Factors
Clinical factors
Metastatic disease at presentation
Patients who have metastases at the time of presentation indicative of a poor prognosis
Tumor necrosis after chemotherapy
Good response to chemotherapy (>90 % tumor necrosis) is suggestive of a good survival
Tumor location
Truncal tumors appears to be indicative of a poor prognosis
Tumor suppressor genes
Rb gene
Loss of heterozygosity at the Rb locus is a predictor of poor outcome
Oncogene
ErbB2
Overexpression was correlated with decreased event-free survival
Increased levels of ErbB2 was associated with good survival
Angiogenesis
VEGF
Patients with high serum VEGF had poor survival
Immunology
PBF
PBF-positive osteosarcoma conferred poorer prognosis
Cyclooxygenase inhibitor
COX-2
Patients with strong COX-2 expression had a poor prognosis
6.2 Clinical Prognostic Factors
The single most predictive factor in osteosarcoma is the presence or absence of detectable metastatic disease at presentation. As mentioned, the survival rate for patients who have metastases at the time of presentation is between 10 and 20 % [1, 2]. Those who present with bone or skip metastases fare even worse [3, 4]. The degree of tumor necrosis after neoadjuvant chemotherapy is also an important prognostic factor. Patients who have tumors with a good response to chemotherapy (>90 % tumor necrosis) have a considerably better long-term survival rate than those who have tumors with a poor response (<90 % tumor necrosis) [5–7]. The response to chemotherapy is commonly assessed by histological analysis, although it is difficult to evaluate the chemotherapeutic effects before tumor excision. Miwa et al. evaluated the impact of various radiological examinations on overall survival and event-free survival. They concluded that 99mTc-MIBI scintigraphy and combined radiological score (CRS) could be considered as significant predictor of overall survival and event-free survival [8]. Large tumor size has been implicated as a negative prognostic indicator in several studies; however, inconsistent methods of determining size in these studies make it difficult to ascertain its true influence. Other poor prognostic variable was patient’s age at diagnosis. The prognosis of elderly patients was generally considered to be worse compared to those of the young patients. Iwata et al. conducted the multi-institutional retrospective study to investigate clinical features and prognostic factors in patients older than 40 years with osteosarcoma. They demonstrated the distinct clinical features, such as the high incidence of truncal tumors or metastasis at diagnosis, in patients older than 40 years with osteosarcoma. Additionally, prognostic factor analyses revealed that tumor site, metastasis at diagnosis, definitive surgery, and surgical margins were significant prognostic factors, whereas chemotherapy did not influence survival [9]. A tumor located in the pelvis, proximal part of the femur, or proximal part of the humerus also appears to be indicative of a poor prognosis [10].
6.3 Molecular and Genetic Considerations
6.3.1 Tumor Suppressor Genes
A tumor suppressor gene is any gene that by its loss of function contributes to the pathogenesis or progression of a tumor. This can occur at the level of the gene or at the level of the protein for which it codes. Often, tumor suppressors function as cell-cycle regulators. The hallmark of a putative suppressor gene is loss of the genetic material coding for a protein that is important in the regulation of the cell cycle or its proliferation. The known tumor suppressor gene p53 and the retinoblastoma (Rb) gene are the most frequently mutated in osteosarcoma (mutated in 25–80 %) and are localized to chromosome arm 17p and 13q, respectively [11].
The retinoblastoma (Rb) gene was the first characterized tumor suppressor gene. It acts as a negative transcriptional regulator of genes involved in the cell-cycle progression from G1 to S phase. Loss of this function allows cells to progress through the cell cycle unchecked. Allele loss of the Rb gene has been reported in approximately 50–60 % of osteosarcomas [11]. A recent study has demonstrated that loss of heterozygosity at the Rb locus on chromosome arm 13q is a predictor of poor outcome in patients with osteosarcoma [12].
6.3.2 Oncogenes
The effect of oncogenes on tumorigenesis is different from that of tumor suppressors in that mutation of a normal proto-oncogene to an oncogene confers a gain of function, as opposed to a loss, driving the cell toward a malignant phenotype.
Her2/erbB-2 is a cellular proto-oncogene that encodes the human epidermal growth factor receptor 2 (Her2). Overexpression of this oncogene induces malignant transformation of rodent fibroblasts and has been implicated in decreased survival of patients with breast carcinoma. Recently, two studies have shown overexpression in approximately 40 % of the osteosarcomas and a correlation with decreased event-free survival and histological response to neoadjuvant chemotherapy [13, 14]. With the development of additional prospective studies, the presence of the Her2/erbB-2 receptor eventually may emerge as a significant prognostic indicator. In contrast, Akatsuka et al. demonstrated that the presence of increased levels of ErbB2 in tumor cells was associated with a significantly increased probability of event-free and overall survival in patients with high-grade osteosarcoma without metastatic disease at presentation and treated with surgery and chemotherapy [15].
The MDM2 gene codes for a p53 binding protein and is located on chromosome arm 12q13, a region that is often amplified in a variety of sarcomas. It has the ability to inhibit the transcriptional activity of p53, providing an alternative pathway of p53 inactivation. MDM2 has been found to be amplified in approximately 4–7 % of osteosarcomas. It is marginally associated with locally recurrent and metastatic disease but cannot be used currently as a prognostic marker [16].
6.4 Angiogenesis
One of the most interesting topics in cancer therapy is that of anti-angiogenesis. Very little work on sarcomas has been done in this field. Anti-angiogenic agents have been shown to inhibit tumor growth and cause tumor regression in mouse models [17]. There are currently many anti-angiogenic agents being tested in Phase I and II clinical trials of their effects on human cancers. Two of the targets of these trials are vascular endothelial growth factor and its receptors. Kaya et al. recently demonstrated expression of vascular endothelial growth factor in 17 (63 %) of 27 osteosarcomas [18]. They also correlated this expression with a high prevalence of pulmonary metastasis, suggesting that expression of vascular endothelial growth factor may play a role in the metastatic cascade of osteosarcoma [18]. Kaya et al. also evaluated the prognostic significance of the serum levels of vascular endothelial growth factor (VEGF) in predicting the survival of patients with osteosarcoma prospectively. Patients with a serum VEGF >1000 pg/ml had significantly worse survival than those with a level <1000 pg/ml (p = 0.002). They concluded that serum VEGF level might be useful in predicting the prognosis for survival in patients with osteosarcoma [19]. It may also become a treatment target, and anti-angiogenic therapy using antivascular endothelial growth factor antibody and a vascular endothelial growth factor receptor inhibitor is expecting to offer a potentially useful strategy for lung metastasis from osteosarcoma. This was supported by the experimental research work by Tanaka et al. They demonstrated that disruption of the vascular barrier and transendothelial migration of syngeneic mouse spontaneous highly metastatic osteosarcoma cell line LM8 is dependent, at least one part, on VEGF [20]. They also demonstrated that daily oral administration of pazopanib reduced the rate and size of pulmonary metastasis in vivo [20].