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.
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.
Thirty-five patients with disseminated skeletal metastases from a variety of tumor types underwent clinical trial of samarium-153 ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) on a day-patient basis. Individual beta radiation dosimetry was based on pharmacokinetic studies of a 20 mCi tracer dose of 153Sm-EDTMP. The retained skeletal activity varied unpredictably from 40% to 95% of the administered dose, but in all patients greater than 98% of the nonosseous activity was cleared in the urine within 6 hours. Prospective calculation of radiation dosimetry in each patient permitted an accurate dosage schedule based upon total red marrow exposure, starting at 100 cGy and escalating to 280 cGy to define the dose-limiting myelotoxicity. Pain was relieved in 22 of 34 evaluable patients (65%) for periods ranging from 4 to 35 weeks, following a single administration of 153Sm-EDTMP. Recurrence of pain responded to retreatment with 153Sm-EDTMP in five of nine patients. The dose-limiting toxicity was myelosuppression manifested particularly by delayed thrombocytopenia. Platelet counts less than 100 x 10(9)/L occurred in 42% of courses when bone marrow radiation absorbed dose exceeded 200 cGy. Myelosuppression was transient and platelet counts had recovered to pretreatment levels within 10 weeks of treatment. 153Sm-EDTMP is effective for the amelioration of pain due to disseminated skeletal metastases particularly with carcinoma of breast or prostate where 83% of patients experienced pain relief. In 15 of the 34 evaluable patients there was evidence of stabilization or regression of skeletal metastases on radiographs and follow-up technetium-99m methylene diphosphonate (99mTc-MDP) bone scans.
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.
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