Zoledronic acid in metastatic osteosarcoma: encouraging progression free survival in four consecutive patients
© Conry et al. 2016
Received: 23 January 2016
Accepted: 29 March 2016
Published: 28 April 2016
Zoledronic acid (ZA) is a third-generation bisphosphonate in widespread clinical use to reduce pain and skeletal events in patients from a variety of malignancies with bone metastases. Pre-clinical studies indicate that ZA inhibits osteosarcoma through direct anti-proliferative effects, immune activation and anti-angiogenic activity.
The purpose of this study was to evaluate the antitumor efficacy of ZA at standard dose until progression in patients with stage IV osteosarcoma lacking a standard of care treatment option proven to influence survival. Researchers retrospectively reviewed medical records of all patients at our institution with high-grade osteosarcoma presumed to be incurable due to metastases progressive after primary combination chemotherapy who received single agent ZA in an effort to delay progression.
In our four-patient cohort following initiation of ZA, the median progression-free survival was 19 months, and median overall survival was 56+ months. Two of four patients have remained progression-free since starting ZA. The other two initially progressed after 18–20 months on ZA followed by metastasectomy of lung or dural metastases and further stability for over a year following resumption of ZA. After a 20-month progression-free interval on ZA alone, one patient had partial response following addition of pazopanib to ZA that likely contributed to long term disease control. The four patients experienced no significant toxicities despite protracted dosing of ZA for up to 5 years, and none have required chemotherapy since beginning ZA.
Single agent ZA was associated with encouraging progression-free survival in four consecutive patients with metastatic osteosarcoma. Prospective trials of single agent ZA are warranted as protracted maintenance therapy in surgically incurable osteosarcoma relapsed or refractory to first line combination chemotherapy with radiographically measurable metastases.
KeywordsZoledronic acid Bisphosphonates Osteosarcoma Metastatic Survival Human
Osteosarcoma is the most common malignant bone tumor in children and young adults. Despite aggressive surgical and medical therapy, the estimated 5-year event-free survivals of patients presenting with localized or metastatic disease are 50–70 % and less than 20 %, respectively . Patients with either unresectable primary tumors or distant metastases progressing after conventional primary chemotherapy have dismal outcomes, little changed over the past 30 years . There is no “standard” second-line systemic therapy for inoperable osteosarcoma progressing after conventional chemotherapy. Results of three cooperative group experiences in this population reveal median survival of 6 months , median time to progression of 2 months with only 6 % event-free survival at 6 months , and a 2-year post-relapse survival <2 % . Thus, novel systemic treatment approaches are urgently needed.
Zoledronic acid (ZA) is a third-generation, nitrogen-containing bisphosphonate analog of endogenous pyrophosphate that strongly binds to calcium-containing hydroxyapatite bone mineral. Although the plasma half-life of ZA is less than 24 h, bisphosphonates are stable in bone with a skeletal half-life of more than 300 days . Osteosarcoma is characterized by the production of osteoid or immature bone containing focal calcium deposits of hydroxyapatite crystals . Thus, ZA may preferentially concentrate in primary osteosarcomas as well as their lung and bone metastases and persist for years. ZA inhibits farnesyl diphosphate synthase, a key enzyme in the mevalonate pathway, and thus reduces protein prenylation essential for normal cell function and survival [8, 9]. Bone-resorbing osteoclasts internalize relatively large quantities of ZA and are thus particularly vulnerable to functional inhibition, underlying the widespread use of this drug to reduce pain and skeletal-related events in adults with bone metastases . However, nitrogen-containing bisphosphonates appear to have direct anti-proliferative and pro-apoptotic effects against normal osteoblasts and a variety of tumor cells, including breast, myeloma, pancreatic and prostate cancers [11–15]. ZA has been shown to reduce primary tumor growth, decrease lung metastases and prolong survival in animal models of osteosarcoma [16–18]. ZA also acts synergistically with mTOR inhibition to decrease proliferation of murine and human osteosarcoma cell lines in vitro and to reduce osteosarcoma tumor growth in two distinct syngeneic murine modals . Ewing’s sarcoma is the second most frequent malignant bone tumor in adolescents and young adults. ZA inhibits Ewing’s sarcoma cell invasion through down regulation of matrix metalloproteinase and significantly reduces development of spontaneous lung metastases in a nude mouse model of human Ewing’s sarcoma cells injected into the tibia .
The Children’s Oncology Group (COG) performed a phase I feasibility trial of monthly ZA for eight cycles with concurrent conventional multi-agent chemotherapy in 24 children with previously untreated, high-grade metastatic osteosarcoma . The maximum tolerated dose (MTD) was equivalent to the standard adult dose for bone metastases, and there was a trend toward improved event-free survival at 2 years compared to historical data from intergroup study INT 0133 (p = 0.079). This manuscript is the first reported clinical experience with ZA as single agent therapy for osteosarcoma.
Treatment outcomes with zoledronic acid
Sites of diseasea
Status at last visit
Lung and hilum
Radiation to hilum/neurosurgery
All four patients presented with high-grade osteosarcoma without detectable metastases. All received neoadjuvant and/or adjuvant chemotherapy with conventional doses of doxorubicin and cisplatin with or without high-dose methotrexate and ifosfamide. All underwent definitive surgical resection of the primary tumor using a limb-sparing approach in the three extremity cases. Patients 2 and 4 had microscopically positive soft tissue margins treated with post-operative external beam radiotherapy. All patients subsequently developed stage IV osteosarcoma involving the lungs that was treated with ZA. Patients 1 and 2 received ZA as consolidative treatment following metastasectomies and a likely transient response to salvage chemotherapy in the case of patient 2. Patients 3 and 4 received ZA for treatment of persistently measurable metastases to the lung and other sites. The University of Alabama at Birmingham Department of Anatomical Pathology histologically confirmed the diagnosis of high-grade osteosarcoma from the primary site of all four patients as well as from resection specimens from lung metastases in patient 1 before and after ZA and patient 2 before ZA. Histological confirmation of metastatic high-grade osteosarcoma was also obtained at our academic center from bronchoscopic biopsy of a hilar lymph node and subsequent resection of a brain metastasis in patient 3.
A 63-year-old male underwent left radical parotidectomy and neck dissection to resect an extraosseous osteosarcoma with no lymph node involvement. Two years after completion of primary therapy a CT scan of the chest revealed a new right lung metastasis which was wedge resected. Repeat chest CT scan 3 months later demonstrated five new pulmonary metastases. He was considered incurable due to rapid progression of multiple, bilateral pulmonary metastases 2 years after completion of optimal adjuvant chemotherapy for a man of his age. He received salvage chemotherapy with four cycles of doxorubicin and dacarbazine since he was unable to tolerate additional cisplatin due to peripheral neuropathy. Chest CT scan showed a complete radiographic response which was followed by three cycles of vinorelbine with oral cyclophosphamide. Since the prognosis was dismal, the patient began ZA at 4 mg every 6 weeks due to lengthy travel to clinic as consolidative therapy. He continued this schedule for 18 months followed by dosing every 3 months for 36 additional months without apparent toxicity or relapse of osteosarcoma as determined by chest CT scans at 3-month intervals. He has been on ZA for 54+ months.
Summary of outcomes
All patients had stage IV osteosarcoma and lacked a standard of care treatment option proven to significantly influence survival. The treatment outcomes with ZA are summarized in Table 1. Following initiation of ZA, the median progression free survival was 19 months, and median overall survival was 56+ months. At the time of this report, two of the four patients have no evidence of disease, and the other two have stable disease. None of the four patients have required chemotherapy since starting ZA. The case of patient 1 is particularly compelling since ZA dramatically extended the progression-free interval following his fifth pulmonary metastasectomy to 20 months. Once another metastasis became detectable, it objectively responded to the addition of pazopanib to ZA for 14 months followed by resection, and he remains progression-free 20 months later on single agent ZA. Patient 3 demonstrated stable hilar and pulmonary metastases for a remarkable 44 months on ZA allowing her to survive long enough to develop a very uncommon metastasis to the dura possibly representing a sanctuary site of relatively poor drug penetration. Following resection of the intracranial metastasis, she has remained stable for an additional 16 months on ZA.
Bisphosphonates are relatively well tolerated with side effects including electrolyte disturbances, flu-like symptoms, nausea and less commonly osteonecrosis of the jaw and renal dysfunction [22, 23]. The four patients reported herein receiving ZA for advanced osteosarcoma experienced no significant toxicities despite protracted dosing for up to 5 years. ZA is a convenient treatment for patients with incurable osteosarcoma with far less detrimental impact on quality of life than conventional chemotherapy.
Pre-clinical studies indicate that ZA inhibits osteosarcoma through direct anti-proliferative effects, immune activation and anti-angiogenic activity. ZA directly inhibits human osteosarcoma cell proliferation and induces apoptosis in vitro [24–26]. γδ T cells recognize small phosphoantigens associated with metabolites of bacterial isoprenoid biosynthesis or the mevalonate pathway in eukaryotes . ZA sensitizes tumor cells to γδ T cell cytotoxicity through accumulation of mevalonate pathway intermediates within bisphosphonate-treated cells . ZA promotes γδ T cell proliferation from peripheral blood mononuclear cells of osteosarcoma patients and enhances γδ T cell cytotoxicity against human osteosarcoma cells [29, 30]. Vascular endothelial growth factor-A (VEGF-A) and vascular endothelial growth factor receptor-1 (VEGFR-1) are highly expressed by aggressive osteosarcoma cells, but not in clonally-related less aggressive cell lines . Plasma levels of VEGF-A are elevated in osteosarcoma patients, and ZA decreases circulating levels of VEGF-A in these patients [32, 33]. ZA inhibits tumor-associated angiogenesis not only via direct inhibition of endothelial cells, but also by decreasing VEGF-A expression in osteosarcoma. Furthermore, evidence indicates that ZA induces apoptosis in aggressive osteosarcoma cells at least partly by inhibiting autocrine stimulation via VEGF-A and VEGFR signaling . Thus, nitrogen-containing bisphosphonates have pleiotropic inhibitory effects on osteosarcoma and tumor-associated endothelial cells.
Inherent limitations in this study include the retrospective nature of the review and the small cohort of patients analyzed. However, this report does include all patients receiving single agent ZA to delay osteosarcoma progression at our institution during the specified timeframe.
COG has demonstrated the feasibility of co-administering ZA with conventional chemotherapy for first line treatment of metastatic osteosarcoma, but the small trial was underpowered to detect efficacy of ZA, particularly in the presence of highly active chemotherapy. A large, randomized French trial of conventional adjuvant chemotherapy with or without ZA for resectable primary osteosarcoma was stopped early due to futility with hazard ratios for event-free survival and death exceeding unity in the ZA cohort. Although not statistically significant, these data suggests that ZA in this context may increase mortality . However, this trial may likewise have been suboptimally designed to evaluate efficacy of ZA in this disease. Direct antiproliferative effects of ZA could actually protect osteosarcoma cells from tumoricidal effects of chemotherapy. Enhancement of antitumor immune responses by ZA could be undermined by concurrent cytotoxic chemotherapy, and antiangiogenic actions of ZA may have little relevance in treating micrometastases in the adjuvant setting. ZA may actually have greater efficacy against surgically incurable macroscopic osteosarcoma used as a single agent or in combination with the mTOR inhibitor everolimus or the VEGFR tyrosine kinase inhibitor pazopanib, targeting tumor cell proliferation and angiogenesis, respectively [19, 35]. The combination of ZA and sirolimus has recently been demonstrated to be effective and tolerable therapy for a young adult with aggressive lymphatic malformations associated with Gorham-Stout disease . Intriguing results from a recent study of the multi-tyrosine kinase inhibitor sorafenib with activity against VEGFR in combination with everolimus further support the use of such agents in recurrent or refractory osteosarcoma . In fact, this trial represents the first positive study in at least 25 years in patients with relapsed osteosarcoma . Interestingly, patient 1 in this report experienced disease control for 20 months on single agent ZA followed by emergence of another lung metastasis that objectively responded for over 14 months to the addition of pazopanib to ZA. We have also observed objective response of multiple pulmonary metastases to combined ZA and pazopanib for over 9 months in a patient with relapsed osteosarcoma not included here due to lack of single agent ZA use.
Zoledronic acid represents a convenient, well tolerated therapy which may provide durable control of incurable osteosarcoma. Therefore, prospective trials of single agent ZA are warranted in surgically incurable osteosarcoma relapsed or refractory to first line conventional combination chemotherapy with radiographically measurable metastases.
mammalian target of rapamycin
positron emission tomography
response evaluation criteria in solid tumors
magnetic resonance imaging
vascular endothelial growth factor
vascular endothelial growth factor receptor
Children’s Oncology Group
Dr. RMC was involved in conception of the study, treating patients and monitoring their antitumor response and toxicities. He was actively involved in writing the manuscript. Dr. MGR comprehensively reviewed patient imaging and provided Figs. 1, 2, and 3. Dr. JGP assisted with study conception, data interpretation and manuscript writing. All authors read and approved the final manuscript.
The authors thank Kendra Gilpin for expert preparation of the manuscript.
The authors declare that they have no competing interests.
Consent for publication
Consent has been obtained from the four patients involved and is on file at the University of Alabama at Birmingham.
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