Cancer Treatment Today » Neuroendocrine Cancer

Afinitor with octreotide for eenuroendocrine cancer – pro

M Levin, MD — Sun, 15 Dec 2013 14:17:59 +0000

Both Afinitor (everolimus) and octreotide are FDA approved for neuroendocrine cancer. The phase III RADIANT-2 trial conducted in 429 patients with advanced neuroendocrine tumors (NETs) previously established that the addition of everolimus to long-acting octreotide led to a clinically meaningful 5.1-month delay in disease progression compared with octreotide alone. However, this value just missed the prespecified boundary for statistical significance (prespecified p value ≤ 0.0246; actual p value = 0.026).

Closer inspection of the data revealed that more patients with a poor prognosis were randomly assigned to the experimental arm versus the control arm, potentially attenuating the observed benefit of everolimus. Future studies will attempt to confirm the benefit of combining these two drugs.

Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group.Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study.Lancet. 2011 Dec 10;378(9808):2005-12. doi: 10.1016/S0140-6736(11)61742-X. Epub 2011 Nov 25.

http://gicasym.org/radiant-2-reanalysis-everolimus-might-be-more-beneficial-against-advanced-nets-previously-recognized

Everolimus is beneficial

Octreotide is beneficial

Chemo for neuroendocrine cancer – pro

admin — Sat, 01 Sep 2012 21:58:34 +0000

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

Used as second-line therapy in combination with trastuzumab (Herceptin®) if previously treated with Herceptin® (trastuzumab) based therapy and has NOT previously received pertuzumab 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. Strossberg et al says that it can be used in first line chemotherapy for such cancers. 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 toxicityand antitumoral effects in a small series of patients with advancedmalignant neuroendocrine tumors and four of these showed radiologicresponses.^{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-56lists chemotherapy or everolimus as an option(category 3) . It says (CARC-6, F.fn. w): “Anticancer agents such as capecitabine, dacarbazine, 5FU, interferonm oxaliplatin, and temozolamide can be useful for patients with progressive disease for whom there are no other treatment options”.

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.

Recently, a retrospective analysis of capecitabine and temozolomide combination chemotherapy has demonstrated good response rates, superior to traditional streptozocin-based chemotherapy. In 30 patients treated with capecitabine and temozolomide, response rates of 70%, progression-free survival of 18 months and overall survival of 92% at 2 years were observed. However, streptozocin-based therapy remains the standard chemotherapy regime for pancreatic NETs given the lack of data from randomised trials demonstrating benefit from other regimes (Strossberg et al).

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

Koumarianou A, Kaltsas G, Kulke M, H, Oberg K, Strosberg J, R, Spada F, Galdy S, Barberis M, Fumagalli C, Berruti A, Fazio N: Temozolomide in Advanced Neuroendocrine Neoplasms: Pharmacological and Clinical Aspects. Neuroendocrinology 2015;101:274-288.

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

Aman Chauhan, Zainab Farooqui, Le Aundra Murray, et al., “Capecitabine and Temozolomide in Neuroendocrine Tumor of Unknown Primary,” Journal of Oncology, vol. 2018, Article ID 3519247, 6 pages, 2018.

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.

J. R. Strosberg, R. L. Fine, J. Choi et al., “First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas,” Cancer, vol. 117, no. 2, pp. 268275, 2011.

Rodrigo Ramella Munhoz. Combination of Irinotecan and a Platinum Agent for Poorly Differentiated Neuroendocrine Carcinomas Rare Tumors. 2013 Jul 1; 5(3): e39.

Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia. 2017;19(12):991-1002.

Octreotide (Sandostatin) for carcinoid and neuroendocrine cancers – pro

admin — Sat, 01 Sep 2012 21:56:03 +0000

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.

On the other hand, Uptodate cites newer evidence to octreotide actually retarding tumor growth and recommends it use even in asymptomatic patient with high volume, unresectable disease. The same would apply to the very similar drug Lanreotide. Lanreotide also shows activity against non-endocrine tumors, including in a 2014 phase III trial, and, along with other somatostatin analogues, is being studied as a possible general antitumor agent.

Sandostatin LAR, Prescribing Information, 2014

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.

Uptodate, Neuroendocrine, 2014

NCCN, Neuroendocrine , 2014

Additional references:

Kvols L, Woltering E (2006). “Role of somatostatin analogs in the clinical management of non-neuroendocrine solid tumors”. Anticancer Drugs. 17 (6): 6018. PMID 16917205. doi:10.1097/01.cad.0000210335.95828.ed.

Jump up ^ Susini C, Buscail L (2006). “Rationale for the use of somatostatin analogs as antitumor agents”. Ann Oncol. 17 (12): 173342.

Martín-Richard M, Massutí B, Pineda E, et al. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study. BMC Cancer. 2013;13:427.

Temodar and Xeloda for neuroendocrine cancer – pro

admin — Sat, 01 Sep 2012 21:54:47 +0000

Neuroendocrine tumors are a rare and heterogeneous group of tumors with a variety of primary origins and variable aggressiveness. Platinum-based chemotherapy has been the cornerstone of treatment for the poorly differentiated tumors. However, well-differentiated neuroendocrine tumors are quite chemoresistant and therapy options are limited. Octreotide analogs and tyrosine kinase inhibitors are widely acceptable treatments due to substantial efficacy and tolerable toxicity.

Cap/Tem is an oral, well-tolerated treatment for the management of the well-differentiated NETs. The toxicity profile is superior compared with streptozocin-based regimens. The recent review by Elais et al, concluded that Cap/Tem chemotherapy appears to be multiple times more efficacious than tyrosine kinase inhibitors and also less toxic. Taking into account that chemotherapy so far has produced poor results against non-pNET tumors, the Cap/Tem regimen proved effective in all neuroendocrine subtypes including GI non-pNETs and bronchial carcinoids. Prospective trials are needed to compare Cap/Tem with streptozocin and tyrosine kinase inhibitors in order to establish a standard of care.

NCCN says that no consensus had been established on chemotherapy for neuroendocrine cancers, but it lists this regimen among those “that are commonly used”. This is a recommendation as category 3.

Elias A Kotteas et al, Profile of capecitabine/temozolomide combination in the treatment of well-differentiated neuroendocrine tumors. Onco Targets Ther. 2016; 9: 699704.

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)

Abbasi S, Kashashna A, Albaba H .Efficacy of capecitabine and temozolomide combination in well-differentiated neuroendocrine tumors: Jordan experience.Pancreas. 2014 Nov;43(8):1303-5.

Afinitor for neuroendocrine cancer – pro

admin — Sat, 01 Sep 2012 21:53:53 +0000

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.

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.

It is now listed by NCCN CARC-6 as Category 3 recommendation after resection, observation or octreotide therapy without regard to the site of origin. A recent study tudy in patients with advanced nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin met primary endpoint. The primary endpoint of this RADIANT-4 was PFS. Secondary endpoints included safety, objective response rate and overall survival.

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

Pusceddu S, Verzoni E, Prinzi N, et al. Everolimus treatment for neuroendocrine tumors: latest results and clinical potential. Ther Adv Med Oncol. 2017;9(3):183-188.

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.

Ping Gu, Treatment of Liver Metastases in Patients with Neuroendocrine Tumors of Gastroesophageal and Pancreatic Origin International Journal of HepatologyVolume 2012 (2012), Article ID 131659, 8 pages

Sutent for neuroendocrine and carcinoid cancer – pro

admin — Sat, 01 Sep 2012 21:52:43 +0000

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 in the 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. There seems to be little medical rationale to restrict this drug to pancreatic NET cancer, especially in patients with metastatic disease. A phase II study(Hobday et al) showed that sorefnib is active in NET from other sites, albeit with significant toxicity.

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

AUPavel M, Baudin E, Couvelard A, Krenning E,Öberg K, Steinmüller T, Anlauf M, Wiedenmann B, Salazar R, ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary.Barcelona Consensus Conference participants SONeuroendocrinology. 2012;95(2):157-76. Epub 2012 Feb 15.

T. J. Hobday, J. Rubin, K. Holen, J. Picus, R. Donehower, R. Marschke, W. Maples, R. Lloyd, M. Mahoney, C. Erlichman MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study.Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4504

FDG PET for neuroendocrine cancer – pro

admin — Sat, 01 Sep 2012 21:49:46 +0000

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.Kunz ET AL, Consensus Guidelines for the Management and Treatmentof Neuroendocrine Tumors. (Pancreas2013;42: 557Y577)

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)

Read the Layperson version here.

SIRT for hepatic mets of colon cancer – pro

M Levin, MD — Mon, 27 Aug 2012 02:30:46 +0000

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.

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.

Interferon for neuroendocrine (carcinoid) cancer – pro

M Levin, MD — Mon, 27 Aug 2012 02:28:32 +0000

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.

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

Arnold R, Rinke A, Klose KJ, Müller HH, Wied M, Zamzow K, Schmidt C, Schade-Brittinger C, Barth P, Moll R, Koller M, Unterhalt M, Hiddemann W, Schmidt-Lauber M, Pavel M, Arnold CN Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol. 2005;3(8):761.

Kölby L, Persson G, Franzén S, Ahrén BRandomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003;90(6):687.

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

Oberg K, Akerström G, Rindi G, Jelic S; ESMO Guidelines Working Group.. Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2010 May;21 Suppl 5:v223-7

nccn.org, neuroendocrine

Afinitor for carcinoid – pro

M Levin, MD — Mon, 27 Aug 2012 02:24:35 +0000

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.

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.

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)