Liver Metastases of Neuroendocrine Tumors and CCC

Concept

TACE of advanced liver metastases of neuroendocrine tumors (retrospective analysis)

26 (10× carcinoid syndrome, 2× midgut tumors, 7× pancreatic tumors, 2× malignant insulinomas, 1× stomach carcinoid, 4× CUP)

Tumor burden

N = 3, <25 %; N = 11, 25–50 %; N = 6, 50–75 %; N = 6: >75 %

Therapy

20–40 mg doxorubicin in 5 ml lipiodol + 250 mg Gelfoam or PVA microspheres

1–4 procedures

Response rates (%)

PR, 8; SD, 54; PD, 19

Survival

Median survival: 14 mo (after TACE), 54 mo (after diagnosis)

5 y survival (%), 48 (after diagnosis)

Toxicity

4× minor complications (hematoma of the groin, lipiodol in the pancreas, nausea/vomiting)

5× major complications (renal failure, hypotension, liver failure)

Conclusions

In this retrospective study, patients with low (50 %) tumor burden and high (150 %) lipiodol uptake responded better to TACE than end-stage patients

mo month

Fiorentini et al. (2004) [12]

Concept	TACE in liver metastases of neuroendocrine tumors (phase II study)
N	10
Inclusion criteria	Unresectable and chemotherapy refractory
Therapy	IA: 10 mg/m² MMC + 50 mg/m² cisDDP + 30 mg/m² epirubicin followed by 15 mg/ml Gelfoam in 5–10 ml lipiodol
Response rates	CR, 2×; PR, 5×
Survival	Median survival: 22 mo
Toxicity	Abdominal pain, elevation of liver enzymes, liver abscess (N = 1)
Conclusions	Chemoembolization improves the clinical condition of patients with liver metastases. Future therapies will be based on specific tumor biology and will be customized for each individual patient combining different procedures including TACE

Touzios et al. (2005) [17]

Concept	Aggressive management of liver metastases of carcinoids and neuroendocrine tumors of the pancreas (retrospective analysis)
N	153 (84 + 69)
N (liver metastases)	60 (36 + 24)
Inclusion criteria	All relevant pat. (01/1990 bis 07/2004)
Treatment (N = 60)	1. Not aggressive (resection of primary tumors) n = 23
	2. Aggressive
	(a) Resection/ablation (R/A) n = 19
	(b) TACE +/− R/A n = 18
	TACE: cisDDP + doxorubicin + MMC
Survival	Parameter	Not aggressive	Aggressivetreatment
	R/A	TACE +/− R/A	42	28
	Morbidity (%)	25	42	28
	Symptomatic improvement (%)	42	95*	88*
	Median OS (Mo)	20	>96*	50*
	5-OS(%) 25 72* 50*	25	72*	50*
Conclusion	Aggressive management improves survival of the patients, and chemoembolization improves the success rate of this strategy

*p < 0.05

McStay et al. (2005) [20]

Concept	HAI of yttrium 90 (⁹⁰Y)-tetraazacyclododecane tetraacetic acid (DOTA) lanreotide
N	23
Inclusion criteria	Progressive large-volume somatostatin receptor-positive liver metastases
Therapy	1 GBq ⁹⁰Y-DOTA +/− PVA particles
Response rates	PR, 3/19 (16 %); SD, N = 12 (63 %); PD, N = 4 (21 %)
Response rates	Clinical improvement, 61 %
Survival	1 y, 63 %
Toxicity	2× acute renal impairment, abdominal pain, nausea, pyrexia, elevation of liver enzymes (N = 11)
Conclusions	Hepatic intra-arterial injection of 90Y-DOTA-lanreotide is a safe and effective palliative treatment for these patients

Gupta et al. (2005) [13]

Concept	TAE or TACE for liver metastases (retrospective analysis)
N	69 (carcinoid) + 54 (pancreatic islet cell carcinoma)
Therapy	TAE: PVA or Gelfoam
	TACE: chemotherapy followed by embolic material
	In patients with hormonal symptoms: octreotide s.c.
Response rates	Carcinoid: PR, 67 %; MR, 9 %
	TAE: 6× likely to respond (p = 0.002)
	Islet cell Ca: PR, 35 %; MR, 2 %
	TACE vs. TAE: 50 % vs. 25 % (p = 0.06)
Survival	Median survival for patients with carcinoid: 34 mo
	PFS: 23 mo
	1 y, 2 y, 5 y: 95, 69, 29 %
	Median survival for patients with islet cell carcinoma: 23 mo
	PfS: 16 mo
	1 y, 2 y, 5 y: 67, 49, 14 %
Toxicity	Postembolization syndrome (SAE: 9 %); hepatorenal syndrome, N = 7; sepsis, N = 6
Conclusions	Patients with carcinoid tumors had a better outcome than patients with islet cell carcinomas. The addition of intra-arterial chemotherapy to HAE did not improve the outcome of patients with carcinoid tumors, but patients with islet cell carcinomas seemed to benefit

y years

Osborne et al. (2006) [16]

Concept	Selective TAE for liver metastases (retrospective analysis)
N	84 (carcinoid, pancreatic neuroendocrine tumors)
Therapy	PVA (250–355 or 500–700 μm)
Therapy	161 embolization procedures (1–4/patient)
Response rates	PR, 11/23 (48 %); SD, 12/23 (52 %)
Survival	Median survival: 36 mo (after TAE), 44 mo (carcinoid), 31 mo (pancreatic endocrine tm), 15 mo (poorly differentiated tm)
Toxicity	Postembolization syndrome (100 %), nausea, fever, elevation of liver enzymes, severe hypertension (11 %)
Conclusions	Hepatic artery embolization frequently results in clinical and radiographic responses in patients with unresectable liver metastases from carcinoid or pancreatic endocrine tumors

Ho et al. (2007) [14]

Concept	TAE or TACE for liver metastases (retrospective analysis)
N	31 (carcinoid) + 15 (pancreatic islet cell carcinoma)
Therapy	TAE: PVA or Gelfoam (7 procedures)
	TACE: 50 mg cisDDP + 20 mg doxorubicin + 10 mg MMC + lipiodol + PVA or Gelfoam (86 procedures)
	1 cycle (4–6 weeks between application in both lobes)
Response rates	Carcinoid: PR, 5/22 (23 %); MR, 5/22; SD, 7/22 (32 %)
Response rates	Islet cell carcinoma: PR, 2/11 (18 %); MR, 3/11 (27 %); SD, 5/11 (45 %)
Survival	Median survival: 978 d (similar for both diagnostic groups)
	PFS: 23 mo
	1 y, 2 y, 3 y, 4 y, 5 y: 80, 66, 41, 38, 29 % (Carcinoid, 86, 79, 43, 38, 32 %; islet cell carcinoma, 73, 52, 52, 52, 35 %)
Toxicity	Postembolization syndrome (all), 4× death, 2× infection, 1× ulcer
Conclusions	The overall survival time after hepatic artery chemoembolization or HAE among patients with neuroendocrine tumors is approximately 3.5 years. The presence of extrahepatic metastasis or an unresected primary tumor should not limit the use of hepatic artery chemoembolization or HAE

d days

Christante et al. (2008) [11]

Concept	HAI + TACE for liver metastases + octreotide (retrospective analysis)
N	77 (61 carcinoid, 16 islet cell carcinoma)
Therapy	HAI (3 × 4 monthly): 5-FU, followed by
Therapy	TACE: 100 mg cisDDP + 30 mg doxorubicin + 15 mg MMC + lipiodol (4 monthly between application in both lobes)
Response rates	RR, 43 (58 %); SD, 16 (22 %); OR, 80 %
	Carcinoid: PR, 60 %; SD,19 %; OR, 79 %
	Islet cell carcinoma: PR, 50 %; SD, 31 %; OR, 81 %
Survival	Median survival (total): 39 mo
	Carcinoid: 51 mo
	Islet cell carcinoma: 29
	TAE or TACE vs. TAE + TACE (total): 36–44 vs. 39
	Carcinoid: 31–80 vs. 51
	Islet cell carcinoma: 20–23 vs. 29
	PFS (total): 19 mo
	1 y, 5 y (total): 78, 27 %
Toxicity	ND
Conclusions	The addition of hepatic artery chemoinfusion to chemoembolization offers a high probability of clinical benefit to patients who, otherwise, have only limited therapeutic options and a dismal survival

Kennedy et al. (2008) [21]

Concept	Radioembolization (retrospective analysis)
N	148
Therapy	185 procedures (resin ⁹⁰Y-microspheres with medium activity of 1.14 GBq)
Response rates	Imaging response (CT/MRI/OctreoScan): 91 %
	SD: 42/185 (22.7 %)
	PR: 112/185 (60.5)
	CR: 5/185 (2.7 %)
	PD: 9/185 (4.9 %)
Survival	Median survival: 70 mo
	PFS (total): 19 mo
	1, 5 y (total): 78, 27 %
Toxicity	None, 67 %; fatigue, 6.5 %; nausea, 3.2; pain, 2.7 %; ascites, 0.5 %
Conclusions	Radioembolization with 90Y-microspheres to the whole liver or lobe with single or multiple fractions is safe and produces high response rates, even with extensive tumor replacement of normal liver and/or heavy pretreatment

Vogl et al. (2009) [18]

Concept	Comparison of two different TACE protocols (retrospective analysis)
N	48
Therapy	TACE 1: 8 mg/m² MMC + lipiodol + DSM
Therapy	TACE 2: 8 mg/m² MMC + 1,200 mg/m² gemcitabine + lipiodol + DSM (4 monthly between application in both lobes) every 4 weeks
Response rates	RR, 43 (58 %); SD, 16 (22 %); OR, 80 %
	Carcinoid: PR, 60 %; SD, 19 %; OR, 79 %
	Islet cell carcinoma: PR, 50 %; SD, 31 %; OR, 81 %
Survival	Median survival (total): 39 mo
	Carcinoid: 51 mo
	Islet cell carcinoma: 29 mo
	TAE or TACE vs. TAE + TACE (total): 36–44 mo vs. 39 mo
	Carcinoid: 31–80 mo vs. 51 mo
	Islet cell carcinoma: 20–23 mo vs. 29 mo
	PFS (total): 19 mo
	1, 5 y (total): 78, 27 %
Toxicity	TACE 1: mild (nausea, vomiting (28 %), abdominal pain (11 %))
Toxicity	TACE 2: mild (nausea, vomiting (17 %), pain (10 %))
Conclusions	Transarterial hepatic chemotherapy using mitomycin C and gemcitabine can be an effective therapeutic protocol for controlling local metastases and improving survival time in patients with hepatic metastases from neuroendocrine tumors