Cancer Treatment Today

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 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-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”.

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

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.