High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone

Abstract

We tested the feasibility and toxicity of high activities Rhenium-186 hydroxyethylidene diphosphonate, with peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. Twenty-five patients received between 2500 and 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate followed 14 days later by the return of peripheral blood peripheral blood stem cells. Activity limiting toxicity was defined as grade III haematological toxicity, lasting at least 7 days, or grade IV haematological toxicity of any duration or any serious unexpected toxicity. Activity limiting toxicity occurred in two of six who received activities of 5000 MBq and maximum tolerated activity was defined at this activity level. Prostate specific antigen reductions of 50% or more lasting at least 4 weeks were seen in five of the 25 patients (20%) all of whom received more than 3500 MBq of Rhenium-186 hydroxyethylidene diphosphonate. The actuarial survival at 1 year is 54%. Administered activities of 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate are feasible using autologous peripheral blood peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. The main toxicity is thrombocytopaenia, which is short lasting. A statistically significant activity/prostate specific antigen response was seen. We have now commenced a Phase II trial to further evaluate response rates. Prostate cancer is becoming the most common cause of cancer death in males. Of patients who die from the condition, between 80 and 100% have bone metastases. Bone metastases frequently result in pain, pathological fracture, deformity and neurological deficit and have enormous social and economic implications. Most patients with bone metastases will initially respond to primary androgen deprivation therapy but the duration of this response is variable with a median of 18 months. Once this strategy has failed, second line treatments including corticosteroids, anti-androgens, diethylstilbesterol and cytotoxic chemotherapy including estramustine have only had limited success in preventing disease progression with short-lasting subjective responses in approximately 30% of cases (Dearnaley, 1994;Tannock et al, 1996;Pisters, 1999). The average survival in patients with hormone refractory prostate cancer metastatic to bone is in the order of 8 months (Fossa et al, 1992;Kelly et al, 1993;Sridhara et al, 1995;Small and Vogelzang, 1997). Radionuclides including strontium-89, rhenium-186 and samarium-153 have been used in the palliation of bone metastases in prostate cancer (Lewington et al, 1991;Porter et al, 1993;Quilty et al, 1994;Kolesnikov-Gauthier et al, 2000). Pain response occurs in about 70% of cases. A correlation between injected activity and rates of pain control in prostate cancer bone metastases have been demonstrated in radionuclide therapy with Strontium-89 (Mertens et al, 1993).Rhenium is a group VII metal with a similar labelling chemistry to Technetium. The ...

Radionuclide Therapy of Bone Metastases

“…The disadvantage of further activity escalation was dose-limiting myelosuppression. A subsequent phase I study demonstrated PSA reduction in CRPC patients treated with high-activity 186 Re-HEDP and peripheral stem cell support [41].…”

Phase 2 Study of a High Dose of 186Re-HEDP for Bone Pain Palliation in Patients with Widespread Skeletal Metastases

“…The standard dose of 1,295 MBq is recommended as safe, even in heavily pretreated patients (13). However, some data support administering higher doses, which are more likely to reduce tumor markers, ablate micrometastasis, and bring about the disappearance of bony lesions (17). In addition, when there is extensive skeletal involvement, the calculated absorbed dose to specific metastatic deposits has been shown to be significantly reduced (18).…”

Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of 186Re-MAG3-conjugated bisphosphonate (186Re-MAG3-HBP), an agent for treatment of painful bone metastases

“…We suppose that it is the reason that 186 Re-MAG3-HBP binds to the hydroxyapatite in bone and is retained for a long term without excretion. peripheral blood stem cell transplant [33,34], the strategy should be more effective. At the same time, the dose absorbed by red marrow, which is known as a dose-limiting factor of bone-seeking radiopharmaceuticals, was not decreased.…”