According to the latest American Society of Health-System Pharmacists drug shortage bulletin for ifosfamide products, Baxter and Hikma ifosfamide products remain affected by shortages, while Fresenius Kabi reports that its ifosfamide lyophilized powder for injection 1 g vials are currently available. Baxter states the shortage is due to increased demand, whereas Hikma did not provide a reason for the shortage. Current affected products include Baxter Ifex and generic ifosfamide 1 g and 3 g vials, as well as Hikma ifosfamide 50 mg/mL 20 mL and 60 mL vials. Regarding supply status, Hikma 20 mL and 60 mL vials are on allocation, Baxter 1 g and 3 g vials are on allocation, Baxter Ifex 1 g vials are on limited allocation, and Baxter Ifex 3 g vials remain on back order with estimated resupply in the third quarter of 2026. [1]
The 2026 National Comprehensive Care Network (NCCN) guidelines for soft tissue sarcoma indicate that both ifosfamide- and cyclophosphamide-containing regimens are established and accepted components of systemic therapy across multiple sarcoma settings, but they are used in different combinations rather than positioned as directly interchangeable or superior to one another. In adult soft tissue sarcoma, the guidelines show that ifosfamide is incorporated into several preferred or commonly used regimens, such as doxorubicin/ifosfamide/mesna (AIM) and epirubicin/ifosfamide/mesna, particularly in neoadjuvant and advanced/metastatic settings. The guidelines explicitly list non-ifosfamide regimens, such as doxorubicin alone or doxorubicin with dacarbazine, as appropriate alternatives when ifosfamide is not used, indicating that omission of ifosfamide is acceptable and routinely managed by switching to other evidence-based regimens rather than replacing it with cyclophosphamide. Cyclophosphamide does not appear as a standard component of the preferred adult soft tissue sarcoma regimens in these sections of the guidelines. However, for non-pleomorphic rhabdomyosarcoma treatment, both cyclophosphamide- and ifosfamide-containing regimens are listed as preferred options, including VAC (vincristine, dactinomycin, cyclophosphamide) and VAI-Europe (vincristine, dactinomycin, ifosfamide). The inclusion of both regimens, along with regimens that alternate cyclophosphamide and ifosfamide (such as VDC-IE), shows that in this specific disease context both agents are accepted components of standard therapy. Importantly, the guidelines do not state that cyclophosphamide is a substitute for ifosfamide, nor do they provide evidence that one is more effective than the other. Instead, they present each drug within specific regimens that have been studied for particular sarcoma subtypes. [2]
Though not specific to the ongoing shortage, the NCCN has provided treatment guidelines for relapsed/refractory B-cell lymphomas, including the use of R-ICE (rituximab, ifosfamide, carboplatin, etoposide) as an effective second-line regimen for patients eligible for transplant. NCCN also lists several non-ifosfamide alternatives, including R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin), R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin), and GemOx (gemcitabine, oxaliplatin) with or without rituximab, as additional second-line options. In the CORAL trial, no significant difference in outcomes was observed between R-ICE and R-DHAP, while a randomized study found GDP to be non-inferior to DHAP for response and transplantation rates, with fewer adverse events. NCCN also includes additional non-ifosfamide later-line options for patients who are not candidates for, or are not proceeding to, transplant or CAR T-cell therapy, including GemOx-based regimens, bispecific antibody combinations, lenalidomide-based therapy, and other systemic therapies, which may help guide treatment selection when R-ICE use is limited. [3]
Due to the ongoing ifosfamide shortage, Baxter released a Medicine Shortage Communication outlining recommended mitigation strategies. These measures emphasize confirming adequate supply is available to complete a treatment course before initiating new patients, prioritizing patients already receiving ifosfamide or those without suitable alternatives, and considering alternative regimens according to treatment guidelines or local protocols when necessary. Applicable drug shortage resources should also be consulted for updated supply information. [4]
A 2024 review article explores the urgent need to advance therapeutic options for Ewing sarcoma, a rare and aggressive malignancy prevalent in adolescents and young adults. In the absence of ifosfamide, and within recurrent or refractory disease, alternative multiagent regimens evaluated in the randomized adaptive rEECur trial include topotecan with cyclophosphamide, irinotecan with temozolomide, and gemcitabine with docetaxel, although comparative findings indicate variable efficacy across these options and generally modest outcomes. Beyond cytotoxic chemotherapy, emerging approaches may offer additional strategies, including single-agent tyrosine kinase inhibitors such as regorafenib and cabozantinib, which have demonstrated modest response rates and progression-free survival in heavily pretreated populations, with activity appearing comparable to conventional salvage regimens in early-phase studies. Additional investigational strategies include combinations targeting DNA damage response, cell cycle regulation, and apoptotic pathways, as well as regimens incorporating agents such as irinotecan with trabectedin, which have shown preliminary activity in early-phase trials. Immunotherapeutic approaches, including CAR T-cell therapies directed at tumor-associated antigens, remain under investigation with evolving but limited clinical data. [5]
A dated narrative review comparing ifosfamide and cyclophosphamide reported that, although comparative clinical trial data were limited, available evidence suggested greater single-agent activity with ifosfamide in selected tumor types. A prospective randomized EORTC study in soft-tissue sarcoma reported superior response rates with ifosfamide, and in ovarian cancer, higher objective response and 2-year survival were observed with ifosfamide (5/19 vs 1/20). In lung cancer, one study reported response rates of 29% versus 5% favoring ifosfamide in non-small cell disease, while another reported median survival of 7 to 9 months with ifosfamide compared with 3 to 4.8 months in small cell and non-small cell lung cancer. Pooled single-agent data further suggested similar or higher response rates with ifosfamide in lung cancer, testicular cancer, and sarcomas, though the authors acknowledged that differences in patient selection, dosing, and pretreatment status limited cross-trial conclusions. The review concluded that ifosfamide demonstrated clinically relevant activity following prior cyclophosphamide exposure and represented an important second-line agent in multiple tumor types. [6]
A 2015 report from the Childhood Cancer Survivor Study (CCSS) established a standardized method to compare cumulative exposure across alkylating agents in >12,000 childhood cancer survivors. In this framework, ifosfamide is assigned a conversion factor of 0.244 relative to cyclophosphamide within the Cyclophosphamide Equivalent Dose (CED), allowing its exposure to be expressed in cyclophosphamide-equivalent terms as part of a broader alkylating agent exposure model. Of note, the study itself focuses on exposure quantification and outcomes assessment rather than clinical substitution or drug shortages, but may potentially provide a structured way to compare total alkylating intensity across different agents. The authors also highlight a 2001 Intergroup Rhabdomyosarcoma Study-IV (IRS-IV) trial evaluating 883 children with nonmetastatic rhabdomyosarcoma. In this randomized study, vincristine-dactinomycin-cyclophosphamide (VAC), vincristine-ifosfamide-dactinomycin (VAI), and vincristine-ifosfamide-etoposide (VIE) showed similar 3-year failure-free survival rates (75%, 77%, and 77%; p= 0.42), with no significant differences between treatment arms. Ultimately, this demonstrates comparable outcomes across cyclophosphamide- and ifosfamide-containing regimens within this disease setting, without directly evaluating therapeutic substitution outside the trial context. [7], [8]
According to a 2017 review article, systemic treatment of advanced soft tissue sarcoma remains largely anchored in cytotoxic chemotherapy, with doxorubicin serving as a standard first-line backbone either alone or in combination with ifosfamide or other agents, although combination approaches have not consistently translated into survival benefit despite higher response rates. Additional commonly utilized regimens include ifosfamide as a subsequent option, gemcitabine-based combinations such as gemcitabine with docetaxel or dacarbazine, and later-line therapies including pazopanib, eribulin, trabectedin, and dacarbazine, with liposomal doxorubicin as a potential substitute for conventional anthracycline in select cases. Certain agents are more relevant in histology-specific contexts, such as paclitaxel or liposomal doxorubicin in angiosarcoma or Kaposi sarcoma, sirolimus in malignant PEComa, and targeted therapies such as imatinib and crizotinib in select molecularly defined subtypes. Overall, therapeutic selection is influenced by prior treatment exposure, histologic subtype, and tolerability considerations, and outcomes from phase III trials suggest that greater benefit is more likely when therapies are evaluated in biologically defined subgroups rather than heterogeneous populations, with increasing attention to progression-based endpoints and quality-of-life measures in clinical trial design. [9]
A Cochrane systematic review aimed to compare the antitumor efficacy and adverse effects of cyclophosphamide versus ifosfamide in young sarcoma patients. Despite extensive searches across databases and conference proceedings, no eligible randomized controlled trials (RCTs) or controlled clinical trials (CCTs) meeting inclusion criteria were found, leaving their comparative effectiveness and impact on quality of life undetermined. While some evidence from adult studies hints at differences in response rates and adverse effects, extrapolation to pediatric populations is fraught with challenges due to differences in disease etiology and drug pharmacokinetics between children and adults. Consequently, definitive clinical recommendations remain elusive without high-quality RCTs specifically in pediatric cohorts. The review underscores an urgent need for further targeted research to inform clinical decisions and optimize outcomes in this vulnerable population. [10]
A 2008 meta-analysis evaluated the impact of ifosfamide-based combination chemotherapy on patients with advanced soft tissue sarcoma. The analysis included data from three randomized phase III trials that compared the efficacy and safety of ifosfamide-containing regimens to those without ifosfamide. The trials specifically investigated combinations where ifosfamide was paired with doxorubicin, and in some cases, with dacarbazine (DTIC). The cumulative analysis revealed that adding ifosfamide significantly enhanced tumor response rates, evidenced by a relative risk of 1.52 (p = 0.009). However, no substantial improvement was noted in 1-year survival rates, with a relative risk of 0.98 (p = 0.76). The review highlighted a notable increase in adverse events among patients receiving ifosfamide-inclusive therapies, with more frequent occurrences of severe myelosuppression (grades 3–4) and higher incidences of treatment-related toxic deaths in two of the analyzed trials. Despite the enhanced response rates, the lack of a survival benefit and the rise in significant adverse effects led to a cautious recommendation against the routine use of ifosfamide addition for first-line treatment in metastatic soft tissue sarcoma. Nevertheless, the authors suggested that in cases of symptomatic, locally-advanced, or inoperable tumors, the enhanced tumor response might justify the use of such combinations if they could render the tumors resectable. [11]
A 2021 publication provides a detailed review of diffuse large B-cell lymphoma (DLBCL), highlighting the advancements in diagnosis, classification, and treatment over recent years. The authors emphasize the complexity and heterogeneity of DLBCL, with an estimated 150,000 new cases globally each year, making it a major subtype of non-Hodgkin's lymphoma. The standard first-line treatment, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), achieves a cure in over 60% of cases. However, there are significant challenges in managing patients whose disease is refractory to first-line therapy or those who relapse. For transplantation eligible patients, the use of platinum based salvage regimens (rituximab with dexamethasone, high-dose cytarabine, and cisplatin [R-DHAP], rituximab with ifosfamide, carboplatin, and etoposide [R-ICE], and rituximab with gemcitabine, dexamethasone, and cisplatin [R-GDP]) have shown similar efficacy in randomized trials, and the choice of regimen may depend on institutional preference or the side-effect profile. The refinement of DLBCL classification, particularly with the identification of molecular subtypes such as the germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes, has pivotal implications for prognosis and tailored therapeutic approaches, given the biological heterogeneity and distinct prognostic outcomes associated with these subtypes. The discussion extends to the potential use of novel treatments, such as CAR T-cell therapy, which represents a paradigm shift for relapsed or refractory cases, providing durable responses despite the challenging toxicity management. Ultimately, the review underscores the need for continued evolution in DLBCL management strategies, embracing both traditional and novel treatment modalities to address the diverse patient needs effectively. [12]
A 2008 retrospective analysis (see Table 1) compared the efficacy and toxicity profiles of the ICE (ifosfamide, carboplatin, etoposide) regimen versus the DHAP (cytosine arabinoside, cisplatin, dexamethasone) regimen as salvage chemotherapy in patients with relapsed or refractory lymphoma. Involving 53 patients, the study included individuals with either primary refractory or relapsed Hodgkin's disease (HD) or non-Hodgkin lymphoma (NHL). The analysis administered a total of 73 courses of ICE and 59 courses of DHAP, subsequently evaluating the response in 49 patients. The overall response rate (ORR), which included complete remission (CR) and partial remission (PR), was reported at 57.5%. Specifically, the ICE group demonstrated a CR rate of 27%, a PR rate of 41%, and an ORR of 68%, while the DHAP group showed rates of 18% for CR, 30% for PR, and an ORR of 48%. Both chemotherapy regimens exhibited manageable toxicity levels, with the primary grade III-IV toxicities being hematological, such as neutropenia and thrombocytopenia. Renal toxicity, the main non-hematological adverse effect, was observed in eight patients. Importantly, the ICE regimen appeared to have a higher response rate compared to DHAP, although the difference in ORR between the two regimens was not statistically significant (p = 0.24). The study also highlighted that successful peripheral blood stem cell mobilization was more frequently achieved in the ICE group. While the findings suggested that ICE might be more effective than DHAP in treating relapsed or refractory HD and NHL, it emphasized the need for prospective randomized trials to draw more definitive conclusions regarding the optimal salvage chemotherapy regimen. [13]
A 1998 intergroup trial (see Table 2) conducted by the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Cancer and Leukemia Group B compared two chemotherapy regimens for the primary treatment of men with advanced disseminated germ cell tumors. This randomized controlled trial allocated a total of 304 male participants to receive either the standard regimen of bleomycin, etoposide, and cisplatin (BEP) or an experimental regimen of etoposide, ifosfamide, and cisplatin (VIP) across four courses. The study aimed to evaluate various clinical outcomes, including complete response rates, favorable response rates, time to treatment failure, and overall survival, while also assessing the associated toxicities of each regimen. The findings indicated that both the BEP and VIP regimens produced comparable favorable response rates and overall survival, with no statistically significant difference in complete remission rates or treatment failure at the two-year mark. However, the VIP regimen was associated with significantly greater hematologic and genitourinary toxicities compared to the BEP regimen. Specifically, VIP treatment resulted in notably higher overall hematologic toxicity, including leukopenia and thrombocytopenia. Despite the promising role of ifosfamide observed in other contexts, such as in salvage therapy for recurrent germ cell cancer, the substitution of ifosfamide for bleomycin did not yield an improvement in outcomes for primary treatment in this patient population. Consequently, the study concluded that four courses of BEP remain the standard treatment for advanced disseminated germ cell tumors. [14]