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Nuclear medicine involves using radioactive materials (or tracers) to diagnose and treat a wide variety of disorders. It differs from X-ray, ultrasound and any other diagnostic test because it looks at the function of the organ, tissue or bone and determines the presence of disease based on structural appearance.
Radio-isotope Scans and Treatments for NETS
One of the main stays of treatment for NET is by administration of targeted radio isotope treatments. The mechanism of how this works is quite complicated and is explained in the “mechanism of action” section after this.
Neuroendocrine tumours often absorb a substance called octreotide. This process is taken advantage of in an octerotide (or octreo) scan which you may have to help determine the presence of disease. A small amount of octreotide is ‘labelled’ with a mildly radioactive tracer to make it show up on scan pictures. The octreotide is then injected into the bloodstream and taken up by NETs, wherever they are.
This is a type of scan that takes place over 2 days in the nuclear medicine department. You are given iodine tablets to take on the morning before the scan (so the tracer isn’t taken up by the thyroid gland), followed by an injection containing the octreotide molecule (see below) with a very small amount of the radioactive tracer attached to it. One scan is taken that day and a second scan is taken the next day to see where the octreotide tracer (which acts like a dye) has been taken up showing up as “hot spots” on the scan.
Sometimes a substance called MIBG, which may be absorbed by NETs, is used for the scan. It’s also made mildly radioactive, and scans are done in a similar way to the scan using octreotide.
This is very similar to an octreoscan in that it uses a molecule (MIBG) to bind to the receptors on the neuro-endocrine cells. It is particularly good for looking at tumours from the adrenal glands (phaeochromocytomas) and similar tumours (e.g. paraganglioma). However many other NETs also show up on this scan, so in some centres it is used at least as much as octreoscanning.
What are the risks of radio-isotope scans and treatments?
In general the amount of radioactivity given during an octreoscan or MIBG scan is so tiny that it is of no more risk to you than an ordinary CT body scan. Larger doses of radio-isotope are needed to achieve therapeutic levels which kill the cancer cells. The nuclear medicine doctors and physicists calculate very carefully the exact amount that is safe for the stronger treatment doses. In general these treatments have very few side effects, but occasionally the kidneys or bone marrow can be affected, this is more likely if several treatments are required.
When should therapeutic radio-isotopes be used?
There are many differing opinions on the best timing for use of radio-isotope therapy. Our preference in Southampton is to use it for patients with disease that is not easy to treat with other modalities such as surgery, embolisation, ablation or chemotherapy.
Radio-isotope therapy is limited by the laws of physics and human biology
- Firstly the human body can only cope with a certain amount of radiation at one time, otherwise the short term effects of radiation sickness take effect. The human bodies tolerance for radiation dosage have been very well documented in the 20th century and clearly safe levels established so in practice toxic dosages are never reached.
- Radiation has a cumulative effect with repeated doses, so treatments cannot be repeated too close together and there is a small long term risk of developing other tumours from these treatments.
- The radio-isotopes are concentrated and excreted by the kidneys so it is important to watch renal function in patients with any kidney problems as they can be damaged by the radiation.
- Tumours must have high concentrations of the receptors on them to make the treatment effective, if they do not have many receptors then not many radiolabelled molecules attach to the tumour cells and consequently only a small dose of radiation is given.
- If there is a very large quantity of tumour then the treatment may not work very well as only a fixed dose of radioactivity can be given, which must be spread around all the tumour sites, again giving a weak or dilute effect.
- Radiation particles emitted by these drugs travel in a straight line and have only a short penetration into adjacent tissue. If a tumour is very small then the radioactive molecules that are released from it mainly pass out of the tumour into the surrounding tissue, so again the dose received by the tumour cells is very small.
Putting all of these points together it becomes apparent that the treatment works best for smaller numbers (<10) of small or medium sized tumours (1-6cm diameter) with high concentrations of receptors and is less effective for very bulky or very diffuse patterns of disease.
Due to these limitations and limited availability of the treatment we tend to hold it back in reserve to treat tumours that are inaccessible or unsuitable for other treatments. Ideally we would use it more frequently than we do, however we are effectively rationed by the limited availability of the products at a national level due to the costs of providing and administering the treatment.
In many centres treatment is limited to patients with severe symptoms and progressive disease.
Mechanism of Action
Neuroendocrine tumour cells often have protein molecules on their surface or cell membrane which act as receptors for specific hormones. Hormones are chemical messengers that the body produces that are released into the blood stream from one organ and then travel in the blood stream to another organ to pass the message on. A receptor acts to give the inside of the cell the message in response to the hormone on the outside; in NETs this message is often the trigger to release other hormones such as Serotonin (5-HT), Gastrin, VIP, Insulin or Glucagon.
The most commonly identified receptor in NETs is the somatostatin hormone receptor. Somatostatin is a hormone that circulates inside all of us in varying levels and it is an important part of our normal make up and function. The somatostatin receptor can be blocked by an inactive molecule called Octreotide, this looks very similar to somatostatin and binds to the somatostatin receptors on the surface of the cell, but it does so in such a way that no message is transmitted to the cell. In this way the receptor can be blocked.
If a radio-active particle (commonly radio-active Iodine) is attached to the octreotide molecule then you effectively have a “magic bullet” that binds preferentially to the receptors on tumour cells, blocking them from acting and delivering radiation to the cell to either make it show up on a scan or damage or kill it. This is the basis of radio isotope scans and treatments.
Peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumours (NET)
Most neuroendocrine tumours have 5 highly specialized receptors that bind to the naturally occurring hormone somatostatin. Octreotide is able to attach to two of these five somatostatin receptors. Peptide receptor radionuclide therapy (PRRT) combinesoctreotide with a radionuclide (a radioactive substance) to form highly specialized molecules called radiolabelled somatostatinanalogues or radiopeptides. These radiopeptides can be injected in the bloodstream and go directly to the tumour cells that havereceptors for them. Once bound, these radiopeptides emit radiation and kill the tumour cells they are bound to. So, almost all of theradiation is absorbed by the tumour and very little goes to normal healthy tissues. That is why it is called ‘targeted therapy’.
There are different radionuclides that are attached to octreotide to create radiopeptides including
- yttrium 90 (90Y) – DOTATOC
- lutetium 177 (177Lu) – DOTATATE
- 131I-MIBG (131I-meta-iodobenzylguanidine)
These radiopeptides differ in the type of radiation they emit, as well as the depth of tissue into which they penetrate. Tissue penetration is an important factor since a certain range of radiation is necessary to kill tumour cells but not damage surrounding, healthy tissues. In radionuclide therapy the dose of radiation that is being used is higher than the one needed for imaging purposes.Individuals whose tumours can be visualized by somatostatin receptor scintigraphy (SRS) and have inoperable NETs that are growing, or individuals whose symptoms are not well managed by somatostatin analogues, may be candidates for PRRT. However, the extent of tumour growth, kidney function, liver function, prior treatments, and many other factors must also be considered. All side effects associated with radionuclide therapy are mild and transient. They comprise nausea, vomiting, abdominal pain, hypotension, fatigue, leucopenia, and thrombocytopenia. Other less-common side effects are bone, liver, and kidney toxicity, and mild hair loss.
Common Questions about PRRT
What is Yttrium-DOTATATE PRRT?
This consists of the radioactive material Yttrium (Y-90), which is added to a carrier (a peptide protein fragment) called DOTATATE. DOTATATE binds to the NET cells and Y-90 emits radiation which destroys these cells.
How is Y-90 DOTATATE given?
It is given as a drip into a vein in your arm over one hour. You will be given amino acids (protein fragment) through another drip before, during and after treatment to help protect your kidneys from the radiation. We will also give you medication to prevent nausea during and after treatment.
Is there any preparation before the treatment?
No special precautions are necessary. However, if you feel unwell before the treatment, please contact us on the number over the page.
If you are being treated with any long acting somatostatin analouge injections, e.g., lanreotide autogel or sandostatin LAR, these must be stopped for approximately four weeks prior to treatment. This is because this medication may block the receptors that the therapy is designed to target and therefore potentially reduce the efficacy of the treatment.
How many treatments will I need?
Usually three to four treatments, ten to twelve weeks apart.
Are there any side effects?
Unlike chemotherapy, the side effects are usually mild and transient and may last up to a few days. You may experience pain, nausea and tiredness. It can also lower your blood count and kidney function.
Can I have treatment if I am pregnant or breast-feeding?
It is important to let us know about this. If you are pregnant or breast-feeding, treatment cannot be given. These precautions are to protect your baby. You are advised not to become pregnant until at least six months following treatment. Men are advised not to father a child for the same period. If you are sexually active, adequate contraceptive care is needed. The treatment should not affect your fertility.
Will I have any investigations or scans before treatment?
Before we can decide if treatment is possible, we will do blood tests to make sure that your kidney function and blood count are normal. You would have had a nuclear medicine octreotide scan (done over two days).
Will I stay in hospital?
You will usually stay for one to two nights in your own room which has a bathroom. This room has been specially designed and built to cater for patients undergoing radioactive treatment. To ensure that you are cared for safely, you will be asked to remain in your room until you are advised that you can go home.
Will I be radioactive?
This type of treatment delivers its radiation within your body and only very small amounts exit your body. No one should visit you on the day of treatment. After this, visitors who are over 18 and not pregnant may visit for up to 30 minutes a day. Visitors should speak to the ward staff before entering the room as they will need to observe the relevant radiation protection measures.
What happens after treatment?
A nuclear medicine scan to assess the distribution of radioactive treatment is done the day after treatment, you will then be discharged home. Once home, we suggest some sensible precautions. For example, double flush the toilet for seven days, restrict close contact (less than one metre) with children/pregnant women for seven days, do not return to work for seven days, restrict close contact with adults and avoid sharing a bed for five days. Further CT and octreotide scans as well as blood tests will be done as part of the follow-up to assess your response to the treatment. Blood tests will be done every two weeks for eight weeks, to monitor your blood count and kidney function.
Your main follow-up will continue to be under the care of the NET clinic at Southampton. You will be seen in clinic after each treatment to reassess your health and response to therapy.
Contact details for your PRRT treatment at Southampton Hospital
Weekdays between 9am and 4.30pm, please contact: Emma Ramsey, NET clinical nurse specialist. Tel: 023 8079 5753 Mobile: 07920 274809
If you are unable to contact Emma and your query is outside the hours of 9am to 4.30pm and also during the weekend, please contact: acute oncology service 023 8079 5304 / 07867 973649
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