificant. Table 4. Univariate analysis of posttrea Local failure Meta su p � 0.007 p � p � 0.002 p � G1–2 vs. TRG3–5 p � 0.013 p � Dpost NS bbreviation: NS � nonsignifant. pT3– 4: 62%, p � 0.005), disease-free survival 0 –1: 83% vs. pT3– 4: 54%, p � 0.001), and overall vival (pT0 –1: 85% vs. pT3– 4: 65%, p � 0.007). ewise, there was a significant decrease in outcomes th increasing pN stage. This included 5-year local lure (pN0: 7% vs. pN1–3: 26%, p � 0.002), metasta- -free survival (pN0: 86% vs. pN1–3: 42%, p � 0.001), ear disease-free survival (pN0: 80% vs. pN1–3: 40%, 0.001), and overall survival (pN0: 86% vs. pN1–3: %, p � 0.001). With the exception of local control, as TRG increased, corresponding 5-year outcomes decreased. The cumula- e rate of distant metastases by TRG was TRG1: 93%, G2: 90%, TRG3: 86%, and TRG4: 56% (p � 0.001). ilar results were seen for 5-year disease-free survival; G1: 96%, TRG2: 90%, TRG3: 74%, and TRG4: 52% � 0.002). The overall rate of death was TRG1: 11%, G2: 5%, TRG3:19%, and TRG4: 42% (p � 0.002); ear survival was TRG1: 91%, TRG2: 85%, TRG3: 79%, d TRG4: 63% (p � 0.016). When TRG was combined into two groups (TRG1–2 vs. G3–5), the differences in outcomes remained significant g. 1). This included 5-year local failure: TRG1–2: 2% vs. G3–5: 17%, p � 0.013 (Fig. 2); metastasis-free survival: G1–2: 91% vs. TRG3–5: 66%, p � 0.004 (Fig. 3); ease-free survival: TRG1–2: 91% vs. TRG3–5: 58%, p� 01 (Fig. 4); and overall survival: TRG1–2: 89% vs. G3–5: 68%, p � 0.004 (Fig. 5). By multivariate analysis, a number of factors significantly dicted 5-year outcomes. These included local failure: pN � 0.020) and TRG (p� 0.035); metastasis-free survival: pT � 0.010), pN (p � 0.001), and TRG (p � 0.005); disease- parameters: Outcome at 5 years tastasis-free survival Disease-free survival Overall survival � 0.05 p � 0.012 NS NS NS NS NS NS NS NS NS p � 0.029 NS NS NS � 0.014 p � 0.049 p � 0.029 NS NS NS parameters: Outcomes at 5 years ree Disease-free survival Overall survival 5 p � 0.001 p � 0.007 1 p � 0.001 p � 0.001 4 p � 0.001 p � 0.004 p � 0.025 p � 0.043 (p tment stasis-f rvival 0.00 0.00 0.00 NS tment Me p fre ov Co po rev 0.0 me an an ter mo Pa ha 90 as pre Th wh ass eso of CM tum 0% TR me fre (T dis me the can TR CM of pC tha Ho hig on pre ret wi (13 the sur RC cin sti ab tum an be wi mi wi cli res Fig 757TRG in rectal cancer ● F. M. VECCHIO et al. e survival: pN (p � 0.001) and TRG (p � 0.003); and erall survival: pN (p � 0.001) and TRG (p � 0.042). mbined multivariate analysis of both pre- and sttreatment factors Multivariate analysis of all pre- and posttreatment factors ealed that local failure, pN (p � 0.024), and age (p � 25) were independent prognostic factors. These included tastasis-free survival: pT (p � 0.037), pN (p � 0.001), d TRG (p� 0.005); disease-free survival: pN (p� 0.001) d TRG (p � 0.011); overall survival: pN (p � 0.001). DISCUSSION Retrospective data suggest that pathologic downstaging af- preoperative radiotherapy with or without concomitant che- therapy is associated with improved outcomes (6–10, 12). tients with pT0–2 stage disease after preoperative therapy ve local failure rates of 0–6% and 5-year survivals of –100%. However, there is heterogeneity in the definitions well as the techniques of identifying and scoring the sence of residual tumor after preoperative therapy. erefore, we have analyzed response using the TRG score, ich offers a more uniform method of assessment. The TRG score was developed by Mandard et al. to ess the response of preoperative therapy in patients with phageal cancer. They examined 93 resected specimens esophageal cancer from patients treated with preoperative T. TRG score predicted 3-year survival independent of or stage; TRG1: 61%, TRG2: 60%, TRG3: 27%, TRG4: , and TRG5: 0%, p � 0.0001. By univariate analysis, G, pN stage, tumor size, and the amount of wall involve- nt by tumor were significantly correlated with disease- e survival (p� 0.05). By multivariate analysis, only TRG RG1–3 vs. TRG4–5) remained a significant predictor of ease-free survival (p � 0.001). The authors recom- nded that TRG should be considered when evaluating rapeutic results after preoperative CMT in esophageal Fig. 1. Tumor regression grade (TRG). cer (25). 0.0 Morgan et al. tested the interobserver reliability using G to assess pathologic tumor response after preoperative T in 21 patients with T3–T4 rectal cancer. A TRG score 1–3 was seen in 62%, and TRG4–5 was seen in 38%. The R rate was 14%. In contrast to our results, they observed t pT and pN stages were not directly related to TRG. wever, the interobserver reliability in scoring TRG was h. The authors did not analyze the impact of TRG grade outcomes (29). Other grading systems to quantify tumor regression after operative treatment have been developed. Wheeler et al. rospectively reviewed surgical specimens of 42 patients th T3/T4 rectal cancer treated with preoperative CMT ). The specimens were analyzed by one pathologist, and Rectal Cancer Regression Grade (RCRG) was mea- ed. The authors defined three grades of regression: RG 1: either pCR or only microscopic foci of adenocar- oma, RCRG 2: marked fibrosis with macroscopic tumor ll present, and RCRG 3: a poor response with little or sence of fibrosis in the presence of abundant macroscopic or. Overall, 46% were RCRG 1, 40% were RCRG 2, d 14% were RCRG 3. The authors speculated that RCRG tter defines regression of disease after CMT compared th the pT or pN stage. The subset of patients with pT3 croscopic foci had a more favorable prognosis compared th those with pT3 macroscopic disease. At Memorial Sloan-Kettering Cancer Center, selected nicopathologic factors, including the extent of pathologic ponse to preoperative radiation or CMT, were retrospec- . 2. Local control according to TRG1–2 vs. TRG3–5 (p � 13). TRG � tumor regression grade. tiv ren pri cat no res W sur wi for ag rec pre an tie mo rel p-5 op ati a res ing of the sio Gr Gr Gr res els 0– fai tha reg sig AI 1.4 be viv W pre po Ki clu sel pa the we Po 5-y an can sig sta Fig (p Fig 758 I. J. Radiation Oncology ● Biology ● Physics Volume 62, Number 3, 2005 ely analyzed to examine the impact on long-term recur- ce-free survival in 69 patients with T3–4 and/or pN� mary rectal cancer. A 5-point grading scale was used to egorize pathologic response to preoperative therapy: 0: response, 1: response �1/3, 2: response 1/3–2/3, 3: ponse �2/3 but � complete, and 4: complete response. ith a median follow-up of 69 months, 5-year relapse-free vival was 79% and was significantly worse for patients th aggressive pathologic features and pN�. Risk ratios relapse-free survival were 3.68 for the presence of gressive pathologic features and 4.64 for node-positive tal cancers. In patients with greater than 95% response to operative therapy, only 1 patient was dead from disease; other died of an unrelated cause, and the remaining pa- nts were free of disease with a minimum follow-up of 47 nths. However, the extent of response did not predict apse-free survival (12). Rodel et al. examined the apoptotic index (AI), Ki-67, 3, and p-2 immunohistochemically on pretreatment bi- sies in 44 patients with T3/4 rectal cancer after preoper- ve CMT (30). The treatment response was assessed with 5-grade system using histopathologic methods on the ected surgical specimen. The AI was obtained by divid- the number of apoptotic tumor cells by the total number tumor cells multiplied by 100; the pathologic response of tumor was defined according to a rectal cancer regres- n grading defined by Dworak et al. (31). This includes ade 0: no regression, Grade 1: minimal regression, . 3. Metastases-free survival according to TRG1–2 vs. TRG3–5 � 0.004). TRG � Tumor regression grade. ade 2: moderate regression, Grade 3: good regression, (p ade 4: total regression. Tumors with Grades 3 or 4 ponse to CMT had significantly higher pretreatment lev- of apoptosis than tumors with lower regression (Grades 2). The pretreatment AI predicted the risk of 5-year local lure: 100% for AI greater than median vs. 74% for AI less n median (p � 0.08). Furthermore, AI predicted tumor ression. Tumors with Grades 3/4 response to CMT had nificantly higher pretreatment levels of apoptosis (mean : 2.06%) than tumors with Grades 0–2 response (AI: 4%, p � 0.003). A significant correlation was also found tween pathologic tumor response and relapse-free sur- al (Grade 3/4: 72% vs. Grade 0/1/2: 28%, p � 0.004). hen the analysis was limited to local control, the only treatment factor significantly correlated with this end int was AI. Moreover, AI significantly correlated with -67 but not with p-53 and bcl2 status. The authors con- ded that AI and tumor regression can be helpful in ecting preoperative therapy (30). In our experience, by univariate analysis, pretreatment rameters (age, circumference, length and distance from anorectal ring, pretreatment T and N stage, and INDpre) re associated with some but not all 5-year outcomes. sttreatment parameters (pT, pN, and TRG) affected all ear outcomes. By multivariate analysis, pooling all pre- d posttreatment parameters, only pN and TRG signifi- tly predicted disease-free survival. Furthermore, TRG nificantly predicted the presence of pN� disease. We have previously reported the impact of pathologic ging and of tumor index after treatment (INDpost) in 165 . 4. Disease-free survival according to TRG1–2 vs. TRG3–5 � 0.001). TRG � tumor regression grade. co tre pT (pT 0.0 12 sta ses an len 5-y rel log iso on pa the IN spe loc rec lim prospective trial. It must be emphasized that it is retrospec- patients with lack of pathologic material for re-review, and variables such as the impact of chemotherapy, radiation do pre rep for the fac sur wi log sel as ENC 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Fig 0.0 759TRG in rectal cancer ● F. M. VECCHIO et al. nsecutive patients with locally advanced rectal cancer, ated with preoperative 5-FU–based CMT (4). Increasing stage was a significant predictor for 5-year survival 0: 91%, pT2: 81%, pT3: 66%, and pT4: 47% [p � 14]), as well as local failure (pT0: 0%, pT1: 17%, pT2: %, pT3: 21%, and pT4: 54% [p � 0.0012]). The pN tus significantly predicted freedom from distant metasta- and overall survival. By univariate and multivariate REFER Rich TA, Skibber JM, Ajani JA, et al. Preoperative infusional chemoradiation therapy for stage T3 rectal cancer. Int J Radiat Oncol Biol Phys 1995;32:1025–1029. Chari RS, Tyler DS, Anscher MS, et al. 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Radiation Oncology ● Biology ● Physics Volume 62, Number 3, 2005 THE RELATIONSHIP OF PATHOLOGIC TUMOR REGRESSION GRADE (TRG) AND OUTCOMES AFTER PREOPERATIVE THERAPY IN RECTAL CANCER INTRODUCTION METHODS AND MATERIALS Eligibility criteria and diagnostic workup Treatment schedules Radiation therapy techniques Surgery Intraoperative radiation therapy Postoperative chemotherapy Follow-up Evaluation of response Tumor regression grade Statistical analysis RESULTS Patient characteristics (pretreatment) Response Surgical procedures Downstaging Patterns of failure and survival Outcome according to pretreatment prognostic factors Outcomes according to posttreatment prognostic factors Combined multivariate analysis of both pre- and posttreatment factors DISCUSSION CONCLUSION REFERENCES