Role of hepatectomy in treating multiple bilobar colorectal cancer metastases

Role of hepatectomy in treating multiple bilobar colorectal cancer metastases Kuniya Tanaka, MD, PhD, Hiroshi Shimada, MD, PhD, Michio Ueda, MD, Kenichi Matsuo, MD, Itaru Endo, MD, PhD, and Shinji Togo, MD, PhD, Yokohama, Japan

Background. Although retrospective studies have demonstrated survival benefit from hepatectomy for metastatic colorectal cancer, few studies have examined patients with multiple bilobar metastases to identify survival-related factors throughout their course. Methods. Among 277 patients with R0 resection for liver metastases from colorectal cancer, 79 patients had 4 or more lesions in a bilobar distribution. To determine impact on long-term outcome, we compared clinicopathologic factors retrospectively between 3-year survivors and patients who died less than 3 years after hepatectomy. Results. Among 79 patients with 4 or more bilobar metastases, 5 patients (6.3%) attained prolonged remission after initial hepatectomy. By multivariate analysis, a lack of adjuvant chemotherapy compromised survival (relative risk or RR, 2.21; P = .036), as did prehepatectomy carcinoembryonic antigen exceeding 12 ng/mL (RR, 2.12; P = .039). Treatment-related variables such as repeat resections in the event of liver recurrence (P < .01) or lung metastases (P < .05), as well as adjuvant chemotherapy (P < .01), differed significantly between 3-year survivors and nonsurvivors, as did the differences in number of metastases, maximum size of metastases, concomitant extrahepatic metastases at the time of initial hepatectomy, and disease-free interval preceding initial recurrence. Conclusions. Although not effective as a sole treatment for multiple hepatic metastases of colorectal cancer, liver resection is important in multimodal therapy. Reoperations for recurrence of metastases, followed by additional chemotherapy, frequently obtained long survival. (Surgery 2008;143:259-70.) From the Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Japan

HEPATECTOMY is accepted as the most effective therapy for metastases of colorectal cancer to the liver. However, most surgical experience reported to date has involved patients with small numbers of metastatic lesions in a distribution confined to the right or left lobe. Benefits from resection for patients with more complex and extensive hepatic metastasis have not been defined well, and the effectiveness of liver resection for bilateral or multiple metastases is controversial. The natural history of nonresectable colorectal liver metastases allows for only 3 to 24 months of survival,1 and survival is

Accepted for publication August 25, 2007. Reprint requests: Kuniya Tanaka, MD, PhD, Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2007.08.015

more limited still—to 3 to 10 months—when both lobes of the liver are involved.2,3 Many studies have attempted to identify factors that predict survival and nonrecurrence after hepatic resection in patients with colorectal liver metastases, aiming to guide decision making concerning hepatectomy or adjuvant chemotherapy. A factor frequently found to show prognostic significance has been liver tumor volume as measured or estimated from number, size, weight, extent, or distribution of metastases.4 In most reported series, patients with fewest metastases survived longer after hepatic resection.4 Fong et al5 favored the total number of tumors as a way to stratify patients in clinical trial because the number of tumors correlates well with long-term outcome, which concludes that survival after hepatectomy was poorer in patients with 4 or more liver tumors than in patients with 1, 2, or 3 metastases. A multi-institutional study by the Registry of Hepatic Metastases6 reported that patients with 3 metastases had significantly poorer survival than those SURGERY 259

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with 1 or 2 metastases, whereas patients with 4 or more metastases seemed to do at least as poorly. Nordlinger et al7 demonstrated similarly that 4 or more liver metastases was an independent poor prognostic factor for survival after liver resection. Although bilobar involvement was a poor prognostic factor after hepatic resection in some reports,5,8,9 other reported series found distribution of metastases in itself to have little effect on patient survival after hepatectomy. However, previously reported series indicate clearly that survival is related closely to the extent of liver involvement by tumor, and a consensus has been reached that patients with 4 or more metastases in a bilobar distribution receive little benefit from liver resection.6,10-12 On the other hand, recent advances involving new anticancer drugs and chemotherapy regimens for colorectal cancer metastases now result in a median survival of approximately 20 months.13 In addition, several local ablative techniques such as freezing, heat, or introduction of chemical agents have shown promise in treatment of unresectable liver cancers, either alone or as an adjunct to liver resection.14 Given the implications of such recent advances in treatment for colorectal cancer metastases, indications for liver resection need to be reassessed as one of several complementary treatment modalities for multiple bilobar liver metastases. We analyzed retrospectively patients treated at our institution to estimate the survival benefit from hepatectomy performed to remove 4 or more bilobar liver metastases from colorectal cancer. PATIENTS AND METHODS Patients. From 1990 to 2006, our Department of Gastroenterological Surgery at the Yokohama City University Graduate School of Medicine performed liver resection with curative intent in 297 patients who were found to have liver metastasis from colorectal cancer. The mean follow-up duration for these 297 patients was 42 months (median, 29 months; range, 1--195 months). Among them, 1 patient (0.3%) with solitary metastases died within 60 days of operation from postoperative bleeding, sepsis, and multiple organ failure. Ninety patients (30.3%) had 4 or more liver metastases in a bilobar distribution; the other 206 patients (69.7%) had 3 or fewer metastases and/or unilobar metastasis. Among the 90 patients with 4 or more liver metastases in a bilobar distribution, curative hepatectomy was precluded in 3 patients and concomitant extrahepatic metastases precluded R0 resection status in another 8 patients even though they underwent curative-type liver

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resections. Among the 206 patients with 3 or fewer metastases and/or unilobar metastasis, curative hepatectomy was precluded in 1 patient and concomitant extrahepatic metastases precluded R0 resection status in another 7 patients. Preoperative staging included a physical examination, measurement of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9, colonoscopy, barium enema, abdominal ultrasonography, abdominal computed tomography (CT), and chest imaging by routine chest radiography or CT. Imaging by positron-emission tomography (PET) was introduced for preoperative staging after 2002. Hepatectomy procedures. Hepatectomy was not performed necessarily according to anatomic principles of resection; the guiding principle was assurance of tumor-free margins. To determine whether a hepatectomy procedure was acceptable for a given patient, we employed the prediction score (PS) system introduced by Yamanaka.15 PS was calculated using the formula PS = –84.6 + 0.933a + 1.11b + 0.999c. The 3 variables were a, resection fraction (%) calculated from CT volumetry; b, indocyanine green retention rate at 15 min; and c, the age of the patient. A PS below 50 indicated that a given hepatectomy would be acceptable. When a 1-stage combined resection was precluded by insufficient estimated postoperative liver volume, excessive indocyanine green retention rate, or patient age considerations,15 portal vein embolization (PVE) or 2-stage hepatectomy16 was performed. Intraoperative ultrasonography was used to identify any occult tumors not detected preoperatively and to confirm relationships between tumors and vasculobiliary structures. Parenchymal dissection was performed using ultrasonic dissectors. When necessary, the liver pedicle was clamped intermittently in cycles, including 15 min of clamping and 5 min of reperfusion. The Brisbane 2000 terminology of the International HepatoPancreato-Biliary Association was used to categorize operative procedures.17 Any extrahepatic metastases were resected whenever possible, as decided case by case. In the presence of resectable metastases in both liver and lung, liver resection and primary tumor resection were performed before pulmonary resection, aiming to eliminate the liver as a source of potentially disseminating neoplastic cells. When liver metastases were associated with extrahepatic intra-abdominal metastases, both were resected at the same time. Principles underlying selection criteria for resection of recurrent hepatic metastases were the same

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as those for initial hepatectomy. Technical considerations predominated in surgical decisions regarding feasibility of repeat hepatic resection. Because quality and quantity of remaining hepatic parenchyma were important factors, patients were excluded from repeat hepatic resection when the PS based on volumetry, indocyanine green retention rate, and patient age of more than 50 years.15 Whenever safe and complete (R0) resection of all sites of extrahepatic disease was deemed possible after identification of extrahepatic recurrences, resection was performed irrespective of recurrence sites. Neoadjuvant chemotherapy. Some patients with multiple liver metastases in a bilobar distribution whose metastases initially would have posed difficulties in safe removal 1st received neoadjuvant hepatic arterial chemotherapy with a combination of 5-fluorouracil (5-FU), l-folinic acid (FA), and cisplatin (CDDP). Treatment consisted of a 5-day course of infusions into the hepatic artery through an implanted arterial access port (Vital-Port; Cook Vascular, Leechburg, Pa). On each of 5 days, 5-FU (500 to 600 mg/m2/day), FA (100 mg/m2/day), and CDDP (10 mg/m2/day) were delivered. This 5-day course was repeated 4 or more times at 9day intervals. Adjuvant therapy. After resection for initial liver metastases, liver recurrence, or extrahepatic recurrence, adjuvant chemotherapy was carried out via hepatic artery infusion (HAI) or intravenous infusion, generally with 5-FU and FA with or without addition of CDDP or irinotecan. Perioperative factors analyzed. The following patient and tumor-related variables were analyzed to identify prognostic factors: age, sex, site of colorectal primary, Dukes stage, timing of metastases (synchronous vs metachronous), presence or absence of extrahepatic metastases at the time of hepatectomy, and serum CEA concentration. Each resected specimen was examined grossly and microscopically to determine the number of liver tumors, size of the largest liver tumor, histologic differentiation, and hepatectomy margin status. The number of liver tumors was evaluated by preoperative CT with arterioportography and intraoperative ultrasonography and was determined finally by histologic examination of the resected specimen. Ablated tumors were confirmed to be liver metastases by intraoperative histologic examination of needle biopsy specimens. PVE before hepatectomy, staged hepatectomy, local ablation as an adjunct to hepatectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy were assessed as treatment variables.

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Patient follow-up. Patients underwent follow-up evaluation monthly at our outpatient clinic. Data were obtained and recorded from each patient’s clinical record. Long-term outcome was ascertained through clinical follow-up, tumor registry follow-up, and when necessary, through contact with the patient, family, or referring physician. No patients were lost to follow-up. Serum CEA was measured every month, a CT was performed every 3 months, and a chest roentgenogram was obtained every 6 months for 5 years after the most recent operation. Statistical analysis. Statistical comparisons of baseline data were performed by the Mann-Whitney U test, the v2 test, or the Fisher exact test. Survival rates were calculated by the Kaplan–Meier method. Multivariate regression analysis was carried out by a proportional hazard method using a Cox model, beginning with the factors identified in univariate analysis by a P value below .05. Differences between survival curves were analyzed by the log-rank test. A difference was considered significant when the 2-sided P value was below .05. RESULTS Rates for 1-, 3-, 5-, and 10-year overall survival of all 297 patients after hepatectomy were 88.8%, 58.5%, 45.7%, and 28.5%, respectively. Among these survival rates, rates for 1-, 3-, 5-, and 10-year overall survival of the 207 patients with 3 or fewer metastases or a unilobar distribution after hepatectomy were 91.0%, 62.6%, 49.2%, and 34.4%, respectively; of the 90 patients with 4 or more metastases in a bilobar distribution, the survival rates were 83.7%, 49.0%, 37.2%, and 12.4%, respectively (P < .01) at the same time points. Among the 277 patients who underwent an R0 resection, disease-free survival after hepatectomy was poorer in patients with 4 or more metastases in a bilobar distribution than in patients with 3 or fewer metastases or a unilobar distribution (P < .01). Overall survival also was poorer in the former group than in the latter group (P = .03); nonetheless, the 5-year overall survival rate in patients with 4 or more metastases in a bilobar distribution was 42.5% (Fig). Prognostic factors for patients with 4 or more metastases in a bilobar distribution. During preoperative staging, in the 90 patients with 4 or more metastases in a bilobar distribution, a chest CT was performed in 82 patients, whereas PET was undertaken in 45 patients. Among these 90 patients, the number of metastatic lesions [<6 (n = 43) vs $6 (n = 47), P = .02], maximum size of metastases [<40 mm (n = 46) vs $40 mm (n = 44), P = .02],

262 Tanaka et al

Surgery February 2008

Figure. Overalland disease-free survival for 277 patients with hepatic colorectal cancer metastases, in postoperative years. When patients were divided into those with 4 or more liver metastases in a bilobar distribution (continuous lines, n = 79) versus other patients (broken lines, n = 198), overall rates (A) and disease-free survival rates (B) were worse in the group with multiple bilateral metastases.

concomitant extrahepatic metastases [presence (n = 25) vs absence (n = 65), P < .01], and prehepatectomy CEA concentration [<12 ng/mL (n = 46) vs $12 ng/mL (n = 44), P < .01] were selected as patient-related and tumor-related prognostic variables by univariate analysis. Table 1 shows univariate analysis of overall survival after hepatectomy with respect to various clinicopathologic variables in the 79 patients who had an R0 resection status among the 90 patients with multiple bilobar metastases. The number of metastatic lesions (P = .02), maximum size of metastases (P = .01), and prehepatectomy CEA (P < .01) were associated significantly with survival outcome. As for treatmentrelated variables, PVE performed as an adjunct to hepatectomy (P < .01), staged hepatectomy procedure (P < .01), and adjuvant chemotherapy after hepatectomy (P < .01) also were associated significantly with survival outcome. Specifically, survival was significantly poorer in patients with 6 or more metastases, a liver tumor 40 mm or more in maximum diameter, serum CEA concentration before hepatectomy exceeding 12 ng/mL, a staged procedure with or without PVE, and no adjuvant chemotherapy after hepatectomy. By multivariate analysis, factors affecting survival independently in an adverse manner were CEA before hepatectomy exceeding 12 ng/mL (RR, 2.12; P = .039) and no adjuvant (posthepatectomy) chemotherapy (RR, 2.21; P = .036; Table 2).

Comparison of 3-year survivors with 3-year nonsurvivors among patients with at least 4 metastases in a bilobar distribution. To identify factors with greatest influence on prognosis, we divided the 79 patients who underwent R0 resection of 4 or more bilobar metastases into 3-year survivors with or without recurrence throughout their clinical course (n = 29), patients who died before 3 years (n = 29), and patients whose follow-up duration during the study was shorter than 3 years (n = 21); the last of these groups was excluded from this analysis. When characteristics were compared between 3-year survivors and patients known to have died of disease before 3 years, 3-year survivors were more likely to have fewer metastatic lesions (P < .05), smaller maximum liver tumor size (P < .01), and lower serum CEA before hepatectomy (P < .05), but they were less likely to have concomitant extrahepatic metastases at the time of hepatectomy (P < .05). Three-year survivors were more likely to have had adjuvant chemotherapy (P < .01) and were less likely to have undergone staged hepatectomy (P < .05) than 3-year nonsurvivors. During follow-up, 24 of the 29 3-year survivors (79%) had an initial recurrence (liver only, 14 patients; liver plus extrahepatic, 1 patient; lung, 6 patients; and other extrahepatic sites, 3 patients). All 3year nonsurvivors had recurrence during followup (liver only, 7 patients; liver plus extrahepatic, 6 patients; lung, 8 patients; and other extrahepatic

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Table 1. Univariate analysis of overall survival after hepatectomy for 79 patients with four or more liver metastases in a bilobar distribution undergoing R0 resection Overall survival (%)

P value (log-rank)

No. of patients

1-year

3-year

5-year

46 33

88.0 90.9

47.3 64.8

28.4 56.1

49 30

89.3 89.4

59.5 50.7

44.6 39.5

43 36

87.9 91.2

54.5 57.8

46.7 36.8

23 56

90.9 88.7

49.7 59.6

44.2 41.0

33 46

87.5 90.8

61.0 51.7

39.2 47.0

61 18

89.7 88.2

55.7 55.5

41.0 46.2

40 39

84.5 94.4

44.0 68.3

25.1 56.9

.02

40 39

84.6 94.5

43.9 69.6

28.0 59.7

.01

Extrahepatic metastases Present Absent

17 62

94.1 88.1

19.6 62.6

19.6 46.9

Prehepatectomy CEA >12 ng/mL #12 ng/mL

37 42

83.3 95.0

41.4 69.7

17.7 62.0

<.01

26 53

73.1 98.1

34.8 68.1

21.7 56.1

<.01

60 19

91.1 84.2

65.7 30.7

52.5 18.4

<.01

22 57

85.2 90.9

49.8 57.5

24.9 46.6

40 39

92.0 86.6

54.0 57.7

38.6 44.9

32 47

90.6 88.3

57.6 54.3

35.4 49.8

51 28

100.0 68.5

64.3 38.4

51.5 23.0

Variables Age, years $60 <60 Gender Male Female Primary lesion Site Colon Rectum Dukes stage A/B C Histology Well Mod/others Liver metastases Type Synchronous Metachronous No. of metastatic lesions $6 <6 Size of metastatic lesions $40 mm <40 mm

Treatment-related variables PVE as adjunct to hepatectomy Performed Not performed Initial hepatectomy Single procedure Staged Local ablation as adjunct to hepatectomy Performed Not performed Prehepatectomy chemotherapy Performed Not performed Tumor-free margin 0 mm >0 mm Adjuvant chemotherapy Performed Not performed

Well, well differentiated adenocarcinoma; Mod, moderately differentiated adenocarcinoma.

<.01

264 Tanaka et al

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Table 2. Multivariate analysis of prognostic factors for 79 patients with 4 or more liver metastases in a bilobar distribution, by the Cox proportional hazards method Variable Serum CEA (ng/mL) >12 vs #12 Adjuvant chemotherapy Not performed vs performed

Relative risk*

P value

2.12 (1.04–4.33)

.039

2.21 (1.06–4.64)

.036

*Values in parentheses are 95% confidence intervals. The inclusion criterion for variables, P < .05 by univariate analysis, admitted number and maximum size of liver metastases, prehepatectomy CEA, portal vein embolization as an adjunct to hepatectomy (performed/not performed), initial hepatectomy procedure (single/staged), and adjuvant chemotherapy.

sites, 8 patients). The disease-free interval preceding an initial recurrence was longer in 3-year survivors (median, 399 days) than in 3-year nonsurvivors (161 days, P < .01). Hepatic recurrence developed at some time in 18 of the 3-year survivors and in 20 of the 3-year nonsurvivors. A 2nd liver resection was performed in 12 of 18 survivors (67%) with liver recurrence in the former group, whereas only 2 of 20 nonsurvivors (10%) with hepatic recurrence underwent repeat hepatectomy (P < .01). Pulmonary resection was undertaken in 7 of the 14, 3-year survivors (50%) who developed a lung recurrence at some time, whereas only 2 of the 22 nonsurvivors with such a recurrence had a lung resection (P < .05, Table 3). Characteristics of 3-year survivors throughout the clinical course (n = 29). At the time of this writing, 3 or more years after the initial hepatectomy, 8 of the 29, 3-year survivors have no evidence of disease, including 3 patients who had recurrence at 1 or more sites after hepatectomy but again became free from metastatic colorectal cancer after repeat resections. Another 8 patients have had recurrences, but they still are alive more than 3 years after initial resection. The other 13 patients died of disease after more than 3 years. After the initial hepatectomy, 14 patients developed recurrence in the liver alone, 1 patient developed recurrence in the liver plus a distant site, 6 patients developed recurrence in the lung alone, and 3 patients developed recurrence in a distant nonpulmonary site alone. A 2nd liver resection was performed in 11 of the 15 patients who had liver recurrence with or without an associated extrahepatic recurrence. Pulmonary resection was undertaken in 4 of the 6 patients with isolated lung recurrence. Of these 15 patients with repeat resections for a 1st liver or lung recurrence, 1 patient remained free of tumor. Among the other 14 patients who developed a 2nd recurrence, 9 patients were treated with a 3rd resection (liver resection, 4 patients; lung resection, 4 patients;

local resection, 1 patient). A 3rd recurrence followed in all 9 patients; 6 patients underwent a 4th resection (liver resection, 3 patients; lung resection, 1 patient; adrenalectomy, 2 patients). A 4th recurrence followed the 4th resection in all 6 patients. Among these patients, 1 patient with multiple liver recurrences was treated with radiofrequency ablation (RFA) followed by liver resection and obtained prolonged remission. Another patient ultimately was free of tumor after a 5th resection for liver recurrence. Another patient had multiple brain metastases and was treated with cknife radiosurgery and palliative resection for 1 brain tumor. In all, the number of surgical procedures was 2.1 ± 1.4 (mean ± SD; range, 1--5 procedures; median, 2 procedures), whereas the number of hepatectomies was 1.7 ± 1.0 (range, 1--5 procedures; median, 1 procedure). In addition to resection of recurrent tumor, local ablation for liver recurrence using RFA, either by itself or as an adjunct to systemic chemotherapy, was undertaken in 3 patients, whereas cknife therapy was performed for brain metastases in 2 patients. One patient with an initial liver recurrence was treated with heavy-particle radiotherapy as an adjunct to hepatic arterial infusion chemotherapy. With respect to perioperative chemotherapy, neoadjuvant chemotherapy (ie, chemotherapy before initial hepatectomy) was carried out in 10 patients, whereas adjuvant chemotherapy was administered to 27 of 29 patients after the 1st liver resection (93%). Among 15 patients with a 2nd resection (for a 1st recurrence), adjuvant chemotherapy was given subsequently via the hepatic artery and/or systemically in 13 patients (87%). Among 9 patients with a 3rd resection (for a 2nd recurrence), 6 patients (67%) received prophylactic chemotherapy after operation. Of the 6 patients who underwent a 4th resection (for a 3rd recurrence), 4 patients (67%) had prophylactic chemotherapy (Table 4).

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Table 3. Demographic and clinical characteristics in patient groups defined by long-term outcome 3-Year survivors (n = 29)

3-Year nonsurvivors (n = 29)

59 (32–73)

63 (38–79)

18 11

17 12

14 15

16 13

9 20

10 19

16 13

11 18

23 6 5 (4–38) 30 (8–110) 6.6 (1–4498)

22 7 7 (4–27) 51 (8–185) 64 (2–2021)

1 28

9 20

8 21

16 13

5 24

13 16

10 19

14 15

6 23

8 21

16 13

13 16

27 2

15 14

<.01

399 (51–1449)

161 (29–462)

<.01

Proportion with liver recurrence undergoing repeat resection (%)*

12/18 (67)

2/20 (10)

<.01

Proportion with lung metastases undergoing resection (%)*

7/14 (50)

2/22 (9)

<.05

Variables Age* Gender Male Female Primary tumor Site Colon Rectum Dukes stage A/B C Histology Well Mod/Others Liver metastases Timing Synchronous Metachronous Number* Maximum size, mm* Serum CEA, ng/mL* Extrahepatic disease Present Absent Treatment related PVE as adjunct to hepatectomy Performed Not performed Staged hepatectomy Performed Not performed Neoadjuvant chemotherapy Performed Not performed Local ablation as adjunct to hepatectomy Performed Not performed Tumor-free margin, mm =0 >0 Adjuvant chemotherapy Performed Not performed Disease-free interval between hepatectomy and initial recurrence, days*

Well, well differentiated adenocarcinoma; Mod, moderately differentiated adenocarcinoma. *Median with range.

P value

<.05 <.01 <.05 <.05

<.05

266 Tanaka et al

DISCUSSION Numerous retrospective and prospective series that include large numbers of patients have demonstrated a long-term survival benefit of liver resection for patients with hepatic metastases from colorectal cancer, and these studies have examined various factors that affect survival. Such studies have reported success in predicting survival outcomes in patients who underwent liver resection for colorectal metastases based on tumor stage at time of diagnosis of the primary tumor; liver tumor bulk, either measured directly or estimated according to number, size, specimen weight, extent or distribution, or preoperative CEA;4 and presence or absence of extrahepatic disease.8,18-20 Identification of factors associated with overall survival and with recurrence is an important clinical priority in patients who underwent hepatectomy for colorectal metastases. However, the previous studies were designed mainly to identify patients likely to attain survival benefit through hepatic resection. Surgical management can be offered to only 10% to 20% of patients with colorectal cancer liver metastases.18 Thus, to improve overall survival of all patients with colorectal cancer and with liver metastases, the possibility of long-term survival using effective treatment modalities must be extended even to patients with poor prognostic factors. According to a meta-analysis by Minagawa et al,21 intrahepatic tumor distribution pattern and tumor number were reported to influence significantly outcomes in 23% and 37% of 21 reports analyzed, respectively. Many patients with multiple intrahepatic lesions in a bilobar distribution have not been considered candidates for complete surgical resection, even given recent innovations such as preoperative portal vein embolization22,23 and two-stage resections.16,24 On the other hand, despite macroscopically complete resection, tumor frequently recurred relatively soon after operation. However, recent advances in chemotherapy for colorectal cancer have achieved a median survival of 20 months,13 especially when treatments include administration of a monoclonal antibody such as bevacizumab25 or cetuximab.26 Furthermore, neoadjuvant chemotherapy given before hepatectomy allows expansion of indications for operation in the presence of multiple metastases, which permits long-term survival in chemotherapy responders.27-29 Local ablation as an adjunct preceding hepatectomy for multiple bilobar liver metastases remains controversial,30 but several reports have indicated that ablation indeed can be combined with

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resection, which extends effective treatment to a greater proportion of patients and improves survival.31-33 In this context, the surgeon can perform liver resection for multiple metastases as part of a multimodality therapeutic strategy that can offer high-quality, long-term survival, whether diseasefree or not. This study compared patients with 4 or more liver metastases in a bilobar distribution with others showing less involvement. Although overall and disease-free survivals were worse in the former than in the latter group, 5-year survival in patients with multiple bilobar metastases was 40%, which was comparable with survival rates for patients with conventional hepatectomy reported in recent published series. Among 79 patients with 4 or more liver metastases in a bilobar distribution who underwent R0 resection, prolonged remission after initial hepatectomy was obtained in only 5 patients (6.3%). This result was significantly worse than for the 43 patients (21.7%) who are now disease-free for over 3 years after the initial hepatectomy among our 198 patients with metastases limited to 1 lobe or to small numbers (P < .01, data not shown). With respect to prognostic factors associated with survival differences after hepatectomy among patients with multiple bilobar metastases with R0 resection status, the number of metastases, maximum size of metastases, prehepatectomy CEA, PVE as an adjunct to hepatectomy, a staged hepatectomy procedure, and adjuvant chemotherapy after hepatectomy were related significantly to differences in survival in our univariate analysis. As reported previously,34 concomitant extrahepatic metastasis was selected as a prognostic factor when all 90 patients with multiple bilobar metastases were considered together, but it was not a prognosticator when analysis was limited to patients with R0 resection. These results suggested that extrahepatic metastasis ceased to be a prognostic factor when curative resection was accomplished. Staged hepatectomy with or without PVE, another negative prognosticator, was considered to reflect closely the disease stage. In our multivariable analysis, only prehepatectomy CEA and adjuvant chemotherapy were associated independently with improved survival. Considering the current results, the factors whose prognostic significance was established most frequently and strongly were related to anatomic and structural characteristics of the liver metastases, although a treatment-related variable, adjuvant chemotherapy, remained an independent prognostic factor that favored survival after hepatectomy. Previously reported evidence also has indicated a survival benefit from

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Site

Tx

Site

Tx

4th recurrence Adjuvant

3rd recurrence Adjuvant

2nd recurrence Adjuvant

Neoadjuvant

1st recurrence

Adjuvant after Hx

Number of procedures

No: of metastases

Gender Timing

Age

Patient No:

Table 4. Course of 29, 3-year survivors after liver resection

Site

Tx

1 2 3 4 5 6 7

64 73 59 52 68 55 47

M M M M M F F

S 4 1 (1) – M 4 1 (1) – S 7 1 (1) Y S 12 1 (1) – M 10 1 (1) Y S 5 5 (4) Y M 4 5 (5) –

Y Y Y Y Y Y Y

– – – – – Lung Liver

Resect Resect

Y Y

Liver Resect Y Liver Resect Y

Liver Resect Y Liver Resect Y

8 9 10 11 12 13 14 15

63 69 32 51 55 55 48 53

F M F F F M M F

S 5 2 (2) – S 4 4 (3) – S 4 4 (2) – M 13 4 (3) Y S 5 3 (3) – S 5 2 (2) Y S 5 2 (1) – S 4 4 (2) –

– Y Y Y Y Y Y Y

Liver Liver Liver Liver Liver Liver Lung Liver

Resect Resect Resect Resect Resect Resect Resect Resect

– Y Y Y Y Y Y Y

Local Lung Liver Liver Liver Brain Lung

Resect Resect Resect Resect RFA c knife Resect

Y – Y Y

Liver Lung ADR LN Lung

Resect Y Resect – Resect Y SYS SYS

Y

LN

SYS

16 17 18 19 20 21 22 23 24 25

52 56 68 62 64 52 63 59 65 54

M M F M M M M F M M

S 5 3 (2) M 5 4 (1) S 4 2 (1) S 4 2 (2) S 5 2 (2) S 5 1 (1) S 4 1 (1) S 17 1 (1) S 6 1 (1) M 4 1 (1)

– – – – – _ – Y – –

Y Y Y Y Y Y – Y Y Y

Resect Resect Resect Resect Resect SYS SYS SYS SYS SYS

Y – Y Y Y

Lung Lung LN LN LN

Resect – Resect – SYS SYS SYS

26 27 28 29

67 57 64 61

F M M F

S S S S

Y Y Y Y

Y Y Y Y

Liver Lung Lung Liver Liver LN Liver Lung Lung Liver, others Liver LN Brain Liver

24 8 38 6

1 1 1 1

(1) (1) (1) (1)

RFA, SYS SYS c knife Rad, HAI

Lung SYS ADR Resect –

Site

Liver Liver

Tx

Resect RFA, Resect

Survival (months) 158 101 91 90 52 102 96

NED NED NED NED NED NED NED

36 NED Liver RFA, SYS 101 DFD Lung, LN SYS 87 DFD Liver, P SYS 76 DFD 70 DFD 70 DFD 69 AWD Brain Resect, 68 DFD c knife 66 AWD Lung SYS 62 DFD 56 AWD 53 AWD 39 DFD 69 AWD 50 DFD 43 DFD 42 DFD 39 DFD 39 37 36 36

DFD AWD AWD AWD

Values in parentheses following the number of procedures are total number of liver resections in each patient. M, male; F, female; S, synchronous; M, metachronous; Neoadjuvant, chemotherapy prior to hepatectomy; Adjuvant, adjuvant chemotherapy after surgery; Hx, hepatectomy; LN, lymph node; Tx, treatment; SYS, systemic chemotherapy; RFA, radiofrequency ablation; Rad, radiotherapy; HAI, hepatic arterial infusion chemotherapy; ADR, adrenal metastases; NED, no evidence of disease; AWD, alive with disease; DFD, died from disease.

posthepatectomy adjuvant chemotherapy.35 Some reports demonstrated a significant decrement in hepatic recurrence when HAI adjuvant chemotherapy was given. Although this treatment given alone did not reliably yield an overall survival benefit,36,37 Kemeny et al38 reported that postoperative treatment with a combination of HAI and intravenous chemotherapy improved outcomes for patients who underwent resection of liver metastases. Because oxaliplatin has been approved for use by the Japanese health insurance system only since April 2005, CDDP in combination with

5-FU and FA sometimes was given to many of the patients studied currently. Better survival may be obtained by including administration of oxaliplatin and/or a monoclonal antibody. When characteristics were compared between 3year posthepatectomy survivors and nonsurvivors, treatment-related variables such as the proportion of patients with liver recurrence or with lung metastases who underwent repeat resections differed significantly between groups, as did differences in number of metastases, maximum size of metastases, prehepatectomy CEA concentrations

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in serum, concomitant extrahepatic metastases, and disease-free interval up to the initial recurrence. Repeat hepatectomy is known to carry risks and outcomes similar to those observed for initial liver resection.39-42 Even a 3rd hepatectomy for liver recurrences after a 2nd hepatectomy has been reported to be safe and to provide additional survival benefit, in a manner similar to the 1st and 2nd liver resections.43 Resection of colorectal cancer metastasis to the lung also has been reported to be safe and effective,44 even with a history of liver metastasis.45 Repeat pulmonary surgery for recurrent lung metastases also has yielded results comparable with those following the 1st pulmonary resection.46 When we considered details of the clinical course in 3-year survivors, these 29 patients often had postoperative adjuvant chemotherapy and multiple repeat resections as well as local ablation for recurrent disease. Thus, to make every effort to resect or to ablate recurrent disease, followed by repetition of chemotherapy, was crucial to improve patient survival, even though survival after hepatectomy was restricted greatly by tumor characteristics. In general, repeat liver resection has been found to be useful in patients with fewer recurrent tumors39,41 and with longer disease-free intervals between initial resection and recurrence.40,42 However, among our 11 patients who underwent repeat resection for initial liver recurrence (patients 7 to 13, 15, 16, 19, and 20 in Table 4), only 5 patients had a solitary liver recurrence, whereas the other patients had multiple liver recurrences; the maximum number of liver tumors in a repeat resection patient was 7. The disease-free interval between initial liver resection, and recurrence was 1 year or less in 8 of the 12 patients with repeat resection. Even so, in addition to the 5 patients who attained disease-free status with a single liver resection, 3 patients ultimately became disease-free after multiple repeat resections and chemotherapy. This proportion of disease-free patients is greater than the proportion of complete responders to recently reported chemotherapy regimens.47 Furthermore, the studied patients include 16 actual 5-year survivors out of 79 patients with bilobar multiple metastases. Weber et al48 reported 12, 5-year survivors among 155 patients treated with resection for 4 or more liver metastases, but the proportion of patients with a bilobar distribution was unknown. The same group of investigators more recently reported results for 98 patients with 4 or more metastases, including 63 patients with bilobar metastases; they concluded that in most patients, the disease ultimately will recur, even though

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long-term survival is possible. Accordingly, patients should be counseled to anticipate the likely need to undergo multiple treatment regimens.34 We believe that perioperative chemotherapy combined with aggressive surgical therapy to treat recurrence influenced results more than favorable tumor characteristics. As for toxicities of chemotherapy before hepatectomy, no consensus exists concerning operative feasibility or perioperative course. However, we reported previously that some alteration in postoperative liver function and an increase in occurrence of morphologic change in nonmalignant liver occur after neoadjuvant chemotherapy, whereas chemotherapy did not increase morbidity or mortality.49 Furthermore, no significant difference in morbidity after hepatectomy was observed between our patients with multiple bilobar metastases (18% or 16/90 patients) and patients with fewer tumors or a unilobar distribution (20% or 41/207 patients; P = .75; data not shown). In this study, almost all patients with 4 or more bilobar liver metastases observed after 1993 underwent hepatectomy. In our institution, PVE and staged hepatectomy have been in common use since 1993. Newer chemotherapy regimens, including oxaliplatin, have been adopted at our institution only since 2005, which reflects the policies of the Japanese health insurance system as mentioned above. Accordingly, the treatment strategy for colorectal liver metastases has changed relatively little throughout this study period. In our retrospective study, survival of patients with multiple metastases that occur in 2 liver lobes apparently was determined predominantly by tumor biology. Yet, therapeutic benefits of multiple reoperations for multiple recurrences of metastases and additional chemotherapy were considered to increase likelihood of long survival despite recurrence after hepatectomy. Surgical resection was observed to offer immediate and substantial mass reduction in both initial liver metastases and recurrences at any site. In the presence of recurrence after hepatectomy, achievement of survival requires aggressive multimodality treatment, including repeat resection, local ablation, and effective chemotherapy. REFERENCES 1. Hughes KS, Sugarbaker PH. Resection of the liver for metastatic solid tumors. In: Rosenberg SA, editor. Surgical treatment of metastatic cancer. Philadelphia, Pa: Lippincott; 1987. p. 125-64. 2. Wood CB, Gillis CR, Blumgart LH. A retrospective study of the natural history of patients with liver metastases from colorectal cancer. Clin Oncol 1976;2:285-8.

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