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Feasibility of modified short-course radiotherapy combined with a chemo-radiosensitizer for T3 rectal cancer

BACKGROUND: 5-fluorouracil based chemotherapy is considered to be a radiosensitizer; however, conventional short-course radiotherapy combined with chemotherapy is generally thought to not be feasible due to the prevalence of side effects. OBJECTIVE: To evaluate the feasibility of modified short-course radiotherapy combined with a chemo-radiosensitizer for T3 rectal cancer. DESIGN AND SETTINGS: Retrospective study using a prospectively collected database. PATIENTS: Subjects with T3 rectal cancer located below the peritoneum reflection. INTERVENTIONS: A total dose of 25 Gy of radiotherapy was administered in 10 fractions of 2.5 Gy each for five days. Radiotherapy was performed with S-1 as a radiosensitizer from days 1 to 10. Surgery was targeted to be performed four weeks after radiotherapy. MAIN OUTCOME MEASUREMENTS: The morbidity, sphincter-preserving rate, anal function and long-term outcomes were assessed. RESULTS: All patients (n=170) completed the radiotherapy regimen and 166 (97.6%) completed the combination regimen with chemotherapy. Sphincter-preserving rate was 87.6% (double stapling technique, 58 patients; intersphincteric resection, 91 patients; abdominoperineal resection, 21 patients) and postoperative complications were relatively mild (anastomotic leakage: 15.4%, intra- abdominal infection: 8.2%). Favorable five-year local relapse-free survival was confirmed in the patients treated with sphincter-preserving surgery (double stapling technique, 94.3%; intersphincteric resection, 89.8%). With respect to the anal function, the Wexner score the first year after stoma closure for the double stapling technique group was 6 and that for intersphincteric resection was 15; however, the score for the intersphincteric resection group was improved to 8 at four years after stoma closure. LIMITATIONS: An uncontrolled, one-arm, retrospective review with a small sample size. CONCLUSIONS: Modified short-course radiotherapy combined with chemo-radiosensitizer is a feasible approach for treating T3 rectal cancer. Using the short-course approach, efforts to reduce the incidence of side effects by appropriately prolonging the waiting period enable the administration of combination treatment with short-course radiotherapy and chemotherapy.

Key words Rectal cancer, Short-course radiotherapy with delayed surgery, Chemo-radiosensitizer

Introduction There are two broad approaches to providing preoperative radiotherapy for advanced rectal cancer: conventional short-course radiotherapy (SRT) and long-course chemoradiotherapy (CRT). The advantages of conventional SRT include patient convenience and lower costs.1 In contrast, advocates of CRT highlight the ability to safely combine radiation with concurrent systemic chemotherapy, lower surgical complications and higher rate of sphincter preservation.1 Among CRT regimens, radiotherapy in combination with 5-fluorouracil (5-FU)-based chemotherapy results in improved local control compared with radiotherapy alone. Therefore, combination therapy is used as a standard treatment for rectal cancer.2,3 5-FU is considered to be a radiosensitizer, a substance that makes tumor cells more sensitive to radiotherapy. Recently, it was reported that patients with a pathological complete response (pCR) or nearly pCR to CRT exhibit good long-term outcomes, and several clinical trials to investigate the pCR rate using other concomitant chemotherapeutic agents are currently ongoing.4,5 On the other hand, conventional SRT is reported to be associated with a higher incidence of surgical complications due to the high dose of radiotherapy used in each fraction (5 Gy/fraction) and the need to rapidly perform surgery within a few days.6-8 In order to address this problem, a new SRT approach, in which the waiting period is prolonged to four to eight weeks to avoid acute radiation reactions, was recently developed (short-course radiotherapy with delayed surgery: SRT-delay).9-12 This approach has been described as a feasible treatment with low toxicity. However, the side effects of the combination use of SRT-delay and chemotherapy have not yet been evaluated. Then, the aim of this study was to investigate the feasibility of modified SRT combined with a chemo-radiosensitizer (short-course chemoradiotherapy with delayed surgery: SCRT-delay) for treating T3 rectal cancer.

Patients and Methods From 2003 through 2012, a total of 516 patients with rectal cancer located below the peritoneum reflection were registered in our computerized database. Our general strategy for treating rectal cancer included primary surgery without preoperative therapy in cases of clinical T1 and T2 rectal cancer and total mesorectal excision (TME) following SCRT-delay in cases of clinical T3 rectal cancer. However, patients with clinical T4 rectal cancer or lateral lymph node involvement, defined as a node size of ＞ 8 mm, were treated with CRT, as the treatment effect of the SCRT-delay approach has not been confirmed in cases of highly advanced rectal cancers. During the study period, a total of 201 patients were treated for T3 rectal cancer with a histopathologically confirmed diagnosis of adenocarcinoma. We excluded 12 patients with lateral lymph node involvement of ＞8 mm and 19 patients with synchronous metastasis(Fig. 1). The remaining 170 patients who received curative resection following SCRT-delay were included in this study. Prior to SCRT-delay, all patients underwent staging work-ups, which included digital rectal examinations, measurement of the tumor marker levels (CEA and CA19-9), chest radiography, abdominal and pelvic computed tomography (CT), magnetic resonance imaging (MRI) and colonoscopy with a biopsy. In the present study, endorectal ultrasonography was performed in selected patients in whom it was difficult to obtain a diagnosis of the clinical stage using other modalities. The clinical stage and treatment algorithm were confirmed in each patient at a board meeting of colorectal surgeons, gastroenterologists, radiologists, radiotherapists and oncologists.

Short-course chemoradiotherapy with delayed surgery (SCRT-delay) All patients received SCRT-delay. A total dose of 25 Gy of radiotherapy was administered in 10 fractions of 2.5 Gy each for five days (25 Gy/10 fractions/5 days). Two fractions, separated by an interval of at least six hours, were administered per day. The protocol recommended that radiotherapy be given on five consecutive days. The radiotherapy regimen included S-1 (Taiho Pharmaceutical Co., Tokyo, Japan) as a radiosensitizer from days 1 to 10, with an S-1 dose of 60 mg/m2/day; S-1 has been shown to be a radiosensitizer.13-16 The detailed protocol for the radiotherapy regimen applied in this study has been described previously.17 The target interval between the completion of radiotherapy and surgery was four weeks. The toxicity of the preoperative treatments was assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE v3.0).18

Surgical procedure All patients underwent curative resection with TME. Sphincter-preserving surgery was primarily recommended in all patients, regardless of the tumor height, even if the internal anal sphincter was involved. Our detailed indications for abdominoperineal resection (APR) were as follows: 1) it was difficult to achieve a negative distal or resection margin due to factors such as invasion of the external anal sphincter, levator ani muscle, anal intersphincteric groove or ischiorectal fossa; 2) the patient exhibited diffusely infiltrating carcinoma of the rectum, such as linitis plastica, lesions with an annular shape or poorly differentiated adenocarcinoma, mucinous adenocarcinoma or signet ring cell carcinoma on a preoperative biopsy; 3) the patient presented with incontinence before surgery or had comorbidities, such as cerebral infarction or dementia. During the sphincter-preserving surgery, restoration of bowel continuity was achieved according to the double-stapling technique (DST) or intersphincteric resection (ISR) with a diverting stoma. Reconstruction with DST was primarily used to treat tumors located more than 5 cm from the anal verge. In contrast, tumors located less than 5 cm from the anal verge were primarily treated with ISR and classified into four groups according to the location of the tumor from the anal sphincter, as described by E. Rullier, as follows: coloanal anastomosis (CAA), partial ISR (pISR), total ISR (tISR) and APR.19 A colonic J- pouch was routinely created if technically feasible for the patients reconstructed with ISR. However, the cases with DST did not undergo the creation of a colonic J-pouch. Anastomotic leakage, intra- abdominal infection, wound infection, ileus and the need for reoperation within 30 days were investigated as surgical complications, with all grades of complications according to the CTCAE v3.0 criteria included.18 The diverting stoma was targeted to be closed three months after the initial surgery. The pathological findings of the resected specimens were recorded according to the American Joint Committee on Cancer (AJCC) TNM cancer staging system, 7th edition, with the exception of the tumor regression grade (TRG) in response to radiotherapy, which was determined based on the predominant pattern according to the Japanese General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus, 7th edition.20

Functional assessments All eligible patients were asked to complete a questionnaire each year after stoma closure in order to determine the time-dependent Wexner score. The Wexner score consists of five items describing the degree of incontinence in the terms of formed stools, liquid stools, gas, the need for pads and limitations in social life. The time-dependent severity of each item is calculated on a scale ranging from 0 to 20, with a score of 20 indicating major incontinence. In addition, the satisfaction score was investigated to assess the ‘satisfaction regarding the anal function’and‘satisfaction with removing the diverting stoma’at the point of one year after stoma closure. The responses to these questions included “satisfied,” “dissatisfied” or “neither satisfied nor dissatisfied.”

Patient follow-up The median follow-up period was 53.5 months (range, 9–117 months). Adjuvant oral 5FU-based chemotherapy was recommended in all patients after surgery. Patient surveillance was subsequently performed as follows: chest-abdominal CT every six months, colonoscopy annually and blood tests (including measurement of the CEA and CA 19-9 levels) at three-month intervals. Local recurrence was defined as the detection of a recurrent tumor within the pelvis, and systemic recurrence was defined as the presence of recurrent disease outside the pelvis. Local recurrence was classified into two subgroups: central pelvic recurrence and lateral pelvic recurrence.21 Statistical analysis Clinical variables were compared using the chi-square test, and the time to recurrence was measured from the date of surgery. The survival and recurrence rates were estimated according to the Kaplan- Meier method and compared using the log-rank test. All tests were two-sided, and P values of <0.05 were considered to indicate statistically significant differences. The data were analyzed using the JMP 10.0 software program (SAS Institute Inc., Cary, NC).

Results Outcomes of T3 rectal cancer treated with SCRT-delay Surgery was performed 32.5±12.5 days after the completion of radiotherapy. The patient characteristics are summarized in Table 1, and the toxicities of the preoperative treatments are presented in Table 2. The median patient age was 63.0 years (range, 35-85), and the primary tumor was located 4.6±2.3 cm (median 4, range 0-8) from the anal verge. No patients experienced grade 4 toxicities preoperatively, although four patients exhibited grade 3 toxicities (anorexia: 1, nausea: 2, diarrhea: 1). The S-1 chemotherapy regimen was discontinued in these four patients, while the remaining 166 patients (97.6%) completed the chemotherapy protocol. The radiotherapy regimen was completed in all patients. The type of operation was DST in 58 patients (34.1%), ISR in 91 patients (53.5%) and APR in 21 patients (12.4%), with a rate of sphincter preservation of 87.6%. Of the 21 patients who received APR, four who could have otherwise undergone sphincter-preserving surgery underwent APR due to sphincter incontinence or medical comorbidities. Of the 91 patients in the ISR group, 67 patients (73.6%) underwent the creation of a colonic J-pouch at ISR. The distribution of postoperative complications is described in Table 3, and the results were as follows: anastomotic leakage was found in 15.4% and intra-abdominal infection was found in 8.2% of cases. The pathological findings of the resected specimens are described Table 1. Downstaging to ypT0-2 was confirmed in 75 patients (44.1%), and downstaging to ypN (-) was confirmed in 122 patients (71.8%), and the pCR rate was 4.1%. A total of 139 patients (81.8%) received adjuvant chemotherapy after surgery. The reasons for not receiving chemotherapy included the following: an elderly status or comorbidities in 19 patients, postoperative complications in eight patients and other reasons in four patients.

Long-term outcomes The rates of five-year local relapse-free survival (LFS) in the DST, ISR and APR groups were 94%, 90% and 76% (p=0.28), the rates of five-year recurrence-free survival (RFS) were 87%, 85% and 58% (p=0.003), and the rates of five-year overall survival (OS) were 90%, 92% and 68% (p=0.05), respectively (Figs. 2a-c). These results indicated that the long-term outcomes of the cases which were unable to avoid APR due to radical surgery had a poor prognosis. With respect to the type of recurrence, eleven patients developed local recurrence after undergoing sphincter-preserving surgery (DST, ISR). The type of recurrence was central pelvic recurrence in four patients and lateral pelvic recurrence in seven patients. Of the four patients with central pelvic recurrence, one patient developed anastomotic recurrence, the details of which were as follows: the tumor was located 7 cm from the anal verge and anastomosis was performed via DST with a distal margin measuring 30 mm in length; however, a tumor was subsequently found within the bowel space 21 months after the surgery. Consequently, the rate of anastomotic recurrence was 0.67% (1/149). Among the patients treated with APR, three exhibited local recurrence, including central pelvic recurrence in one patient and lateral pelvic recurrence in two patients.

Bowel function The median Wexner scores determined annually after stoma closure are described in Fig. 3a. The score of the DST group was 6 and that of the ISR group was 15 at one year after stoma closure. However, the scores improved over time, especially in the ISR group, and the score is decreased to 8 at four years after stoma closure. In addition, the satisfaction scores with regard to their anal function according to the surgical procedure (DST, ISR) are described in Figs. 3b and c. Only about 30% of patients in the DST group and only about 20% of patients in the ISR were satisfied with their bowel function; however, about 80% of patients were satisfied with the removal of the diverting stoma, and none of the patients wanted to have their anastomosis reverted to a stoma.

Discussion This study demonstrated that the combined use of modified SRT and 5-FU-based chemotherapy is a feasible approach in patients undergoing treatment with delayed surgery. In addition, our results demonstrated a favorable local control rate and relatively mild postoperative complications, with high rate of sphincter preservation. Regarding CRT, the oncological advantages of combined therapy with preoperative radiotherapy and chemotherapy have been well documented in a variety of studies. 2,3 In contrast, conventional SRT with chemotherapy is generally thought to not be feasible due to the high rate of side effects.1,6-8 The timing of surgery is an important factor when considering the side effects of radiotherapy. The Stockholm Ⅲ trial investigated the feasibility, compliance and complications associated with the fraction dose and timing of surgery.9 The authors subsequently demonstrated that the patients receiving SRT with surgery 6-12 days after the completion of radiotherapy exhibited the highest incidence of complications. In addition, a high rate of complications after SRT has been reported among patients receiving surgery in the sub-acute period.22,23 An impaired leukocyte response after surgery may be one reason for the increased risk of toxicities.24,25 Conversely, the Canadian Phase II trial and a Swedish trial demonstrated that the use of SRT with a longer waiting period (4-8 weeks) is feasible, with an acceptable level of toxicity.10,11 Furthermore, the SRT-delay approach may be applied in patients with an advanced age (median age: 82), a poor performance status and/or significant comorbidities.12 Considering these results, the SRT-delay approach is safe and feasible, and acute radiation reactions are likely to subside during the treatment period. In this study, we also sought to change the method of irradiation from conventional SRT to a modified approach with 2.5 Gy/10 fractions/5 days to reduce the per fraction dose. This fractionated irradiation approach is known to reduce the side effects in patients with lung cancer and head and neck cancer.26-29 The mechanism underlying the reduction in side effects is thought to be associated with the administration of irradiation twice daily with a smaller dose per fraction, which subsequently exploits differences in the capacity for repair between normal and tumor cell populations, resulting in a greater effect in sparing normal tissue. With respect to rectal cancer, there is no strong evidence that fractionated radiotherapy can reduce the side effects; however, some reports of rectal cancer have described the efficiency of fractionated radiotherapy, and we applied this regimen in the hope of decreasing the incidence of side effects.30-33 Regarding the chemo-radiosensitizer, we used S-1, a novel mild 5-FU-based chemotherapeutic agent. This drug is an oral anticancer medication that contains tegafur (a prodrug of 5-FU) with two modulators, gimeracil and oteracil potassium, at a molar ratio of 1:0 and 4:1, respectively. Gimeracil was added to increase the blood fluorouracil concentration and degree of blood fluorouracil stability by inhibiting the metabolism of 5-FU induced by dihydropyrimidine dehydrogenase, the primary metabolizing enzyme of 5-FU, which is primarily expressed in the liver. Oteracil potassium is widely distributed to gastrointestinal tissues and inhibits the effects of orotate phosphoribosyl transferase, thereby reducing the gastrointestinal toxicity of fluorouracil. In patients with metastatic colorectal carcinoma, S-1 monotherapy exhibits a response rate of approximately 40%, with acceptable toxicity.34 In addition, S-1 is known to function as a radiosensitizer and has been previously investigated in various clinical trials.13-16 The dose of S-1 as a sensitizer is generally three-fourths of the treatment dose in order to prevent side effects. In the present study, most of the patients (97.6%) were able to undergo treatment with SCRT-delay, and all side effects were relatively mild. In addition, a favorable treatment effect was confirmed according to the pathological assessments as T-down staging (ypT0-2) in 75 patients (44.1%) and ypN(―) in 122 patients (71.8%), and the long-term outcomes of this approach were favorable. In particular, approximately 60% of the included patients were treated with ISR and achieved favorable local control. These results are due to the reduction in the rate of side effects associated with the use of delayed surgery with a chemo-radiosensitizer. A high rate of sphincter preservation has been reported in specialized centers of colorectal surgery,35 and a variety of trials have investigated factors affecting sphincter preservation.36,37 For example, the Lyon R90-01 trial confirmed a higher rate of sphincter-preserving surgery in the longer interval group than in the shorter interval group,36 while the Lyon R96-02 trial showed that dose escalation increases the rate of sphincter preservation.37 However, no previous trials of conventional SRT have demonstrated an increase in the frequency of sphincter preservation because the administration of conventional SRT does not result in downstaging, as surgery is performed within a few days.38 As to the efficacy of the SRT-delay approach in achieving sphincter preservation, the rate of sphincter preservation associated with this approach in the Stockholm III trial, Canadian Phase II trial and a Swedish trial was 60.0%, 73.0% and 45.5%, respectively. 9-11 Surely, these trials aimed to investigate the short-term outcomes and pathological response, not the rate of sphincter preservation. For instance, the Swedish study did not strive for sphincter-preserving surgery whenever possible. 11 On the other hand, at our institution, we primarily recommend sphincter-preserving surgery, regardless of the tumor height subsequently demonstrated a high rate of sphincter preservation (87.6%) for T3 rectal cancer located below the peritoneum reflection, which was defined as 8 cm from the anal verge, and not 15 cm, as in the previous series.9-11 However, we did not accurately measure any downstaging between the pre- and post-chemoradiotherapy results, and therefore, we cannot provide reliable evidence, but believe that the SCRT-delay approach might have the potential to increase the sphincter preservation rate. The degree of fecal incontinence was examined using the Wexner score in this study. Among the patients who underwent reconstruction with DST, the median Wexner score remained 4.5 to 6. On the other hand, the median Wexner score at the first year after stoma closure in the ISR group was 15, although this value decreased over time and after four years, the score was decreased to 8. In general, the functional outcomes were considered ‘poor’ if the Wexner score was greater than 10.39 Preoperative chemoradiotherapy was the risk factor with the great negative impact on the bowel function after ISR. Therefore, we have made efforts to maintain the bowel function not only by creating a colonic J-pouch to replace the reservoir functions, but also by making bulk and softening the stool to prevent soiling and incontinence by using constipating agents. However, it takes four years to improve the Wexner score to less than 10; therefore, the indications for ISR following chemoradiotherapy are controversial with regard to the functional outcomes. On the other hand, the indications for sphincter preservation should be considered based on subjective factors such as the lifestyle, culture, and occupation, and those cultural biases induced the dissociation between the Wexner score and satisfaction score. This is something important to consider when deciding on the surgical procedure, while providing the patients with objective information about incontinence before the decision is made. There were no differences in the long-term outcomes between the DST and ISR groups in this study. Nevertheless, the patients treated with APR demonstrated significantly worse prognoses than those treated with sphincter-preserving surgery, exhibiting bulky and diffusely infiltrating carcinoma lesions. Such patients may be indicated for more aggressive approaches with intensive chemotherapy and radiotherapy, such as those evaluated in the RAPIDO study and other trials.40,41 The present study is associated with several limitations. First, this study was an uncontrolled retrospective review with a small sample size, although the patient data were collected prospectively. Second, while we demonstrated the feasibility of our modified approach based on both short- and long-term outcomes, we did not perform controlled trials comparing our regimen with other better established regimens. Third, regarding the bowel function, we did not perform a manometric test. In addition, the Fecal Incontinence Quality of Life Score (FIQL score), which is a disease-specific tool formed from four subscales: Lifestyle, Coping, Depression and Embarrassment, and Low Anterior Resection Syndrome Score (LARS score), which is a simple self-administered questionnaire measuring bowel dysfunction after rectal cancer surgery, were not assessed in this study.42,43 Those scales would be particularly useful, because the Wexner score is for incontinence, and is not a scale for assessing low anterior resection syndrome. In conclusion, we herein confirmed the feasibility of the SCRT-delay approach for treating T3 rectal cancer. Using this short-course approach, efforts to reduce the rate of side effects by appropriately prolonging the waiting period enable the use of combination treatment with SRT and chemotherapy. In addition, our results demonstrated favorable local control rates and relatively mild postoperative complications, with high rates of sphincter preservation. This treatment algorithm has the potential to remedy the defects of the SRT approach. Although CRT is currently the standard treatment strategy in cases of locally advanced rectal cancer, the benefits of the SRT approach include improved patient convenience and lower costs. We hope to conduct more extensive examinations of this treatment strategy in order to gain a more complete understanding of the results.

Acknowledgments The authors are grateful to Professor Hirota, Professor Nishigami and Professor Terada, Department of Pathology, Hyogo College of Medicine for performing the pathological assessments.

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Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer--the RAPIDO trial. BMC Cancer. 2013;13:279- 87. 41) Maréchal R, Vos B, Polus M, et.al. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Ann Oncol. 2012;23:1525-30. 42) Park JS, Kang SB, Kim DW, Namgung HW, Kim HL. The efficacy and adverse effects of topical phenylephrine for anal incontinence after low anterior resection in patients with rectal cancer. Int J Colorectal Dis. 2007;22:1319-24. 43) Emmertsen KJ, Laurberg S. Low anterior resection syndrome score: development and validation of a symptom-based scoring system for bowel dysfunction after low anterior resection for rectal cancer. Ann Surg. 2012;255:922-8. FIGURE LEGENDS Fig. 1. Flow diagram of the study SCRT-delay, short-course chemoradiotherapy with delayed surgery DST, double-stapling technique ISR, intersphincteric resection APR, abdominoperineal resection ※Patients with lateral lymph node involvement defined as a node size of ＞8 mm were excluded because they received conventional chemoradiotherapy.

Fig. 2a. Local relapse-free survival (LFS) according to the type of operation DST, double-stapling technique ISR, intersphincteric resection APR, abdominoperineal resection

Fig. 2b. Recurrence-free survival (RFS) according to the type of operation DST, double-stapling technique ISR, intersphincteric resection APR, abdominoperineal resection Fig. 2c. Overall survival (OS) according to the type of operation DST, double-stapling technique ISR, intersphincteric resection APR, abdominoperineal resection

Fig. 3a Wexner scores in the DST and ISR groups (median) DST, double-stapling technique ISR, intersphincteric resection

Fig. 3b Satisfaction with the anal function at the point of one year after stoma closure DST, double-stapling technique ISR, intersphincteric resection

Fig. 3c Satisfaction with removing the diverting stoma at the point of one year after stoma closure DST, double-stapling technique ISR, intersphincteric resection

Table 1. Characteristics of the patients receiving SCRT-delay (n=170) The data are presented as the number (%). ※1 Distance between the tumor and the anal verge. ※ 2 TRG, tumor regression grade determined according to the General Rules of the Japanese Research Society for Cancer of the Colon and Rectum. DST, double-stapling technique ISR, intersphincteric resection CAA, coloanal anastomosis pISR, partial intersphincteric resection tISR, total intersphincteric resection APR, abdominoperineal resection

Table 2. Adverse effects of preoperative therapy (≧ grade 3)

Table 3. Postoperative complications The data are presented as the number (%). ※The rate of anastomotic leakage was calculated in the anastomotic leakage/sphincter-preserving surgery patients. DST, double-stapling technique ISR, intersphincteric resection APR, abdominoperineal resection

Table 1. Characteristics of the patients receiving SCRT-delay (n=170)

Age (years) Median 63.0 Range 35-85 SEX Male 120 (70.6) Female 50 (19.4) Clinical T3 170 Clinical N 67 (39.4) 103 (60.6) ＋ M0 170 Distance (cm)※1 Mean±SD 4.6±2.3 Range 0-8 Size of tumor (cm) Mean±SD 3.4±1.7 Range 1-8 Type of operation DST 58 (34.1) ISR 91 (53.5) CAA 10 pISR 29 tISR 52 APR 21 (12.4) ypT 0 7 (4.1) 1 23 (13.5) 2 45 (26.5) 89 (52.4) 3 6 (3.5) 4 ypN 122 (71.8) 48 (28.2) ＋

CRM ― 165 (97.1) ＋ 5 (2.9) Differentiation Well 40 (23.5) Moderately 115 (67.6) Poorly / mucinous/signet 15 (8.8) Lymphovascular invasion Negative 125 (73.5) Positive 45 (26.5) Perineural invasion Negative 144 (84.7) Positive 26 (15.3) TRG※2 1a 72 (42.4) 42 (24.7) 1b 49 (28.8)

2 7 (4.1) 3 Adjuvant chemotherapy No 31 (18.2) Yes 139 (81.8) Table 2. Adverse effects of preoperative therapy (≧ grade 3)

Toxicity Grade 3 Grade 4 Leukocytopenia 0 0 Neutropenia 0 0 Thrombocytopenia 0 0 Anemia 0 0 Anorexia 1 0 Nausea 2 0 Diarrhea 1 0 Cystitis 0 0 Dermatitis 0 0

Table 3. Postoperative complications DST ISR APR Total (n=58) (n=91) (n=21) (n=170) Anastomotic leakage 8 (12.7) 15 (16.5) ― 23※ (15.4) Intra-abdominal infection 6 (9.5) 7 (7.7) 1 (5.9) 14 (8.2) Wound infection 4 (6.3) 7 (7.7) 7 (41.2) 18 (10.6) Ileus 4 (6.3) 9 (9.9) 5 (29.4) 18 (10.6) Re-operation within 30 days 1 (1.6) 2 (2.2) 1 (5.9) 4 (2.4) Fig. 1a. Local relapse-free survival (LFS) according to the distal margin

0.0 0 365 730 1095 1460 1825 2190

33 27 23 17 14 13 7

58 50 29 29 23 17 12

Fig. 1b. Recurrence-free survival (RFS) according to the distal margin

0.0 0 365 730 1095 1460 1825 2190

33 23 19 18 14 13 5

58 49 33 29 23 17 12

Fig. 1c. Overall survival (OS) according to the distal margin

0.0 0 365 730 1095 1460 1825 2190

33 27 23 18 14 13 5

58 52 41 30 23 17 12

Surgery Ref.: Ms. No. 20140591R2 Pathological Evaluation of the Response of Mesorectal Positive Nodes to Preoperative Chemoradiotherapy in Patients with Rectal Cancer

Dear Dr. Beppu, I am pleased to tell you that your work has now been sent to the publisher for publication.

Thank you for submitting your work to this journal.

With kind regards,

Kerri Crowley Managing Editor Surgery