Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
ORIGINAL CONTRIBUTION Prognosis Factors for Recurrence in Patients With Locally Advanced Rectal Cancer Preoperatively Treated With Chemoradiotherapy and Adjuvant Chemotherapy Jorge Arredondo, M.D.1 • Jorge Baixauli, Ph.D.1 • Carmen Beorlegui, Ph.D.2 Leire Arbea, Ph.D.3 • Javier Rodríguez, M.D.4 • Jesús Javier Sola, Ph.D.5 Ana Chopitea, M.D.4 • José Luís Hernández-Lizoáin, Ph.D.1 1 Department of General Surgery, Clínica Universidad de Navarra, Pamplona, Spain 2 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain 3 Department of Radiation Oncology, Clínica Universidad de Navarra, Pamplona, Spain 4 Department of Medical Oncology, Clínica Universidad de Navarra, Pamplona, Spain 5 Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain BACKGROUND: Neoadjuvant chemoradiotherapy followed by total mesorectal excision has improved the outcome of locally advanced rectal carcinoma. OBJECTIVE: The aim of this study was to identify independent prognosis factors of disease recurrence in a group of patients treated with this approach. DESIGN AND PATIENTS: This study was retrospective in design. Data from patients with locally advanced rectal cancer who had completed treatment from 2000 to 2010 were reviewed. SETTINGS: The analysis was performed in a tertiary referral center. MAIN OUTCOME MEASURES: The primary outcomes measured were the recurrence risk factors. RESULTS: The cohort consisted of 228 patients; 69.3% of them were men, and median age was 59 years. Stage III rectal cancer was found in 64.9% of patients. The most frequently administered therapy was concurrent capecitabine, oxaliplatin, and 7-field radiotherapy, followed by 3-field radiotherapy and fluoropyrimidines. After a median follow-up of 49 months, 23.7% of the patients experienced disease recurrence: 2.6% had local Financial Disclosures: None reported. Correspondence: Jorge Arredondo, M.D., Department of General Surgery, Clínica Universidad de Navarra, 36 Pio XII Ave, Pamplona 31008, Navarra, Spain. E-mail: [email protected]. Dis Colon Rectum 2013; 56: 416–421 DOI: 10.1097/DCR.0b013e318274d9c6 © The ASCRS 2013 416 recurrence, 21.1% had distant metastases, and 0.5% had both. Factors significantly correlated with recurrence risk in multivariate logistic regression were y-pathological stage (III vs I/II: OR = 2.51), tumor regression grade (1/2 vs 3+/4: OR = 3.34; 3 vs 3+/4: OR = 1.20), and low rectal location (OR = 2.36). The only independent prognosis factor for liver metastases was tumor regression grade (1/2 vs 3+/4: OR = 4.67; 3 vs 3+/4: OR = 1.41), whereas tumor regression grade (1–2 vs 3+/4: OR = 5.5; 3 vs 3+/4: OR = 1.84), low rectal location (OR = 3.23), and previous liver metastasis (OR = 7.73) predicted lung recurrence. LIMITATIONS: This is a single institutional experience, neoadjuvant combined therapy is not homogeneous, and the analysis has been performed in a retrospective manner. CONCLUSIONS: Patients with low third locally advanced rectal cancer with a poor response to neoadjuvant chemoradiotherapy (high y-pathological stage or low tumor regression grade) are at high risk of recurrence. Intense surveillance and the design of alternative therapeutic approaches aimed to lower the distant failure rate seem warranted. KEY WORDS: Locally advanced rectal cancer; Neoadjuvant combined therapy. R ectal cancer is a frequent disease with an annual incidence of 39,670 cases in the United States.1 Preoperative radiotherapy (RT) decreases local recurrence rates in comparison with surgery alone,2,3 and Diseases of the Colon & Rectum Volume 56: 4 (2013) 417 Diseases of the Colon & Rectum Volume 56: 4 (2013) the widespread performance of total mesorectal excision (TME) has improved survival rates.2,4 Preoperative chemoradiotherapy (CRT), in comparison with postoperative combined modality therapy, improves local control, treatment compliance, sphincter preservation, and toxicity profile.5–12 On this basis, for locally advanced rectal cancer (LARC), neoadjuvant CRT followed by surgery is currently the preferred treatment option.5,13–15 Adjuvant chemotherapy (ChT) is usually recommended, although controversy exists in patients who have been rendered node negative by preoperative treatment.15,16 The multidisciplinary management of LARC has translated into a decrease in the rate of local failure. However the incidence of distant metastases remains in the range of 25% to 30%. In this setting, strategies aimed to reduce the burden of metastases are a priority of research. The aim of this study was to identify prognosis factors correlated with the risk of recurrence in LARC patients treated with a multidisciplinary approach based on neoadjuvant CRT, TME, and adjuvant ChT. MATERIAL AND METHODS Medical records of LARC patients who completed preoperative CRT and surgery in Clínica Universidad de Navarra (Spain) between January 2000 and December 2010 were retrospectively reviewed. The cohort consisted of 235 consecutive patients with biopsy-proven resectable rectal adenocarcinoma with the inferior margin within 15 cm from the anal verge. Tumors were classified by location in the lower (0–5 cm), middle (5.1–10 cm), or upper rectum (10.1–15 cm) by flexible endoscopy. Eligibility criteria included clinical stage II or III rectal cancer by physical examination, endorectal ultrasound and CT of the chest, abdomen, and pelvis. Tumors were staged according to the American Joint Committee on Cancer Cancer Staging Manual.17 All patients had a World Health Organization performance status of 0 or 1. Patients were excluded in cases of previous cancer aside from nonmelanoma skin cancer, previous therapy with ChT or RT to the pelvis, or medical contraindications to receive CRT. This retrospective analysis was approved by the institutional review board. Two different protocols of neoadjuvant ChT were used: 5-fluorouracil (5-FU) alone (225 mg/m2 on days 1–4 and 24–28); or capecitabine (825 mg/m2 twice daily Monday to Friday) in combination with oxaliplatin administered at a dose of 60 mg/m2 on days 1, 8, and 15.18 Concomitant preoperative external beam irradiation was delivered either by using a 3- or 4-field technique, or by 7-field intensity-modulated technique. The results of the former approach have been reported elsewhere.19 Surgery was scheduled 5 to 6 weeks after the completion of CRT. Patients underwent TME according to a standardized technique, and sphincter preservation was preferable if this was both technically and oncologically feasible. Pathological analyses were performed by a specialized GI pathologist (J.S.). Staging was performed according to TNM classification.17 Tumor regression grade (TRG) was obtained based on a modification of the 5-point scale proposed by Ruo et al.7 This classification takes into account the percentage of tumor cells that remain visible in the surgical specimen: grade 0 (no response to treatment), grade 1 (response <33%), grade 2 (response between 33 % and 66%), grade 3 (response between 66% and 94%), grade 3+ (95%–99% response, focus or microscopic residual), and grade 4 (no viable tumor identified, pathological complete response (pCR)). In the present study, a 3-point TRG scale was used by grouping grades 0-1-2, grade 3, and grades 3+ and 4. In addition, distal resection margins and lymphovascular or perineural invasion were documented. Circumferential radial margins were not available in most patients of this historical study; thus, this variable was not included in the analysis. The relationship of age, sex, clinical (tumor location, tumor volume, clinical N, clinical T, clinical stage, type of surgery, neoadjuvant ChT, RT, and adjuvant ChT) and pathological variables (total number of lymph nodes, lymphovascular invasion, perineural invasion, distal resection margin, ypT, ypN, yp stage, TRG) with the risk of distant relapse was analyzed by univariate logistic regression. Patients were followed-up every 3 months for 2 years, every 6 months for the next 3 years, and afterward annually, according to National Comprehensive Cancer Network guidelines.20 Local recurrence was defined as clinical or radiologic tumor regrowth within the previous pelvic treatment field. Distant recurrence was considered as tumor growth in any other area. Diagnosis of relapse was based on 2 consecutive CT within 4 to 6 weeks. Histopathological verification was performed when feasible. Statistical Analysis All the statistical analyses were done by using the SPSS/ PC v.15 for Windows statistical package (SPSS, Chicago, IL). Results were expressed as mean or median (P25 to P75) for continuous variables, depending on whether or not normal distribution was followed, and proportion for qualitative variables. Relationship between variables and development of metastases (global and both hepatic and pulmonary) were studied by Student t (or MannWhitney U, depending on whether or not data followed a normal distribution) and χ2 tests. All factors with p < 0.2 were considered in the multivariate logistic regression analyses with a semimanual backward (likelihood ratio) variable selection. 418 Arredondo et al: Prognosis Factors in Rectal Cancer TABLE 1. Demographic and treatment characteristics n (%) Age Sex Male Female Rectal third location Lower Middle Upper Clinical stage II III Chemotherapy regimen Oxaliplatine-based Fluoropyrimidine-based Radiotherapy 3–4 fields 7 fields Surgical procedure LAR APR Hartmann 59 (24–85) a 158 (69.3) 70 (30.7) 128 (56.1) 73 (32) 27 (11.8) 80 (35.1) 148 (64.9) 165 (72.4) 63 (27.6) 96 (42.1) 132 (57.9) 174 (76.3) 48 (21.1) 6 (2.6) LAR = low anterior resection; APR, abdominoperineal resection. a Median (rank). RESULTS Patients Characteristics and Surgical Findings The final cohort consisted of 228 LARC patients with a median age of 59 years (range, 24–85), of whom 158 (69.3%) were men. At the time of diagnosis, clinical stage II and III were found in 35.1% and 64.9%. The tumor was located in the lower, middle, and upper rectum in 56.1%, 32.0%, and 11.8% of the patients. Concurrent fluoropyrimidines plus oxaliplatin were administered to 165 patients (72.4%), whereas 63 patients (27.6%) received 5-FU-based CRT. The number of RT fields was 7 in 132 patients (57.9%) and 3 to 4 in the remaining 96 (42.1%). Demographic and treatment variables are summarized in Table 1, and pathological stage and TRG are outlined in Table 2. A sphincter-preserving surgery was performed in 60.2% of patients with low rectal cancer. A total of 155 patients (68%) received adjuvant ChT, of whom 84.5% completed the planned treatment. Evolution of the Disease The median follow-up for the entire cohort was 49 months (range, 30–73). Fifty-four (23.7%) patients had disease recurrence: 6 (2.6%) local recurrence (median time to relapse, 12.5 months) and 47 (20.6%) had distant metastases (median time to relapse, 15.7 months); 16 patients developed liver metastases, 34 lung metastases, and 8 metastases in other locations. Only 1 patient (0.5%) had both local and distant recurrence. Fourteen of 34 lung metastases and 11 of 16 liver metastases were histologically confirmed. Of the patients who primarily had a relapse in the liver, 77.8% had lung metastases in the course of the disease. The median disease-free survival was not reached. The estimated 5- and 10-year disease-free survival was 75.3% and 65.0%. At the time of the final analysis, 25 patients (11.0%) had died of disease progression. Figure 1 shows the flow of patients through the study. Prognosis Factors for Recurrence Results of the univariate analyses regarding the risk of distant metastases are presented in Table 3. Factors significantly associated to distant recurrence by multivariate logistic regression analysis were y-pathological stage (III vs I/II: OR = 2.51, 95% CI 1.25–5.05; p = 0.010), TRG (1/2 vs 3+/4: OR = 3.34, 95% CI 1.24– 9.02; 3 vs 3+/4: OR = 1.20, 95% CI 0.47–3.02; p = 0.014), and low third location (OR = 2.36, 95% CI 1.15–4.85; p = 0.016). The inclusion of patients with local recurrence did not change these results. Among all the variables related to the development of liver metastases by univariate analysis (Table 3), only the 3-point TRG retained its significance in logistic regression multivariate analysis (1/2 vs 3+/4: OR = 4.67, 95% TABLE 2. Posttreatment pathological characteristics and TRG scores n (%) y-pathological T T0 T1 T2 T3 T4 y-pathological N N0 N1 N2 Resected nodesa Lymphovascular invasion Perineural invasion Distal margin status <0.5 cm 0.5–1 cm >1 cm Distal margin distancea TRG 0 1 2 3 3+ 4 Final AJCC/UICC stage 0 I II III 26 (11.4) 15 (6.6) 76 (33.3) 108 (47.4) 3 (1.3) 158 (69.3) 58 (25.4) 12 (5.3) 9 (5–15) 35 (15.4) 43 (18.9) 6 (2.6) 22 (9.7) 200 (87.7) 6 (0.5–8) 0 (0) 5 (2.2) 47 (20.6) 96 (42.1) 49 (21.5) 26 (11.4) 52 (22.8) 96 (42.1) 75 (32.9) 26 (11.4) 70 (30.7) 62 (27.2) 70 (30.7) TRG = tumor response grade; AJCC = American Joint Committee on Cancer; UICC = Union for International Cancer Control. a Median (rank). 419 Diseases of the Colon & Rectum Volume 56: 4 (2013) DISCUSSION 235 patient candidates for treatment 7 excluded: 3 with contraindication to CRT. 4 with previous cancer 228 patients completed neoadjuvant treatment 2 lost to 1-year follow-up 226 13 lost to 3-year follow-up 213 FIGURE 1. Flow of patients through the study. CRT = chemoradiotherapy. CI 1.18–18.5 and 3 vs 3+/4: OR = 1.41, 95% CI 0.36–6.09; p = 0.007). Table 3 also highlights the risk factors associated to lung recurrence in univariate analyses. Only the low third location (OR = 3.23, 95% CI 1.27–8.13; p = 0.009) and the TRG (1–2 vs 3+/4: OR = 5.5, 95% CI 1.74–17.3; 3 vs 3+/4: OR = 1.84, 95% CI 0.66–5.67; p = 0.007) were significantly correlated with lung relapse by multivariate analysis. Previous liver metastasis was also an independent prognostic factor for pulmonary recurrence (OR = 7.73, 95% CI 2.16–21.9; p = 0.002; data not shown in Table 3). This study shows several clinical and pathological factors that may be related to disease relapse in a large cohort of LARC patients after a long-term follow-up. By multivariate analysis, y-pathological stage, TRG, and lower third location were found to be independently associated with the risk of distant relapse. Although lung metastases were related to lower third location, TRG, and previous disease relapse in the liver, only TRG seemed to influence the development of liver metastases. These data should be viewed with caution, however, given the low number of relapses seen in this cohort of patients. The grouping that we have used for the y-pathological stage coincides with the nodal involvement, a well-known prognosis factor for the development of metastases. The lower risk of recurrence in patients with good TRG shown in this study is in agreement with the results reported by other groups.9,21–24 pCR was achieved in 11.4% of the patients, and none of them experienced a relaps at any site. No patients with ypT0 had positive lymph nodes. Previously reported pCR rates range from 8% to 38%.21,22,25 Despite of the high percentage TABLE 3. Univariate analyses of factors significantly related to distant recurrence Recurrence/metastases Distant n (%) y-pTNM I,II (n = 156). N− III (n = 66). N+ Tumor regression grade 1,2 (n = 50) 3 (n = 93) 3+,4d (n = 75) Rectal third location Lower (n = 124) Middle, upper (n = 98) Lymphovascular invasion Yes (n = 33) No n = (179) Perineural invasion Yes (n = 41) No (n = 181) Chemotherapy regimen Oxaliplatin-based (n = 160) Fluoropyrimidine-based (n = 62) Radiotherapy 3–4 fields (n = 92) 7 fields (n = 130) Surgical procedure LAR (n = 171) APR (n = 46) Local recurrence has been excluded. LAR = low anterior resection; APR = abdominoperineal resection. a 2 χ. b Fisher exact test. c 2 χ linear trend. d All tumor which relapsed were 3+. Liver p n (%) 0.001a 24 (15.4) 24 (36.4) p <0.001c 0.002c 0.042a 0.974a 6 (18.2) 10 (5.3) <0.001a 0.085b 0.002a 0.023a 11 (26.8) 23 (12.7) 0.003b 6 (3.8) 10 (16.1) 0.001a 30 (32.6) 18 (13.8) 0.002a 11 (33.3) 23 (12.2) 6 (14.6) 10 (5.5) 26(16.3) 22(35.5) 0.024a 25 (20.2) 9 (9.2) 0.018b <0.001a 17 (41.5) 31 (17.1) <0.001c 16 (32) 12 (12.9) 5 (6.7) 9 (7.3) 7 (7.1) 18 (54.5) 30 (15.9) <0.001a 16 (10.0) 18 (29) <0.001a 14 (15.2) 2 (1.5) <0.001a 0.009a 21 (22.8) 13 (10.0) 0.181b 9 (5.3) 5 (10.9) p 0.005 a 17 (10.9) 15 (25.8) 8 (16) 5 (5.4) 1 (1.3) 33 (26.6) 15 (15.3) n (%) 0.087b 8 (5.1) 8 (12.1) 21 (42.0) 17 (18.3) 8 (10.7) 26 (15.2) 20 (43.5) Lung 0.002a 20 (11.7) 14 (30.4) 420 of patients with low rectal cancer in the present series (56.1%), our local recurrence rate (2.6%) is lower than that reported by most authors,5,6,9–12,21,23–25 whereas the distant metastases rate (21.1%) is similar to other published results.5,6,9,10,21,24,26 We have also found a posttreatment nodal involvement (30.7%) slightly higher than in other studies.5,8–11,14,24 Total mesorectal excision was performed by the same senior surgical team 5 to 6 weeks after neoadjuvant treatment. Sphincter preservation was achieved in 51 patients (60.2%) with low rectal cancer. These results compare f avorably with other reported series. Different rates of sphincter-sparing surgery, which range from 35% to 62%, have been presented, possibly owing to the different s urgeons’ criteria, variations on the interval between radiation and surgery, and different stage of disease.5,7,9,11,26,27 The rate of lung metastases is 2-fold that of liver metastases. Recently published studies are in agreement with this finding.28–30 Different theories have been proposed to explain the pattern of metastases, although this process seems to be multifactorial.30 The most accepted is the one based on the nature of the venous drainage of the rectum.31,32 However some studies have suggested that tumors may metastasize to specific organs independently from the vascular anatomy, given the existence of different organ-specific microenvironments.33 Moreover, a differential sensitivity to 5-FU-based chemotherapy in lung pattern compared with liver metastases34 has also been described because of a different expression of thymidilate synthase.35 The chest CT scan-based follow-up used in this study may be another reason for the higher rate of lung metastases in comparison with other works in which surveillance was based simply on chest x-ray.36 This attitude is in agreement with the National Comprehensive Cancer Network surveillance guidelines and the American Society of Clinical Oncology.20,37 There is a growing evidence suggesting that new follow-up strategies are warranted.29,30,32,38 Whether a more intensive follow-up will translate into a survival benefit remains to be determined.39 This study has some limitations that deserve consideration. This is a single institutional experience, recorded in a retrospective way, and the neoadjuvant CRT regimen used is not homogeneous, as a consequence of the evolution that the chemotherapy schedules have presented in the past decade. This is a frequent matter in long-term retrospective analysis. On the other hand, we had few patients who developed metastasis, which obligates the results of the comparisons to be handled with caution, especially those referred to h epatic metastases. This is one of the reasons why factors predicting local recurrence could not be assessed. Therefore, further studies in a larger series of patients with LARC are w arranted to validate these results. Arredondo et al: Prognosis Factors in Rectal Cancer CONCLUSIONS Patients with low third LARC with a poor response to neoadjuvant CRT (advanced y-pathological stage or low TRG) have a higher likelihood of relapse. In this subset of patients, intensive surveillance and the design of alternative therapeutic approaches aimed to lower the distant failure rate seem warranted. Acknowledgment The authors thank Isabel de Salas Tornos for helping in editing the manuscript. REFERENCES 1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300. 2. van Gijn W, Marijnen CA, Nagtegaal ID, et al; Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year followup of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12:575–582. 3.Medical Research Council Rectal Cancer Working Party. Randomised trial of surgery alone versus surgery followed by radiotherapy for mobile cancer of the rectum. Lancet. 1996;348:1610–1614. 4.MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet. 1993;341:457–460. 5. 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;351:1731–1740. 6. Bosset JF, Collette L, Calais G, et al; EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–1123. 7. Ruo L, Tickoo S, Klimstra DS, et al. Long-term prognostic significance of extent of rectal cancer response to preoperative radiation and chemotherapy. Ann Surg. 2002;236:75–81. 8. Pucciarelli S, Friso ML, Toppan P, et al. Preoperative combined radiotherapy and chemotherapy for middle and lower rectal cancer: preliminary results. Ann Surg Oncol. 2000;7:38–44. 9. Valentini V, Coco C, Cellini N, et al. Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation. Int J Radiat Oncol Biol Phys. 1998;40:1067–1075. 10. Guillem JG, Chessin DB, Cohen AM, et al. Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg. 2005;241:829–836. 11.Feliu J, Calvilio J, Escribano A, et al. Neoadjuvant therapy of rectal carcinoma with UFT-leucovorin plus radiotherapy. Ann Oncol. 2002;13:730–736. 12. Grann A, Feng C, Wong D, et al. Preoperative combined modality therapy for clinically resectable uT3 rectal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2001;49:987–995. 13.Scott NA, Susnerwala S, Gollins S, Myint AS, Levine E. Preoperative neo-adjuvant therapy for curable rectal cancer–reaching a consensus 2008. Colorectal Dis. 2009;11:245–248. Diseases of the Colon & Rectum Volume 56: 4 (2013) 14. Jin J, Meng H, Zhou G, et al. Preoperative radiotherapy combined with capecitabine chemotherapy in Chinese patients with locally advanced rectal cancer. J Gastrointest Surg. 2011;15:1858–1865. 15. Bujko K, Glynne-Jones R, Bujko M. Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials. Ann Oncol. 2010;21:1743–1750. 16. Kiran RP, Kirat HT, Burgess AN, Nisar PJ, Kalady MF, Lavery IC. Is adjuvant chemotherapy really needed after curative surgery for rectal cancer patients who are node-negative after neoadjuvant chemoradiotherapy? Ann Surg Oncol. 2012;19:1206–1212. 17. Dalton L, Page DL. Grading breast cancer on microarray samples: comparison with Nottingham grade, and use of boosting classification. Histopathology. 2012;61:497–508. 18. Aristu JJ, Arbea L, Rodriguez J, et al. Phase I-II trial of concurrent capecitabine and oxaliplatin with preoperative intensity-modulated radiotherapy in patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2008;71:748–755. 19. Arbea L, Martínez-Monge R, Díaz-González JA, et al. Fourweek neoadjuvant intensity-modulated radiation therapy with concurrent capecitabine and oxaliplatin in locally advanced rectal cancer patients: a validation phase II trial. Int J Radiat Oncol Biol Phys. 2012;83:587–593. 20.NCCN Clinical Practice Guidelines in Oncology. Available at: http://www.nccn.org. Accessed April 17, 2012. 21.Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11:835–844. 22.Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg. 2012;99:918–928. 23. García-Aguilar J, Hernandez de Anda E, Sirivongs P, Lee SH, Madoff RD, Rothenberger DA. A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision. Dis Colon Rectum. 2003;46:298–304. 24. Vecchio FM, Valentini V, Minsky BD, et al. The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer. Int J Radiat Oncol Biol Phys. 2005;62:752–760. 25. Rödel C, Liersch T, Becker H, et al; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012;13:679–687. 421 26. Burke SJ, Percarpio BA, Knight DC, Kwasnik EM. Combined preoperative radiation and mitomycin/5-fluorouracil treatment for locally advanced rectal adenocarcinoma. J Am Coll Surg. 1998;187:164–170. 27. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006;93:1215–1223. 28. Kobayashi H, Mochizuki H, Sugihara K, et al. Characteristics of recurrence and surveillance tools after curative resection for colorectal cancer: a multicenter study. Surgery. 2007;141:67–75. 29. Mitry E, Guiu B, Cosconea S, Jooste V, Faivre J, Bouvier AM. Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study. Gut. 2010;59:1383–1388. 30. Ding P, Liska D, Tang P, et al. Pulmonary recurrence predominates after combined modality therapy for rectal cancer: an original retrospective study. Ann Surg. 2012;256:111–116. 31. Tepper JE, O’Connell M, Hollis D, Niedzwiecki D, Cooke E, Mayer RJ; Intergroup Study 0114. Analysis of surgical salvage after failure of primary therapy in rectal cancer: results from Intergroup Study 0114. J Clin Oncol. 2003;21:3623–3628. 32. Watanabe K, Saito N, Sugito M, Ito M, Kobayashi A, Nishizawa Y. Predictive factors for pulmonary metastases after curative resection of rectal cancer without preoperative c hemoradiotherapy. Dis Colon Rectum. 2011;54:989–998. 33.Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–458. 34. Assersohn L, Norman A, Cunningham D, Benepal T, Ross PJ, Oates J. Influence of metastatic site as an additional predictor for response and outcome in advanced colorectal carcinoma. Br J Cancer. 1999;79:1800–1805. 35. Yamada H, Ichikawa W, Uetake H, et al. Thymidylate synthase gene expression in primary colorectal cancer and metastatic sites. Clin Colorectal Cancer. 2001;1:169–174. 36. Kirke R, Rajesh A, Verma R, Bankart MJ. Rectal cancer: incidence of pulmonary metastases on thoracic CT and correlation with T staging. J Comput Assist Tomogr. 2007;31:569–571. 37. Desch CE, Benson AB 3rd, Somerfield MR, et al; American Society of Clinical Oncology. Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2005;23:8512–8519. 38. Lee WS, Yun SH, Chun HK, et al. Pulmonary resection for metastases from colorectal cancer: prognostic factors and survival. Int J Colorectal Dis. 2007;22:699–704. 39.Tjandra JJ, Chan MK. Follow-up after curative resection of colorectal cancer: a meta-analysis. Dis Colon Rectum. 2007;50:1783–1799.