Original Paper Received: September 18, 2015 Accepted: January 17, 2016 Published online: April 27, 2016 Dig Surg 2016;33:382–391 DOI: 10.1159/000444097 Clinicopathological Factors Associated with Recurrence and Prognosis after R0 Resection for Stage IV Colorectal Cancer with Peritoneal Metastasis Harunobu Sato a Kenjiro Kotake c Kenichi Sugihara d Hiroshi Takahashi b Kotaro Maeda a Ichiro Uyama a on behalf of the Study Group for Peritoneal Metastasis from Colorectal Cancer By the Japanese Society for Cancer of the Colon and Rectum Departments of a Surgery and b Medical Statistics, Fujita Health University School of Medicine, Toyoake, c Department of Surgery, Tochigi Cancer Center, Utsunomiya, and d Department of Surgery, Tokyo Medical and Dental University, Tokyo, Japan Abstract Background/Aims: Peritoneal metastasis (PM) is a wellknown predictor of poor prognosis. This study aims at identifying factors affecting recurrence and prognosis after R0 resection for colorectal cancer (CRC) with synchronous PM. Methods: A multi-institutional, retrospective analysis of 172 patients with R0 surgery for CRC with PM was conducted. Clinicopathological variables were analyzed for their significance in contributing toward recurrence and prognosis. Results: Lymph node (LN) metastasis was an independent factor affecting recurrence as indicated by logistic regression analyses. The following factors were independent predictors of poor prognostic using the Cox proportional hazard model: LN metastasis, no postoperative adjuvant chemotherapy, five or fewer dissected LNs, and preoperative high serum carbohydrate antigen 19-9 levels. Of the patients undergoing postoperative adjuvant chemotherapy, no significant differences were observed in recurrence rate and disease- © 2016 S. Karger AG, Basel 0253–4886/16/0335–0382$39.50/0 E-Mail email@example.com www.karger.com/dsu free interval between those with intensive adjuvant chemotherapy and those with non-intensive chemotherapy. After R0 surgery for PM, 90 patients (76.3%) experienced recurrence by 18 months, and hematogenous recurrence occurred significantly more often than peritoneal recurrence. Conclusion: Harvesting of more than 5 LNs and administration of postoperative adjuvant chemotherapy after R0 surgery are recommended for prognosis improvement. Intensive follow-up should be performed within 18 months after R0 surgery for CRC with synchronous PM. © 2016 S. Karger AG, Basel Introduction Colorectal cancer (CRC) is the third most common cause of cancer death in Japan, and its incidence is increasing. Synchronous peritoneal metastasis (PM), found in 4–10% of primary CRC patients, is a well-known predictor of poor prognosis in CRC patients [1, 2]. The TNM classification of malignant tumors classifies CRC with PM as stage IV-B, which includes patients with multiple organ metastases . Appropriate treatment for synchroDr. Harunobu Sato Department of Surgery, School of Medicine Fujita Health University, 1-98 Dengakugakubo Kustukake-cho, Toyoake, Aichi 470-1192 (Japan) E-Mail harsato @ hotmail.co.jp Downloaded by: Kings's College London 220.127.116.11 - 10/29/2017 8:48:40 AM Key Words Colorectal cancer · Peritoneal metastases · R0 surgery · Recurrence · Prognosis Methods Patients Data were collected from 1,217 consecutive patients with CRC and synchronous PM who underwent an initial surgery between January 1997 and December 2007 using the databases of 16 referral hospitals of the Japanese Society for Cancer of the Colon and Rectum (JSCCR). Of the 1,217 patients, 224 received R0 resections, and 172 of them had sufficient background records for the final analysis. No patients underwent HIPEC in our series. Parameters The parameters used in this study were as follows: age, gender, location of primary tumor (PT), distant metastases, liver metastasis, size of PT, lymph node dissection, number of dissected lymph nodes, histology, depth of tumor invasion, lymph node metastases, postoperative adjuvant chemotherapy, lymphatic invasion, venous invasion, grade of PM according to JSCCR classification, maximum size of PM, number of PM, extent of PM, and preoperative serum levels of the carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). Clinical and pathological data were recorded according to the JSCCR classification system . The depth of tumor invasion and lymph node metastases was classified according to the seventh TNM classification system . The cutoff values for CEA and CA19-9 were 5.0 ng/ml and 37.0 U/ ml, respectively. Serial univariate analyses were conducted on all dissected lymph nodes (66 times in total), all metastatic lymph nodes (30 times in total), all PM nodules (cases including all cases with 11 or more PM nodules 10 times in total), and all regional PM (8 times in total) to determine cut-off values in the analysis of factors that affected recurrence and prognosis. The lowest p value for Peritoneal Metastases of CRC the number of dissected lymph nodes, metastatic lymph nodes, PM nodules, and number of regional PM cases was defined as the cut-off value for each. Surgical charts were thoroughly reviewed and scrutinized with respect to narrative descriptions, figures, and comments. Patients were classified according to the size of the largest disseminated lesions, number of disseminated lesions, and number of regional disseminated lesions. The number and size of the PM nodules were converted to numerical data based on the original descriptions provided in the surgical charts. For example, ‘a few’ disseminated lesions were recorded as ‘≤3’, ‘miliary’ and ‘rice-sized’ lesions as ‘≤5 mm’, and ‘azuki bean-sized’ and ‘thumbsized’ lesions as ‘5–20 mm’. The PM site was classified into 9 areas, and the extent of the PM was evaluated as the number of sites as described in a previous study . The grade of PM was classified using the Japanese PM classification defined by JSCCR as follows: P0, no PM; P1, metastasis localized to the adjacent peritoneum; P2, metastases limited to the distant peritoneum; and P3, diffuse metastases in the distant peritoneum . Intensive chemotherapy was defined as the regimen that contained fluorouracil (5FU) or 5FU derivatives and camptothecin (CPT-11) or oxaliplatin. The median follow-up period was 27.2 months (range 0.5–209.0 months). Statistical Analysis Differences between continuous variables and categorical variables were identified using the Mann–Whitney U test and the chisquare test or Fisher’s exact test, respectively. Factors affecting recurrence were analyzed using binomial logistic regression analyses. All data are expressed as medians and ranges, and survival rates were calculated using the Kaplan–Meier method and compared using the log-rank test to examine the associations between survival and the clinical and pathological variables. Survival analyses were performed using Cox regression models for factors that influenced the survival of patients in the Kaplan–Meier analysis, and the differences were identified using the log-rank test. Multiple comparisons were performed by Bonferroni adjustment. The differences between groups and the associations with the survival of CRC patients with PM were considered significant when p < 0.05. All analyses were performed using JMP 11 Statistical Software (SAS Institute Inc., Cary, N.C., USA). Results Patient Characteristics (Table 1) The median age of the 172 patients was 62.0 (range 18–91). Of the 172 patients, 66 had a PT in the right colon, including the cecum, ascending colon, and transverse colon; 79 in the left colon, including the descending colon, sigmoid colon, and rectosigmoid colon; and 27 in the rectum. Synchronous distant metastases as well as PM were found in 54 patients (31.4%). Synchronous liver metastases were found in 27 patients (15.7%), distant lymph node metastases in 13 (7.6%), and other organ metastases in 21 (12.2%). The number of patients with P1, P2, and P3 was 103 (59.9%), 56 (32.6%), and 13 (7.6%), respectively. Dig Surg 2016;33:382–391 DOI: 10.1159/000444097 383 Downloaded by: Kings's College London 18.104.22.168 - 10/29/2017 8:48:40 AM nous PM can improve the prognosis of CRC patients; in this regard, aggressive cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been performed [4–7], and recent intensive chemotherapies are expected to improve the prognosis. Most PM classifications determine the degree of PM based on focal number, range, and size of PM and are used to make prognostic predictions and decisions about treatment strategies [7–11]. Previous reports have identified histological types, presence of lymph node metastases, and R0 surgery as prognostic variables for CRC with PM [12, 13]. However, there has been no detailed report regarding the clinical outcomes of CRC with PM after R0 surgery. Factors affecting recurrence and prognosis are important for postoperative follow-up and decisions about adjuvant chemotherapy administration, yet such factors have not yet been identified for CRC with PM. The aim of this study was to identify the factors associated with recurrence and prognosis in stage IV CRC with synchronous PM after R0 resection for determining appropriate postoperative follow-up and treatment strategies. Table 1. Univariate and multivariate analyses of factors affecting recurrence in CRC patients with peritoneal metastases after R0 resec- tion Univariate analysis number Age, years ≤70 70< Gender Male Female Tumor location Colon Rectum Distant metastases + – Liver metastasis + – Size of PT, mm ≤70 70< LN dissection D1 D2, D3 Number of dissected LN ≤5 5< Unknown Histology Differentiated type Undifferentiated type Depth of invasion T1–T3 T4 LN metastases – + Postoperative chemotherapy + – Unknown Lymphatic invasion – + Venous invasion 0+1 2+3 JSCCR classification of PM P1 P2 P3 Size of PM, mm ≤5 6–20 21≤ 384 recurrence, % Multivariate analysis p value HR 95% CI p value 3.02 1.60–5.69 0.0007 0.005 3.44 0.82–14.3 0.88 0.004 2.24 0.95–5.30 0.07 0.53 122 50 98 (80.3) 38 (76.0) 80 92 63 (78.8) 73 (79.3) 145 27 113 (77.9) 23 (85.2) 54 118 47 (87.0) 89 (75.4) 27 145 22 (81.5) 114 (78.6) 130 42 104 (80.0) 32 (76.2) 9 163 7 (77.8) 129 (79.1) 8 162 2 7 (87.5) 128 (79.0) 1 (50.0) 135 37 108 (80.0) 28 (75.7) 44 128 31 (70.5) 105 (82.0) 27 145 13 (48.1) 123 (84.8) 117 35 20 101 (86.3) 26 (74.3) 9 (45.0) 14 158 7 (50.0) 129 (81.6) 92 80 65 (70.7) 71 (88.8) 103 56 13 77 (74.8) 48 (85.7) 11 (84.6) 95 59 18 75 (78.9) 44 (74.6) 17 (94.4) 0.92 0.39 0.08 0.74 0.60 0.92 0.56 0.57 0.10 0.00001 0.09 0.10 0.62 Dig Surg 2016;33:382–391 DOI: 10.1159/000444097 Sato et al. Downloaded by: Kings's College London 22.214.171.124 - 10/29/2017 8:48:40 AM Variable Table 1. (continued) Univariate analysis number Number of PM 1 2≤ Regional number of PM 1 2≤ Preoperaive CEA level High Low Unknown Preoperative CA19-9 level High Low Unknown recurrence, % p value HR 95% CI p value 0.03 1.81 0.74–4.44 0.55 0.02 1.93 0.83–4.51 0.13 0.06 68 104 49 (72.1) 87 (83.7) 108 64 81 (75.0) 55 (85.9) 104 54 14 88 (84.6) 38 (70.4) 10 (71.4) 73 81 18 64 (87.7) 59 (72.8) 13 (72.2) 0.07 Ninety-five patients (55.2%) had PM measuring 5 mm or smaller. Although 104 patients (60.5%) had <4 PM, 38 patients (22.1%) had ≥10 PM. One regional dissemination lesion was observed in 108 of 172 patients (62.8%). Postoperative adjuvant chemotherapy was administered in 117 patients (68.0%) after R0 surgery, and involved intensive chemotherapy in 28 patients (16.3%) and oxaliplatin in 9 (5.2%). Oral postoperative adjuvant chemotherapy, such as carmofur, UFT ± Uzel, TS-1, and doxifluridine, was administrated in 40 patients (23.3%), and regimes using intravenous 5FU ± leucovorin were used in 49 patients (28.5%). Factors Affecting Recurrence after R0 Surgery Recurrence was found in 136 patients (79.1%) after R0 surgery. An association between lymph node metastases (p = 0.00001), lymphatic invasion (p = 0.005), venous invasion (p = 0.004), preoperative high serum CEA levels (p = 0.03), and preoperative high serum CA19-9 levels (p = 0.02) was revealed using the chi-square test (table 1). Logistic regression analyses revealed that, of these factors, only lymph node metastases independently affected recurrence (table 1). Although there was no significant association between the recurrence rate and postoperative adjuvant chemotherapy, the median disease-free interval was 10.9 months (range 0.9–99.6) in patients with postoperative adjuvant chemotherapy and 9.5 months (range 1.4–39.5) in those without (p = 0.07). Among the patients who received postoperative adjuvant chemotherapy, there was no significant difference in the recurrence rate or disease-free Peritoneal Metastases of CRC Multivariate analysis interval between those who received intensive postoperative adjuvant chemotherapy and those who received nonintensive postoperative adjuvant chemotherapy. Furthermore, among the patients who received postoperative intensive adjuvant chemotherapy, there was no significant difference in the recurrence rate between those treated with oxaliplatin as the postoperative adjuvant chemotherapy (88.9%) and those not treated with oxaliplatin (89.5%). There was no significant difference in the recurrence site between patients with PM alone and patients with PM plus metastases to other organs. Hematogenous recurrence occurred in 44.8% of all patients who experienced recurrence; 29.7% of these patients experienced peritoneal recurrence (table 2). The median disease-free interval was 10.8 months (range 0.9–99.6) in 118 patients whose recurrence day was known. Of them, 67 (56.8%) had a recurrence within 12 months after R0 surgery, and 90 (76.3%) within 18 months (fig. 1). Surgery for recurrent lesions after R0 surgery was performed in 25 patients (21.2%), more commonly in patients who had a recurrence after 18 months (10 of 28 cases; 35.7%) than in the patients who had a recurrence within 18 months (15 of 90 cases; 16.7%; p = 0.03; fig. 1). Factors Affecting Prognoses after R0 Surgery The overall 3- and 5-year survival rates of patients with PM after R0 surgery were 42.0 and 36.2%, respectively. Five or fewer dissected lymph nodes (p = 0.01), lymph node metastases (p = 0.008), postoperative chemotherapy (p = 0.008), lymphatic invasion (p = 0.02), venous invasion (p = 0.049), regional number of PM (p = 0.04), and Dig Surg 2016;33:382–391 DOI: 10.1159/000444097 385 Downloaded by: Kings's College London 126.96.36.199 - 10/29/2017 8:48:40 AM Variable 90 cases (76.3%) 67 cases (56.8%) 11 cases (9.3%) Number 40 30 20 10 0 0–6 6–12 12–18 18–24 24–30 30–36 36–42 42–48 48–54 54–60 60–66 Months Number 26 41 23 8 4 5 3 4 2 1 1 Surgery (%) 5 (19.2) 5 (12.2) 5 (21.7) 3 (37.5) 1 (25.0) 1 (20.0) 2 (66.7) 1 (25.0) 2 (100) 0 0 Fig. 1. Disease-free interval after R0 surgery in patients with peritoneal metastases of CRC and the surgery rate for recurrent lesions according to the disease-free interval. Table 2. Recurrence site after R0 surgery PM PM + others Total Number Recurrence, % Via blood, % Liver, % Lung, % Others, % PM, % 118 54 172 50 (42.4) 27 (50.0) 77 (44.8) 31 (26.3) 18 (33.3) 49 (28.5) 19 (16.1) 9 (16.7) 28 (16.3) 9 (7.6) 4 (7.4) 13 (7.6) 37 (31.4) 10 (8.5) 14 (11.9) 14 (25.9) 7 (13.0) 6 (11.1) 51 (29.7) 17 (9.9) 20 (11.6) 89 (75.4) 47 (87.0) 136 (79.1) LN, % Local, % Multiple organ, % 30 (25.4) 13 (24.1) 43 (25.0) Others include hematogenous matastases and distant lymph node metastases. 386 Dig Surg 2016;33:382–391 DOI: 10.1159/000444097 the patients with five or fewer dissected lymph nodes (2 of 8 patients, 25.0%; p = 0.01). The prognosis was significantly better in patients who underwent surgery after 2005 than in those who underwent surgery before 2004 (fig. 2a); there was no significant difference in the follow-up periods after surgery between those treated after 2005 (median 34.5 months; range 1.0–70.3) and those treated up until 2004 (median 23.7 months; range 0.5–209.0; p = 0.55). Furthermore, among the patients with postoperative adjuvant chemotherapy, prognosis was significantly better in those who received intensive postoperative adjuvant chemotherapy using CPT-11 or oxaliplatin than in those who received postoperative non-intensive adjuvant chemotherapy (fig. 2b). Among the patients who received postoperative intensive adjuvant chemotherapy, there was no significant difference in prognosis between those who were treated with oxaliplatin as postoperative adjuvant chemoSato et al. Downloaded by: Kings's College London 188.8.131.52 - 10/29/2017 8:48:40 AM preoperative high serum CA19-9 levels (p = 0.045) were associated with poor prognosis using the log-rank test (table 3). Of these factors, lymph node metastases, no postoperative adjuvant chemotherapy, five or fewer dissected lymph nodes, and preoperative high serum CA199 levels were independent poor prognostic factors using the Cox proportional hazard model (table 3). The median number of metastatic lymph nodes was 4 in 172 patients. Fifty-two patients (30.2%) had seven or more metastatic lymph nodes, and 35 (20.3%) had 10 or more metastatic lymph nodes. The number of lymph node metastases was significantly higher in patients with more than five dissected lymph nodes (median 7; range 0–79) than in patients with five or fewer dissected lymph nodes (median 1; range 0–3) (p = 0.005). There were significantly more patients with more than one lymph node metastases among the patients with more than five dissected lymph nodes (115 of 162 patients, 71.0%) than in Table 3. Univariate and multivariate analyses of factors affecting survival in CRC patients with peritoneal metastases Univariate analysis number Gender Male Female Tumor location Colon Rectum Distant metastases + – Liver metastasis + – Size of PT, mm ≤70 70< LN dissection D1 D2, D3 Number of dissected LN ≤5 5< Unknown Histology Differentiated type Undifferentiated type Depth of invasion T1–T3 T4 LN metastases – + Postoperative chemotherapy + – Unknown Lymphatic invasion – + Venous invasion 0+1 2+3 JSCCR classification of PM P1 P2 P3 Size of PM, mm ≤5 6–20 21≤ Number of PM 1 2≤ Peritoneal Metastases of CRC Multivariate analysis 3-year SR, % 5-year SR, % 80 92 39.1 44.4 31.1 33.8 145 27 42.4 40.0 34.3 23.3 54 118 41.0 42.5 31.7 33.1 27 145 39.0 42.5 29.7 33.2 130 42 43.3 37.9 32.3 33.7 9 163 25.0 42.9 25.0 33.0 8 162 2 12.5 42.7 12.5 32.6 135 37 44.8 31.0 33.4 31.0 44 128 47.1 40.3 38.8 30.3 27 145 60.2 37.7 55.2 26.7 117 35 20 44.2 28.4 33.6 19.0 14 158 62.3 40.2 62.3 30.0 92 80 46.5 36.9 40.7 23.1 103 56 13 45.7 39.5 25.0 35.2 32.5 16.7 95 59 18 40.5 46.9 33.3 28.6 42.9 22.2 68 104 49.7 36.9 42.2 26.2 p value HR 95% CI p value 2.84 1.20–6.69 0.02 0.008 2.55 1.06–6.11 0.03 0.008 1.75 1.11–2.78 0.02 0.02 1.32 0.99–2.29 0.28 0.049 1.34 0.89–2.04 0.16 0.95 0.61 0.097 0.21 0.84 0.43 0.01 0.68 0.71 0.32 0.13 0.13 Dig Surg 2016;33:382–391 DOI: 10.1159/000444097 387 Downloaded by: Kings's College London 184.108.40.206 - 10/29/2017 8:48:40 AM Variable Table 3. (continued) Variable Univariate analysis Regional number of PM 1 2≤ Preoperaive CEA level High Low Unknown Preoperative CA19-9 level High Low Unknown Multivariate analysis number 3-year SR, % 5-year SR, % 108 64 46.7 34.2 36.9 25.4 104 54 14 36.9 42.9 24.7 40.5 73 81 18 33.1 44.9 23.8 36.4 After 2005 Until 2004 0.8 0.6 95% CI p value 0.04 1.50 0.99–2.29 0.06 1.58 1.05–2.38 0.03 0.26 1.0 Intensive postoperative chemotherapy Non-intensive postoperative chemotherapy 0.8 0.6 53.8% 41.4% 0.4 0.4 28.6% 0.2 a HR 0.045 1.0 0 p value p = 0.03 0 50 26.3% 0.2 60 100 150 200 0 250 Months b p = 0.01 0 50 60 100 150 200 250 Months Fig. 2. Overall survival curves according to the eras (a, p = 0.03) and the regimen of adjuvant chemotherapy after R0 surgery (b, p = 0.01). Discussion Synchronous PM is a poor prognostic factor for primary CRC patients . A majority of patients with synchronous PM of CRC have hematogenous metastases, and 388 Dig Surg 2016;33:382–391 DOI: 10.1159/000444097 most patients with PM are exclusively managed with palliative care for symptom relief with or without chemotherapy . However, aggressive surgery improves the prognosis of synchronous PM of CRC if performed as an R0 surgery. To improve the treatment outcomes of CRC patients with PM, CRS combined with HIPEC has been attempted [4–7], with significant prognostic improvement shown in a randomized controlled trial . However, this approach has not been performed as a standard treatment due to frequent and significant morbidity and mortality. Furthermore, a recent retrospective international registry study showed that a complete CRS was associated with overall survival, while HIPEC was not . Intensive systemic chemotherapy is expected to improve survival. Retrospective multicenter analyses have reported that R0 resection is an independent favorable prognostic facSato et al. Downloaded by: Kings's College London 220.127.116.11 - 10/29/2017 8:48:40 AM therapy and those who were not (p = 0.94). In the patients with recurrence, the 3- and 5-year survival rates after recurrence were 12.3 and 3.5%, respectively. The prognosis after recurrence was significantly better for patients who underwent surgery for recurrent lesions than in those who underwent other treatments (fig. 3) and was significantly better in those who had recurrence within 18 months than in those who had recurrence after 18 months (fig. 4). 1.0 Others 0.8 0.6 0.4 17.3% 0.2 0 p = 0.0005 0% 0 10 20 30 40 50 60 70 80 Months Fig. 3. Overall survival curves after recurrence according to treat- ment for recurrent disease (p = 0.0005). DFI >18 months 1.0 DFI 18 months 0.8 0.6 0.4 0.2 0 14.3% p = 0.002 0% 0 10 20 30 40 50 60 70 80 Months Fig. 4. Overall survival curves after recurrence according to the disease-free interval (p = 0.002). tor in patients with synchronous PM caused by CRC [12, 13]. However, recurrence occurs frequently, even if R0 surgery is performed. The recurrence rate in the present study was 79%. Lymph node metastasis was an independent factor that affected recurrence after R0 resection in patients with synchronous PM caused by CRC in the present study. Lymph node metastases, no postoperative adjuvant chemotherapy, five or fewer dissected lymph nodes, and preoperative high serum CA19-9 levels were independent poor prognostic factors. Focal number, Peritoneal Metastases of CRC range, and size of PM have been used to classify the progression of PM [8–11]; the JSCCR classification according to the focal number and range of PM is reported to be one of the factors affecting R0 resection and prognostic factors . However, the number of patients eligible for R0 surgery is limited – most belonged to P1 or P2 in the present study. As a result, the focal number, range, and size of PM, which are used in many classifications, were not associated with recurrence and prognosis in patients after R0 surgery. Hematogenous metastasis is reportedly associated with R0 resection, and liver metastasis is an independent poor prognostic factor in CRC patients with PM . However, in this study, neither distant metastasis nor liver metastasis was a prognostic factor in the R0 surgery case. The TNM classification of malignant tumors classifies CRC with PM as stage IV-B, which includes patients with multiple organ metastases . We believe that there was no difference in the recurrence rate or prognosis between patients with and without distant metastases because the treatment outcome was poor in CRC patients with PM, regardless of distant metastases. On the other hand, among these patients with nodal metastasis, more than 35% actually had seven or more nodal metastasis and included patients who underwent R0 surgery. For this reason, lymph node metastasis was an independent factor affecting recurrence and poor prognosis. Five or fewer dissected lymph nodes constitute one of the poor prognostic factors in this study. Among the patients with five or fewer dissected lymph nodes, the number of node metastases and the fraction of patients with node metastasis ≤1 were significantly lower than those among the other patients. Examination of a minimum of 12 lymph nodes is recommended to prevent stage migration and to accurately identify the N stage, particularly in stage II disease . In synchronous PM cases in which R0 surgery was possible, our outcomes suggest that the harvest of more than five lymph nodes through suitable lymph node dissection was important in the prediction of prognosis . Although there was no significant association between the recurrence rate and postoperative adjuvant chemotherapy, we believe that postoperative adjuvant chemotherapy contributed to prognostic improvement by extending the disease-free interval, although it did not prevent recurrence. A pooled analysis of two large prospective randomized trials (N9741 and N9841) investigating the efficacy of chemotherapy for metastatic CRC showed that the median survival time of patients with PM was significantly shorter than that of patients without PM . Actually, the efficacy of chemotherapy (even intensive chemotherapy such as FOLFOX/FOLFIRI ± bevacizumab/ Dig Surg 2016;33:382–391 DOI: 10.1159/000444097 389 Downloaded by: Kings's College London 18.104.22.168 - 10/29/2017 8:48:40 AM Surgery cetuximab) for the treatment of PM has not been demonstrated [19–21]. However, in this study, hematogenous recurrence occurred more frequently than peritoneal recurrence after R0 surgery for PM of CRC, even in patients without distant metastases. Most patients who underwent R0 surgery belonged to P1 or P2 in this study. Furthermore, 84.3% of patients had lymph node metastasis, which was one of the risk factors for hematogenous recurrence. These facts are thought to underlie the frequent hematogenous recurrence observed in these patients and may explain why postoperative adjuvant chemotherapy after R0 surgery was effective in decreasing recurrence and improving prognosis. The prognosis was significantly better in patients who received postoperative intensive adjuvant chemotherapy than in those who received nonintensive adjuvant chemotherapy, although there were no significant differences in recurrence rate and diseasefree interval between the two groups. Furthermore, the prognosis was significantly better in patients who underwent surgery after 2005 than in those who underwent surgery before 2004, when oxaliplatin was approved for use in CRC in Japan. These outcomes suggest that intensive chemotherapy better improves the prognosis of patients with PM after R0 surgery. Thus, intensive chemotherapy such as oxaliplatin might not be necessary as postoperative adjuvant chemotherapy for stage IV CRC patients with PM who have undergone R0 surgery. Recurrence occurred in almost 60% of patients with PM within 12 months after R0 surgery and in 75% within 18 months. Recurrence, particularly hematogenous recurrence, should be a significant concern until 18 months after R0 surgery for CRC with PM. The disease-free interval has been associated with the resection rate of recur- rent disease and prognosis after recurrence, and the resection rate was lower and prognosis was poor in patients who had a recurrence within 18 months after R0 surgery. Complete cancer removal by surgery followed by postoperative adjuvant therapy may extend the disease-free interval and improve prognosis. There are several potential limitations to this retrospective study. The first involves the accuracy of data due to the inconsistent format of surgical records collected at 16 institutions. Some patients had to be excluded from further analysis due to lack of sufficient background records. To ensure the accuracy of our data, we carefully omitted all inappropriate and uncertain data, thereby, unfortunately, decreasing the data by as much as 23%. Therefore, our observations warrant further consideration and validation in a larger series of patients with CRC. In conclusion, lymph node metastasis was an independent factor for recurrence and prognosis after R0 resection in patients with synchronous PM of CRC. In addition, the number of dissected lymph nodes, postoperative adjuvant chemotherapy, and preoperative serum CA19-9 levels were independent prognostic factors. In PM cases of CRC, the harvesting of more than five lymph nodes through suitable curative lymph node dissection and the administration of adjuvant chemotherapy after R0 surgery are recommended for the prediction and improvement of prognosis. Disclosure Statement All authors declare that there is no conflict of interest in this study. References 390 Dig Surg 2016;33:382–391 DOI: 10.1159/000444097 toreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 2009;27:681–685. 5 Franko J, Ibrahim Z, Gusani NJ, Holtzman MP, Bartlett DL, Zeh HJ 3rd: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis. 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