Prescribing Characteristics of Octreotide Immediate-Release and Long-Acting Release in Patients with Neuroendocrine Tumors

Abstract

Background

Treatment recommendations for patients with neuroendocrine tumors (NETs) include the use of octreotide long-acting release (LAR) for long-term therapy and immediate-release (IR) as rescue therapy to control the breakthrough symptoms of carcinoid syndrome (CS). High doses of LAR are commonly used in clinical practice. This study aimed to evaluate the real-world utilization of LAR and preceding IR use at the prescription and patient levels.

Methods

We used an administrative claims database (2009-2018) containing privately insured enrollees. We calculated the normalized LAR dose from pharmacy claims and the initial mean IR daily dose at the prescription level. At the patient level, we conducted a retrospective cohort study that included patients continuously enrolled with ≥1 pharmacy claim of LAR and evaluated the frequency and the clinical reason for dose escalation of LAR. The definition of the above-label maximum dose of LAR was ≥30 mg/4 weeks.

Results

Nineteen percent of LAR prescriptions had an above-label maximum dose. Only 7% of LAR prescriptions had preceding IR use. There were 386 patients with NETs or CS vs. 570 with an unknown diagnosis. Comparing patients with NETs or CS to those with an unknown diagnosis, 22.3% vs. 11.0 % experienced dose escalations and 29.0% vs. 26.6% had IR use before dose escalation, respectively. LAR dose escalation occurred in 50.9% vs. 39.2% for symptom control, 12.3% vs. 7.1% for tumor progression control, and 16.6% vs. 6.0% for both reasons in NETs/CS and unknown groups, respectively.

Conclusion

Octreotide LAR dosing above the label-maximum dose is common and IR rescue dosing appears to be underutilized.

Treatment recommendations for patients with neuroendocrine tumors (NETs) include the use of octreotide long-acting release (LAR) for long-term therapy and immediate-release (IR) as rescue therapy to control the breakthrough symptoms of carcinoid syndrome. This article evaluates the real-world utilization of LAR and preceding IR use at the prescription and patient levels.

Implications for Practice.

Octreotide immediate-release (IR) and long-acting release (LAR) are commonly used in patients with neuroendocrine tumors. Previous studies showed that dose escalation and high-dose LAR are commonly used for symptom control and tumor progression. However, supplemental IR is essential in comprehensive management for controlling symptoms beyond the dose escalation of LAR. Currently, the real-world utilization of LAR and IR is not well described. Anecdotally, it appears that IR is underused to manage symptoms and instead the LAR dose is escalated to try and manage symptoms. We also believe octreotide LAR dosing is above the FDA label-maximum dose. This study characterizes prescribing patterns and evaluates the potential reason for dose escalation of LAR.

Introduction

Neuroendocrine tumors (NETs) are rare and slow-growing neoplasms originating from widely diffused neuroendocrine cells throughout the body, most frequently occurring in the gastrointestinal tract, pancreas, and lungs.¹ Histologically well-differentiated NETs, previously called carcinoid tumors, are the most common NETs.¹ The incidence of NETs increased from 1.09 to 6.98 per 100,000 in the US from 1973 to 2012.² The primary clinical symptoms in patients with advanced, functional NETs is called carcinoid syndrome (CS),³ which includes flushing, diarrhea, cardiac valvular fibrosis, mesenteric fibrosis, abdominal pain, and decreased health-related quality of life.⁴

Octreotide acetate is a somatostatin analog that helps manage NETs and is considered the first-line therapy for metastatic disease.^5,6 Octreotide is available in 2 formulations: a long-acting release (LAR) depot intramuscular injection and a subcutaneous immediate-release (IR) injection.⁷ Octreotide alleviates diarrhea and flushing symptoms of CS and has a tumor antiproliferative effect. At a cellular level, it binds to somatostatin receptors (predominately somatostatin receptor type 2), which inhibits/minimizes tumoral secretion of peptide hormones and vasoactive amines. Resistance to standard doses of octreotide LAR depot formulation can be overcome in some patients with dose escalation.

Based on the pharmacology, once all receptors are occupied with the drug, higher doses will not convey a benefit; however, there are 5 somatostatin receptors with low, intermediate, and high octreotide binding affinity, which may impact clinical efficacy. LAR dosing is recommended at 20 mg/4 weeks in patients with NETs who showed a response to IR.⁷ A dose increase to 30 mg/4 weeks should occur in patients who require recurring IR for symptom control.⁷ A dosage higher than 30 mg/4 weeks is not definitively recommended for NETs.⁷ IR should be given 2-3 times a day because of the short half-life,⁸ and is not recommended for long-term therapy but rather as “rescue” therapy in patients with CS.⁹ The optimal therapeutic dosage of LAR remains unclear for NETs therapy. Doses above 30 mg/4 weeks have not shown to be better; however, controlled clinical trials typically titrated to symptomatic efficacy and used doses over 30 mg/4 weeks.¹⁰ In patients with NETs, dose escalation and high doses of LAR are commonly seen in clinical practice and can lead to better symptom control and tumor response.^11,12

IR also provides a unique benefit in NETs management. It can be used as initial therapy to test the tolerability and efficacy before giving LAR; it is also indicated as a rescue medication for a breakthrough after starting LAR. Routine use of IR in patients on LAR should lead to a dose escalation assuming it is effective and without adverse effects.¹³ One study showed LAR long-term therapy could not achieve the nearly complete saturation of somatostatin receptors without IR.¹⁴ Supplemental IR can control symptoms beyond the dose escalation of LAR to provide more comprehensive management when a sudden increase of serotonin may cause breakthrough symptoms in certain situations for patients using LAR.¹

To our knowledge, there needs to be more evidence on the real-world utilization and dose escalation of octreotide LAR and preceding IR. We hypothesized that above-label maximum doses of octreotide LAR were common (30 mg/4 weeks) based on clinical trial methodology and anecdotal clinical experience. We also hypothesized that physicians underused IR before LAR dose escalation. This study aimed to examine octreotide use at both the prescription- and patient levels. At the prescription level, the aim was to measure the above-label maximum dose of LAR utilization and IR use before the LAR use. At the patient-level, the objective is to evaluate the dose escalation of LAR, and IR use before dose escalation of LAR, and the potential clinical reasons for the dose escalation.

Materials and Methods

Data Source

This study used IBM MarketScan Research Databases and the Medicare Supplemental and Coordination of Benefits database from January 01, 2009 to December 31, 2018. These data include approximately 135 million individuals and privately ensured employees comprising inpatient and outpatient medical claims, outpatient pharmacy claims, and enrollment data. All data were deidentified and this study was exempted from Institutional Review Board (IRB) review.

Study Design

Prescription-Level Analyses

We included all pharmacy claims for IR and LAR prescriptions identified using Medi-Span Generic Product Identifier (GPI) codes. We excluded prescriptions for which the corresponding patients did not have 4 weeks of continuous enrollment before the fill date to allow for evaluation of preceding IR use. We also excluded patients with a missing value of days of supply of LAR or quantity of preceding IR use among LAR users. Each prescription episode started from the fill date and ended at the fill date plus days of supply. For each LAR prescription, we calculated a normalized dose (see Section “Definition of Octreotide LAR Normalized Dose”) and compared it to above-label maximum dose. Due to the dose availability (10, 20, and 30 mg), we summed dosages that covered the same time period for dose calculations. Preceding IR daily dose of each LAR prescription was also calculated and described in Section “Definition of Octreotide IR Use Before Octreotide LAR Use”.

Patient-Level Analyses

A retrospective cohort study included adult patients (aged ≥18 years) with ≥1 pharmacy claim of LAR between January 01, 2010 and December 01, 2018. The index date was defined as the fill date of the first prescription of LAR for each patient. We required patients to have at least 365 days (baseline period) of continuous enrollment before the index date. We excluded patients with at least one inpatient or outpatient diagnosis of acromegaly during the baseline. The follow-up time for a given patient was from the index date and ended on the first occurrence of any of the following: date of the last LAR prescription (ie, last LAR prescription date plus days of supply); the end of the study period (December 31, 2018); or the last date of continuous enrollment for patients.

In addition, patients in the study were analyzed in 2 groups: (1) patients with at least one inpatient or outpatient diagnosis of NETs or CS (NETs/CS group), and (2) patients with an unknown diagnosis (ie, no acromegaly or NETs/CS diagnosis) during the baseline period (unknown group). Since grade 1 or 2 NETs have a longer median survival time, this could lead to missing recent year diagnoses in the database. We evaluated these 2 groups separately to compare their characteristics. Diagnoses were identified by the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) codes, and 10th Revision, Clinical Modification (ICD-10-CM) codes. Diagnosis of NETs was identified by ICD-9-CM code 209, ICD-10-CM code D3A, C7A, and C7B. Diagnosis of CS was identified by ICD-9-CM code 259.2, and ICD-10-CM code E34.

Definition of Octreotide LAR Normalized Dose

For each LAR prescription, we calculated the normalized dose per 4 weeks using the equation: $\mathrm{L}\mathrm{A}\mathrm{R}\mathrm{n}\mathrm{o}\mathrm{r}\mathrm{m}\mathrm{a}\mathrm{l}\mathrm{i}\mathrm{z}\mathrm{e}\mathrm{d}\mathrm{d}\mathrm{o}\mathrm{s}\mathrm{e}\mathrm{p}\mathrm{e}\mathrm{r}4\mathrm{w}\mathrm{e}\mathrm{e}\mathrm{k}\mathrm{s}=\frac{Strength\ast quantity}{daysofsupply}\ast 28days$

According to the administration dose per 4 weeks, LAR prescriptions were categorized into 7 groups (mg/4 weeks): <11, [11-21), [21-31), [31-41), [41-51), [51-61), and >61. Above-label maximum dose of LAR was defined as the normalized dose greater than 30 mg/4 weeks.

Definition of Octreotide IR Use Before Octreotide LAR Use

The average daily dose of IR was calculated for the 4 weeks before each LAR prescription. First, IR prescriptions were selected by GPI codes. Continuous IR episodes were constructed in which each episode started at the fill date and ended the day before the refill. If it was the last prescription without refill, the IR episode ended on the last date plus days of supply. Second, we calculated episode weights by counting the days that each IR episode overlapped with the 4 weeks before the corresponding LAR prescription. Daily IR dose within 4 weeks before LAR was calculated using the following equation:

$${\displaystyle \begin{array}{ll}& \mathrm{I}\mathrm{R}\mathrm{d}\mathrm{o}\mathrm{s}\mathrm{e}/\mathrm{d}\mathrm{a}\mathrm{y}\mathrm{i}\mathrm{n}4\mathrm{w}\mathrm{e}\mathrm{e}\mathrm{k}\mathrm{s}\mathrm{b}\mathrm{e}\mathrm{f}\mathrm{o}\mathrm{r}\mathrm{e}\mathrm{L}\mathrm{A}\mathrm{R}\mathrm{p}\mathrm{r}\mathrm{e}\mathrm{s}\mathrm{c}\mathrm{r}\mathrm{i}\mathrm{p}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n}=\\ & \frac{{\displaystyle \sum _{i=0}^n}Episodeweight{}_i\times {[TotalquantityofIRepisode/(durationofIRepisode)]}_i}{28days}\end{array}}$$

where n = the total number of IR prescription episodes within 4 weeks period prior to LAR prescription, i = the ith of IR prescription episode in 4 weeks prior to LAR prescription

Finally, we categorized IR daily dose (dose/day) as no use, low (0-0.5], (0.5-1], intermediate (1-2], and high >2.

Definition of Dose Escalation and Reasons for Dose Escalation of Octreotide LAR

Dose escalation of LAR was defined as LAR prescription that changed to a higher normalized dose group compared to the preceding LAR prescription within 6 months.

Furthermore, we incorporated patient diagnosis, biochemical evaluation, and imaging studies recommended by National Comprehensive Cancer Network (NCCN) guidelines¹⁵ to identify the reason for each dose escalation and categorized patients into 4 groups: dose escalation for (1) symptom control, (2) tumor progression control, (3) multiple (both) reasons, and (4) unknown reason (Supplementary Table S1). Patients were included in the symptom control group if they had ≥1 outpatient or inpatient diagnosis of diarrhea (using ICD-9 codes 564.5, 787.91 or ICD-10 codes K59.1, R19.7) or diagnosis of CS (since symptom of diarrhea is often coded as CS) or received ≥1 IR prescription within 30 days before dose escalation of LAR.^,16,17 Patients were included in the tumor progression control group if they received 24-h urine/plasma collection for 5-hydroxyindoleacetic acid (5-HIAA) to evaluate serotonin secretion¹⁸ or received ≥1 imaging studies (computed tomography (CT) or magnetic resonance imaging (MRI)) within 30 days identified by Current Procedural Terminology codes before dose escalation of LAR. Patients were included in the multiple reasons group if they met the criteria in both the symptom control and tumor progression groups. Patients were included in the unknown reason group if they were not in the other 3 groups. Specific codes are summarized in Supplementary Table S2.

Statistical Analysis

At the prescription level, we calculated the number of LAR prescriptions in each LAR dose categories as well as in each preceding IR daily dose group.

At the patient level, patient characteristics were described in the baseline, including age at index date, sex, and comedications. Medications used for the common comorbidities and endocrine disease were evaluated and defined as at least one pharmacy claim of the drug during the baseline.¹⁹ We evaluated the number of patients who experienced dose escalation including their IR daily dose before dose escalation and the potential reason for dose escalation. All analyses were conducted using SAS 9.4 software (SAS Institute, Cary, NC).

Results

Prescription-Level

In total, there were 27 082 LAR prescriptions with 5412 (19.4%) above label-maximum dose (≥30 mg/4 weeks). Among those, the most common categorical dose groups were 31-41 mg/4 weeks (3725, 68.8%) and 51-61 mg/ 4 weeks (1408, 26.0%). In addition, only 1960 (7.0 %) of LAR prescriptions had preceding IR use, and the majority of those had low-dose IR use [0-0.5 dose/day (1230, 62.8%), 0.5-1 dose/day (270, 13.8%)] (Table 1). Moreover, higher LAR dose groups were more likely to have IR use (Fig. 1), but lower IR daily dose use (IR >2 dose/day: <11 mg (n = 11, 15.1%), 11-21 mg (88, 19.9%), 21-31 mg (69, 9.6%) vs. 31-41 mg (17, 4.7%), 51-61 mg (22, 8.2%), ≥61 mg (3, 3.2%), 41-51 mg (n = 0)) (Table 1). Supplementary Fig. S1 shows prescription-level selection flow chart.

Table 1.

Octreotide long-acting release (LAR) dose groups and octreotide immediate release (IR) utilization in the 4 weeks prior to octreotide LAR prescriptions.

Octreotide LAR dose a	Total LAR	Number of octreotide LAR prescriptions with octreotide IR use within 4 weeks prior to LAR start (dose/day) c
		No IR use	Low (0-0.5]	Low (0.5-1]	Intermediate (1-2]	High >2	Total LAR with IR >0
<11 mg	1944	1871 (96.2%)	32 (1.6%)	15 (0.8%)	15 (0.8%)	11 (0.6%)	73 (3.8%)
[11-21) mg	10 131	9688 (95.6%)	205 (2.0%)	62 (0.6%)	88 (0.9%)	88 (0.9%)	443 (4.3%)
[21-31) mg	10 315	9599 (93.1%)	456 (4.4%)	93 (0.9%)	98 (1.0%)	69 (0.7%)	716 (6.9%)
[31-41) mg b	3725	3361 (90.2%)	274 (7.4%)	41 (1.1%)	32 (0.9%)	17 (0.5%)	364 (9.8%)
[41-51) mg b	56	55 (98.2%)	0	0	1 (1.8%)	0	1 (1.8%)
[51-61) mg b	1408	1140 (81.0%)	182 (12.9%)	50 (3.6%)	14 (1.0%)	22 (1.6%)	268 (19.0%)
≥61 mg b	223	128 (57.4%)	81 (36.3%)	9 (4.0%)	2 (0.9%)	3 (1.3%)	95 (42.6%)
Total	27 802	25842 (93.0%)	1230 (4.4%)	270 (1.0%)	250 (0.9%)	210 (0.8%)	1960 (7.0%)

Note: The denominator of percentages in this table was total number of octreotide long-acting release prescriptions in each dose group.

^aOctreotide long-acting release dose groups were classified by the normalized dose per 4 weeks of each prescription using the following equation: LAR normalized dose per 4 weeks = $\frac{Strength\ast quantity}{daysofsupply}\ast 28days$

^bRepresented above-label high dose of octreotide LAR (≥30 mg/4 weeks).

^c $\mathrm{O}\mathrm{c}\mathrm{t}\mathrm{r}\mathrm{e}\mathrm{o}\mathrm{t}\mathrm{i}\mathrm{d}\mathrm{e}\mathrm{i}\mathrm{m}\mathrm{m}\mathrm{e}\mathrm{d}\mathrm{i}\mathrm{a}\mathrm{t}\mathrm{e}\mathrm{r}\mathrm{e}\mathrm{l}\mathrm{e}\mathrm{a}\mathrm{s}\mathrm{e}\mathrm{d}\mathrm{o}\mathrm{s}\mathrm{e}\mathrm{p}\mathrm{e}\mathrm{r}\mathrm{d}\mathrm{a}\mathrm{y}\mathrm{i}\mathrm{n}4\mathrm{w}\mathrm{e}\mathrm{e}\mathrm{k}\mathrm{s}\mathrm{p}\mathrm{r}\mathrm{i}\mathrm{o}\mathrm{r}\mathrm{t}\mathrm{o}\mathrm{L}\mathrm{A}\mathrm{R}\mathrm{p}\mathrm{r}\mathrm{e}\mathrm{s}\mathrm{c}\mathrm{r}\mathrm{i}\mathrm{p}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n}=\frac{\sum _{i=0}^{n}Episodeweight{}_i\times {[TotalquantityofIRepisode/(durationofIRepisode)]}_i}{28days}$

n = the total number of octreotide IR prescription episodes within 4 weeks period prior to LAR prescription, i = the ith of IR prescription episode in 4 weeks prior to LAR prescription; more specific definition in Section “Definition of Octreotide IR Use Before Octreotide LAR Use”.

‘[‘or “]” represent including the limit number in the dose group; ‘(‘or “)” represent not including the limit number in the dose group

Abbreviations: LAR, long-acting releasing; IR, immediate release.

Figure 1.

The percentage of preceding octreotide immediate-release (IR) use by octreotide long-acting release (LAR) dose groups at prescription level.

Patient Level

We identified 956 LAR users with 386 in the NETs/CS group and 570 in the unknown group. Fig. 2 showed the patient selection flow chart. Patient baseline characteristics were similar between groups (Supplementary Table S3). The mean age at the index date was 62 and 60.1 years old, and 48.5% and 44% were male, respectively in NETs/CS and unknown groups. Patients with an unknown diagnosis were more likely to receive antidepressants (41.8% vs. 29.5%) and levothyroxine (26.9% vs. 13.8%) compared to patients with a NETs/CS diagnosis (Supplementary Table S3).

Figure 2.

Patient selection flowchart. Abbreviations: LAR, long-acting releasing; NETs, neuroendocrine tumors; CS, carcinoid syndrome.

In the NETs/CS group, 22.3% (86/386) of patients experienced 114 dose escalations and 29% (25/86) had IR use prior to dose escalation (Supplementary Table 4). In the unknown group, 10.5% (60/570) of patients had 84 dose escalations and 26.6% (16/60) had preceding IR use. Among dose escalations in the NETs/CS and unknown groups, 48.3% (55/114) and 28.6% (24/84) had a dose increase to above label dose (>30 mg/4 week) respectively. (Supplementary Table S5). The most common dose escalations were 11-21 mg to 21-31 mg (n = 48/114, 42%), 21-31 mg to 31-41 mg (30/114, 26.3%) in NETs/CS group, and ≤11 mg to 11-21 mg (n = 19/84, 22.6%), 11-21 mg to 21-31 mg (33/84, 39.3%), and 21-31 mg to 31-41 mg (n = 16/84, 19%) in unknown group (Supplementary Table S5). Daily IR use dose was low before dose escalation in both groups (0-0.5 dose/day: 68% (17/25) in NETs/CS group; 45% (9/20) in the unknown group; 0.5-1 dose/day: 16% (4/25) in NETs/CS group, 10% (2/20) in the unknown group) (Supplementary Table S5). The unknown group had a higher number of high daily doses of octreotide IR use before dose escalation (>1 dose/day: 16% (4/25) in NETs/CS group vs. 45% (9/20) in unknown group) (Supplementary Table S5).

We found that 50.9% vs. 39.2% had LAR dose escalation due to symptom control, 12.3% vs. 7.1% for tumor progression control, and 16.6% vs. 6.0% for both reasons in NETs/CS and unknown group, respectively (Table 2). Dose escalation for an unknown reason accounted for 28.9% in the NETs/CS group vs. 47.6% in the unknown group (Table 2).

Table 2.

Reasons for dose escalation of octreotide long-acting releasing.

Reason for dose escalation	NETs/CS group		Unknown group
	IR use/diarrhea/CS	5-HIAA/CT/MRI	IR use/diarrhea/CS	5-HIAA/CT/MRI
Symptom control	58 (50.8%)	NA	33 (39.2%)	NA
Tumor progression control	NA	14 (12.3%)	NA	6 (7.1%)
Multiple reasons	19 (16.6%)		5 (6.0%)
Unknown reason	33 (28.9%)		40 (47.6%)
Total	114		84

Patients were included in symptom control group if they have evidence of diarrhea or diagnosis of CS or receive IR prescription before dose escalation of octreotide LAR. Patients were included in tumor progression control group if they receive 24-h urine/plasma collection for 5-hydroxyindoleacetic acid (5-HIAA) to evaluate serotonin secretion or receive ≥1 imaging studies (computed tomography (CT) or magnetic resonance imaging (MRI)) before dose escalation of octreotide LAR. Patients were included in multiple reasons group if they met criteria in both symptom control and tumor progression group. Patients were included in unknown reason group if they do not meet any criteria in the other 3 groups.

Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; CS, carcinoid syndrome; CT, computed tomography; IR, immediate release; MRI, magnetic resonance imaging; NETs, neuroendocrine tumors.

Discussion

We found that the above label-maximum dose (>30 mg/4 weeks) prescribing of LAR was common. Patients on higher doses of LAR patients tended to receive preceding IR use but at low doses. In addition, there was very limited IR use before the dose escalation of LAR which most patients needed for symptom control.

Above-label maximum doses of LAR were common in our study (19.4%) but slightly lower than in previous studies (range: 25.6%-40%).^20-23 Also, we found 22.3% of LAR users with NETs/CS had a dose escalation primarily for symptom control (50.8%) compared to tumor control (12.3%) and both (16.9%) which was consistent with other studies. A retrospective study found 40% of patients needed LAR dose escalation primarily for symptom control (40%), radiological progression (33%), and rising urine 5-HIAA (6%).²⁴ Another retrospective study showed that 55.6% of patients required dose escalation: 43.3% for symptom control, 33% for radiological progression, and 23.3% for both.¹¹ Strosberg et al. showed that the primary reason for dose escalation was carcinoid or hormonal syndrome (62%) and 81% of patients experienced clinical improvement after the first dose escalation in NETs patients.²⁵ Anthony et al. showed that nearly 30% of patients received higher than 30 mg/month of LAR.²⁰ Two systematic reviews reported that above-label high doses of LAR (>30 mg/month) were effective in controlling symptoms and tumor progression and had an acceptable safety profile.^,26,27 In an Italian multicenter study, earlier adoption of the above label-maximum dose of somatostatin analogs was associated with greater progression-free survival (hazard ratio: 2.12) compared to later use as third-line treatment in patients with well-differentiated NETs previously treated with standard dose.¹²

Our study showed that IR was underused in clinical practice in this population. In our study, only 7% of LAR prescriptions had preceding octreotide IR use. However, in a multi-center RCT, approximately 40% of patients in all dose cohorts of LAR required IR as “rescue” to reach a steady level of octreotide.²⁸ This trial also showed lower LAR dose group (10 mg/4 weeks) needed smaller number of rescue IR medication doses compared to higher LAR dose treatment group (20 mg or 30 mg/4 weeks). The 24-week study reported the number of “rescue” doses in the 10 mg LAR cohort to be 10-20 doses/4 weeks; in the 20 mg LAR cohort, range from 10-20 to 70-80 doses/4 weeks; in the 30 mg LAR cohort range from 10-20 to 40-50 doses/4 weeks.²⁸ This was consistent with our finding that lower LAR doses had a smaller percentage of preceding IR use. However, the doses of daily IR use were relatively low in the higher LAR group in our study. Anthony et al. stated that LAR cannot adequately and consistently saturate the SSTR receptors and lose bioactivity overtime. Consequently, IR had unique advantage in combination with LAR to provide consistent bioavailability and better control CS symptoms.¹

Our study also indicated the under-utilization of IR before LAR dose escalation. Although the majority of dose escalation was by 10 mg/4 weeks, rapid increases were not rare (eg, 11-21 to 51-61 mg). Patients with larger dose escalation had little prior IR use. In clinical practice, if rescue IR was needed periodically during the dosing interval, the dose of LAR could be increased (by 10 mg/month and up to 60 mg/month).¹³ A trial of IR prior to LAR dose escalation could identify the patient with drug-induced steatorrhea rather than poorly controlled carcinoid syndrome secretory diarrhea. One potential reason for IR under-utilization may be the inaccessibility and inconvenience of self-injections, up to 4 times a day as compared to a healthcare provider-administered LAR injection once every 4 weeks. However, using octreotide IR may predict the efficacy of a larger LAR dose and use of IR can be cost-effective. The price of IR at a 100 μg 4 times a day was $13.42/day as compared to LAR 0.35 mg/day (10 mg every 28 days) which cost $71.46/day according to the Medicare Part B Drug and Biological Average Sales price in the last quarter of 2018.²⁹

Our study had several limitations. First, because data are collected for billing purposes, quality control and lack of clinical records can be limiting. Second, LAR can be given in clinical setting and be identified by procedure code. Our study only included LAR in pharmacy claims because procedure codes do not provide dose information. This could lead to the small sample size and selection bias. Third, there is no validation study to identify clinical reasons for dose escalation of LAR. We used medical and pharmacy claims to indicate disease progression or symptom management, but no clinical results were provided in the dataset. Switching from octreotide LAR to lanreotide can also indicate disease progression or insufficient symptomatic control. However, given the few patients (2%) that used lanreotide in our study cohort, we did not discuss this in this paper. Lastly, we included patients with unknown diagnosis, which could lead to the inclusion of patients with acromegaly. Since LAR can be a lifelong medication and may not have diagnosis during the study period, we included those patients with unknown diagnosis separately. A similar approach was also applied in prior studies using insurance data.¹⁹

Conclusion

An above-label maximum dose of LAR use was common for patients with NETs. Octreotide IR may be under-utilized with high-dose LAR and prior to dose escalation in the comprehensive management of NETs. Future studies should be conducted to evaluate if the use of IR predicted response to an LAR dose escalation in excess of the label maximum dose. Additionally, studies to determine IR avoidance and barriers to use in the real-world should be captured.

Funding

This research was partially supported by the Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558).

Conflict of Interest

Lowell Anthony reported research grants from Camurus and is a consultant for TerSera, Curium, and Boehringer Ingelheim. Aman Chauhan reported a consulting/advisory relationship with Novartis, Ipsen, Lexicon, and Tersera and research grants from BMS, Clovis, Lexicon, TerSera, EMD Serono, Nanopharmaceuticals, and ECS Progastrin, and is an advisor for Crinetics, Lexicon, Ipsen, Novartis, ECS Progastrin, and TerSera. The other authors indicated no financial relationships.

Author Contributions

Conception/design: All authors. Provision of study material or patients: Y.C., L.A., C.D., V.A. Collection and/or assembly of data: Y.C., V.A. Data analysis and interpretation: All authors. Manuscript writing: All authors. Final approval of manuscript: All authors.

Data Availability

The data underlying this article were provided by International Business Machines Corporation as part of one or more IBM MarketScan Research Databases under license. Summarized data results can be shared on request to the corresponding author with the permission of International Business Machines Corporation. Specific dataset cannot be shared based on contract.