Elsevier

Bone

Volume 39, Issue 1, July 2006, Pages 35-41
Bone

Combined therapy of Sr-89 and zoledronic acid in patients with painful bone metastases

https://doi.org/10.1016/j.bone.2005.12.004Get rights and content

Abstract

Purpose

We evaluated the pain response and daily discomfort in patients with painful bone metastases treated by merging 89Sr-chloride and zoledronic acid. The results were compared with those of patients who received 89Sr-chloride or zoledronic acid separately.

Methods

25 patients (12 women; mean age 65Ā Ā±Ā 13 years) chronically treated with zoledronic acid underwent bone pain palliation with 150 MBq of 89Sr-chloride at least 6 months later that bisphoshonate therapy started (group A). 13 patients (6 women; mean age 70Ā Ā±Ā 12 years) received 89Sr-chloride alone (group B) and 11 patients (5 women; mean age 69Ā Ā±Ā 12 years) were chronically treated and continued to receive only zoledronic acid therapy (group C), both constituted the control groups. Patients kept a daily pain diary assessing both their discomfort and the pain of specific sites by using a visual analog scale (VAS), rating from 0 (no discomfortā€“no pain) to 10 (worst discomfortā€“pain). These diaries were reviewed weekly for 2 months and three different physicians rated the pain response on a scale of āˆ’2 (considerable deterioration) to +2 (considerable improvement).

Results

Baseline characteristics were similar in the three groups. The reduction of total discomfort and of bone pain in the group A was significantly greater as compared to group B (PĀ <Ā 0.01) and group C (PĀ <Ā 0.01). During the monitored period, a significant improvement of clinical conditions was observed in the group A, varying the rate from āˆ’1 to 1 as compared to both groups B and C in which the rate changed from āˆ’1 to 0.

Conclusion

Our findings indicate that combined therapy of 89Sr-chloride and zoledronic acid in patients with painful bone metastases is more effective in treating pain and improving clinical conditions than 89Sr-chloride or zoledronic acid used separately.

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.

References (81)

  • P.O. Carey et al.

    Treatment of painful prostatic bone metastases with oral etidronate disodium

    Urology

    (1988)
  • F. Saad

    Zoledronic acid significantly reduces pathologic fractures in patients with advanced-stage prostate cancer metastatic to bone

    Clin. Prostate Cancer

    (2002)
  • E.C. Li et al.

    Zoledronic acid: a new parenteral bisphosphonate

    Clin. Ther.

    (2003)
  • A.T. Porter et al.

    Results of a randomized phase III trial to evaluate the efficacy of strontium-89 adjuvant to local field external-beam irradiation in the management of endocrine-resistant metastatic prostate cancer

    Int. J. Radiat. Oncol., Biol., Phys.

    (1993)
  • P.M. Quilty et al.

    A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer

    Radiother. Oncol.

    (1994)
  • S. Tu et al.

    Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial

    Lancet

    (2001)
  • N.A. Hamdy et al.

    The palliative management of skeletal metastases in prostate cancer: use of bone-seeking radionuclides and bisphosphonates

    Semin. Nucl. Med.

    (2001)
  • A. Bonabello et al.

    Long-term analgesic effect of clodronate in rodents

    Bone

    (2003)
  • V.J. Lewington et al.

    A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone

    Eur. J. Cancer

    (1991)
  • S.S. Hwang et al.

    Dynamic cancer pain management outcomes: the relationship between pain severity, pain relief, functional interference, satisfaction and global quality of life over time

    J. Pain Symptom Manage.

    (2002)
  • A.H. Reddi et al.

    Mechanisms of tumor metastasis to the bone: challenges and opportunities

    J. Bone Miner. Res.

    (2003)
  • O.S. Nielsen et al.

    Bone metastases: pathophysiology and management policy

    J. Clin. Oncol.

    (1991)
  • R.E. Coleman et al.

    The clinical course of bone metastases in breast cancer

    Br. J. Cancer

    (1987)
  • E.T. Keller et al.

    Prostate cancer bone metastases promote both osteolytic and osteoblastic activity

    J. Cell Biol.

    (2004)
  • M. Ribiero et al.

    Low serum testosterone and a younger age predict poor outcome in metastatic prostate cancer

    Am. J. Clin. Oncol.

    (1997)
  • E.M. Posadas et al.

    The emerging role of bisphosphonates in prostate cancer

    Am. J. Ther.

    (2004)
  • P.F. Choong

    The molecular basis of skeletal metastases

    Clin. Orthop.

    (2003)
  • L.G. Raisz

    Physiology and pathophysiology of bone remodeling

    Clin. Chem.

    (1999)
  • J.J. Body

    Bone metastases and tumor-induced hypercalcaemia

    Curr. Opin. Oncol.

    (1992)
  • C.S. Marcus et al.

    Lack of effect of a bisphosphonate (pamidronate disodium) infusion on subsequent skeletal uptake of Sm-153 EDTMP

    Clin. Nucl. Med.

    (2002)
  • V.J. Lewington

    Bone-seeking radionuclides for therapy

    J. Nucl. Med.

    (2005)
  • W.C. Mertens

    Radionuclide therapy of bone metastases: prospects for enhancement of therapeutic efficacy

    Semin. Oncol.

    (1993)
  • G. Auclerc et al.

    Management of advanced prostate cancer

    Oncologist

    (2000)
  • D.A. Karnofsky

    Meaningful clinical classification of therapeutic responses to anticancer drugs

    Clin. Pharmacol. Ther.

    (1961)
  • A.N. Serafini et al.

    Palliation of bone pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial

    J. Clin. Oncol.

    (1998)
  • C. Collins et al.

    Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial

    J. Nucl. Med.

    (1993)
  • N. Pandit-Taskar et al.

    Radiopharmaceutical therapy for palliation of bone pain from osseous metastases

    J. Nucl. Med.

    (2004)
  • D. Tong et al.

    The palliation of symptomatic osseous metastases: final results of the Study by the Radiation Therapy Oncology Group

    Cancer

    (1982)
  • O.M. Salazar et al.

    Single-dose half-body irradiation for palliation of multiple bone metastases from solid tumors. Final Radiation Therapy Oncology Group report

    Cancer

    (1986)
  • C.D. Reich

    Advances in the treatment of bone metastases

    Clin. J. Oncol. Nurs.

    (2003)
  • Cited by (0)

    View full text