Long-term survival and toxicity in patients with neuroendocrine tumors treated with 177 Lu-octreotate peptide radionuclide therapy.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) has shown favorable results in neuroendocrine tumors (NETs). Long-term safety and efficacy data for 177 Lu-octreotate PRRT, particularly in combination with chemotherapy, is lacking. METHODS: The authors conducted a retrospective review of the long-term toxicity and survival outcomes of 104 patients with advanced NETs treated on 4 phase 2 clinical trials with Lutetium-177-octreotate (177 Lu-octreotate) PRRT, mostly in combination with chemotherapy. Median follow-up was 68 months, which represents the longest follow-up study of 177 Lu-octreotate PRRT for NETs to date. RESULTS: Median progression-free survival (PFS) was 37 months, and median overall survival (OS) was 71 months. Five- and 10-year OS were 62% and 29%, and 5- and 10-year PFS were 36% and 21%, respectively, demonstrating 177 Lu-octreotate can provide durable responses. PRRT was well tolerated with 1.9% of patients developing chronic renal impairment and 1% of patients developing long-term thrombocytopenia. Interestingly, there was a relatively high rate of myelodysplasia (MDS)/leukemia (6.7%), possibly attributable to the longer follow-up (with all except 1 case occurring more than 4 years after PRRT treatment) or to the addition of concurrent chemotherapy. CONCLUSIONS: Lutetium-177-Octreotate PRRT remains an efficacious and well tolerated treatment in long-term follow-up. For clinicians deciding on the timing of PRRT for individual patients, the 6.7% long-term risk of MDS/leukemia needs to be balanced against the 21% PFS at 10 years.

Pancreatic Neuroendocrine Tumor Control: Durable Objective Response to Combination 177Lu-Octreotate-Capecitabine-Temozolomide Radiopeptide Chemotherapy.

BACKGROUND/METHODS: Thirty patients with advanced progressive grade 1 or 2 pancreatic neuroendocrine tumors (pNETs), treated on a prospective phase II single-center study, were followed up for up to 4 years after 4 cycles of 7.9 GBq 177Lu-octreotate combined with chemotherapy. Each 8-week cycle of treatment combined radiopeptide therapy with 14 days of capecitabine at 1,500 mg/m2 and 5 days of temozolomide at 200 mg/m2. RESULTS: The overall response rate was 80% (95% CI 66-93), and there was complete remission in 13% (95% CI 4-30) and partial response in 70% (95% CI 52-83) of the cases. No patient manifested progressive disease on treatment. Median progression-free survival was 48 months. Median overall survival had not been reached at a median follow-up of 33 months. No patient was lost to follow-up, all but 1 received 4 cycles of outpatient therapy, and all were evaluated for response and toxicity. No one required hospital admission. The treatment was well tolerated, and no serious dose-limiting toxicities were seen. The commonest toxicity was transient nausea of grade 2 (33%) or 3 (7%). Hematological toxicity was limited to grade 3 thrombocytopenia (10%) and anemia (10%). There were no grade 4 adverse events, and no renal functional impairment was evident. CONCLUSION: Combined 177Lu-octreotate-capecitabine-temozolomide radiopeptide chemotherapy is a well-tolerated, highly effective outpatient regimen for control of advanced progressive pNETs, achieving a durable objective response.

Hematological toxicity of combined 177Lu-octreotate radiopeptide chemotherapy of gastroenteropancreatic neuroendocrine tumors in long-term follow-up.

BACKGROUND: The combination of radiopeptide therapy [peptide receptor radionuclide therapy (PRRT)] with radiosensitizing chemotherapy of gastroenteropancreatic neuroendocrine tumors (GEP NETs) may improve efficacy, but has the potential to increase myelotoxicity. In a prospective clinical study of GEP NET patients treated with (177)Lu-octreotate PRRT in combination with capecitabine and temozolomide, as a prelude to a planned Australasian Gastro-Intestinal Trials Group (AGITG) international randomized controlled trial, we characterized the incidence and degree of hematological toxicity. MATERIALS AND METHODS: Well-differentiated progressive metastatic GEP NETs in 65 patients were treated with 4 cycles of 7.8 GBq (177)Lu-octreotate, 1,650 mg/m(2) capecitabine (n = 28) and 1,500 mg/m(2) capecitabine with 200 mg/m(2) temozolomide (n = 37), and monitored for hematological toxicity over a 5-year period. RESULTS: Short-term, self-limited hematological toxicity grade 3/4 comprised anemia in 1 patient (3.5%) in the 28 patient-cohort of patients treated with (177)Lu-octreotate and capecitabine. One of these patients (3.5%) later developed significant anemia and one developed thrombocytopenia (3.5%) over a median follow-up of 60 months (SD 20). The incidence of short-term grade 3/4 reversible myelosuppression in 37 patients after (177)Lu-octreotate/capecitabine/temozolomide was zero. Long- term follow-up for a median of 36 months (SD 11) showed significant thrombocytopenia in 2.7% and neutropenia in 2.7% of the patients and anemia in 10.8% of the patients (n = 4). The 3-year median hemoglobin and platelet and neutrophil counts trended downwards, but remained within normal ranges. Two patients in this cohort developed myelodysplastic syndrome. CONCLUSION: The modest reversible hematological toxicity of PRRT of GEP NETs is not significantly increased by the addition of radiosensitizing chemotherapy with capecitabine and temozolomide in combination with (177)Lu-octreotate, which has the potential to enhance the efficacy of radiopeptide therapy.

Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours.

PURPOSE: In this phase II study we investigated the safety and efficacy of combination capecitabine and (177)Lu-octreotate for the treatment of disseminated, progressive, unresectable neuroendocrine tumours (NETs). METHODS: Enrolled in the study were 33 patients with biopsy-proven NETs, positive (111)In-octreotide scintigraphy and progressive disease measurable by CT/MRI who were to receive four cycles of 7.8 GBq (177)Lu-octreotate 8-weekly, with 14 days of 1,650 mg/m(2) capecitabine per day. RESULTS: Of the 33 patients, 25 completed four cycles. Minimal transient myelosuppression at 3-4 weeks caused grade 3 thrombocytopenia in one patient but no neutropenia. Nephrotoxicity was absent. Critical organ radiation dosimetry provided median estimates of the dose per cycle to the kidneys of 2.4 Gy and to the liver of 4.8 Gy, and showed cumulative doses all below toxic thresholds. Objective response rates (ORR) were 24% partial response (PR), 70% stable disease (SD) and 6% progressive disease. Median progression-free survival and median overall survival had not been reached at a median follow-up of 16 months (range 5-33 months). Survival at 1 and 2 years was 91% (95% CI 75-98%) and 88% (95% CI 71-96%), respectively. CONCLUSION: The addition of capecitabine radiosensitizing chemotherapy does not increase the minimal toxicity of (177)Lu-octreotate radiopeptide therapy and led to an ORR of 24% PR and 70% minor response or SD in patients with progressive metastatic NETs. Tumour control and stabilization of disease was obtained in 94% of these patients.

Long-term hematologic toxicity of 177Lu-octreotate-capecitabine-temozolomide therapy of GEPNET.

Thirty-seven patients with advanced gastroenteropancreatic neuroendocrine tumors (GEPNETs) were treated on a prospective phase II single-center study with four cycles of 7.8 GBq 177Lu-octreotate combined with capecitabine and temozolomide chemotherapy (CAPTEM). Each 8-week cycle combined radiopeptide therapy with 14 days of capecitabine (1500 mg/m2) and 5 days of temozolomide (200 mg/m2). The incidence of grade ≥ 3 hematologic toxicity was analyzed. At a median follow-up of 7-years (range 1-10), six (16%) patients developed persistent hematologic toxicity (PHT) (defined as sustained grade ≥ 3 hematologic toxicity beyond 36-months follow-up) and three (8%) developed MDS/AL with a median time-to-event of 46 and 34 months, respectively. The estimated cumulative incidence of MDS/AL was 11% (95% CI: 3.45-24.01). Development of PHT was the only significant risk factor for secondary MDS/AL (RR, 16; 95% CI: 2.53 to 99.55; P < 0.001). The median PFS was 48 months (95% CI: 40.80-55.20), and the median OS was 86 months (95% CI: 56.90-115.13). Twenty-one deaths were recorded, including 13 (62%) due to progressive disease and all 3 (14%) patients with MDS/AL. 177Lu-octreotate CAPTEM therapy for GEPNETs is associated with a risk of long-term hematologic toxicity. The rising cumulative incidence of MDS/AL > 10% mandates the long-term monitoring of treated patients. However, time to onset is unpredictable, and incidence does not correlate with conventional baseline risk factors. Novel methods are required for the stratification of prospective patients based on genetic risk.

NeuroEndocrine Tumor Therapy with Lutetium-177-octreotate and Everolimus (NETTLE): A Phase I Study.

OBJECTIVE: To establish the optimal safe dose of everolimus in combination with (177)Lu-octreotate peptide receptor radionuclide therapy (PRRT) of advanced progressive gastro-entero pancreatic neuroendocrine tumors (GEP-NETs) and to define dose-limiting toxicity. PATIENTS AND METHODS: Patients with advanced unresectable progressive well-differentiated GEP-NETS avid for (68)Ga-octreotate on positron emission tomography-computed tomography imaging underwent PRRT with four cycles of 7.8 GBq (177)Lu-octreotate at 8 week intervals. Successive cohorts of 3 patients received escalating doses of everolimus comprising 5, 7.5, and 10 mg daily for 24 weeks. RESULTS: Sixteen patients comprised 4 at 5 mg, 9 at 7.5 mg, and 3 at 10 mg everolimus. Patient cohorts at 5 and 7.5 mg received 83% and 80% of the total planned dose of everolimus over 24 weeks. All patients required dose reduction or complete cessation of everolimus at the 10 mg level, which induced neutropenia and thrombocytopenia, and reduced creatinine clearance. The overall response rate was 44% (7 of 16 patients), and no patient progressed over the 6 month period of treatment. Four of 5 pancreatic NET patients achieved PR 80%. No patient progressed on study. CONCLUSION: In combination, PRRT with (177)Lu-octreotate, the maximum tolerated dose of everolimus is 7.5 mg daily.

131I-Anti CD20 radioimmunotherapy of relapsed or refractory non-Hodgkins lymphoma: a phase II clinical trial of a nonmyeloablative dose regimen of chimeric rituximab radiolabeled in a hospital.

In order to increase the availability and affordability of radioimmunotherapy of refractory or relapsed non-Hodgkins lymphoma, we developed and evaluated radioiodinated rituximab in an ongoing physician-sponsored Phase II Clinical Trial. The chimeric 1gG(1) anti CD 20 monoclonal antibody rituximab was radiolabeled with iodine-131 using a modified Chloramine T method with high radiochemical purity (98% +/- 0.82) and preservation of immunoreactivity. All patients received therapeutic loading doses of unlabeled rituximab (375 mg/m(2)) immediately prior to administration of tracer (200 MBq (131)I) or therapy (1.7-4.3 GBq (131)I) activities of (131)I-rituximab to provide additive immunotherapy and enhance tumor uptake of the radiolabeled antibody. Objective response rate (ORR) was 71% in 35 patients with a median follow-up of 14 months (range 4-28 months). Complete remission (CR) was achieved in 54% of patients, with median duration 20 months. Toxicity evaluation included an additional 7 patients followed for at least 3 months. Tracer dosimetry studies were performed in each patient and the whole body radiation absorbed dose was limited to a mean prescribed dose (MPD) of 0.75 Gy. Myelosuppression was reversible and in only 2 of 42 patients was grade IV hematological toxicity observed. No hemopoietic support was required in any patient. There was no instance of hemorrhage or infection in this group of patients in each of whom individual prospective dosimetry was performed prior to (131)I rituximab radioimmunotherapy for relapsed or refractory non-Hodgkins lymphoma.

A kit formulation for the preparation of 188Re-lipiodol: preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma.

A lyophilized kit formulation for the efficient labelling of lipiodol with generator-produced rhenium-188 is described. The preliminary preparation of the lipophilic complex bis-(diethyldithiocarbamato)nitrido rhenium-188 (188ReN-DEDC) was carried out using a two-vial kit containing S-methyl-N-methyl-dithiocarbazate, SnCl2 and sodium oxalate in the first vial, and diethyldithiocarbamate and a carbonate buffer in the second vial. After mixing of the reaction solution with lipiodol, the complex 188ReN-DEDC was quantitatively extracted and retained by this hydrophobic substance, thus allowing the stable incorporation of the beta-emitting radionuclide. The radiochemical purity of the complex 188ReN-DEDC was 97+/-2%. The activity extracted into the lipiodol phase was 96+/-3% of the initial activity, indicating that the complex 188ReN-DEDC was almost quantitatively removed from the aqueous reaction solution. In vitro stability studies in human plasma, at 37 degrees C, demonstrated the release of less than 15% of the activity within three half-lives. The biodistribution of Re-lipiodol in non-tumour-bearing Wistar rats at 6, 24, 48 and 72 h after intraportal venous injection showed one-third of total activity in the liver at 6 h, declining to 2% retention at 72 h. Bowel uptake at 6 and 24 h declined to low levels at 48 and 72 h. Renal activity peaked at 1.7%, diminishing to 0.6% over 48 h. Rat whole body gamma imaging showed gut activity in addition to hepatic uptake at 6 and 24 h, but only liver was evident from 48 to 72 h. Kidneys were not demonstrable at any imaging time point. In nine patients, activity was localized in the tumours immediately following intrahepatic arterial injection. Computed tomography/single-photon emission computed tomography (CT/SPECT) imaging at 1 and 24 h confirmed the retention of 188Re-lipiodol in the hepatoma, with minimal gut uptake and no lung activity over 24 h. These patients were subsequently treated with activities of 2.5-5 GBq of 188Re-lipiodol fractions without adverse effects. Six patients followed for up to 2 years in the pilot study achieved stable disease and there was objective partial response in one patient. Repeated treatments were performed on two to three occasions in three patients without evident toxicity. An additional patient given 6 GBq of 188Re-lipiodol demonstrated myelosuppression, which recovered with granulocyte colony-stimulating factor (GCSF) and platelet support. It is concluded that 188Re-lipiodol, prepared using our novel kit formulation, is stable in vivo and provides safe and effective therapy of unresectable hepatocellular carcinoma when given via the hepatic artery, either alone or in combination with transarterial chemoembolization.

Phase I-II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors.

Abstract We conducted a phase I-II clinical trial to assess the safety and efficacy of combining lutetium-177 ((177)Lu)-octreotate with capecitabine and temozolomide in treating advanced low-grade neuroendocrine tumors (NETs). All 35 patients received fixed activities of 7.8 GBq (177)Lu-octreotate each 8 weeks, with 14 days of capecitabine 1500 mg/m(2) for 4 cycles. In phase I, successive cohorts of patients received escalating doses of temozolomide in groupings of 100, 150, and 200 mg/m(2) in the last 5 days of each capecitabine cycle. In phase II, patients were treated with 200 mg/m(2) temozolomide. Treatment was well tolerated in all dosage groups. No dose-limiting grade 2, 3, or 4 toxicities were seen in cohorts 1 (100 mg/m(2)) or 2 (150 mg/m(2)). Twenty-eight patients completed treatment at the 200 mg/m(2) temozolomide level. Adverse events were mild to moderate. The commonest toxicities were transient nausea grade 2 (18%), grade 3 (3%), thrombocytopenia grade 2 (24%), and neutropenia grade 3 (6%). There were no grade 4 events. Thirty-four patients were evaluable for tumor response. Overall, complete response (CR) was achieved in 15% (95% CI 3-27); partial response (PR), in 38% (95% CI 22-55); stable disease (SD), in 38% (95% CI 22-55); and 3 patients failed to respond to treatment. Median progression free survival (PFS) was 31 months (95% CI 21-33), and median overall survival (OS) has not been reached with 90% surviving at 24 months follow-up (range 21-30). Overall objective response rate (ORR) in patients with gastroenteropancreatic NETs showed CR 16% (95% CI 3-28), PR 41% (95% CI 24-58), SD 37% (95% CI 21-54), and PD 6% (95% CI 0-15). Response rates were higher in patients with gastropancreatic NETs than in those with bowel primaries (enteric-NETs); CR 18% versus 13%, PR 64% versus 13%, SD 12% versus 67%. (177)Lu-octreotate, in combination with capecitabine and temozolomide, is well tolerated in patients with advanced low-grade NETs, and shows substantial tumor control rates.

Therapies for the medical management of persistent hypoglycaemia in two cases of inoperable malignant insulinoma.

OBJECTIVE: Hypoglycaemia poses a significant management challenge in patients with unresectable functional malignant insulinoma. Novel agents such as mammalian target of rapamycin (mTOR) inhibitors and radiolabelled peptides may be effective where there is failure of conventional therapy. DESIGN: We present the cases of two men diagnosed with inoperable malignant insulinoma and hepatic metastases who developed severe symptomatic hypoglycaemia, and review potential therapies for glycaemic support. METHOD: Despite treatment with diazoxide, frequent oral carbohydrate, prednisolone and somatostatin analogue therapy, both men required hospital admission for treatment with continuous i.v. dextrose. Both were treated with Lutetium-177 octreotate. One man was also treated with everolimus, a mTOR inhibitor. RESULT: Use of Lutetium-177 octreotate, and in one case everolimus, successfully achieved normoglycaemia, facilitating safe discharge from hospital. Both men also had regression in the size and number of hepatic metastases. CONCLUSION: Lutetium-177 octreotate and everolimus are options for managing hypoglycaemia due to unresectable malignant insulinoma when refractory to conventional supportive therapies.