Hagit Tulchinsky, MD, 1,2 Einat Shmueli, MD, 3 Arie Figer, MD, 3 Joseph M. Klausner, MD, 2 and Micha Rabau, MD 1,2

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1 Annals of Surgical Oncology DOI: /s An Interval [7 Weeks between Neoadjuvant Therapy and Surgery Improves Pathologic Complete Response and Disease Free Survival in Patients with Locally Advanced Rectal Cancer Hagit Tulchinsky, MD, 1,2 Einat Shmueli, MD, 3 Arie Figer, MD, 3 Joseph M. Klausner, MD, 2 and Micha Rabau, MD 1,2 1 Proctology Unit, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 2 Department of Surgery B, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Department of Oncology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Background: We assessed whether the time interval between neoadjuvant therapy and surgery affects the operative and postoperative morbidity and mortality, the pathologic complete response (pcr) rate, and disease recurrence in locally advanced rectal cancer. Methods: One hundred and thirty-two patients with locally advanced low and mid rectal cancer underwent neoadjuvant chemoradiation followed by radical resection (October 2000 to December 2006). Data on the neoadjuvant regime, neoadjuvant surgery interval, final pathology, type of operation, operative time, intraoperative blood transfusions, postoperative complications, length of hospital stay, disease recurrence, and mortality were reviewed. The patients were divided into two groups according to the neoadjuvant surgery interval: 7 weeks (group A, n = 48), and [7 weeks (group B, n = 84). Results: The groups were demographically comparable except for the group A patients being younger at operation. The median interval between chemoradiation and surgery was 56 days (range days). Thirty-seven patients (28%) had a pcr and near pcr. Fifty three patients (40%) had complications. There was no in-hospital mortality. Surgery type, operative time, number of intraoperative blood transfusions, postoperative complications, and length of hospitalization were not influenced by the interval length. The pcr and near pcr rates were higher with longer interval: 17% in group A, 35% in group B (P = 0.03). Patients operated at an interval [7 weeks had significantly better disease free survival (P = 0.05). Conclusions: A neoadjuvant surgery interval [7 weeks was associated with higher rates of pcr and near pcr, decreased recurrence and improved disease free survival. Key Words: Rectal cancer Preoperative chemoradiation Neoadjuvant Interval. Address correspondence and reprint requests to: Hagit Tulchinsky, MD; hagitt@tasmc.health.gov.il Published by Springer Science+Business Media, LLC Ó 2008 The Society of Surgical Oncology, Inc. Preoperative neoadjuvant chemoradiation as an adjunct to surgery for locally advanced mid and low rectal cancer has been shown to achieve pathologic downstaging, with improvement of resectability and sphincter saving surgery, in addition to improving local control. 1 4 The optimal time interval between completion of neoadjuvant treatment and performing surgery (the neoadjuvant surgery interval) is still indefinite. Few studies have looked at the influence of the length of the neoadjuvant surgery interval on morbidity, resectability, and tumor response. 5 8 One of them, by Francois et al., 5 showed

2 H. TULCHINSKY ET AL. that an interval of 6 8 weeks provided increased tumor downstaging when compared to a 2 week interval. The purpose of the current study was to assess the influence of different neoadjuvant surgery intervals on the following parameters: perioperative morbidity and mortality, tumor pathologic complete response (pcr), disease free survival (DFS), and overall survival (OS). METHODS We performed a retrospective review of a prospectively entered database on 146 consecutive patients with biopsy proven locally advanced (T3-4 or N1 and/or clinically bulky) low (at or below 5 cm from the anal verge) and mid (6 11 cm from the anal verge) rectal adenocarcinoma who underwent neoadjuvant therapy followed by radical resection with total mesorectal excision (TME) for curative intent between October 2000 and December The examined parameters included the neoadjuvant regime, the neoadjuvant surgery interval, the type of operation, operative time, intraoperative blood transfusions, postoperative complications (minor and major, operation related and none related), length of hospital stay, and mortality. Pathologic reports were reviewed to assess the tumor node metastasis (TNM) staging and the pcr and near pcr rates (the latter being defined by the finding of microscopic foci of adenocarcinoma in the rectal wall with no cancer cells in the lymph nodes). Fourteen patients were excluded from analysis: liver metastases were found at operation in two, two underwent an R2 resection, one had a pelvic exenteration, three were lost to follow-up and 6 patients received only radiation as neoadjuvant. The remaining 132 patients compose the study population. Patients were divided into two groups according to the neoadjuvant surgery interval: 7 weeks (group A) and [7 weeks (group B). The pre-treatment staging was based on rigid rectoscopy for localization of the tumor in the rectum, endorectal ultrasonography (EUS), and computerized tomography (CT) of the pelvis for local tumor status, abdominal CT, chest X-ray, and/or chest CT to rule out distant metastases. The neoadjuvant regimen included high dose radiation therapy of Gy, usually with concomitant 5-fluorouracil (FU) based chemotherapy. Radiotherapy was administered 5 days per week for 5.5 weeks. Patients were treated with 5-FU either in continuous infusion (180 mg/m 2 / day) for 5 days per week during 5 weeks or as oral preparations. Surgery was planned 6 8 weeks following the completion of preoperative therapy but was changed according to bed availability on the surgical ward. Routine postoperative follow-up of patients included physical examination and serum carcinoembryonic antigen every 3 4 months in the first 2 years after surgery and then every 6 months. Colonoscopy was performed a year after surgery and if normal every 3 years thereafter. CT of the chest, abdomen, and pelvis was done yearly in the first 2 years of follow-up. Survival was considered the interval between surgery and last follow-up or death (OS) or the date of last follow-up or recurrence (DFS). Patterns of disease recurrence (local and/or distant), DFS, and OS were analyzed. All the selected study parameters were compared between the groups. The institutional Helsinki Committee approved this study. Statistical Analysis Clinical and demographic data were entered into an Excel database using Microsoft Office software (Microsoft, WA). Continuous parameters were presented as medians and ranges or means and standard deviations. The patients were divided into two groups according to neoadjuvant surgery intervals (intervals of 7 weeks and [7 weeks). Comparisons between these groups of patients with regard to demographics, surgical parameters, and the various outcome variables were performed using independent samples t- tests, Mann Whitney, chi-square and Fisher s exact tests, as applicable. Pairwise comparisons between patient groups were done using the Gabriel and Games Howell multiple comparison tests. Comparisons between the groups with regard to OS and DFS were done by the log-rank test and were demonstrated by Kaplan Meier curves. Statistical significance was set at 0.05, and the SPSS for Windows software (Chicago, IL), Version 13.0 was used for the analysis. RESULTS A total of 132 patients who had locally advanced mid and low rectal cancer received neoadjuvant therapy followed by low anterior resection (LAR) or abdominoperineal resection (APR) with TME. There were 89 (67%) males and 43 females with a median age at operation of 64 years (range years). Abdominopelvic CT was performed on all patients prior to treatment, and 125 (95%)

3 EFFECT OF NEOADJUVANT-SURGERY INTERVAL TABLE 1. Demographics and clinical characteristics Interval 7 weeks (n = 48), n (%) Interval [7 weeks (n = 84), n (%) Mean age at operation (years) (P = 0.007) Gender (P = 0.31) Male Female Mean tumor distance from the anal verge (cm) (P = 0.46) EUS stage (utnm) (P = 0.27) Pathologic staging (ytnm) (P = 0.24) Preoperative radiation dose (P = 0.07) Postoperative chemotherapy (P = 0.63) 42 (87.5) 74 (86) Colorectal surgeon (P = 1.00) 44 (92) 76 (90) Median follow-up time (months) (P = 0.61) EUS, endorectal ultrasound. patients underwent EUS. Of these latter patients, 102 had ut3n0 disease and 23 had node positive disease (3 ut2n1, 20 ut3n1). EUS could not be performed in the other seven patients due to a bulky tumor. The neoadjuvant surgery interval ranged from 13 to 173 days (median 56 days). Almost all of the patients (n = 129, 98%) were operated at an interval of 4 17 weeks. There were 48 patients in group A and 84 in group B. Their demographic and clinical characteristics are outlined in Table 1. Group A patients were younger at operation (P = 0.007). The mean tumor distance from the anal verge, pre treatment EUS staging, postoperative pathologic staging by TNM classification, as well as the total cumulative delivered radiation dose, were comparable between the groups. Most of the patients (91%) were operated on by a colorectal surgeon, and there was no difference in the proportion of colorectal surgeons who performed the procedure between the groups. Type of surgery (LAR 62%), operative time (median 205 min), number of blood transfusions given during surgery (mean 0.8), length of hospital stay (median 9 days), and the use of diverting stoma in patients undergoing sphincter saving procedures were not influenced by the interval length (Table 2). There were no in hospital deaths. Minor and major complications were recorded in 53 (40%) patients (Table 3). Ten of the 82 patients (12%) who underwent a restorative operation (LAR) had anastomotic complications: four patients in group A and six in group B. Of these, two patients developed an anastomotic vaginal fistula and one an anastomotic leak that necessitated reoperation and diversion, and seven patients were treated conservatively with antibiotics. Of the 50 patients who underwent APR, three (6%) had a perineal wound infection and two had a pelvic abscess drained under CT guidance. Patients who were operated on after a neoadjuvant surgery interval 7 weeks had a complication rate of 48%, while only 36% of the patients operated on after an interval [7 weeks had complications (P = 0.17). Factors Predictive of Tumor Response to Neoadjuvant Therapy Thirty seven patients (28%) had pcr (n = 26) and near pcr (n = 11). The relationship between important predictors of outcomes (age at surgery, gender, tumor location, pre-treatment EUS staging, preoperative radiation dose, and neoadjuvant surgery time interval) and the rate of pcr and near pcr were examined using univariate and multivariate analysis. The only independent predictor of pcr and near pcr was neoadjuvant surgery time interval. The rate of pcr and near pcr increased with longer neoadjuvant surgery interval and was 17% in group A, and 35% in group B, a difference that was statistically significant (P = 0.03) (Fig. 1).

4 H. TULCHINSKY ET AL. TABLE 2. The effect of neoadjuvant surgery interval P value 7 weeks (n = 48), n (%) [7 weeks (n = 84), n (%) Operation type APR/LAR /30 32/52 Complications (48) 30 (36) Blood transfusions (40) 40 (48) Diverting ileostomy (46) 39 (46) Mean length of stay (days) Mean operation time (min) APR, abdominoperineal resection; LAR, low anterior resection. TABLE 3. Postoperative complications Number of patients Treatment Minor Wound Infection: Abdominal 4 Drainage Perineal 3 Drainage Colostomy 1 Drainage Dehiscence 2 Conservative Fever Phlebitis 6 IV line excision Port a cath infection 3 Excision Atelectasis 3 Physiotherapy Gastrointestinal SBO 1 Conservative Prolonged ileus 3 Conservative Urinary Infection 2 Antibiotics Retention 3 Catheterization Others 6 Major Anastomosis related Leak 7 Antibiotics 1 Diverting loop ileostomy Vaginal fistula 2 Diverting loop ileostomy Pelvic abscess post APR 2 Percutaneous drainage DVT 2 Anticoagulation PE 2 Anticoagulation SBO, small bowel obstruction; APR, abdominoperineal resection; DVT, deep vein thrombosis; PE, pulmonary embolism; IV, intravenous. Factors Prognostic for Disease-free and Overall Survival The median follow up period was 33 months (range 6 80 months) and it was similar for the two groups. A total of 23 patients (17%) had disease recurrence, of which 13 patients (two thirds) were from group A (P = 0.03). Fifteen patients died, again two thirds were from group A (P = 0.04). Table 4 summarizes the patterns and rates of disease recurrence and death rates according to interval groups. The effect of potential prognostic factors for DFS (age at surgery, gender, tumor location, pre-treatment EUS staging, preoperative radiation dose, surgical procedure, pathologic staging, postoperative chemotherapy, and neoadjuvant surgery time interval) was examined by univariate and multivariate analysis. The only independent prognostic factor was neoadjuvant surgery time interval. Figure 2 demonstrates the significantly improved DFS in patients operated on [7 weeks post neoadjuvant treatment (group B) compared with those operated on at an interval 7 weeks (group A) (P = 0.05). No difference in OS rates was observed between the groups (P = 0.07). Complete response (%) 40% 30% 20% 10% 0% Complete response according to interval groups 16.7% 34.5% <=7 Weeks (N=48) >7 Weeks (N=84) Interval Groups FIG. 1. Complete response rates according to interval groups (P = 0.03). DISCUSSION The standard surgical treatment of locally advanced low and mid rectal adenocarcinoma is LAR or APR with TME, according to tumor location. Surgical resection alone has high rates of locoregional failure. 9,10 Large clinical trials have demonstrated that preoperative chemoradiation reduces tumor size, increases the probability of tumor resectability and allows sphincter saving surgery for patients who otherwise would have required permanent colostomy. 2,11 15 A decrease in local recurrence rates and improved survival have been reported. 4,16 19 Furthermore, neoadjuvant therapy may result in complete eradication of all viable tumor cells from the rectal wall

5 EFFECT OF NEOADJUVANT-SURGERY INTERVAL TABLE 4. Patterns of disease recurrence according to study groups No. of patients (%) Interval 7 weeks (n = 48) Interval [7 weeks (n = 84) P value Total (n = 132) Local recurrence 3 (6%) 3 (4%) (4.5%) Metastases 9 (19%) 5 (6%) (11%) Local recurrence and metastases All recurrences 13 (27%) 10 (12%) (17%) Deaths 9 (19%) 6 (7%) (11%) as well as from the mesorectum, representing pcr in this setting. As the use of preoperative therapy broadens, it becomes more important to establish the optimal neoadjuvant surgery interval to achieve cure in the greatest number of patients. Sphincter saving procedures were possible in about two-thirds of our study patients (62%), a rate that correlates with that reported in other series in which neoadjuvant therapy was used. 2,20,21 The length of the neoadjuvant surgery interval had no influence on the rate of sphincter saving procedures, confirming the findings of other studies. 5,6,8 Our postoperative complication rate of 40% can be partially attributed to the fact that we included all grade 1 4 complications (according to Clevian et al. s classification 22 ) and, to some extent, to neoadjuvant therapy. These rates are in concordance with other series reporting on patients with rectal cancer who were operated on after neoadjuvant therapy. 21,23 A French prospective multicentric study published by Alves et al. 21 reported 43% morbidity following resection of mid and low rectal cancers. Whether preoperative radiation places additional risk on a low anastomosis after TME has been the subject of some debate. Several studies demonstrated a greater number of postoperative complications in patients treated by neoadjuvant chemoradiation. 18,24 26 For example, Buie et al. 24 showed that the addition of neoadjuvant chemoradiation to mesorectal excision increased the rate of pelvic sepsis threefold. In contrast, other studies showed no significant increase in postoperative complications. 23,27,28 Anastomotic dehiscence is the most serious early complication following a coloanal or low colorectal anastomosis. Our anastomotic leak rate of 12% correlates well with the incidence reported in previous large series (10 20%). 1,7,24,26,29,30 We could not demonstrate any difference in the rate of anastomotic complications between the groups, but the numbers of events were small. The Lyon R90-01 trial 5 randomized patients into two groups: patients in the short interval group were operated within 2 weeks after completion of radiotherapy and those in the long interval group at 6 8 weeks. The authors found no significant difference in the incidence of anastomotic complications between the groups (18% and 17%, respectively). We retrospectively examined different neoadjuvant surgery intervals for two main reasons: (1) to assess the influence on postoperative complications and mortality and (2) to determine whether we achieved higher rates of pcr and improved survival with longer intervals. Our findings showed decrease in the rate of overall morbidity in patients operated on after an interval [7 weeks but it did not reach statistical significance (36% versus 48%). Moore et al. 8 stratified 155 patients by median neoadjuvant surgery interval into those with a short interval ( 44 days) and those with a long interval ([44 days). Unlike our current findings, they observed a trend toward prolonged postoperative hospital stay in the long interval group (10 versus 8 days). Overall morbidity was similar between their groups, but anastomotic complications were more frequent in the long interval group (7% versus 0%). Stein et al. 6 divided 33 patients into two groups according to the time interval between completion of chemoradiation and surgical resection: 19 patients had an interval of 4 8 weeks (group A) and 14 patients had a time interval of weeks (group B). Three patients in their group A had anastomotic leaks and two underwent reoperation. None of the patients in their group B had leaks. The overall perioperative morbidity (27%) was not statistically different between their two groups. The pcr rate of 20% in the present study compares favorably with previous studies. 3,31 33 We observed a statistically significant increased rate of pcr and near pcr in patients operated on after an interval [7 weeks (group B) compared to those operated on after an interval 7 weeks (group A) (35% versus 17%, respectively). In the Lyon randomized trial, 5 Francois et al. showed that patients in the long interval group had either a pcr or a few residual cells more often than patients in the short interval group (26% versus 10%, respectively; P = ). Moore et al. 8 also demonstrated a trend toward an increased pcr rate with increasing the

6 H. TULCHINSKY ET AL. FIG. 2. Kaplan Meier estimation of the disease free survival. Comparison between patients operated after a neoadjuvant-surgery interval of 7 weeks and [7 weeks (P = 0.05, log rank test). prognostic factor for better DFS (P = 0.89). Thus, the better DFS of patients operated at an interval [7 weeks cannot be attributed to older age. Our results support the hypothesis that pcr is a favorable prognostic factor for improved local recurrence and DFS. It may represent a subgroup of rectal cancers with better biological behavior. Theodoropoulos et al. 34 reviewed 88 patients with ut3, T4 low and mid rectal cancers. Those with a pcr were characterized by significantly better DFS rates (P = 0.04), and the overall 5-year survival of patients with a pcr was 100% compared with 82.5% for patients without a pcr (P = 0.08). Garcia-Aguilar et al. 35 found a DFS of 95.2% for 21 patients with a pcr versus 55.4% for 140 patients without a pcr (P = 0.03). Kaminsky-Forrett et al. 36 evaluated the prognostic value of tumor downstaging and showed that the 3 and 5-year cancer specific survival rates were 100% for ypt0n0 and ypt2n0, 89% and 68% for ypt3n0, and 64% and 0% for ypt2t3n1. CONCLUSION neoadjuvant surgery interval, but their figures did not reach statistical significance. Conversely, Stein et al. 6 reported no significant difference in the rate of pcr when patients operated on after an interval of 4 8 weeks were compared to those operated on at an interval of weeks. Data on the impact of different neoadjuvant surgery intervals on long term disease recurrence and survival are limited. We were able to demonstrate better DFS rates in patients operated on at least 7 weeks after completion of neoadjuvant therapy. There were no differences in OS. In contrast, the long-term results of the Lyon R90 01 randomized study, 7 with a median follow up of 6.3 years showed no differences in local relapse and survival between the short and long interval groups. There are two important issues to address. The first is the potential drawback of this study due to its retrospective nature, but given the paucity of prospectively collected data, we believe that the results of this study are of value. The second is the homogeneity of the two groups. Comparisons between the two groups of patients with regard to demographics, clinical characteristics, and operative data revealed that they were similar and comparable in all parameters except for age at operation. Patients operated at an interval [7 weeks were older at operation (P = 0.007). We were able to show that age at operation was not a predictor for pcr and near pcr (P = 0.57) and not a The findings of the current study suggest that a neoadjuvant-surgery interval [7 weeks may be associated with improved rates of pcr and near pcr, decreased disease recurrence, and improved DFS. Prospective randomized trials are required to examine the optimal time interval that is needed to achieve minimum morbidity, maximal tumor downstaging, and minimum disease recurrence. ACKNOWLEDGEMENT Esther Eshkol is thanked for editorial assistance. REFERENCES 1. Chari RS, Tyler DS, Anscher MS, et al. Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 1995; 221: Janjan NA, Khoo VS, Abbruzzese J, et al. Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 1999; 44: Read TE, McNevin MS, Gross EK, et al. Neoadjuvant therapy for adenocarcinoma of the rectum: tumor response and acute toxicity. Dis Colon Rectum 2001; 44: Sauer R, Becker H, Hohenberger W, et al. German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: Francois Y, Nemoz CJ, Baulieux J, et al. Influence of the interval between preoperative radiation therapy and surgery on

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