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Neoadjuvant chemoradiotherapy and multivisceral resection for primary locally advanced adherent colon cancer: A single institution experience*
M. Cukier a, A.J. Smith a, L. Milot b, W. Chu c, H. Chung c, D. Fenech a, S. Herschorn d, Y. Ko e, C. Rowsell f, H. Soliman c, Y.C. Ung c, C.S. Wong c,*
Division of Surgical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada c Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada d Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada e Department of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada f Department of Pathology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada Accepted 1 May 2012 Available online 24 May 2012
a

Abstract Background: Although there is an extensive body of literature on the role of neoadjuvant chemoradiotherapy (CRT) in the management of rectal cancer, its role in primary locally advanced adherent colon cancer (LAACC) is unclear. Objective: To analyzed the outcomes of neoadjuvant CRT and multivisceral resection in the management of LAACC patietns. Methods: We retrospectively reviewed our institutional Colorectal Carcinoma Database for 33 patients with potentially resectable, nonmetastatic primary LAACC who received neoadjuvant CRT followed by multivisceral resection. CRT consisted of external beam radiation (45e50 Gy in 25 daily fractions) and concurrent 5-FU infusion (225 mg/m2/day). Results: There were 21 males and 12 females. Median age was 64 (31e83) and median follow-up was 36 months. All patients had microscopically clear resection margins (R0). Complete pathologic response was documented in 1 patient (3%) and 66% had ypT4b disease. Post-operative complications were observed in 36% of patients with no 30-day mortality. The 3-year overall survival and 3-year disease-free survival were 85.9% and 73.7% respectively. Two patients developed a local recurrence. Conclusions: Neoadjuvant CRT and en-bloc multivisceral resection may result in high rates of R0 resection and excellent local control with acceptable morbidity and mortality in selected patients with LAACC. 2012 Elsevier Ltd. All rights reserved.
Keywords: Neoadjuvant therapy; Radiotherapy; Multivisceral resection; Colon cancer; Multimodality treatment

Introduction Colorectal cancer is the second leading cause of death in Canada and the fourth most common cancer overall with 22,200 new cases estimated in 2011.1 In North America, approximately 10e15% of patients are diagnosed with a colon cancer that directly invades or is adherent to adjacent
* Presented at the American Society of Clinical Oncology Annual Meeting (ASCO) 2011, Chicago, IL (ID: 3544). * Corresponding author. Tel.: 1 416 480 4619; fax: 1 416 480 6002. E-mail address: shun.wong@sunnybrook.ca (C.S. Wong).

organs or structures. This is referred to as locally advanced adherent colon cancer (LAACC).2 In LAACC, it has been well documented that when tumor involvement of other organs is suspected, 50e80% of cases is due to direct tumor inltration when veried on permanent histologic examination. Therefore, intraoperative assessment of organ involvement is often inaccurate.3 Resections with microscopic negative margins (R0) have a strong prognostic impact on patient survival and recurrence rates. Several studies have demonstrated that multivisceral R0 resections resulted in equivalent overall survival (OS) compared to those not requiring resection

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of additional organs when controlled for stage.3,4 However, results from multiple single institution publications have suggested that R0 resections rates are achieved in 40e90% in patients with LAACC despite multivisceral resections.3e5 The role of radiotherapy in the treatment of locally advanced colon cancer has only been evaluated in a few studies6e8 and at present, minimal evidence is available regarding its use. The role of neoadjuvant chemoradiotherapy (CRT) in the management of locally advanced rectal cancer is well documented. Based on data that neoadjuvant CRT resulted in superior outcome compared to post-operative adjuvant chemoradiotherapy,9,10 our colorectal unit has developed a novel neoadjuvant CRT approach for patients with potentially resectable LAACC. These are patients considered to have signicant risk of compromised circumferential radial margins and local recurrence despite multivisceral resection. We hypothesized that neoadjuvant CRT may represent an approach for highly selected patients with LAACC to improve R0 resection and local control rates. The purpose of this study is to determine the outcome of neoadjuvant CRT and multivisceral resection for patients with LAACC treated in our institution. Materials and methods We retrospectively reviewed our institutional prospectively collected Colorectal Carcinoma Database from January 2000 to December 2009 for patients with nonmetastatic primary LAACC who underwent neoadjuvant CRT followed by multivisceral resection. A total of 33 patients were included and analyzed. Six patients were included from 2000 to 2006, and 27 patients from 2007 to 2009. Patients were considered candidates for neoadjuvant treatment if, after discussion in our Multidisciplinary Cancer Conferences, they had a locally advanced non-metastatic adenocarcinoma of the colon (biopsy proven) believed to be involving other organs/structures and with a potentially compromised circumferential margin of resection based on imaging studies (CT scan and/or MRI). Multivisceral resections were dened as removal of the colon segment with the primary tumor with enbloc resection of one or more organs or structures. Patients with a primary extending to within 15 cm from the anal verge were excluded. Patients were staged prior to the neoadjuvant CRT and restaged before surgical intervention with CT scan of the chest/abdomen/pelvis with or without MRI of abdomen/pelvis. From the database and hospital records, we collected the following: patient demographics, clinical stage and site of the primary tumor, details of chemotherapy (chemotherapy prior to radiation if any, concurrent chemotherapy and chemotherapy after radiation but before surgery, and post-operative adjuvant chemotherapy after multivisceral

resection), details of neoadjuvant radiotherapy (dates, techniques, dose fractionation schedules), complications during and after chemoradiation, details of any surgery prior to referral (we included only patients in whom the initial surgical intervention did not attempt to remove the primary), operative details of the multivisceral resection (operative length, organs/structures resected, morbidity, 30-day mortality), the surgical pathology report, and nally late complications as well as locoregional and distant recurrences were also recorded. The neoadjuvant CRT consisted of intravenous infusional 5-uorouracil (5-FU) at 225 mg/m2/day for the duration of external beam radiation therapy. All 33 patients received concurrent chemotherapy during the radiation treatment. Four patients had chemotherapy prior to referral (3 patients received 12 cycles of FOLFOX and one 12 cycles of FOLFIRI). All 4 patients went on to have neoadjuvant CRT as the tumor was considered borderline resectable or at signicant risk of positive microscopic (R1) or macroscopic (R2) resection margins. Target volume denition was performed according to the guidelines of the International Commission on Radiation Units and Measurements Report 50. The volume irradiated was dened using CT-based planning. The gross tumor volume (GTV) was the macroscopic colonic tumor visible on CT or MRI. The GTV included a one-cm margin at any site of adherence or organ involvement. The clinical target volume (CTV) was dened as the GTV with a margin of 2 cm while respecting normal anatomic boundaries. The planning target volume (PTV) was dened as the CTV with an expansion of 1 cm. Radiation was delivered using 6 or 18 MV photons using 3-D conformal technique with either 3 or 4 elds in 26 patients. Tomotherapy was used in 6 and AP-PA in a single patient. Patients were planned for a dose of 45 Gy/25 fractions with the exception of 10 patients who were prescribed 50 Gy/25 (n 7) and 50.4 Gy/28 (n 3) where there was limited small bowel volume within the PTV. Organ constraints included V20 kidneys <30% and V30 liver <30% where applicable. The surgical intervention (multivisceral en-bloc resection) was generally scheduled 6e8 weeks after completion of neoadjuvant CRT. Staging was based on the 7th edition of The American Joint Committee on Cancer Cancer Staging Manual. Acute complications related to neoadjuvant CRT were classied according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.02). Late radiation morbidity was categorized using the Radiation Therapy Oncology Group (RTOG) Late Radiation Morbidity Scoring System. Grade 3 and 4 complications as well as postoperative complications were included in the analysis. Post-operative adjuvant chemotherapy was individualized by the most responsible medical oncologists. Patients were followed at 1, 3 and 6 months post-operatively, and every 6 months for 5 years and yearly thereafter. For the rst 5 years CT scans and CEA levels

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were obtained every 6 months. The type of recurrence was recorded (local or distant). Local recurrence was dened as any recurrence within the PTV. The median follow-up was 36 months as measured from the start date of neoadjuvant CRT. Overall survival and disease-free survival rates were estimated using the KaplaneMeier method. A p value of <0.05 was considered statistically signicant. The statistical analysis was performed using SPSS for Windows, Version 13.0 (SPSS Inc., Chicago, United States). This retrospective review was approved by the institutional Research Ethics Board. Results Patient and treatment characteristics are shown in Table 1. Prior to referral, 22 patients (67%) underwent laparotomy and surgical exploration without resection of the primary tumor as it was felt that there was a low likelihood of R0 resection (Table 1). All 33 patients had a staging CT scan of the chest/abdomen/pelvis and 23 had an abdominal/pelvic MRI before neoadjuvant CRT. The median time between nishing neoadjuvant CRT and multivisceral resection was 9.2 weeks (6.1e30 weeks). In Table 2, the surgical outcome and pathological staging are presented. The median operative time was 320 min (175e700 min) and the median length of stay in hospital after surgery was 13 days (6e150 days). Histological evidence of invasion of adjacent organ(s) was present in 67% of the cases. One patient had a complete pathological response. In all cases, resection margins were considered negative. The median largest dimension of the tumor by
Table 1 Patient and multimodality treatment characteristics. No. (%) Initial surgery prior to neoadjuvant treatment Laparotomy ileostomy Laparotomy colostomy Laparotomy ileocolic anastomosis Laparoscopic ileostomy Laparoscopic colostomy Neoadjuvant radiation (dose/no of fractions) 45 Gy/25 50 Gy/25 50.4 Gy/28 36 Gy/18 (prescribed 50 Gy, stopped at 36 Gy due to dehydration/vomiting) Neoadjuvant chemotherapy 5-FU FU-FA Adjuvant chemotherapy (post-op) None FOLFOX Capecitabine FU-FA 22 12 7 1 1 1 23 6 3 1 (67%) (36%) (21%) (3%) (3%) (3%) (70%) (18%) (9%) (3%)

Table 2 Surgical and pathological outcomes. No. (%) Location of primary Sigmoid Cecum Ascending colon Transverse colon Descending colon Multivisceral resection (organs/structures resected)a Small bowel Bladder/ureter (total or partial) Abdominal wall Uterus/ovaries Psoas/iliacus Non-adjacent colon Vagina Pancreas Stomach Spleen Duodenum/gallbladder Diaphragm Number of organs resectedb 6 5 4 3 2 ypT category ypT0 ypT1 ypT2 ypT3 ypT4b Grade Low High Lymphovascular invasion No Yes ypN category N0 N1 N2
a

21 6 2 2 2

(64%) (18%) (6%) (6%) (6%)

19 (56%) 18 (54%) 10 (30%) 8 (24%) 6 (18%) 5 (15%) 4 (12%) 4 (12%) 3 (9%) 2 (6%) 2 (6%) 2 (6%) No. of patients (%) 3 (9%) 5 (15%) 9 (28%) 11 (33%) 5 (15%) 1 1 1 8 22 (3%) (3%) (3%) (24%) (67%)

30 (91%) 3 (9%) 26 (79%) 7 (21%) 26 (79%) 7 (21%) 0 (0%)

All patients had 2 organs/structures resected, therefore, percentages add up to more than 100%. b In addition to involved colon.

32 (97%) 1 (3%) 19 11 3 1 (56%) (33%) (9%) (3%)

5-FU: 5-uorouracil; FU-FA: uorouracil and folinic acid; FOLFOX: folinic acid, 5-uorouracil and oxaliplatin.

radiological assessment before treatment was 8 cm (Fig. 1). The median dimension of the residual tumor documented in the pathology report was 4.5 cm, and in 3 cases was reported as microscopic residual foci. The morbidity and mortality related to the multimodality approach are described in Table 3. The neoadjuvant CRT was generally well tolerated. Two patients had CRT interrupted, one due to small bowel obstruction requiring a loop jejunostomy, and another requiring surgery for prolapsed colostomy. A single patient did not complete CRT (discontinued at 36 Gy) due to dehydration, diarrhea, vomiting and oral mucositis. Three patients had chemotherapy discontinued due to severe oral mucositis (n 1), erythema multiforme (n 1) and chest pain (n 1).

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Figure 1. CT scan of the abdomen showing a locally advanced colon cancer prior to (A and B) and after (C and D) neoadjuvant chemoradiation. The lesion is seen extending to the duodenum, pancreas, gallbladder fossa, mesentery and Gerotas fascia. Prior to chemoradiation, the radial margins are threatened (A and B, curved arrows) and the lesion involves the mesenteric vessels medially (A and B, straight arrows). After chemoradiation, there is signicant shrinkage of the lesion and marked improvement of all the margins (C and D).

Table 3 Acute and late complications. No. (%) Complications during CRT (grade 3 or 4)a Small bowel obstruction Prolapsed colostomy Erythema multiforme Post-operative complicationsb Delayed wound healing Surgical site infection Prolonged Ileus Leg weakness Anastomotic leak Hemorrhage Acute coronary syndrome Aspiration pneumonia Deep venous thrombosis Arrythmia Late complications (grade 3 or 4)c Small bowel obstruction requiring surgery Enterocutaneous stula Urinary tract stula Subphrenic abscess Portal vein thrombosis Deaths (30-day surgical mortality) 3 1 1 1 12 11 6 3 3 2 1 1 1 1 1 4 3 1 1 1 1 0 (9%) (3%) (3%) (3%) (36%) (33%) (18%) (9%) (9%) (6%) (3%) (3%) (3%) (3%) (3%) (12%) (9%) (3%) (3%) (3%) (3%) (0%)

CRT: neoadjuvant chemoradiation. a CTCAE version 4.02. b Some patients had more than 1 complication. c Radiation therapy oncology group (RTOG) late radiation morbidity scoring system.

There was no 30-day post-operative mortality. Postoperative complications are listed in Table 3. One patient developed recurrent small bowel obstruction 5 months after multivisceral resection (en-bloc right hemicolectomy, partial cystectomy, right ureterectomy and small bowel resection); he underwent ileostomy at 7 months and died postoperatively due to an enterocutaneous stula and sepsis. One patient developed a chronic enterocutaneous stula post-operatively that remained unhealed at last follow-up 3 years after surgery (en-bloc right hemicolectomy, distal gastrectomy, wedge liver resection and abdominal wall resection). Two additional patients required surgical intervention for small bowel obstruction. One other patient developed a small bowel anastomotic leak following closure of his temporary ileostomy. This healed following conservative management. One patient was found to have asymptomatic portal vein thrombosis that required anticoagulation. At last follow-up, ve patients have died. The 3-year overall survival was 85.9% (Fig. 2) and the 3-year disease-free survival was 73.7% (Fig. 2). We found no statistical difference in terms of disease-free survival when analyzing subgroups stratied by nodal status, ypN0 vs ypN1 ( p 0.29). Distant metastases were documented in 6 patients (18%). Lung metastasis was the most common rst site of distant recurrent disease (4 patients), followed by liver (1 patient) and retroperitoneal lymph node involvement (1 patient). Two patients developed local recurrence. One of the patients with local recurrence had a sigmoid cancer

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Figure 2. Overall and disease-free survival in patients with non-metastatic locally advanced adherent colon cancer following neoadjuvant chemoradiation and multivisceral resection.

invading uterus and vagina (ypT4bN0) with a recurrence 5 months after surgery in the vulva and iliac lymph nodes. The other patient with local recurrence had a sigmoid tumor at 18 cm invading bladder and prostate (ypT4bN1) with a recurrence in the laparotomy incision 10 months after surgery. Both patients went on to die of metastatic disease. Discussion In our study, two thirds of the patients were initially explored surgically prior to referral to our institution due to presentation with bowel obstruction. In all cases, no attempts were made to remove the primary tumor once the locally advanced and adherent nature of the lesion was identied. The treatment offered was diversion of the gastrointestinal tract proximal to the primary. Incomplete removal of the tumor with residual disease left behind (R1 resection) in colon cancer has been shown to be a signicant predictor of poor survival.11 Current guidelines recommend that en-bloc multivisceral resection be the standard surgical procedure for LAACC.12 In a recent analysis of LAACC patients identied from the Surveillance, Epidemiology and End Results (SEER) database, only a minority of patients were managed by multivisceral resection, but in those who had it performed, there was improved overall survival.13 All 33 cases in the present series had en-bloc multivisceral resection according to current guidelines. Despite en-bloc multivisceral resections, 7e60% of patients with LAACC have been reported to have incomplete removal of the tumor (Table 4). Compared to these series evaluating multivisceral resection for colon cancer without neoadjuvant CRT, we report an excellent rate of R0 resections in our present study. In our series, 79% of the cases were node negative, which was in contrast to earlier publications describing

nodal involvement in 69% of the cases,14 but more comparable with recent reports of 56e60% of node negative cases.4 It is possible that the high pN0 rate in our series is related to the neoadjuvant CRT.15 As previously stated, nodal involvement is a major prognostic factor3,14 but we did not nd a signicant difference between node positive versus negative patients in terms of overall survival. The sigmoid colon was the most frequent site of LAACC in our cohort (64%), and this is consistent with other series.3,4,8 Sixty-seven percent of the patients with colon cancer that were considered to be invading adjacent organs or structures preoperatively on imaging studies were conrmed after histopathological analysis. Whether this could be attributed to the neoadjuvant CRT or to the limitations of the preoperative imaging, is uncertain. Furthermore, we also found a single patient with a complete pathological response and 3 patients with microscopical residual disease, suggesting that neoadjuvant CRT might have an effect in downstaging the disease by sterilizing peripheral extent of tumor inltration as well as minimizing tumor burden. Despite that 9% of the patients had grade 3 or 4 complications related to the neoadjuvant approach, all except one were able to complete the radiation component of the neoadjuvant therapy. The 36% rate of 30-day post-operative complications described in our study is similar to other reports.4,16 This is rst study to date that reports the outcome of LAACC patients managed by neoadjuvant CRT and multivisceral resection with or without adjuvant post-operative chemotherapy. To our knowledge, this approach has not been reported in the literature. The role of neoadjuvant CRT in locally advanced rectal cancer (compromised circumferential radial margin, tumor penetration through the bowel wall or positive nodes) has been well established.9,10
Table 4 Published series of multivisceral resection for primary locally advanced colorectal cancers. R0 Heslov et al. 198818 Curley et al. 199219 Hermanek et al. 199220 Rowe et al. 199714 Gebhardt et al. 19995 Lehnert et al. 20023 Taylor et al. 20028 Croner et al. 20094 Park S et al. 201116 Current study 56% 54% 40% NR 81% 65% 80% 93%c NR 100% Morbidity Mortality OS (5-year) NR 25% 20e40% NR 11% 28% 30% 26% 35% 36% 5% 4% 3% 3.5% 3.6% 9% 0% 7% 8% 0% 38% 54% 52% 56% 51% No. of patients 58b 78b 197b 118b 140b

51% 139a 49% 25a NR 174a NR 54b 85.9% 33a (3-year OS)

NR: not reported; OS: overall survival. a Only colon cancer. b Combined colon and rectal cancer. c 14/174 had intraoperative tumor cell dissemination.

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For colon cancer, the role of adjuvant radiation alone or combined with chemotherapy is controversial. Several retrospective studies6,17 have suggested the potential advantage of post-operative radiotherapy for a subset of locally advanced colon cancer patients in local control and survival. These data prompted a randomized trial evaluating the role of adjuvant post-operative CRT in colon cancer.7 This study randomized 222 patients with resected colon cancer with tumor adherence or invasion of surrounding structures, or node positive tumors to receive postoperative 5-FU and levamisole therapy with or without radiation therapy. There was no difference in 5-year overall or disease-free survival amongst the 187 evaluable patients. Grade 3 toxicity was signicantly higher in the CRT group compared to the chemotherapy alone arm. Unfortunately, this study lacked statistical power (due to poor accrual) and had a high number of ineligible patients. Additionally, only a fraction of patients had disease adherent to or invading adjacent organs. The use of neoadjuvant CRT or radiation for locally advanced colon cancer has rarely been reported. In the series from Croner et al,4 174 patients with LAACC underwent multivisceral resection but only 2 were reported to have received neoadjuvant treatment prior to surgery. The only report of patients with locally advanced colon cancer treated with a multimodality approach was published by Taylor et al.8 In this series with locally advanced and recurrent colon cancer from the Mayo Clinic, a subset of patients with primary LAACC were managed by a combination of perioperative chemotherapy, external beam radiotherapy and intraoperative radiotherapy with electrons and surgery. However, only 9 had neoadjuvant CRT and surgery as primary treatment, the remaining 14 had prior R1 or R2 resection and were referred for salvage therapy. A 5-year survival of 49% and local failure rate of 12% were reported. The present series excluded patients who had prior R1 or R2 resections. We achieved a 100% R0 resection rate and a 3-year local control of 94%. Although the cohorts from the present series and the Mayo Clinic series8 are not similar, these results suggest a potential benet of neoadjuvant CRT in LAACC in terms of local control. This may translate into an improved survival given several studies have demonstrated a survival benet when complete resection is achieved and controlled by stage.3,4 We acknowledge that the small number of patients in our study and relatively short follow-up period limit an appropriate multivariate analysis for overall survival and disease-free survival. Patients with LAACC who are at risk for positive radial resection margins should be evaluated and considered for neoadjuvant CRT to improve R0 resection rates and decrease local failure. These results also underscore the value and importance of thorough preoperative imaging and

multidisciplinary discussion in order to plan an en-bloc multivisceral resection for LAACC. Conicts of interest The authors have no conicts of interest to disclose. References
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