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Journal of Clinical Oncology, Vol 26, No 13 (May 1), 2008: pp. 2124-2130 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.2553 Treatment With the Radiolabeled Somatostatin Analog [177Lu-DOTA0,Tyr3]Octreotate: Toxicity, Efficacy, and Survival
From the Departments of Nuclear Medicine, Internal Medicine, and Surgery, Erasmus Medical Center, Rotterdam, the Netherlands Corresponding author: Dik 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 Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slow-growing, median overall survival (OS) in patients with liver metastases is 2 to 4 years. In metastatic disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate. Here we report on the toxicity and efficacy of this treatment, performed in over 500 patients. Patients and Methods Patients were treated up to a cumulative dose of 750 to 800 mCi (27.8-29.6 GBq), usually in four treatment cycles, with treatment intervals of 6 to 10 weeks. Toxicity analysis was done in 504 patients, and efficacy analysis in 310 patients. Results Any hematologic toxicity grade 3 or 4 occurred after 3.6% of administrations. Serious adverse events that were likely attributable to the treatment were myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. Complete and partial tumor remissions occurred in 2% and 28% of 310 GEPNET patients, respectively. Minor tumor response (decrease in size > 25% and < 50%) occurred in 16%. Median time to progression was 40 months. Median OS from start of treatment was 46 months, median OS from diagnosis was 128 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis. Conclusion Treatment with [177Lu-DOTA0,Tyr3]octreotate has few adverse effects. Tumor response rates and progression-free survival compare favorably to the limited number of alternative treatment modalities. Compared with historical controls, there is a benefit in OS from time of diagnosis of several years.
Gastroenteropancreatic neuroendocrine tumors (GEPNETs) are relatively rare. The two most common types of GEPNETs, carcinoids and pancreatic neuroendocrine tumors, have incidence rates of one to 2.5 in 100,000 population per year and approximately one in 100,000 population per year, respectively.1-8 However, since 5-year survival rates in patients with GEPNETs, irrespective of stage of disease, are over 60%,5,8-11 their prevalence is much higher. Despite the fact that most GEPNETs are slow-growing tumors, and the popular notion that these are relatively benign tumors, median overall survival (OS) in patients with metastatic liver disease is 2 to 4 years.9,11-14 In this respect, data from an analysis in over 10,000 carcinoid patients, reporting nonlocalized disease at diagnosis in 32% to 47% of cases, is of great impact.8 This finding is in line with another epidemiological study that reports liver metastases at diagnosis in 22% to 33% of cases.5 Also, metastases may become apparent only years after the initial presentation of a carcinoid. In case of metastatic disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs. Here we report on the toxicity and efficacy of treatment with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate), performed in over 500 patients with somatostatin receptor–expressing tumors. The radionuclide 177Lu has a half-life of 6.7 days and emits both beta-radiation and gamma-radiation, allowing imaging and dosimetry after therapy. Here we present long-term follow-up and survival data in over 300 patients with GEPNETs and compare these to historical controls and published results for other treatment modalities in comparable patient groups.
Patients From January 2000 to August 2006, 1,772 treatments were given in 504 patients who were treated according to protocol. Tumor types were divided into carcinoids, pancreatic neuroendocrine, and neuroendocrine of unknown origin. Gastrinoma, insulinoma, and vasoactive intestinal peptide-secreting tumor (VIPoma) were only used in case of syndromes caused by hormonal hypersecretion. Inclusion criteria were tumor uptake during [111In-DTPA0]octreotide scintigraphy (OctreoScan, Mallinckrodt, Petten, the Netherlands) preceding the therapy that was at least as high as that in normal liver tissue, no prior treatment with other radiolabeled somatostatin analogs, serum hemoglobin  6 mmol/L, WBC count 2·109/L, platelet count 75·109/L,serum creatinine concentration  150 umol/L or creatinine clearance 40 mL/min, and Karnofsky performance status (KPS) 50. Preliminary results in 131 patients with GEPNETs were also reported previously.15 All patients gave written informed consent to participate in the study, which was approved by the hospital's medical ethical committee.
Methods Granisetron 3 mg or ondansetron 8 mg was injected intravenously and an infusion of amino acids (lysine 2.5%, 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. The radiopharmaceutical was coadministered via a second pump system. Cycle dosages were 100 mCi (3.7 GBq) in seven patients, 150 mCi (5.6 GBq) in 16, and 200 mCi (7.4 GBq) in the remaining patients, 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),16 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 500 to 700 mCi. Routine hematology, liver, and kidney function tests were performed before each therapy, as well as at follow-up visits. Computer tomography (CT) or magnetic resonance imaging (MRI) was done 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
Toxicity In the 504 patients, acute adverse effects occurring within 24 hours after the administration of the radiopharmaceutical were nausea after 25% of administrations, vomiting after 10%, and abdominal discomfort or pain after 10%. Six patients were hospitalized within 2 days of the administration because of hormone-related crises. All recovered after adequate care. Subacute, hematological toxicity, WHO grade 3 or 4, occurred 4 to 8 weeks after 3.6% of administrations, or, expressed patient-based, after at least one of several treatments in 9.5% of patients. Temporary hair loss (WHO grade 1; no baldness) occurred in 62% of patients. Serious delayed toxicities were observed in nine patients. There were two cases of renal insufficiency, both of which were probably unrelated to 177Lu-octreotate treatment. One patient had pre-existent kidney function deterioriation and the other had increasing tricuspid valve insufficiency. There were three patients with serious liver toxicity. In one patient with diffuse liver metastases, liver functions deterioriated in the weeks following the first administration. The patient died of hepatic failure after 5 weeks. Because this patient experienced a similar deterioriation due to rapid tumor growth after his previous course of chemotherapy, the liver failure after 177Lu-octreotate treatment was considered more likely tumor growth–related than radiation induced. Two other patients, who both had multiple liver metastases, had temporary rises in serum ALT, AST, and bilirubin concentrations. In both patients, this condition resolved without causative treatment and both resumed treatment at half doses uneventfully. Lastly, myelodysplastic syndrome (MDS) occurred in four patients. In one patient, previous chemotherapy with alkylating agents was the more likely cause of MDS. In the other three patients, MDS was diagnosed 2 to 3 years after the last treatment with 177Lu-octreotate, and was probably treatment related.
Efficacy Patient characteristics of the remaining 310 patients are listed in Table 1. There were 164 men and 146 women; mean age at treatment start was 59 years (range, 21 to 85 years).
Forty-seven patients did not receive their intended total cumulative dose of 177Lu-octreotate. In 37 this was because of evident clinical disease progression or death. Treatment responses according to tumor type at 3 months after the last therapy cycle are listed in Table 2. Overall objective tumor response rate, comprising complete response (CR), partial response (PR), and MR, was 46%. Response rates in patients with gastrinomas, insulinomas, VIPomas and nonfunctioning pancreatic NETs were higher than in carcinoid tumor patients. CRs were only called if both conventional imaging (CT scanning or MRI) and the OctreoScan had normalized.
Potential prognostic factors for predicting tumor remission (CR, PR, or MR) as treatment outcome, that were analyzed using (multivariate) logistic regression are marked with an asterisk in Table 1. Two significant factors resulted: uptake on the OctreoScan (P < .01), and KPS greater than 70 (P < .05). A small percentage of patients who had either SD or MR at their first two evaluations after therapy, had a further improvement in categorized tumor response at 6 months and 12 months follow-up, occurring in 4% of patients and 5% of patients, respectively. Three of four patients with clinically nonfunctioning neuroendocrine pancreatic tumors that were judged inoperable before treatment with 177Lu-octreotate, and who had PR, were succesfully operated 6 to 12 months after their last treatment, whereas one died of postoperative complications.
Time to Progression and Survival Median OS in our 310 GEPNET patients was 46 months (median follow-up 19 months; 101 deaths). Median disease related survival was more than 48 months (median follow-up 18 months; 81 deaths). Median progression-free survival was 33 months. Survival analysis using Cox regression and using the factors from Table 1 marked with an asterisk, with in addition a variable indicating whether initial tumor response was PD, SD, or remission (CR, PR, or MR), resulted in the same six significant factors both for OS and for disease-specific survival (Table 3). The most important factor predicting survival was treatment outcome (Fig 1). Median time from diagnosis to referral was 21 months, median follow-up from diagnosis 48 months. Median OS from diagnosis was 128 months, median disease-specific survival was more than 180 months.
From our data, we conclude that the treatment with 177Lu-octreotate has few adverse effects and is relatively safe. With adequate clinical scrutiny, patients who have an increased risk to develop hormone-related crises can be identified and adequate measures to contain such events can be taken. Less dramatic acute adverse effects, like nausea and vomiting, occur in a minority of patients and can usually be successfully countered by administering additional antiemetics. Also, serious hematologic toxicity is rare. Other, delayed, serious adverse events that were likely caused by the therapy with 177Lu-octreotate, comprising MDS and liver toxicity, were rare and occurred in approximately 1% of patients. The MDS cases require further attention and indicate that either the radiation absorbed dose to the bone marrow or the susceptibility of the stem cells to radiation varies between patients. Models, based on the biodistribution of radioactivity in the individual patient, will therefore have to be developed for future optimization of this therapy. Using such individualized dosimetry for kidney radiation–absorbed doses, in combination with kidney-protective amino acid infusion, resulted in the absence of serious kidney toxicity in any of our patients. Such renal toxicity has been reported in patients treated with [90Y-DOTA0,Tyr3]octreotide, especially if no amino acids were coadministered.18-20 We found tumor size reductions, including MR, in 46% of our patients. MR was included as a separate response class because of the usual slow growth of GEPNETs, and their often partly cystic appearance, making major tumor size reductions less likely than in fast growing solid tumors after, for instance, chemotherapy or external-beam radiation. PR and CR were observed in 30% of patients. This percentage compares favorably to recent chemotherapy studies in GEPNETs, which mostly report CR and PR in less than 20% of patients. Also, the duration of the response, progression-free survival and OS are more favorable after 177Lu-octreotate (Table 4).
Antiproliferative treatment options for patients with inoperable GEPNETs are limited. Somatostatin analogs, interferon-alfa, and their combination have their specific merit in reducing symptomatology from hormonal overproduction by GEPNETs. However, CT-assessed responses are rare, occurring in less than 5% to 10% of cases.31-33 Other, nonsystemic, local ablative therapies for liver metastases are radiofrequency ablation (RFA), and liver embolization or chemoembolisation. Studies in usually small patient series report objective response rates of 30% to 80% with response durations of 6 to 42 months.34 Recent single center overviews in larger series of over 50 patients report symptomatic relief, with a mean duration of 11 months, in 70% of patients after RFA, but no data on objective responses,11 whereas an objective response was found in 37% of patients after chemoembolization, with a median duration of 14 months.35 Serious procedure-related morbidity was reported in 5% of patients after RFA, and in 10% of patients after chemoembolization. Clearly, these serious adverse effects are fewer in our patients treated with 177Lu-octreotate, and also the response duration is longer. Also, it is of note to realize that both methods, RFA and chemoembolization, are performed only if major tumor load is restricted to the liver. In addition to other criteria relating to tumor size and number, intact portal bloodflow, and tumor localization in relation to blood vessels have to be met. Treatment with the radiolabeled somatostatin analog [90Y-DOTA0,Tyr3]octreotide has been and is still performed in a number of centers. PR and CR have been reported in 8% to 33% of patients, mostly in small patient groups.19,36-39 Differences in treament outcome evaluation (Response Evaluation Criteria in Solid Tumors, WHO, versus Southwest Oncology Group criteria), but especially patient inclusion bias, may account for this. In the present analysis, the two significant factors predicting favorable treatment outcome were high patient performance score and high uptake on the pretreatment OctreoScan. It is obvious that different studies can only be reliably compared if stratification for these factors is applied. From the published data, such stratified comparison cannot be performed. In our own institution, CT-assessed CR/PR occurred in only 8% of patients after treatment with [90Y-DOTA0,Tyr3]octreotide.39 Also, when we compared the residence time in tumors for [177Lu-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate in the same patients in a therapeutical setting, we found a factor of 2.1 in favor of [177Lu-DOTA0,Tyr3]octreotate.40 Therefore, we think that 177Lu-octreotate is the radiolabeled somatostatin analog of choice when performing PRRT. In a small number of patients who had inoperable pancreatic NETs that had not metastasized, tumor shrinkage subsequent to treatment with 177Lu-octreotate made these patients candidates for surgery. This neoadjuvant use of PRRT, although applicable in select cases only, is of great interest, as it may cure such patients. An important feature of the tumor response after treatment with 177Lu-octreotate that we observed, is that the eventual maximal shrinkage of the tumor may take months after completing the therapy. This is most likely due to the slow growing nature of these tumors; radiation biology axioms state that radiation damage to the DNA usually results in cell death only after their reproductive integrity is tested by one or more attempts at mitotic division.41 Therefore, if such attempts at cell division are few, tumor size reduction will be slow. Time to progression in patients having CR, PR, MR, or SD was significantly shorter for patients having high tumor load in the liver or having bone metastases. These are well-known prognostic factors of poor disease evolution. More puzzling is the fact that patients with gastrinoma, VIPoma, or insulinoma had significantly shorter response durations than other patients. A faster growth pattern of tumor cells must be assumed, but direct comparisons for tumoral growth between these tumors and other NETs, like carcinoids, are lacking. Median OS was shorter in patients having a poor PS and those having extensive liver involvement. This implies that treatment with 177Lu-octreotate should preferably be started early in the disease evolution. Because neuroendocrine tumors can be clinically stable for years, however, it is, in our opinion, good clinical practice to wait for signs of disease progression if the tumor load is moderate. Such signs should not be restricted to CT-assessed tumor growth, but also include rises in serum tumor markers, increase in symptoms, or involuntary weight loss. In patients with limited tumor load and in whom cure is potentially possible, treatment should be initiated without further delay, and the same holds true for patients with extensive tumor load, hepatomegaly, or significant weight loss, when waiting for formally assessed tumor progression would place these patients in an unfavorable starting position for treatment or would even qualify them as ineligible. We found OS and disease-specific survival at and above 48 months. Because the treatment with 177Lu-octreotate is still open for new patients, and median follow-up in relation to survival is relatively short, we also analyzed our local Dutch patients separately, with subgroups that had longer follow-up. Also in these analyses, OS and disease-specific survival time were consistently at or above 48 months (data not shown). Comparing survival data in our group, either from time of diagnosis or from time of referral, with data from different epidemiologic studies or studies pertaining to a specific intervention, and limiting our data to similar subgroups of patients, we found a benefit in OS for patients treated with 177Lu-octreotate, which ranged from 40 to 72 months from diagnosis (Table 5). Of course, our patients were selected on the basis of a positive somatostatin receptor status of their tumors. In theory, not including patients with poorly differentiated, somatostatin receptor–negative tumors in our series could have caused a selection bias. We therefore also calculated OS for the subgroups listed in Table 5 with the addition of fictitious patients with a survival of 6 months from diagnosis, assuming their incidence at 5% of patients. (The incidence of poorly differentiated NETs is estimated at < 3% for foregut NETs42). Even with these assumptions, the survival benefit for patients treated with 177Lu-octreotate was 23 to 69 months (data not shown). We are aware that comparisons with historical controls should be interpreted with caution, but we also think that such a consistent difference with many other reports in similar patient groups cannot be ignored, and is most probably caused by a real difference in survival.
In conclusion, the therapy with 177Lu-octreotate has few serious adverse effects and can be regarded safe. Tumor response rates and progression-free survival compare favorably to the limited number of alternative treatment modalities in patients with inoperable or metastasized GEPNETs. Compared to historical controls, there is a benefit in OS of several years from time of diagnosis.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Eric P. Krenning, Biosynthema (U), Mallinckrodt (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Dik J. Kwekkeboom, Eric P. Krenning Financial support: Eric P. Krenning Provision of study materials or patients: Dik J. Kwekkeboom, Wouter W. de Herder, Casper H. van Eijck, Richard A. Feelders, Maarten O. van Aken Collection and assembly of data: Dik J. Kwekkeboom, Boen L. Kam, Martijn van Essen, Peter P. Kooij Data analysis and interpretation: Dik J. Kwekkeboom, Eric P. Krenning Manuscript writing: Dik J. Kwekkeboom Final approval of manuscript: Dik J. Kwekkeboom, Wouter W. de Herder, Boen L. Kam, Casper H. van Eijck, Martijn van Essen, Peter P. Kooij, Richard A. Feelders, Maarten O. van Aken, Eric P. Krenning
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 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. 
