188Re-HEDP combined with capecitabine in hormone-refractory prostate cancer patients with bone metastases: a phase I safety and toxicity study

Abstract

Purpose188Re-HEDP is indicated for the treatment of pain in patients with painful osteoblastic bone metastases, including hormone-refractory prostate cancer patients. Efficacy may be improved by adding chemotherapy to the treatment regimen as a radiation sensitizer. The combination of 188Re-HEDP and capecitabine (Xeloda®) was tested in a clinical phase I study.MethodsPatients with hormone-refractory prostate cancer were treated with capecitabine for 14 days (oral twice daily in a dose escalation regimen with steps of 1/3 of 2,500 mg/m2 per day in cohorts of three to six patients, depending on toxicity). Two days later patients were treated with 37 MBq/kg 188Re-HEDP as an intravenous injection. Six hours after treatment post-therapy scintigraphy was performed. Urine was collected for 8 h post-injection. Follow-up was at least 8 weeks. The primary end-point was to establish the maximum tolerable dose (MTD) of capecitabine when combined with 188Re-HEDP. Secondary end-points included the effect of capecitabine on the biodistribution and pharmacokinetics of 188Re-HEDP.ResultsThree patients were treated in the first and second cohorts, each without unacceptable toxicity. One of six patients in the highest cohort experienced unacceptable toxicity (grade 4 thrombopaenia). The MTD proved to be the maximum dose of 2,500 mg/m2 per day capecitabine. No unexpected toxicity occurred. Capecitabine had no effect on uptake or excretion of 188Re-HEDP.ConclusionCapecitabine may be safely used in combination with 188Re-HEDP in a dose of 2,500 mg/m2 per day and 37 MBq/kg, respectively. Efficacy will be further studied in a phase II study using these dosages.

Internal radiotherapy of painful bone metastases

“…The toxicity did not correlate with the response of pain [125]. 89 Sr demonstrate similar toxicity as the other common radiopharmaceuticals, such as 186 Re-HEDP, 188 Re-HEDP, and 153 Sm-EDTMP [127].…”

“…Sm-EDTMP 233 Ra 186 Re-HEDP 188 Re-HEDP 117m Tin-DTPA a b s t r a c t Internal radiotherapy is effective in the treatment of metastatic bone pain and can improve quality of life. A number of controlled studies using various agents have shown a mean response rate in pain relief of 70-80% of treated patients.…”

“…treatment of liver metastases or primary liver cancer with labeling to lipoidal [176] or microsphere [177], treatment of arthritis with labeling to colloids [178]. Other therapeutic options included 188 Re-labeled antibodies for treatment of leukemia [179,180], or variety of 188 Re-labeled agents in intracoronary brachytherapy [181][182][183].…”

“…Eary et al [175] reported a red marrow dose of 12.7-22.5 Gy in an high dose group of 111 MBq/kg 153 Sm-EDTMP combined with a reversible bone marrow toxicity (Table 3). Radiolabeling of various agents with 188 Re provides a variety of different therapeutic options outside the bone pain palliation, e.g. treatment of liver metastases or primary liver cancer with labeling to lipoidal [176] or microsphere [177], treatment of arthritis with labeling to colloids [178].…”

“…the commercial available agents 153 samarium-ethylenediaminetetramethylene phosphonate [145] and 186 rhenium-hydroxethylidene diphosphonate [146]; as well as agents used more in trials or in single cases such as 188 rhenium-hydroxethylidene diphosphonate [147], 188 rhenium-DMSA [148], 90 yttrium [149], 131 iodine alpha-amino-(4-hydroxybenzylidene-diphosphonate (BDP3) [150], and 117m tin stannic diethylenetriaminepentaacetic acid [151,152].…”