Combined therapy of Sr-89 and zoledronic acid in patients with painful bone metastases
Introduction
Most patients with advanced cancer are affected from bone metastasis [1], [2], [3], [4]; this untreatable progression of the disease weights heavily on cancer-related mortality and morbidity. The exact molecular mechanisms of the metastatic process in cancer are widely argued. As a result, therapeutic strategies to prevent the evolution of the disease and its complications are being persistently investigated [5], [6], [7]. The pathophysiology of bone metastasis and its associated complications is composite [8], [9], [10]. Normal bone undergoes constant remodeling and systemic factors, such as the parathyroid hormone, local osteoclast-activating cytokines, and growth factors, play a role into the process [11]. When bone metastases take place, osteolytic activity increases. This leads to osteopenia and increased risk of developing fractures. The calcium released from the bone matrix in the course of this process can lead to a severe metabolic condition, the hypercalcemia of malignancy. Although bone metastases are often clinically quiet, both the above-mentioned conditions may sustain bone pain [12], [13]. Moreover, bone pain may also represent a primitive, unrelated symptom as a part of the metastatic disease, reducing the performance status and decreasing the quality of life. In addition, bone pain is referred to as a particularly invalidating condition. Among the different, mostly palliative, therapies used to treat bone metastases, bone-targeted approaches using bisphosphonates, radiopharmaceuticals, or endothelin receptor antagonists currently hold great promise in terms of efficacy and tolerability. The possibility of using two or more approaches to metastatic bone pain has not been completely investigated so far. Instead, it was speculated about the interference between the different therapies [14], [15], [16], [17]. This study investigated the effects of a combined palliative therapy on the bone pain and the overall performance status of patients affected by metastatic prostate or breast cancer using a bisphosphonate, the zoledronic acid, and the 89Sr-chloride.
Section snippets
Patients
All patients had painful bone metastases from prostate or breast cancer refractory to conventional treatment. They had definite diagnosis of metastatic bony lesions (blastic or mixed lytic/blastic) from primary cancer. Each was requested to have a 99mTc-MDP bone scan before receiving therapy. Pain at one or more sites presenting increased tracer uptake was required for participation in the study. They were required to have a performance status of 40 or greater on the Karnofsky scale [18] and an
Bone pain assessment
There was no significant difference in baseline demographic and clinical characteristics between the three groups (Table 1). One-way ANOVA demonstrated no differences in baseline VAS and PGA values between the three groups. VAS was 7.4Ā Ā±Ā 0.8 in group A, 6.8Ā Ā±Ā 1.3 in group B, and 8.2Ā Ā±Ā 1.4 in group C, respectively (PĀ =Ā 0.10). A significant reduction of bone pain and total discomfort throughout the time was detectable in the overall study population (PĀ <Ā 0.0001) (Fig. 1). However, in the group
Discussion
In the present study, we found that in patients with painful bone metastases from prostate or breast cancer the combined therapy with 89Sr-chloride and zoledronic acid is significantly more effective in treating pain and improving the overall performance status than 89Sr-chloride and zoledronic acid used separately.
At present, the treatment of bone pain remains palliative and bone metastases are treated by means of several therapeutic modalities. Nevertheless, most of these treatments are
Study limitations
Our study has some limitations. First, it is a retrospective non-randomized trial bringing itself some intrinsic limits. Second, a partial placebo effect cannot be excluded in the patients receiving combined therapy. Our patients were consecutive and those receiving only 89Sr-chloride had been treated before zoledronic acid marketing. It would have been unethical to give them a placebo. Nevertheless, our data on pain response to zoledronic acid alone allow making an inference between groups
Conclusion
Combined therapy of Sr-89 and zoledronic acid in patients with painful bone metastases is more effective in treating pain and improves clinical conditions more than Sr-89 or zoledronic acid alone leading to considerable analgesic drug discontinuation. The benefit is achieved despite an additional, but not significant, hematological toxicity. Considering the encouraging results, further trials employing bisphosphonates and radionuclides, with adequate number of subjects, are required.
Acknowledgments
The authors wish to thank Mr. C. Di Nuzzo and Mr. G. Cascone for assistance in performing the studies. The study complies with the current laws of Italy inclusive of ethics approval.The authors have no financial conflict of interest.
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