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

Abstract

Ifosfamide is used to treat soft-tissue sarcoma (STS) and bone sarcoma (BS), with improved efficacy at doses above 9 g/m2/cycle. To mitigate treatment-associated toxicity with higher doses, continuous infusional ifosfamide is increasingly used. However, clinical outcome data remain limited. Single-centre retrospective analysis of patients treated with four-weekly infusional ifosfamide (14 g/m2/14d) between August 2012 and February 2019 was conducted. Radiological response, progression-free survival (PFS), overall survival (OS) and toxicity were evaluated. Eighty patients were treated—46 with STS and 34 with BS. Patients received a median of three cycles of infusional ifosfamide (1–24). Overall disease control rate (DCR) in STS was 50% (23 of 46 patients), with a median PFS of 3.8 months, and median OS of 13.0 months. In synovial sarcoma (SS), DCR was 80% (12/15), median PFS 8.1 months and median OS 20.9 months. Overall DCR in BS (34 patients) was 30%, with a median PFS of 2.5 months and median OS of 6.2 months. Five patients (6%) stopped treatment due to toxicity alone within the first two cycles. A further 10 patients stopped treatment due to toxicity during later treatment cycles (12%) and 18 patients (23%) required dose modification. Forty-five patients (56%) experienced grade (G) 3/4 haematological toxicity, with 12 episodes of febrile neutropenia and one treatment-related death. Twenty-seven patients (34%) experienced G3/4 non-haematological toxicity, most commonly nausea and vomiting (10, 13%). In summary, infusional ifosfamide has efficacy in STS, most notable in SS. Benefit appears limited in BS. Treatment is associated with toxicity that requires specialist supportive care.

Prolonged 14-day continuous infusion of high-dose ifosfamide for patients with relapsed and refractory high-grade osteosarcoma: a retrospective multicentre cohort study

“…Ifosfamide-induced encephalopathy, although rare, is a well-known adverse event which can occur in 2–5% of patients who have received the drug either intravenous or orally [ 36 , 37 ] It can occur 12 to 146 h after the start of the infusion with different clinical features (from mild to life-threatening symptoms) [ 36 , 37 ]. Notably, the cohort of patients analyzed in this study didn’t show any neurological toxicities, consistent with the previously reported association with continuous infusion and fewer side-effects, including low incidence of neurological events [ 19 – 22 ]. In fact, a prolonged infusion induces a reduction in the half-life of the active metabolites of ifosfamide, increasing their clearance and giving rise to a lower plasma peak, without changing the drug’s alkylating activity [ 19 – 22 ].…”

“…Ifosfamide is an alkylating chemotherapy agent that has been widely used in R/R OS treatment [ 12 – 18 ], either alone or in combination with other agents (Table 1 ), demonstrating a role in improving both Disease Control Rate (DCR) and Progression Free Survival (PFS) [ 12 – 19 ].…”

First-in-Human Phase I Study of ABBV-085, an Antibody–Drug Conjugate Targeting LRRC15, in Sarcomas and Other Advanced Solid Tumors

“…In the setting of locally advanced or metastatic sarcoma, these aggressive regimens achieve response rates of only 12% for doxorubicin and 6% to 8% for ifosfamide as single agents (17). For ifosfamide treatment in osteosarcoma, one retrospective study yielded a single case of improvement among 13 patients (18). A second study reported an ORR of 20% after high-dose ifosfamide treatment in patients with relapsed osteosarcoma; the median DOR was 7 months, similar to that seen in the presented study (8 months; ref.…”

Chemotherapeutic drugs for soft tissue sarcomas: a review

“…However, gemcitabine, docetaxel, and dacarbazine show only weak activity against synovial sarcoma ( Table 10 ). Retrospective studies confirmed these conclusions ( Ferrari et al, 2015 ; Sanfilippo et al, 2015 ; Desar et al, 2018 ; Pender et al, 2018 ; Stacchiotti and Van Tine, 2018 ; Carter et al, 2020 ; Kogushi et al, 2020 ). A retrospective study demonstrated that trabectedin had activity in synovial sarcoma ( Sanfilippo et al, 2015 ).…”

“…Therefore, doxorubicin is still considered the first choice of chemotherapy for advanced STSs ( Lorigan et al, 2007 ). However, ifosfamide may be superior to doxorubicin in synovial sarcoma ( Nielsen et al, 2000b ; Carter et al, 2020 ).…”