Simultaneous Liver and Colorectal Resections Are Safe for Synchronous Colorectal Liver Metastases

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1 J Gastrointest Surg (2010) 14: DOI /s x ORIGINAL ARTICLE Simultaneous Liver and Colorectal Resections Are Safe for Synchronous Colorectal Liver Metastases Yanxin Luo & Lei Wang & Chuangqi Chen & Dianke Chen & Meijin Huang & Yihua Huang & Junsheng Peng & Ping Lan & Ji Cui & Shirong Cai & Jianping Wang Received: 1 April 2010 /Accepted: 30 June 2010 /Published online: 30 July 2010 # 2010 The Society for Surgery of the Alimentary Tract Abstract Background Hepatic resection (HR) is the only option offering a potential cure for patients with synchronous colorectal cancer liver metastases (SCRLM). The optimal timing of HR for SCRLM is still controversial. This study aimed to determine whether simultaneous HR is similar to staged resection regarding the morbidity and mortality rates in patients with SCRLM. Methods Four hundred and five consecutive patients with SCRLM were treated with either simultaneous (n=129) or staged (n=276) HR. The postoperative complications were analyzed retrospectively according to the documented records and hepatectomy databases at the Gastrointestinal Institute. Results Perioperative morbidity and mortality did not differ between simultaneous resections and staged resections for selected patients with SCRLM (morbidity, 47.3% versus 54.3%; mortality, 1.5% versus 2.0%, respectively; both p>0.05). Simultaneous liver resections of three or more segments would not increase the rate of complications compared to staged resections (56.8% and 42.4%, respectively; p=0.119). Meanwhile, patients with simultaneous resections experienced shorter duration of surgery and postoperative hospitalization time as well as less blood loss during surgery (all p<0.05). Conclusions Simultaneous resections of colorectal cancer primary lesions and hepatic metastases were safe and could serve as a primary option for selected SCRLM patients. Keywords Colorectal cancer. Complication. Liver metastasis. Surgical resection Yanxin Luo, Lei Wang, and Chuangqi Chen contributed equally to this work. Y. Luo : L. Wang : D. Chen : M. Huang : J. Peng : P. Lan : J. Wang (*) Department of Colorectal Surgery, Gastrointestinal Institute, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancunerheng Rd, Guangzhou , People s Republic of China wangjply@yahoo.com.cn C. Chen : Y. Huang : J. Cui : S. Cai Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People s Republic of China Introduction Up to 50% of patients with colorectal cancer (CRC) might have liver metastases during the course of their disease. 1,2 Of these, 15% to 25% present with synchronous colorectal liver metastases (SCRLM), 3 5 whereas an additional 20% to 25% develop metachronous hepatic tumors. 6 8 In 20% of patients with synchronous or metachronous liver metastases, the liver is the only site of metastatic disease. 9 Without treatment, these patients survived a median of 2.3 to 21.3 months. 10,11 Hepatic resection (HR) is the main mode of treatment offering a potential cure for patients with colorectal liver metastases (CRLM). Patients with curatively resected CRC with isolated liver metastases can expect a 5-year overall survival of 22% to 65% The 10-year survival rates have been even reported as 22~26%. 15,16

2 J Gastrointest Surg (2010) 14: Most series reporting on the surgical management of SCRLM have recommended a staged approach with initial resection of the primary lesion followed by HR 2 to 3 months later. 17,18 However, the paradigm for the surgical management of SCRLM has begun to change in two ways. First, the safety and efficacy of simultaneous resection of colorectal and liver tumors has improved, and second, we have seen the emergence of neoadjuvant chemotherapy for unresectable metastasis as well as resectable synchronous metastasis. 21,25,26 Thereby, the recommendations calling for the staged management for SCRLM patients are being debated. The optimal timing and indication of surgical resection for synchronous metastasis are still controversial. The primary goal of this study was to investigate whether simultaneous HR is similar to staged resection with regards to morbidity and mortality in SCRLM patients. Materials and Methods Subjects Patients who underwent resections of SCRLM between January 1994 and February 2008 were identified from hepatectomy databases at the Gastrointestinal Institute (Guangzhou, Guangdong, People's Republic of China). This study was approved by the institutional review board at the Sixth Affiliated Hospital of Sun Yat-sen University. The inclusion criteria for patients to be considered for the study were as follows: (1) liver metastasis/metastases as the first manifestation of M1 disease accompanied by no documented non-hepatic disseminated disease in preoperative imaging; (2) no prior history of liver-directed treatment such as HR, radiofrequency ablation, or other local modalities; (3) histologically proven colorectal carcinoma; and (4) age 18 years. In the present study, SCRLM were defined as hepatic lesions discovered before or during primary tumor resection. Hepatic lesions were typically detected via computed tomography, magnetic resonance imaging, position emission tomography, or at exploration with intraoperative ultrasound before colorectal resection. Whether patients underwent simultaneous or staged resection depended on three primary aspects: (1) the sizes and distribution of the liver metastases, (2) surgeons' own opinion regarding the safety of the resection, and (3) the patients' preferences and physical situation. Demographics, clinicopathologic data, medical and surgical treatments, and postoperative outcomes of patients who underwent simultaneous resections of primary lesions and SCRLM were compared to staged patients who underwent hepatectomy after colorectal resection. Duration of surgery was defined as the time from the initial skin incision to closure. HRs were described according to standard nomenclature. 27 Potential postoperative complications were reviewed for at least 30 days following partial hepatectomy. Hepatic complications included perihepatic or subphrenic abscess, right-sided pleural effusion, bile leak and/or biloma, liver insufficiency or failure, and the need for reoperation due to bleeding at the transaction edge. Colorectal complications included ileus, anastomotic leak, and pelvic abscess. Complications were graded according to the method described by Dindo et al., 28 except the need for blood product transfusions was not considered a complication here. Postoperative mortality was defined as any death during postoperative hospitalization or within 30 days after hepatectomy. Methods Chi-square and Student's t tests for nominal and continuous variables were used to evaluate the association of independent variables to surgical complications. Proportional hazards analyses were performed on all variables determined to be significant by univariate analysis. Differences of p<0.05 were considered significant. Statistical analysis was performed using SPSS 13.0 software. Results A total of 405 patients were treated for SCRLM. There was an even distribution of women (43%) and men (57%), with a median age of 59 years (range, 42 to 70 years). The primary colorectal adenocarcinoma was located within the anal canal in 22 patients (5.4%), within the sigmoid or rectum in 190 patients (46.9%), within the distal transverse colon or descending colon in 71 patients (17.5%), and within the right colon in 114 patients (28.1%). Additionally, synchronous multiple primary colorectal adenocarcinomas were detected in eight patients (1.98%). Of 405 patients, 129 underwent simultaneous primary colorectal tumor resection (group I). Compared to the 276 patients who underwent staged resection (group II), patients in group I had fewer numbers of hepatic metastases (Table 1) and were less often treated with chemotherapy before liver resection (Table 2). There was a similar distribution of gender, age, coexisting cardiac and pulmonary disease, numbers of rectal primary tumors, and T3/T4 primary tumors in both groups of patients (Table 1). Overall, patients had equivalent risk levels in terms of long-term prognosis as defined by the clinical risk score (Table 1). 15 As shown in Table 2, some statistical differences in surgical procedures were found between the two groups.

3 1976 J Gastrointest Surg (2010) 14: Table 1 Comparisons of Demographics and Tumor Characteristics Between Patients Who Underwent Simultaneous and Staged Resections of Colorectal Cancer and Hepatic Metastases Variable Simultaneous (n=129) Staged (n=276) P value Age (years) 58 (42 69) 60 (43 70) Male 76 (58.9%) 156 (56.5%) Cardiac disease history 26 (20.2%) 61 (22.1%) Pulmonary disease history 22 (17.1%) 69 (25.0%) Rectal primary tumor 69 (53.5%) 137 (49.6%) T3/T4 primary tumor 104 (80.6%) 241 (87.3%) Lymph nodes positive 86 (66.7%) 173 (62.7%) CEA >5 ng/ml 41 (31.8%) 75 (27.2%) Number of hepatic metastases 1 81 (62.8%) 97 (35.1%) < >1 48 (37.2%) 179 (64.9%) CRS 1 24 (18.6%) 35 (12.7%) (33.3%) 103 (37.3%) (28.7%) 85 (30.8%) (17.1%) 46 (16.7%) (2.3%) 7 (2.5%) More patients in group I received abdominal perineal resections than those in group II (15.0% and 8.3%, respectively; p=0.049). In addition, hepatic wedge resection was more often performed in group I versus group II (35.7% and 4.4%, respectively; p<0.0001), whereas more patients in group II were treated with right hepatectomy (15.9% and 5.4%, respectively; p=0.003) or unisegmentectomy (19.6% and 7.8%, respectively; p=0.002). The median duration of surgery for group I was 255 min (range, 121 to 575 min). The duration of surgery for group II was significantly longer with a median of 415 min (range, 233 to 712 min; p<0.0001). Similarly, total blood loss was higher in group II, with a median of 650 ml (range, 300 to 1,100 ml) as compared with group I, which had a median of 400 ml blood loss (range, 200 to 1,000 ml; p<0.0001). Additionally, the postoperative hospitalization was significantly shorter after simultaneous resections (group I) than combined postoperative hospitalizations of staged colorectal and HRs (group II; Table 3). Table 2 Comparisons of Medical and Surgical Treatments Between Patients Who Underwent Simultaneous and Staged Resections of Colorectal Cancer and Hepatic Metastases Treatment Simultaneous (n=129) Staged (n=276) P value Chemotherapy before liver resection 51 (40.0%) 169 (61.2%) < Primary resection Right colectomy 41 (31.8%) 73 (26.5%) Left colectomy 17 (13.2%) 54 (19.6%) Low anterior resection 49 (38.0%) 121 (44.0%) Abdominal perineal resection 19 (15.0%) 23 (8.3%) Total colectomy 3 (2.3%) 5 (1.8%) Hepatectomy Extended right hepatectomy 6 (4.7%) 21 (7.6%) Extended left hepatectomy 11 (8.5%) 37 (13.4%) Right hepatectomy 7 (5.4%) 44 (15.9%) Left hepatectomy 17 (13.2%) 20 (7.3%) Other trisegmentectomy 3 (2.3%) 11 (4.0%) Left lateral segmentectomy 4 (3.1%) 7 (2.5%) Right posterior sectionectomy 3 (2.3%) 14 (5.1%) Other bisegmentectomy 22 (17.1) 56 (20.3%) Unisegmentectomy 10 (7.8%) 54 (19.6%) Wedge resection 46 (35.7%) 12 (4.4%) <0.0001

4 J Gastrointest Surg (2010) 14: Table 3 Comparison of Outcomes After Simultaneous or Staged Resection Outcomes Simultaneous (n=129) Staged (n=276) P value Duration of surgery (min) 255 ( ) 415 ( ) < Total blood loss (ml) 400 (200 1,000) 650 (300 1,100) < Postoperative hospitalization (days) 8 (7 15) 14 (11 22) < Laparotomy complications Wound infection 5 (3.9%) 7 (2.5%) Pulmonary disease 11 (8.5%) 18 (6.5%) Cardiac disease 14 (10.9%) 19 (6.9%) Colorectal surgery complications Ileus 11 (8.5%) 16 (5.8%) Anastomotic leak 4 (3.1%) 11 (4.0%) Pelvic abscess 8 (6.2%) 19 (6.9%) Hepatectomy complications Hepatic insufficiency or failure 11 (8.5%) 17 (6.2%) Subphrenic or perihepatic abscess 6 (4.7%) 7 (2.5%) Bile leak and biloma 8 (6.2%) 21 (7.6%) Pleural effusion 10 (7.8%) 11 (4.0%) Severity of all complications Grade I or II 67 (50.4%) 179 (59.5%) Grade III or IV 64 (48.1%) 116 (38.5%) Grade V 2 (1.5%) 6 (2.0%) Overall, postoperative complications occurred in 211 of 405 patients (53.5%). In group I, 133 complications occurred in 61 patients (47.3%). In group II, 301 complications occurred in 150 patients (54.3%) when considering both hospitalizations. When comparing the morbidity after simultaneous resections to the combined morbidity after staged colorectal and hepatic procedures, the rates of laparotomy and colorectal and hepatic complications were similar between groups (all p>0.05). Concerning the severity of all complications, no differences were found in the distribution of mild complications (grade I or II, 50.4% in group I versus 59.5% in group II; p=0.078), moderate complications (grade III or IV, 48.1% in group I versus 38.5% in group II; p=0.062), and perioperative mortality (grade V, 1.5% in group I versus 2.0% in group II; p=1.0; Table 3). No specific factor was associated with overall morbidity after simultaneous or staged colorectal and HRs (Table 4). Discussion Surgical resection is the most effective treatment for metastatic CRC isolated to the liver. 1,7 Long-term survival is beyond the scope of this paper and has been the subject of other excellent studies ,29 Our findings suggested that perioperative morbidity and mortality did not differ between simultaneous resections and staged procedures for selected patients with SCRLM. Meanwhile, patients undergoing simultaneous resections could expect a shorterduration surgery and postoperative hospitalization as well as less blood loss during surgery. Although the treatment for patients with SCRLM remains controversial, surgical resection of both the primary tumor and liver metastases is the only option offering a potential cure. Given the natural history of this disease, the majority of untreated SCRLM patients displayed median survival times of 3.8 to 21.3 months. 11,15 Fortunately, due to substantial improvements in chemotherapeutics over the past several decades, greater numbers of patients benefit significantly from adjuvant chemotherapy and/or radiotherapy. Effective treatment with chemotherapy can prolong survival for up to 4 years, with a median survival of around 20 months. 30 Yet, patients who receive curative surgical resections of SCRLM can expect not only a 5-year survival but also a 10- or even a 20-year survival rate of 18% in some studies. 7,15 It appears that surgical resection is an effective treatment option for patients with SCRLM and could even offer a cure. Both simultaneous and staged resections for patients with SCRLM are associated with similar disease-free survival. 23 Since the perioperative risk of staged resection could be less than that associated with simultaneous resection, some studies have proposed that staged resection is safer and therefore a better option. 17,18 However, this perspective has been under some debate in the last decade due to the significant advancements achieved in surgical techniques and anesthetic management, as well overall

5 1978 J Gastrointest Surg (2010) 14: Table 4 Univariate Analysis of Factors Associated with All Complications After Simultaneous or Staged Colorectal and Hepatic Resections Variable Simultaneous resection Staged resection n=129 Overall complications, n=61 P value n=276 Overall complications, n=150 P value Age (years) < (43.6%) (52.4%) (52.9%) (56.0%) Gender Male (51.3%) (49.4%) Female (41.5%) (60.8%) Cardiac disease history Yes 26 9 (34.6%) (50.8%) No (50.5%) (55.3%) Pulmonary disease history Yes (59.1%) (60.9%) No (44.9%) (52.2%) CEA (ng/ml) < (50.0%) (52.2%) (41.5%) (60.0%) Chemotherapy before liver resection Yes (56.9%) (50.9%) No (41.0%) (59.8%) Primary tumor distribution Rectal (55.1%) (59.1%) Colon (38.3%) (49.6%) Primary tumor stage T (49.2%) (57.1%) Others (45.6%) (45.3%) Primary nodal status Positive (46.5%) (58.0%) Negative (48.8%) (47.6%) No. of metastases (43.2%) (54.6%) > (54.2%) (54.2%) Size of largest metastasis (cm) < (42.1%) (51.6%) (54.7%) (57.7%) No. of segments removed < (42.4%) (51.7%) (56.8%) (57.1%) critical care. Those advancements and others make simultaneous resection both readily available and safe. 31 In this study, in terms of overall perioperative morbidity and mortality, we found that there was no significant difference between simultaneous resection and staged resection of SCRLM in selected patents. Both surgical options appear to share similar severity of total complications, as defined by Dindo et al. 28 Although in this study, those patients who underwent simultaneous liver resections had more wedge resections whereas more patients who underwent staged resections had more extensive resections, neither the number of metastases nor the number of segments removed was found to be associated with the overall morbidity after simultaneous or staged colorectal and HRs in the present set of patients (Table 4). Additionally, the overall mortality in this study was less than 2%. Even with simultaneous HR of equal to or more than three hepatic segments, we noted no differences in complication

6 J Gastrointest Surg (2010) 14: morbidity between the two procedures. A similar observation was described in a recent study led by Martin et al. 31 As with their findings, we demonstrated that simultaneous resections are as safe as staged procedures for SCRLM patients and do not increase morbidity, mortality, or severity of complications. Importantly, staged resections of primary tumors and hepatic lesions require repeated anesthesia as well as surgery. It was expected that staged procedures would have a longer duration of surgery and postoperative hospitalization time as well as more blood loss during surgery. These findings are consistent with previously studies However, even though the magnitude of liver resection alone did not appear to affect mortality or postoperative complication rates in this study, we had to keep in mind that patients with staged resections underwent more extensive liver resections, which could have impacts on increasing the blood loss during surgery and duration of surgery to some extent. In summary, the present study provides evidence that simultaneous resection of CRC primary tumors and hepatic metastases is safe and is associated with a shorter duration of surgery, reduced postoperative hospitalization time, and decreased blood loss. However, this study does have some limitations. First, our data was analyzed retrospectively, and all the patients enrolled in the study were preselected. Second, outcomes associated with increased follow-up should be documented, as we might have missed additional complications that occurred after 30 postoperative days. Third, there could be surgical bias in the training of different groups, which could affect the clinical outcome to some extent. On consideration of those limitations, better-designed prospective studies are needed to confirm those findings. Finally, although HR is associated with low morbidity and low mortality rates and encouraging survival rates, 13,29 only up to 20% of SCRLM patients are deemed to be resectable with an intent to cure at presentation. 7,21 This fact highlights the importance of not only appropriate SCRLM treatment but also early detection of CRC. Acknowledgements We thank Dr. Andrew Kaz and Pin-Zhu Huang for his critical comments regarding this study. This work was supported by the Guangdong Provincial Scientific Research Grants ( , JP Wang), the National Natural Scientific Foundation of China Grants ( AQ3, L Wang), and Yat-sen Innovative Talents Cultivation Program for Excellent Tutors ( , YX Luo and JP Wang). 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