Cancer Treatment

Goblet cell carcinoid

Goblet cell carcinoid (GCC) also known as crypt cell consists of a neuroendocrine component and a conventional carcinoma. Since it was identified in 1969 there has been greater understanding of this disease but issues remain regarding its histogenesis (the formation and differentiation of tissues), nomenclature, and management, particularly amongst pathologists and surgeons. There are no recommendations or evidence based guidelines for this rare cancer. A recent(2010) review had been published.

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.

 

Somatuline Depot (lanreotide acetate) for carciniod syndrome.

Somatuline Depot (lanreotide acetate) is an injectable, sustained-release formulation of lanreotide, an octapeptide somatostatin analog that inhibits Insulin-like growth factor-1 (IGF-1) and growth hormone (GH).

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.

Debulking carcinoid

Surgery is the only potentially curative treatment for patients with carcinoid tumors. Patients with localized disease even with lymph node metastases can be resected for potential cure. It is no known how to best optimally follow competely resected non-metastatic tumors. these patients. NCCN says: "Conaiser abdominopelvic CT or MRI 3-12 months post resection: Otherswise followup is clinical and:"consider markers".
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.

Afinitor for carcinoid

Everolimus has been approved by the US Food and Drug Administration (FDA) as the first oral, daily therapy (5 mg and 10 mg tablets) to treat advanced kidney cancer after failure of treatment with sunitinib or sorafenib. New data demonstrate that treatment with Afinitor® (everolimus) in combination with Sandostatin® LAR® (octreotide acetate suspension for injection) and Afinitor monotherapy may have the potential to stabilize tumour growth in patients with advanced pancreatic neuroendocrine tumours (NET).

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.

Yao, et al. A Phase II Trial of Daily Oral RAD001 (Everolimus) in Patients With Metastatic Pancreatic Neuroendocrine Tumours (NET) After Failure of Cytotoxic Chemotherapy. 33rd European Society for Medical Oncology Congress, Stockholm, Sweden.

Yao, et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. New Eng J Med 2011;364:514-23.

Yao, et al. Everolimus versus placebo in patients with advanced pancreatic neuroendocrine tumors (pNET) (RADIANT-3). 12th World Congress on Gastrointestinal Cancer, Barcelona. July 1, 2010.

Intermittent versus continued infusions of octreotide.

Some claim that LA Sandostatic absorbtion is only 68% and octreotide delivered by pump is more effective. This is not proven, to my knowledge.

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.

IN-111 octreotide to scan and treat carcinoid

The 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.

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.

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.

However, NCCN)2011 CARC-5) only lists octreotide and there are no guidelines to my knowledge that recommend combined therapy.

 

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 patients 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. SIRT using SIR-Spheres microspheres is approved for use in Australia, New Zealand, the United States of America. 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 increased 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 applications automatically not investigational and unlike medications is not binding on a plan. . The most recent guideline on this subject is referenced. It is being investigated in a number of trials.

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

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

Hendlisz, A., Van den Eynde, M., Peeters, M., Maleux, G., Lambert, B., Vannoote, J., et al. (2010) Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. Journal of Clinical Oncology, 28 (23), 3687 – 3694

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)

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.

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.
There are no definitive randomized studies but various reviews and meta-analyses suggest that it is effective. 

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.