Several pilot studies have shown an advantage for weekly low-dose zoledronic acid in inducing an early significant and long-lasting decrease of VEGF levels in cancer patients [7, 17]. Recently, after completion of a randomized study comparing weekly low-dose zoledronic acid with conventional-dose zoledronic acid in breast cancer patients with bone metastases, it has shown an advantage for weekly low-dose zoledronic acid. Low-dose zoledronic acid is shown to be more effective than the conventional regimen and generates sustained reductions in circulating VEGF and NTx levels, as well as stabilization of serum CA 15-3 levels . The analysis presented in this article was undertaken to evaluate clinical or biochemical factors, which might predict the outcome after weekly low-dose or conventional-dose zoledronic acid in these breast cancer patients with bone metastases with poor prognostic factors; therefore, improve an individualization of the patient management.
In the first step of our analysis, we investigated the prognostic effect of the clinical and biochemical factors on progression-free survival in a patient population, which was treated in a randomized study protocol . In a univariate analysis, after adjustment for treatment, clinical factors such as pretreated chemotherapy regimens, ER status, lymph nodes status, 2-year DFI, and biochemical factors such as serum VEGF level after 3 months of intervention, baseline CEA, CA 15-3, and NTx showed a statistically significant influence on progression-free survival. Patients with poor prognostic factors such as heavily treated with chemotherapy, ER negativity, more than 3 lymph nodes, DFI less than 2 years, high levels of CEA, and CA 15-3 had a significantly higher probability of relapse/death during follow-up, which is consistent with other reports [13, 14, 18–22]. For bone metastases and potential antiangiogenic effect of zoledronic acid, we added NTx and VEGF into analysis. We first claimed that patients with low level of baseline NTx and VEGF after intervention had a better prognosis than patients with high level of baseline NTx and VEGF after intervention tumors. No influence on progression free survival could be shown for other factors including age, tumor size, tumor grade, menopause, bone metastasis sites, baseline VEGF and NTx, CEA, and CA 15-3 levels after intervention.
In the multivariate analysis of the clinical and biochemical factors, numbers of pretreated chemotherapy regimens, ER status, baseline NTx, and serum VEGF level after 3 months of intervention were independent prognostic factors for progression free survival, showing that these factors were associated with a significant downward progression free survival. The results for numbers of pretreated chemotherapy regimens and ER status are in line with data of several other studies reporting a prognostic effect of these factors for breast cancer patients [18, 20]. The result for the prognostic effect of NTx seems to be consistent with some studies in the literature. Several clinical studies suggest that the bone resorption marker, NTx, is associated with the presence and extent of metastases, response to treatment, and prognosis [23–25]. Arguably, the serum VEGF levels at 3-month time point, not the baseline serum VEGF levels was shown as the independent prognostic factor for PFS both in the univariate and multivariate analyses. Four published studies, which evaluated the prognostic value of serum VEGF level, revealed that high levels of circulating VEGF levels is associated with poor survival . The explanation for prognostic value of serum VEGF level at 3-month time point could be that the VEGF values at that time reflect the dynamics of tumor biology interacting with zoledronic acid. However, this effect may need to be sustained with higher frequency and a longer duration of zoledronic acid administration.
The second aim of our study was to investigate whether the clinical or biochemical factors have predictive effects (i.e., if treatment effects of weekly low-dose zoledronic acid compared with conventional schedule are different in subgroups defined by the clinical or biochemical factors). This is the first study to investigate the predictive factors of breast cancer patients with bone metastases receiving weekly low-dose zoledronic acid. Several former studies have shown some predictive factors of conventional zoledronic acid or bisphosphonates naïve in bone metastases of several kinds of cancers. Lein et al. investigated in a study in 117 prostate cancer patients with bone metastases receiving zoledronic acid the predictive effect of a range of bone turnover markers, they created cox regression models with clinical factors and bone markers and eventually showed the baseline NTx level as predictor of SREs (HR, 3.33; 95%CI, 1.66-6.72, P = 0.0007) . Coleman et al. investigated in three large, randomized trials of 1824 patients with bone metastases receiving bisphosphonates the prognostic effects of NTx, and bone alkaline phosphatase (BAP) and found that high NTx level in each solid tumor category were associated with a 4- to 6-fold increased risk of death compared with low NTx levels and BAP showed correlation with negative outcomes . Brown et al. investigated two phase III randomized trials in 431 bisphosphonate-naïve patients with bone metastases secondary to prostate cancer, non-small-cell lung cancer, and other solid tumors from the predictive and prognostic effect of a range of factors. They found the predictive relationships for NTx and BAP levels for the NSCLC, prostate cancer, and other tumors. Their analysis showed that a high BAP level at baseline was associated with an increased risk of negative clinical outcomes compared to patients with low baseline BAP levels (RR, 1.49; 95% CI, 1.02 to 2.17, P = 0.041). Furthermore, it also revealed a statistically significant association between baseline NTx levels, time to a first skeletal related event (P = 0.026), risk of disease progression (P = 0.029) and death (P = 0.001) .
The major finding of our study was a predictive value of NTx on treatment strategies. Patients with high level of baseline NTx showed a higher progression-free survival with weekly low-dose zoledronic acid compared with conventional q-4 weeks regimen. Our results obtained for the patients with weekly low-dose zoledronic acid are different from other reports. First, several previous studies have evaluated some predictive or prognostic value of NTx level, but the treatment they used were old generation of bisphosphonates such as pamidronate and clodronate, which is not potent as zoledronic acid in anti-bone resorption and potential antitumor effects [23, 25]. Several study use zoledronic acid, but NTx prognostic or predictive value was obtained from bisphosphonates naïve patients or patients receiving the conventional dose of zoledronic acid [11, 12, 26]. Secondly, the endpoint or evaluation indicators of amount of study which investigated the predictive effects of bone turnover markers. (i.e. NTx was SRE or progression of bone metastases) [11, 16, 26]. Although some studies found weekly low-dose zoledronic acid could induce serum VEGF level reduction, and had potential antitumor effects, they did not do the prognostic or predictive factors analysis [7, 17]. As a lot of reports used urine NTx [11, 12, 23–26], we used serum NTx due to the precision of time points of sample collection because several biochemical markers such as VEGF in our previous study was collected concomitantly . By doing this, we can make the study more manageable and decrease the impact of other factors like time, temperature, and storage, etc .
There are several strengths in our trial. First, it is a prospective and randomized trial to investigate the prognostic and predictive clinical or biochemical factors in patients with bone metastases as the bone turnover markers. NTx, especially, can be a predictive factor in cancer patients with bone metastases receiving conventional schedule of bisphosphonates. Our study further investigates the NTx predictive value in a new weekly schedule of low dose zoledronic acid. Secondly, recruitment of patients were strictly limited to breast cancer patients with bone metastases , thus the predictive effect of NTx may be helpful for the individualized therapy. High levels of baseline serum NTx may favor the weekly low-dose zoledronic acid; however, there are several drawbacks and limitation in our trial. First, weekly low-dose zoledronic acid was no longer given in the metronomic arm one month after the first drug administration. During the first month, the metronomic arm showed a significant reduction of VEGF and NTx compared with the conventional arm. This effect may need to be sustained, with higher frequency of zoledronic acid administration, over a longer time period. Second, this is a single center phase II trial. If the prognostic and predictive factors are analyzed from several randomized phase III, double blind studies, the results will be more credible. Thirdly, in our previous study, all patients received chemotherapy or hormonal therapy for a minimum of 28 days after the first infusion of zoledronic acid according to our institutional guidelines. No significant differences were observed between the 2 arms in the use of different agents due to a small sample size. This may potentially have impact on PFS. Finally, the overall survival results may be more credible for the evaluation of prognostic or predictive factors; the results will be further reported.