Background: Histologic response (HR) to neoadjuvant chemotherapy (NACT) is a robust prognosticator in non-metastatic osteosarcoma, however, it is accessible only after NACT completion. We need to identify novel early phase prognostic markers to individualize therapy.

Methods: Prognostic markers were studied in a large cohort of osteosarcoma patients treated with 3 sequential non-high dose methotrexate(HDMTX) based combination chemotherapy protocols in a single tertiary care center in India for over 2 decades.

Results: A total of 41, 94 & 385 treatment naive, consecutive, non-metastatic, extremity osteosarcoma patients received OGS-99(year 2000-2005), OGS-99-enhanced (2010) & OGS-12 protocols (2011-2016) respectively. At a median follow-up of 19(2-160), 86(2-99) & 39(6-78) months, the 5 year EFS rates were 38%, 50%, 62% and 5 year OS rates were non-evaluable, 60% & 77% in OGS-99, OGS enhanced & in OGS-12 respectively. Apart from HR to NACT, we found, other novel prognosticators like ECOG PS, completion of the protocol (compliance), female gender, and occurrence of febrile neutropenia (FN) (Table). ECOG PS can affect tolerance & thereby compliance; which can also be affected by undue concern for safety, resource constraints, and other patient-related factors and can affect survival. FN may be an indicator of chemosensitivity. Further, an infection may cause an immune-mediated antitumor activity resulting in better survival. Historically, “Coley- toxins” was known to induce remission in sarcoma. Interestingly, there is a possible link between cancer outcome, circadian system & varied, gender-specific clock-controlled gene expression. This might explain superior survival in females.Table: 408O
Prognostic markers in univariate & multivariate analysis

Study Protocol Parameters Univariate analysis Multivariate analysis
OGS -99 enhanced Protocol(n = 94)
EFS ECOG PS 0.034 0.041
Albumin 0.045
Necrosis 0.008 0.034
OS Compliance to Rx 0.039 -
Necrosis 0.004 0.031
Hemoglobin 0.036 -
Albumin 0.053 -
OGS -12 Protocol :Intention to Treat Analysis(ITT) (n = 385)
EFS Size 0.004 -
ECOG PS 0.002 0.073
Albumin 0.015 -
Necrosis 0.000 0.031
Completed protocol 0.000 0.066
Febrile neutropenia 0.036 -
Anaemia 0.039 -
OS Size 0.003
ECOG PS 0.000 0.071
Albumin 0.045 0.069
Necrosis 0.000 0.005
Completed protocol 0.000 0.001
Febrile neutropenia 0.012 -
Anaemia 0.043 -
OGS -12( Per- Protocol Analysis)(n = 333)
EFS Gender 0.059 0.053
Necrosis 0.006 0.011
Febrile neutropenia 0.034 0.021
Thrombocytopenia 0.073 -
Anaemia 0.069 -
OS Gender 0.051 0.056
Necrosis 0.002 0.005
Febrile neutropenia 0.044 0.038
Summary: OS= Overall survival, EFS= Event Free survival, ECOG PS= Eastern Cooperative Oncology Group Performance status, ITT=Intention to Treat

Conclusions: Based on this comparatively large cohort of successive nonmetastatic osteosarcoma patients experience for over 2 decades, we conclude that besides histological response, female gender, ECOG -PS, compliance, and FN are reliable novel, early phase predictors, and merits further exploration to establish their role.