Kam, B.L.

Peptide receptor radionuclide therapy (PRRT) for GEP-NETs (Article)

2012-12-01T00:00:00Z

Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues plays an increasing role in the treatment of patients with inoperable or metastasised gatroenteropancreatic neuroendocrine tumours (GEP-NETs).90Y-DOTATOC and177Lu-DOTATATE are the most used radiopeptides for PRRT with comparable tumour response rates (about 15-35%). The side effects of this therapy are few and mild. However, amino acids should be used for kidney protection, especially during infusion of90Y-DOTATOC. Options to improve PRRT may include combinations of radioactive labelled somatostatin analogues and the use of radiosensitising drugs combined with PRRT. Other therapeutic applications of PRRT may include intra-arterial administration, neo-adjuvant treatment and additional PRRT cycles in patients with progressive disease, who have benefited from initial therapy. Considering the mild side-effects, PRRT may well become the first-line therapy in patients with metastasised or inoperable GEP-NETs if more widespread use of PRRT can be accomplished.

Tumor response assessment to treatment with [ 177Lu-DOTA 0,Tyr 3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors: Differential response of bone versus soft-tissue lesions (Article)

2012-09-01T00:00:00Z

We have noted that bone lesions on CT respond differently from soft-tissue lesions to treatment with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). We therefore compared the response of bone lesions with that of soft-tissue lesions to treatment with177Luoctreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors (NETs). Methods: Forty-two patients with well-differentiated NETs who had bone metastases that were positive on [111In-DTPA0]octreotide somatostatin receptor scintigraphy (SRS) before treatment, and who had soft-tissue lesions, were studied. All patients had had a minimum of 1 follow-up CT scan. Lesions were scored on CT and bone lesions also on SRS before and after treatment. Tumor markers (chromogranin A and 5-hydroxyindoleacetic acid) before and after treatment were compared. Results: Because bone lesions were not visible on CT before treatment in 11 of 42 patients (26%), bone and softtissue lesions were evaluated in 31 patients. Whereas bone lesions increased in size, soft-tissue lesions decreased in size. The percentage change in bone and soft-tissue lesions was significantly different at all time points up to 12 mo of follow-up (P < 0.001). The intensity or number of bone lesions on SRS decreased after treatment in 19 of 23 patients (83%) in whom SRS after treatment was available. The tumor markers also decreased significantly after treatment. In 1 patient, bone lesions became visible on CT after treatment, mimicking progressive disease with "new" bone lesions, although there was an overall treatment response. Conclusion: In patients with NETs, the apparent increase in size of bone lesions or the appearance of new bone lesions on CT after treatment with177Lu-octreotate should be interpreted cautiously, as this finding may be therapy-related rather than indicative of tumor progression. Copyright

Treatment of Gastroenteropancreatic Neuroendocrine Tumors with Peptide Receptor Radionuclide Therapy (Article)

2012-01-10T00:00:00Z

The primary treatment of gastroenteropancreatic neuroendocrine tumors (GEPNETs) is surgery with curative intent or debulking of the tumor mass. In case of metastatic disease, cytoreductive options are limited. A relatively new therapeutic modality, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs, is currently available in a number of mostly European centers. Complete and partial responses obtained after treatment with [90Y-DOTA0,Tyr3]octreotide are in the same range as after treatment with [177Lu-DOTA0,Tyr3]octreotate (i.e. 10-30%). However, significant nephrotoxicity has been observed after treatment with [90Y-DOTA0,Tyr3]octreotide. Options to improve PRRT may include combinations of radioactive labeled somatostatin analogs, intra-arterial administration, and the use of radiosensitizing drugs combined with PRRT. Other therapeutic applications of PRRT may include additional therapy cycles in patients with progressive disease after benefit from initial therapy, PRRT in adjuvant or neoadjuvant setting, or PRRT combined with new targeted therapies, such as sunitinib or everolimus. Randomized clinical trials comparing PRRT with other treatment modalities, or comparing various radioactive labeled somatostatin analogs should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs. Copyright

Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [ 177Lu-DOTA 0,Tyr 3]octreotate (Article)

2011-09-01T00:00:00Z

Quality of life (QOL) is an important outcome in cancer therapy. In this study, we investigated the QOL and symptoms after [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) therapy in patients with inoperable or metastasized gastroenteropancreatic or bronchial neuroendocrine tumors (NETs). Methods: Two hundred sixty-five Dutch patients completed the QOL questionnaire of the European Organization for the Research and Treatment of Cancer after being treated for NETs. ANOVA was used for statistical analyses, with a P value of 0.05 or less being considered significant. Differences of at least 10 points in global health status (GHS)/QOL scores, symptom scores, and Karnofsky performance scores (KPS) before and after therapy were regarded as indicating an improvement. Results: Regardless of the treatment outcome, GHS/QOL, insomnia, appetite loss, and diarrhea improved significantly in the total group. These improvements were also seen in patients with bone metastases or a decrease of 50% or more in chromogranin A. Improvement in the scores by at least 10 points was also analyzed in a subgroup of patients with decreased GHS/QOL or symptoms at the start of therapy: in 36% of these patients, GHS/QOL improved after therapy; in 49%, fatigue; in 70%, nausea plus vomiting; in 53%, pain; in 44%, dyspnea; in 59%, insomnia; in 63%, appetite loss; in 60%, constipation; and in 67%, diarrhea. Additionally, we did not see a statistically significant deterioration in patients who had GHS/QOL 100, KPS 100, or no symptoms at the start. In patients with initial stable disease or remission after treatment, GHS/QOL and KPS decreased significantly when re-growth of the tumors occurred. Conclusion: GHS/QOL, KPS, and symptoms improved significantly after177Lu-octreotate therapy, and there was no significant decrease in QOL in patients who had no symptoms before therapy. In patients who had suboptimal scores for GHS/QOL or symptoms before therapy, a clinically significant improvement was demonstrated. Our results indicate that177Lu-octreotate therapy not only reduces tumors and prolongs overall survival but also improves the patients' self-assessed QOL. Copyright

Preclinical and Clinical Studies of Peptide Receptor Radionuclide Therapy (Article)

2010-05-01T00:00:00Z

In the 1980s, the111In-labeled somatostatin analog OctreoScan (Covidien, Hazelwood, MO) was developed for imaging of somatostatin receptor subtype 2 (sst2) overexpressing tumors. On the basis of this success, peptide receptor radionuclide therapy (PRRT) was developed using similar somatostatin analogs with different therapeutic radionuclides. Clinical application of PRRT demonstrated impressive results on tumor response, overall survival, and quality of life in patients with gastroenteropancreatic neuroendocrine tumors. The peptides 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), Tyr3-octreotate (DOTATATE) and DOTA, Tyr3-octreotide (DOTATOC) (brand name Onalta), predominantly targeting sst2, have been granted Orphan Drug status by the European Medicines Agency and the US Food and Drug Administration for application in PRRT. Besides somatostatin receptor-targeting peptides, multiple other radiopeptide analogs were developed targeting several other receptors overexpressed on various tumors. Some of these peptide analogs, including cholecystokinin, gastrin, gastrin-releasing peptide, arginine-glycine-aspartate (RGD)-peptides, and glucagon-like peptide 1 analogs appeared very promising in preclinical and clinical imaging and PRRT studies. Although the success of PRRT with radiolabeled somatostatin analogs has been established, there is still room for improvement. The therapeutic window of PRRT could be enlarged by the use of new and improved targeting compounds, of which new antagonists with excellent tumor to background ratios are very promising. Furthermore, locoregional administration, improved healthy tissue protection, and combination treatment can be applied to increase the effectiveness of PRRT. Combination treatment might include cocktails of different peptide analogs of different therapeutic radionuclides and of radiolabeled peptides with chemotherapeutic or radiosensitizing agents. This review summarizes results of PRRT and describes clinical and preclinical studies regarding PRRT optimizing strategies.

Somatostatin receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors (Article)

2010-03-01T00:00:00Z

Somatostatin receptor imaging (SRI) with [111In-DTPA 0]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors (GEPNETs). Newer radiolabeled somatostatin analogs which can be used in positron emission tomography (PET) imaging, and which have a higher affinity for the somatostatin receptor, especially receptor subtype-2, have been developed. It would be desirable, however, if one radiolabeled analog became the new standard for PET imaging, because the current application of a multitude of analogs implies a fragmented knowledge on the interpretation of the images that are obtained in clinical practice. In our view, the most likely candidates for such a universal PET tracer for SRI are [68Ga-DOTA0,Tyr3]octreotate or [68Ga-DOTA0,Tyr3]octreotide. Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all 111In-, 90Y-, or 177Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy (PRRT). The results that were obtained with [ 90Y-DOTA0,Tyr3]octreotide and [ 177Lu-DOTA0,Tyr3]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months respectively. The patients' self-assessed quality of life increases significantly after treatment with [177Lu-DOTA0,Tyr 3]octreotate. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with [177Lu-DOTA0,Tyr3]- octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable GEPNETs.

Peptide Receptor Radionuclide Therapy in Patients With Gastroenteropancreatic Neuroendocrine Tumors (Article)

2010-03-01T00:00:00Z

Somatostatin receptor imaging with [111In-DTPA0)octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors. Treatment with radiolabeled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized, well-differentiated neuroendocrine tumors. Symptomatic improvement may occur with all111In,90Y, or177Lu-labeled somatostatin analogues that have been used for peptide receptor radionuclide therapy. The results that were obtained with [90Y-DOTA0, Tyr3]octreotide and [177Lu-DOTA0, Tyr3]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months, respectively. The patients' self-assessed quality of life increases significantly after treatment with [177Lu-DOTA0, Tyr3]octreotate. Finally, compared with historical controls, there is a benefit in overall survival of several years from time of diagnosis in patients treated with [177Lu-DOTA0, Tyr3]octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of peptide receptor radionuclide therapy can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable gastroenteropancreatic neuroendocrine tumors.

Salvage therapy with177Lu-octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumors (Article)

2010-03-01T00:00:00Z

Regular therapy with the radiolabeled somatostatin analog177Lu-octreotate (22.2-29.6 GBq) in patients with gastroenteropancreatic or bronchial neuroendocrine tumors results in tumor remission in 46% of patients, including minor response. We present the effects of additional therapy with177Lu-octreotate in patients in whom progressive disease developed after an initial benefit from regular therapy. Methods: Thirty-three patients with progressive disease after an initial radiologic or clinical response were treated with additional cycles of177Lu-octreotate. The intended cumulative dose of additional therapy was 14.8 GBq in 2 cycles. Responses were evaluated using Southwest Oncology Group criteria, including minor response (tumor size reduction of ≥25% and <50%). Results: Median time to progression (TTP) after regular therapy was 27 mo. In 4 patients, the intended cumulative dose was not achieved (2 had progressive disease, 2 had long-lasting thrombocytopenia). Hematologic toxicity grade 3 was observed in 4 patients, and grade 4, in 1. The median follow-up time was 16 mo (range, 1-40 mo). No kidney failure or myelodysplastic syndrome was observed. Renewed tumor regression was observed in 8 patients (2 partial remission, 6 minor response), and 8 patients had stable disease. Median TTP was 17 mo. Treatment outcome was less favorable in patients with a short TTP after regular cycles. Treatment effects in patients with pancreatic neuroendocrine tumors were similar to those in patients with other gastroenteropancreatic neuroendocrine tumors. Conclusion: Most patients tolerated additional cycles with177Lu-octreotate well. None developed serious delayed adverse events. Additional cycles with177Luoctreotate can have antitumor effects, but effects were less than for the regular cycles. This may be because of a worse clinical condition, more extensive tumor burden, or changed tumor characteristics. We conclude that this salvage therapy can be effective and is safe. Copyright

Peptide-receptor radionuclide therapy for endocrine tumors (Article)

2009-07-01T00:00:00Z

Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a promising option for the treatment of somatostatin-receptor- positive endocrine tumors. Treatment with somatostatin analogs labeled with 111 In, 90 Y or 177 Lu can result in symptomatic improvement, although tumor remission is seldom achieved with 111 In-labeled analogs. In this Review, the findings of several studies on the use of PRRT for endocrine tumors are evaluated. Large variation in the antitumor effects of 90 Y-octreotide was reported between studies: an objective response (50% tumor regression) was achieved in 9-33% of patients. After treatment with 177 Lu-octreotate, an objective response was achieved in 29% of patients and a minor response (25-50% tumor regression) was achieved in 16% of patients; stable disease was present in 35% of patients. Treatment with 177 Lu-octreotate resulted in a survival benefit of several years and markedly improved quality of life. Serious, delayed adverse effects were rare after PRRT. Although randomized, clinical trials have not yet been performed, data on the use of PRRT compare favorably with those from other treatment approaches, such as chemotherapy. If these results can be replicated in large, controlled trials, PRRT might become the preferred option in patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors.

Treatment with the radiolabeled somatostatin analog [177Lu- DOTA0,Tyr3]octreotate: Toxicity, efficacy, and survival (Article)

2008-09-22T00:00:00Z

Purpose: Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slowgrowing, 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.

Report on short-term side effects of treatments with 177Lu- octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours (Article)

2008-04-01T00:00:00Z

Purpose: Treatment with the radiolabelled somatostatin analogue177Lu-octreotate results in tumour remission in 47% of patients with gastroenteropancreatic neuroendocrine tumours. Adding capecitabine to177Lu-octreotate, as a radio-sensitiser, may enhance these anti-tumour effects. We now present the short-term toxicity profile of this novel combination. Methods: Seven patients were treated with 7.4 GBq177Lu-octreotate and capecitabine (1650 mg/m2per day) for 2 weeks with an intended number of four cycles. Toxicity, and especially haematological and renal parameters, were monitored on a weekly basis for the first two cycles and 4 and 6 weeks after subsequent cycles. Results: None of the patients had hand-foot syndrome. One patient had grade 1 stomatitis occurring after one of four cycles. Grade 3 or 4 leukopenia or neutropenia did not occur. One patient had grade 3 anaemia, but none had grade 4 anaemia. One patient had grade 2 thrombocytopenia after the fourth cycle, and one had grade 3 thrombocytopenia. Grade 4 thrombocytopenia did not occur. No significant changes in serum creatinine levels were observed. None of the patients had symptoms of cardiac ischaemia. Conclusions: Treatment with the combination of177Lu-octreotate and capecitabine was feasible and safe considering acute and subacute side effects. We therefore started a randomised, controlled clinical trial to compare this combination with177Lu-octreotate as single agent with regard to anti-tumour effects and side effects.

Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr 3]octreotate (Article)

2008-04-01T00:00:00Z

Introduction: Receptor radionuclide therapy is a promising treatment modality for patients with neuroendocrine tumors for whom alternative treatments are limited. The aim of this study was to investigate the incidence of hormonal crises after therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). Materials and methods: All177Lu- octreotate treatments between January 2000 and January 2007 were investigated. Four hundred seventy-six patients with gastroenteropancreatic neuroendocrine tumors and three patients with metastatic pheochromocytoma were included for analysis. Results: Four hundred seventy-nine patients received a total of 1,693 administrations of177Lu-octreotate. Six of 479 patients (1%) developed severe symptoms because of massive release of bioactive substances after the first cycle of177Lu-octreotate. One patient had a metastatic hormone-producing small intestinal carcinoid; two patients had metastatic, hormone-producing bronchial carcinoids; two patients had vasoactive intestinal polypeptide-producing pancreatic endocrine tumors (VIPomas); and one patient had a metastatic pheochromocytoma. With adequate treatment, all patients eventually recovered. Conclusion: Hormonal crises after177Lu- octreotate therapy occur in 1% of patients. Generally,177Lu- octreotate therapy is well tolerated.

Treatment of Patients Who Have Endocrine Gastroenteropancreatic Tumors with Radiolabeled Somatostatin Analogues (Article)

2007-06-01T00:00:00Z

Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients who have inoperable or metastasized endocrine tumors. Symptomatic improvement may occur with all111In-,90Y-, or177Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy. The results that were obtained with [90Y-DOTA°,Tyr3]octreotide and [177Lu-DOTA°,Tyr3]octreotate are encouraging in tumor regression. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild. These data compare favorably with the limited number of alternative treatment approaches.