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Journal of Clinical Oncology, Vol 23, No 12 (April 20), 2005: pp. 2754-2762 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.08.066 Radiolabeled Somatostatin Analog [177Lu-DOTA0,Tyr3]Octreotate in Patients With Endocrine Gastroenteropancreatic TumorsFrom the Departments of Nuclear Medicine, Internal Medicine, and Surgery, Erasmus Medical Center, Rotterdam, the Netherlands Address reprint requests to D.J. Kwekkeboom, MD, Department of Nuclear Medicine, Erasmus Medical Center, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands; e-mail: d.j.kwekkeboom{at}erasmusmc.nl
PURPOSE: There are few treatment options for patients with metastasized or inoperable endocrine gastroenteropancreatic (GEP) tumors. Chemotherapy can be effective, but the response is usually less than 1 year. Here, we present the results of treatment with a radiolabeled somatostatin analog, [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). PATIENTS AND METHODS: One hundred thirty-one patients with somatostatin receptor-positive tumors were treated with up to a cumulative dose of 600 to 800 mCi (22.2 to 29.6 GBq) of 177Lu-octreotate. RESULTS: One patient developed renal insufficiency, and another patient developed hepatorenal syndrome. Creatinine clearance did not change significantly in the other patients. WHO hematologic toxicity grade 3 or 4 occurred after less than 2% of the administrations. We observed complete remission in three patients (2%), partial remission in 32 patients (26%), minor response (tumor diameter decrease of 25% to 50%) in 24 patients (19%), stable disease (SD) in 44 patients (35%), and progressive disease (PD) in 22 patients (18%). Higher remission rates were positively correlated with high uptake on pretherapy somatostatin receptor imaging and a limited number of liver metastases, whereas PD was significantly more frequent in patients with a low performance score and extensive disease. Median time to progression in 103 patients who either had SD or tumor regression was more than 36 months. CONCLUSION: Treatment with 177Lu-octreotate results in tumor remission in a high percentage of patients with GEP tumors. Serious side effects are rare. The median time to progression compares favorably with chemotherapy. Results are better in patients with a limited tumor load. Therefore, early treatment, even in patients who have no PD, may be better.
Endocrine gastroenteropancreatic (GEP) tumors, which comprise pancreatic islet-cell tumors, nonfunctioning endocrine pancreatic tumors, and carcinoids, are usually slow growing. When metastasized, treatment with somatostatin analogs results in reduced hormonal overproduction and symptomatic relief in most cases. However, treatment with somatostatin analogs is seldom successful in terms of tumor size reduction.1-3 A new treatment modality for inoperable or metastasized endocrine GEP tumors is the use of radiolabeled somatostatin analogs. The majority of endocrine GEP tumors possess somatostatin receptors and can, therefore, be visualized using the radiolabeled somatostatin analog [111In-DTPA0]octreotide (OctreoScan; Mallinckrodt, St Louis, MO). Therefore, a logical sequence to this tumor visualization in patients was to also try to treat these patients with radiolabeled somatostatin analogs. Initial studies with high dosages of [111In-DTPA0]octreotide in patients with metastasized neuroendocrine tumors were encouraging, although partial remissions (PRs) were exceptional.4,5 This is not surprising because 111In-coupled peptides are not ideal for peptide receptor radionuclide radiotherapy (PRRT) because of the small particle range and, therefore, short tissue penetration of the Auger electrons. Another radiolabeled somatostatin analog that is used for PRRT is [90Y-DOTA0,Tyr3]octreotide. Several phase I and II PRRT trials have been performed using this compound. Complete remissions (CRs) and PRs have been reported in 7% to 33% of patients with neuroendocrine tumors.6-11 The somatostatin analog [DOTA0,Tyr3]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 compared with [DOTA0,Tyr3]octreotide in vitro.12 Also, labeled with the beta- and gamma-emitting radionuclide 177Lu, this compound was shown to be successful in terms of tumor regression and animal survival in a rat model.13 In a comparison in patients, we found that the uptake of radioactivity, expressed as percentage of the injected dose of [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate), was comparable to that after [111In-DTPA0]octreotide for kidneys, spleen, and liver but was three- to four-fold higher for four of five tumors.14 In a preliminary report on the results of this treatment in the first 35 patients with endocrine GEP tumors,15 we found CRs and PRs in 38% of the patients. No serious side effects were observed. Here, we present the results of treatment with 177Lu-octreotate in a large series of patients with endocrine GEP tumors. Also, we analyzed whether certain patient or tumor-related factors predict a favorable treatment response or predict the duration of such a response.
Patients One hundred thirty-one patients with endocrine GEP tumors were studied. All patients had tumor tissue uptake during [111In-DTPA0]octreotide scintigraphy preceding the therapy that was at least as high as the uptake in the normal liver tissue. None of the patients had received prior treatment with other radiolabeled somatostatin analogs. Four patients had previously been treated with embolization, and one patient was treated with chemoembolization for liver metastases. Prerequisites for treatment were hemoglobin (Hb)  6 mmol/L, WBC 2 * 109/L, platelets 80 * 109/L, creatinine  150 µmol/L or creatinine clearance 40 mL/min, and Karnofsky performance score (KPS) 50. The preliminary results in 35 patients were also reported previously elsewhere.15 All patients gave written informed consent to participate in the study, which was approved by the medical ethical committee of the hospital.
Methods Granisetron 3 mg was injected intravenously, and an infusion of amino acids (lysine 2.5% and arginine 2.5% in 1 L 0.9% NaCl; 250 mL/h) was started 30 minutes before the administration of the radiopharmaceutical and lasted 4 hours. Via a second pump system, the radiopharmaceutical was coadministered. Cycle dosages were 100 mCi (3.7 GBq) in seven patients, 150 mCi (5.6 GBq) in 16 patients, and 200 mCi (7.4 GBq) in the remaining 108 patients. The treatment doses of 100 mCi were injected in 20 minutes, and the doses of 150 and 200 mCi were injected in 30 minutes. The interval between treatments was 6 to 10 weeks. Patients were treated up to a cumulative dose of 750 to 800 mCi (27.8 to 29.6 GBq; corresponding with a radiation dose to the bone marrow of 2 Gy),14 unless dosimetric calculations indicated that the radiation dose to the kidneys would then exceed 23 Gy; in these cases, the cumulative dose was reduced to 600 to 700 mCi. Routine hematology, liver and kidney function tests, and hormone measurements were performed before each therapy, as well as at follow-up visits. Computed tomography (CT) or magnetic resonance imaging was performed within 3 months before the first therapy, and 6 to 8 weeks, 3 months, and 6 months after the last treatment, and thereafter every 6 months.
In Vivo Measurements
Statistics
One hundred thirty-one patients with metastasized or inoperable endocrine GEP tumors were treated between January 2000 and September 2003. Two patients were lost to follow-up; in all of the other 129 patients, follow-up data for at least 3 months after the last therapy were available. There were 66 women and 65 men; the mean age was 56 years (range, 19 to 83 years). Eight patients had gastrinoma, two had insulinoma, 33 had nonfunctioning endocrine pancreatic tumors, 18 had endocrine tumors of unknown origin, and 70 had carcinoid tumors (one thymic, one gastric, four bronchial, and 64 small bowel carcinoids). In 18 patients, the liver was the only known site of tumor spread; in two patients, this was the skeleton; and in 11 other patients, sites such as lymph nodes or pancreas were the sole known tumor sites. In the remaining 100 patients, combinations of these tumor sites were present (Fig 1). Sixty-three patients had previously been operated on, seven had had external-beam radiation, 20 had been treated with chemotherapy, and 66 had used somatostatin analogs (usually Sandostatin; Novartis, Basel, Switzerland). Fifty-two patients used somatostatin analogs in between treatments. In all but three patients, short-acting somatostatin analogs were stopped at least 1 day before the treatment, and long-acting somatostatin analogs were stopped at least 6 weeks before the treatment. In three patients with severe symptoms of carcinoid syndrome, the administration of somatostatin analogs was not stopped; in these three patients, a pretreatment OctreoScan during continued somatostatin analog treatment had shown sufficient uptake of the radiolabeled analog in the tumor sites. Fifty-five (42%) of the 131 patients had documented progressive disease (PD) within 1 year before the start of the therapy, 37 patients (28%) had stable disease (SD), and in 39 patients (30%), information on disease progression was absent. Treatment intervals were 6 to 10 weeks, except in four patients who had persistent thrombocytopenia and in 13 other patients because of reasons unrelated to the treatment. In 116 patients, the final intended cumulative dose of 600 to 800 mCi was administered. Ten of the 15 remaining patients died of PD before completing their treatment; two elderly patients stopped treatment after having received 600 mCi because they felt the treatment was too tiring; one patient stopped early because of developing kidney failure; one patient stopped early because a colorectal carcinoma was diagnosed; and one patient stopped early because of social reasons.
Nausea and vomiting (WHO toxicity grade 1 to 2) within the first 24 hours after the administration were present in 31% and 14% of the administrations, respectively. Mild abdominal pain was noticed by 12% of the patients, especially those with liver enlargement. Increased hair loss (WHO toxicity grade 1) was noticed by 64% of the patients; hair regrowth occurred within 3 months after the last administration. Serious side effects occurred in two patients. One patient in whom, in the year preceding the therapy, serum creatinine concentrations had risen from 60 to 70 µmol/L to 90 to 100 µmol/L and who had a urinary creatinine clearance of 41 mL/min when entering the study eventually developed renal insufficiency 1.5 years after receiving her last treatment (cumulative dose, 600 mCi). A kidney biopsy demonstrated tubular depositions and microangiopathy. Eventually, the patient refrained from hemodialysis and died shortly thereafter. In another patient who had diffuse liver metastases from an endocrine pancreatic tumor that had grown rapidly in the months preceding the therapy, an increase in upper abdominal pain and a deterioration of liver functions occurred in the days and weeks after the first administration. The patient developed hepatorenal syndrome and died after 5 weeks.
WHO toxicity grade 3 or 4 anemia (Hb, 4.0 to 4.9 or < 4.0 mmol/L, respectively), leukocytopenia (WBC, 1.0 to 1.9 or < 1.0 * 109/L, respectively), and thrombocytopenia (platelets, 25.0 to 49.9 or < 25 * 109/L, respectively) occurred after 0.4% and 0.0%, 1.3% and 0.0%, and 1.5% and 0.2% of the administrations, respectively. Patients who had been treated with chemotherapy had significantly more frequent thrombocytopenia toxicity grade
Serum creatinine, creatinine clearance, and serum HbA1c did not change significantly. Excluding five patients who were hypothyroid before the treatment and in whom, subsequently, replacement therapy was started and also excluding another six patients who already used thyroid medication, serum thyrotropin levels did not change significantly during or after treatment, whereas free thyroxine concentrations were significantly lower (mean, 18.3 pmol/L before therapy; and 15.5 to 17.5 pmol/L 3 to 24 months after therapy). In women, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and inhibin-B concentrations did not change significantly. In men, serum testosterone concentrations decreased significantly in the follow-up period (from a mean of 14.4 nmol/L before treatment to 10.4 nmol/L 24 months after the last treatment; P < .01, analysis of variance, Bonferroni tests), whereas serum LH concentrations did not change significantly. Serum inhibin-B concentrations decreased significantly (from a mean of 179 ng/L before treatment to a nadir of 23 ng/L 3 months after the last treatment) accompanied by a rise in serum FSH concentrations, but both returned to values not significantly different from pretreatment levels 18 to 24 months after the last treatment (Fig 3).
Tumor size could be evaluated in 125 patients (two patients were lost to follow-up, and in four patients, no measurable disease was documented). A CR was found in three patients (2%), PR was found in 32 patients (26%), minor response (MR) was found in 24 patients (19%), SD was found in 44 patients (35%), and PD was found in 22 patients (18%), including the 10 patients who died before the intended cumulative dose was reached (Table 1; Fig 4). Higher remission rates were positively correlated with high uptake during pretherapy [111In-DTPA0]octreotide scintigraphy and a limited number of liver metastases, whereas PD was significantly more frequent in patients with a low KPS and extensive disease (logistic regression, Table 2, Figs 5 and 6). A high tumor uptake during [111In-DTPA0]octreotide scintigraphy and gastrinoma tumor type were significantly correlated; also, a low KPS and weight loss and extensive liver involvement were also significantly correlated (Pearson's correlation test, P < .05). On the posttherapy scans after the third or fourth treatment, if compared with the scan after the first treatment, a reduced tumor uptake was frequently seen in patients who eventually experienced a tumor regression (Figs 7 and 8).
Median follow-up time in the 103 patients who had either SD or tumor regression was 16 months (range, 7 to 44 months). Median time to progression was more than 36 months; in the eight patients who had gastrinoma, median time to progression was 20 months (P < .01, log-rank test; Fig 9). Also, in patients with extensive liver involvement, the median time to progression was significantly shorter at 26 months (P = .05, log-rank test). Neither initial tumor response nor any other of the factors listed in Table 2 were significant in predicting the time to progression when tested separately. In a multivariate model, however, gastrinoma tumor type and the presence of bone metastases were the factors that indicated a significantly shorter time to progression (Cox regression, P = .004 and P = .037, respectively).
In this study in a large number of patients with endocrine GEP tumors who were treated with 177Lu-octreotate, we found a favorable effect on tumor size (MR, PR, or CR) in 47% of patients. Serious side effects that were potentially treatment related were found in only two patients. Renal insufficiency occurred in one of our patients. It has also been reported in patients who were treated with [90Y-DOTA0,Tyr3]octreotide, especially if no amino acids were coadministered to reduce the kidney radiation dose.7,10,17 Therefore, our protocol, which used amino acid coinfusion and limited the estimated cumulative dose to the kidneys to 23 Gy or less, seems adequate in reducing the chances of therapy-related kidney failure. One patient who had extensive and diffuse liver metastases developed lethal hepatic failure. This grave complication, which was probably a result of a much higher radiation dose to the relatively limited number of viable hepatocytes than in patients with a limited tumor burden in the liver, has also been reported in three patients who were treated with [111In-DTPA0]octreotide5 and one patient who was treated with [90Y-DOTA0,Tyr3]octreotide,10 all of whom also had extensive liver disease. Therefore, in such patients, extra caution, in terms of additional testing for liver-synthesizing capacity and, if necessary, lowering the cycle dose, seems well advised. In previous studies with 111In- and 90Y-labeled somatostatin analogs, myelodysplastic syndrome and leukemia have been reported as infrequent side effects, especially in patients treated with high cumulative doses.4,10 In the present study, none of the patients had this grave complication, and this is probably because of the fact that we limited our maximum cumulative dose to a relatively safe upper value, which corresponds to a bone marrow radiation-absorbed dose of 2 Gy. Transient and relatively mild bone marrow suppression was found in a minority of patients and in a lower percentage than reported in most studies with 111In- and 90Y-labeled somatostatin analogs.4,5,9,10,17 Transient hair loss, but no turning bold, was present in two thirds of the patients; this is probably a result of the fact that 177Lu-octreotate has a slower urinary excretion rate than [111In-DTPA0]octreotide,14 thus causing a longer retention of radioactivity in the whole body. To date, there are no reports on the presence of somatostatin receptors in, for instance, hair follicles. The pituitary gland possesses somatostatin receptors. Therefore, theoretically, treatment with 177Lu-octreotate could impair pituitary function. In our patients, we saw no decrease in serum gonadotroph or thyrotroph hormone concentrations, so obviously the absorbed radiation dose to the pituitary was low. In men, a transient significant decrease in serum inhibin-B concentrations and a concomitant increase in serum FSH levels were found during and after therapy. This radiation effect on the testicular Sertoli cells has also been described after therapy with 131I in patients with thyroid cancer.18 Longer lasting, significant decreases of testosterone in men and of free thyroxine in the whole patient group were also found. These were not accompanied by significant increases in serum LH or TSH concentrations, and therefore, although statistically significant, the decreases were clinically not significantly relevant. It can also be hypothesized that these minor decreases in testosterone and thyroid hormone concentrations were caused by chronic illness as well. We found antitumor effects (CR, PR, or MR) in 47% of our patients. The reasons to categorize tumor size reductions of 25% to 50% as MRs and to regard these as favorable therapeutic effects are that endocrine GEP tumors usually grow slowly and also because many of these tumors are cystic, which makes it unlikely that their response to therapy is comparable to that of fast-growing solid tumors. CR and PR occurred in 28% of the patients. With [90Y-DOTA0,Tyr3]octreotide, remission rates of 7% to 33% in GEP tumor patients have been reported.6,7,9-11 The differences in remission rates may, in part, be a result of differences in study design and dosages used, but the differences may also be a result of patient selection. In our patients, we found that a high uptake during [111In-DTPA0]octreotide scintigraphy and limited liver involvement were predictive factors for a favorable tumor response, whereas a low KPS and, to a lesser extent, a high tumor load were significant factors in predicting tumor progression. In the studies using [90Y-DOTA0,Tyr3]octreotide, which were performed in relatively small patient groups, insufficient data on these important factors are available. This lack of comparable data underscores the need for randomized trials comparing [90Y-DOTA0,Tyr3]octreotide and 177Lu-octreotate. Indeed, we plan to perform such a study comparing 90Y- and 177Lu-labeled somatostatin analogs. We treated both patients who had PD at baseline and those who were stable or in whom disease progression was not documented. The reason for this was that, in many of these patients, waiting for disease progression would have implied a serious deterioration of their clinical condition. As the present analysis shows, this would also have implied diminished chances of a successful therapy. Unfortunately, we did not have a control group of untreated patients. However, Faiss et al19 recently reported tumor remissions in four (5%) of 80 GEP tumor patients who had PD at study entry and were treated with somatostatin analogs and/or interferon alfa. By contrast, we found tumor remissions in 47% of our patients, whether or not they had PD at study entry. It seems highly unlikely that such a difference could have been caused by patient selection. Apart from the proportion of patients with a tumor remission, the duration of such a response is another important treatment outcome parameter. Reported response rates for single-agent and combination chemotherapy in patients with endocrine GEP tumors are as high as 40% to 60% for well-differentiated pancreatic tumors and poorly differentiated tumors of any origin, whereas success rates for midgut tumors rarely exceed 20% in recent studies (Table 3, 20-29 see review in30). High response rates have been reported in older series20-22 (Table 3), but in these studies, the response evaluation also included biochemical responses (changes in serum tumor marker levels) as well as physical examination for the evaluation of hepatomegaly. Indeed, much of the discrepancy between older and more recent studies can be ascribed to differences in response criteria, as is illustrated in a more recent study by Cheng and Saltz23 who maintained that their percentage of patients with an objective response would have increased from 6% to 25% if they had accepted not only measured CT scan changes as response criteria, but also decreases of hepatomegaly assessed with physical examination. Despite the varying percentages of objective responses that have been reported for chemotherapy, the median time to progression in most of the studies is less than 18 months. In this respect, our treatment with 177Lu-octreotate performed considerably better, with a median time to progression of more than 36 months. However, some caution in the interpretation of these data is warranted because the median follow-up in this ongoing study is 16 months. Also, cardiac and renal toxicity, as well as vomiting and hematologic toxicity, are much more frequent with chemotherapy than with treatment with 177Lu-octreotate (Table 3).
Unexpectedly, we found that patients with gastrinomas had a shorter time to progression than other patients who had, for instance, carcinoids or nonfunctioning endocrine pancreatic tumors. In theory, this could be caused by a faster growth pattern of gastrinomas. There are only a few reports in relatively small numbers of neuroendocrine tumor specimens on proliferative markers like Ki-67. To date, there are reports that evidence that a high Ki-67 proliferative index correlates with a fast tumor growth and short survival in vivo for both functioning and nonfunctioning endocrine GEP tumors,31-33 but as far as the authors are aware, there is no direct evidence that proliferative indices differ between metastasized gastrinomas and other endocrine GEP tumors. However, an interesting difference is that, on immunostains, gastrinomas, in contrast to other endocrine pancreatic tumors, frequently coexpress neuroendocrine and exocrine markers, such as carcinoembryonic antigen, cytokeratin 19, and epithelial membrane antigen.34 This could imply the different origins of gastrinomas and, it can be speculated that gastrinomas also have different behavior in vivo. Tumor remission was positively correlated with a high uptake during [111In-DTPA0]octreotide scintigraphy and a limited number of liver metastases, whereas disease progression was significantly more frequent in patients with a low performance status and a high tumor load. This implies that the chances of a successful treatment are greater if patients are treated in an early stage of their disease. In contrast to what we reported earlier in a much smaller group of patients,15 the percentage of patients with a remission does not differ significantly between those patients who have disease progression at baseline and those who do not; therefore, to wait for disease progression has no advantage in terms of chances of success. However, firm conclusions on the effect of our therapy on overall survival cannot be drawn from this or any other study with radiolabeled somatostatin analogs because randomized trials comparing treatment with radiolabeled analogs with no additional treatment have not been performed. Treatment with the radiolabeled somatostatin analog 177Lu-octreotate results in tumor remission in a high percentage of patients with endocrine GEP tumors. Serious side effects are rare. The median time to progression is more than 36 months, which compares favorably with chemotherapy. Results are better in patients with a limited tumor load. Therefore, early treatment, even in patients who have no PD, may be better.
The authors indicated no potential conflicts of interest.
We thank all supporting personnel of the Departments of Nuclear and Internal Medicine (Erasmus Medical Center, Rotterdam, the Netherlands) for their expert help and effort.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests (or, if applicable, Fisher's exact tests), Pearson's correlation tests, and logistic regression were used. For survival analysis, log-rank tests and Cox regression models were used. 
