Patients with metastatic disease who have progressed following first-line SSAs may be suitable for systemic radionuclide therapy (or PRRT). A major criteria for selection is sufficient expression of somatostatin receptors as demonstrated on molecular imaging, typically with 68Ga-DOTATATE PET/CT scan. These provide the suitable target for systemically administered radiopharmaceutical. Imaging with 18F-FDG PET provides additive in-vivo evaluation of grade with the ideal situation being high somatostatin receptor expression (ideally Krenning score 3-4) without discordant FDG avidity.

PRRT can be delivered concurrently with chemotherapy when appropriate, such as in patients with extensive tumour burden, pNETs, rapid disease progression or those with higher grade disease at diagnosis (GI Cancer Institute 2021). This treatment option should only be recommended following patient review at an appropriate NET multidisciplinary team. Some expert centres may use PRRT as first-line in selected cases.

There are several centres around Australia with expertise to deliver PRRT for NETs. PRRT is usually an outpatient (day admission) therapy (refer to Appendix E). An infusion of amino acids is administered at the time of PRRT to help protect the kidneys from nephrotoxicity. The radiopharmaceutical itself is usually infused over 15–20 minutes following appropriate premedication.

PRRT is most often given as an induction course of four treatments, with each dose/cycle separated by six to eight weeks.

During the recent NETTER-1 trial (Strosberg et al. 2017), patients were able to tolerate standard doses of ¹⁷⁷Lu-DOTATATE without any significant decline in renal function compared with patients who received high-dose SSA therapy. Both amino acid infusions and intravenous radiopharmaceuticals can result in nausea and so antiemetic medication is given routinely to reduce the risk of nausea and vomiting.

In case of eventual future NET progression, the patient’s multidisciplinary team should consider repeating PRRT treatment as salvage therapy. In many countries, including Australia, PRRT can continue to be offered, with appropriate intervals, providing there was initial objective and symptomatic treatment response.

PRRT is also suited to patients with poorly controlled NET symptoms, even when there is only stable or slowly progressive tumour burden.

There are several different radionuclides that can be used for PRRT. Those currently used in Australia include:

• ¹⁷⁷Lu-DOTATATE is currently the radiopharmaceutical of choice.
• Yttrium-90 (Y-90 or 90Y) was the original isotope used in PRRT but is now largely replaced by ¹⁷⁷Lu-DOTATATE due to its lower cost and toxicity.
• Actinium-225 (Ac-225 or 225Ac) is the newest radionuclide used in PRRT. It is still an investigational agent but its compassionate use in Australia is slowly increasing.
• Copper-67 (Cu-67 or 67Cu) is one of the additional emerging radionuclides. At this time of writing, it is not funded in Australia, but trials are underway.

Monitoring of PRRT side effects

PRRT is well tolerated and can be used in nearly all patients, including elderly patients. Due to its renal excretion, moderate renal impairment at baseline (GFR < 30 ml/min/1.73m2) is generally considered an absolute contraindication to PRRT, while it should be used with caution in those with milder renal impairment (GFR < 50 mL/min). Nephrotoxicity from PRRT is more likely in those with baseline renal impairment, and so close monitoring of renal function is required.

PRRT is also myelotoxic and so should be used cautiously in patients with impaired bone marrow reserve who have previously received combination chemotherapy, particularly with regimens containing alkylating agents, and in patients who are also receiving concurrent, radio-sensitising chemotherapy at the time of their PRRT. The nadir count is usually at three to four weeks after treatment, so close monitoring is recommended. Accurate CTCAE grading of cytopaenias will guide scheduling and dosing. An increase in the interval between treatments and reduction in the radiation dose of PRRT may be required in such patients.

A potential uncommon but serious side effect of PRRT is carcinoid crisis (Kaltsas et al. 2017). This can be a worsening of carcinoid symptoms or could precipitate a carcinoid crisis. Acute intravenous administration of octreotide has been reported to provide rapid reversal of a carcinoid crisis, and the current focus of carcinoid therapy is to prevent mediator release with octreotide prophylaxis. This has largely replaced the use of other drugs for acute treatment. See section 6.5 for more information on carcinoid crisis.

Timeframes for starting treatment

When PRRT is necessary (for patients who have sufficient expression of somatostatin receptors that have progressed on SSAs or where initial PRRT is considered appropriate), treatment should start as soon as possible.

Training and experience required of the appropriate specialists

Fellow of the Royal Australian and New Zealand College of Radiologists or Royal Australasian College of Physicians (or equivalent) with adequate training and experience that enables institutional credentialing and agreed scope of practice in NETs.

The training and experience of the nuclear medicine specialist should be documented.

Health service characteristics

To provide safe and quality care for patients having PRRT, health services should have these features:

• sterile radiopharmaceutical manufacturing facilities, which are licensed by the relevant state or territory authority, with access to full radiopharmaceutical quality control techniques
• a shielded room in which to deliver radionuclide therapies, authorised for such purposes by the relevant state or territory body – this room should contain emergency call provisions and medical gases with capacity for patient resuscitation if required (e.g. carcinoid crisis)
• on-site nuclear medicine specialist, medical physicist and nursing staff with training/expertise in PRRT
• capacity for immediate administration of SC or IV octreotide fluid resuscitation in the event of worsening carcinoid symptoms or crisis, as well as overnight admission for those at high risk of carcinoid crisis
• on-site gamma camera facilities for post-therapy and, where available, dosimetric scans, nuclear medicine technologist staff with training/expertise in post-therapy and dosimetric scanning and available medical physics support
• capacity for inpatient or intensive care transfer in the event of a medical emergency (e.g. carcinoid crisis).