Review Article

Surgical Management of Noncolorectal Cancer Liver Metastases Andrew J. Page, MD; Matthew J. Weiss, MD; and Timothy M. Pawlik, MD, MPH, PhD

The number of hepatectomies performed for metastatic cancer has dramatically increased over the past 2 decades. Hepatectomy for stage IV colorectal cancer is now considered the standard of care for resectable patients with isolated hepatic disease and acceptable performance status. However, the indications for resection of noncolorectal origin liver metastases are not as clearly defined. This review focuses on emerging data for the resection of noncolorectal metastatic disease to the liver, with a focus on indications for surgical resection. Specifically, we review the current data on the surgical management of nonneuroendocrine and neuroendocrine C 2014 American Cancer Society. tumors metastatic to the liver. Cancer 2014;120:3111-21. V KEYWORDS: hepatic metastases, noncolorectal, neuroendocrine, melanoma, breast cancer, renal cell carcinoma, sarcoma.

INTRODUCTION There is an increasing trend toward performing hepatectomies in the setting of metastatic disease.1,2 Technical modifications, improved patient selection, and advances in perioperative care have made liver resection safer and more feasible. Because of improvements in perioperative outcomes as well as more effective chemotherapeutic agents, resection of colorectal liver metastasis is now well established, with most centers reporting a 5-year survival following surgery ranging from 40% to 58%.3-9 In contrast, surgical resection of liver metastasis secondary to other noncolorectal primary tumors is more controversial. Although some groups have reported surgical resection of a wide variety of histological subtypes, the data for resection of noncolorectal metastatic disease to the liver are not well established, and the available data are still somewhat limited.10,11 In this review, we provide an overview of the surgical management of patients with noncolorectal liver metastasis. Specifically, we review select data in the literature that have examined the role of liver-directed therapy for noncolorectal hepatic metastasis. Nonneuroendocrine Hepatic Metastases Breast

Twenty percent of patients diagnosed with breast cancer will develop metastases at some point during the course of their disease, with 50% of these metastases occurring in the liver.12-15 In patients with metastatic liver disease, approximately 90% is multifocal and found with concomitant extrahepatic disease, making hepatic resection both technically and biologically inappropriate.16,17 Furthermore, because of the tendency for breast cancer to be systemic in nature when liver metastases are present, surgeons have historically been less enthusiastic for hepatic resection in this population. However, for the 10% of patients with solitary, technically resectable disease, the role of hepatic metastasectomy has been examined in several small, retrospective studies.18,19 One of the largest studies examining this patient population was by Adam et al who examined 454 patients who underwent hepatectomy for metastatic breast cancer (Table 1).19 The overall 5-year survival was 41%, with a 5-year disease-free survival of 21%.19 On multivariate analysis the authors noted that an R2 resection (OR, 5.6; P < .01) and failure to respond to preoperative chemotherapy (OR, 3.5; P < .01) were both associated with worse survival. Interestingly, in this very select group of patients, the presence of extrahepatic disease did not correlate with worse survival (P 5 NS), although the numbers were very small and the lack of an association undoubtedly was related to selection bias and the study being underpowered to detect a possible difference. In a separate study, Mariani et al compared 51 patients with

Corresponding author: Timothy M. Pawlik, MD, MPH, PhD, Chief, Division of Surgical Oncology, Professor of Surgery and Oncology, John L. Cameron Professor of Alimentary Tract Surgery, Department of Surgery, Blalock 688, 600 N. Wolfe Street, Baltimore, MD 21287; Fax: (410) 502-2388; [email protected] Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland DOI: 10.1002/cncr.28743, Received: February 19, 2014; Revised: March 15, 2014; Accepted: March 25, 2014, Published online June 26, 2014 in Wiley Online Library (wileyonlinelibrary.com)

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3111

3112

Cancer

40

2006 2006

Adam19

2012

Turley64a

2001

Dematteo62

2006

2012

Hatzaras59a

Pawlik63

2003

Alves58

2013

40

2010

Ryu

22

2007

49

64 61

2006 2006

Adam19 Adam (pancreas, ampullary)19 Gleisner (ampullary, duodenal, biliary, pancreas)31 de Jong (pancreas, ampullary, biliary, duodenal)36 Pawlik50

39

66

56

43

14

31

148

19

2002

Okano22

51 21

2013 1994

86

Mariani20 Ochiai26

2012

454

n

2.6

4.5

0

2.3

0

0

NR

5

5

9.1

NR NR

0

NR NR

0

NR

% Perioperative Mortality

Abbreviations: NR, none reported; ER, estrogen receptor; RFA, radiofrequency ablation. a Outcomes listed at 3-year interval b Outcome listed at 3-year interval, in combination with postoperative imatinib only.

Sarcoma and GIST

Renal cell cancer

Melanoma

Periampullary

Gastric

Abbott

2006

Adam19

Breast

21

Year

Study (First Author)

Primary Tumor

34.6b

16.4

20

27.3a

0

0

NR

NR

0

0

NR NR

NR

NR NR

NR

21

% 5-Year Disease-Free Survival

67.4a

27.1

30

62.1a

0

20.5 (uveal) 0 (cutaneous) 21 (uveal), 22 (cutaneous) 44 (uveal), 39 (cutaneous)

0

27 20 (pancreas), 46 (ampullary) 0

34

50.1 19

43.6

41

% 5-Year Overall Survival

Not reached

47.2

39

Not reached

26

29.4 (uveal), 23.6 (cutaneous) 19 (uveal), 27 (cutaneous) 29 (uveal), 29 (cutaneous)

13 (pancreas/ bilary), 23 (ampullary/ duodenal)

5.9

15 NR

NR

NR 18.3

57

45

Median Survival (Months)

Microscopically positive hepatic margins and major hepatectomy (Equivalent for uveal and cutaneous subtypes) Interval between nephrectomy and development of liver metastasis 50 mm Interval between nephrectomy and development of liver metastasis 12 months, extrahepatic disease Incomplete resection of liver metastatic disease, interval to development of liver disease 24 months, and the size of the largest metastasis 2 years) was associated with improved survival (P 5 .002). Interestingly, Dematteo and colleagues also noted that the size of the largest metastatic lesion and the presence of extrahepatic disease did not seem to impact overall survival. Pawlik et al examined 35 patients with metastatic sarcoma to the liver.63 These authors demonstrated that GISTs treated with the tyrosine kinase inhibitor imatinib mesylate had better median survival compared with all other true sarcoma subtypes (not reached versus 37.1 months, respectively; P 5 .003). More recently, recognizing the unique prognostic value of GISTs and targeted therapy with imatinib, Turley et al examined the role of imatinib combined with resection for metastatic GIST to the liver.64 These authors found that patients treated with resection and imatinib had the best overall survival, with a 3-year survival of 91.7%. 3115

Review Article TABLE 2. Summary of Recent Studies of Patients Who Underwent Resection With Neuroendocrine Liver Metastases (NELM)

First Author

Year

n

Combined Modality (Resection 1 RFA)

% Perioperative Mortality

% 5-Year Survival

Elias74

2003

47

11

5

71

Osborne75 House76 Landry77 Ahmed78 Glazer79 Mayo80

2006 2006 2008 2009 2010 2010

61 26 23 50 159 339

18 8 57 NR 14 20

0 0 0 0 0 75%-80%) of the liver disease can be removed.72-81 Although the study by Mayo et al included patients treated with resection1ablation or ablation alone, other studies have more explicitly examined the role of ablative therapies for NELM.82,83 Ablation techniques typically involve the use on an energy source (eg, radiofrequency [RFA], microwave) to destroy the NELM. Most series on ablation of NELM have reported on the use of RFA rather than microwave.84 Either technique can be delivered during a laparotomy, laparoscopically, or percutaneously. Cancer

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Noncolorectal Liver Metatases/Page et al

Figure 2. (A) Overall survival following liver resection for patients with metastatic neuroendocrine tumors to the liver. (B) Overall survival stratified by the presence of extrahepatic disease prior to the first liver-directed operation. (C) Overall survival stratified by margin status (R0/R1 vs R2) and the hormonal function of the NET. Patients with hormonally functioning tumors who had R0/ R1 resection had a better survival than other groups (P 5.008). Used with permission from Mayo et al.80

Whatever the approach, ultrasound is used to both localize tumors and confirm appropriate probe placement. Although there are no prospective studies that examine the role of ablation for NELM, several large retrospective series have demonstrated relief of symptoms and a possible survival benefit from ablation. Mazzaglia et al reported their 10-year experience with RFA for NELMs and noted a 6.3% local recurrence rate and a median survival of 3.9 years.85 On multivariate analysis, the size of the dominant lesion (>3 cm) was associated with worse median survival (30.0 months vs not reached, P 5 .005). In a study by Taner et al, the authors examined the role of ablation used in combination with resection.86 In this series of 94 patients who underwent combined resection1RFA, the incidence of complications was not higher than that reported in other series using resection alone. Long term, resection1RFA was associated with 5- and 10-year survival of 80% and 59%, respectively. In another study of 119 patients who underwent laparoscopic RFA of NELM, Berber et al reported that ablation led to symptomatic relief in 97% of patients.87 However, the incidence Cancer

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of recurrence following ablation was high (22%), and many patients developed additional intrahepatic lesions (63%). With the high incidence of recurrence after hepatic resection for NELM, the role of surgery in the management of NELM has been called into question by some investigators who believe intra-arterial therapy (IAT) as a primary therapy may be better suited for patients with NELM.88,89 Like most hepatic metastases, NELMs derive the majority of their blood supply from the hepatic artery, and there is intuitive appeal for IAT.90 At present, IAT most commonly consists of bland embolization, transarterial chemoembolization (TACE), drug-eluting bead (DEB) therapy (DEB-TACE), or Yttrium-90 (Y-90) therapy. Gupta et al compared conventional TACE versus bland embolization for the treatment of NELM and reported a better response rate (50% vs 25%, P 5 .004) and survival (31.5 vs 18.2 months, P 5 .001) for TACE.90 In a different study, Liapi et al examined the response of NELM to TACE using cisplatin, doxorubicin, 3117

Review Article

and mitomycin C based on Response Evaluation Criteria In Solid Tumors (RECIST) and World Health Organziation (WHO) criteria, as well as functional MRI assessment.91 Although long-term outcomes did not correlate with RECIST and WHO criteria, the percentage of enhancement on functional MRI did. DEB-TACE has also been investigated as a possible IAT approach to NELM. In a recent phase II study by Bhagat et al 13 patients were treated with DEB-TACE.92 Although 62% of patients had an objective response, with a mean decrease in tumor size of 12% (P < .0003) and a 56% decrease in tumor enhancement (P < .001), there were unexpected biliary complications in more than half of patients (54%). Based on the findings of these studies, many centers now avoid DEB-TACE for patients with NELM—especially those with small miliary lesions— instead reserving this therapy only for patients with large tumors (smallest lesion >4 cm). Patients with small miliary disease may be better treated with Y-90 radioembolization, as this therapy tends to be more “lobar” in nature, less embolic, and may be better suited to more disseminated disease. In a large phase II study, Rhee et al reported on a cohort of 42 patients treated with Y-90.93 The authors noted minimal complications and a median survival of about 2 years for a group of patients with extensive liver disease. In a separate study, Memon et al reported on the use of Y-90 and noted a complete response in only 1.2% using WHO criteria, but a higher incidence of response of 20.5% using European Association for the Study of the Liver criteria; 1-, 2-, and 3-year survival was 72.5%, 62.5%, and 45%, respectively.94 Variables associated with improved survival included performance status (P < .001), tumor burden 25% hepatic tumor burden undergoing either intraarterial therapy (IAT) or hepatic resection of neuroendocrine liver metastasis (NELM). Patients with high-volume symptomatic disease benefited the most from surgical management (median survival: surgery, 87 months, vs IAT, 51 months; P 5.04). Used with permission from Mayo et al.9

their baseline clinicopathologic characteristics. The median overall survival was 38.9 months for IAT patients compared with 84.0 months for patients treated surgically. Further analysis revealed that patients with lowvolume (>25% liver involvement) symptomatic disease benefited the most from surgical management. In contrast, patients with high-volume disease (>25% liver tumor burden) benefited less from surgery; in particular, those patients with high-volume asymptomatic disease derived the least benefit from surgery compared with IAT (median survival: surgery, 16.7 months, vs IAT, 18.5 months; P 5 .78; Fig. 3). As such, surgical management of NELM should likely be reserved for patients with lowvolume disease or for those patients with symptomatic high-volume disease. In addition to the surgical and ablation techniques incorporated into the multidisciplinary care of patients with NELM, there are emerging systemic options. Yao et al recently evaluated the role of everolimus in patients with advanced pancreatic NETs as part of the phase III RAD001 in Advanced Neuroendocrine Tumors (RADIANT) trial.96 In this study, 92% of patients had evidence of metastases to the liver and the primary outcome measured was progression-free survival based on RECIST criteria. Compared with placebo, patients treated with everolimus had improvement in median progression-free survival (4.6 vs 11.0 months; HR, 0.35; P < .001). In a separate prospective study by Raymond et al, sunitinib was compared with placebo for advanced pancreatic NETs.97 Similar to the RADIANT trial, a high Cancer

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Noncolorectal Liver Metatases/Page et al

proportion of patients had hepatic disease, 95% in the sunitinib cohort and 94% in the placebo cohort. Median progression-free survival was improved—11.4 months in the sunitinib group compared with 5.5 months in the placebo group (HR, 0.42; P < .001). In another trial, Rinke et al reported on a placebo controlled, randomized study on the effect of octreotide in the control of tumor growth in patients with metastatic neuroendocrine MIDgut (PROMID) tumors.98 In this study of patients with unresectable or metastatic midgut NETs, patients were randomized to receive placebo or octreotide, and the primary outcome was progression-free survival measured by WHO criteria. Of all the patients enrolled, 86% had liver metastases. The study demonstrated improvement in median time to tumor progression compared with placebo (6 vs 14.3 months; HR, 0.34; P < .001). Conclusion

Although the indications for resection of noncolorectal liver metastases are not well defined, the available data would suggest that select patients may be appropriate candidates for surgical resection. Given the more indolent natural history of most NELM compared with other noncolorectal liver metastases, operative management of NELM patients is generally more common. Management of NELM patients, however, should generally be reserved for those with low-volume disease in whom complete or nearcomplete debulking can be accomplished. Similarly, for those patients with noncolorectal, nonneuroendocrine liver metastasis, liver resection should generally only be utilized for those patients with limited disease who have demonstrated good tumor biology. It is important to note that most data on surgical management of noncolorectal liver metastasis come from small, retrospective studies. As such, empiric data to support surgical management of these patients are still lacking. The importance of early, multidisciplinary input and care needs to be strongly emphasized. Although surgery is critical to the curative therapeutic paradigm, strides in survival have been largely due to more effective chemotherapy that is integrated into a multimodality plan. Systemic therapy and patient selection are critical to surgical outcomes (eg, response to chemotherapy prior to hepatectomy). Surgeons should therefore use good clinical judgment, as well as involve a multidisciplinary team when treating these patients and deciding whether surgical resection will ultimately benefit any given individual patient with noncolorectal liver metastasis. FUNDING SUPPORT No specific funding was diclosed.

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CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.

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73. 74.

75.

76. 77. 78. 79. 80.

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