Safety and Efficacy Study of Concomitant Radiotherapy and Zoledronic Acid for Bone Metastases Palliation

A Phase I Pilot Trial to Study the Safety and Efficacy of Concomitant Radiotherapy and Zoledronic Acid for the Palliation of Bone Metastases From Breast Cancer, Prostate Cancer and Lung Cancer

Zoledronic acid (Zometa) belongs to a class of drugs called bisphosphonates. Bisphosphonates are used in bone metastases to keep the cancerous lesion under control in the bone and to help prevent calcium level elevations in the blood. Cancer cell-culture studies at the Cleveland Clinic showed that zoledronic acid and radiation together have more cell killing effect than either one used alone. The purpose of this study is to monitor the healing of bone lesions when using zoledronic acid together with radiation treatment.

Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. Skeletal complications due to metastatic disease include (severe) bone pain, impaired mobility, spinal cord compression, pathological fractures, and hypercalcemia. Radiotherapy and surgery are the options for the specific local treatment of bone metastases. Chemotherapy, hormonotherapy and bisphosphonates are systemic weapons used in the treatment of bone metastases with or without hypercalcemia. Cancers with propensity to metastasize to bones such as breast, prostate, lung and myeloma may possess the capacity to interact with osteoclasts. Osteoclasts are specialized bone cells, which erode mineralized bone by secreting acids and lysosomal enzymes. In normal bone remodeling, osteoclastic bone resorption is coupled to and is in equilibrium with osteoblastic bone formation. The lytic bone destruction associated with malignant bone metastases develops because tumor cells synthesize and release soluble factors that stimulate osteoclasts to resorb bone. The malignant activation of osteoclasts results in a disruption of normal bone remodeling wherein the equilibrium between bone resorption and bone formation is shifted toward increased bone resorption. This relative increase in osteoclastic bone resorption results in a net loss of bone.

Zoledronic acid (Zometa®, CGP42446) is a member of a class of compounds known as bisphosphonates. Bisphosphonates are effective inhibitors of osteoclastic bone resorption. They have therapeutic efficacy in the treatments of hypercalcemia of malignancy, lytic bone disease associated with multiple myeloma, and mixed lytic and blastic bone metastases associated with breast cancer, prostate cancer and lung cancer. In the clinical setting, zoledronic acid is the most potent bisphosphonate.

Conventionally, external beam radiotherapy (RT) is a primary treatment method for the palliation of bone metastases. The aim of RT in bone metastases treatment is to eradicate malignant cells without damaging surrounding normal cells. RT is typically given to the lesion area, in order to spare as much bone marrow as possible. RT is indicated in solitary, lytic and painful bone lesions of multiple myeloma as well as bone metastases from solid tumors such as breast, prostate and lung cancer to prevent the fracture risk or to relieve the pain.

The goal of this study will be to evaluate the safety and efficacy of concomitant standard RT and standard zoledronic acid on the bone metastases of breast, prostate or lung cancer patients. We chose zoledronic acid to use in this study, as it is the most effective FDA approved aminobisphosphonate.

Inclusion Criteria:

• >18 years of age
• biopsy proven breast, lung, and/or prostate cancer
• boney metastases with an indication for radiation, either diagnosed radiologically or biopsy proven
• Karnofsky Performance Status >60
• Life expectancy of at least 6 months
• Serum creatinine level ≤ 2.0 mg/dL and calculated creatinine clearance of > 60 mL/min
• Leukocyte count ≥ 3500/mm3
• Hemoglobulin > 11 g/dl
• Platelets > 100,000 / mm3
• Total bilirubin < 2.5 mg/dl

Exclusion Criteria:

• pregnant and lactating women (breast and lung cancer)
• hormonotherapy started less than 3 months prior to randomization (prostate cancer)
• history of allergic reactions to bisphosphonates
• receiving concomitant nephrotoxic chemotherapy
• participation in another clinical trial with an investigational drug or completed an investigational drug trial within the past 30 days
• liver function tests > 1.5 times normal values
• IV calcitonin administration less than 30 days prior to randomization
• laboratory evidence of renal disease
• previous RT to the region of bone metastasis which will be treated in this study
• currently receiving oral or IV bisphosphonate therapy
• presence of ascites
• clinically significant electrocardiographic changes
• hypercalcemia, pathologic fracture, or epidural spinal cord compression
• other organ metastasis
• known hypersensitivity to Zometa® (zoledronic acid) or other bisphosphonates
• current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.
• recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants)