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Escape of the response to a long-acting somatostatin analogue (SMS 201–995) in patients with VIPoma
GASTROENTEROLOGY 1987;92:527-31
Escape of the Response to a Long-Acting Somatostatin Analogue (SMS 201-995)in Patients With VIPoma ANNEMARIE KOELZ, MARIUS KRAENZLIN, KLAUS GYR, VERENA MEIER, STEPHEN R. BLOOM, PHILIPP HEITZ, and HANS
STALDER
Department of Medicine, Kantonsspital, Liestal, Switzerland; Departments Pathology, and Medical Research, University Hospital, Basel, Switzerland; Endocrinology, Hammersmith Hospital, London, United Kingdom
Two patients with severe secretory diarrhea due to metastatic vasoactive intestinal peptidoma were treated with a synthetic somatostatin analogue in an attempt to control the patients’ vasoactive intestinal peptide-related symptoms. In both patients, a good initial response to this treatment could be demonstrated; not only did diarrhea subside but there was also a dramatic fall in vasoactive intestinal peptide plasma levels. However, after 11 and 4 days respectively, diarrhea recurred accompanied by a rise in vasoactive intestinal peptide plasma levels. In fact, under treatment with the somatostatin analogue and with natural somatostatin, a significant rebound state was observed regarding diarrhea as well as vasoactive intestinal peptide levels, which caused considerable difficulty in the clinical management in 1 patient. This patient had to undergo surgery. In the second patient, the responsiveness to somatostatin analogue returned a few days after discontinuation of the treatment, lasting, however, for a short period only. The possible mechanism of this escape and rebound with somatostatin treatment is discussed. Somatostatin or growth hormone release inhibiting factor, a potent endogenous inhibitor of peptide release, has been shown to suppress hormonal hypersecretion in patients with vasoactive intestinal peptidoma (VIPoma), and thus to reduce the watery Received April 14, 1986. Accepted July 24, 1986. Address requests for reprints to: Dr. Klaus Gyr, Kantonsspital Liestal, University of Basel, CH-4410 Liestal, Switzerland. The authors thank Cornelia Schulthess for determining vasoactive intestinal peptide, Dr. Otten for measuring neurotensin, L. Varga for determining pancreatic polypeptide, and Carita Frei for typing the manuscript. 0 1987 by the American Gastroenterological Association 0016-5085/87/$3.50
of Medicine, Department of
diarrhea that occurs in this condition (1,Z). However, the use of somatostatin for such purposes has been limited by its short half-life, which necessitates intravenous administration. Recently a new, longacting somatostatin-octapeptide analogue (SMS 201-%X), which can be used subcutaneously, has been given successfully to patients with VIPoma to suppress peptide secretion and watery diarrhea as short-term or long-term treatment. In addition, longterm control of pancreatic cholera has been reported in 3 patients for between 3 and 14 mo with two daily subcutaneous injections of up to 100 pg each of SMS 201-995 (3-5). This report describes 2 patients treated with SMS 201-995 for pancreatic cholera due to metastatic VIPoma originating from the pancreas. After good initial responses, the inhibition of diarrhea and vasoactive intestinal peptide (VIP] release subsided in both patients, and a significant rebound state developed while treatment with SMS 201-995 and with the natural tetradecapeptide of somatostatin continued.
Case Reports Case 1 The patient is a 54-yr-old white man who suffered from intermittent profuse watery diarrhea up to 15 times daily since February 1978. The diagnosis of a VIPoma of the pancreas was made in March 1980 based on the findings of elevated plasma levels of VIP (85 pmol/L, normal Cl5 pmol/L) and the presence of a tumor in the tail of the pancreas on computed tomography. In April 1980, the patient underwent hemipancreatectomy, splenectomy, and partial resection of the omenturn for a multiloculated nodular pancreatic tumor measuring 12 by 12.9 cm. Histologic examination showed an islet cell tumor. On immunocytochemical examination,
528
KOELZ ET AL.
GASTROENTEROLOGY Vol. 92, No. 2
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JANUARY1985
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Figure 1. Effect of SMS 201-995 and the natural tetradecapeptide somatostatin (SST-14) on stool output and VIP plasma concentrations in case 1.
choriongonadotropin, a-choriongonadotropin, and VIP could be detected. After surgery, the patient was free of symptoms until late 1982 when he noticed loose stools again. In March 1983, watery diarrhea recurred with -30 bowel movements a day and a volume of about 1600 ml/24 h. Several liver metastases and a retrogastric tumor mass could be detected by sonography and computed tomography. Vasoactive intestinal peptide plasma levels were again elevated (32.5 pmol/L, normal <5 pmol/L). Five courses of combined chemotherapy (streptozotocin and 5-fluorouracil) given between March 1983 and December 1984 provided only temporary relief of symptoms, and the patient was severely incapacitated. In December 1984, the patient had to be readmitted with severe watery diarrhea, severe dehydration, and acidosis [blood pH 7.2). Fecal volume varied between a minimum of 1500 and a maximum of 5080 ml/day. Increased growth of the previously detected liver metastases was confirmed by computed tomography. As conventional means such as loperamide, nifedipine, and prednisone failed to control the severe diarrhea, SMS 201-995, 50 p,g twice daily, was started on December 24, 1984. This was followed by a dramatic remission of the diarrhea. The patient passed l-2 formed stools daily and he was temporarily discharged from hospital (Figure 1). However, 11 days later despite
continued SMS 201-995 treatment, profuse watery diarrhea recurred with a weight loss of 3 kg within 2 days; the patient had to be readmitted. Increasing the dose of SMS 201-995 to 600 pglday subcutaneously reduced the diarrhea markedly (Figure 1) but only for the first 4 days. The VIP plasma level was 62 pmol/L at that time, and plasma levels of neurotensin, pancreatic polypeptide, and secretin were within the normal range. In a further attempt to control the diarrhea, SMS 201-995 was given intravenously at a rate of 50 p&h; however, the diarrhea continued. To exclude tachyphylaxis to the somatostatin analogue, the natural somatostatin (Stilamin, Istituto Farmacologico Serono S. p. A., Rome, Italy) was given by continuous infusion at a rate of 250 &h. Despite this high dose of somatostatin, diarrhea increased further to up to 16 L daily for several days, and the VIP plasma levels rose to values of 300-425 pmol/L. As hepatic artery embolization was technically not feasible, surgery was performed on January 24, 1985. Tumors from the pancreas, liver, and peritoneum were removed, which showed the same histochemical features as the original tumor. Diarrhea ceased on the day of operation and VIP plasma levels fell to a minimum of 15 pmol/L on the eighth postoperative day. The patient has remained free of symptoms for -6 mo without treatment.
SOMATOSTATIN IN VIPoma; ESCAPE AND REBOUND 529
February 1987
HEPATIC AATEAY EMBOLlSAllON
‘.
Figure 2. Effect of SMS 201-995 on bowel motions and VIP plasma concentrations in case 2.
Case 2 A 48-yr-old Egyptian woman presented in 1980 with a 3-yr history of intermittent severe watery diarrhea. A pancreatic tumor was removed with remission of the diarrhea. In 1981 she had a recurrence of diarrhea and on referral to the Hammersmith Hospital she was found to have further pancreatic tumor secreting VIP (VIP plasma level 400 pmol/L, normal <30 pmol /L). Computed tomography revealed two hepatic metastases in addition to the pancreatic tumor. A further pancreatectomy and removal of the two hepatic metastases was carried out. After surgery, diarrhea resolved and her VIP plasma levels fell to <5 pmol/L. Histologic examination of the resected tumor and metastases showed the typical features of a pancreatic islet cell tumor. Immunocytochemically, the tumor cells were reactive to VIP, pancreatic polypeptide, neuron-specific enolase, and weakly to neurotensin. Several recurrences of symptoms produced by this VIPsecreting pancreatic tumor between 1980 and 1983 were treated with combined chemotherapy (streptozotocin and !%fluorouracil), surgery (removal of hepatic secondaries), or hepatic artery embolization. However, these measures produced only temporary relief; furthermore, chemotherapy had to be discontinued because of nephrotoxic side effects. In August 1983 the patient had a further recurrence of
severe watery diarrhea, and the VIP plasma levels were markedly elevated (180-300 pmol/L). In addition, elevated plasma levels of peptide histidine isoleucine were found (300-400 pmol/L, normal ~50 pmol/L); other peptide plasma levels such as pancreatic polypeptide, neurotensin, gastric inhibitory peptide, glucagon, and insulin were within the normal range. A growing tumor mass around the inferior vena cava was found on computed tomography and there was evidence of further metastases in the liver. It was then decided to start the patient on the new long-acting somatostatin analogue SMS 201-995 in an attempt to control her severe diarrhea. SMS 201-995 was given twice daily subcutaneously. This resulted in a marked improvement of her diarrhea, and the VIP levels fell from 300 to 100 pmol/L [Figure 2). However, 4 days after starting the SMS 201-995 treatment the diarrhea recurred and there was a marked rise in the VIP levels to a maximum of 760 pmol/L (Figure 2). The somatostatin analogue treatment was discontinued for 2 days. On a second attempt, the patient again responded dramatically to SMS 201-995 for a few days only. Therefore hepatic artery embolization was repeated but this still failed to control her symptoms. There was an initial rise of the VIP levels after hepatic artery embolization, and this was probably due to necrosis of the tumor cells induced by embolization. A third trial of SMS 201-995 was started with initial success. After 11 days, despite increasing the
530 KOELZETAL.
SMS 201-995dose, the diarrhea recurred accompanied by a marked rise of the VIP levels (650-700pmoI/L). As a high dose of corticosteroids frequently has a beneficial although transient effect on the diarrhea produced by VIPomas, the patient was then started on prednisolone (60 mg daily). She has been on prednisolone treatment now for about 1.5yr; her diarrhea is still poorly controlled, and she has developed the full clinical picture of a severe Cushing’s syndrome.
Discussion In contrast to other tumors of the pancreas, morbidity and mortality of endocrine pancreatic tumors are closely related to the metabolic abnormalities induced by hormonal hypersecretion from such tumors (l-3). It is also well recognized that suppression of tumor-related peptide secretion can produce a relatively long-lasting symptomatic and biochemical remission even in the absence of treatment aimed at the reduction of tumor growth (1,6-11).
Natural somatostatin appears to be a very successful suppressant in such patients (7-10,12). More recently, the new somatostatin analogue SMS 201-995 has been demonstrated to represent a valuable alternative treatment for pancreatic endocrine tumors, effectively suppressing hormonal release from these tumors not only on a short-term, but also on a long-term basis (3-5,~). In the first case reported herein, the long-acting somatostatin analogue SMS 201-995was given in an attempt to control the patient’s VIP-related symptoms temporarily while investigations were undertaken in preparation for a more definite surgical approach. In the second case, SMS 201-995 was given as a last therapeutic attempt as surgery, chemotherapy, and hepatic artery embolization produced only very short-lived relief of symptoms. In both patients, there was initially a good response to this treatment; diarrhea subsided and there was a dramatic fall in the VIP plasma levels (Figures 1 and 2). However, after about 11 days of treatment in the first patient and about 4 days in the second, diarrhea recurred accompanied by a rise in VIP plasma levels (Figures 1 and 2). The VIP levels not only returned to the pretreatment concentrations, but markedly exceeded the levels before starting the SMS 201-995 treatment. The excessive rise of the VIP plasma levels was accompanied in both cases by severe watery diarrhea exceeding that observed before SMS 201-995 treatment. In fact, the watery diarrhea was so excessive in the first patient (up to 16 L/day) that it led to a serious water and electrolyte imbalance necessitating close hospital supervision and fluid replacement therapy in an intensive care unit. Thus, after an initial response, both patients
GASTROENTEROLOGYVol. 92,No.Z
showed an escape from the somatostatin analogue treatment and a rebound rise of the peptide secretion from the VIPoma, resulting in recurrence of the watery diarrhea. This phenomenon, as seen in the first patient, was not only observed with the somatostatin analogue SMS 201-995, but also with the naturally occurring somatostatin (Stilamin). Rebound of symptoms and peptide secretion from endocrine pancreatic tumors after cessation of somatostatin or its analogue has been described previously (2,10,14,15). Yet there is no satisfactory explanation for the rebound effect. Perhaps somatostatin inhibits release of VIP from tumor cells, but does not over a few days inhibit the synthesis of this secretagogue in tumor cells. There is no report in the literature referring to an escape from diarrhea control and VIP secretion inhibition while short-term treatment with somatostatin or its analogues continued. Recently Ekelund et al. (16) demonstrated an escape from gastric acid secretion inhibition during continuous infusion of somatostatin in the rat. Desensitization or down-regulation to somatostatin with a declining biologic response in the presence of a constant stimulus could be explained in various ways. The escape phenomenon could reflect accelerated enzymatic breakdown of somatostatin. Alternatively, ligand-induced changes of somatostatin receptors on the target cell could be involved, e.g., a conformational change in the receptor that is incompatible with further internalization of the hormone receptor complexes and their subsequent effect and degradation (i7-20). However, the observed rebound phenomenon is rather against the internalization hypothesis. Perhaps the target cells gradually adapt to intracellular effects of somatostatin. Whatever the underlying cellular mechanism responsible for our findings may be, one possibility to overcome this problem of desensitization to somatostatin, and thus to prevent the escape from symptom control and the rebound effect, might be an intermittent administration of somatostatin, as has been shown for the application of gonadotropinreleasing hormone or for somatostatin in the rat (16,21). Case 2 described herein seems to support this possibility, as there was recovery of the response to the somatostatin treatment after cessation of the latter for a few days. In relating receptor loss and down-regulation causally, it is tempting to speculate that an intermittent application permits regeneration of the receptors. As there are several reports of successful treatment of endocrine-active tumors with a somatostatin analogue for prolonged periods of time, such desensitization or down-regulation to somatostatin as ob-
February
1987
served in our cases would fortunately appear not to occur in all subjects. It is our opinion and our experience that the long-acting somatostatin analogue SMS 201-995represents a valuable symptomatic treatment for endocrine-active tumors. However, it should be kept in mind that an escape from control or even a rebound effect with exacerbation of symptoms may occasionally occur during treatment.
SOMATOSTATIN
2.
3.
4.
5.
6. 7. 8.
9.
S. Control of severe diarrhea with somatostatin (lett). N Engl J Med 1984;311:598-9. Ruskone A, Rene E, Chayvialle JA, et al. Effect of somatostatin on diarrhea and on small intestinal water and electrolyte transport in a patient with pancreatic cholera. Dig Dis Sci 1982;27:459-66. Kraenzlin ME, Ch’ng JLC, Wood SM, Carr DH, Bloom SR. Long-term treatment of a VIPoma with somatostatin analogue resulting in remission of symptoms and possible shrinkage of metastases. Gastroenterology 1985;88:185-7. Maton PN, O’Dorisio TM, Howe BA, et al. Effect of a longacting somatostatin analogue (SMS 201-995) in a patient with pancreatic cholera. N Engl J Med 1985;312:17-21. Santangelo WC, O’Dorisio TM, Kim JG, Severino G, Krejs GJ. Pancreatic cholera syndrome: effect of a synthetic somatostatin analog on intestinal water and ion transport. Ann Intern Med 1985;103:363-7. Friesen SR. Tumors of the endocrine pancreas. N Engl J Med 1982;306:580-90. Wood SM, Polak JM, Bloom SR. Gut hormone secreting tumours. Stand J Gastroenterol 1983;18:165-79. Kaplan EL. The carcinoid syndromes. In: Friesen SR, ed. Surgical endocrinology: clinical syndromes. Philadelphia: Lippincott, 1978:120-%7. Sohier J, Jeanmougin M, Lombrail P, Passa P. Rapid improvement of skin lesions in glucagonomas with intravenous somatostatin infusion. Lancet 198O;i:40.
AND REBOUND
531
K, Sherwin RS, Cataland S, Jaffe B, Dob10. Dharmsathaphorn bins J. Somatostatin inhibits diarrhea in the carcinoid syndrome. Ann Intern Med 1980;92:68-9. 11. Long RG, Bryant MG, Yuille PM, Polak JM, Bloom SR. Mixed pancreatic apudoma with symptoms of excess vasoactive intestinal polypeptide and insulin: improvement of diarrhoea with metoclopramide. Gut 1981;22:505-11. 12. Gyr K, Kayasseh L, Keller U. Somatostatin as a therapeutic agent. In: Bloom SR, Polak JM, eds. Gut hormones. Edinburgh: Livingstone, 1981:581-5. 13. Wood SM, Kraenzlin ME, Adrian TE, Bloom SR. Treatment of
References 1. Rem? E, Bonfils
IN VIPoma; ESCAPE
14.
15.
16.
17. 18.
19.
20.
21
patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue: symptomatic and peptide responses. Gut 1985;26:438-44. Bonfils S, Rene E, Pignal F, Rambaud JC. Rebound effect after somatostatin treatment in Verner Morrison syndrome. Lancet 1979;ii:476. Long RG, Peters JR, Bloom SR, et al. Somatostatin, gastrointestinal peptides, and the carcinoid syndrome. Gut 1981; 22:549-53. Ekelund M, Ekman R, Hakanson R, Sundler F. Continuous infusion of somatostatin evokes escape of gastric acid inhibition in the rat. Gastroenterology 1984;86:861-5. Rang HP, Ritter JM. On the mechanism of desensitization of cholinergic receptors. Mol Pharmacol 1970;6:357-82. Schlessinger J, Shechter Y, Willingham MC, Pastan I. Direct visualization of binding, aggregation and internalization of insulin and epidermal growth factor on living fibroblastic cells. Proc Nat1 Acad Sci USA 1978;75:2659-63. Reyl FJ, Lewin MJ. Intracellular receptor for somatostatin in gastric mucosal cells: decomposition and reconstitution of somatostatin stimulated phosphoprotein phosphatases. Proc Nat1 Acad Sci USA 1982;79:978-82. Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. Hypophysical responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science 1978;202:631-2. Hurley DM, Brian R, Outch K, et al. Induction of ovulation and fertility in amenorrheic women by pulsatile low-dose gonadotropin-releasing hormone. N Engl J Med 1984;310: 1069-74.
Escape of the Response to a Long-Acting Somatostatin Analogue (SMS 201-995)in Patients With VIPoma ANNEMARIE KOELZ, MARIUS KRAENZLIN, KLAUS GYR, VERENA MEIER, STEPHEN R. BLOOM, PHILIPP HEITZ, and HANS
STALDER
Department of Medicine, Kantonsspital, Liestal, Switzerland; Departments Pathology, and Medical Research, University Hospital, Basel, Switzerland; Endocrinology, Hammersmith Hospital, London, United Kingdom
Two patients with severe secretory diarrhea due to metastatic vasoactive intestinal peptidoma were treated with a synthetic somatostatin analogue in an attempt to control the patients’ vasoactive intestinal peptide-related symptoms. In both patients, a good initial response to this treatment could be demonstrated; not only did diarrhea subside but there was also a dramatic fall in vasoactive intestinal peptide plasma levels. However, after 11 and 4 days respectively, diarrhea recurred accompanied by a rise in vasoactive intestinal peptide plasma levels. In fact, under treatment with the somatostatin analogue and with natural somatostatin, a significant rebound state was observed regarding diarrhea as well as vasoactive intestinal peptide levels, which caused considerable difficulty in the clinical management in 1 patient. This patient had to undergo surgery. In the second patient, the responsiveness to somatostatin analogue returned a few days after discontinuation of the treatment, lasting, however, for a short period only. The possible mechanism of this escape and rebound with somatostatin treatment is discussed. Somatostatin or growth hormone release inhibiting factor, a potent endogenous inhibitor of peptide release, has been shown to suppress hormonal hypersecretion in patients with vasoactive intestinal peptidoma (VIPoma), and thus to reduce the watery Received April 14, 1986. Accepted July 24, 1986. Address requests for reprints to: Dr. Klaus Gyr, Kantonsspital Liestal, University of Basel, CH-4410 Liestal, Switzerland. The authors thank Cornelia Schulthess for determining vasoactive intestinal peptide, Dr. Otten for measuring neurotensin, L. Varga for determining pancreatic polypeptide, and Carita Frei for typing the manuscript. 0 1987 by the American Gastroenterological Association 0016-5085/87/$3.50
of Medicine, Department of
diarrhea that occurs in this condition (1,Z). However, the use of somatostatin for such purposes has been limited by its short half-life, which necessitates intravenous administration. Recently a new, longacting somatostatin-octapeptide analogue (SMS 201-%X), which can be used subcutaneously, has been given successfully to patients with VIPoma to suppress peptide secretion and watery diarrhea as short-term or long-term treatment. In addition, longterm control of pancreatic cholera has been reported in 3 patients for between 3 and 14 mo with two daily subcutaneous injections of up to 100 pg each of SMS 201-995 (3-5). This report describes 2 patients treated with SMS 201-995 for pancreatic cholera due to metastatic VIPoma originating from the pancreas. After good initial responses, the inhibition of diarrhea and vasoactive intestinal peptide (VIP] release subsided in both patients, and a significant rebound state developed while treatment with SMS 201-995 and with the natural tetradecapeptide of somatostatin continued.
Case Reports Case 1 The patient is a 54-yr-old white man who suffered from intermittent profuse watery diarrhea up to 15 times daily since February 1978. The diagnosis of a VIPoma of the pancreas was made in March 1980 based on the findings of elevated plasma levels of VIP (85 pmol/L, normal Cl5 pmol/L) and the presence of a tumor in the tail of the pancreas on computed tomography. In April 1980, the patient underwent hemipancreatectomy, splenectomy, and partial resection of the omenturn for a multiloculated nodular pancreatic tumor measuring 12 by 12.9 cm. Histologic examination showed an islet cell tumor. On immunocytochemical examination,
528
KOELZ ET AL.
GASTROENTEROLOGY Vol. 92, No. 2
L.J d
5000
TUMOR
t
RESECTION
+\ 1000 3000 1 i z 600 t7 2 a
200
is
400 0 I 500 -
400 -
:
3w
-
a = 0 >
200 -
100 _
‘\
‘\e_ii____--------
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15.
96_
&
Jl r-l
12 -
~.__._____.._-----~--
3-
normal
O18 DECEMBER
22 1984
26
formed stmk
30
A
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normal fomedstwk -_______
1
JANUARY1985
11
15
19
23
27
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4
8
10
FEBFAJARV
Figure 1. Effect of SMS 201-995 and the natural tetradecapeptide somatostatin (SST-14) on stool output and VIP plasma concentrations in case 1.
choriongonadotropin, a-choriongonadotropin, and VIP could be detected. After surgery, the patient was free of symptoms until late 1982 when he noticed loose stools again. In March 1983, watery diarrhea recurred with -30 bowel movements a day and a volume of about 1600 ml/24 h. Several liver metastases and a retrogastric tumor mass could be detected by sonography and computed tomography. Vasoactive intestinal peptide plasma levels were again elevated (32.5 pmol/L, normal <5 pmol/L). Five courses of combined chemotherapy (streptozotocin and 5-fluorouracil) given between March 1983 and December 1984 provided only temporary relief of symptoms, and the patient was severely incapacitated. In December 1984, the patient had to be readmitted with severe watery diarrhea, severe dehydration, and acidosis [blood pH 7.2). Fecal volume varied between a minimum of 1500 and a maximum of 5080 ml/day. Increased growth of the previously detected liver metastases was confirmed by computed tomography. As conventional means such as loperamide, nifedipine, and prednisone failed to control the severe diarrhea, SMS 201-995, 50 p,g twice daily, was started on December 24, 1984. This was followed by a dramatic remission of the diarrhea. The patient passed l-2 formed stools daily and he was temporarily discharged from hospital (Figure 1). However, 11 days later despite
continued SMS 201-995 treatment, profuse watery diarrhea recurred with a weight loss of 3 kg within 2 days; the patient had to be readmitted. Increasing the dose of SMS 201-995 to 600 pglday subcutaneously reduced the diarrhea markedly (Figure 1) but only for the first 4 days. The VIP plasma level was 62 pmol/L at that time, and plasma levels of neurotensin, pancreatic polypeptide, and secretin were within the normal range. In a further attempt to control the diarrhea, SMS 201-995 was given intravenously at a rate of 50 p&h; however, the diarrhea continued. To exclude tachyphylaxis to the somatostatin analogue, the natural somatostatin (Stilamin, Istituto Farmacologico Serono S. p. A., Rome, Italy) was given by continuous infusion at a rate of 250 &h. Despite this high dose of somatostatin, diarrhea increased further to up to 16 L daily for several days, and the VIP plasma levels rose to values of 300-425 pmol/L. As hepatic artery embolization was technically not feasible, surgery was performed on January 24, 1985. Tumors from the pancreas, liver, and peritoneum were removed, which showed the same histochemical features as the original tumor. Diarrhea ceased on the day of operation and VIP plasma levels fell to a minimum of 15 pmol/L on the eighth postoperative day. The patient has remained free of symptoms for -6 mo without treatment.
SOMATOSTATIN IN VIPoma; ESCAPE AND REBOUND 529
February 1987
HEPATIC AATEAY EMBOLlSAllON
‘.
Figure 2. Effect of SMS 201-995 on bowel motions and VIP plasma concentrations in case 2.
Case 2 A 48-yr-old Egyptian woman presented in 1980 with a 3-yr history of intermittent severe watery diarrhea. A pancreatic tumor was removed with remission of the diarrhea. In 1981 she had a recurrence of diarrhea and on referral to the Hammersmith Hospital she was found to have further pancreatic tumor secreting VIP (VIP plasma level 400 pmol/L, normal <30 pmol /L). Computed tomography revealed two hepatic metastases in addition to the pancreatic tumor. A further pancreatectomy and removal of the two hepatic metastases was carried out. After surgery, diarrhea resolved and her VIP plasma levels fell to <5 pmol/L. Histologic examination of the resected tumor and metastases showed the typical features of a pancreatic islet cell tumor. Immunocytochemically, the tumor cells were reactive to VIP, pancreatic polypeptide, neuron-specific enolase, and weakly to neurotensin. Several recurrences of symptoms produced by this VIPsecreting pancreatic tumor between 1980 and 1983 were treated with combined chemotherapy (streptozotocin and !%fluorouracil), surgery (removal of hepatic secondaries), or hepatic artery embolization. However, these measures produced only temporary relief; furthermore, chemotherapy had to be discontinued because of nephrotoxic side effects. In August 1983 the patient had a further recurrence of
severe watery diarrhea, and the VIP plasma levels were markedly elevated (180-300 pmol/L). In addition, elevated plasma levels of peptide histidine isoleucine were found (300-400 pmol/L, normal ~50 pmol/L); other peptide plasma levels such as pancreatic polypeptide, neurotensin, gastric inhibitory peptide, glucagon, and insulin were within the normal range. A growing tumor mass around the inferior vena cava was found on computed tomography and there was evidence of further metastases in the liver. It was then decided to start the patient on the new long-acting somatostatin analogue SMS 201-995 in an attempt to control her severe diarrhea. SMS 201-995 was given twice daily subcutaneously. This resulted in a marked improvement of her diarrhea, and the VIP levels fell from 300 to 100 pmol/L [Figure 2). However, 4 days after starting the SMS 201-995 treatment the diarrhea recurred and there was a marked rise in the VIP levels to a maximum of 760 pmol/L (Figure 2). The somatostatin analogue treatment was discontinued for 2 days. On a second attempt, the patient again responded dramatically to SMS 201-995 for a few days only. Therefore hepatic artery embolization was repeated but this still failed to control her symptoms. There was an initial rise of the VIP levels after hepatic artery embolization, and this was probably due to necrosis of the tumor cells induced by embolization. A third trial of SMS 201-995 was started with initial success. After 11 days, despite increasing the
530 KOELZETAL.
SMS 201-995dose, the diarrhea recurred accompanied by a marked rise of the VIP levels (650-700pmoI/L). As a high dose of corticosteroids frequently has a beneficial although transient effect on the diarrhea produced by VIPomas, the patient was then started on prednisolone (60 mg daily). She has been on prednisolone treatment now for about 1.5yr; her diarrhea is still poorly controlled, and she has developed the full clinical picture of a severe Cushing’s syndrome.
Discussion In contrast to other tumors of the pancreas, morbidity and mortality of endocrine pancreatic tumors are closely related to the metabolic abnormalities induced by hormonal hypersecretion from such tumors (l-3). It is also well recognized that suppression of tumor-related peptide secretion can produce a relatively long-lasting symptomatic and biochemical remission even in the absence of treatment aimed at the reduction of tumor growth (1,6-11).
Natural somatostatin appears to be a very successful suppressant in such patients (7-10,12). More recently, the new somatostatin analogue SMS 201-995 has been demonstrated to represent a valuable alternative treatment for pancreatic endocrine tumors, effectively suppressing hormonal release from these tumors not only on a short-term, but also on a long-term basis (3-5,~). In the first case reported herein, the long-acting somatostatin analogue SMS 201-995was given in an attempt to control the patient’s VIP-related symptoms temporarily while investigations were undertaken in preparation for a more definite surgical approach. In the second case, SMS 201-995 was given as a last therapeutic attempt as surgery, chemotherapy, and hepatic artery embolization produced only very short-lived relief of symptoms. In both patients, there was initially a good response to this treatment; diarrhea subsided and there was a dramatic fall in the VIP plasma levels (Figures 1 and 2). However, after about 11 days of treatment in the first patient and about 4 days in the second, diarrhea recurred accompanied by a rise in VIP plasma levels (Figures 1 and 2). The VIP levels not only returned to the pretreatment concentrations, but markedly exceeded the levels before starting the SMS 201-995 treatment. The excessive rise of the VIP plasma levels was accompanied in both cases by severe watery diarrhea exceeding that observed before SMS 201-995 treatment. In fact, the watery diarrhea was so excessive in the first patient (up to 16 L/day) that it led to a serious water and electrolyte imbalance necessitating close hospital supervision and fluid replacement therapy in an intensive care unit. Thus, after an initial response, both patients
GASTROENTEROLOGYVol. 92,No.Z
showed an escape from the somatostatin analogue treatment and a rebound rise of the peptide secretion from the VIPoma, resulting in recurrence of the watery diarrhea. This phenomenon, as seen in the first patient, was not only observed with the somatostatin analogue SMS 201-995, but also with the naturally occurring somatostatin (Stilamin). Rebound of symptoms and peptide secretion from endocrine pancreatic tumors after cessation of somatostatin or its analogue has been described previously (2,10,14,15). Yet there is no satisfactory explanation for the rebound effect. Perhaps somatostatin inhibits release of VIP from tumor cells, but does not over a few days inhibit the synthesis of this secretagogue in tumor cells. There is no report in the literature referring to an escape from diarrhea control and VIP secretion inhibition while short-term treatment with somatostatin or its analogues continued. Recently Ekelund et al. (16) demonstrated an escape from gastric acid secretion inhibition during continuous infusion of somatostatin in the rat. Desensitization or down-regulation to somatostatin with a declining biologic response in the presence of a constant stimulus could be explained in various ways. The escape phenomenon could reflect accelerated enzymatic breakdown of somatostatin. Alternatively, ligand-induced changes of somatostatin receptors on the target cell could be involved, e.g., a conformational change in the receptor that is incompatible with further internalization of the hormone receptor complexes and their subsequent effect and degradation (i7-20). However, the observed rebound phenomenon is rather against the internalization hypothesis. Perhaps the target cells gradually adapt to intracellular effects of somatostatin. Whatever the underlying cellular mechanism responsible for our findings may be, one possibility to overcome this problem of desensitization to somatostatin, and thus to prevent the escape from symptom control and the rebound effect, might be an intermittent administration of somatostatin, as has been shown for the application of gonadotropinreleasing hormone or for somatostatin in the rat (16,21). Case 2 described herein seems to support this possibility, as there was recovery of the response to the somatostatin treatment after cessation of the latter for a few days. In relating receptor loss and down-regulation causally, it is tempting to speculate that an intermittent application permits regeneration of the receptors. As there are several reports of successful treatment of endocrine-active tumors with a somatostatin analogue for prolonged periods of time, such desensitization or down-regulation to somatostatin as ob-
February
1987
served in our cases would fortunately appear not to occur in all subjects. It is our opinion and our experience that the long-acting somatostatin analogue SMS 201-995represents a valuable symptomatic treatment for endocrine-active tumors. However, it should be kept in mind that an escape from control or even a rebound effect with exacerbation of symptoms may occasionally occur during treatment.
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