Systemic therapies that should be considered for patients are:

• adjuvant chemotherapy for some patients with resected high-grade NETs
• SSAs
• concurrent chemotherapy / PRRT
• chemotherapy for patients with neuroendocrine carcinoma
• chemotherapy for patients with advanced high-grade / unresectable high-grade NETs
• PRRT for patients with well differentiated NETs – refer to section 4.2.4
• targeted therapies.

Medications for less common subtypes of NETS include proton pump inhibitors (gastrinomas), diazoxide (insulinomas), alpha blockers (paragangliomas and pheochromocytomas) and dopamine receptor agonists (ectopic cushings in bronchial carcinoids).

Somatostatin analogues

SSAs are the mainstay of medical treatment for most patients with NETs. Two studies show the growth delay effect with SSAs–PROMID (Rinke et al. 2016) and CLARINET (Caplin et al. 2021).

SSAs are the most common first-line treatment of G1/G2 NETs. They have antisecretory and antiproliferative effects. Depot injections of SSAs (octreotide, lanreotide) are available to control some symptoms caused by NETs. Injections of these analogues can stop the overproduction of hormones (e.g. serotonin) that cause symptoms such as flushing and diarrhoea. These are usually given every four weeks – sometimes more frequently (two or three weekly).

Short-acting octreotide may be considered to control symptoms for two to three days until a correct dose of long-lasting SSA can be prescribed. In some cases, short-acting SSA may be used ongoingly to treat breakthrough symptoms of severe diarrhoea and flushing in patients with active/severe carcinoid syndrome.

Once commenced, SSA therapy is usually continued for life unless there are intolerable poorly tolerated side effects, even when second-line therapies have been instituted.

Molecular targeted therapies

An mTOR inhibitor (everolimus) has been developed to treat advanced NETs of the gastrointestinal tract, lung and pancreas. This drug can help slow down the growth of these tumours in some patients, but it does not usually shrink tumours.

Sunitinib, a drug with multiple targets, is also effective in slowing down the growth of pNETs.

Other targeted therapies for NETs are being researched in clinical trials. They include drugs that interfere with new blood vessel formation or with specific survival pathways of cancer cells.

Chemotherapy

Chemotherapy may be considered for some patients, especially for NET patients with pancreatic, bronchial or high-grade (G2/G3) NETs. Not all NETs respond equally to chemotherapy, therefore careful selection is required to improve the chance of response and avoid unnecessary side effects and toxicity. The histological grade and the primary site of the tumour (how it looks under the microscope after biopsy or operation) may help determine the type of treatment that is recommended. Although there is little data to guide practice, chemotherapy may sometimes be recommended after surgery (adjuvant chemotherapy) (NCCN 2021).

PRRT has now emerged as an effective therapy for paragangliomas/phaeochromocytomas, although combination chemotherapy may sometimes be used in some cases for patients with phaeochromocytomas and paragangliomas.

Timeframes for starting treatment

When active treatment is considered necessary, treatment should start within four weeks of the treatment decision.

Training and experience required of the appropriate specialists

Medical oncologists and endocrinologists must have training and experience of this standard:

Fellow of the Royal Australian College of Physicians (or equivalent) with adequate training and experience that enables institutional credentialing and agreed scope of practice in NETs (ACSQHC 2015).

Documented evidence of the medical oncologist and endocrinologist’s training and experience, including their specific (sub-specialty) experience with NETs should be available.

There is strong evidence to suggest that institutions with a high volume of NET patients have better clinical outcomes due to comprehensive multidisciplinary management (Magi et al. 2019; Tsoli et al. 2018).

Cancer nurses should have accredited training in these areas:

• anti-cancer treatment administration
• specialised nursing care for patients undergoing cancer treatments, including side effects and symptom management
• the handling and disposal of cytotoxic waste (ACSQHC 2020).

Systemic therapy should be prepared by a pharmacist whose background includes this experience:

• adequate training in systemic therapy medication, including dosing calculations according to protocols, formulations and/or preparation.

Some therapies may be delivered by a general practitioner or nurse with training and experience that enables credentialing and agreed scope of practice within this area. This should be in accordance with a detailed treatment plan or agreed protocol, and with communication as agreed with the medical oncologist or endocrinologist with NET interest or as clinically required.

Health service characteristics

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

• a clearly defined path to emergency care and advice after hours
• access to full-suite diagnostic pathology including basic haematology and biochemistry, NET-specific biochemistry, experienced histopathology and molecular pathology and advanced imaging
• cytotoxic drugs prepared in a pharmacy with appropriate facilities
• occupational health and safety guidelines regarding handling of cytotoxic drugs, including preparation, waste procedures and spill kits (eviQ 2019)
• guidelines and protocols to deliver treatment safely (including dealing with extravasation of drugs)
• coordination for combined therapy with radiation therapy, especially where facilities are not co-located
• coordination for combined medical and systemic radiation therapy
• appropriate molecular pathology access

Lead NET team characteristics

To provide safe and quality care for patients, the lead NET team should have these features:

• significant case volume
• documented expertise in managing NETs
• ideally involved in ongoing NET research
• multidisciplinary NET coordinated care.