Lutetium-177 DOTATATE Therapy

Dr Lizette Louw explains how peptide receptor radionuclide therapy using Lutetium-177 radiation targets neuroendocrine tumours.

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What are neuroendocrine tumours?

Neuroendocrine tumours (NETs) are a group of rare cancers that originate in cells found throughout the body, and act as a bridge between the nervous and endocrine systems. The most common sites of origin are bowel, lung, or pancreas. Tumours are categorised as grade 1, 2 or 3 based on tumour cell growth rate, measured by the Ki-67 index on histology. A high Ki-67 indicates a faster-growing and more aggressive tumour.

The central role that somatostatin plays

Somatostatin is a normal hormone which interacts with neuroendocrine cells via a receptor on the cell surface. Most NETs overexpress somatostatin receptors, and thus overreact to normal somatostatin stimulus, leading to excessive tumour growth.

Nuclear medicine makes use of a peptide which is a somatostatin analogue and binds to these somatostatin receptors, for both imaging and therapy for NETs. This analogue only binds to the somatostatin receptors but doesn’t cause the same reaction inside the cell as somatostatin.

The somatostatin analogue available in SA is called DOTATATE. This DOTATATE can be linked to different types of radiation, depending if it’s being used for imaging (PET/CT), or for peptide receptor radionuclide therapy (PRRT).

PRRT, in simple terms, is when the peptide (DOTATATE) binds to a receptor (somatostatin receptor) and carries radiation (Lutetium-177(Lu-177)) which is used for therapy. PRRT is often called targeted therapy, as it delivers radiation therapy predominantly to cells that DOTATATE binds to, without significant harm to healthy surrounding tissue.

Once the DOTATATE binds to somatostatin receptors, the Lu-177 is transported to the inside of the cell, where it emits beta particle radiation that travels only up to 2mm. This radiation damages the nucleus of the cell, thereby killing the cell, and/or slows down the cellular growth.

Who would qualify for PRRT?

Patients with confirmed grade 1 or grade 2 NETs in who curative surgery isn’t possible, and those who have progression of disease despite other treatments, would be considered.

Confirmation of DOTATATE uptake by the cancer cells with a DOTATATE PET/CT scan is, however, essential. The brighter the DOTATATE uptake in the cancer sites (more intense than in the normal liver), the more likely it’s that the patient will benefit from PRRT. If there is very little or no DOTATATE uptake in the cancer sites, the patient will not benefit from PRRT, and other therapy options should be explored.

Patients must be in a reasonably good physical condition, with adequate bone marrow, kidney, and liver function. It’s best for patient cases to be discussed at a multi-disciplinary meeting (MDM), where a group of specialists can collectively make decisions on the treatment plan.

How is PRRT given?

Treatment consists of four cycles, given eight to 12 weeks apart. Blood tests to monitor bone marrow, kidney, and liver function is done prior to every cycle, to determine if it’s safe to proceed or not.

PRRT can be done as an out-patient at a facility with a radiation licence for Lu-177. Something for nausea is given first, as well as a once-off steroid dose to minimise inflammation caused by the radiation therapy. After this, a special amino acid infusion to protect the kidneys will be started and runs over four hours. The PRRT infusion is administered at any time after at least one hour of this amino acid infusion.

A scan is commonly done the day after treatment, but due to logistics this scan can be done even three to four days after treatment. This scan isn’t a PET/CT, and appears blurrier than a PET/CT. The purpose of this scan is to visualise the absorption of treatment, and when the scans are compared after each cycle, it’s an early indication of treatment response.

In other countries, this scan (done at a minimum of three-time points) is also used to calculate the amount of radiation absorbed in the whole body, but the skills and computer software for this is unfortunately not widely available in SA.

What are the side effects of PRRT?

The most common side effect is nausea related to the amino acid infusion, which is why the treatment procedure starts with anti-nausea medication first.

Most patients experience fatigue, which can last from a few days up to a few weeks. This is, however, usually mild. Some patients report pain in the areas of cancer, which happens because of radiation-induced inflammation in the cancer areas, causing swelling of those areas. This is unpredictable, and most patients need only mild to moderate pain medication.

Patients with functional tumours may experience a hormone surge during the PRRT infusion, with flushing and palpitations, but a life-threatening hormone reaction is extremely rare.

Bone marrow suppression may occur due to PRRT, even in patients who don’t have cancer spread to the bones. In many patients, this is mild and temporary, and doesn’t preclude them from further PRRT cycles. Severe bone marrow suppression is rare, occurs in only 1–2% of patients, and in most patients, the bone marrow makes a full recovery even though transfusions may be needed.

Myelodysplastic syndrome or bone marrow failure occurs in < 1% of patients and usually only months or years after the last PRRT. Risk factors for this includes patients who previously received chemotherapy, patients who had multiple PRRT cycles, older patients, and patients who have an unrelated underlying bone marrow problem.

What is the mechanism of bone marrow suppression due to PRRT?

Apart from the expected direct action on surrounding bone marrow due to cancer in or close to bones, the Lu-177 may separate from the DOTATATE peptide and settle within the bone marrow.

In patients with poor kidney function, the Lu-177 is cleared slower from the body, potentially leading to prolonged exposure to bone marrow and other tissues.

However, studies show that the radiation-absorbed dose to bone marrow from a standard four-cycle PRRT protocol is below the threshold for permanent damage in most patients. It must be highlighted that PRRT generally causes far less bone marrow suppression than most types of chemotherapy, with a lower risk of myelodysplastic syndrome or future leukaemia.

Response to PRRT

A DOTATATE PET/CT to assess treatment response is done after completion of the four PRRT cycles. Although PRRT doesn’t offer cure in patients with metastatic NETs, it slows tumour growth in 80–90% of patients, reduces symptoms in up to 80% of patients within weeks of the first cycle, and thereby improves quality of life.

According to the NETTER-1 trial, there is about a 20-month interval before the disease progresses again. Less than 10% of patients will have progression while on PRRT.

What comes after PRRT?

No two patients are alike. Further treatment would be best discussed at a MDM. Various options are possible, depending on the sites and extent of residual cancer after PRRT: octreotide injections for maintenance, everolimus, surgery, radiofrequency ablation of liver lesions, or even chemotherapy.

Should there be disease progression in the future, further PRRT cycles may be given, provided the patient has adequate bone marrow, kidney, and liver function.

Final thoughts

Although the cost of PRRT per cycle is high (+-R100 000), the total annual cost is more affordable than high-dose octreotide, or other therapies with worse side effects.

PRRT is a well-tolerated and effective treatment choice, with minimal side effects. The treatment effect can last for months or even years.

Although every patient with a NET has a unique treatment journey, PRRT will benefit most patients.