Radiol Oncol 2021; 55(4): 439-448. doi: 10.2478/raon-2021-0028 439 research article Preoperative intensity-modulated chemoradiotherapy with simultaneous integrated boost in rectal cancer: five-year follow-up results of a phase II study Jasna But-Hadzic1,2, Anja Meden Boltezar1, Tina Skerl1, Vesna Zadnik2,3, Vaneja Velenik1,2 1 Institute of Oncology Ljubljana, Division of Radiotherapy, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Ljubljana, Slovenia Radiol Oncol 2021; 55(4): 439-448. Received 17 February 2021 Accepted 26 April 2021 Correspondence to: Assist. Prof. Jasna But-Hadžić, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia. E-mail: jbut@onko-i.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Background. We conducted a phase II study to investigate the feasibility and safety of preoperative radiochemo- therapy experimental fractionation, using intensity-modulated radiation therapy with simultaneous integrated boost (IMRT SIB) to shorten the overall treatment time without dose escalation in intermediate/locally advanced rectal cancer with the aim to improving treatment outcome. Patients and methods. A total of 51 patients with operable stage II–III rectal carcinoma were included between January 2014 and January 2015. Fifty patients completed preoperative IMRT treatment with an elective dose of 41.8 Gy and simultaneously delivered 46.2 Gy to T2/T3 and 48.4 Gy to T4 tumour in 22 fractions, with concomitant capecit- abine (825 mg/m2/12 h, including at weekends). Median follow-up was 70 months (range 11–80 m). Results. Forty-seven patients completed treatment per protocol. Acute toxicity occurred in 2 (4%) patients. R0 resec- tion was achieved in all but 1 and pathologic complete response (pCR) in 12 (25.5%) patients who had 5-year overall survival (OS), disease-free survival (DFS) and local control (LC) of 91.7%, 100% and 100%, respectively. The intention- to-treat analysis showed that the type of surgery significantly moderated OS and DFS, while total downstaging and pN were predictive for DFS only. For treatment per protocol 5-year OS, DFS and LC were 80.9% (95% confidence interval [CI] 69.7–92.1), 77.1% (95% CI 65.1–89.1) and 95.2% (95% CI 88.7–100), respectively. The proportion of patients with severe late (CTCAE G ≥ 3) gastrointestinal, urinary and sexual toxicity was 15%, 2% and 8% respectively, with one reported secondary carcinoma. Conclusions. Preoperative IMRT-SIB without dose escalation was well tolerated, with a low acute toxicity profile, we achieved a high rate of pCR and showed encouraging 5-year OS, DFS and LC. Key words: rectal cancer; IMRT; simultaneous integrated boost; preoperative radiochemotherapy; acute toxicity, pathologic complete response; overall survival; disease-free survival; local control; late toxicity; quality of life Introduction In recent years, many different treatment strategies have been tested to improve outcomes for patients with locally advanced rectal cancer, with toxicity being the main obstacle for intensification of the standard treatment.1-4 Changing the preoperative radiotherapy (RT) technique from 3D conformal (3D CRT) to intensity-modulated radiotherapy (IMRT) allowed better sparing of normal tissue in dosimetric analyses5-8 and was used in several phase II studies to achieve dose escalation with si- Radiol Oncol 2021; 55(4): 439-448. But-Hadzic J et al. / Preoperative intensity-modulated chemoradiotherapy of rectal cancer440 multaneous integrated boost (SIB) with or without another drug in addition to standard concomitant capecitabine.9-14 The published reports showed en- couraging results for pathologic complete response (pCR) and local control (LC)9,11, but with no impact on gastrointestinal toxicity with the addition of oxaliplatin15 and important late toxicity with dose escalation.10 Due to the promising impact on clinical out- come, but, conflicting toxicity results of treatment intensification with IMRT-SIB dose escalation in preoperative locally advanced rectal cancer (LARC) treatment, we conducted a prospective phase II study, where we kept the biologically ef- fective dose (BED) of experimental IMRT SIB frac- tionation similar to the standard 3D CRT protocol of 45 Gy elective dose and boost of 4.5 Gy to T3 and 9 Gy to T4 tumour. Our previously published results have shown that radiochemotherapy with IMRT-SIB without dose escalation, concomitantly with capecitabine, achieved a high rate of pCR (25.5%) and downstag- ing rate, with favourable acute toxicity profile and excellent compliance.16 In this paper, we report LC, disease-free survival (DFS), overall survival (OS), late toxicity and quality of life (QoL) after median follow-up of 70 months. Patients and methods Study design and inclusion criteria Details about the trial (the eligibility criteria, treat- ment details and trial design) are available else- where.16,17 In short, to enter the study patients had to present with operable, histologically proven, in- termediate/locally advanced (cT ≥ 3 and/or cN ≥ 1 on MRI), non-metastatic (M0 confirmed on CT tho- rax and abdomen) rectal adenocarcinoma, located up to 15 cm from the anal verge with no contrain- dications for systemic therapy. Written consent was signed before entering the trial, which was ap- proved by the National Medical Ethics Committee of the Republic of Slovenia (No. 41/12/13) and com- plied with the Declaration of Helsinki. The study was registered in the ClinicalTrials.gov database (NCT02268006). Treatment protocol The target volumes and dose prescription were described in detail.16 Visible primary tumour was contoured as the gross tumour volume (GTV) and was extended with a 1 cm margin to represent a boost volume (clinical target volume 2 – CTV2). Clinical target volume 1 (CTV1) encompassed CTV2, mesorectum, and regional lymph nodes. The nodes along the arteria illiaca externa were in- cluded in case of substantial genitourinary struc- ture infiltration, and the ischiorectal fossa and anal canal if the musculus levator ani or anal canal were involved. CTV 1 was extended anteriorly due to bowel movement as internal target volume (ITV). ITV + 1cm (7 mm posterior/lateral) represented the planning target volume (PTV). PTV 1 received 41.8 Gy in 22 fractions and SIB was prescribed to tumour (PTV 2) concomitantly to doses of 46.2 Gy and 48.4 Gy to T ≤ 3 and T4 tumours in 22 frac- tions, respectively, 5 times per week (Monday to Friday). Concomitant capecitabine was prescribed from the first to the last day of the radiation treat- ment (including at weekends) at a daily dose of 825 mg/m2/12 h. The treatment was delivered on Clinac 2100 CDI (Varian, Palo Alto, USA) using the dynamic multileaf collimator technique with 6MV photons and a daily position verification (ExacTrac X-ray 6D system, BrainLAB AG, Feldkirchen, Germany). After total mesorectal excision (TME), that was scheduled 6–8 weeks after preoperative treatment, six cycles of adjuvant chemotherapy with capecit- abine were offered to patients with residual tu- mour on pathologic examination. Pathologic stage and tumour regression grade (TRG) were recorded according to the American Joint Committee on Cancer (AJCC) 7th edition18 and criteria by Dworak et al.19, respectively. All patients were followed up with clinical and serum CEA evaluation every 3 months for two years, and later on a bi-annual basis with abdomi- nal ultrasound every 6 months and a chest radio- graph annually. Statistics This prospective phase II study in patients with intermediate/locally advanced rectal cancer was designed to evaluate the pathologic complete re- sponse after experimental preoperative treatment as a primary endpoint. The key secondary end- points were to evaluate the acute toxicity of pre- operative treatment, tumour response, local con- trol (LC), disease-free survival (DFS) and overall survival (OS). In this report, we focus on survival, late toxicity and quality of life (QoL) after a 5-year follow-up. A statistical analysis was performed with the Statistical Package for Social Sciences, v. 25.0 (SPSS Radiol Oncol 2021; 55(4): 439-448. But-Hadzic J et al. / Preoperative intensity-modulated chemoradiotherapy of rectal cancer 441 Inc., Chicago, IL, USA). Descriptive statistics were used to present frequencies. Survival was calculat- ed with the Kaplan-Meier method and the influence of possible prognostic factors verified by means of the log-rank test. Time intervals were defined from the end of treatment (operation or radiotherapy completion for non-operated patients) until the last follow-up or death for OS and additionally until lo- cal or distant recurrence for DFS. For the intention- to-treat analysis (all patients), LC and DFS were counted as 0m for non-operated patients and DFS as 0m for M1 patients. Patients surgically treated after chemoradiotherapy completion (N = 47) en- tered treatment per protocol analysis. Late adverse events data were available in the medical records for all patients and telephone inter- views were additionally performed in November 2020, discussing patients’ late adverse effects and quality of life, following the Common Terminology Criteria for Adverse Events (CTCAE) v 5.0.20 QoL was recorded with the EORTC cancer-spe- cific core questionnaire QLQ-C3021 and colorectal- specific questionnaire QLQ-C2922, that were collect- ed before treatment (T0), and 1 year (T1) and 5 years (T5) after treatment. Data from all questionnaires were available for 31 patients for which the recorded answers were transformed into dimensions in the range 1– 100.23 Higher scores represented a higher level of functioning (for functional scales and single items) and lower scores displayed a lower symp- tom level (for symptom scales and single items). Statistical significance for QLQ scores changes over time was verified by comparing means with the Wilcoxon signed-rank test and with the t-test for EORTC reference value comparison. A p- value < 0.05 was considered statistically significant. Results Between January 2014 and January 2015, 51 (N = 51) patients were included. The patients’ character- istics are described in detail elsewhere16, but brief- ly – median age was 66 years (range: 33–81 years) and nearly half of the tumours were located in the lower third of the rectum. The tumour invaded the mesorectal fascia in 20 patients and 15 patients had suspicious extramesorectal lymph nodes on MRI. Clinical stages were: T2N1M0 (n = 1), T3N0M0 (n = 6), T3N1M0 (n = 15), T3N2M0 (n = 22), T4N1M0 (n = 4), T4N2M0 (n = 2), and T3N1M118, with small lung lesion prior to inclusion revealed as lung me- tastasis on control CT after the treatment in the last patient. Preoperative radiochemotherapy was com- pleted by 50 patients and 1 received preoperative short-course radiotherapy due to ischaemic stroke. Altogether, 48 patients underwent surgery (47 treated per protocol). In 3 patients, surgery was omitted due to patient refusal, synchronous pan- creatic cancer and rectal varices haemorrhage. Low anterior resection (LAR) was performed in 40 pa- tients, abdominoperineal resection (APE) in 7, and pelvic exenteration in 1. One patient had a positive circumferential margin. Extramesorectal nodes ex- ploration was based upon surgeon discretion and nodes were removed in 4 patients. The total downstaging rate was 87% (41/47 pa- tients), with a decrease in T and N stage observed in 32 and 39 patients, respectively. Pathologic com- plete response was achieved in 12 patients. In median follow-up of 70 months (range 11–80 m) we recorded 13 deaths, 7 due to rectal cancer. Among the 6 remaining patients, 3 died of cardio- vascular disease and one each of pancreatic cancer, alcohol hepatic cirrhosis and grade 5 (G5) ileus. One isolated local relapse and 1 with synchronous distant metastasis occurred 41 and 42 months af- ter LAR and APE, respectively. Time to distant re- lapses was 0 m and 18 m (lung), 6 and 11 m (liver), 41 m (adrenal gland) and 42 m (abdominal lymph nodes). At the latest date of follow-up on 30.1.2021, there were 37 patients alive without disease and one patient on systemic treatment for disseminated rectal cancer. Survival We performed an intention-to-treat analysis for all 51 patients and for 47 patients that were treated ac- cording to protocol (Table 1). For the entire cohort, cumulative 5-year OS, 5-year DFS and 5-year LC were 76.5% (95% CI 64.9–88.1), 72.4% (95% CI 60.4– 84.6), and 89.7% (95% CI 81.1–98.3), respectively. In the treatment per protocol group 5-year OS, 5-year DFS and 5-year LC were 80.9% (95% CI 69.7–92.1), 77.1% (95% CI 65.1–89.1) and 95.2% (95% CI 88.7– 100), respectively. Five-year colostomy-free surviv- al was 76% (29/38). The potential influence of prognostic factors on survival was determined by means of the log-rank test (Table 2). There was no association between age at diagnosis, performance status, tumour grade, positive mesorectal fascia or suspicious extrame- sorectal lymph nodes, removal of ekstramesorectal lymph nodes, clinical stage (cT, cN), decrease in T and N stage or pathologic T stage on survival. We found no predictive value for pCR, TRG prognostic Radiol Oncol 2021; 55(4): 439-448. But-Hadzic J et al. / Preoperative intensity-modulated chemoradiotherapy of rectal cancer442 group or NAR prognostic group as survival sur- rogates. Significantly better DFS was found in pa- tients where total downstaging was achieved and in patients with pathologically negative lymph nodes (Figure 1). There was significantly better OS and DFS with LAR compared with APE or pelvic exenteration (p = 0.000 and 0.013, respectively). Gender was a predictive prognostic factor for OS and treatment per protocol was associated with better OS and DFS. We recorded no local or distant relapses in the group of patients with pCR, with one death due to G5 adverse event, leading to 91.7% 5-year OS and 100% 5-year DFS and 5-year LC for this group of patients. Late toxicity Late toxicity data are available for all patients and are listed in Table 3. Patients reported mean 5 late adverse events (range 0–19) at last follow up. Major adverse events (CTCAE version 5.0 G ≥ 3)20 TABLE 1. Number of events after median follow-up of 70 months (11–80 m) and 5-year survival Intention to treat (N = 51) Per protocol (N = 47) 5-year OS* 76.5% 80.9% 5-year DFS 72.5% 76.5% 5-year LC 90.2% 95.7% Number of events (%) Number of events (%) OS status Alive 38 (74.5) 37 (78.7) * Dead 13 (25.5) 10 (21.3) DFS status Alive without disease 37 (72.5) 36 (76.5) Local/distant relapse/death 14 (27.5) 11 (23.5) LC status Local relapse - 46 (90.2) 45 (95.7) Local relapse + 5 (9.8) 2 (4.3) * = Numbers differ from OS status due to one noncancer death > 5-year after surgery; DFS = disease-free survival; LC = local control; OS = overall survival; for non-operated patients and patient with M+ disease local or distant recurrence was calculated as 0 months. FIGURE 1. Prognostic significance of (A) pathologic nodal stage (pN) and (B) total downstaging on 5-year disease-free survival, (C) prognostic significance of surgery procedure on 5-year disease-free survival and (D) overall survival in rectal cancer after preoperative radiochemotherapy and surgery. APE = abdominoperineal excision; LAR = low anterior resection A B C D Radiol Oncol 2021; 55(4): 439-448. But-Hadzic J et al. / Preoperative intensity-modulated chemoradiotherapy of rectal cancer 443 occurred in 12 patients (23%), of which 7 patients had one, 3 patients two and 1 patient had three G3 toxicities. Following protective stoma closure, 1 patient died due to G5 ileus complication 29 months after LAR. Gastrointestinal toxicity (GI) ≥ 3 was recorded in 7 (15%) and genitourinary (GU) in 5 (10%) patients. Two men have erectile dysfunc- tion and two women are reporting problems due to dyspareunia, vaginal dryness and vaginal stric- ture. Due to complete faecal incontinence, perma- nent stoma was required in two patients, 10 and 36 months after LAR. Urgent surgical intervention was required for anastomotic dehiscence and her- nia incarceration in one case where the patient later developed enterocutaneous fistula. In the remain- ing two patients with anastomotic dehiscence, protective stoma closure was omitted in one pa- tient and permanent stoma was placed 23 months after LAR in the other patient. Permanent stoma placement was also required due to rectoprostatic fistula in one patient 36m after LAR. Altogether, 6 patients with sphincter-preserving surgery had stoma closure omitted or later placed as perma- nent due to late toxicity (faecal incontinence, anas- tomotic dehiscence and fistula). The last recorded serious adverse event possibly related to treatment was recorded after 60m of follow up in a patient with bladder carcinoma (Figure 2). Quality of life evaluation (QoL) Of 38 eligible patients, 31 (81.6%) completed the EORTC QLQ-C30 and QLQ-C29 questionnaires before treatment (T0), 1 year (T1) and ≥ 5 years (T5) after treatment at median age 75 years (range 37–86 years). The global QoL mean scores have not significantly changed over time (mean T0 vs. T5 was 57.0 vs. 60.8; p = 0.384), but were significantly lower compared to the general Slovenian popula- tion (p = 0.035). Also, no significant differences in mean scores over time were observed for any of the core functional and physical scales (data shown in Supplement 1). Significant changes in CR29 scales occurred 1 year after treatment and remain signifi- cant > 5-year post treatment. There was a signifi- cant drop in reported blood and mucus (mean T0 vs. T1 vs. T5 was 33.9 vs.7.5 vs.4.3; T0/T1 and T0/T5 p < 0.000) and anxiety score (mean T0 vs. T1 vs. T5 was 67.7 vs. 39.3 vs. 42.2; T0/T1 p = 0.000 and T0/T5 p = 0.005), but higher scores were recorded for fae- cal incontinence/leakage, hair loss, and body im- age (T0/T1 p = 0.027, 0.046, and 0.007, respectively). There was no difference in mean scores for urinary incontinence between T0/T1, but mean scores rose TABLE 2. Influence of probable prognostic factors on OS and DFS Intention to treat (N = 51) Per protocol (N = 47) Prognostic factor OS DFS OS DFS Age at diagnosis (≥ 65 years vs. <65 years) ns ns ns ns Gender (male vs. female) p = 0.044 ns p = 0.064 ns PS WHO ns ns ns ns Tumour grade ns ns ns ns Tumour location (upper/ middle/lower rectal third) ns ns ns ns MRI + ns ns ns ns Extramesorectal lymph nodes (positive/negative) ns ns ns ns Time to treatment (≤ 7w / > 7w) p = 0.045 ns ns ns Surgery procedure (APE and pelvic exenteration/LAR) p = 0.000 p = 0.013 p = 0.020 p = 0.016 cT stagea ns ns ns ns cN stagea ns ns ns ns Decrease in T stage ns ns ns ns Decrease in N stage ns ns ns ns Total downstaging ns p = 0.029 ns p = 0.029 pT stage (0-2 vs. 3-4) ns ns ns ns pN stage (0 vs. +) ns p = 0.044 ns p = 0.019 Ekstramesorectal lymp node removal ns ns ns ns pCR ns ns ns ns TRG prognostic group ns ns ns ns NAR prognostic group ns ns ns ns Adjuvant chemotherapyb (5-6 / ≤ 4 cycles) ns ns ns ns Treatment per protocol p = 0.006 p = 0.001 / / a according to AJCC, 7th edition18; b calculated for 36 patients with indication for adjuvant chemotherapy; APE = abdominoperineal excision; DFS = disease free survival; LAR = low anterior resection; MRI+ = positive mesorectal fascia; N = nodal; NAR = neoadjuvant rectal cancer score32; ns = not specific (p > 0.05). OS = overall survival; pCR = pathologic complete response; PS WHO = WHO performance status; T = tumour; TRG = tumour regression grade19 FIGURE 2. Time to occurrence of G ≥ 3 adverse events. Radiol Oncol 2021; 55(4): 439-448. But-Hadzic J et al. / Preoperative intensity-modulated chemoradiotherapy of rectal cancer444 TABLE 3. Late toxicity after preoperative radiochemotherapy, surgery and adjuvant chemotherapy according to CTCAE version 5.020 G1, n (%) G2, n (%) G3, n (%) G4, n (%) G5, n (%) Anastomotic dehiscence - 1 (2.1) 3 (6.3) - - Anastomotic stenosis 4 (10.0) - - - - Ileus - - - - 1 (2.1) Hernia 4 (8.3) 1(2.1) 1(2.1) - - Abdominal or pelvic pain 11 (22.9) 3 (6.3) - - - Anal stenosis 5 (10.4) - - - - Fistula - 1 (2.1) 2 (4.2) - - Bloating 21 (43.8) 3 (6.3) - - - Constipation 10 (20.8) 4 (8.3) - - - Diarrhoea 9 (18.8) 5 (10.4) - - - Faecal incontinence 6 (15.4) 12 (30.8) 3 (7.7) - - Faecal urgency* 5 (13.2) 1(2.6) - - - Flatulence 25 (52.1) 6 (12.5) - - - Haemorrhoidal haemorrhage 1 (2.1) - - - - Haemorrhoids 3 (6.3) - - - - Proctitis 1 (2.1) - - - - Intestinal stoma leak 2 (8.3) - - - - Dysuria 1 (2.1) - - - - Urinary frequency 13 (27.1) - - - - Urinary incontinence 9 (18.8) 4 (8.3) 1 (2.1) - - Urinary retention 1 (2.1) 1 (2.1) - - - Urinary urgency 21 (43.8) 1 (2.1) - - - Ejaculation disorder (n = 20) 5 (25) 1 (5) - - - Erectile disfunction (n=20) 2 (10.0) 6 (30.0) 2 (10.0) - - Dyspareunia (n=18) 1 (5.6) 2 (11.1) 1 (5.6) - - Vaginal dryness (n = 18) 1 (5.6) 3 (16.7) 1 (5.6) - - Vaginal stricture (n = 18) 1 (5.6) 1 (5.6) 1 (5.6) - - Treatment-related secondary malignancy - - 1 (2.0) - - Other** - - - - - * = data not available for all patients; ** = other: anal pain, anal, rectal or colonic haemorrhage, anal necrosis, anal or rectal fissure, anal ulcer, rectal obstruction or stenosis CTCAE = Common Terminology Criteria for Adverse Events version 5.0.; G = grade from 7.5 pre-treatment to 21.5 with > 5-year follow up (p = 0.008). T1 and T5 comparison showed a small but significant deterioration of pain, fatigue and nausea (p = 0.09, 0.017 and 0.033, respectively) after treatment with longer follow-up. According to QLQ-C30, our patient cohort had significantly lower QoL in comparison to the gen- eral Slovenian population (Table 4). Nearly all functional scales’ mean scores were lower with the exception of emotional function. Patients re- ported more fatigue, constipation, diarrhoea and financial problems. Compared to EORTC refer- ence values for colorectal (CRC) cancer patients, our cohort had borderline significant lower cog- nitive functioning and reported higher financial problems. Radiol Oncol 2021; 55(4): 439-448. But-Hadzic J et al. / Preoperative intensity-modulated chemoradiotherapy of rectal cancer 445 Discussion Preoperative use of IMRT for LARC is increasing rapidly with great variations in clinical practice among centres24 indicating a lack of quality clinical studies reporting treatment outcome and toxicity for different fractionation regimes. To date, only four prospective phase II studies have been pub- lished with short-term outcome data after preop- erative IMRT concomitant with capecitabine in pa- tients with LARC9,16,25,26, but none of them reported long-term results. Our study is the first to report a 5-year treatment outcome with late toxicity and QoL. With shorter treatment time and no dose esca- lation with SIB to primary tumour only, our pCR rate improved from 10% to 25.5%.16,27 With dose es- calation in a Chinese study (41 Gy elective; 56 Gy tumour/lymph node; 22 fractions) and a Spanish study (46 Gy elective; 57.5 Gy tumour/lymph nodes; 23 fraction) they reported 31% and 30.6% pCR, respectively.9,11 The higher pCR rate can re- flect higher BED in these trials, but pCR of 32.6% recently reported by Simson et. al. in a prospec- tive observational study with single target dose of 50.4 Gy in 28 fractions suggests other possible factors influencing treatment results, since there are important differences in target definition and treatment verification between studies.28 With no boost to pathologic lymph nodes, but with detailed contouring guidelines, added internal safety mar- gin and image-guided radiation therapy (IGRT), we have achieved an equal or better N downstag- ing rate (83%) in comparison to the Chinese and Spanish trials (79.2% and 47.2%, respectively) where a 5 mm uniform margin was used. The encouraging total downstaging rate of 87% in our study translated into excellent 5-year OS, DFS and LC of 80.9%, 77.1% and 95.2%, respective- ly. OS and DFS were significantly higher compared to our historic cohort29 (OS 61.4%, p = 0.03 and DFS 52.4%, p = 0.01). Studies with more intensified es- calated IMRT regimes with added concurrent ox- aliplatin12,30, are reporting 5-year OS of 63–82% and 5-year DFS of 60–66%, that are comparable to our study. A reported death from cardiovascular disease in three male patients can probably explain why TABLE 4. Health-related quality of life analysis: Mean scores comparisons 5 years after treatment with general Slovenian population38 and with EORTC reference values for colorectal cancer patients39 for all scales of EORTC QLQ-C30 Scale 5-year post-surgery mean (SD) General Slovenian population mean (SD) p value* Colorectal reference values mean (SD) p value* Global health status/QoL 60.8 (26.1) 71.1 (21.4) 0.035 62.1 (23.4) 0.759 Functional scales Physical function 78.9 (24.5) 91.8 (14.0) 0.006 83.0 (21.1) 0.285 Role function 77.4 (26.0) 88.7 (20.1) 0.022 70.4 (32.8) 0.238 Emotional function 74.7 (25.0) 82.0 (18.5) 0.115 68.9 (24.5) 0.192 Cognitive function 78.0 (24.5) 90.2 (16.0) 0.009 85.2 (20.4) 0.052 Social function 78.5 (24.8) 90.9 (17.3) 0.009 76.0 (28.6) 0.629 Symptom scales Fatigue 29.4 (23.2) 19.8 (19.8) 0.029 34.7 (28.4) 0.302 Nausea/vomiting 6.5 (10.3) 3.3 (10.6) 0.097 7.3 (17.2) 0.796 Pain 21.0 (23.2) 14.5 (20.2) 0.130 24.0 (29.6) 0.575 Dyspnoea 10.8 (23.4) 5.3 (15.3) 0.204 17.4 (26.3) 0.160 Insomnia 30.1 (30.3) 19.8 (25.1) 0.067 30.5 (32.6) 0.946 Appetite loss 12.9 (22.2) 5.3 (15.5) 0.067 19.1 (30.2) 0.256 Constipation 20.4 (26.8) 6.9 (16.9) 0.009 15.8 (27.9) 0.363 Diarrhoea 16.1 (22.6) 4.2 (13.6) 0.006 16.6 (27.6) 0.920 Financial problems 22.6 (29.0) 6.6 (17.5) 0.005 13.6 (26.3) 0.059 * = values (p < 0.050) are bolded Radiol Oncol 2021; 55(4): 439-448. But-Hadzic J et al. / Preoperative intensity-modulated chemoradiotherapy of rectal cancer446 male gender is significant prognostic factor for OS but not for DFS. Surprisingly, the type of op- eration significantly affected OS and DFS. In con- cordance with other studies, we found significant association between total downstaging and pN0 with the improvement of DFS31, but we found no predictive value for pCR, TRG prognostic group19 or NAR prognostic group32 as survival surrogates. However, we found excellent prognosis for the group of patients with pCR who had 91.7% 5-year OS and 100% 5-year DFS and 100% 5-year LC, con- firming observations from other studies.33 Previously, we reported low acute toxicity of preoperative treatment and postoperative compli- cations (G ≥ 3 of 4% and 8% respectively). All pa- tients with LAR had protective stoma placement, so we recorded no anastomotic leakage, but with time, 4 (8%) cases of anastomotic dehiscence were detected, as expected from the published litera- ture.34 In median follow-up of 70 months, we re- corded 17 G ≥ 3 late adverse events in 12 patients (25% of patients who underwent surgery), with 15% of GI, 2% urinary and 8% sexual late toxicity, significantly lower than to our historic cohort (40%, 19.2% and 51.7%, respectively)29 and less than 35% reported late surgical complications after 3D CRT concomitant with 5-Fu/oxaliplatin.35 The only com- parable IMRT study reporting late adverse events is a Belgian study, with preoperative IMRT-SIB to 46/55.2 Gy in 23 fractions and median 54 months of follow-up.10 Their estimated G ≥ 3 late toxic- ity was 13% and is lower than the 25% observed in our study with much lower GI and GU toxic- ity rates (9% vs. 15% and 4% vs. 10%, respectively) compared to ours. With different recording of late effects in our study, the late toxicity could have been overestimated. Anastomotic dehiscence was discovered late, when protective stoma closure was planned and was not counted as a postoperative complication. Late events were recorded with the actuarial method, so faecal incontinence, although not present at the time of the last follow-up, oc- curred previously in two patients. Also, we had no data on sexual activity and GI disorder prior to treatment, so all GI events are counted as late se- quelae, although no difference in sexual function- ing before and 5 years after treatment was found on QoL analysis. Exclusion of anastomotic dehis- cence and two cases of faecal incontinence decreas- es our rate of GI G ≥ 3 toxicity to 8%, which is in concordance with 9% in the Belgian study and 9% reported after 3D CRT.34 The occurrence of G ≥ 2 late diarrhoea (10%) is also within the range of re- ported rates in the literature, with 9.5% of patients from the EORTC 22921 trial who reported grade 2 diarrhoea or higher after 5-year follow-up.34 The Spanish and Chinese investigators reported 2 and 4 fistulas in median follow-up at 17 m and 22 m. The occurrence of fistula in our study is similar, with 3 fistulas that occurred 29, 34 and 36 months after surgery, showing the importance of longer follow- up and subsequently underreporting of long toxic- ity events in clinical studies. Since the first publica- tion with a reported sphincter preservation rate of 62% in our series, 6 patients with LAR ended up with permanent stoma due to faecal incontinence, anastomotic dehiscence and fistula, but still, we re- port a high rate of 5 y colostomy-free survival of 76%, comparable to other studies.35 Regarding ma- jor toxicity, 1 patient (2%) died due to treatment-re- lated toxicity, consistent with a 1.4% and 2% death rate in the EORTC 22921 and German CAO/ARO/ AIO-94 trial, respectively.34,36 Our patient cohort have significantly lower quality of life compared to the general Slovenian population37 according to EORTC QLQ-C30 scores comparison, with inferior global function and functional mean scales with problems with fatigue, constipation, diarrhoea and finance. However, comparison to EORTC reference scores38 for CRC patients shows no difference in any of the QLQ-C30 items with borderline lower cognitive function, re- flecting advanced patient age (median 75 years) at 5-year data collection. Time analysis of EORTC QLQ-C30 and QLQ-C29 median scores showed that improvement or deterioration of function/ symptom appeared one year after treatment and remained stable with longer follow-up. We record- ed improvement in body image and a drop of anxi- ety and as expected after surgery, there was less mucus/blood in stool, and after radiation patients reported hair loss. A significant rise in reported faecal incontinence/leakage, is in concordance with the reported late toxicity but late detection of urinary incontinence (significant after 5 but not 1 year) indicates the importance of long follow-up for reliable reporting of late toxicity. Contrary to 8% sexual late toxicity findings, there were no dif- ferences in sexual end points in the QoL analysis, reflecting the possibility of overestimation of these late events in our cohort. Together with uncertainty in the reporting of late toxicity, the main limitation of our study design is the small sample size and lack of randomization. According to definition of “locally advanced rectal cancers” before new subgroup division consensus in 2013, we used the term locally advanced also for the intermediate/bad group, without additional Radiol Oncol 2021; 55(4): 439-448. But-Hadzic J et al. / Preoperative intensity-modulated chemoradiotherapy of rectal cancer 447 subdivision of T3 tumours. Nevertheless, our re- sults are comparable to above mentioned studies, for they used the same definition in that time. The advantages of our study are the very strict radio- therapy protocol and quality control with the pre- cise recording of acute and late toxicity events. In comparison to other IMRT studies for preoperative LARC, we were the only one not to intensify treat- ment with dose escalation and/or novel drug ad- dition. By shortening the overall treatment time us- ing SIB, we reported excellent 25.5% pCR and af- ter 5-year follow-up, our OS and DFS (80.9% and 77.1%, respectively) are in the survival range of more intensified treatments12,30, suggesting possi- ble overtreatment for certain patients with LARC. In the era of high local control, more effort should be directed to reducing acute and late toxicity. Our fractionation regime showed a very low acute tox- icity profile with a non-negligible late events rate. More high-quality data with longer follow-up is needed to determine the true effect on QoL and possibly determine relevant tolerances of the organ at risk for late consequences to optimize treatment planning. Conclusions The results of this long-term study confirm that IMRT SIB is feasible for preoperative treatment of intermediate/locally advanced rectal cancer. By shortening the overall treatment time, without dose escalation, we achieved high pCR, five-year overall survival, disease-free survival and local control. Due to the favourable acute toxicity pro- file, our treatment regime is suitable for treatment intensification with another drug in addition to capecitabine. More long-term data is needed for late toxicity assessment. References 1. Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Lafay I, Hennequin C, Etienne PL, et al. Clinical outcome of the ACCORD 12/0405 PRODIGE 2 ran- domized trial in rectal cancer. J Clin Oncol 2012; 30: 4558-65. doi: 10.1200/ JCO.2012.42.8771 2. Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, et al. 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