This summary provides an overview of the types of therapy known for treating Neuroendocrine Cancer. They will have been approved at least by one national or regional approval agency, may not be available or approved in your own country; and may appear in clinical guidelines for the treatment of Neuroendocrine Cancer.
Clinical trials will not be covered, although it’s noted that some of the approved treatments listed may be in follow on trials either to prove new coverage or used in combination with another drug. For a list of clinical trials covered by the author, click here.
This summary will not include complementary or alternative treatment.
Who recommends the best treatment for my condition?
Different types of doctors often work together to create a patient’s overall treatment plan that combines different types of treatments. This is called a multidisciplinary team (MDT) (in US the term “tumor board” can be used) and is very important for people with Neuroendocrine Cancer. These teams may comprise a variety of professionals, such as oncologists, surgeons, gastroenterologists, radiologists, endocrinologists, and many more as permanent members or co-opted for specific cases.
Treatment options and recommendations can depend on several factors, including:
- The type of Neuroendocrine Neoplasm (NEN) (a term covering well differentiated Neuroendocrine Tumour (NET) and poorly differentiated Neuroendocrine Carcinoma (NEC))
- Stage and grade
- The patient’s preferences and overall health
- The guidelines in place (e.g. ENETS/NANETS/UKINETS/CommNETS)
Treatment vs ‘Watch & Wait’
Watchful waiting or watch-and-wait, sometimes called ‘Active Surveillance, may be recommended for reasons that should always be explained. Ask why this approach is being taken and what the main risks are – you deserve to know. With this approach, the tumour is closely monitored with regular tests, including but not limited to:
Surgery is a common treatment for most NETs but less so with NECs. Surgeons, where possible, will try to remove all tumours and most localised NETs are successfully treated with surgery alone, often with curative intent. Additionally, the surgeon will usually remove some tissue surrounding the tumour to achieve a margin between cancerous cells and normal tissue. Check your post-operative biopsy report to see the details.
In cases of more extensive spread in NETs, a procedure called debulking surgery is sometimes recommended. Debulking surgery removes as much of the tumour bulk as possible (to an extent recommended in local guidelines) and may also provide some relief from symptoms caused by the tumour location and size or by hormonal secretions. Debulking surgery should not be considered curative. Surgery is not normally considered in NEC (poorly differentiated Neuroendocrine Carcinomas).
Often surgery is deemed not to be possible citing an “inoperable” tumour. Consequently, in these situations, the MDT will recommend another type of treatment. However, some surgeries can be very complex, sometimes risky, and one surgeon’s inoperable could be another’s operable. Many patients will seek a 2nd surgical opinion, always compare risks.
Surgery can be a very different experience from patient to patient. There are different types of NEN, different stages, different ages. You can read some of my surgery blog posts which contain links and videos with expert comment.
Surgery – to cut or not to cut. General surgery.
Small Intestine, Large Surgery. The small intestine is not not routine bowel surgery.
Pancreatic Neuroendocrine Tumours – surgical decisions – about surgery for Pancreatic NETs
For Gamma Knife/Stereotactic Radiosurgery (SRS), see Radiation therapy below.
Somatostatin is a hormone that controls the release of several other hormones, such as insulin and glucagon. Somatostatin analogues are drugs similar to the hormone somatostatin and used to control the symptoms created by the hormone-like substances released by a NET. They may also slow the growth of a NET, although they do not generally shrink the tumours.
There are 2 somatostatin analogues used to treat NETs, octreotide (Sandostatin) and lanreotide (Somatuline). Octreotide is available in 2 forms: short-acting is given under the skin (subcutaneously) and long-acting is given as an intramuscular (IM) injection. Lanreotide is given as a long-acting deep subcutaneous injection. The most common side effects are high blood sugars, the development of gallstones, and mild digestive system upset, such as bloating and nausea. There’s actually a third one approved called Pasireotide (Signifor) but that is aimed at Acromegaly and Cushing’s Syndrome.
These drugs work better on somatostatin receptor positive tumours.
Who can get these drugs? It’s generally approved for those with locally advanced and metastatic cases of Gastroenteropancreatic NETs (GEP NETs) with or without syndrome. In many cases, this will be a first line therapy even administered before surgery in many cases, particularly those with a syndrome.
Read some of my blog posts about somatostatin analogues:
Lanreotide vs Octreotide – a side by side comparison.
Lanreotide – it’s calling the shots – my own experience with Lanreotide since 2010.
Peptide receptor radionuclide therapy (PRRT)
PRRT is the generic name for a nuclear therapy which uses a radioactive ‘peptide’ to attach to receptors on a tumour’s cell. With NETs, the somatostatin receptors which enable this treatment, exist in around 80% of patients. It’s a treatment not normally offered to poorly differentiated cases which are known not to express these receptors, although trials are ongoing.
The main treatment used is called Lutathera (the brand name) or Lutetium 177 (Lu177) which indicates the radioactive isotope used to attack tumour cells when combined with a somatostatin analogue variant which leads the payload to the tumour cells due to its known binding effect.
Who can get these drugs? The treatment is currently only approved for somatostatin receptor positive Gastroenteropancreatic NETs (GEP NETs). Different healthcare systems may have different patient selection criteria.
Read more here.
Targeted therapy is a treatment that targets the tumour’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of tumor cells while limiting damage to healthy cells.
Not all tumors have the same targets. The main ones in use to treat NETs involve mammalian Target of Rapamycin (mTOR) inhibitors and Tyrosine Kinase Inhibitors (TKI). There are several new targeted therapies in the clinical trial pipeline, so it’s worth taking a look at the link above to see more on this type of therapy.
The two main targeted therapies currently in use are:
Everolimus (Afinitor) is a targeted therapy, an mTOR inhibiter approved for the treatment of advanced non-functional NETs of the GI tract, lung, and pancreas. This drug can help slow down the growth of these tumours in some patients. Read more here.
Sunitinib (Sutent) targets a protein called Vascular Endothelial Growth Factor (VEGF), is approved for the treatment of advanced pancreatic NETs. Read more here.
Who can get these drugs? It’s generally approved for those with advanced and nonfunctional cases of Gastroenteropancreatic NETs (GEP NETs) but in the case of Sunitinib, only for pancreatic NETs.
These drugs are not dependent on somatostatin receptors.
If cancer has spread to the liver, the treatments below may be used at some point. These procedures are usually performed by an experienced interventional radiologist and may require an overnight hospital stay.
- Liver Embolization. NETs are known to be highly vascular, that is they live on blood supply. Tumour embolization is a procedure to shrink a liver tumour by cutting off its blood supply. The doctors put a thin, flexible tube, called a catheter, into an artery near your groin or in your arm. He or she guides the catheter into the liver artery (the hepatic artery) that supplies blood to the tumour. So, the theory is if you block the blood supply to a tumour, the tumour will reduce or die. It’s a procedure carried out by an interventional radiologist – it’s very much image guided. Other countries may use other appropriately trained personel and they may have different names. There are essentially 3 types of liver embolization:
Bland – Often known as Hepatic Arterial Embolization (HAE) or TransArterial Embolization (TAE). The technique is as described above.
Chemo – Transarterial Chemo Embolization (TACE). As per the bland type but they add some chemo (normally Fluorouracil (5-FU) but could be different depending on where you are). There is currently some debate about the actual advantages of that over bland.
Radioembolization – Transarterial Radio Embilization (TARE). Also often called selective internal radiotherapy (SIRT), uses tiny radioactive beads (microspheres). It damages the blood vessels to the tumour so that it can’t get the nutrients it needs, and the radiation given off by the SIRT beads damages the cancer cells and hopefully stops them growing. The radiation used is mostly always Yttrium 90 or Y90. (Should not be confused with the Y90 version of Peptide Receptor Radio Therapy (PRRT) which is a different type of treatment and for the whole body).
Ablation Techniques. Radiofrequency ablation (RFA) and microwave ablation (MWA) use heat to destroy cancer cells or tumours (more than just the liver). The heat is supplied by electrical currents passed through a special needle placed directly into the liver. This may also be known as a percutaneous ablation. RFA/MWA is undertaken by doctors with special experience, and it may not be available at all treatment centres. There are several other ablation techniques used worldwide: including Interstitial laser ablation, high-intensity focused ultrasound (HIFU), cryoablation, and irreversible electroporation interstitial laser ablation, high-intensity focused ultrasound (HIFU), cryoablation, and irreversible electroporation.
Read more here.
Chemotherapy (chemo) is the use of drugs to destroy cancer cells, usually by keeping the cancer cells from growing, dividing, and making more cells. When people talk about “Chemo”, particularly patients and caregivers, they will anticipate this being the cytotoxic type of therapy commonly associated with toxic side effects including hair loss as the most well-known one. To a certain extent, this is accurate but worth pointing out that some chemo is more toxic than others (but still necessary depending on cancer type), some chemo is oral (tablet form) and not everyone suffers hair loss, and side effects usually go away after treatment is finished. Chemotherapy is normally administered via intravenous route (IV) but there are also oral (tablet) forms and may also be injected through a catheter (thin tube) directly into the abdominal cavity. This is called intraperitoneal (IP) chemotherapy. The latter is only for specific areas of anatomy.
Who gets Chemo in Neuroendocrine Neoplasms (NEN) ?
There’s a longstanding myth in patient groups that “it doesn’t work with NETs”. This is only partly true. It is known not to be sufficiently effective with low grades, it does not appear to like their slow cytokinetic growth. However, it’s normally a first line treatment for poorly differentiated Neuroendocrine Carcinomas. It may also be a strong option for well differentiated Grade 3 NETs and in certain scenarios for Grade 2 NETs, more likely at the higher end readings of Ki67/mitotic count. The type of chemo (combo) you receive will be based on your grade/Ki67 and primary location.
Platinum-based drugs (informally called platins) are chemotherapeutic agents used to treat many types of cancer including Neuroendocrine. These drugs are used to treat almost half of people receiving chemotherapy for cancer. Commonly used chemo includes Cisplatin, Oxaliplatin, and Carboplatin.
Other Cytotoxic chemo include:
- Fluorouracil (5-FU),
- Streptozotocin (Zanosar)
- Irinotecan (Campto)
- Paclitaxel (Taxol)
and the oral (tablet) versions:
- Capecitabine (Xeloda),
- Temozolomide (Temodal),
- Etoposide (Etopophos, Vepesid)
Known combos used in NENs.
Cisplatin and Etoposide appear to be the most commonly used combo for high grade.
Capecitabine (Xeloda) and Temozolomide (Temodal) (CAPTEM) are used in cases of Grade 2 and Grade 3 NET but also listed as a second- or third-line treatment for NEC.
FOLFOX. Also known as Oxaliplatin de Gramont or OxMdG, which means modified Oxaliplatin de Gramont. It is made up of folinic acid (also called leucovorin, FA or calcium folinate), fluorouracil (5FU) and oxaliplatin.
FOLFIRI. Also known as irinotecan de Gramont or irinotecan modified de Gramont. It includes folinic acid (also called leucovorin, calcium folinate or FA), fluorouracil (5FU) and irinotecan.
Read more here.
Immunotherapy is designed to boost the body’s natural defences to fight the tumour. It uses materials made either by the body or in a laboratory to improve, target, or restore immune system function. Sometimes it is called biologic therapy.
There’s actually been an immunotherapy drug used in Neuroendocrine Neoplasms for some time and some of the long-term patients may have heard of it or have had it administered. Known as Interferon alpha (IFNα) it helps the body’s immune system work better and can lessen diarrhea and flushing. It may also shrink tumors. I still see this listed in some texts but less so recently, probably due to low efficacy and high toxicity.
When people talk about Immunotherapy today, they really mean the new drugs. While there are many clinical trials (some of which have already been declared not suitable), only two Neuroendocrine Neoplasms have at least one modern Immunotherapy drug approved:
- Merkel Cell Carcinoma has Pembrolizumab (Keytruda) and Avelumab (Bavencio).
- Small Cell Lung Cancer (SCLC) has Atezolizumab (Tecentriq) in combination with carboplatin and etoposide for extensive stage along with Nivolumab (Opdivo) for third-line treatment of metastatic SCLC.
Worth also mentioning that Pembrolizumab (Keytruda) is also approved to treat adult and pediatric patients with unresectable or metastatic solid tumors that are tissue tumor mutational burden (TMB) –high (≥10 mutations/megabase) and have progressed following prior therapy and who have no satisfactory alternative treatment options. This is part of a more targeted use of immunotherapy looking at specific gene mutations that may be present in any cancer.
Immunotherapy is exciting, but we also need to be aware of the risks of taking the brakes off the immune system. We have seen and heard more and more stories about people with grim cancer diagnoses who became cancer-free after treatment with immunotherapy. This offers hope to those with cancer, but we need to be cautious when discussing immunotherapy. This treatment method is still new, and the cancer community is still learning about how it affects the body. An unfettered immune system may end up attacking healthy, functioning parts of a person’s body, causing unpredictable side effects that may be life-threatening EVEN if not treated early.
Nonetheless, our specialists continue to look for breakthroughs and this nice summary from ENETS 2021 is useful to those who are watching the immunotherapy story unfold.
Radiation therapy is the use of high-energy x-rays or other particles to destroy tumour cells. A radiation therapy schedule usually comprises a specific number of treatments given over a set period of time. When people mention “radiation therapy” they normally mean something called “external-beam therapy“, the most common type given from a machine outside the body. Pepetide Receptor Radionuclide Therapy (PRRT) listed above is a totally different type of treatment.
This is not a common treatment for most Neuroendocrine Cancers, particularly for lower grade NETs. It is most often used as part of supportive or palliative care to relieve symptoms, such as pain, caused by cancer that has spread to the bone and other areas of the body. In terms of an anti-tumour approach, it’s more likely to be seen in difficult to reach areas and where precision is important.
Many patients ask about other types of radiotherapy but there’s little information to suggest these are effective and/or widely used in Neuroendocrine Cancers. I have therefore included the following state of the art technology after noting that at least one patient had experienced one of these advanced types of radiotherapy/radiosurgery:
- Stereotactic radiosurgery (SRS)/Stereotactic body radiation therapy (SBRT). Uses 3-D imaging to determine the exact coordinates of a tumor. The highly focused gamma rays or x-rays then converge on the tumor to treat it.
- Gamma Knife® is a radiation therapy that uses computerized treatment planning software to help physicians locate and irradiate small targets within the head and brain with very high precision. The treatment delivers intense radiation doses to the target area while sparing surrounding tissue. It can be used as a tool in SRS.
- Linear accelerators can also be used to deliver stereotactic radiation therapy to the brain. Other parts of the body can be treated with stereotactic body radiation therapy (SBRT). Emerging areas for using SBRT include lung, liver and bone.
- Proton beam or heavy-charged-particle radiosurgery is another form of external beam radiation therapy that uses cyclotrons or synchrotrons to produce charged atoms that destroy tumors.
- Image-guided radiation therapy (IGRT) is a technique used in SRS/SBRT which uses medical imaging to confirm the location of a tumor immediately before, and in some cases, during the delivery of radiation. IGRT improves the precision and accuracy of the treatment as it can allow for adjustments during treatment in areas of the body that are prone to movement, such as the lungs, and tumors located close to critical organs and tissues.
- Intensity-modulated radiotherapy (IMRT) uses linear accelerators to safely deliver precise radiation to a tumor while minimizing the dose to surrounding normal tissue.
- Intraoperative radiation therapy (IORT) is an intensive radiation treatment that’s administered during surgery.
Telotristat Ethyl (XERMELO)
Telotristat Ethyl is a significant introduction to the treatment of Carcinoid Syndrome diarrhea. It’s the first addition to the standard of care in more than 16 years and the first-time an oral syndrome treatment has been developed. The drug was previously known as Telotristat Etiprate but was changed to Ethyl in Oct 2016. ‘Etiprate’ was previously a truncation of ‘ethyl hippurate’. The brand name is XERMELO®
This drug is approved for the treatment of carcinoid syndrome diarrhea in patients inadequately controlled by somatostatin analogue therapy, i.e. it doesn’t replace somatostatin analogues – it is an additional treatment alongside and only when the diarrhea is caused by hormone oversecretion, i.e. it may not work to prevent post-operative diarrhea or other causal reasons.
In the simplest of terms, the drug is an inhibitor of the enzyme tryptophan hydroxylase (TPH). TPH is the rate-limiting enzyme in serotonin synthesis which converts tryptophan (an essential amino acid which comes from diet) to 5-hydroxytryptophan, which is subsequently converted to serotonin, one of the main causes of carcinoid syndrome effects including carcinoid heart disease. The trial data indicates that Telotristat ethyl significantly reduced the frequency of bowel movements.
Read more here
I wanted to provide a summary of the main treatments for Neuroendocrine Cancer without going into too much detail but still delivering something of use to the average patent. Not everyone will have access or need access to all of these treatments. I’m sure this is not an exhaustive list and I’m happy to listen to feedback on areas of both the quality and quantity of the information.
If you are in need of further information about your own treatment options, you should of course speak directly to your specialist. If you need to hear the experience of others who have gone through these treatments, you should post in my group. For those wishing to join, there’s a green button below with a link.
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