The management of refractory carcinoid syndrome: challenges and opportunities ahead

Neuroendocrine tumors (NETs) can secrete serotonin and other vasoactive substances, giving rise to the carcinoid syndrome, a constellation of symptoms characterized by diarrhea, flushing, wheezing, and right-sided valvular heart disease¹. Carcinoid syndrome occurs in about one fifth of patients with extrapancreatic NET at diagnosis², while the exact proportion of patients who will develop this condition during the disease course is currently unknown. The recommended first-line treatment of carcinoid syndrome symptoms involves the use of somatostatin analogs (SSAs), and major improvements in flushing and diarrhea are observed in roughly 75% of patients treated with long-acting octreotide or lanreotide³. No significant difference has been demonstrated between the two SSAs in terms of carcinoid syndrome palliation⁴. Loss of response to SSAs that occurs over time has been associated with multiple mechanisms including desensitization and/or down-regulation of somatostatin receptors (SSTRs) on the tumor cell surface, acquisition of mutations by SSTR genes, and formation of autoantibodies anti-SSA^5,6.

Strategies for management of patients with carcinoid syndrome refractory or resistant to SSAs have evolved in recent years (Table 1). Above-label doses of SSAs have demonstrated efficacy at palliating hormonal symptoms, leading to improvement or resolution of diarrhea and flushing in ∼80% of patients⁷. Addition of short-acting octreotide is known to be effective in controlling breakthrough symptoms⁵, while the novel multi-receptor-targeted SSA pasireotide has failed to demonstrate superior symptom control over octreotide long-acting repeatable (LAR) at 40 mg monthly⁸. On the other hand, peptide receptor radionuclide therapy (PRRT) has been shown to reduce the carcinoid-related symptoms and improve the quality-of-life⁹, but its exact positioning in the therapeutic algorithm of the carcinoid syndrome still needs to be elucidated. The oral serotonin synthesis inhibitor telotristat ethyl has recently been investigated in the phase III TELESTAR trial¹⁰. In patients experiencing more than four bowel movements per day despite SSA therapy, the drug induced a relatively low but statistically significant improvement in bowel movement frequency. On this basis, telotristat has been recently approved by FDA for the treatment of refractory carcinoid syndrome, but the clinical meaningfulness of this drug in daily clinical practice still needs to be fully elucidated.

Table 1. Systemic treatments for refractory carcinoid syndrome: an overview of prospective and retrospective studies.

Interventions	n of patients with refractory carcinoid syndrome	Study design	Symptom response	Reference
SSAs
Octreotide LAR 40–60 mg/4 weeks	148	Retrospective	Diarrhea improvement: 79% Flushing improvement: 81%	Strosberg et al.^7
Octreotide LAR 40–90 mg/4 weeks	20	Retrospective	Symptom response rate: 45%	Chanda et al.^16
Octreotide LAR 30 mg/3 weeks	28	Phase II	Complete symptom control: 60% Partial symptom control: 40%	Ferolla et al.^17
SSA switch (octerotide LAR 20 mg/4 weeks in patients experiencing symptom progression on lanreotide 30 mg/2 weeks	10	Phase II	Symptom response rate: 82%	Ricci et al.^18
Pasireotide 600–900 μg s.c. BID	45	Phase II	Symptom response rate: 27%	Kvols et al.^19
Pasireotide LAR 60 mg/4 weeks	110	Phase III	Symptom response rate: 21%	Wolin et al.^8
Biologic agents
Peg-IFN-α2b	10	Phase II	Symptom response rate: 70%	Pavel et al.^20
Everolimus 10 mg + octreotide at variable doses	10	Retrospective	Symptom response rate: 70%	Bainbridge et al.^21
Telotristat ethyl 150–500 mg TID	15	Phase II	Mean bowel movements decrease: 44% Mean flushing episode decrease: 27%	Pavel et al.^22
Telotristat ethyl 250-500 mg TID	135	Phase III	Symptom response* (telotristat 250 mg): 44% Symptom response* (telotristat 500 mg): 42%	Kulke et al.^10
PRRT
^177Lu-DOTATATE	98	Phase III	Diarrhea improvement: 39% (calculated on the overall ^177Lu-DOTATAE arm)	Strosberg et al.^9
^131I-MIBG	11	Retrospective	Complete symptom control: 27% Partial symptom control: 55%	Ezziddin et al.^23

* Defined as: Bowel movement frequency reduction ≥30% from baseline for ≥50% of the double-blind treatment period

In this issue of Journal of Medical Economics, Huynh et al.¹¹ evaluated the economic impact of carcinoid syndrome symptoms amelioration as a result of treatment with above-standard doses of octreotide LAR. Of interest, the authors demonstrate that resolution or improvement of both diarrhea and flushing by high-dose octreotide LAR is associated with decreased healthcare costs. In particular, based on their analyses, the annual mean total healthcare expenses decrease by $14,766/person in patients with carcinoid symptom improvement as compared with patients without adequate palliation of hormone symptoms. Cost savings increase up to $15,039/person when considering the indirect effects of work loss due to inpatient or outpatient visits, and are mainly related to the reduced need for ambulatory visits. While providing useful data from a payor’s perspective, this study raises several new questions regarding the optimal management of the refractory carcinoid syndrome, namely:

1. Is carcinoid syndrome improvement associated with a significant economic benefit irrespective of the treatment used? There is evidence that median healthcare costs are significantly higher in patients with carcinoid syndrome compared with patients without, and carcinoid syndrome has been suggested to be an independent predictor of healthcare costs¹². If this premise holds true, both systemic and locoregional interventions capable of improving the carcinoid syndrome symptoms should be expected to lower the total healthcare expenditure per patient, and the magnitude of the economic benefit should depend upon the efficacy and the cost of the intervention adopted. Future studies should assess the possible economic benefit associated with other interventions aimed at controlling carcinoid syndrome as telotristat and liver metastasis debulking by surgical or embolic approaches. Data from such studies should be carefully interpreted after controlling for clinical factors including disease stage as well as tumor burden¹³, in order to exclude that the increased resource utilization typically seen in patients with more advanced disease stage may bias the analysis.

2. How can we maximize the economic benefits associated with carcinoid syndrome treatment? As shown in the commented study¹¹, a decrease of costs for outpatients provides the largest percentage of cost savings in patients responsive to the above-standard doses of octreotide LAR. This is arguably due to a reduced need for ambulatory visits in patients with controlled carcinoid syndrome, and implies that interventions characterized by high efficacy/toxicity ratio in palliating hormonal syndromes can ease the financial burden of carcinoid syndrome. It is, therefore, essential to define the optimal sequence of treatment for patients with refractory carcinoid syndrome, and prospective, randomized trials comparing above-standard dose SSAs vs telotristat are particularly warranted in this setting. Ideally, such trials should compare not only the safety and efficacy profile of the agents under investigation, but also their impact on the quality-of-life as well as pharmacoeconomic parameters. In the absence of substantial difference in terms of efficacy and tolerability, interventions characterized by lower costs should be preferred.

3. Is treatment personalization feasible and economically convenient when managing patients with refractory carcinoid syndrome? Matching the right patient with the right therapy is imperative in the “precision medicine” era, and carries the potential of optimizing resource utilization by increasing the cost-effectiveness of treatments¹⁴. However, despite efforts to better characterize and stratify NETs at the molecular level being undergoing, there is currently no biomarker capable of guiding treatment selection in the routine clinical practice. Although the role of SSTR expression in predicting SSA efficacy may seem quite obvious, no definite evidence supports the idea that octreotide or lanreotide should be reserved to patients with SSTR-over-expressing NETs and concurrent carcinoid syndrome³. Similarly, it is unclear whether or not telotristat could be considered in patients with carcinoid syndrome but normal serotonin levels, as assessed by measurement of the urinary metabolite 5-hydoxyindoleacetic acid (5-HIAA). In the TELESTAR trial, indeed, the benefit of the drug was consistent across populations of patients with either elevated or normal urine 5-HIAA¹⁰. So far, the mechanism of this benefit remains uncertain, as it is uncertain whether the expression levels of tryptophan hydroxylase (TPH), the rate-limiting enzyme in the serotonin synthesis that is targeted by telotristat, may predict improved symptom control. In the future, high-throughput sequencing technologies, whose costs dramatically decreased in recent years, allowing their routine clinical use, might deepen our understanding of the molecular features of functioning NETs, possibly leading to the development of tools able to assist physicians in pre-selecting patients more likely to respond to specific treatments, thus reducing unnecessary/ineffective interventions and resulting in quality-of-life improvement¹⁵, as well as a reduction of healthcare costs.

4. What is the optimal time to escalate therapy with an SSA or initiate alternative treatments for an uncontrolled carcinoid syndrome? Does the timing of treatment have an impact on the financial burden of refractory carcinoid syndrome? It is well known that carcinoid heart disease is a late complication of carcinoid syndrome, and results from the chronically elevated levels of circulating serotonin. An argument can be made that reductions of serum serotonin levels by treatment with SSAs or telotristat may decrease the risk of development or progression of heart valvular fibrosis, eventually leading to reduced healthcare resource utilization. However, to date, there are no data in this regard, and no evidence exists that either an early escalation of SSAs or initiation of telotristat in patients with elevated serotonin levels may prevent or delay the recurrence/worsening of hormonal symptoms. The definition of universally accepted criteria for carcinoid symptom progression might help practitioners in identifying the optimal timing for treatment escalation in daily clinical practice.

A few decades ago, when surgery, chemotherapy, and radiotherapy were the only options for the treatment of metastatic small bowel NETs, patients with functioning tumors had shorter median survival as compared with those with non-functioning neoplasms. With the introduction of novel agents, the influence of carcinoid syndrome on NET patient prognosis has substantially diminished¹³. Since improved survival duration translates into increased healthcare resource utilization, pharmacoeconomic considerations will become increasingly important in the next few years for countries with either public or private healthcare systems. Pharmacoeconomic evaluations, as that related to this Commentary, may help healthcare stakeholders to properly allocate resources, avoid financial toxicity, and keep the sustainability of the healthcare system. However, future research is needed to identify new molecular targets for the treatment of carcinoid syndrome and optimize healthcare expenditure by delivering a truly precise medicine to the bed of NET patients.

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Declaration of funding

This manuscript was not funded.

Declaration of financial/other relationships

The authors have disclosed that they have no significant relationships with, or financial interests in, any commercial companies related to this study or article. No assistance in the preparation of this article is to be declared. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.