Improving radionuclide therapy in prostate cancer patients with metastatic bone pain

Abstract

Bone seeking radiopharmaceuticals are indicated in cancer patients with multiple painful skeletal metastases. The majority of these patients are hormone-refractory prostate cancer patients in an advanced stage of their disease. Bone seeking radiopharmaceuticals relieve pain and improve the patients quality of life. The mostly used radiopharmaceuticals are 89SrCl2 (Metastron), 153Sm-EDTMP (Quadramet) and 186Re-HEDP. Differences between 89SrCl2, 153Sm-EDTMP and 186Re-HEDP were investigated. It was found that urinary excretion of activity is rapid in patients treated with 153Sm-EDTMP and 186Re-HEDP, in contrast to 89SrCl2. Together with differences in biodistribution and physical decay this leads to differences in radiation burden to bystanders. The effective doses were <0.1 mSv for 89SrCl2, 0.3 mSv for 186Re-HEDP and 1.6 mSv for 153Sm-EDTMP. In all cases however the calculated effective doses for bystanders were well below the recommended values. A treatment guideline was drawn using these data. In order to improve the patients’ clinical condition it may be beneficial to combine different treatment modalities. This may possibly lead to additive or even synergistic effects. In prostate cancer patients bisphosphonates are used to treat and prevent so called skeletal related events (fractures, hypercalcaemia, spinal cord compression). This may add to the palliative effect of bone seeking radiopharmaceuticals. Nevertheless, the European label of 153Sm-EDTMP includes the contra-indication that “it should not be used concurrently with other bisphosponates if an interference is shown on the 99mTc-labeled bisphosphonate bone scan”. This contra-indication is based on the hypothesis that as both drugs interact at the hydroxyapatite crystal surface of the skeleton, competition might exist for uptake by bone. However, it was shown that the combined use of zoledronic acid has no effect on the uptake of 153Sm-EDTMP in skeletal metastases of hormone-refractory prostate carcinoma. Combined treatment with 153Sm-EDTMP and zoledronic acid was both feasible and safe. The efficacy data on the patients treated in this phase I setting were regarded as pilot phase II data. Although the study comprised small numbers the results confirmed the utility of bone markers (bone specific alkaline phosphatase [BAP], procollagen type I N propeptide [PINP], N-terminal type I collagen peptide [NTX]) as predictors of clinical outcome. And they were first tested in the treatment monitoring of bone seeking radiopharmaceuticals. Bone markers may well prove to be very useful predictors of response in the treatment with bone seeking radiopharmaceuticals. They should be used in future trials. Another combination of 188Re-HEDP and capecitabine (Xeloda) was tested in a phase I capecitabine dose-escalation study. Capecitabine was used as a radiation sensitizer. It proved to be feasible and safe. Phase II efficacy testing using the maximum tolerable dose of 2500 mg/m2/day capecitabine in combination with 37 MBq/kg 188Re-HEDP is underway. It was concluded that patients treated with 89SrCl2, 186Re-HEDP or 153Sm-EDTMP do not lead to unacceptable radiation burden to health care workers and patients’ families. Combined treatment regimens (153Sm-EDTMP / zoledronic acid and 188Re-HEDP / capecitabine) are feasible and safe. Bone markers seem to be good candidates to predict response.