Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases

Abstract

The aim of this study was to determine the maximum tolerated dose of rhenium-188 hydroxyethylidene diphosphonate (HEDP) in prostate cancer patients with osseous metastases who are suffering from bone pain. Twenty-two patients received a single injection of escalating doses of carrier-added 188Re-HEDP [1.3 GBq (35 mCi), 2.6 GBq (70 mCi), 3.3 GBq (90 mCi) and 4.4 GBq (120 mCi)]. Blood counts and biochemical parameters were measured weekly over a period of 8 weeks. Haematological toxicity (WHO grading) of grade 3 or 4 was considered unacceptable. Clinical follow-up studies including methods of pain documentation (medication, pain diary) were performed for 6 months after treatment. In the 1.3-GBq group, no haematological toxicity was observed. First haematotoxic results were noted in those patients with a dose of 2.6 GBq 188Re-HEDP. In the 3.3-GBq group, one patient showed a reversible thrombopenia of grade 1, one a reversible thrombopenia of grade 2 and three a reversible leukopenia of grade 1. In the 4.4-GBq group, thrombopenia of grades 3 and 4 was observed in one and two patients (baseline thrombocyte count <200x10(9)/l), respectively, and leukopenia of grade 3 was documented in one patient. The overall nadir of thrombopenia was at week 4. The individual, maximum percentage decrease in thrombocytes in the 1.3-, 2.6-, 3.3- and 4.4-GBq groups was 17%, 40%, 60% and 86%, respectively. In two patients, a transient increase in serum creatinine was observed (max. 1.6 mg/dl). Pain palliation was reported by 64% of patients, with a mean duration of 7.5 weeks. The response rate seemed to increase with higher doses, reaching 75% in the 4.4-GBq group. It is concluded that in prostate cancer patients, the maximum tolerated dose of 188Re-HEDP is 3.3 GBq if the baseline thrombocyte count is below 200x10(9)/l. In patients with thrombocyte counts significantly above 200x10(9)/l, a dose of 4.4 GBq might be tolerable. Thrombo- and leukopenia are the most important side-effects. Pain palliation can be achieved in 60%-75% of patients receiving a dose of 2.6 GBq or more of 188Re-HEDP. Studies in a larger patient population are warranted to evaluate further the palliative effect of 188Re-HEDP.

Palliation and Survival After Repeated 188Re-HEDP Therapy of Hormone-Refractory Bone Metastases of Prostate Cancer: A Retrospective Analysis

“…Mean survival after the initial therapy improved from 4.5 mo in group A to 9.98 mo in group B and 15.7 mo in group C. The results of survival after the initial rhenium therapy are also presented in Figure 1. As has already been described by Palmedo et al (15), only reversible grade 2 thrombopenia and reversible grade 1 leukopenia were observed.…”

“…The presence of macroscopic amounts of stable rhenium in rhenium-HEDP preparations is decisive with respect to the form of the phosphonate chemical species (15). In carrier-added preparations, these species consist of rhenium-rhenium bonds that cannot be formed using carrier-free 188 Re.…”

“…For neutralization, 1.5 mL of a sterile solution of 39 mg of sodium acetate trihydrate were added, yielding a final pH of 4.5-5.5. Quality control of carrier-added 188 Re-HEDP was performed using instant thinlayer chromatography silica gel strips (15).…”

“…Uptake in the skeleton is between 20% and 30% of the injected dose for 186 Re-HEDP and between 30% and 50% for 153 Sm-EDTMP. Accumulation in metastatic lesions is between 3 and 20 times as high as in normal bone, and the effective half-lives of 188 Re-HEDP and 153 Sm-EDTMP are between 2 and 3 d. 188 Re-HEDP has been used for pain palliation in patients with prostate cancer and bone metastases since the early 1990s (15,16 (18) designed to compare the efficacy of multiple successive injections with that of a single administration of this agent. The effectiveness of 188 Re-HEDP for pain palliation was better in the repeated-treatment group, with a response rate and time of response of 92% and 5.66 mo, respectively.…”

Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection

“…Re (t [1͞2] ϭ 16.9 h) (E max ϭ 2.12 MeV) has recently emerged as an attractive therapeutic radionuclide for cancer radioimmunotherapy, palliation of skeletal bone pain, and endovascular brachytherapy to prevent restenosis after angioplasty (12)(13)(14). 213 Bi (t [1͞2] ϭ 45.6 min) emits a high linear energy transfer ␣-particle with E ϭ 5.9 MeV with a path length in tissue of 50-80 m. Theoretically, a cell can be killed with one or two ␣-particle hits.…”