CTOS Op Ed |
Clinical and Molecular Prognostic Factors in Osteosarcoma
An ESUN Editorial
Editor's Note: This editorial is part of an ongoing series of Op Ed pieces written by one of the members of the Board of Directors of the Connective Tissue Oncology Society (CTOS). Dr. Letson is a member of the CTOS board. These editorials are intended to address important and controversial issues in the field. The "Questions, Comments & Counterpoint" column allows readers to express their opinions in response to these Op Ed pieces. Click here to send in an opinion.
Osteosarcoma is an aggressive disease of bone that predominantly affects young patients.1 Despite tremendous advances in diagnostic modalities, surgical procedures, and chemotherapy options, osteosarcoma confers a generally poor prognosis. Currently, the estimated 5-year survival for patients with osteosarcoma is 65 percent compared with 15 percent in the early 1960s.1 The presence of metastasis at diagnosis has a major impact on patient survival. The estimated survival rate for patients with localized osteosarcoma is about 75 percent compared to 30 percent for patients with metastatic disease.2
Several authors have shown prognostic significance of demographic and clinico-pathological variables in large population based studies.1,3,4,5 Controversy exists regarding the exact prognostic significance of tumor response to chemotherapy, tumor size and site, and the presence of metastases. Controversy also exists about the possibility of discovering novel molecular markers as clear predictors of mortality and/or response to treatment. Currently, good evidence exists for a number of molecular markers in osteosarcoma (in particular, P-glycoprotein, Her-2, CXCR4, uPA/uPAR, and survivin) as being useful both in predicting response to chemotherapy, overall prognosis, the likelihood of metastases at diagnosis, and at the same time providing targets for developing new therapeutic agents.6,7 However, these prognostic tools are not used in every institution in the United States and their real impact has not been assessed in large randomized controlled trials.
Traditional clinical factors influencing prognosis in osteosarcoma have related to the extent of invasion and the stage of tumor as described by Enneking thirty years ago.8 Additional controversial prognostic variables include the type of surgery, local recurrence, and the presence and location of metastases. In this report, we will briefly outline controversial issues in osteosarcoma prognosis relating to local recurrence, the presence of metastasis, and molecular markers.
Local Recurrence
It is widely accepted that limb-sparing surgery generally results in a slightly higher local recurrence rate but improved overall survival with the use of adjuvant therapies. However, studies such as the one by Bacci and co-investigators showed that all patients with local recurrence after limb salvage developed lung metastases at some stage in the course of disease. Regardless of treatment there was a 96% mortality in the local recurrence group, compared with 72% in those with metastases but no local recurrence.9 Similarly, Briccoli and coinvestigators showed that the 5-year survival in patients with local recurrence and lung metastases was 6% compared with 37% in patients with only metastases.10 These results suggest that the combination of local recurrence and metastasis is worse than metastasis alone. In addition, Nathan and co-investigators showed that the strongest correlation with poor prognosis was local recurrence within the first year after resection. Metastasis at the time of recurrence was statistically significant (P = 0.04) compared to local recurrence alone.11
Metastases
Pulmonary metastases found at initial diagnosis are considered to be associated with a poor outcome.8 Yonemoto and co-investigators reported conflicting results that found a 5-year survival rate of 64.8% in patients with lung metastases compared to 62.1% in patients without lung lesions at presentation.12 In addition, patients that developed pulmonary metastases after chemotherapy had a survival rate of 47.5%. Kandioler and co-investigators showed high survival rates at 5 years (48%) in patients that had two or more pulmonary metastasectomies.13 In contrast, Daw and co-investigators concluded that there was a survival advantage for patients with no more than three lung nodules, and unilateral lung metastases.14 They also observed significant survival advantages when the interval between the primary tumor resection and first metastectomy was increased. In two additional studies, Briccoli and Kandioler advocate for lung metastasectomies even after multiple recurrences.10,13 An additional controversial issue related to metastases is the occurrence of skip lesions. Sajadi and co-investigators concluded that patients with skip lesions had a particularly bad prognosis with a mean survival of 27 months. This poor prognosis does not correlate with the current AJCC staging system (stage III for skip metastases and stage IV for lung metastases). 15
Molecular Markers
The relative inaccuracy and limitations of standard prognostic markers (tumour size, and percentage necrosis post-chemotherapy), and the fact that many prognostic indicators only become apparent at a late stage in the clinical course, presents a need for more precise quantitative measures to assist in treatment planning. Table 1 summarizes the current literature regarding molecular markers in osteosarcoma.
| Factor | Action | Levels in OS | Prognostic? | Potential for Therapy? |
|---|---|---|---|---|
| VEGF | Angiogenesis | Up | Controversial 17 | Yes |
| MMP-2, MMP-9 | Extra-cellular matrix invasion | Up | Correlation 18 | Yes, good results in other cancers |
| uPA/uPAR | Increases plasmin and MMPs. Pro-invasion | Up | Correlation 19 | Yes, reduced invasion if down regulated |
| P-glycoprotein | Drug resistance. Other unidentified pathways | Up | Correlation, specific to doxorubicin therapy 20 | Undetermined |
| CXCR4 | Chemotaxis, organ-specific metastasis. Pro-invasion | Up | Correlation 21 | Yes, good evidence in mice |
| p53 | Cell cycle control | Down / mutated | Correlation 22 | Undetermined |
| ErbB-2 | Cell signalling, proliferation | Mixed results | Controversial 23 | Undetermined |
| Survivin | Inhibits apoptosis | Up | Correlation 24 | Undetermined |
| HLA class I | Absence allows immune system evasion | Down | Correlation 25 | Undetermined |
| Ezrin | Cell signalling, cell interaction, metastasis | Up | Correlation 26 | Yes, potentially using Rapamycin |
| Rb | Tumor suppressor, transcription control | Down / mutated | Correlation 27 | Undetermined |
| c-Fos | Transcription | Up | Indirect correlation 28 | Undetermined |
(Modified from Clark and co-investigators: "A review of clinical and molecular prognostic factors in osteosarcoma," in Journal of Cancer Research and Clinical Oncology, 2007)16
Final Comments
Identifying valid prognostic factors in osteosarcoma is of paramount importance for several reasons. Osteosarcoma is characterized by an overall poor prognosis that has not changed significantly since the introduction of chemotherapy in the 1970s. Further study in this area will allow clinicians to provide a more informed outlook to the patient and their family. In addition, it will determine the combination of treatment and the aggression to which this treatment is implemented from an earlier stage in the disease. Also, the identification of key prognostic factors provides a more accurate target on which to focus anti-cancer research.
References
1. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jürgens H, Winkler K (2002) Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20(3):776–790
2. Yonemoto T, Tatezaki S, Ishii T, Satoh T, Kimura H, Iwai N (1998) Prognosis of osteosarcoma with pulmonary metastases at initial presentation is not dismal. Clin Orthop Relat Res 349:194–199
3. Davis AM, Bell RS, Goodwin PJ (1994) Prognostic factors in osteosarcoma: a critical review. J Clin Oncol 12(2):423–431
4. Pochanugool L, Subhadharaphandou T, Dhanachai M, Hathirat P, Sangthawan D, Pirabul R, Onsanit S, Pornpipatpong N (1997) Prognostic factors among 130 patients with osteosarcoma. Clin Orthop Relat Res 345:206–214
5. Tomer G, Cohen IJ, Kidron D, Katz K, Yosipovitch Z, Meller I, Zaizov R (1999) Prognostic factors in non-metastatic limb osteosarcoma: a 20-year experience of one center. Int J Oncol 15(1):179–185
6. Papachristou DJ, Papavassiliou AG (2007) Osteosarcoma and chondrosarcoma: new signaling pathways as targets for novel therapeutic interventions. Int J Biochem Cell Biol 39(5):857–862
7. Varmus H (2006) The new era in cancer research. Science 312(5777):1162–1165
8. Enneking WF, Spanier SS, Goodman MA (1980) A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 153:106–120
9. Bacci G, Donati D, Manfrini M, Forni C, Bertoni F, Gherlinzoni F, Biagini R, Campanacci M (1998) Local recurrence after surgical or surgical-chemotherapeutic treatment of osteosarcoma of the limbs. Incidence, risk factors and prognosis. Minerva Chir 53(7–8):619–629
10. Briccoli A, Rocca M, Salone M, Bacci G, Ferrari S, Balladelli A, Mercuri M (2005) Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer 104(8):1721–1725
11. Nathan SS, Gorlick R, Bukata S, Chou A, Morris CD, Boland PJ, Huvos AG, Meyers PA, Healey JH (2006) Treatment algorithm for locally recurrent osteosarcoma based on local disease-free interval and the presence of lung metastasis. Cancer 107(7):1607–1616
12. Yonemoto T, Tatezaki S, Ishii T, Satoh T, Kimura H, Iwai N (1998) Prognosis of osteosarcoma with pulmonary metastases at initial presentation is not dismal. Clin Orthop Relat Res 349:194–199
13. Kandioler D, Krömer E, Tüchler H, End A, Müller MR, Wolner E, Eckersberger F (1998) Long-term results after repeated surgical removal of pulmonary metastases. Ann Thorac Surg 65(4):909–912
14. Daw NC, Billups CA, Rodriguez-Galindo C, McCarville MB, Rao BN, Cain AM, Jenkins JJ, Neel MD, Meyer WH (2006) Metastatic osteosarcoma. Cancer 106(2):403–412
15. Sajadi KR, Heck RK, Neel MD, Rao BN, Daw N, Rodriguez-Galindo C, Hoffer FA, Stacy GS, Peabody TD, Simon MA (2004) The incidence and prognosis of osteosarcoma skip metastases. Clin Orthop Relat Res 426:92–96
16. Clark JCM, Dass CR, Choong PFM (2007) A review of clinical and molecular prognostic factors in osteosarcoma. J Cancer Res Clin Oncol, Mar;134(3):281-97
17. Mohammed RA, Green A, El-Shikh S, Paish EC, Ellis IO, Martin SG (2007) Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis. Br J Cancer 96(7):1092–1100
18. Foukas AF, Deshmukh NS, Grimer RJ, Mangham DC, Mangos EG, Taylor S (2002) Stage-IIB osteosarcomas around the knee. A study of MMP-9 in surviving tumour cells. J Bone Joint Surg Br 84(5):706–711
19. Choong PF, Fernö M, Akerman M, Willén H, Långström E, Gustafson P, Alvegård T, Rydholm A (1996) Urokinase-plasminogen-activator levels and prognosis in 69 soft-tissue sarcomas. Int J Cancer 69(4):268–272
20. Baldini N, Scotlandi K, Serra M, Picci P, Bacci G, Sottili S, Campanacci M (1999) P-glycoprotein expression in osteosarcoma: a basis for risk-adapted adjuvant chemotherapy. J Orthop Res 17(5):629–632
21. Laverdiere C, Hoang BH, Yang R, Sowers R, Qin J, Meyers PA, Huvos AG, Healey JH, Gorlick R (2005) Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma. Clin Cancer Res 11(7):2561–2567
22. Park YB, Kim HS, Oh JH, Lee SH (2001) The co-expression of p53 protein and P-glycoprotein is correlated to a poor prognosis in osteosarcoma. Int Orthop 24(6):307–310
23. Somers GR, Ho M, Zielenska M, Squire JA, Thorner PS (2005) HER2 amplification and overexpression is not present in pediatric osteosarcoma: a tissue microarray study. Pediatr Dev Pathol 8(5):525–532
24. Osaka E, Suzuki T, Osaka S, Yoshida Y, Sugita H, Asami S, Tabata K, Hemmi A, Sugitani M, Nemoto N, Ryu J (2006) Survivin as a prognostic factor for osteosarcoma patients. Acta Histochem Cytochem 39(3):95–100
25. Tsukahara T, Kawaguchi S, Torigoe T, Asanuma H, Nakazawa E, Shimozawa K, Nabeta Y, Kimura S, Kaya M, Nagoya S, Wada T, Yamashita T, Sato N (2006) Prognostic significance of HLA class I expression in osteosarcoma defined by anti-pan HLA class I monoclonal antibody, EMR8–5. Cancer Sci 97(12):1374–1380
26. Park HR, Jung WW, Bacchini P, Bertoni F, Kim YW, Park YK (2006) Ezrin in osteosarcoma: comparison between conventional high-grade and central low-grade osteosarcoma. Pathol Res Pract 202(7):509–515
27. Wadayama B, Toguchida J, Shimizu T, Ishizaki K, Sasaki MS, Kotoura Y, Yamamuro T (1994) Mutation spectrum of the retinoblastoma gene in osteosarcomas. Cancer Res 54(11):3042–3048
28. Gamberi G, Benassi MS, Bohling T, Ragazzini P, Molendini L, Sollazzo MR, Pompetti F, Merli M, Magagnoli G, Balladelli A, Picci P (1998) C-myc and c-fos in human osteosarcoma: prognostic value of mRNA and protein expression. Oncology 55(6):556–563
V6N6 ESUN Copyright © 2009 Liddy Shriver Sarcoma Initiative.