Approximately 900 new cases of osteosarcoma (OS) are reported each year in the United States.1 It is a malignant cancer of the bone with a high incidence in children and adolescents.2 OS can also occur in adults aged 60 years and above and is usually caused by malignant transformation of other noncancerous bone diseases.3 Morphologically characterized by the presence of osteoid-producing spindle cells, the disease can originate in any bone structure but is commonly seen in metaphyseal portion of long bones including the distal femur, proximal humerus, and proximal tibia.4
Risk factors that are associated with OS include prior radiation treatment, Paget’s disease, and certain heritable genetic defects.4 Children treated with radiation therapy for solid cancer often suffer from OS as a secondary cancer later in life.4 OS cases originating from Paget’s disease (a disorder of bone metabolism resulting in impairment of bone formation and bone resorption) result in poor treatment outcomes. Patients with germline mutation of genes such as TP53 (p53), RB (retinoblastoma), and RECQL4 are also predisposed to OS.4
OS is presented with localized, reproducible pain and inflammation in the affected area.4 Initially, pain is activity related, but as the disease progresses, pain is felt at rest and at night. Macroscopic metastases are usually observed in 20% of cases during presentation. The most common sites of metastasis are the lungs and bones.4 With the combination of aggressive surgery and systemic chemotherapy, about 70% of the localized cases of OS can achieve a long-term remission from the disease. However, patients with overt metastases and recurrent conditions usually do not respond to current treatment options, resulting in a fatal prognosis.4
Over the past 20 years, the survival rate of patients with OS has essentially been static. Therefore, novel therapeutic strategies including site-specific drug delivery have been explored to attain a better therapeutic outcome for the disease. In this article, an update on the cytotoxic anticancer agents currently used in OS and the recent drug development initiatives in this area will be discussed.
Currently Used Cytotoxic Agents
Current treatment protocol includes preoperative chemotherapy and surgical resection followed by postoperative chemotherapy.4 The chemotherapy regimen most commonly employed includes a combination of high-dose methotrexate, doxorubicin (adriamycin), and cisplatin, which is known as the MAP regimen (TABLE 1).4 Other agents that are inconsistently used include etoposide and ifosfamide; detailed discussion of these latter agents is beyond the scope of this article.
Methotrexate is a folic acid derivative that inhibits dihydrofolate reductase (DHFR), a key enzyme in cellular metabolism, which converts dihydrofolate to tetrahydrofolate. Methotrexate-mediated depletion of the intracellular tetrahydrofolate pool impairs de novo biosynthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine.5 Overall, this antifolate drug markedly impairs DNA, RNA, and protein biosynthesis.
Cisplatin (cis-diamminedichloroplatinum[II]) is an inorganic metal complex that acts in similar fashion to a DNA alkylating agent. Cisplatin binds with DNA and forms intra- and interstrand crosslinks resulting in inhibition of DNA synthesis and function.5 The primary DNA binding site of cisplatin is N7 of guanine, although it can also bind to cytosine and adenine bases. Cisplatin can also bind to cytosolic and nuclear proteins of the cancer cells, which may contribute to its antitumor effects.5
Chemically, doxorubicin consists of an anthracycline backbone. It is an anticancer antibiotic that exerts its anticancer effects by the following mechanisms: 1) intercalation of DNA bases resulting in inhibition of DNA and RNA replication; 2) inhibition of topoisomerase-II, an enzyme associated with unwinding of the double-helix structure of DNA; 3) generation of free radicals; and 4) alteration of fluidity and ion transport of cells by binding to the cell membrane.5 In osteosarcoma, doxorubicin is administered at a dosage of 75 mg/m2 per course.6 Methotrexate is administered at a dosage of 12g/m2 along with leucovorin rescue (15 mg/dose) to protect noncancerous cells from cytotoxicity.6 Cisplatin dosage per course is 120 mg/m2.6
Challenges Associated With the Use of Current Chemotherapy: Rare Toxicity and Drug Resistance
In addition to the common adverse effects of myelosuppression, nausea, vomiting, and alopecia, cytotoxic agents used in OS display agent-specific rare toxicities as discussed in the following paragraphs.
Neurotoxicity: Neurologic manifestations associated with high-dose methotrexate treatment have been reported in patients with OS.7,8 Central nervous system (CNS) adverse effects of methotrexate in these patients include inappropriate laughter, coma, lethargy, aphasia, cortical blindness, paresis, and seizures.7,8 Onset of methotrexate-induced neurologic symptoms is transient and usually does not recur.
Nephrotoxicity: Cisplatin-mediated nephrotoxicity includes decreased glomerular filtration, electrolyte disturbances, and damage of renal tubular epithelial cells.6 Hypomagnesemia has been reported in 90% of patients receiving cisplatin therapy.9 In addition to hypomagnesemia, cisplatin can cause hypokalemia and hypocalcemia due to altered renal function and electrolyte losses.6 In acidic pH, methotrexate and its metabolites can precipitate in renal tubules of the kidney, causing renal insufficiency and failure.6 Adequate hydration and alkalinization of urine can markedly decrease methotrexate nephrotoxicity. In OS patients, hemodialysis is partially effective in reducing the toxic serum concentration of methotrexate.10
Cardiotoxicity: This is a serious, dose-limiting adverse effect associated with doxorubicin, which can range between asymptomatic cardiac dysfunction and severe congestive heart failure.6 In patients with OS, incidences of severe cardiotoxicity occur at a rate of 4%.11 Dexrazoxane is a free-radical scavenger that is used to neutralize the deleterious effects of doxorubicin on cardiac tissues. OS patients treated with a combination of dexrazoxane and doxorubicin demonstrated a better left ventricular (LV) systolic function compared to those receiving doxorubicin only, although the occurrence of systolic dysfunction was similar among groups.12
Ototoxicity: Cisplatin-induced ototoxicity (“ear poisoning”) is usually irreversible, with a gradual loss of hearing over time.6 In animal studies, the platinum compound selectively destroys auditory hairy cells and spiral ganglion cells.6 Cisplatin, when administered as a single dose of 120 mg/m2 to patients with OS, has a significantly higher rate of ototoxicity than when the drug is administered as two doses of 60 mg/m2 given 24 hours apart.13
Infertility: In a European study, ifosfamide (a DNA alkylating agent) along with the MAP combination caused early menopause in approximately 6% of postpubertal female patients with OS.14 In a retrospective study from the same institution, semen analysis was performed in OS survivors who received prior chemotherapy. Of patients tested, 50% who received the MAP regimen had azoospermia (no detectable sperm) compared to 88% who received ifosfamide along with the MAP regimen.15
Second Malignant Neoplasm: In one study, second malignant neoplasm was reported in 2% of patients with OS who received adjuvant and neoadjuvant chemotherapy.16 Examples of second malignant neoplasms observed in these patients include leukemia and cancers of the breast, lung, and kidney.16
Chemotherapy Resistance: Chemotherapy resistance has always been a major obstacle in the treatment of different cancers, including OS. Recent studies have shed some light on chemotherapy resistance in OS. For example, resistance to cisplatin is associated with the loss of p53 function as well as expression of multidrug resistance-associated protein 2 (MRP2).17,18 Decreased cellular accumulation of doxorubicin in OS cells results from an increased expression of efflux protein (i.e., multidrug resistance protein 1 [MDR1]).19 However, amplification of the DHFR gene and decreased expression of the reduced folate carrier are associated with methotrexate resistance.20,21
Investigational Agents in OS
There are several drugs currently being evaluated in the treatment of OS; a summary can be found in TABLE 2.
Cytotoxic Agents: The Children’s Oncology Group in the U.S. and several other European cooperative groups has launched a randomized control trial, EURAMOS-1, to determine whether inclusion of ifosfamide and etoposide (a DNA topoisomerase-II inhibitor) to a postoperative MAP regimen in poor responders (>10% viable tumor) will improve event-free and overall survival. EURAMOS-1 will also determine whether addition of pegylated interferon-alfa to a postoperative MAP regimen will improve event-free and overall survival in good responders (<10% viable tumor).6
The combination of gemcitabine and docetaxel has been assessed in patients with OS. Gemcitabine is a fluorine-substituted deoxycytidine analogue that inhibits ribonucleotide reductase, reducing levels of the deoxynucleotide triphosphates (dNTPs) necessary for DNA synthesis. Furthermore, it also inhibits DNA polymerases and incorporates into DNA, leading to inhibition of DNA synthesis and function.5 Docetaxel, a semisynthetic taxane, acts as a mitotic inhibitor. The drug binds to microtubules with high affinity and enhances polymerization of stable, but dysfunctional, microtubules.5
Twenty-two patients (age range 8-23 years) with recurrent soft-tissue and bone sarcoma received 109 courses of gemcitabine and docetaxel.22 Gemcitabine was administered at a dose of 675 mg/m2 IV on days 1 and 8 while docetaxel was administered on day 8 at a dose of 75 to 100 mg/m2.22 While partial response was achieved in three patients with OS, stable disease was reported in one additional patient. Adverse effects were limited to thrombocytopenia and neutropenia.22
In another medical report review of patients with soft-tissue and bone sarcoma, an overall response rate of 43% was observed in 35 cancer patients who received the gemcitabine-docetaxel combination.23 In this report, gemcitabine was administered at a dosage of 675 mg/m2 IV over 90 minutes on days 1 and 8 of a 21-day cycle, whereas the dosage of docetaxel used was 100 mg/m2 IV infused over 60 minutes on day 8.23 Of the four patients with OS, two attained partial response while the other two patients were stabilized.23
Trimetrexate, a structural analogue of methotrexate, has the added advantage of easily getting transported into cancer cells without the requirement of reduced folate carrier protein, which is an absolute requirement for methotrexate transport into OS cells.4 A phase I trial of combination high-dose methotrexate and trimetrexate in patients with recurrent OS has recently been completed.4 The rationale behind this study was that trimetrexate would affect the transport-resistant OS cells, while methotrexate’s effect would be on OS cells where folate transport is intact.4 The results of this trial are not yet available.
IGF-1 Signaling: Insulin-like growth factor type 1 (IGF-1) is a potent mitogen in OS cells.24 IGF-1 receptor (IGF-1R), a dimeric receptor kinase, consists of two extracellular alpha-subunits and two transmembrane beta-subunits.25 Activation of IGF-1R sequentially activates downstream signaling elements associated with cell proliferation and antiapoptotic pathways.25 At least six antibodies against this receptor are currently being evaluated against different malignant diseases, including OS.
In a preclinical study, SCH 717454, an IGF-1R antibody treatment in mice, resulted in a complete response in two OS xenografts.26 A phase II clinical trial of SCH 717454 evaluating patients with OS and Ewing’s sarcoma is currently in progress. Optimal doses of IGF-1R antibody R1507 in children with recurrent or relapsed solid tumors were found to be 9 mg/kg/wk and 16 mg/kg every 3 weeks.27 Seven out of 31 evaluable patients were stable for >12 weeks, including two patients with OS stabilized for at least 52 weeks.27 Two out of 24 patients with refractory solid tumors attained prolonged stabilization in a phase I study with IGF-1R antibody CP-751,871.28
mTOR Inhibition: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a key role in intracellular signaling associated with cell proliferation and growth by phosphorylating target molecules.4 Rapamycin, temsirolimus, everolimus, and ridaforolimus (AP23573) are specific inhibitors of mTOR and may affect abnormal cell growth. For example, rapamycin, a widely used immunosuppressant, inhibits metastases in animal models of OS.4 A phase II study reported 30% of patients with soft-tissue sarcomas and OS attaining partial response or stable state for 16 weeks when treated with 12.5 mg ridaforolimus, 5 days every 2 weeks.29 Most frequent adverse effects were mucositis, rash, hyperlipidemia, fatigue, and thrombocytopenia.29 Studies with other rapalogues are under way.
Ras Pathways: Reovirus is a naturally occurring virus that is relatively harmless in humans but can grow in cells where Ras pathways are activated. Activated Ras pathways inhibit the antiviral effects of a cellular kinase (PKR; double-stranded RNA-activated protein kinase), rendering tumor cells to viral replication and lysis. Reolysin is an IV formulation of reovirus serotype 3 dearing strain used to treat different cancers. In a phase II open-label, single-agent study, Reolysin was administered every 28 days in patients with bone or soft-tissue sarcoma with lung metastasis.30 Preliminary data suggest that reovirus was well-tolerated, with 5 out of 33 patients attaining stable disease for >6 months.30
Vascular Endothelial Growth Factor (VEGF) Inhibition: Cediranib, an orally active pan-VEGF inhibitor, was evaluated in children and adolescents with extracranial solid tumors.31 VEGF is a glycoprotein that promotes angiogenesis needed for growth and metastasis of solid tumors. The dosage in this study population was determined to be 12 mg/m2/day, once daily continuously by oral route.31 Dose-limiting toxicities include grade 3 nausea, diarrhea, and fatigue. Objective responses were observed in patients with different sarcomas, including OS.31
Delivery Systems: To prevent pulmonary relapse, patients with OS were treated with sustained-release lipid inhalation targeting (SLIT) cisplatin, a liposomal preparation of the drug administered by inhalation.32 In a two-center, open-label, phase Ib/IIa study, 14 patients with OS received either 24 mg/m2/dose or 36 mg/m2/dose of cisplatin for over a year.32 Two patients with OS were pulmonary-disease free for a year following initiation of therapy.32 This novel delivery system was well tolerated, with common adverse effects being nausea and respiratory symptoms. The patients did not experience any hematologic toxicity, nephrotoxicity, or peripheral toxicity because of site-specific delivery of the drug.
Pegylated-liposomal doxorubicin was evaluated in patients with different sarcomas including OS in a phase II trial with an initial dosage of 55 mg/m2 per 4-week course.33 Important toxic effects reported were mucositis and hand-foot syndrome.33 Though dose reduction was necessary during the trial, no cardiotoxicity of doxorubicin was observed. Fifteen out of 47 patients benefitted from this intervention.33
Granulocyte-macrophage colony-stimulating factor (GM-CSF), when administered in patients with first lung recurrence of OS at a dose range of 250 to 1,750 mcg twice daily by inhalation on alternate weeks pre- and postthoracotomy, did not produce any major adverse effects.34 The immunomodulatory effects, however, were not observed in these patients.
Miscellaneous Agents: To determine anticancer effects of bisphosphonates, pamidronate was administered at a dosage of 2 mg/kg/dose for 12 doses in 40 patients with OS who were on a MAP regimen.35 The addition of pamidronate was safe and did not interfere with the regimen.35 The agent appears to be useful in limb reconstruction following surgery.35 Its role as an anticancer agent needs to be determined in future studies.
Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a liposomally encapsulated analogue of an immunologic component of the bacille Calmette-Guérin (BCG) cell wall.36 MTP-PE is believed to activate monocytes and macrophages against OS cells.36 Overall survival was improved in patients with OS following addition of MTP-PE to a standard chemotherapeutic regimen. A positive trend toward event-free survival was also observed.36
Patients with osteosarcoma are currently being treated with resective surgery and chemotherapy. Although successfully implemented in localized disease, this treatment option is virtually ineffective in patients with metastatic conditions. In this regard, novel therapeutic agents are being investigated to achieve a better therapeutic outcome along with the reduction of adverse events. Development of targeted, site-specific therapy will help in optimizing patient care in OS.
1. Osteosarcoma. What are the key statistics about osteosarcoma? American Cancer Society.
osteosarcoma-key-statistics. Accessed September 9, 2011.
2. Arndt CA, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med. 1999;341:342-352.
3. Mirabello L, Troisi RJ, Savage SA. International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int J Cancer. 2009;125:229-234.
4. Geller DS, Gorlick R. Osteosarcoma: a review of diagnosis, management, and treatment strategies. Clin Adv Hematol Oncol. 2010;8:705-718.
5. Chu E, Sartorelli AC. Katzung’s Basic and Clinical Pharmacology. 11th ed. New York, NY: McGraw Hill Lange; 2009.
6. Janeway KA, Grier HE. Sequelae of osteosarcoma medical therapy: a review of rare acute toxicities and late effects. Lancet Oncol. 2010;11:670-678.
7. Packer RJ, Grossman RI, Belasco JB. High dose systemic methotrexate-associated acute neurologic dysfunction. Med Pediatr Oncol. 1983;11:159-161.
8. Jaffe N, Takaue Y, Anzai T, et al. Transient neurologic disturbances induced by high-dose methotrexate treatment. Cancer. 1985;56:1356-1360.
9. Lajer H, Daugaard G. Cisplatin and hypomagnesemia. Cancer Treat Rev. 1999;25:47-58.
10. Widemann BC, Balis FM, Kempf-Bielack B, et al. High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma. Cancer. 2004;100:2222-2232.
11. Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000;18:4016-4027.
12. de Matos Neto RP, Petrilli AS, Silva CM, et al. Left ventricular systolic function assessed by echocardiography in children and adolescents with osteosarcoma treated with doxorubicin alone or in combination with dexrazoxane. Arq Bras Cardiol. 2006;87:763-771.
13. Lewis MJ, DuBois SG, Fligor B, et al. Ototoxicity in children treated for osteosarcoma. Pediatr Blood Cancer. 2009;52:387-391.
14. Longhi A, Pignotti E, Versari M, et al. Effect of oral contraceptive on ovarian function in young females undergoing neoadjuvant chemotherapy treatment for osteosarcoma. Oncol Rep. 2003;10:151-155.
15. Longhi A, Macchiagodena M, Vitali G, et al. Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol. 2003;25:292-296.
16. Bacci G, Ferrari C, Longhi A, et al. Second malignant neoplasm in patients with osteosarcoma of the extremities treated with adjuvant and neoadjuvant chemotherapy. J Pediatr Hematol Oncol. 2006;28:774-780.
17. Itoh Y, Tamai M, Yokogawa K, et al. Involvement of multidrug resistance-associated protein 2 in in vivo cisplatin resistance of rat hepatoma AH66 cells. Anticancer Res. 2002;2:1649-1616.
18. Fan J, Bertino JR. Modulation of cisplatinum cytotoxicity by p53: effect of p53-mediated apoptosis and DNA repair. Mol Pharmacol. 1999;56:966-972.
19. Susa M, Iyer AK, Ryu K, et al. Inhibition of ABCB1 (MDR1) expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma. PLoS One. 2010;5:e10764.
20. Serra M, Reverter-Branchat G, Maurici D, et al. Analysis of dihydrofolate reductase and reduced folate carrier gene status in relation to methotrexate resistance in osteosarcoma cells. Ann Oncol. 2004;15:151-160.
21. Guo W, Healey JH, Meyers PA, et al. Mechanisms of methotrexate resistance in osteosarcoma. Clin Cancer Res. 1999;5:621-627.
22. Navid F, Willert JR, McCarville MB, et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008;113:419-425.
23. Leu KM, Ostruszka LJ, Shewach D, et al. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol. 2004;22:1706-1712.
24. Pollak MN, Polychronakos C, Richard M. Insulinlike growth factor 1: a potent mitogen for human osteogenic sarcoma. J Natl Cancer Inst. 1990;82:301-305.
25. Li R, Pourpak A, Morris SW. Inhibition of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase as a novel cancer therapy approach. J Med Chem. 2009;52:4981-5004.
26. Kolb EA, Gorlick R, Houghton PJ, et al. Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;50:1190-1197.
27. Bagatell R, Herzog CE, Trippett TM, et al. Pharmacokinetically guided phase 1 trial of the IGF-1 receptor antagonist RG1507 in children with recurrent or refractory solid tumors. Clin Cancer Res. 2011;17:611-619.
28. Haluska P, Shaw HM, Batzel GN, et al. Phase I dose escalation study of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Clin Cancer Res. 2007;13:5834-5840.
29. Chawla SP, Tolcher AW, Staddon AP, et al. Updated results of a phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas. J Clin Oncol. 2006;24:A9505.
30. Mita AC, Sankhala K, Sarantopoulos J, et al. A phase II study of intravenous (IV) wild-type reovirus (Reolysin) in the treatment of patients with bone and soft tissue sarcomas metastatic to the lung. J Clin Oncol. 2009;27:A10524.
31. Fox E, Aplenc R, Bagatell R, et al. A phase 1 trial and pharmacokinetic study of cediranib, an orally bioavailable pan-vascular endothelial growth factor receptor inhibitor in children and adolescents with refractory solid tumors. J Clin Oncol. 2010;28:5174-5181.
32. Chou AJ, Bell MD, Mackinson C, et al. Phase Ib/IIa study of sustained release lipid inhalation targeting cisplatin by inhalation in the treatment of patients with relapsed/progressive osteosarcoma metastatic to the lung. J Clin Oncol. 2007;25:A9525.
33. Skubitz KM. Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Cancer Invest. 2003;21:167-176.
34. Arndt CA, Koshkina NV, Inwards CY, et al. Inhaled granulocyte-macrophage colony stimulating factor for first pulmonary recurrence of osteosarcoma: effects on disease-free survival and immunomodulation. A report from the Children’s Oncology Group. Clin Cancer Res. 2010;16:4024-4030.
35. Meyers PA, Healey JH, Chou AJ, et al. Addition of pamidronate to chemotherapy for the treatment of osteosarcoma. Cancer. 2011;117:1736-1744.
36. Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children’s Oncology Group. J Clin Oncol. 2008;26:633-638.
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