Quality of Life in a Randomized Trial Comparing Two Neoadjuvant Regimens for Locally Advanced Rectal Cancer – INCAGI004.

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Rodrigo Otavio de Castro Araujo, Fernando Meton Vieira, Ana Paula Victorino Ornellas, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-121936/v2 This work is licensed under a CC BY 4.0 License Status: Under Review Version 2 posted 4 You are reading this latest preprint version Show more versions Abstract Background: Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the standard of care for locally advanced rectal cancer (LARC), but the emergence of different drug regimens may result in different response rates. Good clinical response translates into greater sphincter preservation, but quality of life (QOL) may be impaired after treatment due to chemoradiotherapy and surgical side effects. Objective: To prospectively evaluate the QOL in a randomized trial comparing two neoadjuvant regimens for locally advanced rectal cancer. Methods: Stage II and III rectal cancer patients were randomized to receive neoCRT with either capecitabine (Group 1) or 5-Fu and leucovorin (Group 2) concomitant to long course radiotherapy. Clinical downstaging was accessed using MRI 6-8 weeks after treatment. EORTCs QLQ C30 and CR38 were applied before treatment (T0), after neoCRT (T1), after rectal resection (T2), early after adjuvant chemotherapy (T3), and one year after end of treatment or stoma closure (T4). Wexner scale was used for continence evaluation at T4. A C30SummaryScore (Geisinger et cols) was calculated to compare QOL results. Results: 32 patients were assigned to Group 1 and 31 to Group 2. Clinical downstaging occurred in 70.0% of Group 1 and 53.3% of Group 2 (p=0.288). pCR was 23.3% in group 1 and 10.0% in Group 2(p=0.165). Sphincter preservation was 83.3% in Group 1 and 80.0% in Group 2(p=0.111). No difference in QOL was detected comparing the two treatment groups before and after neoCRT. C30SummaryScore detected improvement comparing T0 to T1 and deterioration comparing T1 to T2 (p=0.025), and global health status improved at T1 and T4 compared to T0(p=0.004). Mean Wexner scale score was 9.2, and a high score correlated with symptoms of diarrhea and defecation problems at T4. Conclusions: Clinical and pathological response rates were equivalent in both treatment groups. QOL was improved after neoCRT corresponding to clinical response but decreased following rectal resection. Wexner score was high after sphincter preservation. C30SummaryScore was a useful tool to detect differences in overall QOL in EORTCs multiple item questionnaire. Trial registration: NCT03428529. Registered 02/09/2018 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03428529. Cancer Biology Oncology Rectal Cancer Quality of Life Neoadjuvant Treatment Radiotherapy Chemotherapy Surgical Oncology Figures Figure 1 Figure 2 Figure 3 Background Colorectal cancer is the third most common malignant neoplasia worldwide (1.4 million new cases/year)( 1 ). In Brazil is the third most frequent cancer in men and second in woman( 2 ). Locally advanced rectal cancer (LARC) is the denomination for tumors centered below the peritoneal reflection, usually <10-12 cm from the anal verge (AV), and that have extended beyond the muscularis propria or the rectum (AJCC clinical stage II and III)( 3 ). Neoadjuvant chemo radiotherapy (neoCRT) using 5-fluorouracil and leucovorin (5-Fu/Lv) followed by total mesorectal excision (TME) is considered the standard of care for locally advanced rectal cancer (LARC) resulting in >70% 5-year survival( 4 , 5 ). Capecitabine is an oral substitute to 5-Fu that has been tested in neoadjuvant phase 2 trials that demonstrated superiority in clinical and pathological response rates ( 6 , 7 ) and phase 3 trials showing comparable efficacy( 5 , 8 , 9 ). It has the potential advantages of synergism with radiation due to thymidine phosphorylase upregulation( 10 ), increased concentration in colorectal tumor tissue ( 11 )and the convenience of oral administration( 12 ). The adoption of total mesorectal excision (TME)( 13 )combined to the neoadjuvant treatment has resulted in excellent local control, with local recurrences occurring in 3-6% of patients ( 5 , 14 ). Therefore, abdominoperineal resection or Miles’s operation ( 15 ) has been avoided progressively in favor of sphincter preserving procedures as low anterior resection and intersphincteric resection( 16 ) when sufficient distal and circumferential negative margins are secured. Besides advances in local control and sphincter preservation for LARC, quality of life (QOL) becomes a great problem after treatment due to temporary or permanent stoma creation ( 17 ), sexual and urinary dysfunction( 18 ) and a myriad of defecation disfunctions now classified as low anterior resection syndrome (LARS)( 19 ). The European Organization for Research and Treatment on Cancer (EORTC) has published in 1993 a questionnaire with 30 questions, the QLQ C30( 20 ), and has been extensively used to measure patient reported outcomes in oncology for all cancer types. It displays the QOL results in 15 domains divided in five functional scales, nine symptom scales and one global QOL scale. In rectal cancer it is usually applied with the addition of specific colorectal modules ( 21 )( 22 ). Nonetheless, QOL analysis using the multi-item scales may lead to conflicting conclusions because some symptoms may ameliorate after treatment whilst other may get worse. For example, some studies favor sphincter preservation ( 23 ) while others suggest equivalent or worse results comparing patients with low rectal anastomosis to definitive stoma ( 24 ). A summary measure to aggregate the multi-dimensional QoL profile and to detect changes in overall QOL over time is particularly important in clinical trials, which are designed to pre-specified endpoints. The original two-item global QOL scale may not be comprehensive enough to detect changes between patient groups and/or changes over time. It has been shown that Global QOL scale could not detect deteriorating QOL in patients with progressive and terminal disease ( 25 ). In this scenario a group of authors recently proposed a higher order summary score that performed well in an empirical model fit ( 26 ). It was calculated by the mean of all C30 scales except for financial problems scale and global QOL scale. This so denominated C30SumScore has been tested in a non-small cell Lung cancer study including 326 patients three months after lung resection and demonstrated better sensitivity to detect postoperative changes compared to the global QOL score( 27 ). In addition, the C30SumScore was demonstrated to perform better than the global QOL scale and the physical functioning scale in predicting all-cause mortality in colon and rectal cancer patients( 28 ). In the present study we performed a QOL evaluation in LARC patients using EORTC’s QOL questionnaires and the new summary score to detect differences associated to the clinical response and to the surgical therapy in a randomized prospective trial comparing two different neoCRT regimens in a Brazilian cancer reference hospital. Objective To prospectively evaluate the impact of clinical response and surgical resection on QOL in a randomized trial comparing two different neoCRT regimens. Methods Study Design This was a longitudinal prospective study approved by Ethics Committee of National Cancer Institute of Brazil (INCA) in 2010 under register number 83/10 (NCT03428529). Patients were randomized to receive neoCRT using either capecitabine or bolus 5-Fu/Lv concomitant to 50,4 Gy radiation on the rectum and adjacent lymph nodes. Figure 1 illustrates the study design. Clinical downstaging was the study primary endpoint and was defined as stage regression 6-8 weeks after neoCRT, using AJCC 7th edition( 29 ). Eligibility criteria A ll eligible consecutive patients from 18 to 80 years with ECOG performance status 0-1 admitted in this single tertiary cancer hospital with rectal adenocarcinoma stage II and III that voluntarily agreed to participate were selected for inclusion. Distance from anal verge (AV) should not exceed 10 cm measured with rigid proctoscopy. Patients were staged before neoCRT and re-staged 6-8 weeks after it with thorax and abdominal computer tomography (CT), endorectal ultrasonography (EUS) and pelvic Magnetic Resonance Imaging (MRI). Patients were excluded if distant metastasis were found on pre-treatment staging, in case of serious comorbidities, pregnancy, or previous oncological treatment. Neoadjuvant treatment Eligible patients were randomized to receive one of the following regimens: oral capecitabine 1650mg/m 2 in two daily divided doses from Monday to Friday for five weeks (Group 1) intravenous bolus 5-Fu (350mg/m 2 ) plus Leucovorin (20 mg/m 2 ) days 1 to 5 and 29 to 33 (Group 2). Both schemes were concomitant to external bean three-dimension radiotherapy (50.4 Gy in 28 fractions). Surgical Treatment Surgical resection consisted of low anterior resection (LAR), intersphincteric resection (ISR) or abdominoperineal resection (APR), according to sphincter invasion using MRI classification of sphincter invasion after neoCRT( 16 ) and it was planned 6-8 weeks after neoCRT completion. Patients without sphincter complex invasion were submitted to LAR; patients with internal sphincter invasion were candidates to ISR if >1mm was predicted; and APR was reserved for patients with external sphincter invasion or intersphincteric plane invasion after neoCRT. Diverting stomas were performed after low colorectal or coloanal anastomosis, and stoma closure was undertaken after the adjuvant chemotherapy completion. Adjuvant treatment Adjuvant chemotherapy was defined by pathological response. Patients with ypT0-2/N0 tumors received bolus 5-Fu 370mg/m 2 and Leucovorin 50mg/m 2 weekly for 30 consecutive weeks. Patients with ypT3-4 and/or ypN1 tumors received Oxaliplatin 85 mg/m 2 on days 1, 15 and 29 of each cycle, and bolus 5-Fu 500 mg/m 2 plus Leucovorin 20 mg/m 2 on days 1, 8, 15, 22, 29 and 36 of each cycle. Each cycle consisted of 6 weeks of chemotherapy followed by 2 weeks of rest, totaling 3 cycles, for a total of 24 weeks. Dose reduction, delay and discontinuation of treatment have followed the Common Terminology for Adverse Events (CTCAE) version 3.0 guideline. Follow-up Patients were followed by medical consultations every three months in the first two years and every six months in the three subsequent years until the completion of five years of follow-up, disease progression or death. CT scans and rectal endoscopy were performed every 6 months for detecting recurrences. Quality of Life Evaluation EORTC QLQ C30( 20 ) and CR38( 21 ) were applied at five different treatment moments: before neoCRT (T0), 6-8 weeks after neoCRT (T1), 30 days after surgery (T2), after adjuvant chemotherapy (T3), and one year after the end of the treatment or stoma closure (T4) (Figure 2). QLQ-C30 grouped in nine multiple item scales and six single item scales and has been tested and validated in the Brazilian population ( 30 ). The multiple item scales comprise five functional scales (physical, cognitive, emotional, social, and role functioning), and three symptom scales (fatigue, pain, and nausea/vomiting), a global health status/ quality of life scale and six single item scales (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All the scales and single-item measures range in score from 0 to 100. A high score for a functional scale and global health status represents a high / healthy level of functioning, but a high score for a symptom scale / item represents a high level of symptomatology /problems. CR38 is a module complementary to C30, comprising 38 questions related to common symptoms and adverse effects of treatment related to colorectal cancer and has been validated for Brazilian patients ( 31 ). C30SumScore was calculated as a mean of all the functional and symptom scores excepting Global Health Status and Financial Problems as recommended by the authors, compiling the mean scores of a total of 13 domains. To calculate C30SumScore, the eight symptom scales scores were inverted, a high score meaning few symptoms and better outcomes. Wexner score ( 32 ), that has been validated for Portuguese( 33 ) comprises 5 questions for fecal incontinence, producing a score from 0 to 20 and it was accessed at T4. Sample size calculation and randomization The study was primarily designed to compare clinical downstaging between the two treatment groups. Assuming 90% of downstaging with capecitabine and 70% with bolus 5-Fu/Lv, the estimated sample size was 48 patients in each arm (alpha: 0.05; beta: 80%). Time for accrual was stipulated in 24 months. Randomization was performed in a proportion 1:1 using R software (R Development Core Team , 2008) with permuted blocks stratified by tumor distance from AV: >5 cm or ≤5 cm. Statistical analysis All statistical analysis was performed using SPSS version 21.0 (SPSS Inc., California, USA). Continuous variables were displayed as means ± Standard Deviation (SD) or median with range (minimum and maximum) according to data distribution. Chi-square tests or Fisher exact tests were used to compare categorical variables, Student’s T test to compare means of parametrical variables and the Mann-Whitney U test to compare values of non-parametric data. To compare mean QOL scores between treatment arms the ANCOVA covariance test adjusted for basal clinical data (age, sex, tumor localization and clinical stage) was used. For comparing longitudinal QOL results ANOVA test with Greenhouse-Geisser correction for lack of sphericity was employed. Mean differences of QOL were considered clinically significant if a minimum discrepancy of 10 points was found. Results 63 patients were randomized between January 2011 and February 2013. All patients completed neoCRT with no severe toxicities except form one patient with Grade 3 diarrhea and abdominal cramps. One patient refused surgery after a complete clinical response. Two patients quitted the study during follow-up. Clinical information was available for 61 patients. 31 patients were assigned to neoadjuvant capecitabine (Group 1) and 30 to 5-Fu/Lv (Group 2). Baseline characteristics and treatment results are depicted in Table 1 . Groups were similar at baseline, and clinical response (downstaging, sphincter preservation and Mandard tumor regression grade) was comparable after neoCRT (Table 1 ). QOL data from 61 patients were available at T0, 60 at T1, 57 at T2, 51 at T3 and 37 at T4. Reasons for no completion of questionnaires at a given moment were death (n=14), disease progression (n=6), no adherence to follow-up (n=3), and desire to quit the study (n=2). Supplementary Table 1 shows the number of patients available for each scale in 5 moments. Figure 3 illustrate the study flow chart. Supplementary Table 2 reports the mean C30 and CR38 scores in all domains including the C30SumScore. Table 1 Clinical, surgical, and pathological data of patients in both groups of treatment. Patients Characteristics Total N=61 Group 1(Cap) N=31 Group 2(5-Fu) N=30 p-value Gender Male Female 33 (54.1) 28 (45.9) 16 (51.6) 15 (48.4) 17 (56.7) 13 (43.3) 0.692* Ethnicity White Black Mixed 47 (77.0) 6 (9.8) 8 (13.1) 22 (71.0) 3 (9.7) 6 (19.4) 25 (83.3) 3 (10.0) 2 (6.7) 0.337* Age (mean, SD) 58.5 (11.4) 56.6 (13.4) 60.5 (8.6) 0.182 # BMI (mean, SD) 26.8 (4.6) 25.8 (4.3) 27.7 (4.7) 0.102 # Tumor ≤ 50 mm AV 30 (49.2) 14 (41.1) 16 (53.3) 0.523* Tumor ≤ 10 mm DL 14 (22.9) 4 (12.9) 10 (33.3) 0.111* Tumor obstructive 17 (27.8) 9 (29.0) 8 (26.6) 0.845* Cm from AV (mean) 4.3 (2.7) 4.9 (2.8) 3.7 (2.4) 0.141 # Sphincter invasion (MRI) 13 (21.3) 6 (19.3) 7 (23.3) 0.747* Basal Clinical Stage (MRI) I II III 3 23 35 3 13 15 0 10 20 0.129* Sphincter preservation 49 (81.6) 25 (83.3) 24 (80.0) 0.111* Sphincter preservation (tumors ≤5cm from AV) 20(66.6) 9(64.2) 11(68.7) 0.550* Clinical Downstaging 37 (61.7) 21 (70.0) 16 (53.3) 0.288* pCR 10 (16.6) 7 (23.3) 3 (10.0) 0.165* Mandard 1-2 21 (35.0) 13 (43,3) 8 (26.6) 0.175* CRM + 9(15.0) 6(20.0) 3(10.0) 0.472* Cap: capecitabine; 5-Fu: 5-Fluorouracil; SD: Standard deviation; BMI: Body mass Index; AV: anal verge; DL: dentate line; MRI: Magnetic Resonance Imaging; pCR: pathologic complete response; CRM +: circumferential resection margin <1mm. * Qui-square test # Student´s t-test. Table 2 shows comparison of QOL scores and the C30SumScore between Group 1 and Group 2 using covariate adjustment for age, gender, clinical stage, and tumor localization before (T0) and after neoadjuvant treatment (T1). At T0, Group 1 patients reported more insomnia (12.3 pts mean difference) but reported less weight loss (-12.1 pts mean difference). After neoadjuvant treatment, no difference in QOL between patients receiving capecitabine or 5-Fu/Lv was shown in any score of C30 questionnaire, but patients in group 1 (capecitabine) reported less miccional problems (15.3 pts mean difference), less gastrointestinal problems (-15.3 pts mean difference), less defecation problems (11.8 pts mean difference) and more sexual satisfaction (13.3 pts mean difference) in CR38 questionnaire modules. C30SumScore was equivalent before and after neoCRT in the two study groups. Table 2: Mean QOL scores (C30 and CR38) comparing Group 1 and 2 before (T0) and after (T1) neoCRT EORTC QLQ-C30 T0 T1 Group 1 (n=31) Group 2 (n=30) p-value Mean difference Group 1 (n=31) Group 2 (n=29) p-value Mean difference Physical functioning 85.2 88.0 0.577 -2.8 86.4 88.3 0.503 -2.9 Role functioning 80.6 82.0 0.849 -1.4 91.7 89.9 0.720 1.8 Cognitive functioning 77.6 79.4 0.793 -1.8 84.9 87.7 0.598 -2.7 Emotional functioning 66.9 64.6 0.782 2.3 71.8 68.0 0.620 3.8 Social functioning 82.9 77.3 0.449 5.6 86.9 84.2 0.695 2.7 Fatigue 21.7 18.1 0.645 3.6 14.7 11.3 0.434 3.4 Pain 28.1 26.5 0.821 1.6 19.6 11.6 0.256 7.9 Dyspnea 10.0 4.0 0.386 6.0 9.1 3.8 0.291 5.3 Insomnia 29.0 16.7 0.244 12.3 15.6 18.5 0.714 -2.9 Appetite Loss 21.9 12.6 0.144 9.3 10.9 3.3 0.213 7.5 Nausea 2.1 5.8 0.258 -3.7 0.0 0.0 - 0 Constipation 33.6 25.4 0.477 8.2 11.0 16.5 0.517 5.4 Diarrhea 24.0 17.3 0.475 6.6 4.1 7.7 0.361 -3.5 Financial difficulties 31.8 37.2 0.612 5.4 21.1 27.3 0.514 -6.2 Global Health Status 71.6 64.2 0.200 7.4 77.5 76.4 0.851 1.0 C30SumScale 78.8 81.8 0.450 -3.0 87.4 88.2 0.788 -0.8 EORTC CR38 T0 T1 Group 1 (n=31) Group 2 (n=30) p-value Mean difference Group 1 (n=31) Group 2 (n=29) p-value Mean difference Miccional problems 30.8 38.8 0.373 -5.0 30.7 46.1 0.525 -15.3 Gastrointestinal problems 24.0 20.4 0.518 3.6 7.6 22.8 0.096 -15.3 Weight Loss 24.8 36.9 0.267 -12.1 12.7 21.3 0.274 -8.6 Chemotherapy side effects 16.7 9.7 0.240 7.0 15.5 11.1 0.219 4.3 Defecation problems 34.1 35.9 0.736 -1.7 15.5 23.3 0.168 -11.8 Male sexual problems* - - - - - - - - Female sexual problems* - - - - - - - - Stoma related problems* - - - - - - - - Body image 8.8 10.7 0.742 -1.9 4.6 2.9 0.611 2.3 Future perspectives 55.5 63.3 0.726 -7.9 57.4 59.2 0.921 -1.8 Sexual functioning 48.5 46.8 0.883 1.6 62.5 60.5 0.848 2.0 Sexual satisfaction 55.3 58.5 0.827 -3.2 71.2 57.9 0.333 13.3 QOL: Quality of Life; neoCRT: neoadjuvant chemoradiotherapy; using ANCOVA multivariate analysis adjusted for age, gender, tumor height and clinical stage. *: insufficient number of valid responses The longitudinal QOL analysis comparing results on five different moments of treatment is depicted in Table 3 . Median time intervals between evaluations were: T0 to T1 median 14( 11 – 18 ) weeks; T1 to T2 median 9( 4 – 19 ) weeks; T2 to T3 median 40(28-95) weeks; T3 to T4 median 175(102-227) weeks or 3.3 years. Also, the median time interval from rectal resection to T2 was five ( 4 – 15 ) weeks, and to T4 was 214 (148-262) weeks. Role functioning scores showed improvement after neoCRT (T1) compared to basal evaluation (T0) and worsened after a median time of five weeks (range 3-15 weeks) after surgical resection, decreasing 24.4 points at T2 evaluation. Patients also significantly improved at the late evaluation (T4) compared to postoperative period (T2). Patients also reported more fatigue and appetite loss after surgical resection (an increase of 15.4 and 17.1 points respectively T2 to T1). Constipation improved after neoCRT (reduction in 11.5 points comparing T0 to T1). Diarrhea was a symptom that worsened at T4 compared to T1 (an increase in 22.2 points), meaning that after stoma closure patients were more symptomatic in this domain than after the chemoradiation period. Both Global Health Status and the new C30SumScore detected improvement in T1 score compared to T0 (after chemoradiation versus basal scores), but only the C30SumScore detected difference in T2 compared to T1 (postoperative period compared to post chemoradiation), but this difference did not reach the 10-points range. Interestingly, Global Health Status score improved at T4 compared to T0 in 15.5 points, a difference that was not identified in any other domain of C30 questionnaire. Table 3 Longitudinal comparison of QOL scores using ANOVA’s repeated measures test and Greenhouse-Geiser correction for lack of sphericity. EORTC QLQ-C30 T0 T1 T2 T3 T4 Sphericity Anova (G.Geisser) Difference Physical functioning 87.9 85.2 78.4 81.0 86.7 0.353 F(3.47-125.01)=2.60 ; p=0.047 No Role functioning 81.0 90.1 65.7 82.0 83.8 0.000 F(3.00-108.18)=5.93; p=0.001 T0T2; T2<T4 Cognitive functioning 79.3 86.9 81.1 81.1 77.4 0.540 F(3.61-129.91)=1.64; p=0.174 No Emotional functioning 64.2 73.0 67.8 68.0 70.7 0.007 F(3.05-109.82)=1.17; p=0.322 No Social functioning 73.8 87.7 73.2 80.3 77.2 0.484 F(3.64-134.65)=2.29; p=0.069 No Fatigue 18.7 15.1 30.5 20.7 15.4 0.305 F(3.43-119.96)=5.28; p=0.001 T2>T1 Pain 27.0 19.4 23.4 21.2 16.7 0.881 F(3.77-135.62)=1.23; p=0.298 No Dyspnea 4.6 3.7 1.8 3.7 4.6 0.002 F(2.92-102.3)=0.307; p=0.815 No Insomnia 19.8 21.6 30.6 26.1 21.6 0.010 F(3.11-112.08)=1.05; p=0.375 No Appetite Loss 12.6 6.3 23.4 11.7 7.2 0.001 F(2.90-104.673)=3.94; p=0.011 T2>T1 Nausea 4.1 0.0 3.2 5.0 2.7 0.000 F(2.27-81.89)=2.15; p=0.116 No Constipation 24.8 13.3 4.7 4.7 13.3 0.000 F(2.86-97.40)=4.69; p=0.005 T0>T2; T0>T3 Diarrhea 21.3 6.5 13.9 15.7 28.7 0.035 F(3.26-114.06)=3.34; p=0.019 T4>T1 Financial difficulties 35.1 24.3 33.3 25.2 26.1 0.384 F(3.51-126.23)=1.40; p=0.243 No Global Health Status 64.7 74.3 71.6 75.2 80.2 0.364 F(3.53-127.07)=4.37; p=0.004 T0<T1; T0<T4 C30SumScale 81.3 87.4 79.6 83.5 83.4 0.001 F(3.08-110.99) =3.195; p=0.025 T0T2; EORTC CR38 T0 T1 T2 T3 T4 p value Miccional problems 38.1 41.4 45.6 39.0 32.4 0.089 F(3.43-123.65)=2.83; p=0.035 T2>T4 Gastrointestinal problems 21.1 15.7 16.9 16.9 19.1 0.440 F(3.56-128.26)=1.07; p=0.368 No Weight Loss 34.2 16.7 39.8 16.7 11.1 0.640 F(3.62-126.73)=8.05; p=0.001 T0>T4; T1T3; T2>T4 Chemotherapy side effects 10.2 12.6 16.1 14.4 17.4 0.090 F(3.17-114.431)=1.65; p=0.179 No Defecation problems 30.1 15.3 - - 19.1 0.318 F(1.76-29.99)=6.93; p=0.004 T0>T1; T0>T4 Male sexual problems 0.0 27.1 52.1 50.0 47.9 0.090 F(2.47-17.28)=3.74; p=0.037 T0<T4 Female sexual problems - - - - - - - N.A. Stoma related problems - - 31.1 35.5 36.8 0.689 F(1.85-18.53)=0.39; p=0.668 No Body image 14.1 12.9 34.4 38.1 24.9 0.028 F(3.27-117-84)=9.60; p<0.001 T0<T2; T0<T3; T1<T2; T1T2; T1>T2; T3>T2;T4>T2 Sexual satisfaction 70.0 63.3 - - - - F(1.00-19.00)=1.65; p=0.214 No N.A.: not applicable due to insufficient number of patient answers. Regarding the CR38 modules specific for colorectal cancer, the longitudinal analysis detected improvement in the late evaluation period (T4) compared to postoperative period (T2) in the following domains: miccional problems (-13.2 pts mean difference); weight loss (-28.7 points mean difference); and sexual functioning (15.5 points mean difference). Comparing the evaluation before treatment (T0) with the available patients at late evaluation at T4, there was a difference at Global Heath Status (15.5 pts mean difference); weigh loss (-23.1 pts mean difference), reduction in defecation problems (-11.0 pts mean difference) but an increase in male sexual problems (47.9 points mean difference). Graphic 1 shows temporal changes in QOL using the C30SumScore for each treatment group and for all patients at the five moments of evaluation. Excluding patients with definitive stoma (n= 8), patients that had no bowel continuity restored (n=4) and patients who had recurrences (n= 16), 27 patients were evaluated using Wexner score at T4 with a mean of 9.2 points (SD 4.1). No difference in mean incontinence score was found comparing ISR to LAR (10.0 vs 9.1, p=0.663)., There were no association between level of anastomosis and incontinence assuming the Wexner score value of 10 as cutoff (p=0.415). Patients with Wexner Score ≥ 10 had more symptoms of diarrhea (p=0.006) and defecation problems (p=0.004) in QOL scores at T4 (Table 4 ). Table 4 Mean QOL scores comparing patients with Wexner Score <10 vs ≥10. Statistically significant values were displayed in bold. EORTC QLQ-C30 Wexner<10 Wexner≥10 Mean Difference p-value Physical functioning 88.2 87.6 0.6 0.930 Role functioning 91.0 79.8 11.3 0.250 Cognitive funcioning 85.9 71.4 14.5 0.140 Emotional functioning 75.0 65.5 9.5 0.354 Social functioning 89.8 73.8 15.9 0.140 Fatigue 11.1 19.8 -8.7 0.202 Pain 19.2 20.2 -1.0 0.935 Dyspnea 5.1 7.1 -2.0 0.754 Insomnia 15.4 11.9 3.5 0.677 Appetite Loss 2.6 5.1 -2.6 0.558 Nausea 1.3 4.8 -3.5 0.395 Constipation 15.4 14.3 1.1 0.906 Diarrhea 15.4 52.4 -37.0 0.006 Financial difficulties 25.6 28.6 -2.9 0.851 Global Health Status 84.6 70.8 13.8 0.077 C30SumScale 88.0 80.1 8.0 0.201 EORTC CR38 Wexner<10 Wexner≥10 Mean Difference p-value Miccional problems 25.6 38.9 -13.3 0.080 Gastrointestinal problems 15.9 27.1 -11.3 0.109 Weight Loss 2.6 15.4 -12.8 0.105 Chemotherapy side effects 11.1 21.4 -10.3 0.187 Defecation problems 14.7 31.5 -16.9 0.004 Male sexual problems 46.7 50.0 -3.3 0.868 Female sexual problems 38.9 50.0 -11.1 0.874 Stoma related problems NA NA NA NA Body image 22.2 25.4 -3.2 0.779 Future perspectives 50.0 59.5 -9.5 0.556 Sexual functioning 18.0 32.2 -14.2 0.179 Sexual satisfaction 33.3 46.7 -13.3 0.524 Conclusions The two neoCRT regimens using either oral capecitabine or intravenous bolus 5-Fu/Lv combined to radiotherapy achieved comparable clinical and pathological response rates. QOL was equivalent between groups after neoCRT except for miccional problems, gastrointestinal problems, defecation problems and sexual satisfaction favoring the capecitabine arm. QOL was improved after neoCRT but decreased following rectal resection. Wexner score was high after sphincter preservation (mean 9.2 points) and was equivalent comparing LAR versus ISR. C30SummaryScore was a useful tool to detect statistical differences in overall QOL comparing different phases of protocol treatment. Discussion The contemporary treatment for LARC provides long-term survival in most patients, but acute and late sequelae are major setbacks and jeopardize the successfulness of medical interventions. Investigation on new treatment strategies should maintain efforts to improve disease control rates, but optimization of the quality of life after successful treatment becomes a prime directive. In consonance, our randomized study was designed to compare clinical response between capecitabine and 5-Fu/Lv combined to radiotherapy in neoadjuvant setting, but also included a dedicated QOL analysis. In the present study we assumed that EORTC’s QOL scores would reflect clinical differences in disease responses according to treatment group results. After neoadjuvant treatment, despite no difference in QLQ-C30 scores between patients receiving capecitabine or 5-Fu/Lv was found, patients in group 1 (capecitabine) reported less miccional problems (15.3 pts mean difference), less gastrointestinal problems (-15.3 pts mean difference), less defecation problems (11.8 pts mean difference) and more sexual satisfaction (13.3 pts mean difference) in CR38 questionnaire specific colorectal modules. Coincidently, the clinical response rate (70.0% vs 53.3%) and the pathological complete response rate (23.3.% vs 10.0%) were higher in the capecitabine group, although not statistically which might have been explained by the sample size enrolled in the study. No previous publications compared QOL after these two drug regimens in neoadjuvant setting, but some reports compared these two drugs in adjuvant or palliative settings. A nonrandomized Taiwanese study published in 2015 evaluated 123 elderly stage III patients after adjuvant CT compared QOL and treatment costs of capecitabine vs 5-Fu/Lv, associated or not to oxaliplatin( 34 ). After adjusting confounding variables and baseline characteristics, QOL using capecitabine was not inferior to 5-Fu/Lv and reduced costs. In accordance, two previous studies compared palliative treatment in metastatic colorectal cancer using capecitabine and 5-Fu/Lv in combination to oxaliplatin showed no difference in QOL between treatment groups( 35 , 36 ). Nevertheless, comparing the moments before and after neoCRT we balanced the effect of surgical resection and excluded the interference of oxaliplatin, which allowed a direct comparison of the two drugs in combination to radiotherapy. The second question to be answered was regarding the functional results after sphincter preservation, which was an important endpoint in our study. Combining accurate preoperative imaging (MRI and EUS) to modern surgical techniques, the sphincter preservation rate was 81.6% in our study, considering all patients. We have accomplished to reestablish the intestinal continuity using coloanal anastomosis and/or intersphincteric resection after good clinical responders even with low rectal cancers close to sphincter complex, although our functional results were often suboptimal (mean Wexner score of 9.2). Interestingly, no functional difference was observed after ISR compared to LAR. Both neoadjuvant schemes were effective in ameliorating general cancer symptoms and health status after neoCRT(T1) compared to baseline (T0), expressed as improvements in role functioning, global health status and C30SumScore scales of QLQ C30 and reduction in defecation problems of CR38 questionnaire, and no worsening of any domain of both questionnaires. In contrast, the adverse effects of rectal resection in QOL were evident: four of the C30 scales and three of the CR38 scales had worse scores comparing T1 to T2. Not surprisingly, patients had nonsignificant improvement in QOL six months after rectal resection, except for weight loss and sexual functioning despite receiving many cycles of adjuvant chemotherapy from T2 to T3. This time interval may have allowed improvement in patients perception of surgical morbidity. And although our sphincter preservation rate was over 80%, patients had to deal with temporary stomas for at least six months. Finally, we included a late fecal continence evaluation one year after stoma reversal using the Wexner score, which has been recently translated and validated in Portuguese( 33 ). We found an average high score of fecal incontinence that did not correlate to anastomosis level but correlated to QOL scores of diarrhea and defecation problems. Our participants have never recovered from some sequelae of the treatment even at late evaluation after a median time interval of 49 months. Comparing to basal evaluation(T0), patients improved from general cancer symptoms (Global Health Status), ameliorated on weight loss and constipation, but developed male sexual disfunction. Comparing the late evaluation (T4) to the postoperative period (T2), patients had improvement in role functioning, weight loss, miccional problems and sexual functioning, which may reflect that some autonomic sequalae can ameliorate with time, but also can reflect a tendency of patients to change the perception of the same condition over time, for example if their cancer is controlled, a phenomenon called “response shift”( 37 , 38 ). The literature supports the findings of symptom improvement over time. A study from the Netherlands identified worse C30SumScore, physical functioning, fatigue and dyspnea in patients who received adjuvant chemotherapy compared to observation, but this difference disappeared 12 months after surgery( 39 ). Other studies demonstrate stabilization of LARS one year after surgery( 40 ) and that patients after long time follow-up still present significant disfunction ( 41 ). Concerning the specific colorectal cancer module, the CR38 was commonly used in adjunct to QLQ-C30 to measure specific domains of quality of life in colorectal cancer patients, but criticism has emerged because questions concerning sexuality are often unanswered on CR38; these questions were suppressed or revised in the CR29 version( 22 ). CR29 emerged later and was in validation when we started our study. Indeed, in our study few patients answered questions about sexual problems (only were 4 available to compare T0 and T1) and sexual satisfaction (only 19 of 61 were available). Our study was the first to use the C30SumScore to compare results of QOL over time in five moments beginning at pretreatment levels, and it detected significant differences in QOL after neoCRT and rectal resection. After neoCRT patients reported an increase in 6.1 points in C30SumScore and after rectal resection a decrease in 7.8 points in mean scores. The C30SumScore appears to add relevant information to clinical practice allowing comparison between treatment groups and detecting relevant temporal changes in QOL. Unfortunately, our study leaves unanswered an old dilemma concerning better selection of patients for sphincter preservation after low rectal cancer resection. We did not detect differences in Wexner scores comparing patients with LAR to ISR, and both groups showed moderate to high levels of incontinence (mean 9.1 versus 10.0 points, respectively). A meta-analysis published in 2015 including 13 studies from 2001 to 2015 comprised data from 1805 patients using QLQ-C30 and CR38( 23 ). Their main objective was to compare QOL in patients submitted to LAR vs APR, and QOL questionnaires were applied after 12 months of surgery. Patients with sphincter preservation had better social functioning, better body image but more symptoms of constipation. One study from Spain evaluated QOL compared APR versus LAR in 84 patients after neoCRT and Surgery ( 42 ). After a mean follow up of 48.7 months, no difference in QLQ-C30 scores was detected. Using the CR29 questionnaire, only stool frequency score was increased in LAR patients (33.3 vs 14.3 points). Another study compared QOL and functional results using Wexner score in 14 patients submitted to ISR versus 22 patients submitted to APR and perineal colostomy( 43 ). ISR patients had worse Physical Functioning (84.1 vs 100.0 points) but less Defecation Problems compared to perineal colostomy (57.1 vs 90.5 points). Wexner score was similar between two groups (median 11 in ISF versus 10 in APR), which was comparable to our results of ISR (median Wexner score of 10). A matched group analysis from Heidelberg, Germany, compared QOL results of LAR, ISR and APR in 131 patients from a prospective database ( 44 ). They found that physical functioning scores were better after LAR and ISR compared to APR (82.2 and 80.2 vs 69.9 points), but constipation and diarrhea were both more frequent in LAR and ISR compared to APR. ISR had mean higher Wexner score compared to LAR (12.9 vs 9.5), a difference that was not significant in our series. A previous study from Illinois, USA, also found better physical functioning scores after sphincter preservation in a retrospective study (94 vs 87 points) but also more constipation (16 vs 8 points) and decreased sexual functioning (27 vs 76 points)( 44 ). These suboptimal functional results after curative resection of low rectal cancer motivates investigation of less aggressive approaches to good clinical responders, including the nonoperative management that has been explored in recent literature, including our own institution’s experience( 45 , 46 ). New strategies are under investigation to decrease toxicity and QOL impairment. Avoiding radiotherapy would probably reduce a degree of pelvic toxicity ameliorating anorectal function after rectal resection, and some studies demonstrated promising response rates using isolated neoadjuvant chemotherapy( 47 , 48 ). One tendency in investigation by our group is the total neoadjuvant treatment, in which all cycles of systemic chemotherapy are delivered before rectal resection with the addition of short-course radiotherapy (SHORT-ICAR Trial, ClinicalTrials.gov Identifier: NCT04674696). This strategy is aimed to improve response, increase compliance rates, prevent distant relapse, allows stoma reversal one month after TME, and the possibility of organ preservation after clinical complete response. Finally, our study was limited due to incomplete accrual which may have limited the statistical power to detect small outcome differences between the two treatment arms, as only 63 of 96 patients were randomized after two years because some stage I and many Stage IV patients were later excluded after ultimate radiological review. Nevertheless, we were able to show significant difference in QOL in different phases of treatment combining the two treatment arms. We also did not include manometric evaluation, which would give additional information regarding the suitable candidates to sphincter preservation in low rectal cancer cases. Despite this possible caveat, manometry is not widely available as it depends on dedicated equipment and expertise, and many QOL of studies after rectal cancer treatment do not report manometry data. Most studies, including ours, focus on patient reported outcomes, as the Wexner scale and EORTC questionnaires, which make our results comparable to literature and applicable into clinical practice. List Of Abbreviations 5-Fu/Lv: 5-Fluorouracil and Leucovorin AJCC: American Joint Commission on Cancer APR: Abdominoperineal Resection AV: Anal Verge C30SumScore: C30 Summary Score CT: Computer Tomography CTCAE: Common Terminology for Adverse Events EORTC: European Organization for Research and Treatment of Cancer EUS: Endorectal Ultrasound INCA: Instituto Nacional de Cancer (National Cancer Institute of Brazil) ISR: Intersphincteric Resection LAR: Low Anterior Resection LARC: Locally Advanced Rectal Cancer LARS: Low Anterior Resection Syndrome MRI: Magnetic Resonance Imaging neoCRT: Neoadjuvant Chemoradiotherapy QLQ-C30: Quality of Life Questionnaire C30 QOL: Quality of Life SD: Standard Deviation TME: Total Mesorectal Excision USA: United States of America Declarations Ethical Approval and Consent to participate : this was a prospective study approved by Ethics Committee of National Cancer Institute of Brazil (INCA) in 2010 under register number 83/10 (NCT03428529). All patients voluntarily agreed to participate after informed consent. Consent for publication : all authors declare that they consented to submit the paper. Availability of supporting data : the datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests : all authors declare that they have no conflicts of interests and consented to submit the paper. Funding : the present study was totally supported by the Division of Clinical Research and Technological Development of the National Cancer Institute of Brazil, subordinated to the Ministry of Health of Brazil. Authors' contributions : all the Authors made substantial contributions to the manuscript as follows: Study concepts: Carlos Gil Ferreira and Eduardo Linhares. Study design: Fernando Meton Vieira, Rodrigo Otavio de Castro Araujo, Ana Paula Ornellas. Data acquisition: Rodrigo Otavio de Castro Araujo, Simone Guaraldi and Claudia Carrada. Quality control of data and algorithms: Ana Paula Ornellas, Ivanir Martins, Claudia Carrada. Data analysis and interpretation: Rodrigo Otavio de Castro Araujo e Luiz Claudio Santos Thuler. Statistical analysis: Rodrigo Otavio de Castro Araujo e Luiz Claudio Santos Thuler. Manuscript preparation: Rodrigo Otavio de Castro Araujo. Manuscript editing: Marcus Vinicius Valadão and Simone Guaraldi. Manuscript review: All the authors above. Acknowledgements : We would like to thank all the supporting team of the mentioned Division, especially Dr. Andreia Cristina de Melo, Isabelle Small, Giovana Kovalesky, Alexandre de Souza Fonseca, Cecilia Ferreira da Silva, and all the staff involved in the protocol. Availability of data and materials : The datasets during and/or analyzed during the current study are publicly available at Mendeley dataset as: Araujo, Rodrigo Otavio (2021), “INCAGI004”, Mendeley Data, V1, doi: 10.17632/75vdm7phv9.1. 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Available from: https://pubmed.ncbi.nlm.nih.gov/28685354/ Supplementary Files SupplementaryTable1QOL.docx SupplementaryTable02.docx Graphic1.jpg Cite Share Download PDF Status: Under Review Version 2 posted Reviews received at journal 01 Dec, 2021 Reviewers invited by journal 07 Nov, 2021 Editor invited by journal 03 Nov, 2021 First submitted to journal 26 Sep, 2021 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-121936","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[{"code":1,"date":"2020-12-08 16:31:45","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":63099721,"identity":"5c52d304-7f2c-4ba3-8518-940f724ed1ed","order_by":0,"name":"Rodrigo Otavio de Castro Araujo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIiWNgGAWjYNACHjDJeICBQYKBH8RMKCBOCwNYi2QDSIsBkZYdABEGEBK3KvP2sw8/88jYyJmzHz5w4MMvC3nj86sTPzwwYJDnFzuAVYvMmXRjaR6eNGPLnrSEgzP7JAy33Xi7WQLoMMOZsxOwapFgSGMAajmcuOEGj8Fh3h4Jxm03zm4AaUkwuI1DC/8z5t/IWuw3zzi7+QdeLRJpbAhbeH5IJG7g792G3xaJZ2yWc4B+MTgD8kuDRPKMG7zbLBIMJHD7hT+N+cbbHhs5g+OHDz748KfOtr//7OabPyps5PmlsWsBA8YeGKMNZEoCJFzwgx8wxh8g5j9AQPUoGAWjYBSMNAAAaoJf1auNiuoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0033-2545","institution":"INCA: Instituto Nacional de Cancer","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Rodrigo","middleName":"Otavio de Castro","lastName":"Araujo","suffix":""},{"id":63099722,"identity":"3783715e-2062-4478-b763-be4c336170c7","order_by":1,"name":"Fernando Meton Vieira","email":"","orcid":"","institution":"Instituto COI","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fernando","middleName":"Meton","lastName":"Vieira","suffix":""},{"id":63099723,"identity":"bd7da367-6fba-4298-a99e-25f8900d81a9","order_by":2,"name":"Ana Paula Victorino Ornellas","email":"","orcid":"","institution":"Instituto COI","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Paula Victorino","lastName":"Ornellas","suffix":""},{"id":63099724,"identity":"63cb34bd-57b1-42a7-a21b-dd2aa46290ab","order_by":3,"name":"Claudia Carrada Torres","email":"","orcid":"","institution":"INCA: Instituto Nacional de Cancer","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Claudia","middleName":"Carrada","lastName":"Torres","suffix":""},{"id":63099725,"identity":"2d40434a-34a3-44b3-9405-d16a5e43ef59","order_by":4,"name":"Ivanir Martins","email":"","orcid":"","institution":"INCA: Instituto Nacional de Cancer","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ivanir","middleName":"","lastName":"Martins","suffix":""},{"id":63099726,"identity":"2ea2bbb1-ad25-429a-a618-ae7f9c4bce98","order_by":5,"name":"Simone Guaraldi","email":"","orcid":"","institution":"INCA: Instituto Nacional de Cancer","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Simone","middleName":"","lastName":"Guaraldi","suffix":""},{"id":63099727,"identity":"8015be42-2938-4599-9a42-2adad50ef23b","order_by":6,"name":"Marcus Vinicuis Valadão","email":"","orcid":"","institution":"INCA: Instituto Nacional de Cancer","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marcus","middleName":"Vinicuis","lastName":"Valadão","suffix":""},{"id":63099728,"identity":"c345a436-beeb-4969-8189-33f935096cbf","order_by":7,"name":"Eduardo Linhares","email":"","orcid":"","institution":"INCA: Instituto Nacional de Cancer","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"","lastName":"Linhares","suffix":""},{"id":63099729,"identity":"341e66c5-824b-49b7-a611-562a2ae25723","order_by":8,"name":"Carlos Gil Ferreira","email":"","orcid":"","institution":"Oncoclinicas Institute for Research and Education","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"Gil","lastName":"Ferreira","suffix":""},{"id":63099730,"identity":"0eb8d850-1cbe-4f25-b3d3-211644cb5369","order_by":9,"name":"Luiz Claudio Thuler","email":"","orcid":"","institution":"INCA: Instituto Nacional de Cancer","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Luiz","middleName":"Claudio","lastName":"Thuler","suffix":""}],"badges":[],"createdAt":"2020-12-04 15:19:08","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-121936/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-121936/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":15547842,"identity":"a745352a-757f-4df8-94ea-e32c3e6c05f4","added_by":"auto","created_at":"2021-11-15 15:24:56","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":127923,"visible":true,"origin":"","legend":"Figure 1 illustrates the study design. Clinical downstaging was the study primary endpoint and was defined as stage regression 6-8 weeks after neoCRT, using AJCC 7th edition(29).","description":"","filename":"fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-121936/v2/0238c18fa9a921b174638165.jpg"},{"id":15547610,"identity":"d352b7e7-2e61-4b5b-96fd-5522b137988c","added_by":"auto","created_at":"2021-11-15 15:21:56","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":74005,"visible":true,"origin":"","legend":"EORTC QLQ C30 (20) and CR38 (21) were applied at five different treatment moments: before neoCRT (T0), 6-8 weeks after neoCRT (T1), 30 days after surgery (T2), after adjuvant chemotherapy (T3), and one year after the end of the treatment or stoma closure (T4) (Figure 2). ","description":"","filename":"fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-121936/v2/511da172873f16f5e2853058.jpg"},{"id":15548275,"identity":"7819e217-51bd-481a-9bdf-e5e4941afd90","added_by":"auto","created_at":"2021-11-15 15:27:57","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":146987,"visible":true,"origin":"","legend":"Figure 3 illustrate the study flow chart. Supplementary Table 2 reports the mean C30 and CR38 scores in all domains including the C30SumScore.","description":"","filename":"fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-121936/v2/d67f645c83fee34dea4b1bd0.jpg"},{"id":15548278,"identity":"e68c0a76-8844-4701-80a6-baf4b9c422df","added_by":"auto","created_at":"2021-11-15 15:28:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":907416,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-121936/v2/d0c72585-a786-4218-974f-931eacb765ce.pdf"},{"id":15547612,"identity":"931734b2-8a9f-4939-8c57-96a4054b8d4c","added_by":"auto","created_at":"2021-11-15 15:21:57","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19623,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1QOL.docx","url":"https://assets-eu.researchsquare.com/files/rs-121936/v2/268a37b47b74667e1a431286.docx"},{"id":15547843,"identity":"aff47334-03d0-4dde-a23e-6f9a9bbcc223","added_by":"auto","created_at":"2021-11-15 15:24:57","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":24074,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable02.docx","url":"https://assets-eu.researchsquare.com/files/rs-121936/v2/9481b037ff8d8e156aaa4ee2.docx"},{"id":15547609,"identity":"d8f9e2f4-71ba-4308-b7cf-ff9749a84a13","added_by":"auto","created_at":"2021-11-15 15:21:56","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":57164,"visible":true,"origin":"","legend":"","description":"","filename":"Graphic1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-121936/v2/86fe0565ce98892eb81ffca1.jpg"}],"financialInterests":"","formattedTitle":"Quality of Life in a Randomized Trial Comparing Two Neoadjuvant Regimens for Locally Advanced Rectal Cancer – INCAGI004.","fulltext":[{"header":"Background","content":"\u003cp\u003eColorectal cancer is the third most common malignant neoplasia worldwide (1.4 million new cases/year)(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In Brazil is the third most frequent cancer in men and second in woman(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Locally advanced rectal cancer (LARC) is the denomination for tumors centered below the peritoneal reflection, usually \u0026lt;10-12 cm from the anal verge (AV), and that have extended beyond the muscularis propria or the rectum (AJCC clinical stage II and III)(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Neoadjuvant chemo radiotherapy (neoCRT) using 5-fluorouracil and leucovorin (5-Fu/Lv) followed by total mesorectal excision (TME) is considered the standard of care for locally advanced rectal cancer (LARC) resulting in \u0026gt;70% 5-year survival(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Capecitabine is an oral substitute to 5-Fu that has been tested in neoadjuvant phase 2 trials that demonstrated superiority in clinical and pathological response rates (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and phase 3 trials showing comparable efficacy(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). It has the potential advantages of synergism with radiation due to thymidine phosphorylase upregulation(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), increased concentration in colorectal tumor tissue (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)and the convenience of oral administration(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe adoption of total mesorectal excision (TME)(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)combined to the neoadjuvant treatment has resulted in excellent local control, with local recurrences occurring in 3-6% of patients (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Therefore, abdominoperineal resection or Miles\u0026rsquo;s operation (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) has been avoided progressively in favor of sphincter preserving procedures as low anterior resection and intersphincteric resection(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) when sufficient distal and circumferential negative margins are secured.\u003c/p\u003e \u003cp\u003eBesides advances in local control and sphincter preservation for LARC, quality of life (QOL) becomes a great problem after treatment due to temporary or permanent stoma creation (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), sexual and urinary dysfunction(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) and a myriad of defecation disfunctions now classified as low anterior resection syndrome (LARS)(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe European Organization for Research and Treatment on Cancer (EORTC) has published in 1993 a questionnaire with 30 questions, the QLQ C30(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), and has been extensively used to measure patient reported outcomes in oncology for all cancer types. It displays the QOL results in 15 domains divided in five functional scales, nine symptom scales and one global QOL scale. In rectal cancer it is usually applied with the addition of specific colorectal modules (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Nonetheless, QOL analysis using the multi-item scales may lead to conflicting conclusions because some symptoms may ameliorate after treatment whilst other may get worse. For example, some studies favor sphincter preservation (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) while others suggest equivalent or worse results comparing patients with low rectal anastomosis to definitive stoma (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA summary measure to aggregate the multi-dimensional QoL profile and to detect changes in overall QOL over time is particularly important in clinical trials, which are designed to pre-specified endpoints. The original two-item global QOL scale may not be comprehensive enough to detect changes between patient groups and/or changes over time. It has been shown that Global QOL scale could not detect deteriorating QOL in patients with progressive and terminal disease (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this scenario a group of authors recently proposed a higher order summary score that performed well in an empirical model fit (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). It was calculated by the mean of all C30 scales except for financial problems scale and global QOL scale. This so denominated C30SumScore has been tested in a non-small cell Lung cancer study including 326 patients three months after lung resection and demonstrated better sensitivity to detect postoperative changes compared to the global QOL score(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). In addition, the C30SumScore was demonstrated to perform better than the global QOL scale and the physical functioning scale in predicting all-cause mortality in colon and rectal cancer patients(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the present study we performed a QOL evaluation in LARC patients using EORTC\u0026rsquo;s QOL questionnaires and the new summary score to detect differences associated to the clinical response and to the surgical therapy in a randomized prospective trial comparing two different neoCRT regimens in a Brazilian cancer reference hospital.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo prospectively evaluate the impact of clinical response and surgical resection on QOL in a randomized trial comparing two different neoCRT regimens.\u003c/p\u003e \u003c/div\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003e This was a longitudinal prospective study approved by Ethics Committee of National Cancer Institute of Brazil (INCA) in 2010 under register number 83/10 (NCT03428529). Patients were randomized to receive neoCRT using either capecitabine or bolus 5-Fu/Lv concomitant to 50,4 Gy radiation on the rectum and adjacent lymph nodes. Figure 1 illustrates the study design. Clinical downstaging was the study primary endpoint and was defined as stage regression 6-8 weeks after neoCRT, using AJCC 7th edition(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cp\u003e \u003cb\u003eA\u003c/b\u003ell eligible consecutive patients from 18 to 80 years with ECOG performance status 0-1 admitted in this single tertiary cancer hospital with rectal adenocarcinoma stage II and III that voluntarily agreed to participate were selected for inclusion. Distance from anal verge (AV) should not exceed 10 cm measured with rigid proctoscopy. Patients were staged before neoCRT and re-staged 6-8 weeks after it with thorax and abdominal computer tomography (CT), endorectal ultrasonography (EUS) and pelvic Magnetic Resonance Imaging (MRI). Patients were excluded if distant metastasis were found on pre-treatment staging, in case of serious comorbidities, pregnancy, or previous oncological treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eNeoadjuvant treatment\u003c/h2\u003e \u003cp\u003eEligible patients were randomized to receive one of the following regimens: oral capecitabine 1650mg/m\u003csup\u003e2\u003c/sup\u003e in two daily divided doses from Monday to Friday for five weeks (Group 1) intravenous bolus 5-Fu (350mg/m\u003csup\u003e2\u003c/sup\u003e) plus Leucovorin (20 mg/m\u003csup\u003e2\u003c/sup\u003e) days 1 to 5 and 29 to 33 (Group 2). Both schemes were concomitant to external bean three-dimension radiotherapy (50.4 Gy in 28 fractions).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSurgical Treatment\u003c/h2\u003e \u003cp\u003eSurgical resection consisted of low anterior resection (LAR), intersphincteric resection (ISR) or abdominoperineal resection (APR), according to sphincter invasion using MRI classification of sphincter invasion after neoCRT(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and it was planned 6-8 weeks after neoCRT completion. Patients without sphincter complex invasion were submitted to LAR; patients with internal sphincter invasion were candidates to ISR if \u0026gt;1mm was predicted; and APR was reserved for patients with external sphincter invasion or intersphincteric plane invasion after neoCRT. Diverting stomas were performed after low colorectal or coloanal anastomosis, and stoma closure was undertaken after the adjuvant chemotherapy completion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAdjuvant treatment\u003c/h2\u003e \u003cp\u003eAdjuvant chemotherapy was defined by pathological response. Patients with ypT0-2/N0 tumors received bolus 5-Fu 370mg/m\u003csup\u003e2\u003c/sup\u003e and Leucovorin 50mg/m\u003csup\u003e2\u003c/sup\u003e weekly for 30 consecutive weeks. Patients with ypT3-4 and/or ypN1 tumors received Oxaliplatin 85 mg/m\u003csup\u003e2\u003c/sup\u003e on days 1, 15 and 29 of each cycle, and bolus 5-Fu 500 mg/m\u003csup\u003e2\u003c/sup\u003e plus Leucovorin 20 mg/m\u003csup\u003e2\u003c/sup\u003e on days 1, 8, 15, 22, 29 and 36 of each cycle. Each cycle consisted of 6 weeks of chemotherapy followed by 2 weeks of rest, totaling 3 cycles, for a total of 24 weeks. Dose reduction, delay and discontinuation of treatment have followed the Common Terminology for Adverse Events (CTCAE) version 3.0 guideline.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up\u003c/h2\u003e \u003cp\u003ePatients were followed by medical consultations every three months in the first two years and every six months in the three subsequent years until the completion of five years of follow-up, disease progression or death. CT scans and rectal endoscopy were performed every 6 months for detecting recurrences.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eQuality of Life Evaluation\u003c/h2\u003e \u003cp\u003eEORTC QLQ C30(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) and CR38(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) were applied at five different treatment moments: before neoCRT (T0), 6-8 weeks after neoCRT (T1), 30 days after surgery (T2), after adjuvant chemotherapy (T3), and one year after the end of the treatment or stoma closure (T4) (Figure 2). QLQ-C30 grouped in nine multiple item scales and six single item scales and has been tested and validated in the Brazilian population (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). The multiple item scales comprise five functional scales (physical, cognitive, emotional, social, and role functioning), and three symptom scales (fatigue, pain, and nausea/vomiting), a global health status/ quality of life scale and six single item scales (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All the scales and single-item measures range in score from 0 to 100. A high score for a functional scale and global health status represents a high / healthy level of functioning, but a high score for a symptom scale / item represents a high level of symptomatology /problems. CR38 is a module complementary to C30, comprising 38 questions related to common symptoms and adverse effects of treatment related to colorectal cancer and has been validated for Brazilian patients (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). C30SumScore was calculated as a mean of all the functional and symptom scores excepting Global Health Status and Financial Problems as recommended by the authors, compiling the mean scores of a total of 13 domains. To calculate C30SumScore, the eight symptom scales scores were inverted, a high score meaning few symptoms and better outcomes. Wexner score (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), that has been validated for Portuguese(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) comprises 5 questions for fecal incontinence, producing a score from 0 to 20 and it was accessed at T4.\u003c/p\u003e\u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSample size calculation and randomization\u003c/h2\u003e \u003cp\u003eThe study was primarily designed to compare clinical downstaging between the two treatment groups. Assuming 90% of downstaging with capecitabine and 70% with \u003cem\u003ebolus\u003c/em\u003e 5-Fu/Lv, the estimated sample size was 48 patients in each arm (alpha: 0.05; beta: 80%). Time for accrual was stipulated in 24 months. Randomization was performed in a proportion 1:1 using R software (R \u003cem\u003eDevelopment Core Team\u003c/em\u003e, 2008) with permuted blocks stratified by tumor distance from AV: \u0026gt;5 cm or \u0026le;5 cm.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analysis was performed using SPSS version 21.0 (SPSS Inc., California, USA). Continuous variables were displayed as means \u0026plusmn; Standard Deviation (SD) or median with range (minimum and maximum) according to data distribution. Chi-square tests or Fisher exact tests were used to compare categorical variables, Student\u0026rsquo;s T test to compare means of parametrical variables and the Mann-Whitney U test to compare values of non-parametric data. To compare mean QOL scores between treatment arms the ANCOVA covariance test adjusted for basal clinical data (age, sex, tumor localization and clinical stage) was used. For comparing longitudinal QOL results ANOVA test with Greenhouse-Geisser correction for lack of sphericity was employed. Mean differences of QOL were considered clinically significant if a minimum discrepancy of 10 points was found.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e63 patients were randomized between January 2011 and February 2013. All patients completed neoCRT with no severe toxicities except form one patient with Grade 3 diarrhea and abdominal cramps. One patient refused surgery after a complete clinical response. Two patients quitted the study during follow-up. Clinical information was available for 61 patients. 31 patients were assigned to neoadjuvant capecitabine (Group 1) and 30 to 5-Fu/Lv (Group 2). Baseline characteristics and treatment results are depicted in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Groups were similar at baseline, and clinical response (downstaging, sphincter preservation and Mandard tumor regression grade) was comparable after neoCRT (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). QOL data from 61 patients were available at T0, 60 at T1, 57 at T2, 51 at T3 and 37 at T4. Reasons for no completion of questionnaires at a given moment were death (n=14), disease progression (n=6), no adherence to follow-up (n=3), and desire to quit the study (n=2). Supplementary Table 1 shows the number of patients available for each scale in 5 moments. Figure 3 illustrate the study flow chart. Supplementary Table 2 reports the mean C30 and CR38 scores in all domains including the C30SumScore.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical, surgical, and pathological data of patients in both groups of treatment.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePatients Characteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003eN=61\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup 1(Cap)\u003c/p\u003e\n \u003cp\u003eN=31\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup 2(5-Fu) N=30\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (54.1)\u003c/p\u003e\n \u003cp\u003e28 (45.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (51.6)\u003c/p\u003e\n \u003cp\u003e15 (48.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (56.7)\u003c/p\u003e\n \u003cp\u003e13 (43.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.692*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eEthnicity\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003cp\u003eBlack\u003c/p\u003e\n \u003cp\u003eMixed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47 (77.0)\u003c/p\u003e\n \u003cp\u003e6 (9.8)\u003c/p\u003e\n \u003cp\u003e8 (13.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (71.0)\u003c/p\u003e\n \u003cp\u003e3 (9.7)\u003c/p\u003e\n \u003cp\u003e6 (19.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (83.3)\u003c/p\u003e\n \u003cp\u003e3 (10.0)\u003c/p\u003e\n \u003cp\u003e2 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.337*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (mean, SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e58.5 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e56.6 (13.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60.5 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.182\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI (mean, SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.8 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.8 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27.7 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.102\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor\u003c/strong\u003e \u003cspan class=\"BoldUnderline\" name=\"Emphasis\" type=\"BoldUnderline\"\u003e\u0026le;\u003c/span\u003e\u003cstrong\u003e50 mm AV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30 (49.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (41.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16 (53.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.523*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor\u003c/strong\u003e \u003cspan class=\"BoldUnderline\" name=\"Emphasis\" type=\"BoldUnderline\"\u003e\u0026le;\u003c/span\u003e\u003cstrong\u003e10 mm DL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14 (22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.111*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor obstructive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17 (27.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (29.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (26.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.845*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCm from AV (mean)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.3 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.9 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.7 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.141\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSphincter invasion (MRI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13 (21.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (23.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.747*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBasal Clinical Stage (MRI)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eI\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eII\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eIII\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.129*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSphincter preservation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e49 (81.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24 (80.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.111*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSphincter preservation (tumors \u0026le;5cm from AV)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20(66.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9(64.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11(68.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.550*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Downstaging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37 (61.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16 (53.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.288*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003epCR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10 (16.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (23.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.165*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMandard 1-2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21 (35.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (43,3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (26.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.175*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCRM +\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9(15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6(20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3(10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.472*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eCap: capecitabine; 5-Fu: 5-Fluorouracil; SD: Standard deviation; BMI: Body mass Index; AV: anal verge; DL: dentate line; MRI: Magnetic Resonance Imaging; pCR: pathologic complete response; CRM +: circumferential resection margin \u0026lt;1mm. * Qui-square test \u003csup\u003e#\u003c/sup\u003eStudent\u0026acute;s t-test.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 shows comparison of QOL scores and the C30SumScore between Group 1 and Group 2 using covariate adjustment for age, gender, clinical stage, and tumor localization before (T0) and after neoadjuvant treatment (T1). At T0, Group 1 patients reported more insomnia (12.3 pts mean difference) but reported less weight loss (-12.1 pts mean difference). After neoadjuvant treatment, no difference in QOL between patients receiving capecitabine or 5-Fu/Lv was shown in any score of C30 questionnaire, but patients in group 1 (capecitabine) reported less miccional problems (15.3 pts mean difference), less gastrointestinal problems (-15.3 pts mean difference), less defecation problems (11.8 pts mean difference) and more sexual satisfaction (13.3 pts mean difference) in CR38 questionnaire modules. C30SumScore was equivalent before and after neoCRT in the two study groups.\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2:\u0026nbsp;\u003c/strong\u003eMean QOL scores (C30 and CR38) comparing Group 1 and 2 before (T0) and after (T1) neoCRT\u003c/p\u003e\n \u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eEORTC QLQ-C30\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eT0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eT1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGroup 1 (n=31)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGroup 2 (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003edifference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGroup 1 (n=31)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGroup 2 (n=29)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003edifference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePhysical functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e85.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e88.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.577\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e86.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e88.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.503\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRole functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e80.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e82.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.849\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e91.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e89.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.720\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCognitive functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e77.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e79.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.793\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e84.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e87.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.598\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eEmotional functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e66.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e64.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.782\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e71.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e68.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSocial functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e82.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e77.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.449\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e86.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e84.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.695\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.645\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.434\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e28.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.821\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e19.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.256\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDyspnea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.386\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.291\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.244\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.714\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAppetite Loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.213\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e25.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.477\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.517\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e24.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e17.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.475\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.361\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFinancial difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e31.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e37.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e27.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.514\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-6.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGlobal Health Status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e71.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e64.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e77.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e76.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.851\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eC30SumScale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e78.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e81.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e87.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e88.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.788\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eEORTC CR38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eT0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eT1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGroup 1 (n=31)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGroup 2 (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003edifference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGroup 1 (n=31)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGroup 2 (n=29)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003edifference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMiccional problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e38.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.373\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e30.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e46.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.525\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-15.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGastrointestinal problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.518\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e22.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.096\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-15.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eWeight Loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.267\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-12.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.274\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-8.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eChemotherapy side effects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.240\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDefecation problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.736\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e23.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-11.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMale sexual problems*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFemale sexual problems*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eStoma related problems*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBody image\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.742\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.611\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFuture perspectives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e55.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e63.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.726\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-7.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e57.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e59.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.921\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSexual functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e48.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e46.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.883\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e62.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e60.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.848\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSexual satisfaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e55.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e58.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.827\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e71.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e57.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.333\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eQOL: Quality of Life; neoCRT: neoadjuvant chemoradiotherapy; using ANCOVA multivariate analysis adjusted for age, gender, tumor height and clinical stage. *: insufficient number of valid responses\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eThe longitudinal QOL analysis comparing results on five different moments of treatment is depicted in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. Median time intervals between evaluations were: T0 to T1 median 14(\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e) weeks; T1 to T2 median 9(\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e) weeks; T2 to T3 median 40(28-95) weeks; T3 to T4 median 175(102-227) weeks or 3.3 years. Also, the median time interval from rectal resection to T2 was five (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e) weeks, and to T4 was 214 (148-262) weeks. Role functioning scores showed improvement after neoCRT (T1) compared to basal evaluation (T0) and worsened after a median time of five weeks (range 3-15 weeks) after surgical resection, decreasing 24.4 points at T2 evaluation. Patients also significantly improved at the late evaluation (T4) compared to postoperative period (T2). Patients also reported more fatigue and appetite loss after surgical resection (an increase of 15.4 and 17.1 points respectively T2 to T1). Constipation improved after neoCRT (reduction in 11.5 points comparing T0 to T1). Diarrhea was a symptom that worsened at T4 compared to T1 (an increase in 22.2 points), meaning that after stoma closure patients were more symptomatic in this domain than after the chemoradiation period. Both Global Health Status and the new C30SumScore detected improvement in T1 score compared to T0 (after chemoradiation versus basal scores), but only the C30SumScore detected difference in T2 compared to T1 (postoperative period compared to post chemoradiation), but this difference did not reach the 10-points range. Interestingly, Global Health Status score improved at T4 compared to T0 in 15.5 points, a difference that was not identified in any other domain of C30 questionnaire.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eLongitudinal comparison of QOL scores using ANOVA\u0026rsquo;s repeated measures test and Greenhouse-Geiser correction for lack of sphericity.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEORTC QLQ-C30\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT2\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT4\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSphericity\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAnova (G.Geisser)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDifference\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePhysical functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.47-125.01)=2.60 ; p=0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRole functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.00-108.18)=5.93; p=0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eT0\u0026lt;T1; T1\u0026gt;T2; T2\u0026lt;T4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCognitive functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.540\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.61-129.91)=1.64; p=0.174\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmotional functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.05-109.82)=1.17; p=0.322\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSocial functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.484\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.64-134.65)=2.29; p=0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.305\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.43-119.96)=5.28; p=0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eT2\u0026gt;T1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.881\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.77-135.62)=1.23; p=0.298\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDyspnea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(2.92-102.3)=0.307; p=0.815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.11-112.08)=1.05; p=0.375\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAppetite Loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(2.90-104.673)=3.94; p=0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eT2\u0026gt;T1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(2.27-81.89)=2.15; p=0.116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(2.86-97.40)=4.69; p=0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eT0\u0026gt;T2; T0\u0026gt;T3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.26-114.06)=3.34; p=0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT4\u0026gt;T1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFinancial difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.384\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.51-126.23)=1.40; p=0.243\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGlobal Health Status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.364\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.53-127.07)=4.37; p=0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u0026lt;T1; T0\u0026lt;T4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eC30SumScale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.08-110.99) =3.195; p=0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eT0\u0026lt;T1; T1\u0026gt;T2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eEORTC CR38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eT0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eT1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eT2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eT4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMiccional problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.089\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.43-123.65)=2.83; p=0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT2\u0026gt;T4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastrointestinal problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.440\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.56-128.26)=1.07; p=0.368\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight Loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.640\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.62-126.73)=8.05; p=0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u0026gt;T4; T1\u0026lt;T2; T2\u0026gt;T3; T2\u0026gt;T4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChemotherapy side effects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.17-114.431)=1.65; p=0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDefecation problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.318\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(1.76-29.99)=6.93; p=0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u0026gt;T1; T0\u0026gt;T4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale sexual problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(2.47-17.28)=3.74; p=0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u0026lt;T4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale sexual problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStoma related problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.689\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(1.85-18.53)=0.39; p=0.668\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBody image\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(3.27-117-84)=9.60; p\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u0026lt;T2; T0\u0026lt;T3; T1\u0026lt;T2; T1\u0026lt;T3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFuture perspectives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(2.8-98.3)=1.71; p=0.171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSexual functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(2.45-71.11)=4.76; p=0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u0026gt;T2; T1\u0026gt;T2; T3\u0026gt;T2;T4\u0026gt;T2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSexual satisfaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF(1.00-19.00)=1.65; p=0.214\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003eN.A.: not applicable due to insufficient number of patient answers.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eRegarding the CR38 modules specific for colorectal cancer, the longitudinal analysis detected improvement in the late evaluation period (T4) compared to postoperative period (T2) in the following domains: miccional problems (-13.2 pts mean difference); weight loss (-28.7 points mean difference); and sexual functioning (15.5 points mean difference). Comparing the evaluation before treatment (T0) with the available patients at late evaluation at T4, there was a difference at Global Heath Status (15.5 pts mean difference); weigh loss (-23.1 pts mean difference), reduction in defecation problems (-11.0 pts mean difference) but an increase in male sexual problems (47.9 points mean difference).\u003c/p\u003e\n\u003cp\u003eGraphic 1 shows temporal changes in QOL using the C30SumScore for each treatment group and for all patients at the five moments of evaluation.\u003c/p\u003e\n\u003cp\u003eExcluding patients with definitive stoma (n= 8), patients that had no bowel continuity restored (n=4) and patients who had recurrences (n= 16), 27 patients were evaluated using Wexner score at T4 with a mean of 9.2 points (SD 4.1). No difference in mean incontinence score was found comparing ISR to LAR (10.0 vs 9.1, p=0.663)., There were no association between level of anastomosis and incontinence assuming the Wexner score value of 10 as cutoff (p=0.415). Patients with Wexner Score \u0026ge; 10 had more symptoms of diarrhea (p=0.006) and defecation problems (p=0.004) in QOL scores at T4 (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMean QOL scores comparing patients with Wexner Score \u0026lt;10 vs \u0026ge;10. Statistically significant values were displayed in bold.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEORTC QLQ-C30\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWexner\u0026lt;10\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWexner\u0026ge;10\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMean Difference\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePhysical functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e87.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.930\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRole functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e91.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e79.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.250\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCognitive funcioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e71.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.140\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmotional functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e65.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.354\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSocial functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e73.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.140\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e19.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-8.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.202\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e20.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.935\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDyspnea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.754\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e11.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.677\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAppetite Loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.558\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.395\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e14.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.906\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e52.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-37.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFinancial difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e28.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.851\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGlobal Health Status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e70.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.077\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eC30SumScale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e80.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.201\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eEORTC CR38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWexner\u0026lt;10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eWexner\u0026ge;10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Difference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMiccional problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e38.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastrointestinal problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e27.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.109\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight Loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e15.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-12.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChemotherapy side effects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e21.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-10.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.187\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDefecation problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e31.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-16.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale sexual problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e50.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.868\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale sexual problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e-11.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.874\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStoma related problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBody image\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e-3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.779\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFuture perspectives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e-9.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.556\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSexual functioning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e-14.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSexual satisfaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e-13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.524\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe two neoCRT regimens using either oral capecitabine or intravenous bolus 5-Fu/Lv combined to radiotherapy achieved comparable clinical and pathological response rates.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eQOL was equivalent between groups after neoCRT except for miccional problems, gastrointestinal problems, defecation problems and sexual satisfaction favoring the capecitabine arm.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eQOL was improved after neoCRT but decreased following rectal resection.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWexner score was high after sphincter preservation (mean 9.2 points) and was equivalent comparing LAR versus ISR.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eC30SummaryScore was a useful tool to detect statistical differences in overall QOL comparing different phases of protocol treatment.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe contemporary treatment for LARC provides long-term survival in most patients, but acute and late sequelae are major setbacks and jeopardize the successfulness of medical interventions. Investigation on new treatment strategies should maintain efforts to improve disease control rates, but optimization of the quality of life after successful treatment becomes a prime directive. In consonance, our randomized study was designed to compare clinical response between capecitabine and 5-Fu/Lv combined to radiotherapy in neoadjuvant setting, but also included a dedicated QOL analysis. In the present study we assumed that EORTC\u0026rsquo;s QOL scores would reflect clinical differences in disease responses according to treatment group results. After neoadjuvant treatment, despite no difference in QLQ-C30 scores between patients receiving capecitabine or 5-Fu/Lv was found, patients in group 1 (capecitabine) reported less miccional problems (15.3 pts mean difference), less gastrointestinal problems (-15.3 pts mean difference), less defecation problems (11.8 pts mean difference) and more sexual satisfaction (13.3 pts mean difference) in CR38 questionnaire specific colorectal modules. Coincidently, the clinical response rate (70.0% vs 53.3%) and the pathological complete response rate (23.3.% vs 10.0%) were higher in the capecitabine group, although not statistically which might have been explained by the sample size enrolled in the study. No previous publications compared QOL after these two drug regimens in neoadjuvant setting, but some reports compared these two drugs in adjuvant or palliative settings. A nonrandomized Taiwanese study published in 2015 evaluated 123 elderly stage III patients after adjuvant CT compared QOL and treatment costs of capecitabine vs 5-Fu/Lv, associated or not to oxaliplatin(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). After adjusting confounding variables and baseline characteristics, QOL using capecitabine was not inferior to 5-Fu/Lv and reduced costs. In accordance, two previous studies compared palliative treatment in metastatic colorectal cancer using capecitabine and 5-Fu/Lv in combination to oxaliplatin showed no difference in QOL between treatment groups(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Nevertheless, comparing the moments before and after neoCRT we balanced the effect of surgical resection and excluded the interference of oxaliplatin, which allowed a direct comparison of the two drugs in combination to radiotherapy.\u003c/p\u003e \u003cp\u003eThe second question to be answered was regarding the functional results after sphincter preservation, which was an important endpoint in our study. Combining accurate preoperative imaging (MRI and EUS) to modern surgical techniques, the sphincter preservation rate was 81.6% in our study, considering all patients. We have accomplished to reestablish the intestinal continuity using coloanal anastomosis and/or intersphincteric resection after good clinical responders even with low rectal cancers close to sphincter complex, although our functional results were often suboptimal (mean Wexner score of 9.2). Interestingly, no functional difference was observed after ISR compared to LAR.\u003c/p\u003e \u003cp\u003eBoth neoadjuvant schemes were effective in ameliorating general cancer symptoms and health status after neoCRT(T1) compared to baseline (T0), expressed as improvements in role functioning, global health status and C30SumScore scales of QLQ C30 and reduction in defecation problems of CR38 questionnaire, and no worsening of any domain of both questionnaires. In contrast, the adverse effects of rectal resection in QOL were evident: four of the C30 scales and three of the CR38 scales had worse scores comparing T1 to T2. Not surprisingly, patients had nonsignificant improvement in QOL six months after rectal resection, except for weight loss and sexual functioning despite receiving many cycles of adjuvant chemotherapy from T2 to T3. This time interval may have allowed improvement in patients perception of surgical morbidity. And although our sphincter preservation rate was over 80%, patients had to deal with temporary stomas for at least six months.\u003c/p\u003e \u003cp\u003eFinally, we included a late fecal continence evaluation one year after stoma reversal using the Wexner score, which has been recently translated and validated in Portuguese(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). We found an average high score of fecal incontinence that did not correlate to anastomosis level but correlated to QOL scores of diarrhea and defecation problems.\u003c/p\u003e \u003cp\u003eOur participants have never recovered from some sequelae of the treatment even at late evaluation after a median time interval of 49 months. Comparing to basal evaluation(T0), patients improved from general cancer symptoms (Global Health Status), ameliorated on weight loss and constipation, but developed male sexual disfunction. Comparing the late evaluation (T4) to the postoperative period (T2), patients had improvement in role functioning, weight loss, miccional problems and sexual functioning, which may reflect that some autonomic sequalae can ameliorate with time, but also can reflect a tendency of patients to change the perception of the same condition over time, for example if their cancer is controlled, a phenomenon called \u0026ldquo;response shift\u0026rdquo;(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). The literature supports the findings of symptom improvement over time. A study from the Netherlands identified worse C30SumScore, physical functioning, fatigue and dyspnea in patients who received adjuvant chemotherapy compared to observation, but this difference disappeared 12 months after surgery(\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Other studies demonstrate stabilization of LARS one year after surgery(\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e) and that patients after long time follow-up still present significant disfunction (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eConcerning the specific colorectal cancer module, the CR38 was commonly used in adjunct to QLQ-C30 to measure specific domains of quality of life in colorectal cancer patients, but criticism has emerged because questions concerning sexuality are often unanswered on CR38; these questions were suppressed or revised in the CR29 version(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). CR29 emerged later and was in validation when we started our study. Indeed, in our study few patients answered questions about sexual problems (only were 4 available to compare T0 and T1) and sexual satisfaction (only 19 of 61 were available).\u003c/p\u003e \u003cp\u003eOur study was the first to use the C30SumScore to compare results of QOL over time in five moments beginning at pretreatment levels, and it detected significant differences in QOL after neoCRT and rectal resection. After neoCRT patients reported an increase in 6.1 points in C30SumScore and after rectal resection a decrease in 7.8 points in mean scores. The C30SumScore appears to add relevant information to clinical practice allowing comparison between treatment groups and detecting relevant temporal changes in QOL.\u003c/p\u003e \u003cp\u003eUnfortunately, our study leaves unanswered an old dilemma concerning better selection of patients for sphincter preservation after low rectal cancer resection. We did not detect differences in Wexner scores comparing patients with LAR to ISR, and both groups showed moderate to high levels of incontinence (mean 9.1 versus 10.0 points, respectively). A meta-analysis published in 2015 including 13 studies from 2001 to 2015 comprised data from 1805 patients using QLQ-C30 and CR38(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Their main objective was to compare QOL in patients submitted to LAR vs APR, and QOL questionnaires were applied after 12 months of surgery. Patients with sphincter preservation had better social functioning, better body image but more symptoms of constipation. One study from Spain evaluated QOL compared APR versus LAR in 84 patients after neoCRT and Surgery (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). After a mean follow up of 48.7 months, no difference in QLQ-C30 scores was detected. Using the CR29 questionnaire, only stool frequency score was increased in LAR patients (33.3 vs 14.3 points). Another study compared QOL and functional results using Wexner score in 14 patients submitted to ISR versus 22 patients submitted to APR and perineal colostomy(\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). ISR patients had worse Physical Functioning (84.1 vs 100.0 points) but less Defecation Problems compared to perineal colostomy (57.1 vs 90.5 points). Wexner score was similar between two groups (median 11 in ISF versus 10 in APR), which was comparable to our results of ISR (median Wexner score of 10). A matched group analysis from Heidelberg, Germany, compared QOL results of LAR, ISR and APR in 131 patients from a prospective database (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). They found that physical functioning scores were better after LAR and ISR compared to APR (82.2 and 80.2 vs 69.9 points), but constipation and diarrhea were both more frequent in LAR and ISR compared to APR. ISR had mean higher Wexner score compared to LAR (12.9 vs 9.5), a difference that was not significant in our series. A previous study from Illinois, USA, also found better physical functioning scores after sphincter preservation in a retrospective study (94 vs 87 points) but also more constipation (16 vs 8 points) and decreased sexual functioning (27 vs 76 points)(\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). These suboptimal functional results after curative resection of low rectal cancer motivates investigation of less aggressive approaches to good clinical responders, including the nonoperative management that has been explored in recent literature, including our own institution\u0026rsquo;s experience(\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNew strategies are under investigation to decrease toxicity and QOL impairment. Avoiding radiotherapy would probably reduce a degree of pelvic toxicity ameliorating anorectal function after rectal resection, and some studies demonstrated promising response rates using isolated neoadjuvant chemotherapy(\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). One tendency in investigation by our group is the total neoadjuvant treatment, in which all cycles of systemic chemotherapy are delivered before rectal resection with the addition of short-course radiotherapy (SHORT-ICAR Trial, ClinicalTrials.gov Identifier: NCT04674696). This strategy is aimed to improve response, increase compliance rates, prevent distant relapse, allows stoma reversal one month after TME, and the possibility of organ preservation after clinical complete response.\u003c/p\u003e \u003cp\u003e Finally, our study was limited due to incomplete accrual which may have limited the statistical power to detect small outcome differences between the two treatment arms, as only 63 of 96 patients were randomized after two years because some stage I and many Stage IV patients were later excluded after ultimate radiological review. Nevertheless, we were able to show significant difference in QOL in different phases of treatment combining the two treatment arms. We also did not include manometric evaluation, which would give additional information regarding the suitable candidates to sphincter preservation in low rectal cancer cases. Despite this possible caveat, manometry is not widely available as it depends on dedicated equipment and expertise, and many QOL of studies after rectal cancer treatment do not report manometry data. Most studies, including ours, focus on patient reported outcomes, as the Wexner scale and EORTC questionnaires, which make our results comparable to literature and applicable into clinical practice.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cp\u003e5-Fu/Lv: 5-Fluorouracil and Leucovorin\u003c/p\u003e\n\u003cp\u003eAJCC: American Joint Commission on Cancer\u003c/p\u003e\n\u003cp\u003eAPR: Abdominoperineal Resection\u003c/p\u003e\n\u003cp\u003eAV: Anal Verge\u003c/p\u003e\n\u003cp\u003eC30SumScore: C30 Summary Score\u003c/p\u003e\n\u003cp\u003eCT: Computer Tomography\u003c/p\u003e\n\u003cp\u003eCTCAE: Common Terminology for Adverse Events\u003c/p\u003e\n\u003cp\u003eEORTC: European Organization for Research and Treatment of Cancer\u003c/p\u003e\n\u003cp\u003eEUS: Endorectal Ultrasound\u003c/p\u003e\n\u003cp\u003eINCA: \u003cem\u003eInstituto Nacional de Cancer\u003c/em\u003e (National Cancer Institute of Brazil)\u003c/p\u003e\n\u003cp\u003eISR: Intersphincteric Resection\u003c/p\u003e\n\u003cp\u003eLAR: Low Anterior Resection\u003c/p\u003e\n\u003cp\u003eLARC: Locally Advanced Rectal Cancer\u003c/p\u003e\n\u003cp\u003eLARS: Low Anterior Resection Syndrome\u003c/p\u003e\n\u003cp\u003eMRI: Magnetic Resonance Imaging\u003c/p\u003e\n\u003cp\u003eneoCRT: Neoadjuvant Chemoradiotherapy\u003c/p\u003e\n\u003cp\u003eQLQ-C30: Quality of Life Questionnaire C30\u003c/p\u003e\n\u003cp\u003eQOL: Quality of Life\u003c/p\u003e\n\u003cp\u003eSD: Standard Deviation\u003c/p\u003e\n\u003cp\u003eTME: Total Mesorectal Excision\u003c/p\u003e\n\u003cp\u003eUSA: United States of America\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to participate\u003c/strong\u003e: this was a prospective study approved by Ethics Committee of National Cancer Institute of Brazil (INCA) in 2010 under register number 83/10 (NCT03428529). All patients voluntarily agreed to participate after informed consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: all authors declare that they consented to submit the paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data\u003c/strong\u003e: the datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: all authors declare that they have no conflicts of interests and consented to submit the paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: the present study was totally supported by the Division of Clinical Research and Technological Development of the National Cancer Institute of Brazil, subordinated to the Ministry of Health of Brazil.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e: all the Authors made substantial contributions to the manuscript as follows:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudy concepts: Carlos Gil Ferreira and Eduardo Linhares. Study design: Fernando Meton Vieira, Rodrigo Otavio de Castro Araujo, Ana Paula Ornellas. Data acquisition: Rodrigo Otavio de Castro Araujo, Simone Guaraldi and Claudia Carrada. Quality control of data and algorithms: Ana Paula Ornellas, Ivanir Martins, Claudia Carrada. Data analysis and interpretation: Rodrigo Otavio de Castro Araujo e Luiz Claudio Santos Thuler. Statistical analysis: \u0026nbsp;Rodrigo Otavio de Castro Araujo e Luiz Claudio Santos Thuler. Manuscript preparation: Rodrigo Otavio de Castro Araujo. Manuscript editing: Marcus Vinicius Valad\u0026atilde;o and Simone Guaraldi. Manuscript review: All the authors above.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e:\u0026nbsp;We would like to thank all the supporting team of the mentioned Division, especially Dr. Andreia Cristina de Melo, Isabelle Small, Giovana Kovalesky, Alexandre de Souza Fonseca, Cecilia Ferreira da Silva, and all the staff involved in the protocol.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e: The datasets during and/or analyzed during the current study are\u0026nbsp;publicly\u0026nbsp;available at Mendeley dataset as: Araujo, Rodrigo Otavio (2021), \u0026ldquo;INCAGI004\u0026rdquo;, Mendeley Data, V1, doi: 10.17632/75vdm7phv9.1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: The present study was totally supported by the Division of Clinical Research and Technological Development of the National Cancer Institute of Brazil, subordinated to the Ministry of Health of Brazil. We would like to thank all the supporting team of the mentioned Division, especially Dr. Andreia Cristina de Melo, Isabelle Small, Giovana Kovalesky, Alexandre de Souza Fonseca, Cecilia Ferreira da Silva, and all the staff involved in the protocol.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians [Internet]. 2018 Nov [cited 2020 Dec 5];68(6):394\u0026ndash;424. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/28685354/\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Rectal Cancer, Quality of Life, Neoadjuvant Treatment, Radiotherapy, Chemotherapy, Surgical Oncology","lastPublishedDoi":"10.21203/rs.3.rs-121936/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-121936/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the standard of care for locally advanced rectal cancer (LARC), but the emergence of different drug regimens may result in different response rates. Good clinical response translates into greater sphincter preservation, but quality of life (QOL) may be impaired after treatment due to chemoradiotherapy and surgical side effects. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To prospectively evaluate the QOL in a randomized trial comparing two neoadjuvant regimens for locally advanced rectal cancer.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Stage II and III rectal cancer patients were randomized to receive neoCRT with either capecitabine (Group 1) or 5-Fu and leucovorin (Group 2) concomitant to long course radiotherapy. Clinical downstaging was accessed using MRI 6-8 weeks after treatment. EORTCs QLQ C30 and CR38 were applied before treatment (T0), after neoCRT (T1), after rectal resection (T2), early after adjuvant chemotherapy (T3), and one year after end of treatment or stoma closure (T4). Wexner scale was used for continence evaluation at T4. A C30SummaryScore (Geisinger et cols) was calculated to compare QOL results. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e 32 patients were assigned to Group 1 and 31 to Group 2. Clinical downstaging occurred in 70.0% of Group 1 and 53.3% of Group 2 (p=0.288). pCR was 23.3% in group 1 and 10.0% in Group 2(p=0.165). Sphincter preservation was 83.3% in Group 1 and 80.0% in Group 2(p=0.111). No difference in QOL was detected comparing the two treatment groups before and after neoCRT. C30SummaryScore detected improvement comparing T0 to T1 and deterioration comparing T1 to T2 (p=0.025), and global health status improved at T1 and T4 compared to T0(p=0.004). Mean Wexner scale score was 9.2, and a high score correlated with symptoms of diarrhea and defecation problems at T4.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Clinical and pathological response rates were equivalent in both treatment groups. QOL was improved after neoCRT corresponding to clinical response but decreased following rectal resection. Wexner score was high after sphincter preservation. C30SummaryScore was a useful tool to detect differences in overall QOL in EORTCs multiple item questionnaire.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTrial registration:\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e NCT03428529. Registered 02/09/2018 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03428529.\u003c/em\u003e\u003c/p\u003e","manuscriptTitle":"Quality of Life in a Randomized Trial Comparing Two Neoadjuvant Regimens for Locally Advanced Rectal Cancer – INCAGI004.","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2021-11-15 15:21:54","doi":"10.21203/rs.3.rs-121936/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-12-01T16:14:18+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-11-07T22:13:28+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Supportive Care in Cancer","date":"2021-11-03T18:54:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2021-09-26T10:33:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"920c45f2-cff8-4735-b1ae-e9b50e4d60cc","owner":[],"postedDate":"November 15th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":8505951,"name":"Cancer Biology"},{"id":8505952,"name":"Oncology"}],"tags":[],"updatedAt":"2022-04-11T12:28:51+00:00","versionOfRecord":[],"versionCreatedAt":"2021-11-15 15:21:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-121936","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-121936","identity":"rs-121936","version":["v2"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}