The poor prognosis of patients who present with metastatic OS highlights the need for new active agents to be identified. We have learned that dose-intensification of conventional cytotoxic agents, while leading to greater necrosis after pre-operative chemotherapy, does not alter the 20% long-term survival of patients with metastatic OS.25, 26
Addition of conventional cytotoxics that appear to have activity in the preclinical setting, such as topotecan, has also not led to improvement in patient survival.1
As an immune modulator, L-MTP-PE has been studied extensively and presents a “novel” avenue of therapy for these patients. The initial analysis of the non-metastatic cohort of INT-0133 detected interaction between the two factors under study.23
This led to a preliminary conclusion that the addition of LMTP-PE to traditional chemotherapy did not confer a survival advantage to these patients.23
However with longer followup of the same cohort, the test of the hypothesis of interaction no longer met a conventional level of significance, allowing us to perform the factorial analyses originally designed for this study. We identified a trend toward improved EFS and a statistically significant improvement in overall survival for those who received L-MTP-PE, independent of chemotherapy regimen.22
Specifically, in the non-metastatic cohort of patients (n=662), the relative risk of death for patients randomized to receive L-MTP-PE was 0.71 (95% confidence interval 0.52 - 0.96, p = 0.03) while the hazard ratio for EFS for patients who received L-MTP-PE was 0.80 (95% confidence interval 0.62 - 1.0, p = 0.08). Interestingly, the same pattern of survival enhancement seen in the non-metastatic, resectable group of patients was also seen in the metastatic cohort reported here: a trend toward improved EFS and overall survival with L-MTP-PE addition to chemotherapy. Additionally, there was no statistically significant difference between the two chemotherapy regimens with respect to EFS or overall survival in the metastatic cohort presented here. The study was not powered to detect differences between the four study arms. We cannot make firm conclusions about the apparent differences of survival between the study arms. A larger, adequately powered study would help to resolve potential differences between chemotherapy regimens.
Previous studies described clinical characteristics in the population of metastatic patients that correlate with outcome, including age, sites of metastases, number of pulmonary nodules, and levels of biochemical markers (AP, LDH).3, 5, 7, 9
Many of these studies were performed at single institutions or described a population of patients who were treated with different protocols over a span of decades. While this study was not powered to detect outcome differences in subpopulation of patients with metastatic disease, it does provide valuable clues as to potentially prognostic clinical characteristics. Several clinical factors in this particular cohort of patients were related to worse outcome, including gender (males), race (non-Caucasians), extent of disease involvement (bone metastases), and non-specific biochemical markers of tumor burden (high AP and LDH). When incorporated into a relative risk regression model, both gender and baseline alkaline phosphatase levels were related to overall and event-free survival. In this study, female patients had better EFS and overall survival. While this recapitulates the findings of published studies by some, but not all, investigators (most notably, the Scandinavian Sarcoma Group recently published data supporting the better prognosis of female OS patients)5, 7, 27
, the reason(s) for this consistent observation remains unclear. Additionally, these results reinforce the notion that increased tumor burden (as implied by higher AP) leads to worse prognosis. Of interest is the lack of impact the number and location of lung nodules had on both EFS and overall survival. This is likely a reflection of the small sample size of the study population. A larger population would have provided an opportunity to detect the impact of lung tumor burden in these patients. Additionally, age at diagnosis did not correlate with outcome in this group of patients. In addition to these two characteristics, race was significantly related to risk of adverse analytic event, with non-Caucasian patients having worse EFS and overall survival.
Although the small number of patients in this cohort preclude precise estimation of treatment effects, it is still important to note that both EFS and overall survival appear to be improved for the patients who received L-MTP-PE. Additionally, the reductions in risk of adverse analytic event and death are very similar to the pattern in the much larger cohort of patients who presented without clinically detectable metastatic disease. These data suggest that L-MTP-PE might provide benefit when added to chemotherapy for the treatment of patients with osteosarcoma who present with metastatic disease. With the recent approval of L-MTP-PE by the European Medicines Agency (EMEA), the agent should become widely available for inclusion in additional, larger studies defining its efficacy in osteosarcoma.