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© 1999 American Society for Clinical Oncology Efficacy and Safety of Prolonged-Release Lanreotide in Patients With Gastrointestinal Neuroendocrine Tumors and Hormone-Related SymptomsFrom the Department of Medical Oncology, University Hospital, Groningen, The Netherlands; Department of Internal Medicine, Division of Endocrinology, University Hospital, Uppsala, Sweden; Department of Internal Medicine, Oulo University Central Hospital, Oulo, and Third Department of Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Medical Gastroenterology, Rikshospitalet, Oslo, Norway; Department of Gastroenterology, University Hospital, Leuven, and Department of Gastroenterology, University Hospital Saint-Luc, Brussels, Belgium; and IPSEN ApS, Copenhagen, Denmark. Address reprint requests to A.N.M. Wymenga, MD, Division of Medical Oncology, University Hospital, PO Box 30.001, 9700 RB Groningen, The Netherlands; email a.n.m.wymenga{at}int.azg.nl
PURPOSE: To evaluate the prolonged release (PR) of the long-acting somatostatin analog lanreotide in patients with gastrointestinal neuroendocrine tumors and its effect on hormone-related symptomatology, tumor markers, tumor size, tolerability, and quality of life (QOL).
PATIENTS AND METHODS: Eligible patients had the following substantial daily symptoms: for patients with carcinoid tumors, three or more stools and/or 1.5 or more flushing episodes; for patients with gastrinoma, greater than 50% elevated basic acid output; and for patients with vasoactive intestinal peptide-secreting tumors (VIPomas), four or more stools and/or a stool volume of RESULTS: Fifty-five patients were included in the study (48 patients with carcinoid tumors, six patients with gastrinoma, and one patient with VIPoma). Symptomatic improvement (> 50% reduction) occurred in 38% of the assessable patients with carcinoid tumors, in 67% of the gastrinoma patients, and in the VIPoma patient. Tumor markers normalized in two of 45 assessable patients, 19 patients exhibited a reduction (> 50%), 19 patients exhibited no change, and tumor markers rose by more than 50% in five patients. Tumor size was reduced in two of 31 assessable patients and remained stable in 25 patients; four patients experienced progression. QOL assessments after 1 month showed improvements in emotional and cognitive function, and diminished fatigue, sleeping disorders, and diarrhea. Eight of 30 assessable patients developed gallstones. CONCLUSION: Lanreotide PR is a well-tolerated somatostatin analog with significant clinical, biochemical, and antitumor effects that bring about a significant improvement in QOL for patients with neuroendocrine tumors.
GASTROINTESTINAL neuroendocrine tumors are rare, sometimes slowly progressive tumors whose varied symptoms depend primarily on the production of various hormones and bioactive substances. The treatment of these tumors is directed toward tumor reduction as well as toward reducing circulating hormone levels and thereby improving symptomatology. Surgery should always be considered for cure, but even in metastatic disease, debulking procedures and bypass operations can be important in alleviating symptoms.1-5 A variety of chemotherapeutic drugs have been investigated in patients with unresectable or metastatic tumors, including streptozotocin, fluorouracil, doxorubicin, dacarbazine, and cisplatin. The overall response rates of combination chemotherapy in patients with endocrine pancreatic tumors have been around 40% to 70%, but the efficacy of chemotherapy in patients with carcinoid tumors is much lower, with response rates between 10% and 30%.2-4 Over the last decade, biotherapy with interferon alpha has been used in patients with carcinoid tumors. Research has shown reductions in tumor markers in about 50% of the patients but objective reduction in tumor size in only 15%. Although clinical symptoms improved in 60% to 80% of patients, a substantial incidence of side effects has also been reported.4,6-8 The somatostatin analog octreotide has been used for more than a decade in patients with malignant carcinoid syndrome, producing a limited effect on tumor size but significant amelioration of clinical symptoms in 50% to 70% of patients with few side effects.9,10 A major disadvantage of octreotide treatment is that it must be administered subcutaneously two or three times per day. Lanreotide, another octapeptide somatostatin analog, has recently been developed in a prolonged-release (PR) formulation. PR allows the patient to receive one injection every 2 weeks. Lanreotide PR has been shown to be effective in patients with acromegaly, thyroid eye disease, and carcinoid syndrome.11-13 In patients with gastrointestinal neuroendocrine tumors, which sometimes exhibit a rather indolent course, hormone-related symptoms can be disabling; therefore, symptom reduction and, consequently, improvement of quality of life (QOL) are extremely important. Until now, QOL has not been studied in patient populations receiving somatostatin analog treatment. Because these tumors are rare, a multicenter trial was performed to include a meaningful number of patients. In this study, efficacy, tolerability, and QOL during 6 months of therapy with the long-acting somatostatin analog lanreotide PR were evaluated in patients with gastrointestinal neuroendocrine tumors.
Study Design and Patient Eligibility The study was designed as a prospective, open, phase II study and conducted at seven sites in five European countries. Patients between the ages of 18 and 75 years old with histologically proven malignant gastrointestinal neuroendocrine tumors were eligible if they experienced specific hormone-related symptoms; patients with carcinoid tumors had to have an average of  three stools and/or 1.5 moderate or severe flushing episodes per day; patients with vasoactive intestinal peptide-secreting tumors (VIPomas) had to have four stools and/or a stool volume of 800 mL per day; patients with gastrinomas had to have a basic acid output of more than 50% above the upper limit of the normal reference range. In addition, patients were required to have a measurable tumor on computed tomography scan or ultrasound investigation and an elevated ( two times the upper limit of the normal reference range) biochemical tumor marker. Previous treatment with somatostatin analogs was only allowed if the analog was administered for less than 1 week. In cases of hepatic artery occlusion, this should have been performed at least 3 months before study entry. Any medical antitumor treatment had to be stopped at least 5 days before study entry, and symptoms should have recurred and have been present for at least 3 days. Serum bilirubin levels had to be within normal levels, and serum creatinine levels could not exceed 1.5 times the upper limit of the normal reference range at study entry. Patients with severe concomitant disease, including other malignancies, a life expectancy of less than a half year, or gallstone disease and women with child-bearing potential were excluded, as were patients who currently received antidiarrheal treatment. Concomitant chemotherapy, immunotherapy, hormone therapy, and antidiarrheal treatment were not allowed. The local ethics committee at each center approved the protocol, and all patients gave informed consent.
Treatment
Efficacy Assessments
The biochemical tumor markers evaluated in patients with carcinoid tumor were 24-hour urinary excretion of 5-hydroxyindoleacetic acid (u-5-HIAA) and plasma chromogranin-A (p-chromogranin-A). The primary tumor markers in patients with gastrinoma and VIPoma were serum gastrin and serum vasoactive intestinal peptide (VIP), respectively. Tumor markers were determined at baseline and at months 1, 3, and 6 for each patient. Respective tumor markers were determined in the same laboratory during the study. The response of the tumor marker was defined as complete response (normalization of tumor marker), partial response ( In addition, echocardiography was performed at baseline and month 6 to evaluate the effect of lanreotide PR on the development of carcinoid heart disease.
Tumor size was measured by a computed tomography scan at baseline and month 6, as well as by ultrasound assessment of the liver at baseline, month 3, and month 6. Response in tumor size was categorized as complete response (disappearance of all evidence of tumor for at least 4 weeks), partial response (decrease of tumor size by The effect on QOL was assessed at baseline and months 1, 3, and 6 with the European Organization for Research and Treatment of Cancer Quality of Life C30 questionnaire (EORTC QLQ-C30).14 The core questionnaire is composed of multi-item scales and single-item measures as follows: five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health status/QOL scale, and six single-item measures (dyspnea, appetite, sleeping problems, constipation, diarrhea, and financial problems). All scales range in score from 0 to 100, and a high score represents a higher response level.
Side Effects
Statistical Methods
Between November 1993 and February 1996, 55 patients (28 men and 27 women) with a mean age of 59.7 years were included in the study. Patients' baseline characteristics are listed in Table 1. Most patients exhibited advanced disease (stage IV, n = 46), and all patients included in the study showed progressive disease. Of the 16 patients previously treated with octreotide, 11 patients received it for more than 1 week. Octreotide was given perioperatively to prevent carcinoid crises (n = 7). When it was administered to treat carcinoid tumors (n = 4), no effect on symptoms or tumor markers was observed in three of four patients. Twelve patients discontinued lanreotide PR treatment early in the study, eight because of progressive disease, three because of adverse events, and one patient with too few symptoms because of erroneous admittance to the study; upon discovery, that patient was withdrawn. The mean (± SD) duration of treatment with lanreotide PR was 20.7 ± 7.0 weeks. In 15 patients, treatment was intensified to weekly injections. This was the case for six patients at month 2, three at month 3, four at month 4, and two at month 5. Despite intensified treatment, four patients discontinued participation in the study shortly after dose escalation because of progressive disease. At the end of treatment, three of the remaining 11 patients with intensified treatment met the criteria for treatment success with respect to symptomatology. After dose escalation, the tumor markers in these 11 patients showed no change (n = 5), temporary partial response (n = 1), or partial response (n = 5).
Efficacy Evaluation
Figure 2 shows the effect of treatment with lanreotide PR on severity of symptoms. Among the patients whose target symptom was diarrhea, the severity score dropped 14.9% (P = .036) after 1 month and 23.7% (P = .005) at EOT compared with before treatment. In patients whose target symptom was flushing, the severity scores decreased, compared with baseline, with 37.0% (P < .001) after 1 month and 44.8% (P = .001) at EOT. For all patients, irrespective of target symptom, there was a significant reduction in both diarrhea and flushing severity scores at month 1 and at EOT.
The biochemical response to treatment is presented in Fig 3. Of the 48 patients with a carcinoid tumor, 33 were assessable for u-5-HIAA. A partial response was obtained in nine patients (27%), 17 patients (52%) scored no change, and the remaining seven patients (21%) showed progressive disease at EOT. Among the 27 patients with carcinoid tumors assessable for p-chromogranin-A, nine (33%) showed partial responses, 13 (48%) showed no change, and five (19%) showed progressive disease at EOT. For both tumor markers, a sustained fall was observed during treatment with lanreotide PR. The mean ratio at 1 month to baseline for u-5-HIAA was 0.64 (95% CI, 0.51 to 0.80; P < .001; n = 39); at EOT, it was 0.8 (95% CI, 0.67 to 0.97; P = .022; n = 41). For p-chromogranin-A, the mean ratio at 1 month to baseline was 0.62 (95% CI, 0.49 to 0.77; P < .001; n = 28), and at EOT, it was 0.63 (95% CI, 0.49 to 0.79; P < .001; n = 29).
Among the six gastrinoma patients, four patients achieved a partial response with serum gastrin and two patients scored no change at EOT. In addition, one patient had a complete response, three patients had a partial response, and two patients had no change with p-chromogranin-A. The serum gastrin ratio to baseline was 0.53 (95% CI, 0.32 to 0.97) at month 1 and 0.35 (95% CI, 0.14 to 0.7) at EOT. For p-chromogranin-A, the ratio to baseline was 0.36 (95% CI, 0.08 to 0.88) at month 1 and 0.23 (95% CI, 0.07 to 1.24) at EOT. In the patient with the VIPoma, the serum VIP level (normal, < 69.5 pmol/L) dropped from 104 pmol/L at baseline to 16 pmol/L at month 1 (complete response) and was 37 pmol/L (complete response) at month 6; the patient's p-chromogranin-A level (normal range, 45 to 120 µg/L) decreased from 695 µg/L at baseline to 164 µg/L at month 6 (partial response). When the whole group was considered, 45 of 55 patients were assessable for at least one tumor marker. When the best response in case of more markers measured in one patient was taken into account, two patients (5%) achieved a complete response, 19 patients (42%) achieved a partial response, 19 patients (42%) exhibited no change, and five patients (11%) exhibited progressive disease for the tumor marker. Table 2 shows the effect of treatment with lanreotide PR on tumor size. A total of 31 patients were assessable for tumor size. None of the patients exhibited a complete response, and only two patients exhibited a partial response. Progressive disease was noted in four patients. The remaining 25 patients exhibited stable disease.
Table 3 presents a summary of the EORTC QLQ-C30. It shows an improvement toward emotional functioning (P = .001), cognitive functioning (P = .009), fatigue (P = .011), global health (P = .001), sleeping problems (P = .037), and diarrhea (P = .051) at month 1 compared with baseline. At EOT, there was still a reduction in diarrhea (P = .009) and a trend in reduction of sleeping problems (P = .063).
Echocardiography was performed in 43 patients. In the six patients with signs of carcinoid heart disease at baseline, either results of the 6-month examination were unchanged (n = 2) or the examination was not repeated (n = 4). In 29 of the 37 patients with no or negative signs of carcinoid heart disease at baseline, results of the examination were unchanged. No 6-month examination was performed in the remaining eight patients.
Side Effects
Neuroendocrine tumors quite often induce troublesome, sometimes life-threatening symptoms because of their excessive hormone production. It is always relevant to attempt to relieve the symptoms, but in these patients, it is even more important because of the rather indolent course of the malignancy. Octreotide, which is able to improve symptoms in 70% to 90% of patients with a carcinoid syndrome,4,9,10 requires multiple daily injections. Patients would obviously benefit from a long-acting somatostatin analog to ameliorate QOL even more. In this study, which included a considerable number of patients with advanced progressive neuroendocrine disease (stages III and IV) with substantial symptoms, treatment with lanreotide PR caused a rapid and sustained fall in both number of episodes and severity of symptoms. These results are in accordance with a previously published study of lanreotide PR in 39 patients with carcinoid syndrome.13 The clinical amelioration coincides with the significant reduction of secreted hormones. In this study, 47% of patients exhibited a reduction (> 50%) of tumor marker. Only 6% of the patients showed a substantial reduction (> 50%) of tumor size, but 81% exhibited stability. These results are compatible with those reported for octreotide in neuroendocrine tumors, with biochemical response rates between 30% and 70% and objective tumor reduction in less than 10% of patients.4 Little data are available about the natural history of liver metastases of digestive endocrine tumors. In one small study of untreated patients (n = 10), progression of tumor size was observed in all, with almost a doubling of tumor mass after 1 year.15 Stable disease with tumor size as a parameter during lanreotide PR treatment, as demonstrated in this study, can therefore be regarded as relevant, especially because all patients showed progressive disease at the start of treatment. Treatment with lanreotide PR was generally well tolerated. Only one complaint about pain or discomfort associated with the intramuscular injection was recorded. However, the lanreotide PR had to be injected immediately after careful reconstitution to prevent clotting of the needle. The side effects observed are quantitatively and qualitatively comparable with those previously published for octreotide.10 Because of the lack of an untreated control group, which was considered unethical for these patients with progressive neuroendocrine tumor, it is difficult to determine whether the most commonly reported gastrointestinal side effects may be attributed completely to the study drug or whether they are (at least partially) provoked by the disease. The same applies for the interpretation of changes in laboratory variables and vital signs. Specifically, the observed rise in serum alkaline phosphatase and AST could be caused by progression of disease/liver metastases. An expected side effect was the development of gallstones, which in the present study occurred in 27% of assessable patients. The incidence of new gallstones during therapy with octreotide is reported to be between 4.9% and 60% in acromegalic patients and over 50% in carcinoid patients.16-18 In a review article, Redfern et al reported the development of new gallstones in 13% of patients treated with octreotide for various other clinical conditions. The development of gallstones seemed to be independent of sex, patient age, and dose of octreotide, but it did correlate with the duration of treatment.17 Trendle et al, however, suggested a relationship between octreotide dose and the chance of development of gallstones. The introduction of an octreotide-free period in order to prevent gallstones has been advocated, but this also causes the return of pretreatment symptoms. In the present study, the incidence of biliary cholelithiasis was less than that reported for octreotide.18 Continuous exposure to a repository of lanreotide does not seem to be more noxious compared with the pulsatile effect of multiple daily injections of octreotide. Lastly, octreotide-associated gallstones are usually asymptomatic and do not require surgical or medical therapy, but doctors and patients should be aware of the potential risks. The observed increase in blood glucose levels is a known side effect of treatment with somatostatin analogs because they inhibit the release of insulin from the pancreas, which is thought to be due to a diminished B-cell sensitivity to glucose and a glucose resistance.10,19,20 Surprisingly, hardly any data are available on QOL in carcinoid patients. The present study is the first that addresses the question of whether a long-acting formulation of a somatostatin analog improves QOL. All baseline values of QOL measured in patients with the EORTC QLQ-C30 were below recently derived population-based norms.21 After 1 month of therapy, emotional and cognitive functioning improved significantly, as did global health status, fatigue, sleeping problems, and diarrhea. However, only the diarrhea remained significantly improved at EOT, and a trend toward amelioration of sleeping problems was observed. A reason for the fading improvement of QOL could be progression of disease and subsequent impairment of functioning. Another explanation could be that patients get accustomed to their new, better condition and therefore underestimate their present situation. In conclusion, the present study shows that lanreotide PR seems as effective as regular somatostatin analogs and has a beneficial effect on symptomatology and tumor markers in patients with neuroendocrine gastrointestinal tumors. Lanreotide PR, however, eliminates the need for multiple daily injections and is therefore more convenient. Moreover, the extensive QOL survey used in this study showed an improved QOL. It would be worthwhile to conduct a randomized clinical trial to compare regular somatostatin analogs with this long-acting somatostatin analog to assess efficacy, adverse events, and QOL. Generally, lanreotide PR is well tolerated, with the most prominent adverse events being gastrointestinal dysfunction and the development of gallstones.
IPSEN Biotech, Paris, France, provided study drug and supported data management.
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Lamberts SWJ, Van der Lely AJ, De Herder WW, et al: Octreotide. N Engl J Med 334:246-254, 1996 11. Heron I, Thomas F, Dero M, et al: Pharmacokinetics and efficacy of a long-acting formulation of the new somatostatin analog BIM 23014 in patients with acromegaly. J Clin Endocrinol Metab 76:721-727, 1993[Abstract]
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Ruszniewski P, Ducreux M, Chayvialle JA, et al: Treatment of the carcinoid syndrome with the longacting somatostatin analogue lanreotide: A prospective study in 39 patients. Gut 39:279-283, 1996 14. European Organization for Research and Treatment of Cancer Study Group on Quality of Life: EORTC QLQ-C30 Scoring Manual. Brussels, Belgium, EORTC Study Group on Quality of Life, 1995 15. Skinazi F, Zins M, Menu Y, et al: Liver metastases of digestive endocrine tumours: Natural history and response to medical treatment. Eur J Gastroenterol Hepatol 8:673-678, 1996[Medline] 16. Dowling RH, Hussaini SH, Murphy GM, et al: Gallstones during octreotide therapy. Metabolism 41:22-33, 1992 (suppl 2) [Medline] 17. Redfern JS, Fortuner WJ: Octreotide-associated biliary tract dysfunction and gallstone formation: Pathophysiology and management. Am J Gastroenterol 90:1042-1052, 1995[Medline] 18. Trendle MC, Moertel CG, Kvols LK: Incidence and morbidity of cholelithiasis in patients receiving chronic octreotide for metastatic carcinoid and malignant islet cell tumors. Cancer 79:830-834, 1997[Medline]
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Kahn SE, Klaff LJ, Schwartz MW, et al: Treatment with a somatostatin analog decreases pancreatic B-cell and whole body sensitivity to glucose. J Clin Endocrinol Metab 71:994-1002, 1990 20. Kuhn JM, Basin C, Mollard M, et al: Effects of the new somatostatin analogue (BIM 23014) on blood glucose homeostasis in normal men. Eur J Clin Invest 22:793-799, 1992[Medline] 21. Klee M, Groenvold M, Machin D: Quality of life of Danish women: Population-based norms for the EORTC QLQ-C30. Qual Life Res 6:27-34, 1997[Medline] Submitted December 7, 1997; accepted December 4, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
"mild" during the 2 weeks preceding the month-3 and month-6 visits, respectively. The patients graded severity on a 4-point scale. Severity of diarrhea was scored as normal = 0, mild loose stools = 1, moderate loose stools = 2, and severe loose stools = 3. The severity of flushing was graded as no flushing = 0, mild flushing = 1, moderate flushing = 2, and severe flushing = 3. Treatment was considered effective for patients with gastrinoma when a 
), partial response (
), no change (box, diagonal lines), and progressive disease (
) of tumor markers after treatment with lanreotide PR at months 1, 3, and 6 and at EOT.
