Abstract
Sarcomas are cancers arising from the mesenchymal layer that affect children, adolescents, young adults, and adults. Although most sarcomas are localized, many display a remarkable predilection for metastasis to the lungs, liver, bones, subcutaneous tissue, and lymph nodes. Additionally, many sarcoma patients presenting initially with localized disease may relapse at metastatic sites. While localized sarcomas can often be cured through surgery and often radiation, controversies exist over optimal management of patients with metastatic sarcoma. Combinations of chemotherapy are the most effective in many settings, and many promising new agents are under active investigation or are being explored in preclinical models.
(...)Risk factors
Sarcoma most typically presents spontaneously without a demonstrable cause. However, several risk factors have been associated with its development, including exposure to radiation and chemotherapeutic agents, viral infections, occupational factors, hereditary syndromes, certain diseases, and hormones.
Radiation and chemotherapeutic agents
Ionizing radiation has been consistently reported to be associated with increased risk of bone and STS of up to 1%. In children, studies have shown increased risk after high-dose fractionated radiation exposure (>10 Gy), which increases approximately linearly in dose until about 40+ Gy.
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MPNST
In 2005–2009, MPNST affected 220 people per year in the USA, accounting for 1.8% of all STS.136Distant metastasis has been shown in 35 (42%) of 84 patients with pathologically confirmed MPNST from 1999 to 2011.149 MPNST presents in the context of neurofibromatosis type 1 (NF1) in about half of patients and occurs spontaneously in the other half. NF1 typically is identified either by family history or characteristic skin findings such as café au lait macules, axillary freckling, and/or multiple cutaneous neurofibromas. NF1 affects 1 in 3500 people and is characterized by a mutation in NF1, a tumor suppressor gene whose protein product, neurofibromin, is an RAS-GTPase activating protein, which negatively regulates RAS.150–153 MPNST occurs with a 10% incidence in patients with NF1 and derives from a known precursor lesion, the deep neurofibroma.154
Current therapy
Therapy for MPNST is similar to that of most adult type STS in the first-line setting, although it tends to be one of the more chemoresistant histologies and has a poorer prognosis than other histologies.155,156An active clinical trial is incorporating etoposide into frontline therapy to establish the response rate and natural history of this malignancy (NCT00304083). Because NF1 patients often have more than one mass and because there are no reliable characteristics that distinguish benign neurofibroma from MPNST by computerized tomography or magnetic resonance imaging, positron emission tomography is particularly useful in distinguishing benign from malignant disease.157
Emerging therapies
MPNST associated with NF1 may represent a targetable malignancy with known RAS pathway activation. Although additional molecular changes are also necessary for oncogenesis, an interesting anecdote supporting the homogeneity MPNST development is a case of monozygous twins with remarkably similar phenotypes.158 Constitutive activation of the RAS/RAF/MEK/ERK pathway through biallelic loss of function of neurofibromin is a uniform and critical event in MPNST pathogenesis.159,160 mTOR inhibitors have been studied alone in clinical trials for plexiform neurofibromas and in combination for MPNST (NCT01412892). No targeted agent has thus far demonstrated activity to replace the standard of care, although a combination of the mTOR inhibitor everolimus and the anti-angiogenic agent bevacizumab are being explored (NCT01661283). Based on the current knowledge of neurofibromatosis and MPNST, it could be predicted that inhibiting pathways downstream of RAS such as MEK/ERK and PI3K/AKT/mTOR may be promising therapeutic strategies.161–166
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Conclusion
There is considerable diversity in pathophysiology, current and emerging therapies, and outcome for pediatric and young adult patients with metastatic sarcoma. Some subtypes, such as alveolar rhabdomyosarcoma, Ewing sarcoma, and synovial sarcoma, are well defined in regard to translocations in a majority of cases; however, events that lead to osteosarcoma and embryonal rhabdomyosarcoma are less well understood. Many patients with MPNST have a uniform first hit of a neurofibromin mutation.
Overall, the burden of disease correlates with prognosis in general. When local control is not possible, patients often have a poor prognosis. Patients who can have all areas of disease addressed by surgery or radiation to visible disease often have the best outcomes. Because of years of collaborative studies on these rare tumors, there is a well-established tumor-specific systemic therapy regimen for each histologic type. These tumors are excellent candidates for novel approaches with additional agents as they affect a portion of the population that is motivated toward curative therapy and have demonstrated that they are chemosensitive. Combinations of chemotherapy are the most effective in most settings, and many promising new agents are under active investigation or are being explored in preclinical models. There is a plethora of opportunities to explore these therapies. Ideally, clinical trials will explore multiple promising agents, be studied in a context where historical outcome is known, and will be used for a specific clinical context for a single histology.
Published online 2013 May 16. doi: 10.2147/CLEP.S28390
Source: National Center for Biotechnology Information
