Sandostatin LAR (long-acting octreotide acetate) for malignant carcinoid syndrome: a 3-year experience

Authors


Correspondence to: Dr M. Caplin, Neuroendocrine Tumour Clinic, Centre for Gastroenterology, Royal Free Hospital, London NW3 2QG, UK. E-mail: m.caplin@rfc.ucl.ac.uk

Summary

Background : Somatostatin analogues are the best therapy for controlling the symptoms of malignant carcinoid syndrome. Octreotide acetate given as subcutaneous injection up to three times daily, intramuscular Lanreotide injection given once per 1–2 weeks and monthly intramuscular Sandostatin LAR have demonstrated similar efficacy in short-term studies.

Aim : To assess the long-term effect of Sandostatin LAR on the management of patients with malignant carcinoid syndrome.

Methods : This was a 3-year retrospective study. Twenty-seven patients were assessed with a median follow-up of 23 months. Thirteen patients were switched from subcutaneous octreotide and 14 patients were octreotide naive. All patients showed avid uptake on indium-111 octreotide imaging.

Results : Ten of the 13 patients previously on subcutaneous octreotide and 13 of the 14 patients who were octreotide naive had good symptom control on Sandostatin LAR. Over the period of follow-up, many patients showed progression of their tumour and required additional therapies. Patients expressed a preference for monthly intramuscular Sandostatin LAR as opposed to daily subcutaneous injections of octreotide. Although Sandostatin LAR was difficult to administer in certain instances, overall it was well tolerated.

Conclusions : Sandostatin LAR provides good long-term symptomatic control in patients with malignant carcinoid syndrome; it is well tolerated and patients expressed improved satisfaction in their management.

Introduction

Carcinoid tumours are derived from enterochromaffin cells and are classically described as originating from the embryological foregut, midgut or hindgut.1, 2 The incidence is approximately 10 per million population and, as patients can live a long time, the prevalence is much higher.3 Carcinoid tumours have been demonstrated in 1% of necropsies, demonstrating the generally indolent nature of these tumours.4 However, a subset of carcinoid tumours act in a ‘malignant’ fashion, metastasizing to the liver and causing ‘carcinoid syndrome’, the result of peptide release directly into the systemic circulation.

The pathognomonic biochemical feature of carcinoid tumour is the abnormal metabolism of tryptophan. Usually, tryptophan is metabolized to nicotinic acid with just a small fraction, less than 1%, converted to 5-hydroxytryptamine. In carcinoid patients, tryptophan is predominantly metabolized to 5-hydroxytryptamine and subsequently deaminated to 5-hydroxyindoleacetic acid, which can be measured in the urine.5–7 However, 24-h urinary 5-hydroxyindoleacetic acid is only a useful marker for midgut carcinoids and much less useful for foregut and hindgut carcinoids.8 Another important feature of carcinoid tumours is their expression of somatostatin (SST) receptors. There are five SST receptors, the most commonly expressed being the type 2 receptor.9 The order of expression of SST receptor type in carcinoid tumours has been assessed as follows: SST2, SST5, SST1, SST3, SST4.10 Native SST is an inhibitory hormone with endocrine, paracrine and neurotransmitter actions, with a half-life of just 2–3 min.11 It inhibits the release of peptides, including those associated with carcinoid syndrome. Its short half-life led to the development of Sandostatin (octreotide acetate), which is a synthetic analogue of SST.12 Octreotide has a half-life of approximately 1.5 h and can be given as a subcutaneous or intravenous injection.11

SST analogues have been shown to be the best therapy for controlling carcinoid symptoms. They reduce flushing in over 70% of patients, reduce diarrhoea in over 60% of patients11 and, in some studies, inhibit tumour growth as monotherapy in up to 8% of treated carcinoid patients.13, 14 They have a greater anti-tumour effect in combination with other agents, for example, interferon-α.15

The usual dose of octreotide for symptomatic control is between 50 and 500 µg, twice or three times daily, as a subcutaneous injection. Longer acting formulations are available, such as Sandostatin LAR (Norvatis), which can be given as an intramuscular injection every 4 weeks,16 and Lanreotide (Ipsen), which can be given as an intramuscular injection every 10–14 days.17 Recently, Lanreotide Autogel (Ipsen), given as an intramuscular injection, has been licensed as a monthly preparation. Intuitively, one would anticipate that these longer acting formulations would simplify patient management and have an impact in terms of the quality of life. There are currently no formal quality of life assessments for carcinoid tumours, although this is in the process of being remedied.18

Sandostatin LAR has been shown to have good efficacy in controlling the symptoms of gastroentero-pancreatic neuroendocrine tumours.19 In a study comparing Sandostatin LAR with subcutaneous octreotide in patients with malignant carcinoid syndrome, Rubin et al. showed that Sandostatin LAR controlled symptoms at least as well as subcutaneous octreotide injections.20

The aim of this 3-year retrospective study was to assess the impact of the new long-acting agent Sandostatin LAR, given as a once-monthly intramuscular injection, on tolerability of injection, efficacy in symptom control, quality of life and therapeutic management in patients with malignant carcinoid syndrome.

Patients and methods

Twenty-seven patients with carcinoid syndrome and biopsy-confirmed metastatic carcinoid tumour were included in this retrospective study. All patients had positive indium-111 octreotide scanning. Thirteen patients were male and 14 female, with a median age at the start of Sandostatin LAR treatment of 60 years (range, 30–78 years). Information for the study was obtained from the patients' hospital notes. The median follow-up time was 23 months (range, 1–38 months). The primary sites of the carcinoid tumours were as follows: ileum, 15; pancreas, 1; caecum, 1; gastric, 1; lung, 1; ovary, 1; unknown primary site, 7.

All patients were symptomatic on presentation, with 25 of the 27 experiencing flushing at any time, 24 of the 27 with diarrhoea, four with wheezing and five with palpitations.

Prior to the commencement of Sandostatin LAR, 13 patients had received subcutaneous octreotide injections for symptomatic control over a median time range of 9 months (Table 1). Fourteen patients had not received previous treatment with subcutaneous octreotide (Table 2).

Table 1.  Demographic data, tumour site and symptoms of carcinoid patients previously on subcutaneous (s.c.) octreotide
PatientAge at start of
Sandostatin LAR
Primary
site
Metastatic siteMonths of
s.c. octreotide
SymptomsControl of symptoms
on s.c. octreotide
  1. D, diarrhoea; F, flushing; P, palpitations; W, wheezing.

 160UnknownLiver29F, D, PGood control
 265BronchialLiver, bone74F, D, PGood control
 358IleumLiver112F, D, W, PPoor control
 458IleumLiver, lymph node13F, DGood control
 560UnknownLiver, lung36FGood control
 662IleumLiver, lymph node, peritoneum5F, DPoor control
 751IleumLiver, peritoneum, lung6F, DGood control
 868IleumLiver, bone9F, DGood control
 957UnknownLiver4F, DGood control
1064IleumLiver, peritoneum, lymph node34FGood control
1175CaecalLiver6DGood control
1270UnknownLiver, peritoneum8F, DPoor control
1365IleumLiver, peritoneum, lymph node4DGood control
Table 2.  Demographic data, tumour site and symptoms of carcinoid patients naive to subcutaneous octreotide
PatientAge at start of Sandostatin LARPrimary siteMetastatic siteSymptoms
  1. D, diarrhoea; F, flushing; P, palpitations; W, wheezing.

1455IleumLiverF, D
1576IleumLiverF, D
1677UnknownLiverF, D
1736IleumLiverF, D
1878UnknownLiver, lungF, D
1945IleumLiverF, D, W
2058IleumLiver, lymph nodeF, D
2136IleumLiverF, W
2262UnknownLiver, boneF, D, P
2334IleumLiver, lymph nodeF, D, P
2450PancreaticLiverF, D
2566IleumLiverF, D, W
2630GastricLiverF, D
2776OvarianLiver, lung, bone,  lymph nodeF, D

Twenty-six patients were started on Sandostatin LAR, 20-mg intramuscular injections once a month, and one patient on 10 mg due to a lower body mass. The first dose was given in hospital and subsequent injections given in the community by district or practice nurses. Patients were seen in the out-patient department, on average, every 3 months.

Patients with progressive disease received additional therapies, including iodine-131 meta-iodobenzylguanidine (131I-mIBG) therapy (six patients), indium-111 octreotide therapy (five patients), yttrium-90 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid (DOTA) Lanreotide (four patients) and transarterial chemoembolization (seven patients).

Results

Of the 13 patients already on subcutaneous octreotide injections, 10 were well controlled in terms of carcinoid symptoms, with a significant or complete reduction in flushing, diarrhoea, wheezing or palpitations. Three patients were still symptomatic despite octreotide injections.

After starting Sandostatin LAR treatment, 10 of the 13 patients previously on subcutaneous octreotide showed good initial control of their symptoms (Table 3). For the octreotide-naive patients (Table 4), 13 of the 14 experienced good initial control of their symptoms.

Table 3.  Response of carcinoid patients, previously on subcutaneous (s.c.) octreotide, to Sandostatin LAR (LAR)
PatientDose
LAR
Symptom
control
on LAR
Progressive/
stable disease
on CT scan
Time on LAR
treatment
(months)
Other therapies
during LAR
treatment
24-h
urinary
5-HIAA*
Satisfaction
on
LAR
Comments
  • CT, computed tomography; DOTA, 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid; 5-HIAA, 5-hydroxyindoleacetic acid; mIBG, meta-iodobenzylguanidine; OCT, octreotide; N/A, not available; TACE, transarterial chemoembolisation.

  • *  At start of LAR therapy/last recorded value, umols/24 hr.

  •  Compared with s.c. octreotide.

 120 mgGoodStable36111 In OCT 144/negativeImprovedStill on LAR
 220 mg increased to
 30 mg after 2 weeks
PoorProgressive, subsequently
 stable after therapy
24131 I-mIBG
Continued with
s.c. octreotide
Negative/negativeNo changeDied of progressive
 disease after 24 months
 320 mg increased to
 30 mg after 2 weeks
PoorProgressive, subsequently
 stable after therapy
13131 I-mIBG
Continued with
 s.c. octreotide
627/1222No changeStopped LAR due to poor
 control after 13 months
 Tried Lanreotide, finally
 on octreotide infusion
 410 mg increased to
 20 mg after 21 months
GoodStable38111 In OCT 227/222ImprovedStill on LAR
 520 mgGoodStable after TACE10TACENegative/negativeImprovedDied of progressive
 disease after 10 months
 620 mgPoorProgressive13Systemic 90Y DOTA
 Lanreotide
405/273No changeDied of progressive
 disease after 13 months
 720 mgGoodProgressive25TACEN/AImprovedChronic renal failure
 Still on LAR
 820 mgGood after
 therapy
Stable25131 I-mIBG 329/420ImprovedStill on LAR
 920 mg increased to
 30 mg after 6  months
Good until
 8 months
Stable13Addition of s.c.
 octreotide after
 8 months
1790/N/ANo changeStopped LAR after
 14 months due to poor
control, continued with
 s.c. octreotide
1020 mgGoodStable24131 I-mIBG 133/242ImprovedStill on LAR
1120 mgGoodProgressive4Systemic 90Y DOTA
 Lanreotide
N/AImprovedDied of progressive
 disease after 4 months
1220 mgGoodProgressive1111 In OCT N/A(Terminal
 disease)
Died of progressive
 disease after 1 month
1320 mgGoodStable5None140/191ImprovedDied of tuberculosis
Table 4.  Response of carcinoid patients, naive to subcutaneous (s.c.) octreotide, to Sandostatin LAR (LAR)
PatientDose
LAR
Symptom
control
on LAR
Progressive/
stable disease
on CT scan
Time on LAR
treatment
(months)
Other therapies
during LAR
treatment
24-h
urinary
5-HIAA*
Satisfaction
on
LAR
Comments
  • CT, computed tomography; DOTA, 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid; 5-HIAA, 5-hydroxyindoleacetic acid; mIBG, meta-iodobenzylguanidine; OCT, octreotide; N/A, not available; TACE, transarterial chemoembolisation.

  • *  At start of LAR therapy/last recorded value, umols/24 hr.

  •  Compared with s.c. octreotide.

1420 mgGoodStable30None1056/N/AImprovedStill on LAR
1520 mgGoodProgressive7131 I-mIBG N/AImprovedDied of progressive
 disease after 7 months
1620 mgGoodStable8None1200/499ImprovedStill on LAR
1720 mgGoodStable23None324/395ImprovedStill on LAR
1820 mgGoodStable2None1709/1340No changeDied of carcinoid
 heart disease
1920 mgGoodProgressiveUnknownTACE1312/N/AImprovedMoved abroad
2020 mg increased to
 30 mg after  21 months
Good until
 18 months
Progressive37111 In OCT, TACE 357/731Initial
improvement
Died of progressive
disease after   37 months
2120 mgGoodStable30None290/127ImprovedStill on LAR
2220 mg increased to
 30 mg after  8 months
Good after
 increased
Stable12Systemic 90Y DOTA
 Lanreotide
180/negativeImprovedStill on LAR
 dose      
2320 mgGoodStable28TACE152/284ImprovedStill on LAR
2420 mg increased to
 30 mg after  16 months
Good until
 16 months;  subsequently  good post-therapy
Progressive,  subsequently
 stable post-therapy
35131 I-mIBG, TACE 319/470ImprovedStill on LAR
2520 mg increased to
 30 mg after  6 months
PoorProgressive,  subsequently
 stable post-therapy
24TACE, addition  of s.c. octreotide409/556No changeStopped LAR due  to poor control;  on s.c. octreotide
2620 mg increased to
 30 mg after 11 months
Good until
 11 months
Progressive19NoneN/A/189ImprovedDied of progressive
 disease after 19 months
2720 mg increased to
 30 mg after 8 months
GoodProgressive23111 In OCT, systemic
 90 Y DOTA Lanreotide
N/A/488ImprovedDied of squamous
 cell lung cancer

One patient (patient 2) required an increased dose of Sandostatin LAR, continued on subcutaneous octreotide for breakthrough symptoms and also received other treatments. She subsequently showed improved symptom control until she died of progressive disease at 24 months. A second patient (patient 3) remained symptomatic despite an increase in the dose of Sandostatin LAR to 30 mg, the addition of subcutaneous octreotide and 131I-mIBG therapy. After 13 months, Sandostatin LAR was stopped, and she was switched to Lanreotide 30 mg with short-lived symptomatic improvement. She subsequently showed better control with a subcutaneous infusion of octreotide. The patient is currently still symptomatic. A third patient (patient 6) initially improved following yttrium-90 DOTA Lanreotide therapy, but deteriorated and died at 13 months of progressive disease.

Most of the other patients showed good control of their symptoms on Sandostatin LAR. One patient (patient 9) was initially well controlled but, at 8 months, when diarrhoea and flushing increased, the dose of Sandostatin LAR was increased to 30 mg and subcutaneous octreotide was added for breakthrough symptoms. She appeared to be developing resistance, eventually stopping Sandostatin LAR due to inadequate control. She received yttrium-90 DOTA Lanreotide therapy and subsequently continued with subcutaneous octreotide with good symptomatic control.

Many patients had been referred with advanced disease and died from progressive disease, although having good symptom control. One patient (patient 13) died from unrelated fulminant tuberculosis.

Overall, 11 of the 13 patients previously on subcutaneous octreotide received additional therapies for either progression of disease on computed tomography imaging or progressive symptoms. These additional therapies would, of course, impact on the overall symptom control.

In the group of 14 patients who were octreotide naive, only one patient (patient 25) failed to achieve any symptom control despite an increased dose of Sandostatin LAR, the addition of subcutaneous octreotide and transarterial chemoembolization. In the other 13 patients who were octreotide naive, there was good initial control. In five patients, there was a relapse of symptoms (median time, 14 months). After increasing Sandostatin LAR to 30 mg and/or the addition of other treatments, three patients regained control of their symptoms. Two patients only had partial control and, despite additional therapies, died of progressive disease.

We do not have complete data on the 24-h urinary 5-hydroxyindoleacetic acid values for all patients. As the patients received other therapies and often had progressive disease, there was no correlation between the 24-h urinary 5-hydroxyindoleacetic acid values and symptoms or disease changes.

Formal quality of life measures were not used, but simple questioning of the patients revealed that they all found the monthly injections to be preferable to the three-times-daily subcutaneous injections. Sandostatin LAR was well tolerated. Four patients complained of loose stools for a few days after the injection and two suffered from a single incident of pain and/or a bump or bruise at the injection site. Some patients reported that the nurse giving the injection had problems with drawing up the Sandostatin LAR and giving the injection. On review of the computed tomography or ultrasound imaging, gallstones were noted to be present in three patients.

Discussion

Sandostatin LAR has previously been demonstrated to be an effective treatment for malignant carcinoid syndrome, although the study followed patients for just 24 weeks.20 We have presented a retrospective study of our 3-year experience of Sandostatin LAR in patients with malignant carcinoid tumour. The results showed that Sandostatin LAR is effective in relieving the symptoms of patients with carcinoid tumours. All patients' tumours were known to express SST receptors, as demonstrated by avid uptake on octreotide scan. Patients who showed good symptom control on subcutaneous octreotide injections all had a good cross-over when starting on Sandostatin LAR with similar efficacy. The dosage used was the recommended dose of 20 mg, although in one patient 10 mg was used. Patients usually continued on subcutaneous octreotide for 7–10 days after Sandostatin LAR injection had been administered. Patients who started directly on Sandostatin LAR reached adequate symptom control within 7–14 days. The decision not to give subcutaneous octreotide initially was because of the practical aspects and logistics of teaching the administration of the injections for such a short period of time. Although we did not have any problems with naive patients receiving Sandostatin LAR, it would be appropriate to give a test dose of subcutaneous octreotide to assess potential acute side-effects.

Patients requiring increased dosages of 30 mg often had progressive disease and, even on this higher dose, some of the symptoms were difficult to control. Resistance is not uncommon in patients with progressive carcinoid syndrome. Additionally, there is some recent evidence to suggest that a few patients develop antibodies to SST analogues, although we have no data on this in our group of patients.21, 22 As our institution is a tertiary referral centre, most patients had advanced disease and evidence of progression on imaging and biochemistry on presentation to us. Patients therefore required additional therapy alongside Sandostatin LAR. Obviously, such additional therapies would contribute to symptom control.

We found no significant evidence for an anti-tumour effect of SST analogue alone. Although there are good in vitro data to suggest an anti-tumour effect of SST analogues,23–25 the data in humans are limited. Some have shown that SST analogues may have an anti-tumour effect,14 and there are anecdotal case reports of tumour regression, but no controlled studies.26 Many patients had tumour stability on Sandostatin LAR.

We did not have complete data on 24-h urinary 5-hydroxyindoleacetic acid values for all patients. However, the effect of SST analogues on 24-h urinary 5-hydroxyindoleacetic acid values in patients with carcinoid syndrome is inconsistent and does not always predict the response to treatment.27–31

Sandostatin LAR did not appear to interfere with octreotide imaging and, when other treatments were given, e.g. high-dose indium-111 octreotide or yttrium-90-labelled Lanreotide, there was no evidence to suggest this affected the uptake of the radio-labelled preparation by the tumour. Intuitively, one might propose that patients undergoing radionuclide octreotide therapies might be better changing to a short-acting preparation and missing the dose of subcutaneous octreotide prior to therapy or imaging, the argument being that Sandostatin LAR would compete with the therapy for receptor sites. Conversely, some argue that Sandostatin LAR up-regulates SST receptors, and dosimetry studies performed on patients post-therapy have confirmed the good uptake by tumours.32 A controlled trial needs to be performed to determine the appropriate strategy.

Patients showed improved satisfaction on once-monthly Sandostatin LAR compared to daily subcutaneous octreotide injections. There were no major problems with the injection. The preparation is viscous and some patients reported problems with the giving of the injection. Occasionally, Sandostatin LAR could not be injected due to blockage in the needle and this was remedied by changing the needle, although there were some instances where the injection was wasted as the mixture had set ‘like glue’. This may be a result of not following specifically the manufacturers' recommendations.

There are issues surrounding the funding of the Sandostatin LAR injections. We have shared care protocols with primary care physicians. The first injection was administered in hospital and it was expected that subsequent injections would be administered and thereby funded by local general practitioners. The price of the once-monthly preparation is comparable with that of subcutaneous octreotide given at high doses (200 µg) three times daily.

In conclusion, Sandostatin LAR is a safe, well-tolerated, effective way to reduce symptoms from carcinoid tumours. The once-monthly administration has led to improved satisfaction with treatment in carcinoid patients. Recently, a new, long-acting SST analogue, Lanreotide Autogel (Ipsen), has been licensed as a once-monthly intramuscular preparation. It will be interesting to compare the efficacy, tolerability and cost of this new agent with Sandostatin LAR.

Ancillary