Liver-directed therapy for neuroendocrine neoplasm hepatic metastasis prolongs survival following progression after initial surgery

Journal of Surgical Oncology 2012;105:342–350

Liver-Directed Therapy for Neuroendocrine Neoplasm Hepatic Metastasis

Prolongs Survival Following Progression After Initial Surgery

AKSHAT SAXENA, BMedSc, TERENCE C. CHUA, BscMed (Hons), MBBS, JING ZHAO, MD, AND

DAVID L. MORRIS, MD, PhD*UNSW Department of Surgery, St George Hospital, Kogarah, Sydney, New South Wales, Australia

Background: Surgery confers the best chance of long-term survival in patients with neuroendocrine neoplasm hepatic metastases (NENHM).

Disease progression invariably occurs in the majority of patients. No previous study has addressed the outcomes after treatment of hepatic

disease progression in patients who initially underwent surgical extirpation of NENHM. This was the principal aim of the current study.

Methods: Seventy-four patients with NENHM underwent surgery for NENHM between December 1992 and December 2009. Of these,

50 patients developed disease progression in the liver. These patients were then treated with specific liver-directed therapies according to

consensus of a multidisciplinary team. The current study evaluates progression-free survival (PFS) and overall survival (OS) following

treatment of hepatic disease progression with specific liver-directed therapies.

Results: No patient was lost to follow up. The median follow-up after treatment of progression was 29 months (range ¼ 2–137). The median

PFS and OS after diagnosis of disease progression were 15 and 48 months, respectively. Specific liver-directed therapies included surgery in

10 patients, radioembolization in 15, cytotoxic chemotherapy in 14, and conservative therapy in 11. Four independent factors associated with

PFS and OS were identified through a multivariate analysis. These were initial progression-free survival (PFS, P ¼ 0.006, HR¼ 0.32), extra-

hepatic disease (OS, P ¼ 0.029, HR ¼ 4.04; PFS, P ¼ 0.004, HR ¼ 4.03), histological grade (PFS, P ¼ 0.006, HR ¼ 4.08), and type of

secondary intervention (PFS, P ¼ 0.024, HR ¼ 0.63).

Conclusion: A multimodality approach towards treatment of disease progression as shown in this study that includes repeat surgery or radio-

embolization has been shown to achieve a superior outcome in the setting of disease progression/recurrence.

J. Surg. Oncol. 2012;105:342–350. � 2011 Wiley Periodicals, Inc.

KEY WORDS: neuroendocrine neoplasm; hepatic metastases; hepatectomy; cryoablation; survival analysis; recurrence;carcinoid

INTRODUCTION

Neuroendocrine neoplasms (NEN) represent a heterogenous group

of rare neoplasms characterized by a relatively indolent clinical

course. They mostly originate from the gastrointestinal tract or tra-

cheobronchopulmonary complex and are generally categorized into

two groups, carcinoids and islet tumors. Although rare, a contempo-

rary analysis of the National Cancer Institute, Surveillance Epidemi-

ology and End Results (SEER) database demonstrated that the

age-related incidence of NEN increased 481% within 30 years,

from 1.09/100,000 in 1973 to 5.25/100,000 in 2004 [1]. The most

common site of metastases from NEN is the liver; between 25–93%

of patients develop neuroendocrine neoplasm liver metastases

(NENHM) throughout their disease process [2–4]. These patients

have a significantly worse prognosis and enhanced symptomatology

related to hormone secretion, pressure on structures, and replacement

of the liver.

Although the optimal management for NENHM remains to

be defined, radical surgery provides symptomatic benefit and is

associated with the best survival outcomes. In expert centres, the

median survival of patients with NENLM who undergo surgery is

between 81 and 125 months, with a 5-year survival in excess of 60%

[2,5–8]. Despite encouraging data in recent years on non-surgical

therapies such as somatostatin analogs [9], radioembolization [10–

12], transarterial embolization [13,14], and systemic peptide receptor

radionucleide therapy [15], patients with unresectable disease or

those managed with non-surgical therapies can generally expect a

5-year survival of <30%. In fact, despite the lack of randomized

data, a recent consensus statement from the European Neuroendo-

crine Tumor Society emphasized that resection of hepatic metastases

should be the first-line treatment in patients within resection criteria

[16].

Unfortunately, although surgery is the only definitive therapy, dis-

ease recurrence or progression following an initial curative attempt

is almost invariable. Studies evaluating surgical management of

NENHM report a median and 5-year progression-free survival is

only 15–25 months and 0–7%, respectively [5,8,17]. Despite a pro-

tracted PFS, the long-term survival is a reflection on ongoing treat-

ment of disease progression that has contributed to the overall

survival (OS) outcome. This aspect of the surgical literature is lack-

ing and is the aim of the current study. We evaluate our institution’s

approach of multimodality treatment of disease progression after ini-

tial hepatic resection of NENHM. The current analysis will hopefully

expand the contemporary literature and elucidate the value of various

therapeutic interventions for progressive disease.

PATIENTS AND METHODS

This retrospective study was approved by an institutional review

board and ethics committee. Seventy-four patients with histologically

confirmed neuroendocrine tumor hepatic metastases (NETHM)

*Correspondence to: Prof. David L. Morris, MD, PhD., Department ofSurgery, St George Hospital, University of New South Wales, Level 3Pitney Building, Gray Street, Kogarah, NSW 2217, Sydney, Australia.Fax: (02) 9113 3997. E-mail: [email protected]

Received 7 May 2011; Accepted 15 September 2011

DOI 10.1002/jso.22114

Published online 17 October 2011 in Wiley Online Library(wileyonlinelibrary.com).

� 2011 Wiley Periodicals, Inc.

underwent resection (with or without cryoablation) between

December 1992 and December 2009. Of these, 50 patients developed

disease progression in the liver during routine post-operative follow-

up. The last time of follow-up for these patients was June 2010. Prior

to surgery, patients were evaluated with a baseline medical history,

clinical examination, serum laboratory tests including measurement

of hormone levels, computed tomography (CT) scan (triple phase),

hepatobiliary ultrasound, magnetic resonance imaging, chest radiog-

raphy, and endocrinopathy-directed evaluation. In more recent years,

Indium-111 octroetide (Octreoscan) was used in some patients to

assist in the radiological evaluation of disease. Patients who under-

went open and close procedures were excluded from this study.

Patients with limited extra-hepatic disease discovered incidentally

during laparotomy were not excluded from this study.

A description of our surgical and cryoablative techniques have

been provided elsewhere [18]. In summary, patients were explored

through a bilateral subcostal incision with vertical midline upward

extension. After a thorough intraoperative exploration and liver ultra-

sound, parenchymal dissection was performed using an ultrasonic

dissector (Cavitron ultrasonic surgical aspirator, CUSA1; Valleylab,

Boulder, CO), with Pringle manoeuvre only in selected patients to

minimize blood loss or to maximize efficacy of cryotherapy. Cryo-

therapy was performed using the LCS 3000 liquid nitrogen system

(Spembly or the Erbe system). Liver resection was the preferred

method for the treatment of large tumors because of the relationship

of cryovolume with cryoshock phenomenon, and the remaining

smaller metastases were treated with a limited resection and/or cryo-

therapy. A more detailed description of our cryotherapy techniques

have been provided elsewhere [19]. Fifteen patients underwent open

and close procedures and were excluded from this study.

Procedures were classified as complete (curative intent) or incom-

plete (palliative intent). In palliative procedures, all patients in the

series had at least 90% of their hepatic disease removed (as calculat-

ed on the basis of preoperative imaging and operative findings).

Complete resection was achieved when there was removal of all

gross metastatic disease (including lymphatic spread).

Follow-up

After discharge from hospital, patients were followed prospective-

ly at monthly intervals for the first 3 months and then at 6-monthly

intervals thereafter with measurement of hormone levels and CT of

the liver. The diagnosis of disease progression was defined as the

earliest radiologic evidence of new tumor recurrence after complete

resection or new tumor growth after incomplete resection. In the cur-

rent series, 60 patients developed disease progression of which 50

developed progressive disease in the liver. Depending on decision

from the multidisciplinary tumor board which was based on the

patient’s performance status, hepatic function, extent of hepatic dis-

ease, and concurrent extrahepatic disease, a management strategy

was decided. Repeat hepatectomy and/or ablation (surgical treat-

ment) were considered the treatment of choice for resectable recur-

rent tumors. For more diffuse disease, non-surgical treatments were

used including somatostatin analogs, selective internal radiation

using yttrium-90 microspheres (SIR-Spheres1, Australia), hepatic

artery embolization/chemoembolization (HAE/HACE), systemic

chemotherapy, hepatic artery chemotherapy, and lipiodol I-131. Best

supportive care represented no attempt at active treatment of disease

with a primary focus on symptomatic management and comfort care.

For patients with more diffuse disease, a change in the treatment

paradigm has taken place. Initially, before the adoption of yttrium-90

microspheres (December 2003) in our department, chemotherapeutic

agents such as systemic chemotherapy, hepatic artery chemotherapy,

and transarterial chemoembolization was used in the management

of more diffuse disease. Since the introduction of yttrium-90

microspheres, radioembolization has been used in the majority of

patients with diffuse disease and chemotherapeutic agents have been

restricted to patients who are unsuitable for radioembolization of

those who have been unresponsive to other treatments. Somatostatin

analogs were used in isolation in patients with symptomatic recur-

rence which was adjudged to be the best managed conservatively.

Patients were observed if they had limited, non-symptomatic disease.

Patients were treated in palliative care if their functional and disease

status precluded any active treatment. Following treatment of pro-

gressive disease, patients were followed up as per the same protocol

as described above.

Data Collection and Statistical Analysis

Patient demographic data, disease-related factors, pathological

factors, and treatment-related factors were collected and analyzed.

The primary endpoint was the time interval between treatment of

initial disease progression to the development of second disease pro-

gression (progression-free survival). The secondary endpoint was the

time interval between the treatment of initial disease progression and

cancer-related death [overall survival(OS)]. Data analyses were per-

formed using SPSS1 for Windows version 17.0 (SPSS, Munich,

Germany). The patient’s characteristics were reported using frequen-

cy and descriptive analyses. The Kaplan–Meier method was used to

analyze progression-free survival and OS. Univariate analysis (log-

rank) was performed to examine the relationship of 14 clinicopatho-

logical and treatment-related factors with progression-free survival

and OS. Multivariate analysis was performed on all factors P < 0.10

using the Cox proportional hazards regression model. The median

time to death was defined as the time where 50% of patients have

died. Follow-up was calculated from the date of treatment of carci-

nomatosis to the date of last follow-up. P < 0.05 was considered

statistically significant.

RESULTS

Between December 1992 and December 2009, a total of

74 patients underwent hepatic resection with or without ablation for

neuroendocrine tumor hepatic metastases. The extent of the initial

hepatectomy is summarized in Table I. Of these, 14 (18%) patients

did not develop disease progression during post-operative follow-up;

this includes two patients in whom radiological recurrence was not

assessed because of death in the early post-operative period (within

2 months). Of the 12 remaining patients, five patients remained dis-

ease-free for more than 3 years after initial hepatectomy and three

patients have remained disease-free between 1–3 years after initial

hepatectomy. The remaining four patients have been followed-up for

less than 1 year.

The remaining 60 (82%) patients developed disease progression

at last follow-up after a median interval of 23 months. The most

common site of initial disease progression was the liver in 50 (69%)

patients, bone in five (7%) patients, lung in two (3%) patients, neck

in one (1%) patient, pancreas in one (1%) patient, peritoneum in one

(2%) patient, and heart in one (1%) patient. Four (6%) patients dem-

onstrated disease progression in multiple organ sites simultaneously.

Patients with disease progression in the liver are the principal focus

of the current study. A summary of progression outcomes and subse-

quent treatment outcomes is given in Figure 1.

Of the 50 patients, there were 26 (54%) male patients. Two

patients (4%) had been previously diagnosed with multiple endocrine

neoplasia type 1 (MEN-I) and one patient (2%) had been previously

diagnosed with Zollinger–Ellison syndrome. The mean age of

patients at the time of disease recurrence was 58 years (S.D ¼ 12,

median ¼ 59, range ¼ 28–83). Twenty-four (48%) patients pre-

sented with symptoms relating to hormone excess secondary to NEN

Neuroendocrine Neoplasm Hepatic Metastasis 343

Journal of Surgical Oncology

at the time of progression. The site of the primary tumor was the

small bowel in 20 (40%) patients, the pancreas in 18 (36%), the

large bowel/rectum in 4 (8%) patients, the bronchus in 3 (6%)

patients, and unknown in 5 (10%). The primary tumor was classified

as carcinoid in 37 (74%) patients, non-functional islet cell tumor in

five (10%) patients, small cell neuroendocrine tumor in two (4%)

patients, VIPoma in two (4%) patients, gastrinoma in two (4%)

patients, glucagonoma in one (2%) patient, and large cell neuroendo-

crine tumor in one (2%) patient.

Twenty (40%) patients underwent isolated hepatic resection at the

time of their initial surgery and 30 (60%) underwent concomitant

hepatic resection and ablation. The mean size of the largest resected

hepatic neoplasm was 51 � 44 mm (range, 10–260). The median

number of lesions ablated in patients who underwent synchronous

resection and cryoablation was 2 (range, 1–10 lesions). Pathological

examination of initial resection sample revealed that 35 (70%)

patients had well differentiated tumor, five (10%) had moderately

differentiated tumor and nine (18%) had poorly differentiated tumor.

Vascular invasion, lymphatic invasion, and perineural invasion were

then noted in 20 (40%), 30 (60%), and 12 (24%) patients, respective-

ly. Tumor necrosis status was recorded in 41 patients; of these,

14 (34%) were noted to have tumor necrosis present. At the time of

progression, extra-hepatic disease was detected in 20 (40%) patients.

Ten (20%) patients had unilobar hepatic disease and 40 (80%)

patients had bilobar hepatic disease. Replacement of the liver paren-

chyma by tumor was 0–25% in 29 (58%) patients, 26–50% in 19

(38%) patients, and 51–75% in 2 (4%) patients.

Treatment of Hepatic Disease Progression

Fifty patients developed progression of liver disease after initial

surgical extirpation. The mean size of hepatic recurrence in these

patients based on imaging was 3.6 cm (S.D ¼ 3.0). These patients

were managed according to consensus of a multidisciplinary team as

earlier described. Ten (20%) patients were treated with surgery

(Group A). The extent of surgery in these 10 patients is summarized

in Table II. Three patients who underwent surgery were also treated

with concomitant cryoablation. The median number of lesions

treated in patients who underwent surgery was 5 (range, 1–13). Ad-

juvant octreotide analogs were used in three patients who underwent

repeat hepatectomy. Postoperative complications developed in three

patients for an overall morbidity rate of 30%. These were bile leak-

age (n ¼ 1,10%), subphrenic abscess (n ¼ 1,10%), and liver dys-

function (n ¼ 1,10%). Fifteen (30%) patients were treated with

yttrium-90 radioembolization (Group B). Postoperative complica-

tions included fatigue in six patients (40%), non-specific self-limiting

abdominal pain in four (27%), nausea in three (20%), anorexia in

two (13%), vomiting in one (9%), and shortness of breath in

one (9%). The mean hospital stay in patients who underwent

resection and radioembilozation was 14 days (S.D ¼ 12) and 1 day

(S.D ¼ 0.5), respectively.

Fourteen (28%) patients were treated with chemotherapeutic

agents (Group C). Of these, 10 (20%) patients were treated with

systemic chemotherapy, three (6%) with hepatic artery chemotherapy

and one (2%) with transarterial chemoembolization. Eleven (22%)

patients were managed with more conservative measures (Group D).

Of these, seven (14%) patients were managed with medical therapy

using somatostatin analogs, two (4%) were closely observed and two

(%) were managed with best supportive care. A comparison between

TABLE I. Operative Procedures Performed in 74 Patients who Under-

went Hepatic Resection for Neuroendocrine Neoplasm Liver Metastases

Type of procedure performed

Patients

(n ¼ 74)

Right hemihepatectomy 8

Left hemihepatectomy 5

Extended left hemihepatectomy 2

Extended right hemihepatectomy 4

Central resection 6

Bisegementectomy

Segments 2 and 3 12

Segments 3 and 4 1

Segments 5 and 6 3

Segments 7 and 8 2

Segments 6 and 7 2

Segments 2 and 4 1

Segmentectomy

Segment 3 1

Segment 4 2

Segment 7 2

Segment 8 2

Subsegmentectomy

Segment 5 1

Segment 4 1

Multiple hepatic resections

Complex bilobar liver resection 1

2� segmental resection

Segments 4 and 6 2

Segments 5 and 7 1

Segments 3 and 7 1

Segments 3 and 6 1

3� segmental resection

Segments 1, 3, and 5 1

Segments 2, 6, and 7 1

Right hemihepatectomy þ subsegmental (segment 3) 1

Right hemihepatectomy þ subsegmental (segment 2) 1

Wedge (segments 2 and 3) and segmental (segment 6) 2

Left hemihepatectomy and segmental (segment 6) 1

Left hemihepatectomy and subsegmental (7) 1

Bisegmentectomy (segments 2 and 3) and segmental (segment 7) 1

Bisegmentectomy (segments 2 and 3) and subsegmental (segment 4) 1



Fig. 1. A summary of progression outcomes and subsequent treat-ment outcomes.

344 Saxena et al.


the baseline characteristics of the four major treatment groups is pro-

vided in Table III. The treatment groups differ in terms of extra-he-

patic disease status (P ¼ 0.005) and the extent of hepatic disease

(P ¼ 0.022).

Overall Survival

No patient was lost to follow-up. The median time of follow-up

from diagnosis of disease progression was 29 months (range ¼ 2–

137). No patient died within 1 month of treatment. The median OS

after treatment of recurrence was 48 months with 1- and 3-year sur-

vival of 75% and 58%, respectively. The median survival from initial

diagnosis of NET was 131 months. The median survival from initial

hepatic resection of NENHM was 95 months with 3-year survival of

73% (Fig. 2).

TABLE II. Operative Procedures Performed in 10 Patients who Under-

went Repeat Hepatic Resection for Neuroendocrine Neoplasm Liver

Metastases

Type of repeat procedure performed Patients (n ¼ 10)

Left hemihepatectomy 1

Right hemihepatectomy 1

Bisegmentectomy

Segment 8 þ 5 1

Segment 7 þ 5 1

Segmentectomy

Segment 4 2

Segment 6 1

Segment 5 1

Segment 7 1

Segment 8 1

TABLE III. Comparison of the Baseline Clinical and Pathological Characteristics Between the Different Treatment Groups

Clinicopathological

and treatment-related factors

Surgery

(Group A)

(n ¼ 10)

Yttrium 90

radioembolization

(Group B) (n ¼ 15)

Observation/medical

therapy (Group C)

(n ¼ 11)

Cytotoxic

chemotherapy/other therapy

(Group D) (n ¼ 14) P-value

Sex 0.144

Male (n ¼ 26) 4 5 8 9

Female (n ¼ 24) 6 10 3 5

Age at time of resection 0.414

<59 years (n ¼ 23) 5 9 3 6

�59 years (n ¼ 27) 5 6 8 8

Location of primary 0.297

Alimentary (n ¼ 24) 4 6 5 9

Pancreas (n ¼ 18) 6 4 4 4

Other (n ¼ 3) 0 1 1 1

Unknown (n ¼ 5) 0 4 1 0

Histopathological subtype 0.691

Carcinoid (n ¼ 37) 6 12 8 11

Other (n ¼ 13) 4 3 3 3

Progression-free interval 0.109

<23 months (n ¼ 32) 4 8 9 11

�23 months (n ¼ 18) 6 7 2 3

Endocrine symptoms 0.185

Yes (n ¼ 24) 2 7 6 9

No (n ¼ 26) 8 8 5 5

Extent of hepatic disease 0.059

Unilobar (n ¼ 10) 4 1 4 1

Bilobar (n ¼ 40) 6 14 7 13

Previous hepatic procedure 0.273

Resection only (n ¼ 20) 6 6 2 6

Resection and ablation (n ¼ 30) 4 9 9 8

Tumor necrosis 0.552

Yes (n ¼ 14) 3 4 3 4

No (n ¼ 27) 6 11 7 3

Histopathological grade 0.156

Well differentiated (n ¼ 35) 7 13 8 7

Moderate/poor differentiation (n ¼ 14) 3 2 2 7

Vascular invasion 0.342

Yes (n ¼ 20) 4 8 2 6

No (n ¼ 30) 6 7 9 8

Lymphatic invasion 0.154

Yes (n ¼ 30) 3 9 8 10

No (n ¼ 20) 7 6 3 4

Perineural invasion 0.917

Yes (n ¼ 12) 3 4 2 3

No (n ¼ 38) 7 11 9 11

Extra-hepatic disease 0.005�Yes (n ¼ 19) 1 3 5 10

No (n ¼ 31) 9 12 6 4

Extent of hepatic disease 0.022�0–25% (n ¼ 29) 8 8 9 4

�26% (n ¼ 21) 2 7 2 10



Progression-Free Survival

The median interval between diagnosis of progression and the

treatment of progression in this group of patients was 1 month

(range ¼ 0–6). Following treatment of initial progression the time to

second progression was assessed in 50 (100%) patients. Of these, 42

(84%) developed progressive disease during post-operative follow-

up. The median time to the second progression was 15 months

(range ¼ 2–57) with 6-month and 1-, 2-, 3-year PFS of 80%, 57%,

33%, and 18%, respectively (Fig. 3). The sites of disease progression

following treatment of hepatic progression included the liver in 34

(68%) patients, bone in 13 (26%), peritoneum in 6 (12%), lung in 3

(6%), ocular muscles of the eye in 1 (2%), kidney in 1 (2%), and the

neck in 1 (2%). Thirteen (26%) patients eventually demonstrated

progression in multiple organ sites. The mean size of hepatic re-

recurrence based on imaging was 3.2 cm (S.D ¼ 2.4). Additional

oncological therapy was used in 36 (of 42, 86%) patients who devel-

oped second progression. These included somatostatin analogs in

18 patients, repeat surgery (resection and/or ablation) in nine, cyto-

toxic chemotherapy in eight, radiotherapy in eight, radioembolization

in seven, HAE/HACE in three, non-hepatic surgical procedures in

two, lipiodol I-131 in two, peptide radionuclide therapy in two, he-

patic artery chemotherapy in one, and interferon- a in one patient.

Prognostic Factors for Overall Survival and

Progression-Free Survival Following Treatment

of Progression

Of 14 clinicopathological and treatment-related variables, seven

variables were shown to influence OS following treatment of

progressive NETHM (Table IV). These included gender (male vs.

female, 38 months vs. NR months, P ¼ 0.036), progression-free in-

terval (�23 months vs. <23 months, NR vs. 35 months, P ¼ 0.042),

extent of hepatic disease (�26% vs. <26%, 27 months vs. NR

months, P ¼ 0.003), histopathological grade (well vs. moderate/poor

differentiation, 79 months vs. 21 months, P ¼ 0.003), extra-hepatic

disease (yes vs. no, 18 months vs. NR months, P < 0.001), and type

of secondary intervention (surgery vs. radioembolization vs. medical

therapy vs. cytotoxic chemotherapy, 79 months vs. NR vs. 59 months

vs. 18 months, P ¼ 0.001).

Six variables were shown to influence progression-free survival

following treatment of progressive NETHM (Table IV). These in-

cluded gender (male vs. female, 13 months vs. 18 months, P ¼0.049), progression-free interval (�23 months vs. <23 months,

22 months vs. 8 months, P ¼ 0.006), extent of hepatic disease

(�26% vs. < 26%, 9 months vs. 20 months, P ¼ 0.048), tumor necro-

sis status (yes vs. no, 6 months vs. 21 months, P ¼ 0.002), histopatho-

logical grade (well vs. moderate/poor differentiation, 20 months vs.

6 months, P < 0.001), extra-hepatic disease (yes vs. no, 6 months

vs. 24 months, P < 0.001), and type of secondary intervention (sur-

gery vs. radioembolization vs. medical therapy vs. systemic chemo-

therapy, 22 months vs. 18 months vs. 16 months vs. 6 months,

P ¼ 0.003).

Variables P < 0.30 in the univariate analysis were subjected to a

Cox proportional hazards regression model for a multivariate analy-

sis. The only independent predictor for OS was extra-hepatic disease

[Hazard Ratio (95% CI), 4.04 (1.15 to 14.18, P ¼0.029)] (Fig. 4).

Independent predictors for progression-free survival included histo-

logical grade [Hazard Ratio (95% CI), 4.08 (1.49 to 11.21,

P ¼ 0.006)], extra-hepatic disease [Hazard Ratio (95% CI), 4.03

(1.56 to 10.47, P ¼ 0.004)], type of secondary intervention [Hazard

Ratio (95% CI), 0.63 (0.42 to 0.94, P ¼ 0.024)] (Fig. 5), and pro-

gression-free interval [Hazard Ratio (95% CI), 0.32 (0.14 to 0.73,

P ¼ 0.006)].

DISCUSSION

NENs are derived from the enterochromaffin cells of the neuroen-

docrine system which are diffusely present in the gastrointestinal

system and the tracheobronchopulmonary complex. These tumors

most frequently metastasize to the liver (NENHM), and thereby

cause significant morbidity and mortality. Liver metastases from car-

cinoid tumors, in particular, cause excessive serotonin production

and induce carcinoid syndrome which is characterized by severe di-

arrhoea, episodic flushing, and bronchospasm [20]. Effective man-

agement of NENHM is thereby critical to improving the quality of

life and survival of affected patients.

Fig. 2. Overall survival after initial diagnosis of neuroendocrineneoplasms (NEN), hepatic resection of neuroendocrine neoplasm he-patic metastases (NENHM), and treatment of disease progressionfollowing primary hepatic resection of NENHM (n ¼ 50). M/S, me-dian survival.

Fig. 3. Progression-free survival after treatment of hepatic diseaseprogression subsequent to resection of neuroendocrine neoplasm he-patic metastases (n ¼ 50). M/PFS, median progression-free survival.

346 Saxena et al.


While there is considerable debate regarding the optimal manage-

ment of NENHM, surgery usually improves symptomatology and

survival. In published series from expert centres, median survival

ranges between 81 and 125 months and 5-year survival often exceeds

60% [2,5–7,17]. In contrast, patients with unresected NENHM only

have a 5-year survival of 13% to 43% [2,21]. Recent data has sug-

gested that non-surgical treatments may have some role in the man-

agement of NENHM; however, 5-year survival rarely exceeds 30%

with these treatments. Cytotoxic agents have not shown substantial

survival benefits [22–24]. The efficacy of transarterial embolization/

chemoembolization is uncertain with 5-year survival varying widely

between 14 and 71% [13,14]. Randomized data suggests that so-

matostatin analogs may increase the progression-free interval but fur-

ther study is required [9]. Intervention-based therapies including

radionuclide therapy and radiolabeled microspheres have shown

some promise [10,11,15]. Even in the absence of randomized data,

the difference in outcomes between patients treated with surgery

compared to patients treated with other therapies has led to a consen-

sus by the European Neuroendocrine Tumor Society, advocating its

use whenever appropriate [16].

TABLE IV. Univariate Analysis of Clinicopathologic and Treatment-Related Factors for Overall Survival and Progression-Free Survival After

Treatment of Progression for Neuroendocrine Neoplasm Hepatic Metastases

Clinicopathological and

treatment-related factors

Patients

(n ¼ 50)

Analysis of post-treatment overall survival Analysis of progression-free survival�

Median overall

survival (months)

Univariate

analysis P-value

Patients

(n ¼ 50)

Median progression-free

survival (months)

Univariate

analysis P-value

Sex 0.036� 0.049�Male 26 38 26 13

Female 24 NR 24 18

Age at time of resection 0.755 0.643

<59 years 23 35 23 13

�59 years 27 57 27 21

Location of primary 0.838 0.498

Alimentary 24 48 24 20

Pancreas 18 44 18 13

Lung 3 NR 3 8

Unknown 5 NR 5 9

Histopathological subtype 0.575 0.577

Carcinoid 37 48 37 17

Other 13 44 13 12

Progression-free interval 0.042� 0.006�<23 months 32 35 32 8

�23 months 18 NR 18 22

Endocrine symptoms 0.889 0.863

Yes 24 57 24 14

No 26 38 26 15

Extent of Hepatic Disease 0.003� 0.048�0–25% 29 NR 29 20

�26% 21 27 21 9

Tumor necrosis 0.261 0.002�Yes 14 38 14 6

No 27 79 27 21

Histopathological grade 0.003� <0.001�Well differentiation 35 79 35 20

Moderate/Poor differentiation 14 21 14 6

Vascular invasion 0.315 0.834

Yes 20 59 20 14

No 30 35 30 14

Lymphatic invasion 0.986 0.663

Yes 30 48 30 15

No 20 44 20 13

Perineural invasion 0.798 0.934

Yes 12 27 12 14

No 38 57 38 15

Extra-hepatic disease <0.001� <0.001�Yes 20 18 20 6

No 30 NR 30 24

Type of secondary intervention 0.001� 0.003�Surgery (Group A) 10 79 10 22

Radioembolization (Group B) 15 NR 15 18

Medical therapy (Group C) 11 59 11 16

Systemic chemotherapy (Group D) 14 18 14 6

These included gender (male vs. female, 13 months vs. 18 months, P ¼ 0.049), progression-free interval (�23 months vs. <23 months, 22 months vs. 8 months,

P ¼ 0.006), extent of hepatic disease (�26% vs. < 26%, 9 months vs. 20 months, P ¼ 0.048), tumor necrosis status (yes vs. no, 6 months vs. 21 months,

P ¼ 0.002), histopathological grade (well vs. moderate/poor differentiation, 20 months vs. 6 months, P < 0.001), extra-hepatic disease (yes vs. no, 6 months vs.

24 months, P < 0.001), and type of secondary intervention (surgery vs. radioembolization vs. medical therapy vs. systemic chemotherapy, 22 months vs.

18 months vs. 16 months vs. 6 months, P ¼ 0.003).



At our institution, 74 patients underwent surgical extirpation of

NENHM over a 17-year period. Treatment failure developed in

the majority of patients after a median interval of 23 months and at

5-year, the PFS was 0%. Survival data was excellent, however, with

a median survival of 95 months and 5-year survival of 65%. The

significant disparity between progression and survival outcomes after

resection has been previously reported. Mayo et al. [5] reported a

median survival of 125 months in a multi-institutional analysis of

339 patients who underwent surgery for NENHM. Median PFS,

however, was only 15 months. Cho et al. [8] similarly reported a

median OS of 91 months despite a median PFS of only 17 months in

a resection series with 70 patients. Given that progression is often

invariable, additional oncological therapies post-progression are like-

ly to extend survival. This important clinical issue, however, has not

been systematically addressed in the literature. Mayo et al. [5] spe-

cifically analysed the impact of repeat hepatectomy on patients with

progressive hepatic disease. In the 46 patients who underwent a sec-

ond liver operation, median OS was 140.9 and 82.9 months from the

time of the first and second operations, respectively. The mean time

to recurrence in these patients was 24.2 months after the initial oper-

ation, 21.5 months after the second, and 15.9 months after the third.

This study demonstrated the repeat resection is efficacious in select-

ed patients, but the outcomes following alternative oncological thera-

pies in the remaining patients with progressive disease were not

discussed.

Ablative techniques in particular radiofrequency ablation (RFA)

and microwave ablation but cryoablation may also be effective in the

management of recurrent disease [25–28]. Mazzaglia et al. [27]

treated 384 lesions in 63 patients via 80 laparoscopic RFA sessions.

After a mean follow-up of 2.8 years, a median survival of 3.9 years

after the first ablation was attained with a 2-year survival of 77%.

Gilliams et al. [25] reported results after RFA of 189 lesions in

25 patients. Sixety-nine percent of patients experienced symptom im-

provement and median survival after ablation was 29 months. In our

institution, three patients underwent concomitant resection and cry-

oablation after disease recurrence but ablation was not used exclu-

sively in the management of recurrence in any patient. This reflects

the general consensus that resection is more efficacious than ablation

in the treatment of NETLM especially when large (>3cm) and nu-

merous (>3) tumors are present. Nevertheless, ablation has the ad-

vantage of lower morbidity and hospital stay compared to resection

and should be considered as a potential treatment option. In our unit,

we have persisted with the use of cryoablation as it is more practical

in the setting of our clinical practice. It must be noted, however, that

RFA is the preferred treatment option in many centres given that it is

equally if not more efficacious and the association of cryoablation

with complications such as cryoshock phenomenon, cracking of

lesions, and intraoperative hypothermia. Although, as per protocol,

we preferentially treated patients with limited disease recurrence

with resection rather than ablation, a prospective comparison of the

two treatment modalities is warranted given that ablation, and partic-

ularly RFA, is a significantly less morbid procedure.

In the current study, 50 patients developed progressive disease in

the liver during follow-up. An individualized, multimodality ap-

proach to the treatment of progression was used based on the con-

sensus of a multidisciplinary team. After treatment of progression,

median survival was 48 months with 5- and 10-year survival of 40%

and 35%, respectively. The median progression-free interval was

15 months. Analysis of prognostic factors demonstrated the poor

prognosis of patients with biologically aggressive tumor and/or ex-

tra-hepatic metastases [5,8]. These findings have been previously

reported [5,8]. Moreover, it showed that the type of intervention was

independently associated with PFS. Median PFS was highest in

patients who underwent repeat surgery (22 months) and lowest in

patients managed with cytotoxic chemotherapy (6 months). Similar-

ly, OS post-treatment was 79 months in surgical patients and only

18 months in chemotherapy patients. Although a direct comparison

of treatment modalities is biased and is inherently confounded by the

differences in baseline characteristics, including extra-hepatic status

and extent of hepatic disease that has led to the selection of therapy,

the important message that this data provide is that repeat hepatecto-

my in progressive disease in selected patients is a strategy that may

contribute to long-term survival. The poorer survival outcome in

patients treated with chemotherapy, who have more advanced and

extensive disease that is unresectable, parallels the results reported

in the contemporary literature on the limited benefits of cytotoxic

therapy on survival for NENHM [22,24]. This reflects the lack of an

effective medical therapy and this should remain a focused research

Fig. 4. Overall survival after treatment of progression subsequentto hepatic resection of neuroendocrine neoplasm hepatic metastases,stratified by extra-hepatic disease (P < 0.001). M/S, mediansurvival.

Fig. 5. Progression-free survival after treatment of hepatic diseaseprogression subsequent to resection of neuroendocrine neoplasmhepatic metastases, stratified by type of secondary intervention(P ¼ 0.024). M/PFS, median progression-free survival.

348 Saxena et al.


initiative in NEN. Although our study demonstrated a significant dif-

ference in outcomes based on treatment modality, these data must be

interpreted with caution. It must be noted that the relatively small

sample size (n ¼ 50) of the current study may have precluded a fair

and robust comparison of the treatment modalities. Small numbers

can produce statistically fragile results in which a small difference in

patients can produce a large effect on the results. A large, prospec-

tive study would be clearly beneficial but is hampered by the rarity

of NENHM.

Recent developments in intervention-based therapies have greatly

expanded the therapeutic options available to treat unresectable

NENHM. Radioembolization using yttrium-90 microspheres is a po-

tential treatment option. It exploits the arterial system that intrahe-

patic malignancies derive their blood supply from compared to

normal liver parenchyma that is supplied mainly by the portal

vein. Microspheres when injected selectively into the hepatic artery

lodge in the tumor microvasculature. Yttrium-90 is a pure b emitter

that consequently delivers a high radiation dose to the tumors

with sparing of the normal liver parenchyma. Published series

have demonstrated that Y90 radioembolization is safe, can produce a

radiological response in up to 63% of patients, and can achieve me-

dian survival of 28–70 months [10–12]. In our series, 15 patients

with unresectable disease after surgery were treated with this

therapy, attaining a median PFS of 16 months. More importantly, the

5-year survival of these patients is 73%. Comparing this modality of

Y90 treatment of hepatic progression with repeat hepatectomy that

achieves a 5-year survival of 68%, the comparable long-term out-

come has suggested that radioembolization and surgery achieves

similar outcome as a secondary treatment for hepatic progression

after initial curative surgery. Although this data appears promising,

the relatively small number of patients (15 in the repeat surgery

group and 10 in the radioembolization group) is a limitation and

further evidence is required before any clear conclusions may be

derived.

The role of conservative strategies in the management of

NENHM requires further study. In the current series 11 patients were

managed with conservative therapy including seven with somatostat-

in analogs. The median PFS and OS were 16 months and 79 months,

respectively. Somatostatin analogs confer anti-symptom effects by

blocking somatostatin receptors, and may exert anti-tumor effects by

inhibiting growth factors, modulating the immune system, and inhib-

iting angiogenesis. The recent PROMID study demonstrated that so-

matostatin analogs compared to placebo, delayed progression from

6 months to 14.6 months[9]. The patients in this treatment group

often had advanced bilobar liver disease (82%) and extra-hepatic dis-

ease (36%). Hence, despite being unresectable and nor suitable for

radioembolization, the use of somatostatin analogs alone may have

delayed further progression. However, there are also patients with

rapidly progressing disease on conservative therapy. Favorable tumor

biology seems imperative for long-term survival with this therapy.

Identification of the patient subgroup that will most likely benefit

from careful observation or medical therapy can avoid unnecessary

treatments and cost.

Although it has not been extensively used at our institution, pep-

tide receptor radionuclide therapy has been of recent clinical interest.

This delivers targeted radiation to tumor by utilizing the ability of

somatostatin analogs to bind somatostatin receptors which are over-

expressed by the tumor. In the largest series of 1,772 treatments of177Lu-octreotate administered in 504 patients with metastases in the

liver and bone, 46% had an objective tumor response. Median time

to progression and OS were 40 and 46 months, respectively [15].

Given that our study demonstrates that the relative incidence of bone

metastases from NEN increases with time, this treatment modality is

likely to become increasingly important and may further improve

post-progression outcomes.

In conclusion, the disparity between PFS and OS after resection

of NENHM underscores the need for an effective strategy to treat

disease progression to achieve the longest survival possible. These

data show that individualised treatment of hepatic progression after

resection of NENHM is associated with excellent overall outcomes.

Although repeat surgery and Y90 radioembolization were shown in

the current series to be efficacious in achieving long-term survival,

further investigation of this important clinical issue is clearly

necessary.

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Liver-directed therapy for neuroendocrine neoplasm hepatic metastasis prolongs survival following progression after initial surgery