Cancer Treatment

FDG PET for neuroendocrine cancer.

 

FDG PET is not all that sensitive in neuroendocrine cancers(NET). One study revealed that for neuroendocrine tumors, 18F-FDOPA was more accurate (sensitivity, 100%; specificity, 91%) in the detection of skeletal lesions than octreotide scintigraphy or CT but was insensitive (sensitivity, 20%; specificity, 94%) in the lung, ostensibly because of respiratory motion during image acquisition. Octreotide scintigraphy yielded its best results in the liver (sensitivity, 75%; specificity, 100%); however, it was less accurate than PET in all organs. However, 18F-FDOPA PET is less sensitive than FDG PET and standard imaging procedures for the staging of small cell lung cancer. Popperl et al recommends that 18F-FDG should be preserved for less differentiated tumors, while amine precursors and somatostatin analogs should be implemented in the diagnostic process of well-differentiated NET. NCCN on p. MS-12 does not recommend FDG PET.

Imaging of Advanced Neuroendocrine Tumors with 18F-FDOPA PET
Alexander Becherer, Monica Szabó, Georgios Karanikas, Patrick Wunderbaldinger, Peter Angelberger, Markus Raderer, Amir Kurtaran, Robert Dudczak, and Kurt Kletter J Nucl Med 45: 1161-1167

D. J. A. Margolis, J. M. Hoffman, R. J. Herfkens, R. B. Jeffrey, A. Quon, and S. S. Gambhir
Molecular Imaging Techniques in Body Imaging
Radiology, November 1, 2007; 245(2): 333 - 356.

Becherer A, Szabo M, Karanikas G, et al. Imaging of advanced neuroendocrine tumors with (18)F-FDOPA PET. J Nucl Med 2004;45:1161–1167.

Jacob T, Grahek D, Younsi N, et al. Positron emission tomography with [(18)F]FDOPA and [(18)F]FDG in the imaging of small cell lung carcinoma: preliminary results. Eur J Nucl Med Mol Imaging 2003;30:1266–1269.

Gabriele Pöpperl PET and PET–CT in Neuroendocrine Tumors Medical Radiology, 2009, Part 5, 471-480

Katrina Ray Imaging: FDG-PET predicts neuroendocrine tumor survival Nature Reviews Clinical Oncology 7, 184 (April 2010)

 

Liver transplantation for metastatic neuroendocrine cancer

Liver transplantation for the treatment of metastatic neuroendocrine tumors (NETs) has a several
decade history and results in an occasional cure. The reported experience with transplantation for
NETs is limited to about 150 cases with widely varying results and few 5-year disease-free
survivors. Liver transplantation is in itself a morbid procedure that requires immunosupresson.
According to a 2010 Consensus recommendation, liver transplantation can be considered in
young patients (below 50 years of age) when the primary tumour originates in the
gastrointestinal tract, is drained by the venous portal system, and has been previously removed
with curative intent, and when disease progression is controlled for at least 6 months before
transplantation. NCCN does not list liver transplantation as an appropriate option in its 2012
guideline.

I found the following statement from the Caring for Carcinoid Foundation: http://www.caringforcarcinoid.org/neuroendocrine-cancer/pancreatic-neuroendocrine-cancer/treatment-and-drugs.

"Currently, there is little clinical evidence on the results of radical, two-part liver resections and orthotopic liver transplantation.  Due to the lack of clinical evidence, the benefit of these procedures, in particular OLT, has yet to be determined."

Lang, Oldhafer, Weimann, Schlitt, Scheumann, Flemming, Ringe, & Pichlmayr,  Liver transplantation for metastatic neuroendocrine tumors ANNALS OF SURGERY 225 (4): 347-354, 1997

nccn, Neuroendocrine, 2012
Kocha W, Maroun J, Kennecke H, Law C, Metrakos P, Ouellet JF, Reid R, Rowsell C, Shah A,
Singh S, Van Uum S, Wong R.
Consensus recommendations for the diagnosis and management of well-differentiated
gastroenterohepatic neuroendocrine tumours: a revised statement from a Canadian National
Expert Group.Curr Oncol. 2010 Jun;17(3):49-64.
Florman S, Toure B, Kim L, Gondolesi G, Roayaie S, Krieger N, Fishbein T, Emre S, Miller C,
Schwartz M.
Liver transplantation for neuroendocrine tumors.J Gastrointest Surg. 2004 Feb;8(2):208-12.
Y. Patrice Le Treut, M.D.,* Jean R. Delpero, M.D.,* Bertrand Dousset, M.D.,et al, Results of
Liver Transplantation in
the Treatment of Metastatic Neuroendocrine Tumors A 31-Case French Multicentric Report
ANNALS OF SURGERY

 

Liver transplantation for neuroendocrine cancer.

Liver transplantation for the treatment of metastatic neuroendocrine tumors (NETs) has a severald ecade history and results in an occasional cure. The reported experience with transplantation for NETs is limited to about 150 cases with widely varying results and few 5-year disease-free survivors. According to a 2010 Consensus recommendation, "liver transplantation can be considered in young patients (below 50 years of age) when the primary tumour originates in the gastrointestinal tract, is drained by the venous portal system, and has been previously removed with curative intent, and when disease progression is controlled for at least 6 months before transplantation." NCCN does not list liver transplantation as an appropraite option in its 2012 guideline.

nccn, Neuroendocrine, 2012

Kocha W, Maroun J, Kennecke H, Law C, Metrakos P, Ouellet JF, Reid R, Rowsell C, Shah A, Singh S, Van Uum S, Wong R.
Consensus recommendations for the diagnosis and management of well-differentiated gastroenterohepatic neuroendocrine tumours: a revised statement from a Canadian National Expert Group.Curr Oncol. 2010 Jun;17(3):49-64.

Florman S, Toure B, Kim L, Gondolesi G, Roayaie S, Krieger N, Fishbein T, Emre S, Miller C, Schwartz M.
Liver transplantation for neuroendocrine tumors.J Gastrointest Surg. 2004 Feb;8(2):208-12.

Y. Patrice Le Treut, M.D.,* Jean R. Delpero, M.D.,* Bertrand Dousset, M.D.,et al, Results of Liver Transplantation in
the Treatment of Metastatic Neuroendocrine Tumors A 31-Case French Multicentric Report ANNALS OF SURGERY
Vol. 225, No. 4, 355-364

Sutent for neuroendocrine and carcinoid cancer

Evidence supporting Sutent of neuroendocrine cancer cancer is was limited but a recent phase III trial was encouraging. 

 A Phase III study in 2008   concluded that Sunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. An editorial by Bajetta et al inm teh Journal of CLinical Oncology questioend whether results for neuroendocrine cancer can be generalized to the more benign carcinoid subtypes. The Phase III clinical trial was among 171 patients who had experienced cancer progression. Half the patients were treated with Sutent, and half were treated with a placebo.

• Progression-free survival was 11.4 months among patients treated with Sutent and 5.5 months among patients treated with placebo.
• Patients treated with Sutent also experienced better overall survival than patients treated with placebo.
• The most common serious side effect of Sutent was neutropenia (a low white blood cell count), which affected 12% of patients.

These results suggest that Sutent may improve outcomes among patients with advanced pancreatic neuroendocrine tumors. This study was publisehd in the NEJM of February 10, 2011 but NCCN has not incorporated the recommendation for Sutent as of March 2nd, 2011. In December 2010,  he European Commission has approved SUTENT® (sunitinib malate) for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors (NET) with disease progression in adults. In May 2011, U.S. Food and Drug Administration (FDA) has approved SUTENT® (sunitinib malate) as the first anti-VEGF therapy to treat progressive, well-differentiated pancreatic neuroendocrine tumors (NET) in patients with unresectable locally advanced or metastatic disease.

References:

Raymond E, Niccoli-Sire P, Bang Y et al. Updated results of the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of advanced pancreatic neuroendocrine tumors (NET). Presented at the 2010 ASCO Gastrointestinal Cancers Symposium. January 22-24, 2010, Orlando, FL. Abstract 127.

Emilio Bajetta, Valentina Guadalupi, Giuseppe Procopio, Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors
JCO Jan 10, 2009:319-320

Matthew H. Kulke, Heinz-Josef Lenz, Neal J. Meropol, James Posey, David P. Ryan, Joel Picus, Emily Bergsland, Keith Stuart, Lesley Tye, Xin Huang, Jim Z. Li, Charles M. Baum, Charles S. Fuchs Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors JCO July 10, 2008 vol. 26 no. 20 3403-3410
 Kulke MH, Lenz H-J, Meropol NJ, et al: Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26:3403-3410, 2008

Afinitor for neuroendocrine cancer

There is evidence that the MTOR pathway plays an important role in renal cell cancer. It is also effective in neuroendocine cancer. Treatment with Afinitor® (everolimus) Tablets in combination with Sandostatin® LAR® (octreotide) produced good results in a study presented  at the 11th World Congress on Gastrointestinal Cancer in Barcelona, Spain, in 2009.84% of patients with advanced pancreatic neuroendocrine tumors (NET) who took Afinitor® combined with Sandostatin® LAR® experienced tumor shrinkage. It is now listed by NCCN. 

AFINITOR® is indicated for the treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of AFINITOR® in the treatment of patients with carcinoid tumors have not been established.

RADIANT-1 (RAD001 In Advanced Neuroendocrine Tumors) was a Phase II study of 160 patients with pancreatic NET resistant to treatment with cytotoxic chemotherapy. The final analysis shows that patients who received Afinitor in combination with Sandostatin LAR, an approved treatment for symptom control in certain types of NET, remained progression-free for a median of 16.7 months, nearly four additional months since the first analysis was reported. In addition, 84% of patients receiving combination therapy experienced a decrease in tumor size. Patients who took Afinitor monotherapy remained progression-free for 9.7 months and nearly 60% of patients experienced a decrease in tumor size.Furthermore, the results of RADIANT-1 were evaluated to explore biomarkers that may help identify the patients most likely to benefit from treatment with Afinitor. An analysis of the study data showed that patients who demonstrated an early response on chromogranin A (CgA) and neuron-specific enolase (NSE) levels experienced longer time without disease progression compared to patients who did not have an early response on CgA and NSE levels. An update was published in 2010 Journal of Clinical Oncology.
More recently, Radiant 2 Phase III study of Afinitor® (everolimus) in combination with Sandostatin® LAR® (octreotide acetate for injectable suspension) extended median progression-free survival (PFS), or time without tumor growth, in patients with advanced neuroendocrine tumors (NET) compared to taking octreotide LAR alone. The study was presented at the 35th European Society for Medical Oncology (ESMO) Congress.

RADIANT-3, a Phase III trial study evaluated the potential of Afinitor plus best supportive care to extend progression-free survival (PFS) and reach overall survival (OS), as well as to examine the biomarker CgA as a secondary objective. Results from the RADIANT-3 trial, which were also presented at the ESMO Congress, show that everolimus more than doubled median time without tumor growth from 4.6 to 11.0 months when compared with placebo in patients with advanced pancreatic NET (hazard ratio=0.35 [95% confidence interval, 0.27 to 0.45]; p<0.0001). Findings from this study were also presented earlier this year at the 12th World Congress on Gastrointestinal Cancer in Barcelona.However, PFS goals based on central radiologic review of the data (p=0.026 versus p=0.024 predefined) were not met.

Yao, et al. Daily Oral Everolimus Activity in Patients with Metastatic Pancreatic Neuroendocrine Tumors After Failure of Cytotoxic Chemotherapy: A Phase II Trial. 11th World Congress on Gastrointestinal Cancer, Barcelona, Spain.

Gunter K, Perren A, Heitz PU The Gastroenteropancreatic Neuroendocrine Cell System and Its Tumors: The WHO Classification. Ann. of the New York Acad of Sci. 2006 Jan 16 2005;1014:1

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.

Yao et al. A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) (RADIANT-3). 35th European Society for Medical Oncology Congress. October 9, 2010.

Temodar and Xeloda for neuroendocrine cancer

Most of the available information about Xeloda and Temodar combination is in abstract form. A retrospective review suggest that a combination of T + C is active, well tolerated and may prolong survival and palliate symptoms in pts with neuroendocrine tumors, a malignancy closely relatd to islet cell (NET).

In the 2008 abstract, 17 patients received this combination as front-line chemotherapy. There were three gastrinomas (17%), two insulinomas (12%), two glucagonomas (12%), and ten nonfunctioning tumors (59%). Twelve patients (71%) had a partial response and five patients (29%) had stable disease. With a median follow-up of 12 months, there were no cases of disease progression. Only 1 patient (6%) experienced a grade 3/4 toxicity (idiosyncratic immune thrombocytopenia secondary to capecitabine).

There is an ongoing study: Phase II Study of Capecitabine and Temozolomide for Progressive, Differentiated, Metastatic Neuroendocrine Cancers. This phase II study is designed to assess whether treatment with capecitabine/temozolomide ('CAP/TEM') is safe and effective in treating subjects with progressive, differentiated, metastatic neuroendocrine tumors (NET).The primary objective of the study is to determine the radiologic response rate to this regimen in progressive, metastatic, differentiated neuroendocrine cancers. Secondary objectives include determining the overall and one year survival rates to this regimen, to determine progression free survival, to assess toxicities, improvement of quality of life, biochemical responses of tumor markers, and relief from NET symptoms.

J. R. Strosberg, J. Choi, N. Gardner, L. Kvols, First-line treatment of metastatic pancreatic endocrine carcinomas with capecitabine and temozolomide. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4612)

Isacoff, W. H., Moss, R. A., Pecora, A. L., Fine, R. L.
Temozolomide/capecitabine therapy for metastatic neuroendocrine tumors of the pancreas. A retrospective review
J Clin Oncol (Meeting Abstracts) 2006 24: 14023

Octreotide (Sandostatin) for carcinoid and neuroendocrine cancers

Octreotide is a synthetic analog of the hormone somatostatin which exerts its effects through binding to somatostatin receptors subtype 2 and, to a lesser extent, 3 and 5. In carcinoid tumours, long-term administration of octreotide can control clinical symptoms due to hypersecretion of hormones. In addition, it may have some anti-proliferative effects. Patients who benefit from octreotide include those with functioning NETs of the gut or pancreas. Octreotide is guideline recommended to control symptoms associated with carcinoid tumours and neuroendocrine tumors. The guidelines says: ".
Because the mechanism of action and the pathophysiology of other secretory neuroendocrine tumours are similar to that of carcinoid tumours, it is reasonable to recommend octreotide to control symptoms associated with secretory neuroendocrine tumours. " The recommended dose is in a subcutaneous dose of 100 micrograms three times daily, or 200 micrograms twice daily, with an increase in the dose of 50 to 100 micrograms every eight or twelve hours until symptom control is achieved. Although initially it had to be dosed more frequenlty, monthly formulations are now available. Sandostatin LAR is one such formulation. Sandostatin LAR Depot 10 mg, 20 mg and 30 mg is indicated in patients in whom initial treatment with Sandostatin Injection has been shown to be effective and tolerated.

Generally, patients are started on the short acting drug and switched to the long acting version (some people empirically use Long Acting (LAR) formulation right away). Patients currently receiving Sandostatin Injection can be switched to Sandostatin LAR Depot in a dosage of 20 mg given IM intragluteally at 4-week intervals for 2 months. Because of the need for serum octreotide to reach therapeutically effective levels following initial injection of Sandostatin LAR Depot, carcinoid tumor and VIPoma patients should continue to receive Sandostatin Injection subcutaneously for at least 2 weeks in the same dosage they were taking before the switch. Failure to continue subcutaneous injections for this period may result in exacerbation of symptoms. (Some patients may require 3 or 4 weeks of such therapy.)

After 2 months, dosage may be adjusted as follows:

•If symptoms are adequately controlled, consider a dose reduction to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks. Many patients can, however, be satisfactorily maintained at a 10-mg dosage every 4 weeks.
•If symptoms are not adequately controlled, increase Sandostatin LAR Depot to 30 mg every 4 weeks if symptoms are not adequately controlled. Patients who achieve good control on a 20-mg dose may have their dose lowered to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks.
•Dosages higher than 30 mg are not recommended.

Sandostatin LAR, Prescribing Information, 2012

Holger Petersen, Jean-Claude Bizec, Helmut Schuetz and Marie-Laure Delporte Pharmacokinetic and technical comparison of Sandostatin® LAR® and other formulations of long-acting octreotide, BMC Research Notes 2011, 4:344

Systemic Treatment Disease Site Group. Major P, Figueredo A, Tandan V, Bramwell V, Charette M, Oliver T. The role of octreotide in the management of patients with cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 Aug [online update]. 30 p. (Practice guideline report; no. 12-7). [57 references]

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.

 

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Dotatec

Radiolabeled somatostatin analogs are used for the localization and treatment of sst-positive tumors, mostly of neuroendocrine origin. A large variety of radiolabeled somatostatin derivatives has been prepared for radionuclide therapy and visualization of these tumors and metastases, and some are in various stages of preclinical and clinical investigation. 90Y-DOTA-Tyr3-octreotide (OctreoTher; Novartis) is an example of a somatostatin analog radiolabeled with the high-energy ß-emitter 90Y. More recent is the peptide 177Lu-DOTA-Tyr3-octreotate, which is a further improved targeted radiopharmaceutical because of its high rate of uptake and increased retention in sst2-positive tumors.

Despite differences between the several protocols used, most of the studies using 90Y-DOTATATE have demonstrated tumour responses of 10–30% (mean 25%), considerably higher than those obtained with 111In-DTPA

In contrast to 111In-DTPA-D-Phe1-octreotide, which binds to SSTR2 and SSTR5 with high affinity, binds to SSTR3 with moderate affinity, and does not bind to SSTR1 and SST4, 111In- and 90Y-DOTA-lanreotide was found to bind to SSTR2–4 and SST5 with high affinity, and to SSTR1 with low affinity. Leimer et al.(1998) initially reported a 25% regression of liver metastasis and substantial symptomatic improvement in a patient with a malignant gastrinoma after four infusions of 1 GBq 90Y-lanreotide. Following that observation, the phase IIa Multicentre Analysis of a Universal Receptor Imaging and Treatment Initiative (MAURITIUS) European study was organized, in which 39 patients with GEP tumours (34 carcinoid tumours) were included. After two cycles of 90Y-DOTA-lanreotide, the treatment was discontinued in the presence of progressive disease; otherwise, a further two cycles were given. Over a 3-year follow-up period, 20.5% of patients achieved regression of their disease, whereas 43.6% demonstrated stable disease. A few patients with malignant chromaffin cell tumours have been treated with 111In-DTPA-octreotide and 90Y-DOTATOC, some obtaining disease stabilization; initial results were encouraging.
    
From these studies, where several different radio-pharmaceuticals have been used for the treatment of NETs, it seems that 177Lu-DOTA-Tyr3-octreotate represents a major advance in the field of treatment with radiopeptides. However, it must be emphasized that direct, randomized, comparative studies of the various forms of radiopharmaceuticals used are lacking.

Treatment with radiolabelled SST analogues is an evolving therapeutic modality for the management of patients with inoperable or metastasized neuro-endocrine, particularly GEP, tumours. Prerequisities for treatment success include demonstration of high tumour uptake relative to non-target tissues on quantitative, diagnostic radionuclide imaging (e.g. OctreoScan) and stable haematological and biochemical function. Targeted therapies are better tolerated than other systemic treatments and deliver higher absorbed radiation doses to the tumour than can be achieved by external beam irradiation. The results obtained with [90Y-DOTA0,Tyr3]-octreotide and [177Lu-DOTA0,Tyr3]-octreotate have also exhibited substantial tumour regression, whereas the combination of these two radiopeptides may be even more effective than either alone. Future directions for improving this type of therapy include multireceptor targeting, attempts to upregulate SSTR expression on tumours and the use of radiosensitizers. At the present time this promising treatment remains experimental.

F. Iten, B. Muller, C. Schindler, C. Rochlitz, D. Oertli, H. R. Macke, J. Muller-Brand, and M. A. Walter
Response to [90Yttrium-DOTA]-TOC Treatment is Associated with Long-term Survival Benefit in Metastasized Medullary Thyroid Cancer: A Phase II Clinical Trial
Clin. Cancer Res., November 15, 2007; 13(22): 6696 - 6702.

G A Kaltsas, D Papadogias, P Makras, and A B Grossman
Treatment of advanced neuroendocrine tumours with radiolabelled somatostatin analogues
Endocr. Relat. Cancer, December 1, 2005; 12(4): 683 - 699.

F. Forrer, H. Uusijarvi, D. Storch, H. R. Maecke, and J. Mueller-Brand
Treatment with 177Lu-DOTATOC of Patients with Relapse of Neuroendocrine Tumors After Treatment with 90Y-DOTATOC
J. Nucl. Med., August 1, 2005; 46(8): 1310 - 1316.

M. de Jong, W. A.P. Breeman, R. Valkema, B. F. Bernard, and E. P. Krenning
Combination Radionuclide Therapy Using 177Lu- and 90Y-Labeled Somatostatin Analogs
J. Nucl. Med., January 1, 2005; 46(1_suppl): 13S - 17S.

E. P. KRENNING, D. J. KWEKKEBOOM, R. VALKEMA, S. PAUWELS, L. K. KVOLS, and M. DE JONG
Peptide Receptor Radionuclide Therapy
Ann. N.Y. Acad. Sci., April 1, 2004; 1014(1): 234 - 245.

Valkema R, Pauwels S, Kvols LK, Barone R, Jamar F, Bakker WH, Kwekkeboom DJ, Bouterfa H, Krenning Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0,Tyr3]octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors.EP.Semin Nucl Med. 2006 Apr;36(2):147-56.

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.

Chemo for neuroendocrine cancer

Lay Summary: Chemotherapy is not very useful for neuroendocrine cancers. A new promising drug, avastin, is being studied.

Neuroendocrine cancers come in different varieties that range from carcinoid to small cell. Carcinoid tumors are rare, slow-growing tumors that originate in the cells of the neuroendocrine system. Treatment decisions for patients with carcinoid tumors are complex and related to the location of the primary tumor and whether or not metastasis has occurred. The role of chemotherapy for NETs is uncertain but is being actively researched. It is essential to consider the tumour types individually in view of their varying response to chemotherapy and the indications to use it. Certain prognostic factors may also help in determining the use of chemotherapy and one paper showed an inverse correlation between imaging with SSRS radioscintigraphy and response to treatment. Response to chemotherapy in patients with strongly positive carcinoid tumours was of the order of only 10% whereas patients with SSRS negative tumours had a response rate in excess of 70%. The highest response rates with chemotherapy are seen in the poorly differentiated and anaplastic NETs: response rates of 70% or more have been seen with cisplatin and etoposide based combinations. These responses may be relatively short lasting in the order of only 8–10 months.Response rates for pancreatic islet cell tumours vary between 40% and 70% and usually involve combinations of streptozotocin (or lomustine), dacarbazine, 5-fluorouracil, and adriamycin. However, the best results have been seen from the Mayo clinic where up to 70% response rates with remissions lasting several years have been seen by combining chemoembolisation of the hepatic artery with chemotherapy. The use of chemotherapy for midgut carcinoids has a much lower response rate, with 15–30% of patients deriving benefit, which may only last 6–8 months. Again, the most commonly used agents will be those listed above. The management of pulmonary carcinoids is more likely to involve a platinum and etoposide combination and may reflect the fact that a pulmonary oncologist will be involved and that bronchial carcinoids may represent one end of the spectrum, which includes small cell lung cancer, which is exquisitely chemosensitive. If possible, patients should be entered into formal trials of new agents. Avastin is a promising new agent which is only now beginning to be studied in carcinoid.Avastin, or Bevacizumab is a monoclonal antibody that may inhibit cancer growth by blocking blood flow to tumors. Adding bevacizumab to combination chemotherapy may be a better way to block tumor growth than giving either type of therapy alone. The FOLFOX plus bevacizumab combination is being studied in patients with neuroendocrine tumors because FOLFOX appears to inhibit the growth of a variety of different tumor types but has not yet been tested in this disease. In addition, neuroendocrine tumors appear to depend on blood vessels for growth suggesting that they may respond to a treatment like bevacizumab. One such trial can be viewed at http://www.carcinoid.org/medpro/docs/USFnetClinTrial2005.pdf.

Chemotherapy response rates are low and some of the agents studied include 5-fluorouracil, BiCNU® (carmustine), CeeNU® (lomustine), doxorubicin, dacarbazine and Zanosar. Temodar is an oral analogue of dacarbazine. Temozolomide as monotherapy had acceptable toxicity and antitumoral effects in a small series of patients with advanced malignant neuroendocrine tumors and four of these showed radiologic responses. ^{Etoposide and cisplatin have been used for over a decade based on several phase II studies showing response rates of around 70% in poorly differentated NET.}

NCCN on CARC-5 lists chemotherapy as an option(category 3)  but does not list etoposide and carboplatin.

 

Researchers from the Dana-Farber Cancer Center have reported that the oral administration of Temodar (temozolomide) and Thalomid (thalidomide) in patients with metastatic neuorendocrine tumors results in a 40% biochemical response rate and a 25% radiologic response rate. The details of this report appeared in the January 20, 2006, issue of the Journal of Clinical Oncology.

There are a number of reports of phase II studies of this regimen and it should be considered "supported" by medical literature.

Afinitor is reviewed separately. Capecitabine ( Krzyzanowska et al. 2006), gemcitabine ( Kulke et al. 2004a) and topotecan ( Ansell et al. 2004) have all been shown to be inactive as monotherapy in these tumours.

Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. Journal of Clinical Oncology . 2006;24:401-406.

Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, et al., for the UKNETwork for Neuroendocrine Tumours. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 2005;;54 (suppl 4):iv1-16

Sara Ekeblad et al, Temozolomide as Monotherapy Is Effective in Treatment of Advanced Malignant Neuroendocrine Tumors Clinical Cancer Research 13, 2986-2991, May 15, 2007

 H. Isacoff, R. A. Moss, A. L. Pecora, R. L. Fine Temozolomide/capecitabine therapy for metastatic neuroendocrine tumors of the pancreas. A retrospective review. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 14023

Strosberg, J. R., Choi, J., Gardner, N., Kvols, L.
First-line treatment of metastatic pancreatic endocrine carcinomas with capecitabine and temozolomide J Clin Oncol (Meeting Abstracts) 2008 26: 4612

Barbro Eriksson et al, ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Chemotherapy in Patients with Neuroendocrine Tumors Neuro-endocrinology, Vol. 90, No. 2, 2009

Bristi Basu, Bhawna Sirohi and Pippa Corrie Systemic therapy for neuroendocrine tumours of gastroenteropancreatic origin Endocr Relat Cancer March 1, 2010 17 R75-R90

Ansell SM, 2004 Topotecan in patients with advanced neuroendocrine tumours: a phase II study with significant hematologic toxicity. American Journal of Clinical Oncology 27 232– 235.

Krzyzanowska MK et al, 2006 Capecitabine plus rofecoxib show no activity in patients with metastatic neuroendocrine tumours. Clinical Oncology 18 88– 89.

Kulke MH, et al, 2004  A phase II trial of gemcitabine for metastatic neuroendocrine tumours. Cancer 101 934– 939.