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Drug therapy of neuroendocrine tumors

Molecular targeted therapy

Today there are two main types of biological medications used to treat neuroendocrine tumors:

  • Somatostatin analogues
  • Interferon

Both medications work by inhibiting growth or reducing the size of the tumor. Interferon is more effective than somatostatin medications, but has significantly more side effects.

Somatostatin analogues

Most neuroendocrine tumors have somatostatin receptors. Somatostatin is an inhibiting peptide having exocrine, endocrine, paracrine, and autocrine effects. Somatostatin analogues are generally most effective on tumors which are somatostatin receptor positive on an octreotide scan.

The treatment is usually well tolerated. The most common side effects are diarrhea, nausea, and a tendency for gallstones .

The most common somatostatin analog is octreotide, which has a half-life of about 90 minutes. For treatment of neuroendocrine tumors, the slow-release formulation is used preferably (Sandostatin LAR® or Ipstyl Autogel®). These substances are usually administered every 28 days as an intramuscular (Sandostatin LAR®) or subcutaneous (Ipstyl Autogel®) injection.

Administration of somatostatin analogues usually has an immediate effect on hormonal symptoms such as diarrhea and flushing. Somatostatin analogues can also cause growth inhibition. In 0-5%, the tumor shrinks, and growth stops in 30-40% . The effect of growth inhibition appears to be proportional to the dose. Median time to progression is as for interferon, about 12 months. 

Interferon

Interferon influences a number of processes in cells including inhibition of growth factor and cell division. Interferon also activates parts of the immune system, especially the cellular part. The normal start dose is subcutaneous interferon alfa-2b (IntronA®) 5 x 106 IU daily. The dose is adjusted according to side effects and blood test results, often down to 3 x 106 IU 3–4 times weekly. Alternatively, peg-interferon alfa-2b (PegIntron®) is administered as 1–1.5 micrograms per kg as a weekly subcutaneous injection.

Approximately 30–40% of the patients must stop taking interferon due to the side effects. The most common are muscle pain, psychological problems and depression, lethargy, blood disturbances, especially leukopenia.

Studies indicate that in 40–50% of treated patients, the tumor stops growing. In 10-15%, the tumor is reduced in size. Interferon may be effective for hormonal symptoms from neuroendocrine tumors, but usually not as effective as somatostatin analogues. The median time to progression is about 12 months. After starting treatment, regular blood tests are important (after 1 week, 2 weeks, 4 weeks, and thereafter every 8 weeks after starting) to discover leukopenia, especially.  

Other

Studies are in progress with a series of other biological therapies, among others, angiogenesis inhibitors, mTor inhibitors, and tyrosine kinase inbibitors. Everolimus and sunitinib has been approved for treatment of highly differentiated tumors originating from the pancreas. These medications are increasingly used in Norway, most often as 3. or 4. line of therapy. In other countries they are often used in 1. or 2. line. 

Chemotherapy 

Chemotherapy is effective on small tumors, especially with KI-67 % in the upper levels. Tumors originating in the pancreas are often more sensitive to chemotherapy than tumors originating in the intestines. Relatively few studies are available involving chemotherapy for neuroendocrine tumors. They often include few patients, and inclusion criteria and effect indicators vary greatly.

Most common regimens

5- Flurouracil (5-FU) combined with streptozocin

This is the first-line chemotherapy combination for tumors originating from the intestines and pancreas. The treatment is given as 5 day treatment, followed by 1 day treatment every 3-4 weeks. Treatment is usually monitored by CT scan every 3 months. For effect beyond 1 year, the interval between 1 day treatments is extended up to 6 weeks.

  • For neuroendocrine pancreatic tumors, a regression is observed in 40–60%. The median time to progression is 4–12 months. 
  • For neuroendocrine tumors orginating from the colon, regression is observed in 6–33%. The median time to progression is 3–8 months.

Cisplatin (or carboplatin) combined with etoposide

This combination is 2. or 3. lie chemotherapy treatment for tumors and 1. line chemotherapy treatment for poorly differentiated carcinomas. The treatment is given as a 3 day treatment in 3 week intervals. For response, 4-6 treatments are given with a break until progression, and then starting with new 3 day treatments with 3 week intervals.

  • Regression is observed in 9.4–81%. The median time to progression is 3–9 months.

Temozolomid/capecitabine

This combinations seems to have good effect on poorly differentiated carcinomas, the studies are, however small and few. This combination is less nephrotoxic than the other combinations.  

Other regimens

There are studies indicating varying degrees of effectiveness of a series of different chemotherapy drugs and combinations, including doxorubicin, temozolomide, gemcitabine, dacarbazine/paclitaxel, leucovorin, and docetaxel.

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