Buoyed by results in patients with hormone-refractory prostate cancer, investigators have begun to push the therapeutic envelope of using bisphosphonates to prevent bone loss and bone-related complications in patients with hormone-sensitive metastatic disease.
Last year results of a randomized, multicenter clinical trial demonstrated that treatment with the bisphosphonate zoledronic acid reduced the rate of skeletal-related events (SREs) in patients with hormone-refractory prostate cancer. Follow-up reports at this years American Urological Association (AUA) meeting showed that zoledronic acid delayed the occurrence of a first SRE by more than 5 months and that the benefits initially observed were maintained for 24 months.
Although encouraging, the findings only apply to a minority of the entire prostate cancer patient population. About 90% of newly diagnosed patients have localized or locoregional disease, New York urologist James M. McKiernan, M.D., said at a program that preceded this years AUA meeting, held in April in Chicago.
Stopping Bone Degredation
Bisphosphonates reduce the risk of cancer-related SREs by inhibiting osteoclastic (the ability to break down bone) activity of bone metastases. For that reason, the agents initially were considered ineffective for prostate cancer bone metastases, which were thought to be characterized by osteoblastic (the ability to build up bone) activity. The emergence of evidence of an osteoclastic component of prostate cancer bone metastases renewed interest in the potential for bisphosphonates to reduce SREs in patients with the most advanced forms of prostate cancer.
In addition to the bone-damaging effects of metastases, androgen-deprivation therapy for prostate cancer increases bone resorption and predisposes patients to osteoporosis and SREs. Bisphosphonates inhibit the resorptive process and help maintain bone mass, suggesting that the drugs might have a role in the treatment of prostate cancer before the disease progresses to an androgen-independent state.
However, the variability in hormone sensitivity figures heavily into deliberations regarding the potential value of using bisphosphonates earlier in the disease process. In many patients, about 7 years pass after initial therapy before treatment failure occurs, which is usually defined by a rising prostate-specific antigen (PSA) level. At that point, patients begin androgen deprivation therapy. On average, patients remain hormone sensitive for 3 to 5 years; however, the timeframe for hormone sensitivity is highly variable.
"For the patient who presents with bone metastases at initial diagnosis, the number is not 3 to 5 years," said McKiernan, assistant professor of urology at Columbia University in New York. "Hormone sensitivity is a very broad-spectrum concept. For the patient who has D1.5 [stage IV cancer with regional metastases] disease and biochemical failure, the time can be quite a bit longer than 3 to 5 years. For the average D2 [stage IV cancer with distant metastases] patient, the time is quite a bit shorter than 3 to 5 years."
A study published more than a decade ago continues to provide insights into the limitations of the concept of "hormone sensitivity" in patients with D2 prostate cancer. The study involved 600 patients randomly assigned to one of two androgen deprivation regimens. On average, patients in both treatment groups progressed clinically to a hormone refractory state in about 1 year.
"The results emphasize that the typical D2 patient cannot be hormone sensitive for long," McKiernan said. "The term hormone-sensitive D2 patient borders on being an oxymoron. There is virtually no doubt that these patients will progress eventually, usually rapidly."
In addition to questions about hormone sensitivity, androgen deprivation therapywhether surgical or pharmacologicaccelerates the osteolytic activity of bone metastases, so that patients with metastatic disease face an increased risk of osteoporosis and fractures. Bisphosphonates have demonstrated the ability to inhibit bone loss and reduce skeletal complications in men with established osteoporosis and in prostate cancer patients receiving hormonal therapy.
Use in Earlier Stages
There is a scientific rationale for using bisphosophonates earlier in prostate cancer patients. In vitro studies have shown that bisphosphonates prevent tumor cell adhesion to bone, prevent tumor cell invasion, inhibit proteolytic activity of tumor cell matrix metalloproteinases, and reduce the growth of prostate cancer cell lines. In preclinical models, bisphosphonates have demonstrated the potential to prevent bone metastases, as reflected in reduced tumor volume, tumor mass, PSA levels, and development of metastases.
In this issue of the Journal, results of a randomized clinical trial provided additional, albeit modest, evidence that bisphosphonates have a role in the treatment of prostate cancer prior to progression to androgen independence (see article, p. 1300). Investigators representing the Medical Research Council in the United Kingdom reported that 3 years of treatment with clodronate improved bone progression-free survival (BPFS) in men with metastatic prostate cancer. Overall, men treated with clodronate had a nonsignificant 21% reduction in the hazard ratio for BPFS and a 20% improvement in overall survival. Patients in the clodronate group were significantly less likely to have deterioration in performance status.
A subgroup analysis revealed a significant trend toward improved BPFS in association with earlier initiation of bisphosphonate therapy. The trend emerged from an analysis of the time from diagnosis of metastatic bone disease to randomization and showed improved BPFS as the interval decreased from more than 6 months to less than 6 weeks. Initiation of clodronate within 6 weeks of diagnosis was associated with a 52% reduction in the relative risk of BPFS.
Promising Results
In an editorial that accompanies the article, Fred Saad, M.D., director of urologic oncology at the University of Montreal, said the findings from the study indicate that starting bisphosphonates earlier and using more potent bisphosphonates might lead to better results (see editorial, p. 1262). He noted that the newer intravenous bisphosphonate zoledronic acid is the only agent in the class that has demonstrated the ability to reduce skeletal complications in patients with hormone-refractory prostate cancer.
"Research into the earlier use of bisphosphonates in metastatic prostate cancer as well as into the potential of bisphosphonates to actually prevent metastases is ongoing," Saad concluded. "With a better understanding of the role of bisphosphonates in treatment-induced bone loss, prevention and treatment of metastases, and antitumor effects, it is most likely that the role they play will expand in the management of advanced prostate cancer."
The ongoing investigation includes an evaluation of zoledronic acid in patients with newly diagnosed metastatic prostate cancer receiving androgen deprivation therapy. Organized by the Cancer and Leukemia Group B (CALGB), the trial will involve almost 700 patients who will be randomly assigned to placebo or the bisphosphonate, in addition to hormonal treatment.
"This trial [CALGB 90202] will provide a definitive answer to the question of whether early initiation of intravenous bisphosphonate therapy in a hormone-sensitive, bone-metastasis population will lead to benefits in terms of a reduction in skeletal-related events and a reduction in bone metastases," said McKiernan.
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