S. Jelic et al,Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol (2010) 21 (suppl 5): v59-v64.

M. Kudo, Hepatocellular carcinoma 2009 and beyond: from the surveillance to molecular targeted therapy.Oncology. 2008;75 Suppl 1:1-12.
Oliveri RS, Gluud C. Transcatheter arterial embolisation and chemoembolisation for hepatocellular carcinoma (Protocol for Cochrane Review). Cochrane Database Systematic Rev. 2004;2:CD004787.
Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology. 2003;37(2):429-442.
Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: Meta-analysis of randomized controlled trials. Radiology. 2002;224(1):47-54.

A systematic review of RCTs published from 1978 to 2002 identified seven RCTs including a total of 516 patients comparing embolization vs. conservative management, five of which assessing chemoembolization with doxorubicin or cisplatin. Survival benefits were obtained in two studies, one of which identifies treatment response as an independent predictor of survival. Meta-analysis showed a beneficial survival effect of embolization/chemoembolization in comparison with the control group. Overall, this effect may be considered modest, as is expected to occur in advanced neoplasms. Survival benefits were not identified with embolization alone, but the number of individuals analyzed is still low. There is no good evidence for the best chemotherapeutical agent and the optimal re-treatment strategy.

Three small RCT assessing either chemoembolization in combination with percutaneous ablation or lipiodolization have been published in this period A German study reported no survival differences between a combination of chemoembolization and PEI vs. chemoembolization alone in 58 patients. Therapy using reservoir intra-arterial infusion has been employed in patients with advanced HCC with disappointing results. A low-quality study assessing lipiodolization with carboplatin (150 mg/m2) compared with doxorubicin (20 mg/m2) in 65 Chinese patients, showed significant survival benefits favoring the carboplatin arm (16.9 vs. 12.1 months, P = 0.0257). Further studies are required to confirm these data.

In summary, there is no conclusive evidence to consider intrahepatic injection to be better or even equivalent to emblolization; however, alcohol ablation is widely used in the USA. Acetic acid is less frequently used and there are no comparative studies of it versus alcohol. NCCN speaks of “ablation” and thus avoids the issue of the agent (alcohol versus acetic acid);however, it considers “ablation” standard of care.

Brunken C, Topp S, Tesch C, et.al. System Effects and Side Effects of Interstitial Techniques Used in Liver Tissue.  American College of Surgeons 1999; 188, No.6: 636-642.

Usha Dutta (2000) Treatment of hepatocellular carcinoma Journal of Gastroenterology and Hepatology 15 (8), 822–824.

Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 429–42.

Akamatsu M, Yoshida H, Obi S, et al. Evaluation of transcatheter arterial embolization prior to percutaneous tumor ablation in patients with hepatocellular carcinoma: a randomized controlled trial. Liver Int 2004; 24: 625–9.

Becker G, Soezgen T, Olschewski M, et al. Combined TACE and PEI for palliative treatment of unresectable hepatocellular carcinoma. World J Gastroenterol 2005; 11: 6104–9.

http://nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf

The most recent evidence comes from the the SIRFLOX study. The addition of selective internal radiation therapy (SIRT), using Y-90 resin microspheres, to FOLFOX-based first-line chemotherapy in patients with metastatic colorectal cancer (mCRC) and liver-dominant metastases did not improve overall progression-free survival (PFS). It achieved a 7,9 month improvement in median PFS in the liver, representing a 31% reduction in risk of disease progression in the liver with no negative impact on duration of systemic therapy. The toxicities were acceptable and as predicted. The results from the SIRFLOX study were presented at the 2015 ASCO Annual Meeting.

The NCCN Guidelines (Version 3.2015) on Colon Cancer states: “Some institutions
use arterially directed embolization using yttrium-90 microspheres in select patients
with chemotherapy resistant/refractory disease, (not first line) without obvious systemic disease, and with predominant hepatic metastases (category 3)”. Category 3 is based on any
level of evidence, there is major NCCN disagreement that the intervention is
appropriate).

Gibbs P, Heinemann V, Sharma N, et al. SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 + selective internal radiation therapy (SIRT) ± bev in patients (pts) with metastatic colorectal cancer (mCRC). Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.

Michl M, Haug AR, Jakobs TF, Paprottka P, Hoffmann RT, Bartenstein P, Boeck S, Haas M, Laubender RP, Heinemann V. Radioembolization with Yttrium-90 microspheres (SIRT) in pancreatic cancer patients with liver metastases: efficacy, safety and prognostic factors. Oncology. 2014;86(1):24-32.

Gary W. Nace et al, Yttrium-90 Radioembolization for Colorectal Cancer Liver Metastases: A Single Institution Experience International Journal of Surgical Oncology Volume 2011 (2011), Article ID 571261

D. L. Bartlett, J. Berlin, G. Y. Lauwers, W. A. Messersmith, N. J. Petrelli, and A. P. Venook
Chemotherapy and Regional Therapy of Hepatic Colorectal Metastases: Expert Consensus Statement
Ann. Surg. Oncol., October 1, 2006; 13(10): 1284 – 1292.

Systemic treatment for NETs includes therapy with somatostatin analogs, interferon-alfa and cytotoxic agents. In addition, other agents can be useful, including loperamide for diarrhea or H1 or H2 blockers for histamine-secreting tumours. Interferon-alfa may be considered in selected cases to control clinical symptoms of hormone hyper-secretion. Symptomatic and biochemical responses are reported in 50% of patients with tumour reduction in 10-15%. There has been biochemical response in 40–60% of patients, symptomatic improvement in 40–70% of patients, and significant tumour shrinkage in a median of 10–15% of patients. In combination with somatostatin analogues, the effect may be enhancedSide effects include flu-like symptoms and autoimmune phenomena (e.g. thyroiditis). It appears to be especially effective  when combined with symptomatic treatment of diarrhea.

In one prospective trial of 68 patients with liver metastases who were randomized to octreotide (100 micrograms twice daily, increased to 200 micrograms three times daily for persistent carcinoid symptoms) with or without IFNa, both treatments were equally effective at reducing urinary 5-HIAA levels. Patients receiving combined therapy had a significantly reduced risk of tumor progression when compared to patients receiving octreotide alone, suggesting that the addition of IFN had a significant antitumor effect. Other studies had less impressive results and soem controversy remains. However, interferon is a category 2B recommendation by NCCN (CARC-5)

http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Gastrointestinal/12+Neuroendocrine/default.htm

J K Ramage et al,Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours Gut 2005;54:iv1-iv16

Early studies have made this claim. In octreotide LAR drug registration trial, levels were in sub-optimal range for complete receptor saturation. Approximately 40% of patients required the use of “rescue “ medication (subcutaneous aqueous octreotide at doses of 100-500 micrograms three times a day) several days per week.Subcutaneous octreotide is commonly used for “rescue”, for the control of symptoms during early phases of LAR therapy (while blood levels are increasing) and during specific times like pre, intra and post-operatively to prevent carcinoid crisis. For subcutaneous octreotide to be effective it would need to be given as a subcutaneous shot every 4-6 hours. It is claimed that the oscilaltion of levels causes a decrease in effectiveness.When a drug is given by bolus injection, the blood levels rise rapidly, and this is associated with progressive binding of the drug to the cell membrane receptor. When the drug levels fall, the drug comes off the receptor and the drug no longer has an effect.

Continuous subcutaneous infusions of octreotide acetate have been used by some physicians to take advantage of the rapid absorption of octreotide by the subcutaneous tissues. In this scenario the blood levels of octreotide begin to rise when the pump is turned on and continue to do so until the “steady state” is achieved—usually about 2-4 hours. Likewise, following the cessation of the subcutaneous infusion of octreotide, blood levels begin to fall and are back to insignificant levels after 6-8 hours (depending on dose used).

Newer studies have questioned this rationale and comparative study found both methods to be eqivalent. There is no credible emdical evidence that of
LA Sandostatin being inferior to pumps and continuous infusion and I consider the latter to be experimental.

Rubin J, Ajani J, Schirmer W, Venook AP, Bukowski R, Pommier R, Saltz L,
Dandona P, Anthony L. Octreotide acetate long-acting formulation versus open-label
subcutaneous octreotide acetate in malignant carcinoid syndrome. J. Clin. Oncol.;
17(2): 600-6, 1999 .

Gunn SH, Schwimer JE, Cox M, Anthony CT, O’Dorisio MS, Woltering EA.
In vitro modeling of the clinical interactions between octreotide and 111In-pentetreotide: is there evidence of somatostatin receptor downregulation?J Nucl Med. 2006 Feb;47(2):354-9.

Biermasz NR, van den Oever NC, Frölich M, Arias AM, Smit JW, Romijn JA, Roelfsema F.Sandostatin LAR in acromegaly: a 6-week injection interval suppresses GH secretion as effectively as a 4-week interval.Clin Endocrinol (Oxf). 2003 Mar;58(3):288-95.

Data from the study, RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors), were first presented last year at the 12th World Congress on Gastrointestinal Cancer in Barcelona. Regulatory submissions for everolimus to treat this patient population are underway worldwide. Results from the trial showed that everolimus more than doubled median PFS from 4.6 to 11.0 months when compared with placebo and reduced the risk of cancer progression by 65% (hazard ratio [HR] =0.35 [95% confidence interval (CI), 0.27 to 0.45]; p<0.001) in patients with advanced pancreatic NET. After 18 months, 34% of patients treated with everolimus (95% CI, 26 to 43) were alive and progression-free versus 9% of those treated with placebo (95% CI, 4 to 16), showing a more prolonged benefit for patients treated with everolimus.

On February 9, 2011, The US Food and Drug Administration (FDA) has granted everolimus priority review designation for the application of advanced NET of gastrointestinal (GI), lung or pancreatic origin based on results of RADIANT-3 and another Phase III trial, RADIANT-2.

The indication also says that the safety and effectiveness of AFINITOR® in the treatment of patients with carcinoid tumors have not been established. however, several recent studies suggest that it is effective also in the carcinoid syndrome(Pavel, Rindi, Ring etal). NCCN lists it for carcinoid.

Yao, James C., Lombard-Bohas, Catherine, Baudin, Eric, Kvols, Larry K., Rougier, Philippe, Ruszniewski, Philippe, Hoosen, Sakina, St. Peter, Jessica, Haas, Tomas, Lebwohl, David, Van Cutsem, Eric, Kulke, Matthew H., Hobday, Timothy J., O’Dorisio, Thomas M., Shah, Manisha H., Cadiot, Guillaume, Luppi, Gabriele, Posey, James A., Wiedenmann, Bertram Daily Oral Everolimus Activity in Patients With Metastatic Pancreatic Neuroendocrine Tumors After Failure of Cytotoxic Chemotherapy: A Phase II Trial
J Clin Oncol 2010 28: 69-76

Yao JC. et al “A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus in patients with advanced pancreatic neuroendocrine tumors (PNET)(RADIANT-3)” ESMO 2010; Abstract LBA 9.

Pavel M, et al “A randomized, double-blind, placebo-controlled, multicenter phase III trial of everollimus + octreotide versus placebo + octreotide LAR in patients with advanced neuroendocrine tumors (NET)(RADIANT-2)” ESMO 2010; Abstract LBA 8.

Pavel M, et al “Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumors associated with carcinoid syndrome: a randomized, placebo-controlled, phase 3 study” Lancet 2011140-6736(11)61742-x.

Rindi G, Caplin M “mTOR inhibitor therapy for patients with carcinoid” Lancet 2011; DOI: 10.1016/S0140-6736(11)61789-3.

Ping Gu, Treatment of Liver Metastases in Patients with Neuroendocrine Tumors of Gastroesophageal and Pancreatic Origin International Journal of HepatologyVolume 2012 (2012)

Patients with distant metastatic disease have been reported to be cured by resection of all tumor. However, long-term follow-up of these individuals suggests that these patients probably will recur. Resection of the tumour can be curative. In widely metastatic disease, debulking and bypassing procedures can facilitate medical treatment. Debulking, laser treatment of metastases, radio-frequency ablation and embolization of liver metastases (either plain or combined with cytotoxic agents), liver resection, and, more recently, liver transplant (in selected patients) are possible options.

J. Maroun, MD,* W. Kocha, MD,† L. Kvols, MD,‡ G. Bjarnason, MD,§ E. Chen, MD,|| C. Germond, MD,# S. Hanna, MD,** P. Poitras, MD,†† D. Rayson, MD,‡‡ R. Reid, MD,§§ J. Rivera, MD,|||| A. Roy, MD,†† A. Shah, MD,## L. Sideris, MD,|| L. Siu, MD,*** and R. Wong, MDGuidelines for the diagnosis and management of carcinoid tumours. Part 1: The gastrointestinal tract. A statement from a Canadian National Carcinoid Expert Group Curr Oncol. 2006 April; 13(2): 67–76.

Somatuline is specifically indicated for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. However, in Europe it is also approved for carcinoid syndrome.

Unfortunately, about 15% of carcinoid patients cannot tolerate Sandostatin or cannot receive IM injections and it will not help them. Subcutaneous monthly (there is also an IM formulation fore very 1-14 day injection) Somatuline would appear to be a resonable option for such patients. In the USA, it is still in a study NCT00774930: An Efficacy and Safety Study of Somatuline Depot (Lanreotide) Injection to Treat Carcinoid Syndrome. Two open multicentre studies in small groups of adult patients (n = 39, n = 18) have been conducted with lanreotide LA for the management of carcinoid syndrome; one is published in full and the other as an abstract report. In both of these studies lanreotide LA significantly reduced the symptoms of flushing and diarrhoea.

Ruszniewski P, Ducreux M, Chayvialle JA, Blumberg J, Cloarec D et al. Treatment of the carcinoid syndrome with the long-acting somatostatin analogue lanreotide: a prospective study in 39 patients. Gut 1996; 39: 279-283.

Kvols L, Woltering E (2006). “Role of somatostatin analogs in the clinical management of non-neuroendocrine solid tumors”. Anticancer Drugs 17 (6): 601–8.

Susini C, Buscail L (2006). “Rationale for the use of somatostatin analogs as antitumor agents”. Ann Oncol 17 (12): 1733–42.

K. Öberg et al, Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system Ann Oncol (2004) 15 (6): 966-973.

van Eeden S, Offerhaus GJ, Hart AA, et al. (December 2007). “Goblet cell carcinoid of the appendix: a specific type of carcinoma”. Histopathology 51 (6): 763–73

Goblet cell carcinoid tumors of the appendix: An overview World J Gastrointest Oncol. 2010 June 15; 2(6): 251-258.

First I discuss Octerotide scan. There are a number of case reports of this modlaity that suggest effectiveness. OctreoScan, using octreotide (Sandostatin) tagged with radiolabeled 111 Indium-pentetreotide is supported by many reprots ans is an FDA approved modality. Indium In-111 pentetreotide is an agent for the scintigraphic localization of primary and metastatic neuroendocrine tumors bearing somatostatin receptors.
Treatment with high dose IN-111 often follows localization. Anthony and others have presented large case series suggesting effectiveness but studies are still ongoing, including: Safety and Efficacy Study of In-111 Pentetreotide to Treat Neuroendocrine Tumors
This study is currently recruiting participants. , NCT00442533. The purpose of this study is to determine if High-dose 111In-Pentetreotide known as NeuroendoMedix®, is an effective treatment for Neuroendocrine Tumors.

S.. A. Kaltsas, G. M. Besser, and A. B. Grossman
The Diagnosis and Medical Management of Advanced Neuroendocrine Tumors
Endocr. Rev., June 1, 2004; 25(3): 458 – 511.

Lowell B. Anthony, Eugene A. Woltering, Gregory D. Espenan, Michele D. Cronin, Tom J. Maloney, Kevin E. McCarthy
Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies
Seminars in Nuclear Medicine – April 2002 (Vol. 32, Issue 2, Pages 123-132
S.. A. Kaltsas, G. M. Besser, and A. B. Grossman
The Diagnosis and Medical Management of Advanced Neuroendocrine Tumors
Endocr. Rev., June 1, 2004; 25(3): 458 – 511.

P. L. Filosso, E. Ruffini, A. Oliaro, E. Papalia, G. Donati, and O. Rena
Long-term survival of atypical bronchial carcinoids with liver metastases, treated with octreotide
Eur. J. Cardiothorac. Surg., May 1, 2002; 21(5): 913 – 917.

nccn.org, carcinoid

Buscombe, J. R.; Caplin, M. E.; Hilson, A. J.W Treating disseminated NETs with high activity In-111 Octreotide.  Nuclear Medicine Communications. 21(6):567, June 2000.