Advances in
Bone Cancer Treatment:
Preventing Metastasis and Bone Loss
Emerging Data on the Prevention of Bone Metastasis
A significant proportion of patients who present with cancer that appears to be localized will eventually develop incurable metastatic disease. In tumors with a propensity to spread to bone, such as breast and prostate cancer, the metastases will frequently affect the skeleton.28 One promising approach is to modify the bone microenvironment to make it less conducive to the survival of tumor cells and minimize the clinical consequences of skeletal involvement. Bone-targeting agents that modify the bone microenvironment have direct effects on cancer cells and enhance the effects of cytotoxic treatments are therefore an attractive therapeutic strategy.
Prevention of Metastases – Clinical Experience
Oral Bisphosphonates
In the clinical setting there have been three trials investigating the potential of adjuvant oral clodronate to prevent bone metastasis, reported by Powles, Diel, and Saarto (Table 3). The long-term outcomes, with results out to 10 years, are inconsistent, however. While two trials showed benefit in terms of disease-free and overall survival at one or more analysis time points,78,79 a third suggested a negative effect on disease outcomes.80 Although the latter trial was confounded by imbalances in covariates, the use of oral bisphosphonates has not been accepted as standard treatment. Additionally, a meta-analysis failed to show significant benefits of clodronate for either relapse or survival rates.81 The role of oral clodronate is thus uncertain until results become available for the NSABP B-34 trial, which is comparing standard adjuvant treatment plus clodronate 1600 mg daily to standard treatment plus placebo in stage I-III breast cancer. Accrual of 3400 patients was completed in 2005 but, because of the high proportion of good-risk stage I patients, the event rate is low and results are not anticipated before 2010.
A recent report from the Danish Breast Group of a trial testing oral pamidronate (150 mg twice daily for 2 years) did not show improvement in survival or any reduction in rates of distant metastases compared with chemotherapy alone.82 This formulation of pamidronate was never registered for clinical use but in short-term studies was shown to have a modest effect on bone resorption markers.83 However, in the Danish trial there was only weak evidence for a protective effect of pamidronate on BMD, suggesting that absorption of this agent may have been poor and treatment adherence by patients limited. In fact, it has been reported that up to 50% of patients stop taking oral bisphosphonates within 6 months due to gastrointestinal side effects, a fact that may well contribute to the inconsistent overall survival results of adjuvant oral bisphosphonates.84
Zoledronic Acid
Compliance is clearly not an issue with IV bisphosphonates such as zoledronic acid. This agent is the most potent bisphosphonate available, and is already widely used in the treatment of metastatic bone disease from a range of tumor types. Several pilot studies have suggested that zoledronic acid is able to clear disseminated tumor cells (DTC) from the bone marrow.85,86 While interesting, the clinical relevance of these observations is uncertain.
In the Austrian Breast Cancer Study Group Trial 12 (ABCSG-12), 1803 premenopausal women were randomized to receive endocrine therapy (goserelin plus tamoxifen or anastrozole) plus zoledronic acid at a dose of 4 mg every 6 months for 3 years, versus the same endocrine therapy alone.71 At a median follow-up of 4 years, the combination of endocrine therapy and zoledronic acid resulted in a 36% improvement in disease-free survival (DFS) (HR 0.64; P=0.01). There was also a trend toward reduced risk of death (HR 0.60; P=0.11), but the number of events was too few for reliable statistical analysis. Subgroup analysis was unable to definitively identify specific patients who derived greater benefit; however, there was a trend suggesting that the effects of zoledronic acid were more marked in patients receiving goserelin plus anastrozole. In the absence of zoledronic acid, this combination is associated with markedly increased bone turnover and accelerated bone loss87 and thus may have created a particularly fertile environment in bone for metastasis that is negated by the concomitant use of zoledronic acid. In addition, zoledronic acid not only decreased the frequency of bone metastases but also of distant metastasis to other sites, as well as loco-regional and contralateral relapses. This suggests that part of its antitumor effect may arise from subtle changes in the bone marrow microenvironment, including the vascular niche, where dormant tumor stem cells may survive for an extended period in a quiescent state.88 This interdependence of tumor cells on the microenvironment and stem cells fuels the "seed-and-soil" hypothesis proposed more than 120 years ago.1
These results are supported in part by the findings in the Z-FAST, ZO-FAST, and EZO-FAST bone protection trials for postmenopausal women (Table 3). In the 36-month update of the ZO-FAST trial evaluating the bone-protective effects of zoledronic acid in postmenopausal women receiving letrozole, patients receiving immediate zoledronic acid experienced fewer relapses compared with the delayed zoledronic acid group (HR 0.57; P=0.018).89 As in ABCSG-12, fewer relapses outside bone were also seen. A reduction in DFS rates in favor of adjuvant zoledronic acid was also noted in the smaller Z-FAST study,90 but this is balanced by a small excess of relapses in the EZO-FAST study.91
(click table to view larger version)
Ongoing Studies – Breast Cancer Metastasis Prevention
In addition to the NSABP B-34 trial discussed above, two other large clinical trials are underway that are expected to contribute important information to our understanding of metastasis prevention. The AZURE study is evaluating the potential efficacy of several bisphosphonates in the adjuvant setting in breast cancer.92 Zoledronic acid may have beneficial effects, not only through inhibition of bone resorption and reduction in growth factors and cytokines in the bone marrow microenvironment that appear to promote the development of metastasis, but also through direct effects on tumor cells in the bone marrow and possible synergy with adjuvant chemotherapy. The AZURE study will assess DFS and time to bone and distant metastasis in patients treated with standard anticancer therapy alone, compared to those treated with standard therapy plus zoledronic acid (4 mg) administered initially monthly for 6 doses, and then every 3–6 months to complete 5 years of treatment. Recruitment was completed in early 2006 and efficacy data are expected in 2010. A third trial, the Southwestern Oncology Group study SWOG 0307, is ongoing and is planned to recruit 5400 women with stage I-III breast cancer. Following completion of adjuvant chemotherapy, patients are randomized to zoledronic acid 4 mg monthly for 6 months then every 3 months, oral ibandronate 50 mg daily, or oral clodronate 1600 mg daily.93 This trial is expected to complete accrual in early 2010 (Table 4).
Prostate Cancer Metastasis Prevention
In prostate cancer, two metastasis prevention trials have been reported. In the first, which was conducted by the Medical Research Council in the United Kingdom, oral clodronate was evaluated in men with a rising PSA.94 A recent updated analysis of this study has confirmed that, in contrast to the small but statistically significant survival advantage seen in the metastatic setting with clodronate, there was no impact on survival in the prevention setting. Zoledronic acid has also been evaluated in men without evidence of metastases but with a rising PSA. However, this study did not select patients on the basis of PSA doubling time or high absolute level of PSA. As a result, the event rate was very low and the trial was abandoned.95
(click table to view larger version)
In the near future we can expect to see results from trials that involve a total of more than 20,000 patients, including AZURE, NSABP B-34, SWOG 0307, SUCCESS, NATAN, AZAC, ZEUS, RADAR, and Study 2419 (Table 4). These will undoubtedly further increase our knowledge about the adjuvant benefits of both oral and IV bisphosphonates across a range of cancers and should clarify several unanswered questions. Recently, results of phase III trials comparing denosumab to zoledronic acid in the metastatic setting have been presented. These show the superiority of denosumab in preventing SREs.41,96 Denosumab is thus an exciting bone-targeted agent, and the results of metastasis prevention trials in prostate cancer (completed) and breast cancer (initiated) are eagerly awaited.
Conclusions
Metastatic bone disease results from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells, thereby providing the rationale for bone-targeted therapies. Bisphosphonates interrupt this vicious cycle and may also have direct effects on tumor cells, especially when administered in combination with chemotherapy. Recent data with zoledronic acid suggest that bone-targeted treatments may indeed modify the course of the disease and reduce recurrence rate. However, results of ongoing large trials assessing bisphosphonates in metastasis prevention in breast, prostate, and lung cancer are required for confirmation before this approach becomes the standard of care. Other bone-targeted agents such as denosumab are being evaluated in metastasis prevention trials in breast and prostate cancer, and these results are eagerly awaited.