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Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease

Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic... Abstract Background Hepatic surgery is presumed to improve survival of patients with liver metastases (LM) from neuroendocrine tumours (NET). This study identified LM-specific variables that could be used as additional selection criteria for aggressive treatment. Methods A novel classification of LM from NET was established based on their localization and presentation. Results From 1992 to 2006, 119 patients underwent staging and treatment of LM. Three growth types of LM were identified radiologically: single metastasis (type I), isolated metastatic bulk accompanied by smaller deposits (type II) and disseminated metastatic spread (type III). The three groups differed significantly in terms of chronological presentation of LM, hormonal symptoms, Ki-67 index, 5-hydroxyindoleacetic acid and chromogranin A levels, lymph node involvement, presence of bone metastases and treatment options. The 3-, 5- and 10-year disease-specific survival rates for the entire cohort were 76·4, 63·9 and 46·5 per cent respectively. There were significant differences in survival between the three groups: 5- and 10-year rates were both 100 per cent for type I, 84 and 75 per cent respectively for type II, and 51 and 29 per cent for type III. Conclusion The localization and biological features of LM from NET defines therapeutic management and is predictive of outcome. Introduction Neuroendocrine tumours (NET) commonly metastasize to the liver1. Neuroendocrine liver metastases (LM) frequently have an indolent clinical course, compared with hepatic metastases from non-endocrine gastrointestinal or pancreatic malignancies, and incapacitating clinical symptoms in the presence of a hormonally active tumour load. A 5-year survival rate of 13–54 per cent in historical groups of patients with untreated neuroendocrine LM reflects the unique biological behaviour of malignant NET2,3. Numerous treatment options have been reported as successful, such as surgical resection with curative intent, palliative cytoreductive resection, liver transplantation, locally effective liver-directed techniques, systemic medical regimens and most, recently, peptide receptor radionuclide therapy (PRRT), but the optimal management is still ill defined4–12. Although an aggressive surgical approach has been considered to prolong survival in patients with NET metastasized to the liver13–15, few data are available on the selection of candidates for liver resection. The survival impact of hepatic resection is difficult to assess for several reasons: the completeness of resection was not determined clearly in several studies, hilar lymph node removal was not included in the hepatic resection in most reports, the frequently used term ‘palliative resection’ is ill defined, results of resection and/or local ablation have often not been determined separately, and consistent follow-up criteria are lacking. In view of the complete resection (R0) rate of only 25–57 per cent16–20, a postresectional 5-year disease-free survival rate of only 16–45 per cent14,17 and a 5-year overall survival of no more than 26–63 per cent after palliative resection21,22, and the risk of operative morbidity and mortality, clear indications for liver resection are needed. Since the authors initial report on the surgical management of NET metastasized to the liver23, it has been observed that LM have distinct localization and presentation patterns regardless of the primary tumour. Even more important, the morphological characteristics of the hepatic metastatic spread seem to be of prognostic value. The aim of this study was, first, to define the role of aggressive treatment in relation to localization patterns of neuroendocrine hepatic metastases and, second, to identify factors associated with these patterns. Methods A prospective database for referred patients with NET was created in September 1992, according to a protocol approved by the local institutional review board. The database includes demographic information, previous diagnosis and treatment, clinical symptoms, laboratory findings including 5-hydroxyindoleacetic acid (5-HIAA) and tumour marker chromogranin A (CgA) levels, results of radiological and nuclear medicine imaging, treatment methods and follow-up data. Imaging mainly comprised computed tomography (CT), magnetic resonance imaging, somatostatin receptor scintigraphy (SSRS) with 111In-labelled diethylenetriamine-penta-acetic acid-D-Phe1-octreotide and, more recently, with 68Ga-labelled 1,4,7,10-tetra-azacyclododedcane-4,7,10-tricarboxy-methyl-1-yl-acetyl- D-Phe1Try3-octreotide (DOTATOC) in a combined positron emission tomography (PET) and CT technique. Tumour typing based on extensive histological and immunohistochemical studies was according to the World Health Organization (WHO) 2000 and 1999 histological classification of endocrine and lung tumours respectively24,25. Analysis of Ki-67 expression was carried out retrospectively on archived pathological specimens until 2000 and prospectively in a routine manner thereafter. Patterns of hepatic metastases were determined exclusively from imaging results and findings of SSRS. For patients who had liver surgery in this institution, the imaging results were compared with intraoperative and histological findings in order to evaluate the classification scheme. LM were classified as synchronous when present simultaneously with the primary tumour or detected within 6 months of diagnosis of the primary tumour. They were also assumed to be synchronous in patients in whom the primary lesion was not found during the observation period. Metachronous metastases were those that became apparent more than 6 months after primary tumour detection. Surgical treatment The spectrum of liver surgery procedures comprised complete resections of various extent including hilar lymphadenectomy, palliative cytoreductive resection (incomplete tumour removal regardless of the amount of residual hepatic tumour mass) and liver transplantation. Resection was the treatment of choice only for patients in whom complete tumour elimination (hepatic and extrahepatic R0 status) was deemed feasible according to the results of the imaging studies. The extent of hepatic resection was defined according to the Brisbane 2000 terminology26. Right portal vein embolization was used to induce hypertrophy of the remaining left lateral section before right trisectionectomy if necessary. Palliative cytoreductive surgery to improve survival and reduce systemic hormonal symptoms and/or symptoms due to tumour expansion was undertaken if less than 70 per cent of the liver was involved by tumour and no unresectable extrahepatic tumour spread was evident. Staged hepatic resections were considered. Indications for liver transplantation were as documented previously27. Briefly, only patients with unresectable LM, no extrahepatic or resectable extrahepatic metastatic spread, progressive hepatic tumour load, symptoms refractory to systemic medical treatment or interventional procedures, and LM exhibiting Ki-67 levels below 10 per cent may benefit from liver transplantation. Perioperatively or before local interventional treatment, all patients received 100–150 µg/h octreotide intravenously for 12 h. Locally ablative surgical treatment Radiofrequency ablation (RFA) was performed with expandable electrodes (RITA Medical Systems, Mountain View, California, USA) placed at operation in conjunction with resection under direct vision of the surgeon and ultrasonographic control. Power levels were increased to maintain temperatures of between 90 and 105 °C around the device for at least 6 min, in accordance with the manufacturer's recommendations. Percutaneous liver-directed treatment Patients with poorly differentiated NET, metastatic involvement of both liver lobes and no evidence of extrahepatic disease were considered as candidates for transcatheter arterial chemoembolization (TACE). Before the procedure the hepatic arterial anatomy, degree of tumour vascularization and patency of the portal vein were assessed by digital subtraction angiography. Superselective embolization was achieved with iodized oil (10–20 ml) and then doxorubicin (40 mg). For selective internal radiation therapy 90Y-radiolabelled microspheres were used. Peptide receptor radionuclide therapy PRRT with DOTATOC was carried out as reported previously28. In this cohort, PRRT started in 2002. For the initial treatment 90Y-labelled DOTATOC was used. If multiple treatments were needed owing to tumour relapse or for biophysical reasons, 177L-labelled DOTATOC was used in order to avoid toxicity that can occur after treatment with the 90Y-labelled radionuclide. To verify the efficacy of the intervention, dynamic contrast-enhanced CT was carried out 4–6 weeks after the completion of treatment. Follow-up Each patient was invited to join the institutional follow-up programme. Supplementary data were obtained from referring physicians or the national cancer registry. Besides standard radiological imaging, endocrinological examinations, including CgA measurement, were carried out every 3 months during the first year and every 6 months thereafter. Patients with suspicious findings were investigated by 111In-labelled octreotide scintigraphy, or 68Ga-labelled DOTATOC PET or PET–CT. Only patients with no clinical and biochemical abnormal findings were considered to be tumour free. All patients who developed resectable tumour recurrence underwent surgery. Palliative treatment was carried out in the event of tumour unresectability or disease progression in patients with primary unresectable metastases. Since 2002, patients with recurrent or progressing unresectable tumour expressing somatostatin receptors were selected for receptor-targeted radiotherapy. Overall and disease-free survival data were recorded. Statistical analysis Data are expressed as median (interquartile range, i.q.r.), unless indicated otherwise. Patient demographics and tumour characteristics were compared by the χ2 test for categorical variables and the non-parametric Kruskal–Wallis test for continuous variables. The Kaplan–Meier method and Cox regression analysis were used to compute time to event (patient survival). Survival was calculated from the date of first treatment of LM. Survival data were censored at 5 years or at the latest date on which a patient's status was known (31 July 2007). The log rank test was used to compare Kaplan–Meier survival curves. A multivariable stepwise Cox regression analysis was applied for variables identified as significant in univariable regression analysis. For all analyses, two-tailed P < 0·050 was considered statistically significant. Statistical analysis was performed using SPSS® version 10.0.6 for Windows® (SPSS, Chicago, Illinois, USA). Results A total of 135 patients with NET included in the database between September 1992 and December 2006 had LM. Sixteen of these patients were excluded from the study for various reasons: unclear histological and/or immunohistochemical results (partial neuroendocrine differentiation of LM; four patients), diffuse tumour dissemination (seven), extremely poor general condition (three) or referral only for a second opinion (two). The remaining 119 patients comprised 64 men (53·8 per cent) and 55 women (46·2 per cent) with a median age of 51 (range 24–76) years. Eleven patients (9·2 per cent) had LM originating from the lung. In 41 patients (34·5 per cent) the primary tumour was localized within the midgut. The pancreas was the primary tumour location in 43 patients (36·1 per cent) (Table 1). Twenty-one patients (17·6 per cent) presented with LM but no primary tumour was identified. One patient had a tumour associated with multiple endocrine neoplasia type 1. Identified primary lesions in 87 (88 per cent) of 99 patients had previously been removed surgically. Table 1 Patient demographics and tumour characteristics as a function of localization type of liver metastases from neuroendocrine tumours . Localization type of LM . . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . P† . Age (years)* 50 (43–59) 51 (47–67) 51 (43–62) 0·126‡ Sex ratio (M : F) 10 : 13 11 : 7 43 : 35 0·302 Primary tumour site  Lung 4 0 7 0·160  Stomach 0 1 1 0·349  Duodenum 1 0 1 0·503  Jejunum 0 1 1 0·349  Ileum 5 7 21 0·459  Colon 1 0 2 0·678  Rectum 1 0 1 0·503  Appendix 0 0 1 0·767  Pancreas 8 5 30 0·599  Unknown 3 4 13 0·741 WHO classification of tumours 0·007  Well differentiated NEC 23 (100) 10 (56) 4 (5)  Poorly differentiated NEC 0 (0) 8 (44) 74 (95) Presentation of LM < 0·001  Synchronous 14 (61) 15 (83) 74 (95)  Metachronous 9 (39) 3 (17) 4 (5) Hormonal symptoms 2 (9) 4 (22) 52 (67) < 0·001 5-HIAA (mg per 24 h)* 10 (9–10) 21 (17–28) 28 (22–38) < 0·001‡ Chromogranin A (µg/l)* 128 (111–170) 213 (144–357) 870 (454–5289) < 0·001‡ Ki-67 index (%)* 3 (2–3) 5 (4–5) 15 (10–20) 0·007‡ Extrahepatic metastases  Lung 0 0 2 0·586  Lymph nodes 0 5 30 < 0·001§  Bone 0 0 11 0·041¶  Adrenal 0 0 1 0·767  Other 0 0 3 0·687 . Localization type of LM . . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . P† . Age (years)* 50 (43–59) 51 (47–67) 51 (43–62) 0·126‡ Sex ratio (M : F) 10 : 13 11 : 7 43 : 35 0·302 Primary tumour site  Lung 4 0 7 0·160  Stomach 0 1 1 0·349  Duodenum 1 0 1 0·503  Jejunum 0 1 1 0·349  Ileum 5 7 21 0·459  Colon 1 0 2 0·678  Rectum 1 0 1 0·503  Appendix 0 0 1 0·767  Pancreas 8 5 30 0·599  Unknown 3 4 13 0·741 WHO classification of tumours 0·007  Well differentiated NEC 23 (100) 10 (56) 4 (5)  Poorly differentiated NEC 0 (0) 8 (44) 74 (95) Presentation of LM < 0·001  Synchronous 14 (61) 15 (83) 74 (95)  Metachronous 9 (39) 3 (17) 4 (5) Hormonal symptoms 2 (9) 4 (22) 52 (67) < 0·001 5-HIAA (mg per 24 h)* 10 (9–10) 21 (17–28) 28 (22–38) < 0·001‡ Chromogranin A (µg/l)* 128 (111–170) 213 (144–357) 870 (454–5289) < 0·001‡ Ki-67 index (%)* 3 (2–3) 5 (4–5) 15 (10–20) 0·007‡ Extrahepatic metastases  Lung 0 0 2 0·586  Lymph nodes 0 5 30 < 0·001§  Bone 0 0 11 0·041¶  Adrenal 0 0 1 0·767  Other 0 0 3 0·687 Values in parentheses are percentages unless indicated otherwise; * values are median (interquartile range). LM, liver metastases; WHO, World Health Organization; NEC, neuroendocrine carcinoma; 5-HIAA, 5-hydroxyindoleacetic acid. † χ2 test unless indicated otherwise; ‡ Kruskal–Wallis test; § type I versus types II and III; ¶ type III versus types I and II. Open in new tab Table 1 Patient demographics and tumour characteristics as a function of localization type of liver metastases from neuroendocrine tumours . Localization type of LM . . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . P† . Age (years)* 50 (43–59) 51 (47–67) 51 (43–62) 0·126‡ Sex ratio (M : F) 10 : 13 11 : 7 43 : 35 0·302 Primary tumour site  Lung 4 0 7 0·160  Stomach 0 1 1 0·349  Duodenum 1 0 1 0·503  Jejunum 0 1 1 0·349  Ileum 5 7 21 0·459  Colon 1 0 2 0·678  Rectum 1 0 1 0·503  Appendix 0 0 1 0·767  Pancreas 8 5 30 0·599  Unknown 3 4 13 0·741 WHO classification of tumours 0·007  Well differentiated NEC 23 (100) 10 (56) 4 (5)  Poorly differentiated NEC 0 (0) 8 (44) 74 (95) Presentation of LM < 0·001  Synchronous 14 (61) 15 (83) 74 (95)  Metachronous 9 (39) 3 (17) 4 (5) Hormonal symptoms 2 (9) 4 (22) 52 (67) < 0·001 5-HIAA (mg per 24 h)* 10 (9–10) 21 (17–28) 28 (22–38) < 0·001‡ Chromogranin A (µg/l)* 128 (111–170) 213 (144–357) 870 (454–5289) < 0·001‡ Ki-67 index (%)* 3 (2–3) 5 (4–5) 15 (10–20) 0·007‡ Extrahepatic metastases  Lung 0 0 2 0·586  Lymph nodes 0 5 30 < 0·001§  Bone 0 0 11 0·041¶  Adrenal 0 0 1 0·767  Other 0 0 3 0·687 . Localization type of LM . . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . P† . Age (years)* 50 (43–59) 51 (47–67) 51 (43–62) 0·126‡ Sex ratio (M : F) 10 : 13 11 : 7 43 : 35 0·302 Primary tumour site  Lung 4 0 7 0·160  Stomach 0 1 1 0·349  Duodenum 1 0 1 0·503  Jejunum 0 1 1 0·349  Ileum 5 7 21 0·459  Colon 1 0 2 0·678  Rectum 1 0 1 0·503  Appendix 0 0 1 0·767  Pancreas 8 5 30 0·599  Unknown 3 4 13 0·741 WHO classification of tumours 0·007  Well differentiated NEC 23 (100) 10 (56) 4 (5)  Poorly differentiated NEC 0 (0) 8 (44) 74 (95) Presentation of LM < 0·001  Synchronous 14 (61) 15 (83) 74 (95)  Metachronous 9 (39) 3 (17) 4 (5) Hormonal symptoms 2 (9) 4 (22) 52 (67) < 0·001 5-HIAA (mg per 24 h)* 10 (9–10) 21 (17–28) 28 (22–38) < 0·001‡ Chromogranin A (µg/l)* 128 (111–170) 213 (144–357) 870 (454–5289) < 0·001‡ Ki-67 index (%)* 3 (2–3) 5 (4–5) 15 (10–20) 0·007‡ Extrahepatic metastases  Lung 0 0 2 0·586  Lymph nodes 0 5 30 < 0·001§  Bone 0 0 11 0·041¶  Adrenal 0 0 1 0·767  Other 0 0 3 0·687 Values in parentheses are percentages unless indicated otherwise; * values are median (interquartile range). LM, liver metastases; WHO, World Health Organization; NEC, neuroendocrine carcinoma; 5-HIAA, 5-hydroxyindoleacetic acid. † χ2 test unless indicated otherwise; ‡ Kruskal–Wallis test; § type I versus types II and III; ¶ type III versus types I and II. Open in new tab Synchronous hepatic metastases developed in 103 patients (86·6 per cent). In four (3·9 per cent), the primary lesion was discovered a median of 24 (i.q.r. 23–29) months after the detection of LM. Metachronous LM occurred in 16 patients (13·4 per cent) with a median time to manifestation of 37 (i.q.r. 35–39) months. Sixty-one patients (51·3 per cent) were asymptomatic regarding hormonal production, whereas 58 presented with functioning tumours and signs of hormonal secretion associated with increased levels of specific peptides. The most common clinical symptoms reported were flush, palpitations, weight loss and diarrhoea. Twenty-six patients (33 per cent) with a significant hepatic tumour load complained of abdominal pain and discomfort. At the time of tumour staging at this institution 68Ga-labelled DOTATOC PET–CT disclosed additional intrahepatic and/or extrahepatic disease not recognized on previous standard imaging in 52 (43·7 per cent) of 119 patients, leading to a change in therapeutic management in 40 (77 per cent). Extent of hepatic metastases Three different patterns of metastatic spread to the liver were identified: single metastasis of any size (type I); isolated metastatic bulk accompanied by smaller deposits, with both liver lobes always involved (type II); and disseminated metastatic spread, with both liver lobes always involved, single lesion of varying size and virtually no normal liver parenchyma (type III) (Fig. 1). Type I LM were noted in 23 patients (19·3 per cent), type II in 18 (15·1 per cent) and type III in 78 (65·5 per cent). The type of metastatic spread in each patient did not change over time. Figure 1 Open in new tabDownload slide The three localization types of neuroendocrine liver metastases: a single metastasis (size independent) (type I), b isolated metastatic bulk accompanied by smaller deposits (both liver lobes always involved) (type II) and c disseminated metastatic spread (both liver lobes always involved, varying size of single lesion, virtually no normal liver parenchyma) (type III) Patient demographics and tumour characteristics in relation to the three types of LM are summarized in Table 1. There were no significant differences between the groups with respect to age, sex and primary tumour site. The three types differed significantly regarding chronological presentation of LM (P < 0·001), hormonal symptoms (P < 0·001), Ki-67 index (P = 0·007), 5-HIAA level (P < 0·001), CgA level (P < 0·001), lymph node involvement (P < 0·001) and presence of bone metastases (P = 0·041). In all 44 patients who had liver resection or transplantation, the intraoperative localization of hepatic disease and histological findings corresponded well with the results documented before surgery. Surgical management of the primary tumour At the time of study entry ten patients presented with a localized primary tumour that had not been removed and in another patient the primary tumour was detected 4 years after entering the study. Surgical treatment of the primary tumour consisted of segmental small bowel resection including regional lymphadenectomy in six patients and various forms of pancreatic resection in five. Two of the latter patients had a Whipple procedure simultaneously with liver transplantation. Management of liver metastases Table 2 shows treatment of LM in relation to the three localization types. All 23 patients with type I LM underwent R0 hepatic resection. The primary tumour was resected before referral to this institution, reflecting selection of cases referred to a unit specialized in hepatobiliary surgery. Surgical procedures included various segmentectomies (14 patients), right posterior sectionectomy (one), right hepatectomy (four), right trisectionectomy with segment I resection (one), left hepatectomy (two) and left lateral sectionectomy (one). Portal vein embolization was necessary before liver resection in one of these patients. The median size of the resected LM was 5 (i.q.r. 4–6) cm. In none of the patients was perihepatic lymph node involvement evident. All 23 patients had solitary tumours on histological examination. Two patients experienced complications, a wound infection and a subphrenic abscess requiring percutaneous drainage. There were no postoperative deaths. Normalization of hormone markers and/or CgA was demonstrable in all patients within 1–3 months. None of the patients received postoperative adjuvant treatment. Table 2 Treatment of hepatic metastases in 119 patients in relation to localization type . Localization type of LM . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . Resection (R0) 23 0 0 Palliative cytoreductive resection 0 2 0 Palliative cytoreduction + radiofrequency ablation 0 2 0 Liver transplantation 0 1 16 Transcatheter arterial chemoembolization 0 9 32 Selective internal radiotherapy 0 0 2 Peptide receptor radionuclide therapy 0 10 23 . Localization type of LM . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . Resection (R0) 23 0 0 Palliative cytoreductive resection 0 2 0 Palliative cytoreduction + radiofrequency ablation 0 2 0 Liver transplantation 0 1 16 Transcatheter arterial chemoembolization 0 9 32 Selective internal radiotherapy 0 0 2 Peptide receptor radionuclide therapy 0 10 23 LM, liver metastases. Open in new tab Table 2 Treatment of hepatic metastases in 119 patients in relation to localization type . Localization type of LM . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . Resection (R0) 23 0 0 Palliative cytoreductive resection 0 2 0 Palliative cytoreduction + radiofrequency ablation 0 2 0 Liver transplantation 0 1 16 Transcatheter arterial chemoembolization 0 9 32 Selective internal radiotherapy 0 0 2 Peptide receptor radionuclide therapy 0 10 23 . Localization type of LM . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . Resection (R0) 23 0 0 Palliative cytoreductive resection 0 2 0 Palliative cytoreduction + radiofrequency ablation 0 2 0 Liver transplantation 0 1 16 Transcatheter arterial chemoembolization 0 9 32 Selective internal radiotherapy 0 0 2 Peptide receptor radionuclide therapy 0 10 23 LM, liver metastases. Open in new tab None of the 18 patients with type II LM was suitable for staged hepatic resection and only one was a candidate for liver transplantation. Four patients received palliative cytoreductive resection with or without RFA. Owing to intrahepatic and/or extrahepatic tumour progression all four patients required additional non-surgical treatment (TACE and/or PRRT) during the study period. There were no complications among the five patients who had surgical treatment. The primary treatment for LM was non-surgical in the remaining 13 patients. The volume and/or distribution of metastases excluded the use of RFA and procedures undertaken are indicated in Table 2. Most required an average of three treatment sessions to achieve either stable disease or tumour volume reduction. Three patients needed additional systemic octreotide treatment to ameliorate clinical symptoms caused by hormonal excess. Two of the 13 patients had a complication, hepatic abscess following TACE in one and anaemia after PRRT in another. There were no treatment-related deaths among patients with type II LM. Sixteen (21 per cent) of the 78 patients with type III LM underwent liver transplantation, as reported previously27. Postoperative complications documented in two patients included arterial thrombosis, lymph fistula and bile leakage. Four patients died as a result of the procedure. Fifty-seven patients (73 per cent) had non-surgical treatment, including TACE in 32 (56 per cent) and PRRT in 23 (40 per cent). RFA was not feasible because of the extent of the tumour load and/or presence of extrahepatic metastases. Postinterventional complications occurred in ten patients, comprising transient toxicity grade 1 after DOTATOC treatment and postembolization fever. Hormonal symptoms were controlled with octreotide in ten patients, in combination with α-interferon at different times in the study in two. Five patients (6 per cent) who were in poor general condition, with rapid hepatic and extrahepatic tumour progression, could not withstand aggressive treatment and were eligible for supportive therapy only. Disease-specific and disease-free survival Fig. 2 shows disease-specific survival regardless of the treatment modality. The median (i.q.r.) follow-up was 60 (29–108), 60 (25–102) and 48 (24–78) months for patients with type I, II and III LM respectively. Analysis by type of metastatic spread revealed significant differences in survival (Fig. 3). Within type II there was no difference in survival between patients who had a palliative resection and those treated non-surgically. The 5-year overall and disease-free survival for patients who had a liver transplant was 67 and 48 per cent respectively27. Survival curves calculated with respect to the WHO classification were no different from survival curves for the three different types of LM. Figure 2 Open in new tabDownload slide Disease-specific survival of 119 patients with neuroendocrine liver metastases (LM) Figure 3 Open in new tabDownload slide Disease-specific survival according to localization type of hepatic metastatic spread. LM, liver metastases. P = 0·052, type I versus type II; P = 0·019, type II versus type III; P = 0·001, type I versus type III (log rank test) One patient with type I hepatic metastasis, diagnosed with a glucagonoma, developed a recurrence at 24 months that was suitable for repeat hepatic resection. At reoperation complete tumour removal was achieved by resection of segments IV, V and VIII, and the patient remained morphologically and biochemically tumour free at 36 months afterwards. All four patients in whom palliative cytoreductive resection was carried out were still alive at 26, 27, 44 and 62 months after surgery; two had stable disease and two with tumour progression underwent PRRT. The localization type of LM was the identified as the only significant independent predictor of survival (hazard ratio 5·45 (95 per cent confidence interval 1·96 to 15·11); P < 0·001). An algorithm based on recommendations for diagnosis and treatment of neuroendocrine LM according to the localization types was created (Fig. 4). Figure 4 Open in new tabDownload slide Algorithm illustrating diagnostic approach and decision making for treatment of patients with neuroendocrine liver metastases (LM). CgA, chromogranin A; FNB, fine-needle biopsy; CT, computed tomography; MRI, magnetic resonance imaging; NET, neuroendocrine tumour; DOTATOC, 1,4,7,10-tetra-azacyclododecane-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe1Try3-octreotide; PET, positron emission tomography; EHD, extrahepatic disease; CRR, cytoreductive resection; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; PRRT, peptide receptor radionuclide therapy; SIRT, selective internal radiotherapy; LT, liver transplantation; REHD, resection of extrahepatic disease Discussion This study has shown that aggressive treatment of neuroendocrine LM improves outcome; 3- and 5-year survival rates for the entire group were 76·4 and 63·9 per cent, in contrast to 39 per cent21 and 25 per cent13 respectively reported for patients undergoing non-aggressive treatment. Surgical resection with a positive impact on long-term survival was feasible in only a small group of patients, whereas a range of non-surgical options provided excellent palliation in both symptomatic and asymptomatic patients. Many previous studies have advocated aggressive surgery for hepatic metastases of NET with the aim of extending survival13–22. Overall survival after hepatic resection ranges from 46 to 76 per cent at 5 years and 35 to 79 per cent at 10 years14,16–18,21,29. Patients in whom hepatic resection was achievable had a significantly better median overall survival30 and 5-year survival16 than those with unresectable hepatic disease18,19. Although the impact of hepatic resection appears striking, it is difficult critically to evaluate the published experience owing to the limited number of patients eligible for surgical treatment and the heterogeneity of terminology used. In some series only a R0 resection is considered as having curative intent17, whereas in others resection is classified as complete without referring to the R status14,16,20,21,29 or defined as a curative procedure when all visible gross disease was removed31. Elias and colleagues17 even considered patients with peritoneal carcinomatosis to have undergone curative resection when complete elimination of peritoneal seeding and consecutive intraperitoneal chemotherapy were carried out. In a more recent report, however, the same group revised their earlier opinion32. Having a mixture of resections and resections in combination with RFA13,15,19,33 and/or TACE13, or inclusion of patients treated with RFA only in the group considered to be curatively resected31, also hinders the objective evaluation of the curative surgical option. The terminology applied to surgical procedures with palliative intent is even more confusing. The historical recommendation that palliative liver resection is justified only if elimination of at least 90 per cent of the tumour bulk is feasible34 lacks evidence because this procedure has never been compared with less extensive palliative resections. More recently it has been postulated that only patients with less than 50–75 per cent hepatic involvement may benefit from an aggressive surgical approach13,21, and that hepatectomy is justified only if all intrahepatic and extrahepatic metastatic disease can be eliminated completely17. In the present series patients with LM from NET were selected for aggressive treatment based on the localization type of hepatic tumour. Three types with distinct patterns of metastatic spread were identified. The three types of LM did not only differ morphologically, but also with regard to chronological presentation, hormonal activity, CgA and 5-HIAA levels, Ki-67 index and presence of extrahepatic metastases. Resection with curative intent was feasible in only 19·3 per cent of patients, all with solitary LM and therefore included in type I. Histopathological examination confirmed complete (R0) resection in all patients, yielding 3- and 5-year overall survival rates of 100 per cent. These results demonstrate strikingly the prognostic relevance of a R0 resection and correspond well with previously reported results of curative resection18,22,30. It is obvious that not only completeness of surgical resection but also meticulous patient selection and the diverse tumour biology of NET influence the outcome. Because of the volume and extent of hepatic metastases, none of the 96 patients with type II or III LM were candidates for resection with curative intent. The extent to which hepatic involvement of metastatic NET limits the benefit of surgery has been increasingly addressed in recent years13,21. In view of these findings and the effectiveness of less invasive treatment methods, such as RFA, TACE, PRRT and selective internal radiation therapy, either as a single technique or in combination, the authors believe that there is not much room for palliative hepatic resection. Mazzaglia and colleagues35 noted a median survival of 3·9 years after the first RFA treatment in a series of 63 patients in whom curative resection was not possible. Using PRRT, the present authors achieved a partial tumour response or stable disease in 25 and 55 per cent of patients with disseminated LM respectively28. In a group of 46 patients with NET treated with TACE or hepatic artery embolization, Ho et al.36 reported a mean overall survival time of 3·5 years and a progression-free survival of 1·5 years. The beneficial effect of percutaneous liver-directed therapies has been confirmed by Gupta and co-workers37 in a group of 123 patients with metastatic NET; TACE was associated with an overall survival of 31·5 months and a radiological response rate of 50 per cent. When balancing palliative hepatic surgery against novel non-surgical options, it should also be borne in mind that unresectable extrahepatic disease can be expected in more than one-third of patients21,28,35. Liver transplantation is a possibility in a small number of highly selected patients with type II or III unresectable LM. In most recent single-centre studies 5-year overall and disease-free survival rates of 67–90 per cent and 20–48 per cent respectively have been reported27,38,39. Accurate assessment of the full extent of metastatic disease is one of the key issues in deciding on the surgical management of patients with NET, particularly those considered as transplant candidates. SSRS has proved highly effective in detecting additional intrahepatic and/or extrahepatic tumours compared with standard radiological imaging40–42. In accordance with experience of others40,43, SSRS amended the staging and influenced the decision about surgical treatment in more than half of the patients in the present study. In terms of survival, it is not unexpected that type I LM were associated with a significantly better outcome than types II and III because hepatic resection with curative intent was performed in all patients with type 1 metastasis. The authors hypothesize that the three patterns of metastatic spread reflect the diverse biological behaviour of neuroendocrine LM and overlap with the grading system proposed recently for foregut NET44. Based on the mitotic count and Ki-67 index, this grading system includes three tumour categories: G1, G2 and G3. G1 and G2 tumours correspond to well-differentiated NET with different levels of aggressiveness, whereas G3 corresponds to poorly differentiated neuroendocrine carcinoma. In the present series the Ki-67 index differed significantly between the three types of metastasis. In agreement with the present results, Boo and colleagues45 found that a high Ki-67 proliferation index correlated strongly with tumour recurrence and histological differentiation in gastric NET, and proposed that Ki-67 determination should be added to the standard pathological classification of NET. In reference to the WHO classification, the present study demonstrated that type I mainly consists of well-differentiated neuroendocrine carcinoma with a lower malignant potential, whereas types II and III encompass more aggressive, well-differentiated and poorly differentiated neuroendocrine carcinoma. The differences between the three types are presumed to represent true differences in biological behaviour rather than a time bias. The distinct type of hepatic disease evident when the LM were detected initially remained unchanged over the study period. Significant differences in chronological presentation of LM and other features between the three groups further underline the differences in biological aggressiveness. In conclusion, as well as consideration of purely morphological characteristics, attention should be paid to the localization and biological features of LM from NET in order to better assess prognosis and implement patient-tailored management. The management algorithm presented, based on three different types of metastatic spread, regardless of primary tumour, involves multimodal treatments and a stepwise approach, and it is recommended that such patients are managed in specialized centres. Acknowledgements The authors thank Dr F. Weber and Dr V. Cicinnati for help and support during the final phase of this study. They are grateful to Professor V. Nicolas for performing radiological interventions in the patients included in this study, and to Professor K. Mann for critical review of the results and the manuscript. The authors declare no conflict of interest. References 1 Modlin IM , Lye KD, Kidd M. A 5-decade analysis of 13 715 carcinoid tumors . Cancer 2003 ; 97 : 934 – 959 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Thompson GB , van Heerden JA, Grant CS, Carney JA, Ilstrup JA. Islet cell carcinomas of the pancreas: a twenty-year experience . Surgery 1988 ; 104 : 1011 – 1017 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 3 Godwin JD . Carcinoid tumors. An analysis of 2837 cases . Cancer 1975 ; 36 : 560 – 569 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Yao JC , Vauthey JN. Primary and metastatic hepatic carcinoid: is there an algorithm? Ann Surg Oncol 2003 ; 10 : 1133 – 1135 . 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Surgery Oxford University Press

Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease

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Oxford University Press
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Copyright © 2022 BJS Society Ltd.
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0007-1323
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1365-2168
DOI
10.1002/bjs.6468
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Abstract

Abstract Background Hepatic surgery is presumed to improve survival of patients with liver metastases (LM) from neuroendocrine tumours (NET). This study identified LM-specific variables that could be used as additional selection criteria for aggressive treatment. Methods A novel classification of LM from NET was established based on their localization and presentation. Results From 1992 to 2006, 119 patients underwent staging and treatment of LM. Three growth types of LM were identified radiologically: single metastasis (type I), isolated metastatic bulk accompanied by smaller deposits (type II) and disseminated metastatic spread (type III). The three groups differed significantly in terms of chronological presentation of LM, hormonal symptoms, Ki-67 index, 5-hydroxyindoleacetic acid and chromogranin A levels, lymph node involvement, presence of bone metastases and treatment options. The 3-, 5- and 10-year disease-specific survival rates for the entire cohort were 76·4, 63·9 and 46·5 per cent respectively. There were significant differences in survival between the three groups: 5- and 10-year rates were both 100 per cent for type I, 84 and 75 per cent respectively for type II, and 51 and 29 per cent for type III. Conclusion The localization and biological features of LM from NET defines therapeutic management and is predictive of outcome. Introduction Neuroendocrine tumours (NET) commonly metastasize to the liver1. Neuroendocrine liver metastases (LM) frequently have an indolent clinical course, compared with hepatic metastases from non-endocrine gastrointestinal or pancreatic malignancies, and incapacitating clinical symptoms in the presence of a hormonally active tumour load. A 5-year survival rate of 13–54 per cent in historical groups of patients with untreated neuroendocrine LM reflects the unique biological behaviour of malignant NET2,3. Numerous treatment options have been reported as successful, such as surgical resection with curative intent, palliative cytoreductive resection, liver transplantation, locally effective liver-directed techniques, systemic medical regimens and most, recently, peptide receptor radionuclide therapy (PRRT), but the optimal management is still ill defined4–12. Although an aggressive surgical approach has been considered to prolong survival in patients with NET metastasized to the liver13–15, few data are available on the selection of candidates for liver resection. The survival impact of hepatic resection is difficult to assess for several reasons: the completeness of resection was not determined clearly in several studies, hilar lymph node removal was not included in the hepatic resection in most reports, the frequently used term ‘palliative resection’ is ill defined, results of resection and/or local ablation have often not been determined separately, and consistent follow-up criteria are lacking. In view of the complete resection (R0) rate of only 25–57 per cent16–20, a postresectional 5-year disease-free survival rate of only 16–45 per cent14,17 and a 5-year overall survival of no more than 26–63 per cent after palliative resection21,22, and the risk of operative morbidity and mortality, clear indications for liver resection are needed. Since the authors initial report on the surgical management of NET metastasized to the liver23, it has been observed that LM have distinct localization and presentation patterns regardless of the primary tumour. Even more important, the morphological characteristics of the hepatic metastatic spread seem to be of prognostic value. The aim of this study was, first, to define the role of aggressive treatment in relation to localization patterns of neuroendocrine hepatic metastases and, second, to identify factors associated with these patterns. Methods A prospective database for referred patients with NET was created in September 1992, according to a protocol approved by the local institutional review board. The database includes demographic information, previous diagnosis and treatment, clinical symptoms, laboratory findings including 5-hydroxyindoleacetic acid (5-HIAA) and tumour marker chromogranin A (CgA) levels, results of radiological and nuclear medicine imaging, treatment methods and follow-up data. Imaging mainly comprised computed tomography (CT), magnetic resonance imaging, somatostatin receptor scintigraphy (SSRS) with 111In-labelled diethylenetriamine-penta-acetic acid-D-Phe1-octreotide and, more recently, with 68Ga-labelled 1,4,7,10-tetra-azacyclododedcane-4,7,10-tricarboxy-methyl-1-yl-acetyl- D-Phe1Try3-octreotide (DOTATOC) in a combined positron emission tomography (PET) and CT technique. Tumour typing based on extensive histological and immunohistochemical studies was according to the World Health Organization (WHO) 2000 and 1999 histological classification of endocrine and lung tumours respectively24,25. Analysis of Ki-67 expression was carried out retrospectively on archived pathological specimens until 2000 and prospectively in a routine manner thereafter. Patterns of hepatic metastases were determined exclusively from imaging results and findings of SSRS. For patients who had liver surgery in this institution, the imaging results were compared with intraoperative and histological findings in order to evaluate the classification scheme. LM were classified as synchronous when present simultaneously with the primary tumour or detected within 6 months of diagnosis of the primary tumour. They were also assumed to be synchronous in patients in whom the primary lesion was not found during the observation period. Metachronous metastases were those that became apparent more than 6 months after primary tumour detection. Surgical treatment The spectrum of liver surgery procedures comprised complete resections of various extent including hilar lymphadenectomy, palliative cytoreductive resection (incomplete tumour removal regardless of the amount of residual hepatic tumour mass) and liver transplantation. Resection was the treatment of choice only for patients in whom complete tumour elimination (hepatic and extrahepatic R0 status) was deemed feasible according to the results of the imaging studies. The extent of hepatic resection was defined according to the Brisbane 2000 terminology26. Right portal vein embolization was used to induce hypertrophy of the remaining left lateral section before right trisectionectomy if necessary. Palliative cytoreductive surgery to improve survival and reduce systemic hormonal symptoms and/or symptoms due to tumour expansion was undertaken if less than 70 per cent of the liver was involved by tumour and no unresectable extrahepatic tumour spread was evident. Staged hepatic resections were considered. Indications for liver transplantation were as documented previously27. Briefly, only patients with unresectable LM, no extrahepatic or resectable extrahepatic metastatic spread, progressive hepatic tumour load, symptoms refractory to systemic medical treatment or interventional procedures, and LM exhibiting Ki-67 levels below 10 per cent may benefit from liver transplantation. Perioperatively or before local interventional treatment, all patients received 100–150 µg/h octreotide intravenously for 12 h. Locally ablative surgical treatment Radiofrequency ablation (RFA) was performed with expandable electrodes (RITA Medical Systems, Mountain View, California, USA) placed at operation in conjunction with resection under direct vision of the surgeon and ultrasonographic control. Power levels were increased to maintain temperatures of between 90 and 105 °C around the device for at least 6 min, in accordance with the manufacturer's recommendations. Percutaneous liver-directed treatment Patients with poorly differentiated NET, metastatic involvement of both liver lobes and no evidence of extrahepatic disease were considered as candidates for transcatheter arterial chemoembolization (TACE). Before the procedure the hepatic arterial anatomy, degree of tumour vascularization and patency of the portal vein were assessed by digital subtraction angiography. Superselective embolization was achieved with iodized oil (10–20 ml) and then doxorubicin (40 mg). For selective internal radiation therapy 90Y-radiolabelled microspheres were used. Peptide receptor radionuclide therapy PRRT with DOTATOC was carried out as reported previously28. In this cohort, PRRT started in 2002. For the initial treatment 90Y-labelled DOTATOC was used. If multiple treatments were needed owing to tumour relapse or for biophysical reasons, 177L-labelled DOTATOC was used in order to avoid toxicity that can occur after treatment with the 90Y-labelled radionuclide. To verify the efficacy of the intervention, dynamic contrast-enhanced CT was carried out 4–6 weeks after the completion of treatment. Follow-up Each patient was invited to join the institutional follow-up programme. Supplementary data were obtained from referring physicians or the national cancer registry. Besides standard radiological imaging, endocrinological examinations, including CgA measurement, were carried out every 3 months during the first year and every 6 months thereafter. Patients with suspicious findings were investigated by 111In-labelled octreotide scintigraphy, or 68Ga-labelled DOTATOC PET or PET–CT. Only patients with no clinical and biochemical abnormal findings were considered to be tumour free. All patients who developed resectable tumour recurrence underwent surgery. Palliative treatment was carried out in the event of tumour unresectability or disease progression in patients with primary unresectable metastases. Since 2002, patients with recurrent or progressing unresectable tumour expressing somatostatin receptors were selected for receptor-targeted radiotherapy. Overall and disease-free survival data were recorded. Statistical analysis Data are expressed as median (interquartile range, i.q.r.), unless indicated otherwise. Patient demographics and tumour characteristics were compared by the χ2 test for categorical variables and the non-parametric Kruskal–Wallis test for continuous variables. The Kaplan–Meier method and Cox regression analysis were used to compute time to event (patient survival). Survival was calculated from the date of first treatment of LM. Survival data were censored at 5 years or at the latest date on which a patient's status was known (31 July 2007). The log rank test was used to compare Kaplan–Meier survival curves. A multivariable stepwise Cox regression analysis was applied for variables identified as significant in univariable regression analysis. For all analyses, two-tailed P < 0·050 was considered statistically significant. Statistical analysis was performed using SPSS® version 10.0.6 for Windows® (SPSS, Chicago, Illinois, USA). Results A total of 135 patients with NET included in the database between September 1992 and December 2006 had LM. Sixteen of these patients were excluded from the study for various reasons: unclear histological and/or immunohistochemical results (partial neuroendocrine differentiation of LM; four patients), diffuse tumour dissemination (seven), extremely poor general condition (three) or referral only for a second opinion (two). The remaining 119 patients comprised 64 men (53·8 per cent) and 55 women (46·2 per cent) with a median age of 51 (range 24–76) years. Eleven patients (9·2 per cent) had LM originating from the lung. In 41 patients (34·5 per cent) the primary tumour was localized within the midgut. The pancreas was the primary tumour location in 43 patients (36·1 per cent) (Table 1). Twenty-one patients (17·6 per cent) presented with LM but no primary tumour was identified. One patient had a tumour associated with multiple endocrine neoplasia type 1. Identified primary lesions in 87 (88 per cent) of 99 patients had previously been removed surgically. Table 1 Patient demographics and tumour characteristics as a function of localization type of liver metastases from neuroendocrine tumours . Localization type of LM . . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . P† . Age (years)* 50 (43–59) 51 (47–67) 51 (43–62) 0·126‡ Sex ratio (M : F) 10 : 13 11 : 7 43 : 35 0·302 Primary tumour site  Lung 4 0 7 0·160  Stomach 0 1 1 0·349  Duodenum 1 0 1 0·503  Jejunum 0 1 1 0·349  Ileum 5 7 21 0·459  Colon 1 0 2 0·678  Rectum 1 0 1 0·503  Appendix 0 0 1 0·767  Pancreas 8 5 30 0·599  Unknown 3 4 13 0·741 WHO classification of tumours 0·007  Well differentiated NEC 23 (100) 10 (56) 4 (5)  Poorly differentiated NEC 0 (0) 8 (44) 74 (95) Presentation of LM < 0·001  Synchronous 14 (61) 15 (83) 74 (95)  Metachronous 9 (39) 3 (17) 4 (5) Hormonal symptoms 2 (9) 4 (22) 52 (67) < 0·001 5-HIAA (mg per 24 h)* 10 (9–10) 21 (17–28) 28 (22–38) < 0·001‡ Chromogranin A (µg/l)* 128 (111–170) 213 (144–357) 870 (454–5289) < 0·001‡ Ki-67 index (%)* 3 (2–3) 5 (4–5) 15 (10–20) 0·007‡ Extrahepatic metastases  Lung 0 0 2 0·586  Lymph nodes 0 5 30 < 0·001§  Bone 0 0 11 0·041¶  Adrenal 0 0 1 0·767  Other 0 0 3 0·687 . Localization type of LM . . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . P† . Age (years)* 50 (43–59) 51 (47–67) 51 (43–62) 0·126‡ Sex ratio (M : F) 10 : 13 11 : 7 43 : 35 0·302 Primary tumour site  Lung 4 0 7 0·160  Stomach 0 1 1 0·349  Duodenum 1 0 1 0·503  Jejunum 0 1 1 0·349  Ileum 5 7 21 0·459  Colon 1 0 2 0·678  Rectum 1 0 1 0·503  Appendix 0 0 1 0·767  Pancreas 8 5 30 0·599  Unknown 3 4 13 0·741 WHO classification of tumours 0·007  Well differentiated NEC 23 (100) 10 (56) 4 (5)  Poorly differentiated NEC 0 (0) 8 (44) 74 (95) Presentation of LM < 0·001  Synchronous 14 (61) 15 (83) 74 (95)  Metachronous 9 (39) 3 (17) 4 (5) Hormonal symptoms 2 (9) 4 (22) 52 (67) < 0·001 5-HIAA (mg per 24 h)* 10 (9–10) 21 (17–28) 28 (22–38) < 0·001‡ Chromogranin A (µg/l)* 128 (111–170) 213 (144–357) 870 (454–5289) < 0·001‡ Ki-67 index (%)* 3 (2–3) 5 (4–5) 15 (10–20) 0·007‡ Extrahepatic metastases  Lung 0 0 2 0·586  Lymph nodes 0 5 30 < 0·001§  Bone 0 0 11 0·041¶  Adrenal 0 0 1 0·767  Other 0 0 3 0·687 Values in parentheses are percentages unless indicated otherwise; * values are median (interquartile range). LM, liver metastases; WHO, World Health Organization; NEC, neuroendocrine carcinoma; 5-HIAA, 5-hydroxyindoleacetic acid. † χ2 test unless indicated otherwise; ‡ Kruskal–Wallis test; § type I versus types II and III; ¶ type III versus types I and II. Open in new tab Table 1 Patient demographics and tumour characteristics as a function of localization type of liver metastases from neuroendocrine tumours . Localization type of LM . . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . P† . Age (years)* 50 (43–59) 51 (47–67) 51 (43–62) 0·126‡ Sex ratio (M : F) 10 : 13 11 : 7 43 : 35 0·302 Primary tumour site  Lung 4 0 7 0·160  Stomach 0 1 1 0·349  Duodenum 1 0 1 0·503  Jejunum 0 1 1 0·349  Ileum 5 7 21 0·459  Colon 1 0 2 0·678  Rectum 1 0 1 0·503  Appendix 0 0 1 0·767  Pancreas 8 5 30 0·599  Unknown 3 4 13 0·741 WHO classification of tumours 0·007  Well differentiated NEC 23 (100) 10 (56) 4 (5)  Poorly differentiated NEC 0 (0) 8 (44) 74 (95) Presentation of LM < 0·001  Synchronous 14 (61) 15 (83) 74 (95)  Metachronous 9 (39) 3 (17) 4 (5) Hormonal symptoms 2 (9) 4 (22) 52 (67) < 0·001 5-HIAA (mg per 24 h)* 10 (9–10) 21 (17–28) 28 (22–38) < 0·001‡ Chromogranin A (µg/l)* 128 (111–170) 213 (144–357) 870 (454–5289) < 0·001‡ Ki-67 index (%)* 3 (2–3) 5 (4–5) 15 (10–20) 0·007‡ Extrahepatic metastases  Lung 0 0 2 0·586  Lymph nodes 0 5 30 < 0·001§  Bone 0 0 11 0·041¶  Adrenal 0 0 1 0·767  Other 0 0 3 0·687 . Localization type of LM . . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . P† . Age (years)* 50 (43–59) 51 (47–67) 51 (43–62) 0·126‡ Sex ratio (M : F) 10 : 13 11 : 7 43 : 35 0·302 Primary tumour site  Lung 4 0 7 0·160  Stomach 0 1 1 0·349  Duodenum 1 0 1 0·503  Jejunum 0 1 1 0·349  Ileum 5 7 21 0·459  Colon 1 0 2 0·678  Rectum 1 0 1 0·503  Appendix 0 0 1 0·767  Pancreas 8 5 30 0·599  Unknown 3 4 13 0·741 WHO classification of tumours 0·007  Well differentiated NEC 23 (100) 10 (56) 4 (5)  Poorly differentiated NEC 0 (0) 8 (44) 74 (95) Presentation of LM < 0·001  Synchronous 14 (61) 15 (83) 74 (95)  Metachronous 9 (39) 3 (17) 4 (5) Hormonal symptoms 2 (9) 4 (22) 52 (67) < 0·001 5-HIAA (mg per 24 h)* 10 (9–10) 21 (17–28) 28 (22–38) < 0·001‡ Chromogranin A (µg/l)* 128 (111–170) 213 (144–357) 870 (454–5289) < 0·001‡ Ki-67 index (%)* 3 (2–3) 5 (4–5) 15 (10–20) 0·007‡ Extrahepatic metastases  Lung 0 0 2 0·586  Lymph nodes 0 5 30 < 0·001§  Bone 0 0 11 0·041¶  Adrenal 0 0 1 0·767  Other 0 0 3 0·687 Values in parentheses are percentages unless indicated otherwise; * values are median (interquartile range). LM, liver metastases; WHO, World Health Organization; NEC, neuroendocrine carcinoma; 5-HIAA, 5-hydroxyindoleacetic acid. † χ2 test unless indicated otherwise; ‡ Kruskal–Wallis test; § type I versus types II and III; ¶ type III versus types I and II. Open in new tab Synchronous hepatic metastases developed in 103 patients (86·6 per cent). In four (3·9 per cent), the primary lesion was discovered a median of 24 (i.q.r. 23–29) months after the detection of LM. Metachronous LM occurred in 16 patients (13·4 per cent) with a median time to manifestation of 37 (i.q.r. 35–39) months. Sixty-one patients (51·3 per cent) were asymptomatic regarding hormonal production, whereas 58 presented with functioning tumours and signs of hormonal secretion associated with increased levels of specific peptides. The most common clinical symptoms reported were flush, palpitations, weight loss and diarrhoea. Twenty-six patients (33 per cent) with a significant hepatic tumour load complained of abdominal pain and discomfort. At the time of tumour staging at this institution 68Ga-labelled DOTATOC PET–CT disclosed additional intrahepatic and/or extrahepatic disease not recognized on previous standard imaging in 52 (43·7 per cent) of 119 patients, leading to a change in therapeutic management in 40 (77 per cent). Extent of hepatic metastases Three different patterns of metastatic spread to the liver were identified: single metastasis of any size (type I); isolated metastatic bulk accompanied by smaller deposits, with both liver lobes always involved (type II); and disseminated metastatic spread, with both liver lobes always involved, single lesion of varying size and virtually no normal liver parenchyma (type III) (Fig. 1). Type I LM were noted in 23 patients (19·3 per cent), type II in 18 (15·1 per cent) and type III in 78 (65·5 per cent). The type of metastatic spread in each patient did not change over time. Figure 1 Open in new tabDownload slide The three localization types of neuroendocrine liver metastases: a single metastasis (size independent) (type I), b isolated metastatic bulk accompanied by smaller deposits (both liver lobes always involved) (type II) and c disseminated metastatic spread (both liver lobes always involved, varying size of single lesion, virtually no normal liver parenchyma) (type III) Patient demographics and tumour characteristics in relation to the three types of LM are summarized in Table 1. There were no significant differences between the groups with respect to age, sex and primary tumour site. The three types differed significantly regarding chronological presentation of LM (P < 0·001), hormonal symptoms (P < 0·001), Ki-67 index (P = 0·007), 5-HIAA level (P < 0·001), CgA level (P < 0·001), lymph node involvement (P < 0·001) and presence of bone metastases (P = 0·041). In all 44 patients who had liver resection or transplantation, the intraoperative localization of hepatic disease and histological findings corresponded well with the results documented before surgery. Surgical management of the primary tumour At the time of study entry ten patients presented with a localized primary tumour that had not been removed and in another patient the primary tumour was detected 4 years after entering the study. Surgical treatment of the primary tumour consisted of segmental small bowel resection including regional lymphadenectomy in six patients and various forms of pancreatic resection in five. Two of the latter patients had a Whipple procedure simultaneously with liver transplantation. Management of liver metastases Table 2 shows treatment of LM in relation to the three localization types. All 23 patients with type I LM underwent R0 hepatic resection. The primary tumour was resected before referral to this institution, reflecting selection of cases referred to a unit specialized in hepatobiliary surgery. Surgical procedures included various segmentectomies (14 patients), right posterior sectionectomy (one), right hepatectomy (four), right trisectionectomy with segment I resection (one), left hepatectomy (two) and left lateral sectionectomy (one). Portal vein embolization was necessary before liver resection in one of these patients. The median size of the resected LM was 5 (i.q.r. 4–6) cm. In none of the patients was perihepatic lymph node involvement evident. All 23 patients had solitary tumours on histological examination. Two patients experienced complications, a wound infection and a subphrenic abscess requiring percutaneous drainage. There were no postoperative deaths. Normalization of hormone markers and/or CgA was demonstrable in all patients within 1–3 months. None of the patients received postoperative adjuvant treatment. Table 2 Treatment of hepatic metastases in 119 patients in relation to localization type . Localization type of LM . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . Resection (R0) 23 0 0 Palliative cytoreductive resection 0 2 0 Palliative cytoreduction + radiofrequency ablation 0 2 0 Liver transplantation 0 1 16 Transcatheter arterial chemoembolization 0 9 32 Selective internal radiotherapy 0 0 2 Peptide receptor radionuclide therapy 0 10 23 . Localization type of LM . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . Resection (R0) 23 0 0 Palliative cytoreductive resection 0 2 0 Palliative cytoreduction + radiofrequency ablation 0 2 0 Liver transplantation 0 1 16 Transcatheter arterial chemoembolization 0 9 32 Selective internal radiotherapy 0 0 2 Peptide receptor radionuclide therapy 0 10 23 LM, liver metastases. Open in new tab Table 2 Treatment of hepatic metastases in 119 patients in relation to localization type . Localization type of LM . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . Resection (R0) 23 0 0 Palliative cytoreductive resection 0 2 0 Palliative cytoreduction + radiofrequency ablation 0 2 0 Liver transplantation 0 1 16 Transcatheter arterial chemoembolization 0 9 32 Selective internal radiotherapy 0 0 2 Peptide receptor radionuclide therapy 0 10 23 . Localization type of LM . . Type I (n = 23) . Type II (n = 18) . Type III (n = 78) . Resection (R0) 23 0 0 Palliative cytoreductive resection 0 2 0 Palliative cytoreduction + radiofrequency ablation 0 2 0 Liver transplantation 0 1 16 Transcatheter arterial chemoembolization 0 9 32 Selective internal radiotherapy 0 0 2 Peptide receptor radionuclide therapy 0 10 23 LM, liver metastases. Open in new tab None of the 18 patients with type II LM was suitable for staged hepatic resection and only one was a candidate for liver transplantation. Four patients received palliative cytoreductive resection with or without RFA. Owing to intrahepatic and/or extrahepatic tumour progression all four patients required additional non-surgical treatment (TACE and/or PRRT) during the study period. There were no complications among the five patients who had surgical treatment. The primary treatment for LM was non-surgical in the remaining 13 patients. The volume and/or distribution of metastases excluded the use of RFA and procedures undertaken are indicated in Table 2. Most required an average of three treatment sessions to achieve either stable disease or tumour volume reduction. Three patients needed additional systemic octreotide treatment to ameliorate clinical symptoms caused by hormonal excess. Two of the 13 patients had a complication, hepatic abscess following TACE in one and anaemia after PRRT in another. There were no treatment-related deaths among patients with type II LM. Sixteen (21 per cent) of the 78 patients with type III LM underwent liver transplantation, as reported previously27. Postoperative complications documented in two patients included arterial thrombosis, lymph fistula and bile leakage. Four patients died as a result of the procedure. Fifty-seven patients (73 per cent) had non-surgical treatment, including TACE in 32 (56 per cent) and PRRT in 23 (40 per cent). RFA was not feasible because of the extent of the tumour load and/or presence of extrahepatic metastases. Postinterventional complications occurred in ten patients, comprising transient toxicity grade 1 after DOTATOC treatment and postembolization fever. Hormonal symptoms were controlled with octreotide in ten patients, in combination with α-interferon at different times in the study in two. Five patients (6 per cent) who were in poor general condition, with rapid hepatic and extrahepatic tumour progression, could not withstand aggressive treatment and were eligible for supportive therapy only. Disease-specific and disease-free survival Fig. 2 shows disease-specific survival regardless of the treatment modality. The median (i.q.r.) follow-up was 60 (29–108), 60 (25–102) and 48 (24–78) months for patients with type I, II and III LM respectively. Analysis by type of metastatic spread revealed significant differences in survival (Fig. 3). Within type II there was no difference in survival between patients who had a palliative resection and those treated non-surgically. The 5-year overall and disease-free survival for patients who had a liver transplant was 67 and 48 per cent respectively27. Survival curves calculated with respect to the WHO classification were no different from survival curves for the three different types of LM. Figure 2 Open in new tabDownload slide Disease-specific survival of 119 patients with neuroendocrine liver metastases (LM) Figure 3 Open in new tabDownload slide Disease-specific survival according to localization type of hepatic metastatic spread. LM, liver metastases. P = 0·052, type I versus type II; P = 0·019, type II versus type III; P = 0·001, type I versus type III (log rank test) One patient with type I hepatic metastasis, diagnosed with a glucagonoma, developed a recurrence at 24 months that was suitable for repeat hepatic resection. At reoperation complete tumour removal was achieved by resection of segments IV, V and VIII, and the patient remained morphologically and biochemically tumour free at 36 months afterwards. All four patients in whom palliative cytoreductive resection was carried out were still alive at 26, 27, 44 and 62 months after surgery; two had stable disease and two with tumour progression underwent PRRT. The localization type of LM was the identified as the only significant independent predictor of survival (hazard ratio 5·45 (95 per cent confidence interval 1·96 to 15·11); P < 0·001). An algorithm based on recommendations for diagnosis and treatment of neuroendocrine LM according to the localization types was created (Fig. 4). Figure 4 Open in new tabDownload slide Algorithm illustrating diagnostic approach and decision making for treatment of patients with neuroendocrine liver metastases (LM). CgA, chromogranin A; FNB, fine-needle biopsy; CT, computed tomography; MRI, magnetic resonance imaging; NET, neuroendocrine tumour; DOTATOC, 1,4,7,10-tetra-azacyclododecane-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe1Try3-octreotide; PET, positron emission tomography; EHD, extrahepatic disease; CRR, cytoreductive resection; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; PRRT, peptide receptor radionuclide therapy; SIRT, selective internal radiotherapy; LT, liver transplantation; REHD, resection of extrahepatic disease Discussion This study has shown that aggressive treatment of neuroendocrine LM improves outcome; 3- and 5-year survival rates for the entire group were 76·4 and 63·9 per cent, in contrast to 39 per cent21 and 25 per cent13 respectively reported for patients undergoing non-aggressive treatment. Surgical resection with a positive impact on long-term survival was feasible in only a small group of patients, whereas a range of non-surgical options provided excellent palliation in both symptomatic and asymptomatic patients. Many previous studies have advocated aggressive surgery for hepatic metastases of NET with the aim of extending survival13–22. Overall survival after hepatic resection ranges from 46 to 76 per cent at 5 years and 35 to 79 per cent at 10 years14,16–18,21,29. Patients in whom hepatic resection was achievable had a significantly better median overall survival30 and 5-year survival16 than those with unresectable hepatic disease18,19. Although the impact of hepatic resection appears striking, it is difficult critically to evaluate the published experience owing to the limited number of patients eligible for surgical treatment and the heterogeneity of terminology used. In some series only a R0 resection is considered as having curative intent17, whereas in others resection is classified as complete without referring to the R status14,16,20,21,29 or defined as a curative procedure when all visible gross disease was removed31. Elias and colleagues17 even considered patients with peritoneal carcinomatosis to have undergone curative resection when complete elimination of peritoneal seeding and consecutive intraperitoneal chemotherapy were carried out. In a more recent report, however, the same group revised their earlier opinion32. Having a mixture of resections and resections in combination with RFA13,15,19,33 and/or TACE13, or inclusion of patients treated with RFA only in the group considered to be curatively resected31, also hinders the objective evaluation of the curative surgical option. The terminology applied to surgical procedures with palliative intent is even more confusing. The historical recommendation that palliative liver resection is justified only if elimination of at least 90 per cent of the tumour bulk is feasible34 lacks evidence because this procedure has never been compared with less extensive palliative resections. More recently it has been postulated that only patients with less than 50–75 per cent hepatic involvement may benefit from an aggressive surgical approach13,21, and that hepatectomy is justified only if all intrahepatic and extrahepatic metastatic disease can be eliminated completely17. In the present series patients with LM from NET were selected for aggressive treatment based on the localization type of hepatic tumour. Three types with distinct patterns of metastatic spread were identified. The three types of LM did not only differ morphologically, but also with regard to chronological presentation, hormonal activity, CgA and 5-HIAA levels, Ki-67 index and presence of extrahepatic metastases. Resection with curative intent was feasible in only 19·3 per cent of patients, all with solitary LM and therefore included in type I. Histopathological examination confirmed complete (R0) resection in all patients, yielding 3- and 5-year overall survival rates of 100 per cent. These results demonstrate strikingly the prognostic relevance of a R0 resection and correspond well with previously reported results of curative resection18,22,30. It is obvious that not only completeness of surgical resection but also meticulous patient selection and the diverse tumour biology of NET influence the outcome. Because of the volume and extent of hepatic metastases, none of the 96 patients with type II or III LM were candidates for resection with curative intent. The extent to which hepatic involvement of metastatic NET limits the benefit of surgery has been increasingly addressed in recent years13,21. In view of these findings and the effectiveness of less invasive treatment methods, such as RFA, TACE, PRRT and selective internal radiation therapy, either as a single technique or in combination, the authors believe that there is not much room for palliative hepatic resection. Mazzaglia and colleagues35 noted a median survival of 3·9 years after the first RFA treatment in a series of 63 patients in whom curative resection was not possible. Using PRRT, the present authors achieved a partial tumour response or stable disease in 25 and 55 per cent of patients with disseminated LM respectively28. In a group of 46 patients with NET treated with TACE or hepatic artery embolization, Ho et al.36 reported a mean overall survival time of 3·5 years and a progression-free survival of 1·5 years. The beneficial effect of percutaneous liver-directed therapies has been confirmed by Gupta and co-workers37 in a group of 123 patients with metastatic NET; TACE was associated with an overall survival of 31·5 months and a radiological response rate of 50 per cent. When balancing palliative hepatic surgery against novel non-surgical options, it should also be borne in mind that unresectable extrahepatic disease can be expected in more than one-third of patients21,28,35. Liver transplantation is a possibility in a small number of highly selected patients with type II or III unresectable LM. In most recent single-centre studies 5-year overall and disease-free survival rates of 67–90 per cent and 20–48 per cent respectively have been reported27,38,39. Accurate assessment of the full extent of metastatic disease is one of the key issues in deciding on the surgical management of patients with NET, particularly those considered as transplant candidates. SSRS has proved highly effective in detecting additional intrahepatic and/or extrahepatic tumours compared with standard radiological imaging40–42. In accordance with experience of others40,43, SSRS amended the staging and influenced the decision about surgical treatment in more than half of the patients in the present study. In terms of survival, it is not unexpected that type I LM were associated with a significantly better outcome than types II and III because hepatic resection with curative intent was performed in all patients with type 1 metastasis. The authors hypothesize that the three patterns of metastatic spread reflect the diverse biological behaviour of neuroendocrine LM and overlap with the grading system proposed recently for foregut NET44. Based on the mitotic count and Ki-67 index, this grading system includes three tumour categories: G1, G2 and G3. G1 and G2 tumours correspond to well-differentiated NET with different levels of aggressiveness, whereas G3 corresponds to poorly differentiated neuroendocrine carcinoma. In the present series the Ki-67 index differed significantly between the three types of metastasis. In agreement with the present results, Boo and colleagues45 found that a high Ki-67 proliferation index correlated strongly with tumour recurrence and histological differentiation in gastric NET, and proposed that Ki-67 determination should be added to the standard pathological classification of NET. In reference to the WHO classification, the present study demonstrated that type I mainly consists of well-differentiated neuroendocrine carcinoma with a lower malignant potential, whereas types II and III encompass more aggressive, well-differentiated and poorly differentiated neuroendocrine carcinoma. The differences between the three types are presumed to represent true differences in biological behaviour rather than a time bias. The distinct type of hepatic disease evident when the LM were detected initially remained unchanged over the study period. Significant differences in chronological presentation of LM and other features between the three groups further underline the differences in biological aggressiveness. In conclusion, as well as consideration of purely morphological characteristics, attention should be paid to the localization and biological features of LM from NET in order to better assess prognosis and implement patient-tailored management. The management algorithm presented, based on three different types of metastatic spread, regardless of primary tumour, involves multimodal treatments and a stepwise approach, and it is recommended that such patients are managed in specialized centres. Acknowledgements The authors thank Dr F. Weber and Dr V. 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Journal

British Journal of Surgery – Oxford University Press

Published: Jan 21, 2009

Keywords: neoplasm metastasis; neuroendocrine tumors; surgical procedures, operative; neoplasms; liver metastases; liver diseases; chromogranin a; ki-67 antigen; survival rate; hydroxyindoleacetic acid; procedures on liver; lymph nodes; hepatic surgical procedures

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