Ann Surg Oncol (2012) 19:4270–4277 DOI 10.1245/s10434-012-2462-8
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Synchronous Resection of Primary and Liver Metastases for Neuroendocrine Tumors Se´bastien Gaujoux, MD, PhD1, Mithat Gonen, PhD2, Laura Tang, MD3, David Klimstra, MD3, Murray F. Brennan, MD, FACS1, Michael D’Angelica, MD, FACS1, Ronald DeMatteo, MD, FACS1, Peter J. Allen, MD, FACS1, William Jarnagin, MD, FACS1, and Yuman Fong, MD, FACS1 Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY; 2Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY; 3Department of Pathology, Memorial SloanKettering Cancer Center, New York, NY 1
ABSTRACT Background. Surgical approach is an accepted approach for metastatic neuroendocrine tumors (NET), but the safety and effectiveness of synchronous liver metastases resection with primary and/or locally recurrent NET is unclear. Methods. From 1992 to 2009, a total of 36 patients underwent synchronous resection of primary NET or local recurrence and liver metastases. Patients and tumor characteristics, surgical procedures, and postoperative and long-term outcome were reviewed. Results. Primary lesions were solitary in 28 patients (80 %), with a median size of 25 mm. Liver metastases were multiple in 32 cases (89 %), with a bilobar distribution in 29 patients (81 %) and a median size of 62 mm. Resections included gastroduodenal (n = 5), ileocolonic (n = 18), pancreatic resection (n = 13), and major hepatectomy (n = 15). Resections were R0, R1, and R2 in 13, 11, and 12 cases, respectively, and tumors were classified as G1 in 20 (56 %) and G2 in 15 (42 %). There was 1 postoperative death after a Whipple/right trisectionectomy, and postoperative complication occurred in 16 patients (44 %). With a median follow-up of 56 months, 31 patients (89 %) experienced recurrence, which was confined to the liver in 90 %. Reduction of disease to liver only allowed subsequent liver-
Electronic supplementary material The online version of this article (doi:10.1245/s10434-012-2462-8) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2012 First Received: 5 October 2011; Published Online: 3 July 2012 Y. Fong, MD, FACS e-mail:
[email protected]
directed therapy, such as arterial embolization or percutaneous ablation, in 25 patients (71 %). Five-year symptomfree survival and overall survival were 60 %, and 69 %, respectively. Conclusions. In highly selected patients, an initial surgical approach combining simultaneous resection of liver metastases and primary/recurrent tumors can be performed with low mortality. Most patients develop liver-confined recurrence, which is usually amenable to ablative therapies that offer ongoing disease and symptom control. Neuroendocrine tumors (NET) are usually slow-growing neoplasms carrying an overall favorable prognosis, but they can exhibit highly variable clinical and biological behavior. The presence of metastases is a major adverse prognostic factor.1,2 The liver is the most common site of metastases that are bilobar and synchronous with the primary tumor in more than 50 % of the patients.3 Accepted treatment of liver metastases can be surgical resection, chemotherapy, ablative therapy, or radiotherapy. Because of the difficulties in conducting comparative trials for this rare disease, the optimal treatment for patients with metastatic NET remains controversial.4 Because of the relative inefficiency of medical treatment for NET, an aggressive surgical approach is widely accepted, even in the presence of synchronous metastases.5–15 Indeed, surgery is the only hope for cure, which is uncommon but may at least offer long-term survival and symptom control in most patients who experience recurrence. This strategy to synchronous resection of both primary/ recurrent and liver metastases has not been well addressed, with consideration for surgery being influenced not only by the expected improvement in survival, but also by the risk– benefit profile regarding morbidity and mortality. The aim
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of this study was to assess the safety of an initial surgical approach combining simultaneous resection of liver metastases with primary and/or locally recurrent disease in selected patients, and the effectiveness in terms of symptom control and survival.
PATIENTS AND METHODS Patient Selection A prospectively maintained liver surgery database at Memorial Sloan-Kettering Cancer Center (MSKCC) was reviewed for all patients who underwent, during the same procedure, resection of liver metastases associated with extrahepatic resection of primary and/or a locally recurrent NET between December 1992 and December 2009. Permission from MSKCC’s institutional review board was obtained before data review. Before surgery, all patients underwent a thorough medical evaluation including laboratory and imaging assessment, as previously reported.5,16 Surgery was indicated when primary disease was resectable and resection of at least 90 % of the hepatic disease was feasible and safe, according to preoperative evaluation. Patients with extraabdominal disease were not excluded if surgery was expected to improve symptoms due to tumor burden or hormone secretion. Follow-up was based on outpatient evaluation, routine postoperative visits with the surgeon or medical oncologist, and correspondence. Patient, tumor characteristics, and operative data were recorded. NET were classified according to site of origin and pathological feature according to the 2010 World Health Organization (WHO) classification (based only on mitotic index as previously reported by our group); they were classified as nonfunctional in the absence of symptoms related to a specific hormone production.5 Resection was classified as complete (R0) in the absence of residual disease, without an involved margin on pathological examination, and as R1 and R2 in the case of microscopic or macroscopic residual disease, respectively. When the procedure was palliative (R2), at least 90 % of the disease was resected. Hepatic resection was classified as major when three or more segments were resected. Minor resections included one or two segments or nonanatomic (wedge/enucleation) resections. Hepatic resections were named according to International HepatoPancreato-Biliary Association (IHPBA) Brisbane’s 2000 terminology of liver anatomy and resections (http:// www.ihpba.org). Postoperative complication were graded according to the Clavien-Dindo classification.17 At recurrence, the treatment strategy pursued for each patient was individualized and discussed in a multidisciplinary hepatobiliary tumor board for treatment recommendations.
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Statistical Analysis Values are expressed as median and interquartile, or percentage, as appropriate. Overall survival (OS) was defined as the time from combined surgery to death (all causes). Progression-free survival was defined as the time from combined surgery to the first recorded evidence of recurrence on imaging (R0, R1), or of tumor increase or new tumor growth after incomplete resection (R2). Symptom-free survival was defined as the time from combined surgery to the first recorded recurrence of symptoms, either as a result of tumor burden or hormone secretion. Survivors were censored at last follow-up. OS and disease-free survival were estimated by the method of Kaplan–Meier, and the log-rank test was used to compare survival curves. Variables with a P \ 0.1 in univariate analysis were entered into a Cox proportional hazard model. All statistical tests were two-sided. For all tests, statistical significance was defined by P \ 0.05. Data were analyzed with Stata 11 statistical software (StataCorp, College Station, TX). RESULTS Patient Characteristics Between December 1992 and December 2009, over 126 patients operated for liver metastases NET, and in part previously reported, 36 had a combined resection, i.e., synchronous resection of primary NET or local recurrent and liver metastases at MSKCC.5 Two patients (6 %) were submitted to operation for local recurrence with metachronous liver metastases, and 34 patients (94 %) were operated on for primary NET associated with synchronous liver metastases. Patient characteristics are summarized in Table 1. Among the 36 patients, 24 (67 %) were female, 30 (83 %) were white, and the median age at combined surgery was 51 (interquartile range 47–59) years. Twentyseven patients (75 %) were symptomatic, mainly because of abdominal pain and/or palpable mass in 12 patients (33 %), loss of weight in 8 (22 %), flushing in 6 (17 %), and moderate tricuspid insufficiency in 1 (3 %). Tumor Characteristics Tumor characteristics are summarized in Table 1. Briefly, 18 primary tumors (50 %) arose from the foregut (stomach, duodenum, pancreas) (Fig. 1), 17 (47 %) from the midgut (jejunum, ileum, caecum, appendix), and 1 (3 %) from an unknown origin. Overall, 8 tumors (22 %) were clinically functional, secreting serotonin in 6 (75 %), gastrin in 1 (12.5 %), and vasoactive intestinal peptide in 1 (12.5 %). In 7 patients (20 %), midgut primary tumors
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TABLE 1 Patient and tumor characteristics Characteristic
Value
a
Patient characteristics Sex Female
24 (67)
Male
12 (33)
Ethnicity White
with unknown status in 7 (19 %). Liver metastases were multiple in 32 cases (89 %), with a median size of 62 (range 30–91) mm. The median number of metastases was 7 (range 3–13), and they had a bilobar distribution in 29 patients (81 %), involving a median number of 6 segments (range 3–7). Overall, 3 patients (8 %) had extrahepatic disease at presentation, involving either bone and lung (n = 1) or peritoneum (n = 2).
30 (83)
African American
4 (11)
Other
2 (6)
Age at combined surgery (y) 2
51 (47–59)
BMI (kg/m )
27 (22–29)
ASA scoreb I–II
24 (77)
III–IV
7 (23)
Symptoms at diagnosis Pain/mass
12 (33)
Loss of weight
8 (22)
Flush
6 (17)
Tricuspid insufficiency
1 (3)
None (incidental diagnosis)
9 (25)
Tumor characteristics Primary tumor location Stomach–duodenum–pancreas (foregut)
18 (50)
Jejunum–ileum–caecum (midgut)
17 (47)
Unknown Size (mm) of primary tumor
1 (3) 25 (17–38)
Nodal status Positive Negative
22 (61) 7 (19)
Unknown
7 (19)
Peptide-hormone secretion Yes
8 (22)
No
28 (78)
Size of largest liver metastasis (mm) No. of liver metastases
62 (30–91) 7 (3–13)
Bilobar distribution Yes No No. of hepatic segment involved
Characteristics of Surgical Procedures Thirty-four patients (94 %) underwent primary and synchronous liver metastases resection, and 2 patients (6 %) were subjected to resections of local recurrence and metachronous liver metastases. Primary and liver procedures are summarized in Table 2. Median operative time was 220 (range 195–260) minutes, and median blood loss was 500 (range 300–950) ml. Regarding the liver procedure, overall 123 wedge/enucleations, 6 right trisectionectomy, 2 left trisectionectomy, 4 right hepatectomies, 2 left hepatectomies, 2 left lateral sectionectomies, 2 right posterior sectionectomies, and 1 segment 4–5–6 resection were performed. Additional thermal ablations were used on 4 patients for 8 lesions. Regarding extrahepatic procedures for primary/recurrent tumors, associated resections included procedures on the digestive tract: 1 total gastrectomy, 2 atypical gastric resections, 2 atypical duodenal resections, 10 small bowel resections, and 8 ileocolectomies. Procedures on the pancreas included 2 Whipple procedures, and 11 distal pancreatectomies, with splenectomies in 10. Associated resections also included 2 nephrectomies, 2 portal vein resections, 2 diaphragmatic resections, 1 oophorectomy, 1 left colectomy, and 1 retroperitoneal mass excision. Procedures are detailed in Supplementary Table 1. Overall, resections were R0, R1, and R2 in 13 (36 %), 11 (31 %), and 12 (33 %) of the cases, respectively, mainly because of the liver. Tumors were classified as G1 in 20 (56 %), G2 in 15 (42 %), and G3 in only 1 (on the metastasis) (3 %).
29 (81) 7 (19)
Postoperative Morbidity and Mortality
6 (3–7)
Extrahepatic disease at presentation Yes
3 (8)
No
33 (82)
BMI body mass index, ASA American Society of Anesthesiology a
Data are presented as n (%) or median (interquartile range)
b
For 31 patients with available data
were multiple, ranging from 2 to 32. The median primary tumor size was 25 (range 17–38) mm, and tumor was node positive in 22 patients (61 %), negative in 7 (19 %), and
Postoperative morbidity and mortality are detailed in Table 3. The 90-day postoperative mortality was 3 % (n = 1). A 50-year-old women died on postoperative day 8 from sepsis and respiratory failure after a Whipple procedure associated with a right trisectionectomy. Sixteen patients (44 %) experienced postoperative morbidity, including 3 with grade 1 complications, 7 with grade 2 complications, 3 with grade 3 complications, 2 with grade 4 complications, and 1 grade 5 complications according the Clavien-Dindo classification. Two patients (6 %) needed reoperation for ileocolic fistula. Additionally, 18 patients
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FIG. 1 Pancreatic neuroendocrine tumor of the tail, invading the spleen (red arrow) and associated with synchronous liver metastases in the right lobe (yellow arrow)
(50 %) needed transfusion. The median length of hospital stay was 9 (range 7–12) days. When we compared surgical complication and perioperative outcome between pancreatic and digestive tract resections, no significant difference were found. OS, Symptoms, and/or Tumor Recurrence and Management There were 12 deaths during follow-up. Median OS in the 36 patients in the cohort was not reached, and the 1- and 5-year OS rates were 94 % (range 80–98 %), and 69 % (range 48–83 %), respectively (Fig. 2). With a median follow-up for survivors of 56 (range 27– 88) months, 31 patients (89 %) experienced recurrence or progression. Median disease-free survival was 10 months, and the 1- and 5-year disease-free survival rates were 46 % (range 29–61 %) and 13 % (range 3–28 %), respectively. Initial recurrence occurred in the liver in 30 patients (96 %), with the liver as the sole site in 28 (90 %). Details of local and systemic treatment in the management of recurrence are listed in Table 3. Overall, 28 patients (80 %) underwent additional oncological therapy. Briefly, 11 patients (31 %) had systemic chemotherapy, started within a median delay of 42 (range 16–102) months after surgery, 4 patients (11 %) had radiometabolic therapy, started within a median delay of 33 (range 15–71) months after surgery, and octreotide was provided to 18 patients (51 %). Liver embolization was used in 21 patients (60 %), and each patient had a median of 2 embolizations (range 1–4), and up to 11. Liver embolization was started within a median delay of 16 (9–26) months after
surgery and was associated with chemotherapy (chemoembolization) in only 1 patient (3 %). Additionally, thermal ablation was performed in 3 patients (9 %), and 7 patients (19 %) underwent additional surgery for recurrence or progression. Overall, 25 patients (71 %) underwent liverdirected therapies, including embolization, ablation, or repeat hepatectomy. Regarding symptoms, 18 patients (51 %) experienced symptomatic recurrence during follow-up. These symptoms were due to bone metastases (n = 11), recurrent hormonal symptoms (n = 5), mass/pain in right upper quadrant (n = 1), or jaundice (n = 1). Median symptomfree survival was 66 months, and the 1- and 5-year symptom-free survival rates were 88 % (range 72–95 %) and 59 % (range 38–75 %), respectively (Fig. 3). DISCUSSION Because of the rarity of the disease, with an incidence of 4–5 cases per 100,000 population per year, the best treatment option for NET, and especially liver metastatic NET, remains controversial in the absence of high-level evidence.4,18 When R0 resection is achievable, an aggressive surgical approach for well-differentiated NET is widely used because of the relative inefficiency of medical treatment and the indolent nature of the disease.12 Despite the increasing safety of surgical resection, the benefit of such an approach should be balanced with the potential morbidity and mortality of the procedure. We report, in highly selected patients, synchronous resection of liver metastases with primary and/or locally recurrent NET, with a low
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TABLE 2 Procedures on primary or recurrent disease and on liver metastases
TABLE 3 Intraoperative and postoperative outcomes, and management of recurrence
Characteristic
Valuea
Characteristic
Operative time (min)
220 (195–260)
Intraoperative and postoperative outcomeb
Blood loss (ml)
500 (300–950)
90-d mortality
Procedures on primary or recurrent disease Gastrectomy (total and atypical) Duodenal resection Small bowel resection Ileocolonic resection Whipple Distal pancreatectomy
3 (8) 2 (6)
Yes
1 (3)
No
35 (97)
Overall postoperative morbidity
10 (28) 8 (22) 2 (6)
Valuea
Yes
16 (42)
No Grade of complicationb
11 (31)
20 (56)
1
3 (8)
Procedures on liver metastases
2
7 (19)
Major hepatectomy (3 segments or more)
3
3 (8)
Yes
15 (42)
4
2 (6)
No
21 (58)
5
1 (3)
Wedge resection or enucleation
Transfusion
Yes
28 (78)
Yes
18 (50)
No
8 (22)
No
18 (50)
Additional ablation
Length of stay (d)
Yes
4 (11)
No
32 (89)
Management of recurrence
Additional oncological therapy
Resection status R0
13 (36)
R1 R2
11 (31) 12 (33)
28 (80)
No
7 (20)
No
11 (31) 24 (69)
Radiometabolic therapy
G1
20 (56)
G2
15 (42)
Yes
4 (11)
G3
1 (3)
No
31 (89)
WHO World Health Organization b
Yes Systemic chemotherapy Yes
2010 WHO classificationb
a
9 (7–12) c
Octreotide
Data are presented as n (%) or median (interquartile range)
Yes
18 (51)
According to mitotic index
No
17 (49)
Embolization/chemoembolization
morbidity and mortality, leading to long-term symptom control and survival despite almost constant recurrence, especially in the liver. The first concern around offering patients extensive surgery is safety because hepatectomy with other intraabdominal resections can be associated with significant morbidity.19 In the current series, the overall morbidity was 42 %, but this was mainly due to minor complications. The single postoperative death occurred after a Whipple procedure combined with a right trisectionectomy. As we previously reported, because major hepatectomy with simultaneous pancreatectomy carries a high morbidity, such procedures should be considered carefully and are indicated mainly in highly selected patients with an expectation for long-term survival, such as patients with NET.20 In this regard, these results are similar to our experience regarding the management of synchronous
Yes
21 (60)
No
14 (40)
Ablation therapy Yes
3 (9)
No
32 (92)
a
Data are presented as n (%) or median (interquartile range)
b
Expressed as percentage of total number of complications
c
For 35 patients (1 postoperative dead patient excluded)
resectable colorectal liver metastases, and we believe that in high-volume centers, with experienced teams, this approach, by avoiding a second laparotomy, can reduce total morbidity and length of stay.21 Even if no significant differences were found between pancreatic and digestive tract resection concerning postoperative morbidity and in general perioperative outcome, we believe that the operative risk should be one of the criteria to consider in the
Resection for NET
FIG. 2 Overall survival (Kaplan–Meier) in the 36 patients undergoing combined resection of liver metastases and neuroendocrine tumors
FIG. 3 Symptom-free survival (Kaplan–Meier) in the 35 patients undergoing combined resection of liver metastases and neuroendocrine tumors
decision-making algorithm. This is especially true regarding the Whipple procedure. It has recently been highlighted in a well-conducted analysis from two large institutions that pancreaticoduodenectomy combined with liver-directed therapy was associated with considerable morbidity, especially hepatic abscess.22 In our opinion, pancreaticoduodenectomy and synchronous liver resection should be only considered for patients highly selected for both operative risk and biological behavior/tumor aggressiveness, and avoided otherwise. In this setting, preoperative biopsy could be performed to assess disease aggressiveness before moving to the operating room. It has previously
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been shown that endoscopic ultrasound fine-needle aspiration is accurate in predicting the malignant behavior of NET as well as 5-year survival, and it consequently may play a role in determining management strategy.23,24 Regarding NET, synchronous resection of both primary/ recurrent and liver metastases could have some additional advantages. First, in patients with a long life expectancy, it could avoid local complications due to tumor bulk, such as bleeding or obstruction for small bowel tumors, or segmental portal hypertension in pancreatic tumors. Second, primary resection even in the setting of metastases has been associated with improved survival, especially regarding pancreatic primary tumor, although this is less clear in the presence of unresectable liver metastases.14,25 Third, because primary recurrence is rare after complete resection, this approach leads to initial recurrences isolated to the liver—90 % of the cases in this report. This allows effective liver-targeted treatment via embolization, ablation, or repeat resection, and it may lead to long-term symptom-free survival. An additional benefit from initial surgery is that cholecystectomy, which should systematically be done when operating for NET, can avoid the gallbladder complications reported with hepatic arterial embolization or the use of somatostatin analogs.26–28 Neuroendocrine liver metastases resection is generally noncurative and associated with frequent recurrence.5,6,8,9,16,29–31 R0 resection is achieved in less than 50 % of cases because of the frequent multiple and bilobar distribution of the liver metastases.32 Additionally, effective adjuvant treatments are lacking.33 However, prognosis of patients with liver metastases seems better than patients with other metastatic localizations, and we believe this justifies the aggressive surgical approaches often needed to achieve complete resection.2,34 Because most patients experience recurrence, with a high frequency of microscopic residual disease undetected at initial operation, we have taken a conservative approach to surgical therapy, favoring preservation of liver parenchyma even at the risk of R1 resection. Thus, we will accept the close margin of enucleations if it allows the preservation of a functional liver. Debulking surgery (R2), which was provided to approximately 30 % of patients in the present series because of the frequent widespread bilobar nature of the disease, might also be justified to palliate the symptomatic patient, particularly if more than 90 % of the disease could be resected because it allows for good symptom control, even if this strategy remains highly controversial.35,36 Others have reported a potential benefit of an initial aggressive surgery to treat liver metastatic NET. Elias et al. reported hepatectomy with extrahepatic tumor resection in 36 of 47 patients, with an overall 71 % 5-year survival.8 Chen et al. reported 15 patients with complete resection of liver metastases, half of whom had a synchronous primary
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tumor resection with an overall 73 % 5-year survival.37 Schurr et al. showed that concomitant resection of primary tumor and metastases when achievable was associated with long-term surgical control.12 Aggressive synchronous resections of primary and liver metastases may improve survival, and in addition, they are associated with excellent symptom control, especially regarding hormonal symptoms.6 At recurrence, patients are best treated with a multidisciplinary approach with either hepatic artery embolization or chemoembolization, ablation, systemic chemotherapy, octreotide, or peptide receptor radionuclide therapy with lutetium or yttrium, according to presentation and available expertise.16 Nevertheless, it is important to understand that most of the available literature on this topic is biased because it is retrospective and based on historical controls. Overall, whether initial surgical resection has better results than liver-directed therapy remain to be proven in a randomized fashion. This is unfortunately very unlikely to occur soon, and we strongly believe that progress in a near future will only come from a national or international collaborative effort. Patients in this cohort are highly selected. Prognostic factors for metastatic NET have been extensively studied. Bilobar disease, massive liver involvement, noncurative intent procedure, rapid preoperative tumor growth, high Ki-67 proliferation and mitotic index, high histologic grade, and poor differentiation may be associated with a decreased survival.8,38,39 Overall, patient selection for surgery should be evaluated on the basis of the natural history of the disease, with the distinction between NET (G1 and G2) and neuroendocrine carcinoma (G3), according to the WHO 2010 classification of digestive NET, being essential.5,40 A distinction can be made at preoperative biopsy with the addition of Ki-67 immunohistochemistry.39,41,42 A few months of observation before surgery can also help to evaluate the biological behavior of such tumors. Additionally, preoperative 18F-FDG PET/CT imaging may help determine metabolic prognostic features.43 Patients with indolent disease, where complete cytoreduction can be achieved, might be the best candidates for surgical resection. On the other hand, surgery should be avoided in patients with poorly differentiated or G3 grade according to the 2010 WHO classification.44 Overall, in selected patients with favorable tumor biology, an initial surgical approach combining synchronous resection of liver metastases with primary and/ or locally recurrent disease appears safe and effective, with a 5-year symptom-free survival and OS of 60 % and 69 %, respectively. Nevertheless, whether an initial surgical approach in liver metastatic patient improves survival compared to liver-directed therapy remain to be proven.
S. Gaujoux et al. ACKNOWLEDGMENT We thank the staff of the Surgery Department for helpful discussions. S.G. was recipient of a grant from the European Society of Surgical Oncology (ESSO), and the Association Franc¸aise de Chirurgie He´pato-Biliaire et de Transplantation He´patique (ACHBT).
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