Preoperative Chemoradiotherapy in Older Patients with Rectal Cancer Guided by Comprehensive Geriatric Assessment within a Multidisciplinary Team—A Multicenter Phase II Trial

Preoperative Chemoradiotherapy in Older Patients with Rectal Cancer Guided by Comprehensive Geriatric Assessment within a Multidisciplinary Team—A Multicenter Phase II Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Preoperative Chemoradiotherapy in Older Patients with Rectal Cancer Guided by Comprehensive Geriatric Assessment within a Multidisciplinary Team—A Multicenter Phase II Trial Wen-Yang Liu, Yuan Tang, Ning Li, Yu Tang, Yun-Jie Cheng, Lin Yang, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2849544/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background and purpose: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as “fit” by comprehensive geriatric assessment (CGA). Methods: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of “fit” (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). Results: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category, Sixty-eight fit patients were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced nonhematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). Conclusion: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. Rectal cancer Preoperative chemoradiotherapy Comprehensive geriatric assessment Geriatric oncology Figures Figure 1 Figure 2 Introduction The patient population with rectal cancer is predominantly of older age [ 1 , 2 ]. However, the choice of treatment regimen is a challenging decision for these patients because older patients are rarely enrolled in specific prospective trials [ 3 ]. For older patients with locally advanced rectal cancer, preoperative concurrent chemoradiotherapy (preCRT) is the preferred option if they are considered fit according to several consensuses [ 3 , 4 ]. Despite the recommendations from these publications, the evidence mostly comes from retrospective studies or subgroup analyses of prospective trials [ 5 – 7 ], until the recent release of one randomized controlled trial (RCT) PRODIGE 42/GERICO 12 study comparing short course radiotherapy with chemoradiotherapy for locally advanced rectal cancer (LARC) in the older patients [ 8 ]. Still, geriatric assessment outcome was analyzed for change after treatment, but not as specific stratification tool for decision making in the PRODIGE 42/GERICO 12 study. Consequently, to date, there are no robust data to support the appropriate therapy for LARC patients with a particular status as judged by a geriatric assessment tool [ 9 ]. A multidisciplinary team (MDT) is essential for developing the complex treatment required by rectal cancer[ 10 ]. The frailty assessment is also important [ 11 ]. Comprehensive geriatric assessment (CGA) is the most widely used evaluation method and is strongly recommended by the International Society of Geriatric Oncology for older cancer patients [ 12 ]. Although time consuming, this tool provides an exhaustive assessment of major dimensions of frailty, including but not limited to comorbid conditions, nutritional status, and cognitive performance. A previous study indicated that CGA could predict the safety of surgery in patients with colorectal cancer [ 13 ]. Recently, multiple randomized trials have demonstrated that CGA can help tailor regimens [ 14 ] and decrease cancer treatment toxicity [ 15 , 16 ]. Nevertheless, in rectal cancer, CGA is seldom investigated for its impact on decision-making [ 3 ]. One randomized trial included frail older patients to receive preoperative GA and accordingly tailored interventions only for surgery; unfortunately, Grade II–V complications were not reduced in these patients who underwent elective surgery for colorectal cancer (CRC) [ 17 ]. Without a CGA evaluation, our previous phase I trial in rectal cancer patients aged 75 years indicated higher levels of toxicity from preCRT, and surprisingly, the planned surgery was conducted in less than half of the patients [ 18 ]. In addition, poor mucositis tolerance and more cardiovascular comorbidities were observed in these patients. Consequently, this multicenter phase II trial, guided by MDT and CGA was designed, in order to validate the concept that “fit” older patients with LARC can receive the same standard of care as younger counterparts. Raltitrexed was combined with concurrent radiotherapy due to its lower incidence of inducing mucositis and cardiac toxicity in this study [ 19 , 20 ]. Our prior finding in the interim analysis showed that preCRT is well tolerated with high compliance in fit older patients [ 21 ]. Here, we report the primary endpoint of 2-year disease-free survival (DFS) according to the TREND statements ( https://www.cdc.gov/trendstatement/pdf/trendstatement_trend_checklist.pdf ). Methods Approval was authorized by the ethics committee for this trial, and registration was on ClinicalTrials.gov. Trial design Details of the design and implementation of this study have been previously reported [ 21 ]. Briefly, eligible patients met the criteria of being fit according to the standard of SIOG1 [ 22 ], with no evidence of serious comorbidity (CISR-G Grade 0, 1 or 2), no dependence in IADL and ADL or malnutrition, and those aged 70 years or above with rectal adenocarcinoma fulfilled the standard of locally advanced risk category (bad and ugly) defined by the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines [ 10 ]. All patients were evaluated carefully and identified as candidates for preCRT by the MDT. Procedures CGA was conducted for all participants by a geriatric oncologist with more than 5 years of experience in CGA after written informed consent was provided. And the components of the CGA were presented in Table 2 . Chest and abdominal computed tomography, endoscopic ultrasound (EUS), and/or pelvic magnetic resonance imaging (MRI) were used for clinical staging evaluation (according to the AJCC 7th edition). Except for patients who refused preCRT, all patients who met the inclusion criteria were enrolled in the study. Preoperative chemoradiotherapy with raltitrexed was delivered to the patients, followed by surgery. Radiotherapy was delivered to a planning target volume (in accordance with the International Consensus [ 23 ]) with a dose of 50 Gy (2.0 Gy daily, 5 days per week) with intensity-modulated radiotherapy or volumetric-modulated arc therapy. Chemotherapy was administered concurrently (altitrexed, intravenous infusion, 3 mg/m 2 on days 1 and 22). The National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. was used for toxicity assessment, and the Clavien–Dindo system was employed for evaluating surgery-related complications. Endpoints and statistical analysis The primary endpoint was DFS, which was defined as the interval between the end of preCRT or surgery and the recurrence or death from any cause firstly occurred. The secondary end points included overall survival (OS, time from the end of preCRT or surgery to death because of any cause), cancer-specific survival (CSS, time from the end of preCRT or surgery to death because of cancer), the ratio of patients occured pathologic complete response (pCR) and the ratio of patients occurred Grade 3 or higher adverse events (During chemoradiotherapy and within 180 days after surgery). Exploratory endpoints included investigating the CGA elements, and willingness evaluation to surgery for predicting the adherence. Fifty-one patients were required to test the hypothesis that the 2-year DFS was equal to or greater than 78% (This value was based on the data from five large European rectal cancer trials) [ 24 ], if the lower bound of 95% CI for 2-year DFS in this study is greater than 63%, with 80% power at a significance level of 5% (one-sided) to reject the null hypothesis, then the study treatment would be considered efficient. Considering a 5% drop-out rate and a 20% rate of surgery refusal, 68 patients had to be included. Analysis was based on the intention-to-treat principle. However, given the instability of older patients' adherence for surgery, per-protocol population (PP) was prospectively defined as those who were willing and attempted to undergo surgery (whether it was successful or not) or were evaluated as complete clinical response (CCR) and suited for receiving the watch-and-wait strategy, in order to provide more information. Survivals were analyzed with the Kaplan-Meier method. Evaluation of the factors influencing the compliance of patients for surgery was analyzed by multivariate logistic regression. Frequency was used to describe the toxicities and treatment completion rate. All statistical analysis except the primary endpoint hypothesis were tested at a two-sided significance level of 0.05. Calculations were conducted by IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. Results Between Sep. 2016 and Oct. 2019, from two cancer centers in China, 109 patients were evaluated by the MDT and CGA, of whom 86, 11, and 12 were classified into the fit, intermediate and frail category, respectively. Among these fit patients, 68 were enrolled into this trial (Fig. 1 ). The intention-to-treat (ITT) population (68) was analyzed for the primary endpoint and safety. The per-protocol (PP) population (51) was also evaluated for the primary endpoint as planned. Patients had a median age of 74 years (range 71–89). The tumor characteristics and CGA evaluation of the patients are shown in Table 1 and Table 2 , respectively. In 55 (80.1%) patients, at least one high-risk factor was observed on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes). Table 1 Baseline characteristics Parameters No. (%) (N = 68) Age in years, median (range) 74 (71–89) 71–74 37 (54.4) 75–79 25 (36.8) 80–89 6 (8.8) Gender Female 25 (36.8) Male 43 (63.2) Tumor stage evaluation Pelvic MRI 65 (95.6) EUS and pelvic CT 3 (4.4) Primary tumor Stage T2 2 (2.9) T3 49 (72.1) T4a 10 (14.7) T4b 7 (10.3) Nodal stage N0 16 (23.5) N1a-b 34 (50.0) N2a-b 28 (26.5) MRF status Negative 20 (29.4) Positive 47 (69.1) NA 1 (1.5) EMVI Negative 46 (67.6) Positive 19 (27.9) NA 3 (4.4) Distance from anal verge (cm) ≤ 5 49 (72.1) 5–10 17 (25.0) 11 2 (2.9) Histology Adenocarcinoma (NOS) 22 (32.4) Well differentiated adenocarcinoma 3 (4.4) Moderately differentiated adenocarcinoma 35 (51.5) Poorly differentiated adenocarcinoma 7 (10.3) Mucinous adenocarcinoma 1 (1.5) Abbreviations: MRI, magnetic resonance imaging. EUS, endoscopic ultrasound. CT, computed tomography. MRF, mesorectal fascia. EMVI, Extramural vascular invasion. NOS, not otherwise specified. Table 2 Baseline geriatric assessment of patients Geriatric Parameters No. (%) (N = 68) KPS 90 1 (1.5) 80 63 (92.6) 70 4 (5.9) CCI 0 46 (67.6) 1 17 (25.0) 2 5 (7.4) CIRS-G score 0 15 (22.1) 1–3 33 (48.5) 4–6 20 (29.4) ADL 100 55 (80.9) 95 7 (10.3) 90 6 (8.8) IADL 8 65 (95.6) 7 2 (2.9) 6 1 (1.5) MNA ≥ 24 49 (72.1) 17–24 19 (27.9) TUG ≤ 10 58 (85.3) 11–15 10 (14.7) GDS15 2 (5.1) ≤ 4 65 (95.6) 4–8 2 (2.9) > 8 1 (1.5) MMSE 26–30 57 (83.8) 20–25 11 (16.2) Abbreviations: ADL, activities of daily living; CCI, Charlson Comorbidity Index; CGA, comprehensive geriatric assessment; CIRS-G, Cumulative Illness Rating Scale for Geriatrics; GDS15, Geriatric Depression Scale 15; IADL, instrumental activities of daily living; MMSE, Mini-Mental State Examination; MNA, Mini Nutritional Assessment; PS, performance status; TUG, Timed "Up & Go". Treatment compliance During the preoperative phase, 94.1% and 79.3% of the patients finished the prescription RT dose and concurrent chemotherapy as scheduled, respectively (five patients received 1650 mg/m 2 capecitabine, three due to physician error and the other two due to the convenience of outpatient oral administration, Table 3 ). Among the 58 candidates for surgery after preCRT, seven personally refused the operation. Of the remaining 10 patients not considered for surgery, there were six due to unresectable disease, three due to distant metastasis and one due to lung cancer confirmed. Table 3 Preoperative CRT and surgery completion profile Items No. (%) (N = 68) RT Dose delivered as planned 64 (94.1) Break required for toxicity 12 (17.6) Break duration [days, median (range)] 4 (2 ~ 26) Concurrent chemotherapy Scheduled dose 54 (79.3) Break required for toxicity 3 (4.4) 50%-90% of scheduled dose for toxicity 14 (20.7) Omitted surgery 20 (29.4) Refusal 7 (10.3) Unresectable 6 (8.8) Metastasis occurred before operation 3 (4.4) Wait-and-see for CCR 2 (2.9) Confirmation of lung cancer 1 (1.5) Adverse event during anesthesia 1 (1.5) Abbreviations: CRT, chemoradiotherapy; RT, radiotherapy; CCR, complete clinical response. Important clinical factors, including sex, age, mesorectal fascia (MRF) status, and especially patient and family willingness, were analyzed. The sole significant factor could predict the surgery compliance was the patient’s own willingness to undergo treatment (relative risk 0.2, 95% CI 0.07–0.58, P = 0.003). The likelihood of receiving surgery was 0.2 of the antecedent value when the score decreased by one point. Safety Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced nonhematological side effects. Leukopenia, diarrhea, and fatigue were the most common serious (G3 and G4) acute toxicities (Table 4 ). Five (10.4%) surgery-related complications occurred. Classified by the Clavien–Dindo system, there were 2 Grade I-II events (intestinal obstruction and dysuria), and one Grade IIIb (poor wound healing requiring skin grafting), Grade IV (stroke with residual functional hemiparesis) and Grade V event each (death within one week after surgery). The 30-day and 6-month mortality rates were both 1.5% (n = 1). Table 4 CRT Toxicity Toxicity All grade (No., %) (N = 68) Grade 3–4 (No., %) (N = 68) Overall 67 (98.5%) 24 (35.3) Hematologic Leukopenia 41 (60.3) 12 (17.7) Anemia 7 (10.3) - Thrombocytopenia 2 (2.9) - Non-hematologic - Anorexia 29 (42.7) 1 (1.5) Fatigue 27 (31.8) 4 (5.9) Diarrhea 21 (30.8) 7 (10.3) Radiation dermatitis 18 (26.5) 1 (1.5) Transaminase elevation 12 (17.6) 2 (2.9) Pain 24 (35.3) - Proctitis 19 (27.9) 1(1.5) Weight loss 9 (10.6) - Fever 4 (5.9) 1(1.5) Vomiting 2 (2.9) - Urinary frequency 3 (4.4) - Hand-foot syndrome - 1 (1.5) Cardiac events 1 (1.5) - Abbreviations: CRT, chemoradiotherapy. Oncological outcome Overall, 48 patients underwent surgery, with a median interval between preCRT and surgery of 9.1 weeks (range: 5.6-104.1 weeks). The pathological response and evaluation are shown in Table S1 . Among 47 MRF + patients, 36 (76.6%) received R0 resection. Three patient (4.4%) was lost to follow-up during a median of 36.0 months (range: 5.9–63.1 months); among the ITT population, eight local progression (2 recurrence included), fourteen metastases and fifteen deaths were observed; therefore, the primary end-point, the 2-year DFS was 75.6% (95% CI: 65.2–86.0), and the 2-year OS, CSS were 89.6% (95% CI: 82.3–96.9), and 92.4% (95% CI: 85.9–98.9), respectively. In the PP population (51), two local recurrence, nine metastases and four deaths were observed; therefore, the 2-year DFS, was 85.3% (95% CI: 75.1–95.5) (Fig. 2 ), and the 2-year OS, and CSS were 96.1% (95% CI: 90.8–100.0), and 98.0% (95% CI:94.1–100.0), respectively. Discussion Despite current guidelines [ 10 ] and consensuses [ 3 ] recommending that “fit” older rectal cancer patients receive the same regimen as their younger counterparts, this concept still awaits verification in more prospective trials, especially the specific repeatable standard of frailty for adjusting the intervention. This study is the first exploration of CGA-driven stratified therapy based on the SIOG1 standard in older patients with LARC to evaluate the safety and efficacy of preCRT combined with the total mesorectal excision (TME) for a “fit” population. Through the ITT regimen, comparable oncological results were achieved between these older individuals and their younger counterparts from our STELLAR trial (about 75% 2-year DFS) during the same period of time [ 25 ], and the overall toxicity profile was generally tolerable. The primary endpoint of the study was met in the context of an effective and regular MDT; hence, the concept originating from guidelines and consensuses was validated. Moreover, a better understanding of the specific problem and challenges for older rectal cancer patients was provided in a quantitative geriatric assessment system. Given that 2-year DFS is a stronger predictor for OS than pCR [ 24 ], this surrogate was selected as the primary endpoint in the current study rather than pCR. Compared with the 75–80% 2-year DFS observed in several RCTs [ 26 – 28 ], the 2-year DFS (75.6%) in the older patients of this study was quite satisfactory. “Fit” older patients have a low burden of comorbidities and are in good physiological and psychological status; thus, a previous study in colorectal cancer showed that the 3-year noncancer mortality was < 2%. Hence, the correlation between the 2-year DFS and OS in this study can be expected in longer follow-up, because the 3-year noncancer mortality was only 1.9%. In the general population with LARC, a personalized neoadjuvant strategy can be properly conducted according to tumor risk stratification [ 10 ]; unfortunately, the utilization of these approaches is severely restricted in patients of advanced age. Recent total neoadjuvant therapy (TNT) studies have demonstrated an improved DFS and more pCR [ 27 , 28 ], but more toxicities and no improvement in OS were observed. This has complicated clinical decision making about neoadjuvant therapy in older patients with high-risk LARC. Short-course preoperative radiotherapy (SCPRT) followed by delayed surgery has greater potential for clinical application in a wider older population without limitation for geriatric status [ 8 ]. However, the final results of the PRODIGE 42/GERICO 12 study indicated that the non-inferiority in R0 resection rate was not achieved through SCPRT (25 Gy, 5 Gy/f) with delayed surgery comparing to the preCRT (50 Gy, 2 Gy/fraction + capecitabine) (R0 resection rate: 84.3% vs. 88.0%) in patients aged > 75 years with WHO physical status (PS) ≤ 2 [ 8 ]. Furthermore, CGA and MRF status were, notably, not used in that study for inclusion criteria or stratification tool (at least, not reported), which may be the reason for the intragroup heterogeneity in the physiological state and the resectability of tumor, making it difficult to extract accurate information on the balance of benefit-risk. Moreover, compared with preCRT, SCPRT was inferior in reaching pCR (11.8% pCR was achieved in Stockholm III and approximately 15–20% in most preCRT studies) [ 29 – 32 ] and resectability conversion for MRF + patients [ 10 ]. Even though the pCR rate in this study might appear to be low, it is still substantial considering that 69.1% of patients were MRF+, comparing with 12.3% of pCR rate was obtained in the control arm from contemporaneous STELLAR trial with 56.2% of patients were MRF+ [ 25 ]. Coupled with 76.6% of R0 resection rate for MRF + patients, overall, the clinical application value of the current results for preCRT merits further research in “fit” older patients, especially for those patients with high-risk factors presented in RAPIDO [ 27 ]. From the perspective of greater surgery-related risk in advanced age patients, it may be prudent to explore some highly intensified treatments (TNT- or MRI-guided tumor boost) when the potential benefit of organ preservation outweighs their risks. This study finally confirms the previous finding in our interim analysis [ 21 ], in which a relatively high proportion of older patients declined surgery. Rationally, it is not surprising that a large number of older patients do not aggressively advocate for surgery, especially in a multiple treatment setting [ 33 ]. This suggests that prediction of surgery omission is important for older individuals, providing an opportunity for timely conduction boost by contact X-ray brachytherapy [ 34 ] or local excision [ 35 ]. In agreement with our previous report [ 21 ], the final result confirmed a role of the willingness evaluation of patients in predicting the compliance with surgery, which should be employed in future investigations. Even more comprehensive communication with patients and training for physicians [ 36 ] may be needed in the shared decision-making era. With respect to safety, compared with other studies, although the frequency of G3 or G4 acute toxicities induced by preCRT in this study was evidently higher than that in a younger population [ 19 ] and seemed to be slightly higher than that in older people [ 6 ], the majority of these toxicities were hematological, which is consistent with our previous interim analysis [ 21 ]. It is worth emphasising that most of the previous studies on older individuals were retrospective. Although the subgroup analysis for the older patients by Francois et al was from a randomized trial[ 6 ], the geriatric assessment tool was not employed as a quantitative standard. Different chemotherapy regimens and lack of CGA in earlier studies make it difficult to compare their findings with those of our study. In addition, the 79.3% completion rate for concurrent chemotherapy appeared to be greater than the scheduled dose delivery rate of 43.6% in a study from Francois [ 6 ] (half of the patients received a combination of capecitabine and oxaliplatin). It is worth mentioning that 32% of G3-5 toxicities in pre-operative phase were observed in chemoradiotherapy group of PRODIGE 42/GERICO study [ 8 ]. On the other hand, although all the patients in the preliminary results from PRODIGE 42/GERICO 12 [ 37 ] and half of the participants in the current study were aged 75 years and older, respectively, the 6-month mortality was much lower in our study (1.7% vs. 10%). The SIOG1 standard has high discriminability for 1-year mortality [ 38 ] and thus contributed more to the safety of this study. Consequently, given the similar acute toxicities frequency found in the newly PRODIGE 42/GERICO study [ 8 ] specifically designed for the older patients, it seems that the toxicity of the current regimen is tolerable and can be selected as a reference for relevant studies in the future. The main limitations of the current study include the single-arm design and relatively short follow-up time. Beside the abovementioned shortcomings, due to the fact that the surgeons and patients were both more cautious for safety when confronted with advanced age and potential vulnerability, 80.1% of the patients included in our study were at high-risk, this may limit extrapolation of the results in general older patients with LARC. On the other hand, the patient-reported outcomes were lacked in the current study. Conclusions Our results confirmed that preCRT is an effective treatment with tolerable toxicities for fit older people with locally advanced rectal cancer. Implementation of CGA before development of a treatment strategy should be considered in future research. Declarations Prior presentation Presented in part at the European Society for Radiotherapy and Oncology 2021 Annual Meeting, 27-31 August, Madrid, Spain. Trial registration The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016). Ethics approval and consent to participate The Ethics Committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College has approved all experimental protocols of the current study. And all methods were carried out in accordance with the Helsinki declaration. Informed consent was obtained from all participants and/or their legal guardian(s). Consent for publication Not applicable. Availability of data and material Research data are stored in an institutional repository and will be shared upon request to the corresponding author. Competing interests None. Funding This project was funded by Beijing Municipal Science & Technology Commission (No. Z181100001718136), National Natural Science Foundation of China (82073352), Beijing Hope Run Special Fund of Cancer Foundation of China (No. LC2018A24 and LC2022A16) Authors' contributions Wen-Yang Liu, Conception and Design, Data Collection, Analysis and Interpretation of Data, Manuscript Writing, Approval of Final Article; Jing Jin, Conception and Design, Analysis and Interpretation of Data, Manuscript Writing, Approval of Final Article; Yuan Tang, Data Collection, Approval of Final Article; Ning Li, Data Collection, Approval of Final Article; Yu Tang, Data Collection, Approval of Final Article; Jun Wang, Data Collection, Approval of Final Article; Yun-Jie Cheng, Data Collection, Approval of Final Article; Lin Yang, Data Collection, Approval of Final Article; Hui Fang, Data Collection, Approval of Final Article; Ning-Ning Lu, Data Collection, Approval of Final Article; Shu-Nan Qi, Data Collection, Approval of Final Article; Bo Chen, Data Collection, Approval of Final Article; Shu-Lian Wang, Data Collection, Approval of Final Article; Yong-Wen Song, Data Collection, Approval of Final Article; Yue-Ping Liu, Data Collection, Approval of Final Article; Ye-Xiong Li, Data Collection, Approval of Final Article; Zheng Liu, Data Collection, Approval of Final Article; Hai-Tao Zhou, Data Collection, Approval of Final Article; Jian-Wei Liang, Data Collection, Approval of Final Article; Wei Pei, Data Collection, Approval of Final Article; Xi-Shan Wang, Data Collection, Approval of Final Article; Hai-Zeng Zhang, Data Collection, Approval of Final Article. 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Valentini V, Gambacorta MA, Barbaro B, Chiloiro G, Coco C, Das P, et al. International consensus guidelines on Clinical Target Volume delineation in rectal cancer. Radiother Oncol. 2016;120(2):195–201. https://doi.org/10.1016/j.radonc.2016.07.017 . Valentini V, van Stiphout RG, Lammering G, Gambacorta MA, Barba MC, Bebenek M, et al. Selection of appropriate end-points (pCR vs 2yDFS) for tailoring treatments with prediction models in locally advanced rectal cancer. Radiother Oncol. 2015;114(3):302–9. https://doi.org/10.1016/j.radonc.2015.02.001 . Jin J, Tang Y, Hu C, Jiang LM, Jiang J, Li N, et al. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J Clin Oncol. 2022;40(15):1681–92. https://doi.org/10.1200/JCO.21.01667 . Valentini V, van Stiphout RG, Lammering G, Gambacorta MA, Barba MC, Bebenek M, et al. Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials. J Clin Oncol. 2011;29(23):3163–72. https://doi.org/10.1200/JCO.2010.33.1595 . Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):29–42. https://doi.org/10.1016/S1470-2045(20)30555-6 . Conroy T, Bosset JF, Etienne PL, Rio E, Francois E, Mesgouez-Nebout N, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(5):702–15. https://doi.org/10.1016/S1470-2045(21)00079-6 . Erlandsson J, Holm T, Pettersson D, Berglund A, Cedermark B, Radu C, et al. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol. 2017;18(3):336–46. https://doi.org/10.1016/S1470-2045(17)30086-4 . Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol. 2012;30(31):3827–33. Tan Y, Fu D, Li D, Kong X, Jiang K, Chen L, et al. Predictors and Risk Factors of Pathologic Complete Response Following Neoadjuvant Chemoradiotherapy for Rectal Cancer: A Population-Based Analysis. Front Oncol. 2019;9:497. https://doi.org/10.3389/fonc.2019.00497 . Qiaoli W, Yongping H, Wei X, Guoqiang X, Yunhe J, Qiuyan L, et al. Preoperative short-course radiotherapy (5 x 5 Gy) with delayed surgery versus preoperative long-course radiotherapy for locally resectable rectal cancer: a meta-analysis. Int J Colorectal Dis. 2019;34(12):2171–83. https://doi.org/10.1007/s00384-019-03433-9 . Kennedy ED, Borowiec AM, Schmocker S, Cho C, Brierley J, Li S, et al. Patient and Physician Preferences for Nonoperative Management for Low Rectal Cancer: Is It a Reasonable Treatment Option? Dis Colon Rectum. 2018;61(11):1281–9. https://doi.org/10.1097/DCR.0000000000001166 . Gerard JP, Montagne L, Thamphya B, Doyen J, Schiappa R, Benezery K, et al. Propensity score analysis of radical proctectomy versus organ preservation using contact X-ray brachytherapy for rectal cancer. Clin Transl Radiat Oncol. 2022;33:70–6. https://doi.org/10.1016/j.ctro.2021.12.007 . Rullier E, Vendrely V, Asselineau J, Rouanet P, Tuech JJ, Valverde A, et al. Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial. Lancet Gastroenterol Hepatol. 2020;5(5):465–74. https://doi.org/10.1016/S2468-1253(19)30410-8 . Geessink NH, Schoon Y, van Herk HC, van Goor H, Olde Rikkert MG. Key elements of optimal treatment decision-making for surgeons and older patients with colorectal or pancreatic cancer: A qualitative study. Patient Educ Couns. 2017;100(3):473–9. https://doi.org/10.1016/j.pec.2016.10.013 . Francois E, Pernot M, Ronchin P, Nouhaud E, Martel Lafay I, Pascal A, et al. NACRE: A randomized study comparing short course radiotherapy with radiochemotherapy for locally advanced rectal cancers in the elderly—Preliminary results. J Clin Oncol. 2021;39(3suppl):4–4. https://doi.org/10.1200/JCO.2021.39.3_suppl.4 . Ferrat E, Paillaud E, Caillet P, Laurent M, Tournigand C, Lagrange JL, et al. Performance of Four Frailty Classifications in Older Patients With Cancer: Prospective Elderly Cancer Patients Cohort Study. J Clin Oncol. 2017;35(7):766–77. https://doi.org/10.1200/JCO.2016.69.3143 . Additional Declarations No competing interests reported. Supplementary Files suppl.doc Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 26 Mar, 2024 Reviews received at journal 11 Mar, 2024 Reviewers agreed at journal 28 Feb, 2024 Reviews received at journal 20 Nov, 2023 Reviewers agreed at journal 28 Oct, 2023 Reviewers agreed at journal 24 Jul, 2023 Reviewers invited by journal 20 Jul, 2023 Editor assigned by journal 20 Jul, 2023 Editor invited by journal 19 Jun, 2023 Submission checks completed at journal 19 Jun, 2023 First submitted to journal 22 Apr, 2023 You are reading this latest preprint version 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. 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00:44:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2849544/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2849544/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":39121106,"identity":"79770d1b-9e88-420c-9bd8-57c386a94e88","added_by":"auto","created_at":"2023-06-26 21:19:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79700,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT diagram\u003c/p\u003e\n\u003cp\u003eAbbreviations: preCRT, preoperative chemoradiotherapy; ITT, intention-to-treat; CCR, complete clinical response; PP, per-protocol.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2849544/v1/11b4bfe571635fa39c80ac8b.png"},{"id":39121108,"identity":"f4bd6bd9-0dd9-4d9d-a8c6-cfc945402253","added_by":"auto","created_at":"2023-06-26 21:19:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":980533,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curve by Kaplan-Meier method. a, Overall survival for the ITT population; b, Disease free survival for the ITT population; c, Overall survival for the per-protocol population; d, Disease free survival for the per-protocol population.\u003c/p\u003e","description":"","filename":"Fig2KMcurve.png","url":"https://assets-eu.researchsquare.com/files/rs-2849544/v1/847536948e4f94149e473f66.png"},{"id":39121109,"identity":"aba874e6-a378-453f-95fb-1034feeae958","added_by":"auto","created_at":"2023-06-26 21:19:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":592285,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2849544/v1/cf4bdc6e-d749-4074-9929-330448f20f05.pdf"},{"id":39121107,"identity":"0bf37e4b-a323-427d-9fed-6b9972a32524","added_by":"auto","created_at":"2023-06-26 21:19:00","extension":"doc","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":37376,"visible":true,"origin":"","legend":"","description":"","filename":"suppl.doc","url":"https://assets-eu.researchsquare.com/files/rs-2849544/v1/502951bf708e04d8a174471d.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Preoperative Chemoradiotherapy in Older Patients with Rectal Cancer Guided by Comprehensive Geriatric Assessment within a Multidisciplinary Team—A Multicenter Phase II Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe patient population with rectal cancer is predominantly of older age [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, the choice of treatment regimen is a challenging decision for these patients because older patients are rarely enrolled in specific prospective trials [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor older patients with locally advanced rectal cancer, preoperative concurrent chemoradiotherapy (preCRT) is the preferred option if they are considered fit according to several consensuses [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Despite the recommendations from these publications, the evidence mostly comes from retrospective studies or subgroup analyses of prospective trials [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], until the recent release of one randomized controlled trial (RCT) PRODIGE 42/GERICO 12 study comparing short course radiotherapy with chemoradiotherapy for locally advanced rectal cancer (LARC) in the older patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Still, geriatric assessment outcome was analyzed for change after treatment, but not as specific stratification tool for decision making in the PRODIGE 42/GERICO 12 study. Consequently, to date, there are no robust data to support the appropriate therapy for LARC patients with a particular status as judged by a geriatric assessment tool [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA multidisciplinary team (MDT) is essential for developing the complex treatment required by rectal cancer[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The frailty assessment is also important [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Comprehensive geriatric assessment (CGA) is the most widely used evaluation method and is strongly recommended by the International Society of Geriatric Oncology for older cancer patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although time consuming, this tool provides an exhaustive assessment of major dimensions of frailty, including but not limited to comorbid conditions, nutritional status, and cognitive performance. A previous study indicated that CGA could predict the safety of surgery in patients with colorectal cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recently, multiple randomized trials have demonstrated that CGA can help tailor regimens [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] and decrease cancer treatment toxicity [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Nevertheless, in rectal cancer, CGA is seldom investigated for its impact on decision-making [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. One randomized trial included frail older patients to receive preoperative GA and accordingly tailored interventions only for surgery; unfortunately, Grade II\u0026ndash;V complications were not reduced in these patients who underwent elective surgery for colorectal cancer (CRC) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWithout a CGA evaluation, our previous phase I trial in rectal cancer patients aged 75 years indicated higher levels of toxicity from preCRT, and surprisingly, the planned surgery was conducted in less than half of the patients [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In addition, poor mucositis tolerance and more cardiovascular comorbidities were observed in these patients. Consequently, this multicenter phase II trial, guided by MDT and CGA was designed, in order to validate the concept that \u0026ldquo;fit\u0026rdquo; older patients with LARC can receive the same standard of care as younger counterparts. Raltitrexed was combined with concurrent radiotherapy due to its lower incidence of inducing mucositis and cardiac toxicity in this study [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Our prior finding in the interim analysis showed that preCRT is well tolerated with high compliance in fit older patients [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Here, we report the primary endpoint of 2-year disease-free survival (DFS) according to the TREND statements (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/trendstatement/pdf/trendstatement_trend_checklist.pdf\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/trendstatement/pdf/trendstatement_trend_checklist.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eApproval was authorized by the ethics committee for this trial, and registration was on ClinicalTrials.gov.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTrial design\u003c/h2\u003e \u003cp\u003eDetails of the design and implementation of this study have been previously reported [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Briefly, eligible patients met the criteria of being fit according to the standard of SIOG1 [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], with no evidence of serious comorbidity (CISR-G Grade 0, 1 or 2), no dependence in IADL and ADL or malnutrition, and those aged 70 years or above with rectal adenocarcinoma fulfilled the standard of locally advanced risk category (bad and ugly) defined by the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. All patients were evaluated carefully and identified as candidates for preCRT by the MDT.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eProcedures\u003c/h2\u003e \u003cp\u003eCGA was conducted for all participants by a geriatric oncologist with more than 5 years of experience in CGA after written informed consent was provided. And the components of the CGA were presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Chest and abdominal computed tomography, endoscopic ultrasound (EUS), and/or pelvic magnetic resonance imaging (MRI) were used for clinical staging evaluation (according to the AJCC 7th edition). Except for patients who refused preCRT, all patients who met the inclusion criteria were enrolled in the study.\u003c/p\u003e \u003cp\u003ePreoperative chemoradiotherapy with raltitrexed was delivered to the patients, followed by surgery. Radiotherapy was delivered to a planning target volume (in accordance with the International Consensus [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]) with a dose of 50 Gy (2.0 Gy daily, 5 days per week) with intensity-modulated radiotherapy or volumetric-modulated arc therapy. Chemotherapy was administered concurrently (altitrexed, intravenous infusion, 3 mg/m\u003csup\u003e2\u003c/sup\u003e on days 1 and 22). The National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. was used for toxicity assessment, and the Clavien\u0026ndash;Dindo system was employed for evaluating surgery-related complications.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints and statistical analysis\u003c/h2\u003e \u003cp\u003eThe primary endpoint was DFS, which was defined as the interval between the end of preCRT or surgery and the recurrence or death from any cause firstly occurred. The secondary end points included overall survival (OS, time from the end of preCRT or surgery to death because of any cause), cancer-specific survival (CSS, time from the end of preCRT or surgery to death because of cancer), the ratio of patients occured pathologic complete response (pCR) and the ratio of patients occurred Grade 3 or higher adverse events (During chemoradiotherapy and within 180 days after surgery). Exploratory endpoints included investigating the CGA elements, and willingness evaluation to surgery for predicting the adherence. Fifty-one patients were required to test the hypothesis that the 2-year DFS was equal to or greater than 78% (This value was based on the data from five large European rectal cancer trials) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], if the lower bound of 95% CI for 2-year DFS in this study is greater than 63%, with 80% power at a significance level of 5% (one-sided) to reject the null hypothesis, then the study treatment would be considered efficient. Considering a 5% drop-out rate and a 20% rate of surgery refusal, 68 patients had to be included.\u003c/p\u003e \u003cp\u003eAnalysis was based on the intention-to-treat principle. However, given the instability of older patients' adherence for surgery, per-protocol population (PP) was prospectively defined as those who were willing and attempted to undergo surgery (whether it was successful or not) or were evaluated as complete clinical response (CCR) and suited for receiving the watch-and-wait strategy, in order to provide more information.\u003c/p\u003e \u003cp\u003eSurvivals were analyzed with the Kaplan-Meier method. Evaluation of the factors influencing the compliance of patients for surgery was analyzed by multivariate logistic regression. Frequency was used to describe the toxicities and treatment completion rate. All statistical analysis except the primary endpoint hypothesis were tested at a two-sided significance level of 0.05. Calculations were conducted by IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBetween Sep. 2016 and Oct. 2019, from two cancer centers in China, 109 patients were evaluated by the MDT and CGA, of whom 86, 11, and 12 were classified into the fit, intermediate and frail category, respectively. Among these fit patients, 68 were enrolled into this trial (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The intention-to-treat (ITT) population (68) was analyzed for the primary endpoint and safety. The per-protocol (PP) population (51) was also evaluated for the primary endpoint as planned. Patients had a median age of 74 years (range 71\u0026ndash;89). The tumor characteristics and CGA evaluation of the patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e, respectively. In 55 (80.1%) patients, at least one high-risk factor was observed on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. (%) (N\u0026thinsp;=\u0026thinsp;68)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge in years, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (71\u0026ndash;89)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e71\u0026ndash;74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (54.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e75\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (36.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e80\u0026ndash;89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (8.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (36.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (63.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor stage evaluation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePelvic MRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (95.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEUS and pelvic CT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary tumor Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (72.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (14.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (10.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNodal stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (23.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN1a-b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN2a-b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (26.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMRF status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (29.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (69.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEMVI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (67.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (27.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistance from anal verge (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (72.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u0026ndash;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma (NOS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (32.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWell differentiated adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerately differentiated adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (51.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoorly differentiated adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (10.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucinous adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eAbbreviations: MRI, magnetic resonance imaging. EUS, endoscopic ultrasound. CT, computed tomography. MRF, mesorectal fascia. EMVI, Extramural vascular invasion. NOS, not otherwise specified.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline geriatric assessment of patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeriatric Parameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. (%) (N\u0026thinsp;=\u0026thinsp;68)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKPS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63 (92.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (5.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46 (67.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (7.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIRS-G score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (22.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33 (48.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (29.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55 (80.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (10.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (8.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIADL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e65 (95.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49 (72.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u0026ndash;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19 (27.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTUG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e58 (85.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u0026ndash;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (14.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDS15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e65 (95.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e26\u0026ndash;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e57 (83.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11 (16.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eAbbreviations: ADL, activities of daily living; CCI, Charlson Comorbidity Index; CGA, comprehensive geriatric assessment; CIRS-G, Cumulative Illness Rating Scale for Geriatrics; GDS15, Geriatric Depression Scale 15; IADL, instrumental activities of daily living; MMSE, Mini-Mental State Examination; MNA, Mini Nutritional Assessment; PS, performance status; TUG, Timed \"Up \u0026amp; Go\".\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eTreatment compliance\u003c/h2\u003e \u003cp\u003eDuring the preoperative phase, 94.1% and 79.3% of the patients finished the prescription RT dose and concurrent chemotherapy as scheduled, respectively (five patients received 1650 mg/m\u003csup\u003e2\u003c/sup\u003e capecitabine, three due to physician error and the other two due to the convenience of outpatient oral administration, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Among the 58 candidates for surgery after preCRT, seven personally refused the operation. Of the remaining 10 patients not considered for surgery, there were six due to unresectable disease, three due to distant metastasis and one due to lung cancer confirmed.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePreoperative CRT and surgery completion profile\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eItems\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. (%) (N\u0026thinsp;=\u0026thinsp;68)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose delivered as planned\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (94.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreak required for toxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (17.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreak duration [days, median (range)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2\u0026thinsp;~\u0026thinsp;26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcurrent chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScheduled dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (79.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreak required for toxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50%-90% of scheduled dose for toxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (20.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOmitted surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (29.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRefusal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (10.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnresectable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (8.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastasis occurred before operation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWait-and-see for CCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConfirmation of lung cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse event during anesthesia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eAbbreviations: CRT, chemoradiotherapy; RT, radiotherapy; CCR, complete clinical response.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eImportant clinical factors, including sex, age, mesorectal fascia (MRF) status, and especially patient and family willingness, were analyzed. The sole significant factor could predict the surgery compliance was the patient\u0026rsquo;s own willingness to undergo treatment (relative risk 0.2, 95% CI 0.07\u0026ndash;0.58, P\u0026thinsp;=\u0026thinsp;0.003). The likelihood of receiving surgery was 0.2 of the antecedent value when the score decreased by one point.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eSerious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced nonhematological side effects. Leukopenia, diarrhea, and fatigue were the most common serious (G3 and G4) acute toxicities (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Five (10.4%) surgery-related complications occurred. Classified by the Clavien\u0026ndash;Dindo system, there were 2 Grade I-II events (intestinal obstruction and dysuria), and one Grade IIIb (poor wound healing requiring skin grafting), Grade IV (stroke with residual functional hemiparesis) and Grade V event each (death within one week after surgery). The 30-day and 6-month mortality rates were both 1.5% (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCRT Toxicity\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToxicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll grade (No., %) (N\u0026thinsp;=\u0026thinsp;68)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade 3\u0026ndash;4 (No., %) (N\u0026thinsp;=\u0026thinsp;68)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (98.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (35.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematologic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (60.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (17.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-hematologic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnorexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (42.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (31.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (5.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (10.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation dermatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (26.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransaminase elevation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (17.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (35.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProctitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (27.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (10.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary frequency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHand-foot syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: CRT, chemoradiotherapy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eOncological outcome\u003c/h2\u003e \u003cp\u003eOverall, 48 patients underwent surgery, with a median interval between preCRT and surgery of 9.1 weeks (range: 5.6-104.1 weeks). The pathological response and evaluation are shown in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. Among 47 MRF\u0026thinsp;+\u0026thinsp;patients, 36 (76.6%) received R0 resection. Three patient (4.4%) was lost to follow-up during a median of 36.0 months (range: 5.9\u0026ndash;63.1 months); among the ITT population, eight local progression (2 recurrence included), fourteen metastases and fifteen deaths were observed; therefore, the primary end-point, the 2-year DFS was 75.6% (95% CI: 65.2\u0026ndash;86.0), and the 2-year OS, CSS were 89.6% (95% CI: 82.3\u0026ndash;96.9), and 92.4% (95% CI: 85.9\u0026ndash;98.9), respectively. In the PP population (51), two local recurrence, nine metastases and four deaths were observed; therefore, the 2-year DFS, was 85.3% (95% CI: 75.1\u0026ndash;95.5) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), and the 2-year OS, and CSS were 96.1% (95% CI: 90.8\u0026ndash;100.0), and 98.0% (95% CI:94.1\u0026ndash;100.0), respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite current guidelines [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and consensuses [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] recommending that \u0026ldquo;fit\u0026rdquo; older rectal cancer patients receive the same regimen as their younger counterparts, this concept still awaits verification in more prospective trials, especially the specific repeatable standard of frailty for adjusting the intervention. This study is the first exploration of CGA-driven stratified therapy based on the SIOG1 standard in older patients with LARC to evaluate the safety and efficacy of preCRT combined with the total mesorectal excision (TME) for a \u0026ldquo;fit\u0026rdquo; population. Through the ITT regimen, comparable oncological results were achieved between these older individuals and their younger counterparts from our STELLAR trial (about 75% 2-year DFS) during the same period of time [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and the overall toxicity profile was generally tolerable. The primary endpoint of the study was met in the context of an effective and regular MDT; hence, the concept originating from guidelines and consensuses was validated. Moreover, a better understanding of the specific problem and challenges for older rectal cancer patients was provided in a quantitative geriatric assessment system.\u003c/p\u003e \u003cp\u003eGiven that 2-year DFS is a stronger predictor for OS than pCR [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], this surrogate was selected as the primary endpoint in the current study rather than pCR. Compared with the 75\u0026ndash;80% 2-year DFS observed in several RCTs [\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], the 2-year DFS (75.6%) in the older patients of this study was quite satisfactory. \u0026ldquo;Fit\u0026rdquo; older patients have a low burden of comorbidities and are in good physiological and psychological status; thus, a previous study in colorectal cancer showed that the 3-year noncancer mortality was \u0026lt;\u0026thinsp;2%. Hence, the correlation between the 2-year DFS and OS in this study can be expected in longer follow-up, because the 3-year noncancer mortality was only 1.9%.\u003c/p\u003e \u003cp\u003eIn the general population with LARC, a personalized neoadjuvant strategy can be properly conducted according to tumor risk stratification [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]; unfortunately, the utilization of these approaches is severely restricted in patients of advanced age. Recent total neoadjuvant therapy (TNT) studies have demonstrated an improved DFS and more pCR [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], but more toxicities and no improvement in OS were observed. This has complicated clinical decision making about neoadjuvant therapy in older patients with high-risk LARC. Short-course preoperative radiotherapy (SCPRT) followed by delayed surgery has greater potential for clinical application in a wider older population without limitation for geriatric status [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, the final results of the PRODIGE 42/GERICO 12 study indicated that the non-inferiority in R0 resection rate was not achieved through SCPRT (25 Gy, 5 Gy/f) with delayed surgery comparing to the preCRT (50 Gy, 2 Gy/fraction\u0026thinsp;+\u0026thinsp;capecitabine) (R0 resection rate: 84.3% vs. 88.0%) in patients aged\u0026thinsp;\u0026gt;\u0026thinsp;75 years with WHO physical status (PS)\u0026thinsp;\u0026le;\u0026thinsp;2 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Furthermore, CGA and MRF status were, notably, not used in that study for inclusion criteria or stratification tool (at least, not reported), which may be the reason for the intragroup heterogeneity in the physiological state and the resectability of tumor, making it difficult to extract accurate information on the balance of benefit-risk. Moreover, compared with preCRT, SCPRT was inferior in reaching pCR (11.8% pCR was achieved in Stockholm III and approximately 15\u0026ndash;20% in most preCRT studies) [\u003cspan additionalcitationids=\"CR30 CR31\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] and resectability conversion for MRF\u0026thinsp;+\u0026thinsp;patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Even though the pCR rate in this study might appear to be low, it is still substantial considering that 69.1% of patients were MRF+, comparing with 12.3% of pCR rate was obtained in the control arm from contemporaneous STELLAR trial with 56.2% of patients were MRF+ [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Coupled with 76.6% of R0 resection rate for MRF\u0026thinsp;+\u0026thinsp;patients, overall, the clinical application value of the current results for preCRT merits further research in \u0026ldquo;fit\u0026rdquo; older patients, especially for those patients with high-risk factors presented in RAPIDO [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. From the perspective of greater surgery-related risk in advanced age patients, it may be prudent to explore some highly intensified treatments (TNT- or MRI-guided tumor boost) when the potential benefit of organ preservation outweighs their risks.\u003c/p\u003e \u003cp\u003eThis study finally confirms the previous finding in our interim analysis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], in which a relatively high proportion of older patients declined surgery. Rationally, it is not surprising that a large number of older patients do not aggressively advocate for surgery, especially in a multiple treatment setting [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. This suggests that prediction of surgery omission is important for older individuals, providing an opportunity for timely conduction boost by contact X-ray brachytherapy [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] or local excision [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. In agreement with our previous report [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], the final result confirmed a role of the willingness evaluation of patients in predicting the compliance with surgery, which should be employed in future investigations. Even more comprehensive communication with patients and training for physicians [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] may be needed in the shared decision-making era.\u003c/p\u003e \u003cp\u003eWith respect to safety, compared with other studies, although the frequency of G3 or G4 acute toxicities induced by preCRT in this study was evidently higher than that in a younger population [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and seemed to be slightly higher than that in older people [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], the majority of these toxicities were hematological, which is consistent with our previous interim analysis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. It is worth emphasising that most of the previous studies on older individuals were retrospective. Although the subgroup analysis for the older patients by Francois et al was from a randomized trial[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], the geriatric assessment tool was not employed as a quantitative standard. Different chemotherapy regimens and lack of CGA in earlier studies make it difficult to compare their findings with those of our study. In addition, the 79.3% completion rate for concurrent chemotherapy appeared to be greater than the scheduled dose delivery rate of 43.6% in a study from Francois [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] (half of the patients received a combination of capecitabine and oxaliplatin). It is worth mentioning that 32% of G3-5 toxicities in pre-operative phase were observed in chemoradiotherapy group of PRODIGE 42/GERICO study [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. On the other hand, although all the patients in the preliminary results from PRODIGE 42/GERICO 12 [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] and half of the participants in the current study were aged 75 years and older, respectively, the 6-month mortality was much lower in our study (1.7% vs. 10%). The SIOG1 standard has high discriminability for 1-year mortality [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] and thus contributed more to the safety of this study. Consequently, given the similar acute toxicities frequency found in the newly PRODIGE 42/GERICO study [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] specifically designed for the older patients, it seems that the toxicity of the current regimen is tolerable and can be selected as a reference for relevant studies in the future.\u003c/p\u003e \u003cp\u003eThe main limitations of the current study include the single-arm design and relatively short follow-up time. Beside the abovementioned shortcomings, due to the fact that the surgeons and patients were both more cautious for safety when confronted with advanced age and potential vulnerability, 80.1% of the patients included in our study were at high-risk, this may limit extrapolation of the results in general older patients with LARC. On the other hand, the patient-reported outcomes were lacked in the current study.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur results confirmed that preCRT is an effective treatment with tolerable toxicities for fit older people with locally advanced rectal cancer. Implementation of CGA before development of a treatment strategy should be considered in future research.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003ePrior presentation\u003c/p\u003e\n\u003cp\u003ePresented in part at the European Society for Radiotherapy and Oncology 2021 Annual Meeting, 27-31 August, Madrid, Spain.\u003c/p\u003e\n\u003cp\u003eTrial registration\u003c/p\u003e\n\u003cp\u003eThe registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Ethics Committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College has approved all experimental protocols of the current study. And all methods were carried out in accordance with the Helsinki declaration. Informed consent was obtained from all participants and/or their legal guardian(s).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch data are stored in an institutional repository and will be shared upon request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project was funded by Beijing Municipal Science \u0026amp; Technology Commission (No. Z181100001718136), National Natural Science Foundation of China (82073352), Beijing Hope Run Special Fund of Cancer Foundation of China (No. LC2018A24 and LC2022A16)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWen-Yang Liu, Conception and Design, Data Collection, Analysis and Interpretation of Data, Manuscript Writing, Approval of Final Article; Jing Jin, Conception and Design, Analysis and Interpretation of Data, Manuscript Writing, Approval of Final Article; Yuan Tang, Data Collection, Approval of Final Article; Ning Li, Data Collection, Approval of Final Article; Yu Tang, Data Collection, Approval of Final Article; Jun Wang, Data Collection, Approval of Final Article; Yun-Jie Cheng, Data Collection, Approval of Final Article; Lin Yang, Data Collection, Approval of Final Article; Hui Fang, Data Collection, Approval of Final Article; Ning-Ning Lu, Data Collection, Approval of Final Article; Shu-Nan Qi, Data Collection, Approval of Final Article; Bo Chen, Data Collection, Approval of Final Article; Shu-Lian Wang, Data Collection, Approval of Final Article; Yong-Wen Song, Data Collection, Approval of Final Article; Yue-Ping Liu, Data Collection, Approval of Final Article; Ye-Xiong Li, Data Collection, Approval of Final Article; Zheng Liu, Data Collection, Approval of Final Article; Hai-Tao Zhou, Data Collection, Approval of Final Article; Jian-Wei Liang, Data Collection, Approval of Final Article; Wei Pei, Data Collection, Approval of Final Article; Xi-Shan Wang, Data Collection, Approval of Final Article; Hai-Zeng Zhang, Data Collection, Approval of Final Article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the patients and their families who participated in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRutten HJ, den Dulk M, Lemmens VE, van de Velde CJ, Marijnen CA. 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J Clin Oncol. 2017;35(7):766\u0026ndash;77. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/JCO.2016.69.3143\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2016.69.3143\" targettype=\"DOI\" class=\"RefTarget\"\u003e\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":"bmc-geriatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bgtc","sideBox":"Learn more about [BMC Geriatrics](http://bmcgeriatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bgtc/default.aspx","title":"BMC Geriatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Rectal cancer, Preoperative chemoradiotherapy, Comprehensive geriatric assessment, Geriatric oncology","lastPublishedDoi":"10.21203/rs.3.rs-2849544/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2849544/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and purpose:\u003c/strong\u003e The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as “fit” by comprehensive geriatric assessment (CGA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of “fit” (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category, Sixty-eight fit patients were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced nonhematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA.\u003c/p\u003e","manuscriptTitle":"Preoperative Chemoradiotherapy in Older Patients with Rectal Cancer Guided by Comprehensive Geriatric Assessment within a Multidisciplinary Team—A Multicenter Phase II Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-06-26 21:18:55","doi":"10.21203/rs.3.rs-2849544/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-03-26T06:37:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-11T11:08:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"57677441-4194-448a-95fe-e1190e63a4ab","date":"2024-02-28T11:25:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-11-20T13:09:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"30ba992e-7ac9-4f30-b40c-f0aee249dd38","date":"2023-10-28T15:47:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"ee72a37c-5d14-4552-8433-9354a0e208a5","date":"2023-07-24T09:42:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-07-20T08:45:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-07-20T07:43:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-06-19T20:11:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-06-19T20:08:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Geriatrics","date":"2023-04-23T00:43:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-geriatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bgtc","sideBox":"Learn more about [BMC Geriatrics](http://bmcgeriatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bgtc/default.aspx","title":"BMC Geriatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c8c73aa9-fd9e-400f-a595-d70ce7efab25","owner":[],"postedDate":"June 26th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-05-06T05:32:04+00:00","versionOfRecord":[],"versionCreatedAt":"2023-06-26 21:18:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2849544","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2849544","identity":"rs-2849544","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}