The identification of effective chemotherapy for the treatment of osteosarcoma (OS) has led to significant improvement in patient outcome.1–2 There are only 4 chemotherapy agents widely accepted to have efficacy against osteosarcoma: doxorubicin, cisplatin, high-dose methotrexate (HDMTX), and ifosfamide.3-7 The Children's Oncology Group (COG) performed a randomized, multi-institution, cooperative trial to test the benefit of the addition of ifosfamide to a regimen of cisplatin, doxorubicin, and HDMTX.8 The addition of ifosfamide did not result in improved event-free survival (EFS) or overall survival. There is a continued need for new therapeutic approaches.
Bisphosphonates are analogues of endogenous pyrophosphates. In vivo, bisphosphonates bind strongly to hydroxyapatite on bone surfaces and are delivered to sites of increased bone formation or resorption. They are widely used to treat hypercalcemia of malignancy. Initially, it was felt that the mechanism of action of bisphosphonates was exclusively to stabilize bone. More recently it has become apparent that bisphosphonates have direct effects on tumor cells.9 In vitro, bisphosphonate treatment of myeloma cells leads to growth inhibition and induction of apoptosis.10 Bisphosphonates induce apoptosis in human breast cancer cell lines.11 Bisphosphonates appear to inhibit adhesion of tumor cells to bone matrix.12 Bisphosphonates may also inhibit matrix metalloproteinases, which are used by tumor cells to invade tissue and establish metastases.13
Numerous in vitro and xenograft studies support the concept that bisphosphonates have activity against osteosarcoma, alone or in combination with chemotherapy. Investigators have studied human and animal cell lines and spontaneous osteosarcoma arising in murine models. They have studied alendronate, clodronate, minodronate, pamidronate, and zoledronate14-37 (Table 1). Oligonucleotide microarray assays of human osteosarcoma offer additional support for the concept of using bisphosphonates in osteosarcoma. Expression profiling of 30 osteosarcoma tumors from patients identified 104 genes differentially expressed between favorable and unfavorable responses to chemotherapy.36 A striking finding was the significant decrease in osteoprotegerin, an osteoclastogenesis inhibitory factor. Additional genes involved in osteoclastogenesis and bone resorption, which were statistically different, included annexin 2, SMAD, PLA2G2A, and TGFbeta1. ECM remodeling genes included desmoplakin, SPARCL1, biglycan, and PECAM. Overexpression of desmoplakin (P = .008), PECAM (P = .028), and SPARCL1 (P = .00,098) were associated with a favorable chemotherapy response, whereas overexpression of annexin2 (P = .05), biglycan (P = .025), and PLA2G2A (P = .025) were associated with an unfavorable chemotherapy response. This suggests the interaction of the tumor with the microenvironment is a determinant of response to chemotherapy. Bisphosphonates may have activity through disruption of these interactions.
Table 1. Preclinical Investigation of Bisphosphonates in Osteosarcoma
|Cheng16||2004||Alendronate|| ||Human lines in vitro|
|Farese19||2004||Alendronate|| ||Dog lines in vitro|
|Molinuevo29||2007||Alendronate|| ||Rat cell line in vitro|
|Heikkila20||2003||Clodronate|| ||Human lines in vitro|
|Kubo27||2006||Minodronate|| ||Human in vitro/xenograft|
|Kubo26||2008||Minodronate||Doxo||Human in xenograft|
|Mackie28||2001||Pamidronate|| ||Rat cell line in vitro|
|Sonnemann35||2001||Pamidronate|| ||Human lines in vitro|
|Ashton14||2005||Pamidronate|| ||Dog lines in vitro|
|Murayama31||2008||Risedronate||Carbo doxo vcr etop||Human lines in vitro|
|Evdokiou18||2003||Zoledronate|| ||Human lines in vitro|
|Heymann21||2005||Zoledronate||Ifosfamide||Rat cell line in vivo|
|Ory33||2005||Zoledronate|| ||Mouse cell line in vivo|
|Horie23||2006||Zoledronate|| ||Mouse cell line in vitro|
|Kubista25||2006||Zoledronate|| ||Human lines in vitro|
|Benassi15||2007||Zoledronate||Cisplatin||Human lines in vitro|
|Dass17||2007||Zoledronate|| ||Human lines in xenograft|
|Horie22||2007||Zoledronate||Doxo paclitaxel gem||Mouse cell line in vitro|
|Iguchi24||2007||Zoledronate|| ||Human lines in vitro|
|Muraro30||2007||Zoledronate|| ||Human lines in vitro|
|Ory32||2007||Zoledronate|| ||Human/rat lines in vitro|
|Ory34||2008||Zoledronate|| ||Human/rat lines in vitro|
|Koto37||2009||Zoledronate|| ||Mouse spontaneous os|
There are a large number of bisphosphonate compounds in clinical use. Osteosarcoma is most common in the second decade of life. We initiated our clinical trial in 2003. We needed to identify a bisphosphonate which had been used in this younger population and demonstrated a good safety profile. We also needed to identify a dose and schedule of administration which could be applied in children and adolescents as well as in adults. Pamidronate had been the most widely used bisphosphonate in children and young adults (Table 2). Pamidronate has been used to treat cancer-related hypercalcemia in children38-40 Pamidronate has been used to treat fibrous dysplasia in children with the McCune-Albright syndrome.41 Pamidronate has been used to treat a teenager with multifocal Langerhans cell histiocytosis.27 Pamidronate has been used to treat osteogenesis imperfecta, including some very young children.43, 45 Pamidronate has been given to children with osteoporosis resulting from a variety of etiologies.46 Pamidronate has been safely given simultaneously with chemotherapy to children with acute lymphocytic leukemia (ALL).44 Although other bisphosphonates were in clinical use, this drove our selection of this agent for this clinical trial.
Table 2. Pamidronate Experience in Pediatrics
|2000||Fibrous dysplasia41||—||0.5-1 mg/kg q.d. x3 d||q 6mo|
|2001||Langerhans cell histiocytosis42||14||2 mg/kg q.d. x3 d||q 1mo|
|2002||Osteogenesis imperfecta43||1-16||0.25-1 mg/kg q.d. x3 d||q 2-4mo|
|2001||ALL44||3-16||1 mg/kg q.d. x3 d||q 3mo|
The purpose of this trial was to determine whether pamidronate can safely be given in conjunction with chemotherapy to young patients with osteosarcoma. We wished to determine the feasibility of this approach and to determine whether the combination of chemotherapy with pamidronate results in increased toxicity or in decreased efficacy against tumor. We wished to assess the ability of pamidronate to improve the survival of endoprosthetic reconstruction.
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- MATERIALS AND METHODS
- CONFLICT OF INTEREST DISCLOSURES
Successful treatment for osteosarcoma requires the combination of effective systemic therapy and surgery to remove all sites of clinically detectable disease. One treatment strategy for osteosarcoma is to administer chemotherapy, followed by definitive surgical resection of primary tumor and metastatic disease if necessary, followed by additional adjuvant chemotherapy. A second strategy is primary definitive surgery followed by adjuvant chemotherapy. Different combinations of the 4 active chemotherapy drugs have been used in both strategies. Large trials from single institutions and cooperative groups have achieved similar outcomes.1, 8, 49-51 We need to identify new agents and treatment strategies.
The bisphosphonates are good candidates to employ in the treatment of osteosarcoma. Osteosarcoma cells demonstrate upregulation of many genes whose normal functions are to participate in osteogenesis and whose functions can be inhibited by bisphosphonates. In addition, evidence is accruing that bisphosphonates may have the ability to interfere with the processes used by tumor cells to establish metastases. The treatment of osteosarcoma requires surgical resection of tumor-bearing bone and reconstruction of the resected area with metal or bone graft. Osteosarcoma occurs predominantly in young patients and long-term survival of the reconstruction is essential. Bisphosphonates may improve the outcome for osteosarcoma by direct antitumor effects, decreasing the risk of metastasis, and improving the durability of reconstruction following tumor resection.
Our experience represents a pilot study with a single bisphosphonate, pamidronate. We chose pamidronate because there was prior experience with pamidronate in children with cancer. Newer bisphosphonates, such as zoledronate, are significantly more potent than pamidronate. There are more data from preclinical studies for zoledronate in osteosarcoma than for any other bisphosphonate. Future clinical trials of bisphosphonates in osteosarcoma will almost certainly employ zoledronate. It is important to recognize that although zoledronate is more potent than pamidronate, it is also associated with a greater risk of osteonecrosis of the jaw, a significant risk associated with bisphosphonate therapy.52 Its risk in young children with deciduous teeth is unknown.
We treated 40 patients with conventional chemotherapy for osteosarcoma and pamidronate. Given the limitations of small patient sample and limited duration of follow-up, we observed no statistically significant increase in toxicity. We saw no osteonecrosis of the jaw. We believe that pamidronate can safely be incorporated into a multiagent chemotherapy regimen for the treatment of osteosarcoma. If zoledronate replaces pamidronate in the treatment strategy, then we will need to acquire similar safety data. We observed EFS and overall survival for our patients very similar to our prior experience and to the published experience in the literature for similar chemotherapy treatment regimens. This was a small single-arm study that included both localized and metastatic patients. We cannot draw any firm conclusions about the impact of pamidronate on the efficacy of treatment for osteosarcoma, but pamidronate does not appear to have impaired the outcome.
In a series of 108 patients with primary bone sarcoma treated at MSKCC, 15 (14%) patients suffered fractures during treatment.53 These children remain at risk for osteoporosis and insufficiency fractures throughout their lifetimes. Treatment-related osteopenia is an under-recognized problem in young patients receiving chemotherapy.54 In adults with osteoporosis, treatments with bisphosphonates resulted in a 50% decrease in fracture rates after 1 year of treatment. These adults achieved bone mass gains of 2-4% per year during the first 4 years of treatment. Even more devastating for these patients, pathologic fractures through a tumor can affect survival and local recurrence rates. In a multicenter, retrospective, matched-control review, patients with osteosarcoma and a pathologic fracture had a 5-year survival rate of 55% compared with 77% for patients without fracture. Local recurrence at 5 years was also increased in the group with pathologic fractures (25% compared with 4%).55
Most patients with osteosarcoma undergo limb-preserving surgical resection with insertion of an endoprosthesis. During chemotherapy, ingrowth into the surface of these prostheses is delayed. Aseptic loosening, with poor bone/implant interface contact remains 1 of the major factors leading to the necessity for implant revision surgery. At MSKCC, 15.8% of prosthetic knee reconstructions require revision for aseptic loosening. Overall prosthesis failure-free rates were 82%, 71%, and 50% at 3, 5, and 10 years, respectively, after initial implantation.56 At the University of California at Los Angeles (UCLA), 11.6% of hip prostheses required revision for aseptic loosening or fatigue failure, and failure-free survival at 7 years was 69%.57 Even recent uncemented prostheses and implants with novel Compression fixation have 12% early failure by 5 years.58 Currently, young patients who survive osteosarcoma can anticipate multiple revisions of their prostheses during their lifetime. Bisphosphonate therapy may contribute to improved prosthetic longevity by several mechanisms including 1) improved bone density and strength, 2) promoting more robust bone ingrowth into porous surfaces of uncemented prostheses, and 3) stabilization of the bone-prosthesis or bone-cement interface retarding osteoclastic bone resorption stimulated by particulate-wear debris. Bisphosphonates improve the fixation interface and can be predicted to improve failure-free implant survival.
We observed a high rate of successful osteointegration of endoprosthetic reconstructions and union following allografts. Overall durability of reconstructions has been good. We did not formally evaluate bone density in patients receiving pamidronate; such prospective evaluation in future trials of more potent bisphosphonates such as zoledronate may provide additional information on the usefullness of bisphosphonates in patients with sarcomas receiving therapy associated with an increased risk of osteopenia. Again, the limitations of a small single-arm study preclude firm conclusions, but these outcomes compare favorably with our prior institutional experience.
Our experience with pamidronate and chemotherapy for the treatment of osteosarcoma suggests that we can safely incorporate pamidronate with chemotherapy. It suggests the efficacy of therapy is comparable to our prior experience. It suggests that bisphosphonates may improve the durability of reconstruction. These results provide feasibility data, support, and justification for a prospective randomized trial of the addition of bisphosphonates to chemotherapy for the treatment of osteosarcoma. It seems appropriate that such a trial should use a newer, more potent bisphosphonate than pamidronate, such as zoledronate. The use of zoledronate will require vigilant monitoring for toxicity.