Targeted therapy in neuroendocrine tumours

teaser

Kjell Öberg
MD PhD

Eva Tiensuu Janson
MD PhD
Department of Medical Sciences
Endocrine Oncology
University Hospital
Uppsala
Sweden
E:[email protected]

Neuroendocrine tumours constitute a group of tumours that originate from neuroendocrine cells throughout the body. This includes endocrine tumours of the thymus, lung, pancreas and gastrointestinal tract. Other tumours that are sometimes included in this group are phaeochromocytomas, paragangliomas and medullary thyroid carcinomas. Most of these tumours produce hormones that can induce clinical symptoms in the patient.(1)

Patients with pancreatic endocrine tumours can develop different syndromes according to the hormone produced. A subgroup (30–40%) of endocrine pancreatic tumours does not produce any hormone that give rises to clinical symptoms, and these tumours are called nonfunctioning pancreatic endocrine tumours.

Patients with gastrointestinal endocrine tumours have traditionally been divided into foregut (thymus, lung, gastric and duodenal), midgut (ileal jejunal) and hindgut (colonic and rectal) carcinoids.

Medullary thyroid carcinoma patients produce excessive amounts of calcitonin that sometimes induce flushes and diarrhoea. In patients with phaeochromocytomas and paragangliomas, catecholamine production may induce tachycardia, palpitations and hypertension.

Recently, a new classification has been proposed by WHO. The tumours are divided into well-differentiated neuroendocrine tumours, well-differentiated neuroendocrine carcinoma, tumours with uncertain behaviour and low-differentiated carcinoma.(2) This classification is now being introduced into the clinic.

Somatostatin and somatostatin analogues
Somatostatin is a peptide hormone that was first isolated in 1973.(3) The primary function attributed to this hormone was the inhibition of growth hormone release. Several other functions of somatostatin have subsequently been identified.(4) The first report discussing the use of natural somatostatin for the treatment of a patient with a carcinoid tumour in order to reduce hormone-related symptoms was published in 1978.(5) However, the use of natural somatostatin for long-term treatment is difficult, since the half-life of this hormone is only 90 seconds, necessitating continuous intravenous infusion. In the early 1980s, the first long-acting somatostatin analogue, octreotide, was introduced for clinical use. Octreotide is an octapeptide with a half-life in the circulation of about 115 minutes after subcutaneous injection.(6) The initial clinical applications were acromegaly and hormone-producing tumours of the gastrointestinal tract.(7) Another somatostatin analogue, lanreotide, is now available.(8) Both analogues have the same receptor-binding profile, with a high affinity for somatostatin receptor subtypes 2 and 5, and these analogues are now available in prolonged-release formulations (Sandostatin LAR(®), Somatuline Autogel(®)), where the patient can take only one injection per month.(8,9)

The primary effect of somatostatin analogue treatment is to inhibit the secretion of excessive hormones produced by the tumour cells. By doing so, the hormone-related symptoms can be dramatically reduced and quality of life improved. In patients with carcinoid crisis or vasoactive intestinal peptide tumour (VIPoma) syndrome, treatment with a somatostatin analogue may be lifesaving. The reduction of symptoms is usually concomitant with reduced hormone levels detected in plasma and urine. In different studies, significantly reduced hormone levels are found in 50–75% of patients treated. In in-vitro experiments, somatostatin analogues have been shown to inhibit proliferation of many different tumour cell lines. However, only very few patients (5–8%) respond by significant reduction (50%) in tumour size during treatment with somatostatin analogues. A controversial issue is whether nonfunctioning tumours should be treated with somatostatin analogues. A stabilisation of tumour growth has been demonstrated in 30–50% of patients, possibly by reduction of growth-promoting factors and inhibition of angiogenesis. The clinical indications have been extended and, today, somatostatin analogues are used in pancreatic surgery and to reduce gastrointestinal bleeding.

New somatostatin analogues with different receptor subtype-binding profiles and biological actions have been reported. It has been argued that analogues with specificity for new subsets of receptors or single somatostatin receptor subtypes may prove valuable for treatment of both malignant and nonmalignant diseases. However, until now, only three analogues with very similar binding and biological profiles have been tested in clinical trials (octreotide, lanreotide and vapreotide). A new somatostatin analogue with a more universal binding profile, SOM230, is being developed. This new analogue binds with high affinity to somatostatin receptors 1, 2, 3 and 5(10) and effectively inhibits secretion of growth hormone in vitro. The in-vivo effect of growth hormone suppression in rats is also very high. These results were confirmed in primates,(11) and SOM230 is now being tested in phase I clinical trials in carcinoid patients.

Somatostatin receptor expression
The expression of somatostatin receptors in neuroendocrine tumours was first shown by autoradiography,(12) which has now been replaced by in-situ hybridisation and reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of somatostatin receptor subtypes by RT-PCR (all subtypes) and immunohistochemistry (subtypes 2, 3 and 5) has been studied,(13) with most tumours expressing subtypes 1, 2, 3 and 5 and only a minority of tumours expressing subtype 4. All patients with gastrinomas and glucagonomas expressed subtype 2, while all somatostatinomas expressed subtype 5. The expression in insulinomas, however, was variable.

The expression of subtypes 1, 2, 3 and 5 in endocrine pancreatic tumours has also been reported,(14) with a high expression of subtypes 2, 3 and 5 and intermediate expression of subtype 1. In carcinoid tumours, expression of subtype 2 has been correlated to responsiveness to treatment with somatostatin analogues.(15) The predictive value of somatostatin receptor expression was investigated in patients with endocrine pancreatic tumours.(16) Tumour specimens from seven patients with endocrine pancreatic tumours were stained for subtypes 1, 2 and 3. The only patient responding to octreotide injection was a patient with an insulinoma who had a very strong expression of subtype 2. In this patient, octreotide could reduce the hypoglycaemias.

The expression of somatostatin receptors has also been reported in carcinoid tumours.(13,14) Results are similar to those obtained for endocrine pancreatic tumours, with a high expression reported for subtypes 2, 3 and 5. The expression of subtype 4 was low, with considerable variations in receptor expression between patients.

The expression of somatostatin receptors has been investigated in medullary thyroid carcinoma patients.(17) Subtypes 2 and 5 were most frequently detected, with some patients expressing subtypes 1 and 3. Expression of mRNA for subtype 4 could not be detected in any of the tumour samples.

In a large series of neuroendocrine tumours, including 62 tumour specimens from carcinoid tumours, endocrine pancreatic tumours, phaeochromocytomas and medullary thyroid carcinoma, the expression of somatostatin receptor subtype 2A was examined.(18) All patients with phaeochromocytoma, of which three had metastatic disease, expressed subtype 2A. Of all the patients in the study, 88% were positive for subtype 2A, including three patients with neuroendocrine carcinomas.

In general, the use of somatostatin analogues is well established for treatment of patients with neuroendocrine tumours. It is used both as a single drug and in combination with alpha-interferon or chemotherapy. The main role of somatostatin analogues is to reduce the secretion of excessive hormones produced by the tumours and thus influence hormone-related symptoms.

Bronchial carcinoid tumours
The use of somatostatin analogues in the treatment of bronchial carcinoid tumours is controversial. In a large study, 126 patients with bronchial carcinoid tumours were subjected to thoracic surgery between 1977 and 1999.(19) Nine patients developed liver metastases; all these patients had atypical carcinoid tumours. These patients had a carcinoid syndrome with high 5-hydroxyindole acetic acid (U-5HIAA) levels, facial flushing and diarrhoea. Seven patients (all operated on after 1993) had a pathological uptake of tracer by somatostatin receptor scintigraphy and presence of somatostatin receptor subtype 2 on tumour cells detected by PCR. These seven patients were treated with octreotide at a dose of 1,500mg daily subcutaneously. All patients had an improvement of their carcinoid syndrome and a concomitant reduction in U-5HIAA levels. Two patients also had a decrease in tumour size by 60%, and in one patient  all signs of liver metastases disappeared. Octreotide treatment also prolonged survival in these patients as compared with historical controls with patients operated on for atypical bronchial carcinoid tumours who developed liver metastases. Patients who did not receive octreotide treatment after development of liver metastases died within a year, while those who received octreotide treatment were still alive after 16–51 months of treatment. In another report, however, the outcomes of octreotide treatment seemed to be less positive.(20)

Further studies will probably be needed before the best way to use somatostatin analogues in bronchial carcinoid tumours can be established. However, in patients with symptoms related to hormone release from the tumour and a positive octreoscan, treatment with somatostatin analogues is justified.

Midgut carcinoid tumours
In patients with midgut carcinoid tumours, the use of somatostatin analogues has been considered to be first-line treatment in the presence of a carcinoid syndrome. The symptomatic and biochemical responses are in the order of 50–60%. The use of somatostatin analogues (octreotide 100mg thrice daily and/or lanreotide 30mg every 14 days) in 35 patients with progressive disease, 12 midgut carcinoid patients, 13 patients with endocrine pancreatic tumours, five with primary tumours in the lung and five with other locations of the primary tumour has recently been studied.(21) A partial reduction in tumour size was observed in one patient, while tumour growth was stabilised in 20 other patients. A significantly lower response rate was found in patients with rapidly progressing tumours, compared with patients with slowly growing tumours (p<0.02). The median duration of treatment in this study was seven months.

Endocrine pancreatic tumours
The use of somatostatin analogues in the treatment of endocrine pancreatic tumours is well established. Single treatment with somatostatin analogues produces good symptomatic and biochemical responses, but the effect on tumour size is disappointing, with only about 5% objective responses. The use of a combination of somatostatin analogues and alpha-interferon has been proposed as a possible strategy to control both hormone symptoms and tumour growth. Such a combination was reported in a study on 21 patients with progressing tumours.(22) One patient had a decrease in tumour size, while 60% of the patients remained stable for a median of 12 months. However, results from this study are difficult to compare with results from other groups because of the methods used.

In a study investigating the potential of this combination to control both symptoms and tumour growth,(23) a total of 16 patients with malignant endocrine pancreatic tumours were treated with a combination of a somatostatin analogue (octreotide or somatuline) and alpha-interferon. Three patients (19%) showed a reduction in tumour size by >50% for about two years (19–25 months). Eleven patients showed stabilisation of tumour size for 13 months (4–32 months), while two patients continued to progress. In 62.5% of patients, a biochemical response was detected for a median of 22 months (range 10–32 months). Five patients remained stable for nine months (4–20 months), and only one patient progressed.

This combination could be considered as an alternative for patients who do not want to receive chemotherapy as first-line treatment.

In another study, 15 patients with malignant gastrinomas were treated with octreotide.(24) All patients had liver metastases and were in a progressive state. The patients were treated with octreotide 200mg twice daily and were eventually switched over to long-acting-release octreotide 20–30mg every month. After three months of treatment, seven patients (47%) had stabilisation of their previously progressive disease and one patient had a reduction in tumour size (6%). The mean duration of response was 25 months (range 5.5–54.1 months), and six of the eight responders were still responding at the time of last follow-up. Patients with slow-growing tumours generally had a higher response rate. During follow-up, only 25% of patients responding to somatostatin analogue treatment died, compared with 71% of the nonresponders.

Thus, octreotide might be considered early in the treatment of patients with endocrine pancreatic tumours.

Phaeochromocytomas
In a recent study, 10 patients with malignant or recurrent phaeochromocytomas were treated with somatostatin analogues to evaluate the effect on hormone secretion and symptoms.(25) Patients were submitted to somatostatin receptor scintigraphy and then treated with 20mg of slow-release octreotide every fourth week for three months. There was no effect on hormone levels or symptoms. There was no difference between patients with a pathological uptake of tracer in the tumour compared with patients without this uptake. Even though short-term treatment may decrease catecholamine concentrations, treatment with a somatostatin analogue in patients with phaeochromocytoma seems of limited value.

Medullary thyroid carcinoma
In a recent paper, five patients with postoperative recurrent medullary thyroid carcinoma were treated with somatostatin analogues for 12 weeks.(26) The effect on calcitonin and carcinoembryonic antigen levels was evaluated. Four out of five patients showed pathological uptake of tracer in tumour lesions. However, only one patient showed a transient decrease in tumour markers. Tumour size remained stable or increased during treatment. Thus, despite the presence of somatostatin receptors in the majority of patients, they failed to respond to somatostatin analogue treatment. Although there seems to be very little effect of treatment with a somatostatin analogue binding to receptor subtypes 2 and 5 on the growth of medullary thyroid carcinoma in vivo, some in-vitro studies indicate that stimulation of somatostatin receptor subtype 1 might be important for growth retardation in medullary thyroid carcinoma cells.(27) By using a receptor subtype 1-selective analogue, both calcitonin secretion and gene expression could be decreased. Thus, a somatostatin analogue such as SOM230 that can bind to this receptor might be worth testing in these patients.

Tumour targeting
During the last few years, the same substances that are used for somatostatin receptor scintigraphy have been used for high-dose radioactive tumour-targeting therapy. There have been some reports on small clinical trials, with good results both on hormone levels and on tumour size.(28,29) Toxicity is limited to impairment of kidney function and bone marrow suppression.

In a phase II study, 41 patients with neuroendocrine gastroenteropancreatic and bronchial carcinoid tumours (34 of which had progressive disease)  were treated with four courses of (90)Y-DOTATOC up to a total dose of 6,000MBq/m(2).(30) Complete remission was found in one patient, while nine out of 41 showed a partial response. A minor response was observed in five patients, and six patients progressed. The rest of the patients remained stable. The median duration of response was not reached after 26 months of follow-up, and the two-year survival rate was 76%. A reduction in morphine-dependent tumour- associated pain was observed, and 83% of patients with a carcinoid syndrome had a reduction in symptoms. Side-effects included grade III pancytopenia (5%) and vomiting (23%).

In a similar study, 39 patients with neuroendocrine tumours were treated with 7.4GBq/m(2) of (90)Y-DOTATOC.(31) The response and bone marrow suppression rates were within the same range as in the previous study. However, one patient developed grade 2 renal insufficiency.

In a small study, 27 patients with advanced gastroenteropancreatic tumours who had failed all forms of conventional therapy were treated with at least two monthly injections of 180mCi (111)In-pentetreotide.(32) A total of 16 patients were considered to get clinical benefit from the treatment. A radiological response was found in two patients, and tumour necrosis in seven patients. Tumour markers decreased by >50% in 81% of the patients. An inclusion criterion for entering this study was that patients should have less than six months’ expected survival. The median survival after treatment was 18 months (range 3–54 months), and the treatment was well tolerated.

Adverse reactions to tumour-targeting treatment with radioactive somatostatin analogues mainly affect bone marrow and kidney function. In a report concerning a patient with midgut carcinoid tumours treated with (90)Y-DOTATOC, a severe deterioration of kidney function occurred 15 months after treatment was discontinued.(33) The patient had received four doses of (90)Y-DOTATOC, reaching a cumulative dose of 9.62MBq. Injections were administrated every sixth week. In an attempt to prevent renal toxicity, the patient received amino acid infusions in addition to the fourth treatment cycle. Before and during treatment, the patient had normal levels of serum creatinine and urea nitrogen. After 15 months, a progressive deterioration of renal function was observed, leading to endstage renal disease. The patient was treated with intermittent haemodialysis when creatinine clearance declined to less than 10ml/min. A contributing factor to this renal failure might be that the patient did not receive treatment with amino acids until the last treatment period.

In nuclear medicine, cationic amino acids are used  to prevent renal damage from high doses of radioactive isotopes. It has been shown that infusion of arginine and lysine can reduce the kidney uptake of 111In-pentetreotide and radiolabelled Fab-fragments both in experimental models and in patients.(34)

New isotopes will be tested in the future in order to treat patients with somatostatin receptor-expressing tumours. One such new isotope is (177)-lutetium ((177)Lu), a beta- and gamma-emitting radionuclide. One of the advantages of this radionuclide over 90Y is that it has a shorter penetration in tissue, making it more suitable for treatment of small tumours. The somatostatin analogue DOTA0 Tyr3-octreotate binds with a very high affinity to somatostatin receptor subtype 2 and can be labelled with (177)Lu. In animal experiments with a rat model, (177)Lu-octreotate had a favourable impact on survival. In a study comparing the uptake of the two different radioactive compounds, 90Y-DOTATOC and (177)Lu-octreotate, performed in six patients with somatostatin receptor- expressing tumours, the uptake in spleen, liver and kidney was equal, while the tumour uptake was three to four times higher in four out of five patients treated with (177)Lu-octreotate.(35) In addition, infusion of amino acids reduced the kidney radiation dose by almost 50%. Thus, a higher absorbed dose can be obtained in most tumours without increase in doses absorbed by potentially dose-limiting organs.

References

1. Oberg K. Ann Oncol 1999;10 Suppl 2:S3-8.
2. Rindi G, Capella C, Solcia E. J Mol Med 1998;76:413-20.
3. Brazeau P, Vale W, Burgus R, et al. Science 1973;179:77-9.
4. Reichlin S. N Engl J Med 1983;309:1495-501, 1556-63.
5. Thulin L, Samnegard H, Tyden G, et al. Lancet 1978;2:43.
6. Bauer W, Briner U, Doepfner W, et al. Life Sci 1982;31:1133-40.
7. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. N Engl J Med 1996; 334: 246-54.
8. Heron I, Thomas F, Dero M, et al. J Clin Endocrinol Metab 1993;76:721-7.
9. Lancranjan I, Bruns C, Grass P. Metabolism 1995;44:18-26.
10. Bruns C, Lewis I, Briner U, et al. Eur J Endocrinol 2002;146:707-16.
11. Weckbecker G, Briner U, Lewis I, Bruns C. Endocrinology 2002;143:4123-30.
12. Rocheville M, Lange DC, Kumar U, et al. Science 2000;288:154-7.
13. Papotti M, Bongiovanni M, Volante M, et al. Virchows Arch 2002;440:461-75.
14. Kulaksiz H, Eissele R, Rossler D, et al. Gut 2002;50:52-60.
15. Janson ET, Stridsberg M, Gobl A, et al. Cancer Res 1998;58:2375-8.
16. Oda Y, Tanaka Y, Naruse T, et al. Surg Today 2002;32:690-4.
17. Mato E, Matias-Guiu X, Chico A, et al. J Clin Endocrinol Metab 1998;83:2417-20.
18. Kimura N, Pilichowska M, Date F, et al. Clin Cancer Res 1999;5:3483-7.
19. Filosso PL, Ruffini E, Oliaro A, et al. Eur J Cardiothorac Surg 2002;21:913-7.
20. Granberg D, Eriksson B, Wilander E, et al. Ann Oncol 2001;12:1383-91.
21. Aparicio T, Ducreux M, Baudin E, et al. Eur J Cancer 2001;37:1014-9.
22. Frank M, Klose KJ, Wied M, et al. Am J Gastroenterol 1999;94:1381-7.
23. Fjallskog ML, Sundin A, Westlin JE, et al. Med Oncol 2002;19:35-42.
24. Shojamanesh H, Gibril F, Louie A, et al. Cancer 2002;94:331-43.
25. Lamarre-Cliche M, Gimenez-Roqueplo AP, Billaud E, et al. Clin Endocrinol (Oxf) 2002;57:629-34.
26. Diez JJ, Iglesias P. J Endocrinol Invest 2002;25:773-8.
27. Zatelli MC, Tagliati F, Piccin D, et al. Res Commun 2002;297:828-34.
28. McCarthy KE, Woltering EA, Espenan GD, et al. Cancer J Sci Am 1998;4:94-102.
29. Tiensuu Janson E, Eriksson B, Oberg K, et al. Acta Oncol 1999;38:373-7.
30. Waldherr C, Pless M, Maecke HR, et al. Ann Oncol 2001;12:941-5.
31. Waldherr C, Pless M, Maecke HR, et al. J Nucl Med 2002;43:610-6.
32. Anthony LB, Woltering EA, Espenan GD, et al. Semin Nucl Med 2002;32:123-32.
33. Cybulla M, Weiner SM, Otte A. Eur J Nucl Med 2001;28:1552-4.
34. Bernard BF, Krenning EP, Breeman WA, et al. J Nucl Med 1997;38:1929-33.
35. Kwekkeboom DJ, Bakker WH, Kooij PP, et al. Eur J Nucl Med 2001;28:1319-25.