High Dose Ifosfamide in Relapsed and Unresectable High-Grade Osteosarcoma Patients: A Retrospective Series

Abstract

Background: The evidence on high-dose ifosfamide (HD-IFO) use in patients with relapsed osteosarcoma is limited. We performed a retrospective study to analyze HD-IFO activity. Methods: Patients with osteosarcoma relapsed after standard treatment [methotrexate, doxorubicin, cisplatin +/− ifosfamide (MAP+/−I)] with measurable disease according to RECIST1.1 were eligible to ifosfamide (3 g/m2/day) continuous infusion (c.i.) days 1–5 q21d. RECIST1.1 overall response rate (ORR) (complete response (CR) + partial response (PR)), progression-free survival at 6-month (6m-PFS), duration of response (DOR), and 2-year overall survival (2y-OS) were assessed. PARP1 expression and gene mutations were tested by immunohistochemistry and next-generation sequencing. Results: 51 patients were included. ORR was 20% (1 CR + 9 PR). Median DOR was 5 months (95%CI 2–7). Median PFS, 6m-PFS, OS, and 2y-OS were 6 months (95%CI 4–9), 51%, 15 months (10–19), and 30%, respectively. A second surgical complete remission (CR2) was achieved in 26 (51%) patients. After multivariate analysis, previous use of ifosfamide (HR 2.007, p = 0.034) and CR2 (HR 0.126, p < 0.001) showed a significant correlation with PFS and OS, respectively. No significant correlation was found between outcomes and PARP1 or gene mutations. Conclusions: HD-IFO should be considered as the standard first-line treatment option in relapsed osteosarcoma and control arm of future trial in this setting.

Future Directions in the Treatment of Osteosarcoma

“…Although MAPIE was disappointing in EURAMOS, it may be related to low efficacy of etoposide [ 38 , 39 ] and low intensity/dose-density of ifosfamide + mesna given in the EURAMOS trial. Ifosfamide + mesna can indeed be given with excellent effectiveness against osteosarcoma with high dose-density (two weeks each month) and intensity (14 g/m 2 per cycle) and less toxicity (e.g., less CNS, renal and thrombocytopenia) when given as a continuous infusion [ 40 , 41 , 42 , 43 ]. Furthermore, ifosfamide + mesna as a continuous infusion can be given in the outpatient clinic, a welcome respite from frequent hospitalization associated with MAP.…”

“…Beyond ifosfamide and etoposide, the rational selection of agents to further modify adjuvant chemotherapy remains difficult. There are limited active treatments for patients with metastatic disease, including ifosfamide-etoposide (IE) [ 44 ], single agent ifosfamide [ 40 , 42 , 43 ], regorafenib [ 45 ], gemcitabine-docetaxel [ 46 ], cabozantinib [ 47 ], pazopanib [ 48 ] ± SBRT [ 49 ] and radium-223 alone or in combination [ 50 , 51 ]. Given the modest response rates to therapies beyond ifosfamide ± etoposide, a thoughtful, likely translational, approach is needed to identify new therapies with a high likelihood of success.…”

Continuous 14 Day Infusional Ifosfamide for Management of Soft-Tissue and Bone Sarcoma: A Single Centre Retrospective Cohort Analysis

“…In contrast, studies investigating conventional high-dose ifosfamide (3 g/m 2 /day for 5 days) in relapsed metastatic osteosarcoma have reported more favourable response rates, especially in paediatric patients (43%; 9/21) and in those with lung-only metastatic disease (21%; 9/35) [28]. Within that cohort, a number of patients underwent consolidation surgery following high-dose ifosfamide with favourable 1-year OS rates in patients achieving surgical complete response [28].…”

“…In a previous study using 14 day infusional ifosfamide, two patients with osteosarcoma were included, both of whom experienced PD on treatment [23], whilst in separate study using an alternative dosing schedule (14 g/m 2 over 6 days), a complete response was seen in a patient with metastatic osteosarcoma who was refractory to standard-dose ifosfamide [27]. In contrast, studies investigating conventional high-dose ifosfamide (3 g/m 2 /day for 5 days) in relapsed metastatic osteosarcoma have reported more favourable response rates, especially in paediatric patients (43%; 9/21) and in those with lung-only metastatic disease (21%; 9/35) [28]. Within that cohort, a number of patients underwent consolidation surgery following high-dose ifosfamide with favourable 1-year OS rates in patients achieving surgical complete response [28].…”

Current Approaches to Management of Bone Sarcoma in Adolescent and Young Adult (AYA) Patients

“…40,41 Chemotherapy is widely used in the management of recurrent pretreated OS, although complete and partial responses are rare and survival benefit has not been well demonstrated in largely, retrospective analyses. 34,42,43 Outcomes depend on disease-free interval with late relapses faring better. 34 There is no accepted standard regimen but cytotoxic agents include, ifosfamide ± etoposide, single agent ifosfamide, gemcitabine and docetaxel, cyclophosphamide, and carboplatin.…”