Some patients may benefit from surgery. The decision to proceed with surgery is often complex and must be tailored to each patient’s disease. Surgery may be undertaken with curative intent, to palliate symptoms, to prevent symptoms, or to prolong survival (Gangi & Anaya 2020).

When the cancer is detected early, is small and has not metastasised, it is treated with curative intent. Completely removing the entire tumour is the standard treatment, when possible. Most patients with localised NETs are successfully treated with surgery alone. If the tumour can be removed in its entirety, then surgery may cure the cancer (NECA 2019a).

The surgical procedure undertaken will depend on the location(s) of the NET and treatment intent.

It may involve different surgical specialties if disease involves more than one organ system.

Patients with NETs of the intestine may develop complications such as bowel obstruction or ischaemia. This can sometimes necessitate emergency surgery, even in the presence of unresectable metastases. Asymptomatic intestinal NETs in the presence of widespread metastases may not require any surgery. When curative intent surgery is undertaken, locoregional lymph nodes should be removed along with the GEP-NET for adequate staging and longer term disease control.

Metastases to the liver from NETs in any part of the body may potentially be managed with surgery, either with curative intent, or to improve survival if more than 70 per cent of the disease can be removed. Overall, surgery for GEP-NET is guided by the grade and degree of differentiation of the disease.

For patients with localised paraganglioma and phaeochromocytoma, surgery is usually undertaken to completely remove the tumour, and for phaeochromocytoma is usually an adrenalectomy (removal of one or both adrenal glands). Pre-operative control of blood pressure (typically with alpha-blockade) is essential for all functioning phaeochromocytomas and paragangliomas. At the time of surgery, tissue and lymph nodes will be checked for metastases, and may be removed. If both adrenal glands are removed, lifelong corticosteroid and mineralocorticoid replacement therapy will be required.

Cardiac or thoracic surgery should be considered for patients with lung NETs, metastases to the lungs, or with carcinoid heart disease who need a cardiac valve replacement.

People who have developed carcinoid syndrome are at risk of experiencing a carcinoid crisis during surgery. These patients should already be treated with somatostatin analogues (SSAs), but if not, consideration should be given to commencing them prior to surgery. To avoid major complications from a carcinoid crisis, the anaesthetic team must be fully aware of this risk before surgery so they can have treatment on hand to control the symptoms.

Intravenous octreotide is usually given before surgery to prevent carcinoid crisis. See section 6.5 for more information on carcinoid crisis.

Palliative surgery may be offered to patients when the tumour or tumours have spread or become too large to remove completely. Palliative surgery aims to ‘de-bulk’ the tumour, which could relieve some symptoms.

Timeframe for starting treatment

Timeframe for surgery will be based on investigation and staging of the NET and surgery intent.

Training and experience required of the surgeon

Fellow of the Royal Australian College of Surgeons (or equivalent) with adequate training and experience that enables institutional credentialing and agreed scope of practice in this area.

Documented evidence of the surgeon’s training and experience, including their specific (sub-specialty) experience with NETs and procedures to be undertaken, should be available.

Different surgeons may be involved such as colorectal, hepatobiliary, and cardiothoracic.

There is strong evidence to suggest that institutions with a high volume of NET resections have better clinical outcomes for complex cancer surgery (Toomey et al. 2016).

Health service characteristics

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

• critical care support
• 24-hour medical staff availability
• 24-hour operating room access and intensive care unit
• diagnostic imaging
• pathology
• nuclear medicine imaging.

No treatment, active surveillance or watchful waiting, may be suitable for some NET patients especially if the NET is not causing symptoms or problems, there is little disease, the disease is stable, or the tumour is low grade (G1). In some circumstances, poor general health or complications secondary to treatments may also make further NET treatment inadvisable.

NETs are usually radiosensitive tumours. A number of patients may benefit from radiation therapy if they have oligometastatic disease, a dominant or critically strategic site of progression or highly symptomatic metastases (e.g. in bone):

• External beam radiation therapy can be used in selected patients with painful skeletal metastases, particularly when peptide receptor radionuclide therapy (PRRT) is unavailable or contraindicated.
• Stereotactic body radiation therapy may be considered for selected patients with solitary liver or lung metastasis, as an alternative to surgery.
• Proton beam therapy – this has not been specifically evaluated in NETs.
• Radioembolisation (selective internal radiation therapy) (see section 4.2.6) – this procedure is performed by an interventional radiologist, with the assistance of a nuclear medicine specialist licensed to administer radionuclides.

External beam radiation therapy for symptom palliation can be given to almost all patients, regardless of their overall health and performance status. More invasive procedures (e.g. radioembolisation) are not generally provided as part of end-of-life care but are offered to patients with advanced metastatic disease if it is anticipated that local disease control will improve overall symptoms or quality of life.

Timeframe for starting treatment

Treatment should start as soon as possible for symptomatic patients.

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 radiation oncologist, interventional radiologist and nuclear medicine specialist should be documented.

Health service unit characteristics

To provide safe and quality care for patients having external beam radiation therapy or stereotactic body radiation therapy, health services should have these features:

• linear accelerator capable of image-guided radiation therapy
• dedicated CT planning
• access to MRI and PET imaging
• automatic record-verify of all radiation treatments delivered
• a treatment planning system
• trained medical physicists, radiation therapists and nurses with radiation therapy experience coordination for combined therapy with systemic therapy, especially where facilities are not co-located
• participation in Australian Clinical Dosimetry Service audits
• an incident management system linked with a quality management system.

For patients undergoing radioembolisation, health services should have these features:

• sterile, licensed radiopharmaceutical dispensing facilities with adequate storage of radioactive waste
• interventional radiology facilities (digital subtraction angiography) and appropriately trained and credentialed radiologists with experience in hepatic artery anatomy and radioembolisation techniques, authorised for use of unsealed radiation sources by the relevant state or territory licensing authority
• trained medical physicists and nurses with nuclear medicine and interventional radiology experience
• capacity for concurrent or sequential trans-catheter chemo-embolisation
• capacity for post-treatment inpatient admission for pain relief if required
• trained nuclear medicine specialists for dose calculation and treatment planning (together with interventional radiologist, referring clinician and medical physicist)
• SPECT or PET facilities for pre-treatment dosimetric planning and post-therapy dose distribution and isodose contouring.

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).

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.

Hepatic artery embolisation (HAE) and transcatheter arterial chemoembolisation (TACE) may benefit patients if the NET tumour has spread to the liver.

Radioembolisation (selective internal radiation therapy) may benefit patients with liver metastases that cannot be removed with surgery.

Embolisation may benefit patients with pheochromocytomas and paragangliomas.

Ablation therapy (radiofrequency or cryoablation) may benefit patients with tumours specific regions (e.g. in the liver).

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

Interventional radiologist (Fellow of the Royal Australian and New Zealand College of Radiologists (or equivalent)) with adequate training and experience in liver-directed therapies and institutional credentialing and agreed scope of practice in NETs.

Tier B (advanced) interventional radiology competency (as defined by the Royal Australian and New Zealand College of Radiologists / Interventional Radiology Society of Australasia) is recommended following fellowship training sufficient to obtain European Board of Interventional Radiology or equivalent standard.

Immunotherapy is a rapidly evolving therapeutic field in different types of cancer. However, the role of immunotherapy in managing NETs is still investigational.

Immunotherapy for NETs management is currently being evaluated in several studies using innovative clinical trial designs, such as basket or umbrella trials, either prescribed alone or in combination with other therapies.

The key principle for precision medicine is prompt and clinically oriented communication and coordination with an accredited NETs multidisciplinary team. Tissue analysis is integral for access to emerging therapies and, as such, tissue specimens should be treated carefully to enable additional histopathological or molecular diagnostic tests in certain scenarios.