Adjuvant Effect of IV Clodronate on the Delay of Bone Metastasis in High-Risk Prostate Cancer Patients: A Prospective Study

Abstract

PurposeHigh-risk prostate cancer patients undergoing treatment often experience biochemical recurrence. The use of bisphosphonates as an adjuvant treatment delays skeletal events, yet whether or not bisphosphonates also delay metastastic development remains to be determined.Materials and MethodsA total of 140 high-risk prostate cancer patients who were undergoing definitive treatment and who had clinically organ-confined disease and who suffered from biochemical recurrence were administered intravenous (IV) clodronate. The patients were treated with a radical retropubic prostatectomy (RP) or curative radiotherapy (RTx). Upon androgen deprivation therapy initiation, tri-monthly IV clodronate was added to the treatment to prevent bone demineralization. Twenty-six out of 60 operated cases and 45 out of 80 irradiated cases received bisphosphonate. The length of time until the first bone metastasis was recorded and analyzed.ResultsNo statistical difference was found for the type of primary treatment (RP or RTx) on the time to the first bone metastasis (95% confidence interval [CI], 0.40 to 2.43; p=0.98). However, there was a clear advantage favoring the group that received bisphosphonate (p<0.001). The addition of bisphosphonate delayed the appearance of the first bone metastasis by seven-fold (95% CI, 3.1 to 15.4; p<0.001).ConclusionTreatment with tri-monthly IV clodronate delayed the time to the first bone metastasis in high-risk prostate cancer patients who were experiencing an increase in the prostate specific antigen level after definitive treatment.

Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer

“…15 Emerging data in prostate cancer trials show improved survival with the use of clodronate in men with metastatic, androgen-sensitive prostate cancer and delays in time to first bone metastasis in high-risk prostate cancer patients. 16,17 Our results favor the introduction of clodronate as a potential anti-angiogenic approach for human ovarian cancer, and may have beneficial effects with the current standard-of-care chemotherapy drugs (e.g., platinum and taxanes). 18…”

“…13 Other studies of clodronate's potential use in cancer treatment have had mixed success. [14][15][16][17] There are conflicting data regarding the ability of clodronate to affect survival rates in early-stage breast cancer. 14 However, a recent meta-analysis concluded that clodronate as adjuvant therapy in breast cancer is beneficial, producing an increased 5-y overall survival rate.…”

Recent advances in bone-targeted therapies of metastatic prostate cancer

“…Clodronate has initially been reported to have no effect on OS or disease-free survival. However, a prospective study of 140 high-risk PCa patients who had clinically organ-confined disease indicated that the addition of Clodronate delayed the appearance of the first bone metastasis by seven-fold (25). Data from two aligned Medical Research Council randomized trials revealed that although there was no evidence of a benefit of OS in the non-metastatic group, Clodronate conferred an overall survival benefit when given in addition to standard hormone therapy in men with metastatic CRPC (26).…”

Osteopontin is a useful predictor of bone metastasis and survival in patients with locally advanced nasopharyngeal carcinoma

“…Conversely, patients with low levels of OPN expression and early nodal classification are predicted to have a low risk of BM, and regular surveillance is preferred. Second, bisphosphonate, labeled as preventing skeletal‐related events in bone metastatic disease from solid tumors, has been proven to prevent the onset of skeletal metastasis in early breast and prostate cancer . As bone is the most frequent site of distant metastasis in NPC, the administration of bisphosphonate to NPC patients with a high risk of BM selected based on the expression level of OPN might decrease BM in locally advanced NPC.…”