Neuroendocrine tumors medical therapy
Neuroendocrine tumors Microchapters
According to Warner, the best care, at least for noncarcinoid GEP-NETs, is provided by "an active [as opposed to wait-and-see] approach using sequential multimodality treatment" delivered by a "multidisciplinary team, which also may include a surgeon, endocrinologist, oncologist, interventional radiologist, and other specialists". This recommendation is based on his view that, except for most insulinomas, "almost all" PETs "have long-term malignant potential" – and in sixty percent of cases, that potential is already manifest. "Indeed, the most common cause of death from PETs is hepatic [that is, liver] failure" (Warner 2005, 4).
Two tricky issues in evaluating therapies are durability (is the therapy long-lasting?) and stasis (are the tumors neither growing nor shrinking?). For example, one therapy might give good initial results – but within months the benefit evaporates. And another therapy might be disparaged by some for causing very little tumor shrinkage, but be championed by others for causing significant tumoristasis.
The half-life of somatostatin in circulation is under three minutes, making it useless for diagnosis and targeted therapies. For this reason, The synthetic forms are typically called somatostatin analogs (somatostatin analogues), but according to the US Food and Drug Administration (FDA), the proper term is somatostatin congeners. (In this article we conform to the old terminology, as the medical community has been slow to adopt the term congener.) The analogs have a much longer half-life than somatostatin, and other properties that make them more suitable for diagnosis and therapy.
The most common nonsurgical therapy for all GEP-NETs is chemotherapy, although chemotherapy is reported to be largely ineffective for carcinoids, not particularly durable (long-lasting) for PETs, and inappropriate for PETs of nonpancreatic origin. 
When chemotherapy fails, the most common therapy, in the United States, is more chemotherapy, with a different set of agents. Some studies have shown that the benefit from one agent is not highly predictive of the benefit from another agent, except that the long-term benefit of any agent is likely to be low.
Strong uptake of somatostatin analogs is a negative indication for chemo.
There are two major somatostatin-analog-based targeted therapies. The first of the two therapies provides symptomatic relief for patients with secretory tumors. In effect, somatostatin given subcutaneously or intramuscularly "clogs up" the receptors, blocking the secretion of hormones from the tumor cells. Thus a patient who might otherwise die from severe diarrhea caused by a secretory tumor can gain additional years of life.
Specific counter-hormones or other hormone-blocking medications are sometimes also used to provide symptomatic relief.
Hormone-delivered radiotherapy – PRRT
The second of the two major somatostatin-analog-based targeted therapies is called peptide receptor radionuclide therapy (PRRT), though we might simply call it hormone-delivered radiotherapy. In this form of radioisotope therapy (RIT), radioactive substances (called radionuclides or radioligands) are chemically conjugated with hormones (peptides or neuroamines); the combination is given intravenously to a patient who has good uptake of the chosen hormone. The radioactive labelled hormones enter the tumor cells, and the attached radiation damages the tumor- and nearby cells. Not all cells are immediately killed this way. The process of tumor cells dying as result of this therapy can go on for several months, even up to two years. In patients with strongly overexpressing tumor cells, nearly all the radiation either gets into the tumors or is excreted in urine. As Rufini et alia say, GEP-NETs "are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane, and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy" (Rufini, Calcagni, and Baum 2006, ).
The use of PRRT for GEP-NETs is similar to the use of iodine-131 as a standard therapy (in use since 1943) for nonmedullary thyroid tumors (which are not GEP-NETs). Thyroid cells (whether normal or neoplastic) tend to be avid for iodine, and nearby cells are killed when iodine-131 is infused into the bloodstream and is soon attracted to thyroid cells. Similarly, overexpressing GEP-NET cells (neoplastic cells only) are avid for somatostatin analogs, and nearby cells are killed when radionuclides attached to somatostatin analogs are infused into the bloodstream and are soon attracted to the tumor cells. In both therapies, hormonal targeting delivers a much higher dose of radiation than external beam radiation could safely deliver.
As of 2006, PRRT is available in at least dozen medical centers in Europe. In the USA it is FDA-approved, and available at the MD Anderson Cancer Center, but using a radionuclide, indium-111, that is much weaker than the lutetium-177 and the even stronger yttrium-90 used on the European continent. In the UK, only the radionuclide metaiodobenzylguanidine (I-MIBG) is licensed (but GEP-NETs are rarely avid for MIBG). Most patients (from all over the world) are treated (with lutetium-177) in The Netherlands, at the Erasmus Medical Center. PRRT with lutetium or yttrium is nowhere an "approved" therapy, but the German health insurance system, for example, covers the cost for German citizens.
PRRT using yttrium or lutetium was first applied to humans about 1999. Practitioners continue to refine their choices of radionuclides to maximize damage to tumors, of somatostatin analogs to maximize delivery, of chelators to bind the radionuclides with the hormones (and chelators can also increase uptake), and of protective mechanisms to minimize damage to healthy tissues (especially the kidneys). 
Hepatic artery-delivered therapies
- One therapy for liver metastases of GEP-NETs is hepatic artery embolization (HAE). Larry Kvols, of the Moffitt Cancer Center and Research Institute in Tampa, Florida, says that "hepatic artery embolization has been quite successful. During that procedure a catheter is placed in the groin and then threaded up to the hepatic artery that supplies the tumors in the liver. We inject a material called embospheres [tiny spheres of glass or resin, also called microspheres] into the artery and it occludes the blood flow to the tumors, and in more than 80% of patients the tumors will show significant tumor shrinkage" (Kvols 2002, ). HAE is based on the observation that tumor cells get nearly all their nutrients from the hepatic artery, while the normal cells of the liver get about 75 percent of their nutrients (and about half of their oxygen) from the portal vein, and thus can survive with the hepatic artery effectively blocked.
- Another therapy is hepatic artery chemoinfusion, the injection of chemotherapy agents into the hepatic artery. Compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are (in theory) delivered to the lesions in the liver.
- Hepatic artery chemoembolization (HACE), sometimes called transarterial chemoembolization (TACE), combines hepatic artery embolization with hepatic artery chemoinfusion: embospheres bound with chemotherapy agents, injected into the hepatic artery, lodge in downstream capillaries. The spheres not only block blood flow to the lesions, but by halting the chemotherapy agents in the neighborhood of the lesions, they provide a much better targeting leverage than chemoinfusion provides.
- Radioactive microsphere therapy (RMT) combines hepatic artery embolization with radiation therapy – microspheres bound with radionuclides, injected into the hepatic artery, lodge (as with HAE and HACE) in downstream capillaries. This therapy is also called selective internal radiation therapy, or SIRT. In contrast with PRRT, the lesions need not overexpress peptide receptors. (But PRRT can attack all lesions in the body, not just liver metastases.) Due to the mechanical targeting, the yttrium-labeled microspheres "are selectively taken up by the tumors, thus preserving normal liver" (Salem et al. 2002, ).
- Radiofrequency ablation (RFA) is used when a patient has relatively few metastases. In RFA, a needle is inserted into the center of the lesion and is vibrated at high frequency to generate heat; the tumor cells are killed by cooking.
- Cryoablation is similar to RFA; an endothermic substance is injected into the tumors to kill by freezing. Cryoablation has been considerably less successful for GEP-NETs than RFA.
- Interferon is sometimes used to treat GEP-NETs; its use was pioneered by Dr. Kjell Öberg at Uppsala. For GEP-NETs, Interferon is often used at low doses and in combination with other agents (especially somatostatin analogs such as octreotide). But some researchers claim that Interferon provides little value aside from symptom control.
- As described above, somatostatin analogs have been used for about two decades to alleviate symptoms by blocking the production of hormones from secretory tumors. They are also integral to PRRT. In addition, some doctors claim that, even without radiolabeling, even patients with nonsecretory tumors can benefit from somatostatin analogs, which purportedly can shrink or stabilize GEP-NETs. But some researchers claim that this "cold" octreotide provides little value aside from symptom control.
Ramage et alia say that "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 (Ramage et al. 2005, ).
For 125 patients with histologically proven unresectable islet-cell carcinomas, "median duration of regression was 18 months for the doxorubicin combination and 14 months for the 5-FU combination" (Arnold et al. 2004, 230).
- A search for "peptide receptor radionuclide therapy", in quotes, at http://pubmed.org, and an examination of the resulting abstracts, shows that PMID 10399029, published in 1999, was the first article stating that indium had been used on humans. Referring to yttrium-90, the article mentions that "the first PRRT trials with [90Y-DOTA0,Tyr3]octreotide started recently". PMID 15653653, published in January, 2005, contains the first results of the use of lutetium and yttrium on humans.
"The liver gets about 80% of its blood and half the oxygen from the portal vein, and only 20% of the blood and the other 50% of the oxygen from the artery.... The liver gets 80% of its blood from the portal vein and 20% from that little hepatic artery. But tumors get 100% of their blood off the hepatic artery, and this has been shown by multiple lines of evidence (Pommier 2003, ).
"The normal liver gets its blood supply from two sources; the portal vein (about 70%) and the hepatic artery (30%)" (Fong and Schoenfield n. d., ).
- "The theoretical advantage is that higher concentrations of the agents can be delivered to the tumors without subjecting the patients to the systemic toxicity of the agents.... In reality, however, much of the chemotherapeutic agents does end up in the rest of the body" (Fong and Schoenfield, ).
- The "microspheres preferentially cluster around the periphery of tumor nodules with a high tumor:normal tissue ratio of up to 200:1". The SIRT-spheres therapy is not FDA-approved for GEP-NETs; "it is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, such as hepatocellular carcinoma and neuroendocrine malignancies" (Welsh, Kennedy, and Thomadsen 2006, ).