Cancer Treatment

IN-111 octreotide to treat carcinoid

GThe most important treatment modality for the carcinoid syndrome (flushing, diarrhea etc) due  to carcinoid secreted hormones)  is octreotide, a synthetic hormone similar in structure to the naturally-occurring hormone, somatostatin. Octreotide, like somatostatin, binds to receptors on the cells of carcinoid tumors and inhibits the manufacture and release of tumor hormones. Octreotide is very effective in controlling the symptoms of flushing and diarrhea that are part of the carcinoid syndrome. Octreotide has been found to reduce the excretion of 5-HIAA in some patients. Octreotide also has been found to slow the growth of carcinoid tumors, and, in a few patients, even reduce the size of the tumors and their metastases. Treatment with octreotide prior to surgery is important in order to prevent life-threatening carcinoid crisis in patients with carcinoid syndrome undergoing surgery.

Octreotide generally is well tolerated. Side effects include nausea, headache, dizziness, abdominal pain, diarrhea, elevated blood sugar levels, and gallstones. The major drawback of octreotide is the need to inject it under the skin three times daily. Other longer-acting synthetic hormones resembling somatostatin (for example, lanreotide) can be given intramuscularly every two weeks, but they are not yet available in the U. 

This patient received this therapy but what is being proposed is high-dose IN-111 octreotide as therapy.
There are a number of cse reports of this modlaity that suggest effectiveness and tumor regression; however, there have been no randomized studies and it remains an unproven treatment. In addition, this patient appears to be enrolled into a clincail study of this treatment.

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.

http://www.liebertonline.com/doi/pdf/10.1089/cbr.2005.20.215?cookieSet=1

Interferon for neuroendocrine (carcinoid) cancer

Lay Sumamry: Interferon is an accepted treatment for carcinoid.

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.

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

nccn.org, neuroendocrine

Revised: 2.19.08

SIRT for hepatic mets of colon cancer

Lay Sammary: SIRT is a new promising treatment for liver cancer or metastases to the liver. Most insurers consider it investigational and active research is ongoing.

SIRT -- a therapy that consists of millions of microscopic, radioactive glass microspheres (20-30 microns diameter) -- is infused into the arteries that feed inoperable liver tumors or metastatic cancer to the liver, bathing the malignancy in high levels of extremely localized radiation. In some studies of highly selected pateints the response rates and stabilization rates ranged between 20-40 percent. Selective internal radiation therapy (SIRT) is used to treat non-resectable hepatic metastases secondary to colorectal cancer, usually in combination with hepatic arterial chemotherapy. The standard method of treatment for patients with liver metastases from colorectal cancer is surgical resection, but fewer than 10% of patients are suitable for operation. For patients with non-resectable hepatic metastases, treatment options include systematic chemotherapy, radiotherapy, cryotherapy, alcohol injection and laser photocoagulation. Radioactive spheres are injected using a syringe into the hepatic artery via a trans-femoral catheter or a permanently implanted port with a catheter to the hepatic artery.

Currently 2 commercial forms of yttrium-90 microspheres are available: TheraSpheres® (Theragenics;Atlanta, GA) and SIR-Spheres® (Sirtex Medical Limited; Lake Forest, IL). Non-commercial forms are used mostly outside the United States. Note also that the U.S. Food and Drug Administration (FDA) granted a premarket approval of SIR-Spheres®, for use in combination with 5-floxuridine (5-FUDR) chemotherapyby HAI, to treat unresectable hepatic metastases from colorectal cancer. Microspheres are taken up by the microvasculature within the liver. A limited randomized trial suggests that this treatment is well tolerated. There are also trials that suggest incresed survival but these are not blinded randomized trials. A Harvard Pilgrim 2005 TEC Assessment found the procedure to be investigational. FDA approval of a technology does not make its apllications automaitcally not investigational and unlike medications is not binding on a plan. The most recent guidelines on this subject is from 2006 and is referenced.

It is beng investigated in a phase II trial, NCT00511862,TheraSphere for the Treatment of Liver Metastases: An Open Label Trial of TheraSphere in Patients With Liver Metastases From Primary Colorectal Cancer, Neuroendocrine Cancer or Non-Colorectal/Non-Neuroendocrine Cancer .

NICE Guidelines - http://www.nice.org.uk/pdf/ip/IPG093guidance.pdf

Australian Guidelines - http://www.tripdatabase.com/spider.html?itemid=282101

Guy Van Hazel et al, Randomised phase 2 trial of SIR-Spheres® plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer J. Surg. Oncol. Volume 88, Issue 2 , Pages 78 - 85

W. Oyen, L Bodei, F Giammarile, H. Maecke, J Tennvall, M Luster, and B Brans
Targeted therapy in nuclear medicine--current status and future prospects
Ann. Onc., April 13, 2007; (2007)

L . Jiao , T . Szyszko , A . Al-Nahhas , P . Tait , R . Canelo , G . Stamp , H . Wasan , C . Lowdell , R . Philips , A . Thillainayagam Clinical and imaging experience with yttrium-90 microspheres in the management of unresectable liver tumours . 
European Journal of Surgical Oncology , Volume 33 , Issue 5 , Pages 597 - 602, 2007

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.

Intrahepatic therapies ablative therapies

Percutaneous ablation is a commonly used modality of treatment when resection is not possible for HCC. Other local modalities are radiofrequency ablation or chemo embolization. When direst intratumor injection is used, alcohol is most commonly used and it is FDA approved for this purpose. However, acetic acid is more potent in animal models. Only a few studies tested the various modlaities against one another.

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

Liver Cancer/TACE

The prognosis for patients with unresectable hepatocellular carcinoma (HCC) tumors is extremely poor. Even in the case of small nodular lesions detected by US screening, patients receiving no treatment showed a mean 3-year survival rate of 12%.. Transcatheter arterial chemoembolization (TACE), most frequently performed by intra-arterially injecting an infusion of antineoplastic agents mixed with iodized oil (Lipiodol), has been extensively used in the treatment of large HCC tumors. However, although massive tumor necrosis can be demonstrated in most cases, a complete necrosis of the tumor has rarely been achieved with TACE, since residual tumor can be found in a non-negligible number of the treated lesions. It si, however, useful prior to liver transplantation.
TACE was found mostly effective in nodules less than 4 cm in diameter, with a thick tumor capsule. In fact, small, encapsulated HCC are almost completely fed by hepatic arterial blood and therefore highly responsive to hepatic arterial embolization. On the contrary, in unencapsulated tumors or in tumors showing extracapsular invasion of neoplastic cells, TACE often fails to induce complete necrosis since tumor cells, either unimpeded by the absence of a capsule or spreading across the capsule itself, invade the adjacent liver parenchyma, thus obtaining additional blood supply from the sinusoidal portal system.
Large HCC lesions can be more effectively treated with combined TACE and PEI. In fact, alcohol diffusion is easier after the occurrence of the necrotic changes produced by TACE, thus allowing the intranodular injection of larger amounts of ethanol. Moreover, after arterial embolization, the normal wash-out of the injected ethanol is more difficult in the tumorous area, resulting in longer retention of the substance. The combination of TACE and PEI seems to be a highly effective treatment for large HCC also in the instances when daughter nodules are associated with a main tumor. The presence of the capsule significantly enhances the chances of success and should be considered an important requirement when selecting patients to be submitted to TACE and PEI.
According to available literature, chemoembolization (TACE) may be indicated for symptomatic treatment of functional neuroendocrine cancers (i.e., carcinoid tumors and pancreatic endocrine tumors) involving the liver, in persons with adequate hepatic function (bilirubin < 2 mg/dl, absence of ascites; no portal vein occlusion; and tumor involvement of < 65 % of liver). For carcinoid tumors, TACE is indicated only in persons who have failed systemic therapy with octreotide to control carcinoid syndrome (e.g., debilitating flushing, wheezing and diarrhea). The safety and effectiveness of more than 4 TACE procedures is unknown.
For unresectable, primary HCC, TACE is indicated in persons with small encapsulated nodules (less than 4 cm in diameter), no evidence of extrahepatic metastases, and with adequate hepatic (serum bilirubin concentration < 2.9 mg/dl) and renal function (serum creatinine < 2.0 mg/dl).

Ramsey DE, Kernagis LY, Soulen MC, Geschwind JF. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol. 2002;13(9 Pt 2):S211-S221.
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.