Australasian Consensus Statement on the Identification, Prevention, and Management of Hormonal Crises in Patients with Neuroendocrine Neoplasms Undergoing Peptide Receptor Radionuclide Therapy

Following the publication of the NETTER-1 randomized control trial [1], peptide receptor radionuclide therapy (PRRT) is becoming an established therapeutic option for patients with progressive metastatic neuroendocrine neoplasms (NENs). NEN patients with symptoms from hormone production may experience worsening symptoms, either acutely due to sudden hormone release or subacutely due to interruption of their long-acting somatostatin analogues (SSAs) during the PRRT treatment period. The clinical manifestation is dependent on the specific hormone involved.

Approximately 20% of NEN patients (mainly midgut NENs) experience carcinoid syndrome [2]. This is due to the secretion of mediators, such as serotonin, histamine, kinins, and other peptides, leading to flushing, diarrhoea, and bronchospasm. There is also an association with carcinoid heart disease, primarily involving valves and myocardium of the right heart. Carcinoid crisis is a life-threatening form of carcinoid syndrome that results from a large amount of vasoactive mediators being released from NENs, manifesting as severe flushing and diarrhoea, significant hypotension, tachycardia, bronchoconstriction, and mental status changes. Furthermore, the haemodynamic changes of carcinoid crisis – including venodilation and reduced cardiac preload – are poorly tolerated in the presence of carcinoid heart disease (that is dependent upon a high central venous pressure to overcome the tricuspid regurgitant jet), leading to a cycle of progressively decompensating cardiac output.

Potential iatrogenic triggers for hormonal crises include tumour manipulation during surgery or tumour biopsy, anaesthesia, liver-directed therapies, and most recently PRRT. A major contributing factor is that PRRT protocols generally require the interruption of long-acting SSAs prior to PRRT administration. Supplementary short-acting SSA formulations may be used before and after PRRT for symptom control [3].

Similarly, hormonal syndromes from functional pancreatic NENs, such as insulinomas or VIPomas, may also worsen following PRRT due to temporary interruption of SSAs or hormone flare [4]. Hormonal crisis is rare and reported in <1% of NEN patients who undergo PRRT [3, 4]. Recent case series have reported NEN patients developing acute flare of carcinoid symptoms or carcinoid crisis during/after PRRT with 177Lu-DOTA-octreotate, as summarized in Table 1.

The purpose of this consensus document is to assist clinicians by providing practical advice on the identification of patients at risk, prevention and treatment of hormonal crises in NEN patients undergoing PRRT. The main focus is on carcinoid crises. The rare hormonal crises seen in functional pancreatic NENs are briefly addressed in a separate section. We have not covered phaeochromocytoma/paragangliomas in our guidelines due to the complexity of their management. Our recommendations have been developed on the basis of the expert opinion of a multidisciplinary NEN team, comprising medical oncologists, endocrinologists, anaesthetists, and nuclear medicine specialists across NEN centres in Australasia.

We used MEDLINE and PUBMED to identify studies reporting on risk factors, management, and follow-up of NEN patients who are at risk or developed carcinoid crises during PRRT. We used the following search terms: “carcinoid crisis,” “carcinoid symptom,” “hormonal crisis,” “neuroendocrine tumour or neoplasm,” and “lutate or Lutathera or PRRT or radionuclide.” The search was limited to human studies published in English.

All recommendations were derived on the basis of the best available evidence supplemented by the authors’ clinical experiences. Nineteen Australian and New Zealand medical oncologists, endocrinologists, anaesthetists, and nuclear medicine physicians with recognized expertise in NENs took part in the consensus process.

It is difficult to identify clear clinicopathologic predictors of peri-procedural carcinoid crisis [9]. Published reports (Table 1) have identified that patients with a prior history of carcinoid crisis, poorly controlled carcinoid syndrome, high tumour burden (especially liver metastases), and carcinoid heart disease are at higher risk of carcinoid crisis [4, 5, 7]. Similarly, these factors are associated with increased risk of intra-operative carcinoid crisis [10]. Carcinoid syndrome in patients with high-volume liver metastases stems from tumour-produced vasoactive mediators bypassing hepatic degradation and entering the systemic circulation.

Carcinoid heart disease represents an independent poor prognostic factor in NEN patients. Its pathophysiology is theorized to be due to excessive circulating vasoactive substances, such as serotonin, causing plaque deposition on endocardial surfaces of valves and surrounding structures, particularly the tricuspid valve [11, 12]. The resultant right-sided cardiac impairment leads to hepatic congestion, reducing clearance of serotonin and thus worsening carcinoid syndrome. Carcinoid heart disease requires special consideration peri-operatively due to risk of right heart failure, arrhythmia and stresses associated with surgery [13], and poor tolerance of reduced central venous pressure associated with carcinoid crisis. Similarly, formal assessment for the presence and optimization of carcinoid heart disease is recommended before PRRT, particularly for patients with midgut NENs and carcinoid symptoms.

Urinary 5-hydroxyindoleacetic acid (5-HIAA) is a breakdown product of serotonin and used as a surrogate marker for serotonin overproduction. The presence of carcinoid heart disease and high 5-HIAA levels has been associated with increased risk of peri-operative carcinoid crisis [14].

We propose that patients be risk stratified into three groups based on the characteristics listed outlined in Table 2: low, moderate, and high risk. This proposed risk stratification enables tailored peri-procedural management.

• All NEN patients undergoing PRRT should be evaluated for the risk of PRRT-related carcinoid crisis and be risk stratified into low-, moderate-, and high-risk groups.

• Multidisciplinary team discussion (with the participation of an endocrinologist/anaesthetist with interest in NENs if possible) should identify tumour and patient characteristics associated with increased risk of carcinoid crisis. Nuclear medicine, high dependency medical unit, emergency response staff, emergency department, and wardstaff should have adequate training and protocols in place to recognize and manage carcinoid crisis.

• Patients at moderate to high risk of carcinoid crisis should ideally undergo PRRT at tertiary centres with experience in the management of carcinoid crisis.

• Patients with NENs of midgut and pulmonary origin should have physical examination and consideration of pre-procedural echocardiogram (particularly if no echocardiogram within the preceding 6 months) to assess for carcinoid heart disease. Chromogranin A and urinary 5-HIAA should be measured as an indicator of serotonin secretion.

Pre-procedural interventions aim to reduce the secretion of vasoactive mediators, such as serotonin and histamines, as well as dampen their effects. There are variable views surrounding the timing of regular SSAs around PRRT. When clinically feasible, the most recent long-acting SSA administration should be 3–4 weeks before PRRT (depending on the patient’s baseline SSA frequency). Any interruption or discontinuation of SSA administration prior to PRRT may lead to increased serum levels of bioactive peptides. This is of particular concern if patients experience carcinoid symptoms upon withholding long-acting SSAs. As such, short-acting SSAs may be used in these individuals as bridging therapy for symptom control around time of PRRT.

The rationale for temporarily interrupting SSA use prior to PRRT is due to the concern of competitive binding between the administered SSA and radiopeptide towards the somatostatin receptor (mainly type 2) compromising the concentration of radiopeptide in the tumour and potentially reducing the effectiveness of PRRT. There is now preliminary evidence that SSAs may not interfere as much with tumour uptake as previously thought and in fact potentially augment the therapeutic index of PRRT by increasing tumour uptake and reducing physiologic activity, although this is still debated [15‒17].

The European Neuroendocrine Tumour Society (ENETS) guidelines recommend stopping short-acting SSAs 8 h prior to PRRT [3]. The American Neuroendocrine Tumor Society (NANETS) and joint International Atomic Energy Agency (IAEA), European Association of Nuclear Medicine (EANM), and Society of Nuclear Medicine and Molecular Imaging (SNMMI) practical guidelines recommends stopping short-acting SSAs 24 h prior [18].

There is no available literature supporting the use of prophylactic SSA in preventing carcinoid crisis. One of the more common iatrogenic precipitants of carcinoid crisis is surgery, and retrospective studies did not find a clinical benefit in patients who receive pre-operative or intra-operative SSA [9, 10, 19]. Differing views are presented in the recommendations proposed by Clinical Oncology Society of Australia (COSA), ENETS, and NANETS. COSA and ENETS recommend octreotide infusion during the peri-operative period [20, 21]. In contrast, NANETS makes note of the lack of evidence supporting prophylactic octreotide but acknowledges the common practice of intra-operative octreotide infusions [22].

Other pre-medications aim to dampen the effect of proteins and cytokines released by NENs during PRRT. Corticosteroid therapy with dexamethasone reduces reactions from non-specific histamine release. Ondansetron/granisetron, loratadine and ranitidine/famotidine block serotonin (5-HT₃), histamine H1 and histamine H2 receptors, respectively. 5-HT₃ antagonists are also given as PRRT pre-medication to reduce potential adverse effects of nausea related to the renoprotective amino acid infusion [1].

Recently, there has been interest in the use of a tryptophan hydroxylase inhibitor, telotristat ethyl, to decrease carcinoid syndrome diarrhoea [23]. Little is known about its effect in the PRRT setting, but our recommendation is that patients on established telotristat ethyl therapy should continue this during PRRT.

For all patients regardless of risk category:

• The most recent long-acting SSA should be administered 3–4 weeks before the PRRT treatment date (depending on dosage frequency). PRRT should be scheduled as close as possible to the next long-acting SSA administration to avoid dose interruption. Short-acting SSA (if used) should be ceased 8 h prior to PRRT.

• Patients should receive pre-medication 1 h prior to PRRT as per local institutional guidelines.

• Patient’s SSA dosing should be optimized and maximized prior to consideration of PRRT. Any intercurrent illness should be treated.

• Prolonged diarrhoea can cause electrolyte disturbance, dehydration, and hypoproteinaemia, worsening carcinoid crises. The treatment of diarrhoea should be optimized before PRRT with loperamide therapy, intravenous hydration, and correction of any electrolyte disturbance as appropriate.

• Octreotide and protocols for its emergency use should be readily available in the department where PRRT is being delivered (most commonly the Nuclear Medicine department).

• A medical oncologist or endocrinologist (with experience managing hormonal crises) should be involved in the hospital care of patients undergoing PRRT.

For moderate-risk patients:

• Consider the addition of antihistamines (e.g., 10 mg PO loratadine and 150 mg PO ranitidine/40 mg PO famotidine) as part of the PRRT pre-medication regimen.

• Short-acting octreotide should be prepared and within easy reach at time of PRRT. Clearly labelled 100 μg octreotide syringes should be available within the department, and PRRT should be carried out in the presence of one or more registered nurses to allow for octreotide administration.

• For patients with carcinoid symptoms on higher dosage of SSA, carcinoid heart disease, and/or increased urinary 5-HIAA levels, consider regular subcutaneous octreotide starting at 100–200 μg TDS for 7 days prior to PRRT.

• For high-risk patients, in addition to management as per moderate-risk patients:

• Patients should be admitted into hospital 24 h prior to PRRT to control diarrhoea, optimize hydration and electrolyte, and optimize right heart failure if present.

• Early input from endocrinology, medical oncology, and high-dependency medical unit is required.

• If symptoms are severe and uncontrollable with cessation of SSAs, consider continuing octreotide until the commencement or even throughout PRRT.

Two case series of high-risk NEN patients undergoing PRRT have reported that the onset of carcinoid crises is usually immediate but may present up to 2 days following PRRT [4, 7]. Almost all reported cases of carcinoid crises started during the first dose of PRRT. Table 3 summarizes the peri-procedural care and outcomes of published NEN patients who had PRRT-related carcinoid crises.

Intravenous octreotide infusion is effective in the acute treatment of carcinoid crisis [24]. Intravenous bolus octreotide is insufficient due to its short plasma half-life of 90–120 min. Intravenous bolus injections followed by continuous infusion is the mainstay of management. Its continuous use corrects blood pressure changes through its inhibition of vasoactive mediator release from tumour and by blocking receptors [25]. ENETS recommends re-starting long-acting SSA following PRRT, with co-administration of short-acting SSA in the first 7–10 days if needed for symptom management [3].

All patients:

Continue medication(s) for symptom control, such as 5-HT₃ antagonists or corticosteroids, as per local institutional guidelines.

For moderate-risk patients:

• Patients who are at moderate risk should have inpatient monitoring for 24–48 h after PRRT.

• Octreotide may be resumed following PRRT at dosage of 100–200 µg subcutaneously TDS. Long-acting SSA should be resumed within 24 h following PRRT.

For high-risk patients:

• In addition to the above, patients at high risk of carcinoid crisis should be closely monitored, ideally in a high-dependency unit for 24 h after PRRT, or inpatient monitoring in a medical ward.

• In the event of carcinoid crisis with haemodynamic instability, bronchospasms, severe flushing, or diarrhoea, immediate involvement of medical and HDU/ICU teams is mandatory.

• The assessment, management, and transfer of patients to other hospital units (if required) following PRRT should consider radiation safety implications and follow local institutional policies.

• IV boluses of 100–200 µg octreotide should be administered 5–10 min apart, followed by continuous infusion of octreotide commencing at 100 µg/h and escalate accordingly based on local experience (usually up to 200 µg/h, but doses up to 500 μg/h have been reported).

• Invasive haemodynamic monitoring (arterial catheter ± central venous catheter) should be placed as soon as practical.

• Intravenous hydration and vasopressors (metaraminol and phenylephrine preferred) should be given with ICU support and expertise.

• If the patient has previously experienced a carcinoid crisis, the dose and schedule of SSA demonstrating control of the previous episode should be the reference starting point.

• Please note that in the event of bronchospasm, β-receptor agonists and theophylline should be avoided if possible, since they may precipitate further mediator release.

• Once haemodynamic stability is achieved, slowly wean octreotide infusion by 25–50 µg/h as tolerated and convert to subcutaneous octreotide with endocrinology input.

• Ondansetron 4 mg IV daily and dexamethasone 4 mg IV daily should be continued until symptoms have returned to baseline.

• In patients who develop PRRT-related carcinoid crisis, additional precautions need to be taken before the administration of further therapy cycles, including prolonged observation in the hospital after therapy and continuing short-acting octreotide.

• In patients who do not experience any PRRT-related carcinoid crisis/severe worsening of symptoms, consider downgrading their risk management by one risk category for the following cycle of PRRT.

Functional pancreatic NENs lead to hormonal syndromes by secreting hormones such as gastrin, insulin, vasoactive intestinal peptide, and glucagon. Case reports and retrospective institutional series on functional pancreatic NENs treated with PRRT have shown high efficacy without significant toxicities or immediate hormonal crisis [26‒30]. De Keizer et al. [4] reported worsening symptoms of VIPoma following PRRT, and supportive measures were undertaken with good effect.

Since there is a paucity of evidence surrounding the risk of hormonal crises with PRRT for functional pancreatic NENs, the above recommendations for clinical management of carcinoid crisis should also be adopted for these patients. Based on our panel’s experience with insulinomas and PRRT, we recommend managing insulinoma patients undergoing PRRT as “high risk.” Also, the principles for peri-operative management of functional pancreatic NENs should be followed. ENETS consensus guidelines recommend optimization of a patient’s symptoms specific to the hormone-secretory syndrome prior to the procedure and continuing supportive measures for hormone-related events post-procedurally [21].

• All patients with pancreatic NENs should have baseline plasma glucagon, gastrin, insulin, and vasoactive intestinal peptide levels such that their secretory syndrome is defined. They should also have maximization of SSAs and specific medical therapies pertinent to the hormone syndrome.

• All patients with symptomatic, functional pancreatic NENs should be admitted into hospital 24 h prior to PRRT and be observed as an inpatient for 24–48 h following PRRT.

• Appropriate endocrinology and intensive care teams should be aware of their admission and the potential for deterioration.

• If symptoms from functional NEN are not adequately controlled, consider continuing SSA as subcutaneous octreotide 100 µg TDS prior to PRRT and resume shortly thereafter.

• Insulinomas patients should be managed like “high-risk” patients. Additionally, they should have frequent blood sugar level measurement as clinically indicated following PRRT for 48 h due to the risk of post-treatment hormonal flare exacerbating initial hypoglycaemia.

• VIPomas should have adequate hydration and electrolyte replacement around the time of PRRT.

• Gastrinomas should have ongoing high-dose proton pump inhibitor therapy.

• Ectopic ACTH syndrome should have electrolyte monitoring and/or replacement due to risk of hypokalaemia.

The incidence of NENs is on the rise, as is the availability of PRRT in tertiary centres worldwide. For patients with functional NENs, comprehensive multidisciplinary care is required to achieve oncologic and symptomatic control. The managing teams should have awareness of the processes required for the prevention and peri-procedural management hormonal crises in the setting of PRRT.

There is a paucity of data on carcinoid crisis following PRRT. In NETTER-1, the largest trial of PRRT in midgut NETs, no patients experienced carcinoid crisis. This may be due to recruitment bias, since patients’ carcinoid symptoms had to be adequately controlled on standard dose long-acting SSAs [1]. The only published reports describing peri-PRRT carcinoid crisis consists of two retrospective series and isolated case reports (Tables 2, 2, 3). Tapia Rico et al. [7] described the peri-procedural management of 7 patients identified to be at high risk of carcinoid crisis in two Australian institutions.

Despite the relatively low reported incidence of carcinoid crisis, careful identification, preparation, and monitoring of patients at risk of developing hormonal crises following PRRT is prudent to avoid the potentially detrimental outcome in these patients. We have stratified patients based on available literature and expert opinion.

Our guidelines have been created on the basis of clinical demand, stemming from the increased availability of PRRT in Australasia and clinician concerns regarding precipitation of hormonal crises. Given the relative paucity of published data, a consensus statement approach was formed by an expert multidisciplinary panel. We hope that this article will offer guidance to physicians struggling with optimal identification and management of hormonal crises in NET patients undergoing PRRT.

Carcinoid or hormonal crisis in patients with progressive metastatic NENs is a rare but life-threatening complication of PRRT. We recognize the scarcity of data in this area. However, clinician awareness, recognition, and management of this phenomenon are crucial for future practice. These recommendations should not be considered prescriptive but should be tailored to the patient, local experience, and resources.

The authors have no conflicts of interest to declare.

No funding to declare.

Nick Pavlakis and Timothy J. Price conceived the original idea. Minmin Li carried out the literature review and drafted the manuscript. David L. Chan and Nick Pavlakis were involved in planning and supervising. All the authors – Minmin Li, David L. Chan, Gonzalo Tapia Rico, Gabrielle Cehic, Ben Lawrence, David K. Wyld, David A. Pattison, Grace Kong, Rodney J. Hicks, Michael Michael, Andrew Ddembe Kiberu, Jennifer Lim, Roderick Clifton-Bligh, Venessa Tsang, Paul J. Roach, John Leydon, Connie I. Diakos, Timothy J. Price, and Nick Pavlakis – discussed the contents of the article and contributed substantially to the final manuscript.