This Article Abstract Full Text (PDF) CME: Take the course for this article: The Pharmacologic Basis of Ifosfamide Use in Adult Patients with Advanced S... eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tascilar, M. Articles by Sleijfer, S. Search for Related Content PubMed PubMed Citation Articles by Tascilar, M. Articles by Sleijfer, S.

Sarcoma Research Series

The Pharmacologic Basis of Ifosfamide Use in Adult Patients with Advanced Soft Tissue Sarcomas

Department of Medical Oncology, Erasmus University Medical Center Rotterdam-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

Key Words. Soft tissue sarcoma • Ifosfamide • Pharmacology • Chemotherapy • Pharmacokinetics • Adults

Correspondence: Stefan Sleijfer, M.D., Ph.D., Department of Medical Oncology, Erasmus University Medical Center Rotterdam-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075EA Rotterdam, The Netherlands. Telephone: 31-0-10-4391733; Fax: 31-0-10-4391003; e-mail: s.sleijfer{at}erasmusmc.nl

Received August 14, 2007; accepted for publication September 24, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

	Learning Objectives

Top Learning Objectives Abstract Introduction Ifosfamide Metabolism Clinical Pharmacology Side Effects of Ifosfamide Ifosfamide in Soft Tissue... Future Perspectives and... References

 
After completing this course, the reader will be able to:

1. Describe the current role of ifosfamide in the treatment of soft tissue sarcomas in adult patients.
   
2. Discuss factors that may affect ifosfamide metabolism and its therapeutic index.
   
3. Explain the advantages of ifosfamide over doxorubicin in the context of new treatment combinations.
   
4. Discuss strategies to improve survival outcome in patients with soft tissue sarcoma.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Ifosfamide Metabolism Clinical Pharmacology Side Effects of Ifosfamide Ifosfamide in Soft Tissue... Future Perspectives and... References

 
The treatment outcome of patients with locally advanced and metastatic soft tissue sarcomas is poor. Doxorubicin is regarded as standard treatment, but its use is featured by the occurrence of cardiotoxicity. This hinders the administration of this drug at high doses or in combination with, in theory, attractive newly developed targeted drugs, such as vascular endothelial growth factor (VEGF) pathway inhibitors. The combination of doxorubicin and VEGF pathway inhibitors has been shown to yield an unacceptable high rate of cardiomyopathy. Ifosfamide is the only drug that consistently shows response rates comparable to those of doxorubicin. The lack of cardiotoxicity renders this drug a much more attractive alternative than doxorubicin to be explored at high doses or as part of new drug combinations. This review addresses the clinical pharmacology, metabolism, and present role of ifosfamide in the treatment of locally advanced and/or metastatic soft tissue sarcomas, excluding gastrointestinal stromal tumors, the Ewing-like sarcomas, and other small blue round cell tumors. Furthermore, this review focuses on the anticipated growing role of ifosfamide in the development of new treatment strategies.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Ifosfamide Metabolism Clinical Pharmacology Side Effects of Ifosfamide Ifosfamide in Soft Tissue... Future Perspectives and... References

 
Soft tissue sarcomas are rare tumors of mesenchymal origin, accounting for approximately 1% of all malignancies [1]. Over 40 different subtypes of soft tissue sarcoma have been described. Despite the great diversity in pathogenesis, histopathological features, and biologic behavior, most soft tissue sarcomas are considered as one group for the purpose of treatment, with the exception of gastrointestinal stromal tumors, the Ewing-like sarcomas of soft tissues and other small blue round cell tumors, dermatofibrosarcoma protuberans, embryonal rhabdomyosarcomas, and some other very rare subtypes.

Although local control can be obtained by surgery and radiotherapy, a substantial percentage of patients will eventually recur at distant sites. Until now, chemotherapy administered as adjuvant treatment has been demonstrated to increase the time to local and distant metastasis recurrence, but failed to improve overall survival [2]. For patients presenting with metastatic disease or locally advanced disease inaccessible to adequate local treatment, chemotherapy should be considered as palliative therapy.

The anthracycline doxorubicin is widely considered standard treatment in metastatic disease because it consistently induces response rates of approximately 16%–27%, with median overall survival times in the range of 7.7–12.0 months [3–6]. A dose–response relationship for doxorubicin has been described, and it is therefore commonly recommended that doxorubicin be administered at doses between 70 mg/m² and 80 mg/m² in 3-week intervals [7, 8]. The use of doxorubicin is mainly limited by myelosuppression and cardiomyopathy. As the latter toxicity occurs significantly more frequently at cumulative doses exceeding 450 mg/m², application of this drug at very high doses is undesirable despite the dose–response relationship.

Besides doxorubicin, ifosfamide is the only drug that also consistently shows activity against advanced soft tissue sarcoma with similar outcomes [7, 9–14]. At first glance, treatment with ifosfamide is less convenient to patients because it should be given over several days while doxorubicin can be given in one day. However, as ifosfamide is not featured by the occurrence of cardiotoxicity, several important advantages exist for this agent. For example, ifosfamide, in contrast to doxorubicin, can be given at high doses. Additionally, in the continuous search for more powerful antitumor therapies, new and promising targeted drugs, such as tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, are being combined with conventional chemotherapy [15]. In this respect, the vascular endothelial growth factor (VEGF)-mediated pathway is an attractive target. Activation of the VEGF receptor (VEGFR) confers resistance against several chemotherapeutic agents through induction of survivin, an antiapoptotic factor [16]. The involvement of VEGF in resistance against chemotherapy is also underlined by the observation that conventional cytotoxic agents induce increased VEGF production by tumor cells in vitro [17], and that high tumor VEGF level is a predictive factor for poor outcome of systemic treatment in humans [18]. Furthermore, inhibition of the VEGFR-2 pathway resulted in greater responsiveness to doxorubicin in preclinical models [19]. An additional mechanism that may underlie the synergistic interaction between inhibitors of the VEGF-mediated pathway and conventional chemotherapy is an effect on interstitial fluid pressure. Inhibitors of VEGFR decrease the interstitial fluid pressure of tumors, thereby increasing (conventional) chemotherapeutic drug uptake into the tumors. As a consequence, synergistic interaction occurs in animal models as well as in humans [20, 21]. Of note, this phenomenon of an increasing transcapillary pressure gradient in tumors is not specific for TKIs involving VEGFR, because it also has been described for imatinib, which inhibits a number of tyrosine kinase receptors including platelet-derived growth factor receptor, c-Kit, and Bcr-Abl [22, 23].

Altogether, these findings justify the exploration of various combinations of VEGF-mediated pathway inhibitors and conventional chemotherapy. However, in patients with advanced soft tissue sarcoma, it was recently revealed that the combination of a VEGF inhibitor with doxorubicin is not feasible because of an unacceptably high incidence of doxorubicin-mediated cardiotoxicity [15]. This strongly suggests that doxorubicin is not suitable for combination with agents inhibiting VEGF-mediated activities or other drugs interfering with cardiac function. In this respect, ifosfamide may be a much more attractive combination treatment partner to explore in soft tissue sarcomas.

Because of these features, ifosfamide is an important drug in the treatment of soft tissue sarcomas, and it can be anticipated that its role is likely to increase in the coming years. This review addresses the use of ifosfamide in patients with locally advanced and/or metastatic soft tissue sarcomas.

	IFOSFAMIDE METABOLISM

Top Learning Objectives Abstract Introduction Ifosfamide Metabolism Clinical Pharmacology Side Effects of Ifosfamide Ifosfamide in Soft Tissue... Future Perspectives and... References

 
Ifosfamide [3-(2-chloroethyl)-2-[(2-chloroethyl)-amino]tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide], first synthesized in the 1960s, is a member of the oxazaphosphorine family of alkylating agents [24, 25]. It was introduced as a chemical modification of cyclophosphamide with a different position of its two chloroethyl groups on the central ring, providing a structure with greater water solubility and antitumor activity and a better toxicity profile [26].

Like cyclophosphamide, ifosfamide is a prodrug that is metabolized into a variety of active and potentially toxic metabolites (Fig. 1). However, despite the structural similarities, cyclophosphamide and ifosfamide have important differences in their metabolism, toxicity, and therapeutic spectrum. Approximately 45% of the therapeutic dose of ifosfamide is typically metabolized via N-dechloroethylation to chloroacetaldehyde (CAA), whereas only 10% of cyclophosphamide is converted to CAA [27]. As CAA is thought to induce neurotoxicity and nephrotoxicity, this is likely to account for the more prevalent occurrence of these particular untoward events among patients treated with ifosfamide.

View larger version (47K): [in this window] [in a new window]   Figure 1. Pathways of metabolism of ifosfamide.

Since 4-hydroxy-ifosfamide is an unstable product, it exists in equilibrium with its tautomeric form aldophosphamide. The latter decomposes spontaneously to isophosphoramide mustard and acrolein. It is assumed that isophosphoramide mustard is the active metabolite because of its DNA alkylating ability. The mechanism of alkylation facilitates interstrand crosslinking that is more difficult to repair and hence promotes a greater cytotoxic effect, pushing cells into apoptosis [31]. The urotoxin acrolein, causing hemorrhagic cystitis, is also an agent capable of forming DNA adducts [32].

The metabolism of ifosfamide can be affected by a number of factors, including autoinduction, drug combinations, and/or polymorphisms of genes encoding enzymes that metabolize and transport ifosfamide [31].

Autoinduction is the process whereby repeated administration of ifosfamide results in an increase in total clearance and shorter elimination half-life because of greater activity of metabolizing enzymes, such as CYP3A4 and CYP2B6 [33]. Autoinduction of ifosfamide has been described to occur within 12–24 hours after the start of treatment. Importantly, metabolic rates return to initial levels within 3 weeks [34]. Autoinduction of ifosfamide metabolism seems to be influenced by dose and dosing schedule. With long infusion durations (24–72 hours) the metabolic rate was 52% lower than with short infusion durations (1–4 hours) [35]. Because this difference is comparable to the interindividual variability of ifosfamide, the clinical importance of autoinduction is not yet established.

Another factor that theoretically may influence ifosfamide metabolism is the chronic administration of CYP modulators, as demonstrated by greater ifosfamide clearance in a patient pretreated with carbamazepine [36], an inducer of CYP3A4. In contrast, earlier attempts failed to show modulation of this CYP-mediated metabolism of ifosfamide in patients using rifamipicin as a CYP3A4/CYP2B6 inducer and ketoconazole, a potent inhibitor of CYP3A4 [37]. Accordingly, Singer et al. [38] could not demonstrate a significant effect of dexamethasone, a CYP3A4 inducer, on ifosfamide metabolism. However, because ifosfamide activation and deactivation are catalyzed by distinct subsets of liver P450 enzymes, it appears to be possible to modulate the therapeutic indices of ifosfamide using P450 form-selective modulators in preclinical models [39]. Collectively, altered metabolism yielding other effects as expected in terms of efficacy and toxicity can occur upon coadministration of CYP3A4 inducers or inhibitors. Obviously, this underlines the importance of taking into account any concomitant medication affecting enzymes involved in the metabolism of ifosfamide. The same holds true for drugs that are substrates for drug transporters, including breast cancer resistance protein, multidrug resistance associated protein (MRP)-1, MRP-2, and MRP-4 [31]. These transporters have been described to be involved in the active uptake and efflux of oxazaphosphorines. Theoretically, compounds that act as substrates for these pumps and that are given concomitantly with ifosfamide can affect the metabolism of the latter. Whether such interactions are indeed clinically relevant remains to be established.

Next to drug–drug interactions, the marked interindividual differences in clinical response rate and toxicity observed in cancer patients can be partly explained by polymorphisms of genes encoding enzymes that metabolize and transport ifosfamide. Such polymorphisms can give rise to different expression and activity of the encoded proteins. As an example, a 20- to 250-fold variability in CYP2B6 expression has been reported [40, 41]. Accordingly, substantial differences among individual human liver samples with respect to total metabolism and the rates of microsomal ifosfamide N-dechloroethylation were observed to result from differences in the expression of CYP protein levels [42, 43]. Clearly, such genetic polymorphisms may contribute to the wide interpatient variability in exposure to cyclophosphamide and ifosfamide and their active metabolites, with important clinical consequences in cancer chemotherapy [44]. Further clinical studies are needed to explore the exact role of polymorphisms within these genes in ifosfamide therapy.

	CLINICAL PHARMACOLOGY

Top Learning Objectives Abstract Introduction Ifosfamide Metabolism Clinical Pharmacology Side Effects of Ifosfamide Ifosfamide in Soft Tissue... Future Perspectives and... References

 
As a consequence of the narrow therapeutic ratio of ifosfamide, its optimal schedule of administration is still questioned [36]. This unfavorable therapeutic ratio led to the exploration of a large number of alternate schedules including oral, s.c., or i.v. administration by continuous or short infusion [45–47]. Early clinical reports suggested that continuous infusion would be better tolerated [48, 49]; however, this approach was challenged later by others warning against loss of efficacy [50]. In an extensive study of the main active and toxic ifosfamide metabolites, it was shown that continuous infusion and short infusion schedules, using ifosfamide as monotherapy with an identical dose (9 g/m²) given over 3 days by either continuous infusion or daily 3-hour infusions, were equivalent in terms of pharmacokinetic endpoints such as area under the concentration–time curve [36].

As is described for doxorubicin, there is also some evidence to support a dose–response relationship in ifosfamide in soft tissue sarcomas: with higher doses of ifosfamide, higher response rates have been described, although benefits in terms of longer survival times remain unproven [9]. At doses of 12–18 g/m² there is no firm dose–response relationship, and unacceptably high incidences of grade 3 and 4 toxicities are encountered [10]. This lack of a dose–response relationship at doses above 12 g/m² is further supported by the finding that ifosfamide doses >14–16 g/m² result in a relatively lower level of the active metabolite isophosphoramide mustard, suggesting a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high-dose ifosfamide [51].

	SIDE EFFECTS OF IFOSFAMIDE

Top Learning Objectives Abstract Introduction Ifosfamide Metabolism Clinical Pharmacology Side Effects of Ifosfamide Ifosfamide in Soft Tissue... Future Perspectives and... References

 
The main acute side effects of ifosfamide involve those commonly seen with other antineoplastic agents such as neutropenia, thrombocytopenia, nausea, vomiting, alopecia, and hypersensitivity reactions. Ifosfamide is also associated with more specific toxicities, including hemorrhagic cystitis, neurotoxicity (encephalopathy), and nephrotoxicity.

Regarding ifosfamide-specific toxicities, the use of ifosfamide was initially limited by the occurrence of hemorrhagic cystitis. After the introduction of mercaptoethane sulfonate sodium (mesna) in 1979, a thiol compound that detoxifies the acrolein metabolite of ifosfamide in the bladder only without affecting its antitumor effect, hemorrhagic cystitis was no longer considered dose-limiting [52].

The incidence of renal toxicity varies in the range of 5%–30%. Risk factors include drug dose, prior nephrectomy, prior renal irradiation, and presence of retroperitoneal masses [53]. Clinical studies of ifosfamide showed that single high doses can result in acute tubular necrosis and renal failure within a few days after administration [54]. This was one of the reasons that fractionated dose schedules were developed for this drug. A lower rate of both bladder and renal toxicity was seen with ifosfamide administration over five consecutive days [55]. There is no known means for preventing ifosfamide renal toxicity.

Ifosfamide-induced encephalopathy can be precipitated by risk factors such as low serum albumin, poor performance status, any degree of renal dysfunction, and age (children are more susceptible than adults) [56]. It is manifested by visual and auditory hallucinations, logorrhea, mental confusion, agitation, seizures, coma, and occasionally death. Severe electrolyte and acid-base disturbances by tubular dysfunction may maintain or worsen neurological symptoms. The etiology of this neurotoxicity remains largely unknown, but it is probably multifactorial. CAA, which is structurally related to acetaldehyde, the neurotoxic metabolite of ethanol, is thought to contribute to this toxicity [57]. The incidence of neurotoxic abnormalities varies in the range of 10%–15%, but for unknown reasons appears to be higher with oral administration than with i.v. administration [58]. Although controlled studies are lacking, i.v. methylene blue and high-dose thiamine are regarded as effective treatments that can result in dramatic reversal of the neurotoxic manifestations [59].

	IFOSFAMIDE IN SOFT TISSUE SARCOMAS

Top Learning Objectives Abstract Introduction Ifosfamide Metabolism Clinical Pharmacology Side Effects of Ifosfamide Ifosfamide in Soft Tissue... Future Perspectives and... References

 
Ifosfamide Monotherapy
Because of the ongoing dispute and the lack of consensus on the best regimen, numerous different ifosfamide regimens have been explored in patients with soft tissue sarcomas (Table 1). In one of the earliest studies performed in patients with advanced soft tissue sarcoma in 1983, ifosfamide monotherapy at 5–8 g/m² by a 24-hour infusion every 3 weeks produced a response rate of 38% [11]. In subsequent studies, ifosfamide consistently yielded response rates of approximately 20%–25% in metastatic disease, with a median overall survival duration of 1 year, results that seem to be comparable to those obtained with doxorubicin [12].

In order to further define the most optimal regimen, in 2002, a study by the same EORTC group demonstrated that, in the first-line treatment of advanced soft-tissue sarcomas, ifosfamide given at 5 g/m² over 24 hours every 3 weeks yielded disappointing response rates compared with 3 g/m² per day given over 4 hours for three consecutive days (total dose, 9 g/m²), with response rates of 10% versus 25%, respectively [12].

There are only two studies that directly compared ifosfamide with other drugs in soft tissue sarcoma. In a randomized phase II study of the EORTC STBSG performed in the early 1980s, ifosfamide at a dose of 5 g/m² given over 24 hours every 3 weeks was compared with cyclophosphamide at a dose of 1,500 mg/m² in nonpretreated patients [13]. In this study ifosfamide showed a response rate of 25% versus 10% for cyclophosphamide with less myelosuppression in the ifosfamide treated patients. Recently, the first study to directly compare doxorubicin with ifosfamide in a phase III trial was published, comparing two schedules of ifosfamide (9 g/m² over 3 days by continuous infusion or 3 g/m² per day in 3 hours over 3 days) with standard-dose doxorubicin (75 mg/m² every 21 days) in advanced or metastatic soft tissue sarcoma [14]. Although grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in both ifosfamide arms, no differences in progression-free survival, response rates, and overall survival were seen among the three treatment arms. On the advice of the data monitoring committee the study was stopped early for futility reasons; a lack of superiority of either of the two ifosfamide arms to doxorubicin was observed.

Collectively, based on above-mentioned studies, ifosfamide is likely to exhibit antitumor activity that is equivalent to that of doxorubicin. Doses of approximately 9–11 g/m² per cycle given at 3-week intervals are recommended for single-agent ifosfamide with no clear preference for continuous infusion or infusion in 3–4 hours. There are no data to suggest that higher doses yield greater antitumor activity, which is likely a result of saturated conversion of ifosfamide into active metabolites at doses >12 g/m².

Ifosfamide in Combination Therapy
Several trials have been performed exploring the feasibility of ifosfamide-containing combinations and whether or not such combinations are more effective than single-drug regimens. In 1990, the EORTC group embarked on a phase II trial of doxorubicin (50 mg/m²) plus ifosfamide (5 g/m²) administered as a 24-hour continuous infusion every 3 weeks. In that study, toxicity was shown to be acceptable, with a response rate of 35% in 175 assessable patients [66]. Several other studies combining doxorubicin with ifosfamide, all performed in a nonrandomized setting, demonstrated apparently high response rates of 50%–60%. Patel et al. [67] achieved a response rate of 66% with doxorubicin (75 mg/m²) in combination with ifosfamide (10 g/m²). The main toxicity was myelosuppression, and despite the use of G-CSF, febrile neutropenia was encountered in 31% of all cycles [67]. Leyvraz et al. [68] published a study of doxorubicin (90 mg/m²) plus ifosfamide (10 g/m²) in combination with G-CSF, which resulted in a response rate of 55%. Of note, this combination induced severe bone marrow toxicity, given World Health Organization grade 4 leukopenia in 58%, grade 3–4 thrombopenia in 42%, and anemia in 31% of cycles. In a phase II study by Reichardt et al. [69], a similar response rate of 55% was reported using the combination epirubicin (90 mg/m²) and ifosfamide (12.5 g/m²) with G-CSF support.

Prompted by the apparent high response rates obtained with ifosfamide-containing regimens, a prospective, randomized trial was performed that compared single-agent doxorubicin (75 mg/m²) with a combination of doxorubicin (50 mg/m²) and ifosfamide (5 g/m²) and also with the four-drug combination CYVADIC (cyclophosphamide, 500 mg/m²; vincristine, 1.5 mg/m²; doxorubicin, 50 mg/m²; and dacarbazine, 750 mg/m²) [70]. In this large multicenter trial with 663 eligible patients, no statistically significant difference was detected among the three treatment arms in terms of response rate, remission duration, and overall survival time. Also, another study randomly comparing the combination of doxorubicin and dacarbazine (60 mg/m² and 1,000 mg/m², respectively) over 4 days, every 3 weeks, with the triplet of doxorubicin and dacarbazine (both administered in the same dosage) and ifosfamide (7.5 g/m² over 3 days) did not reveal a benefit for the ifosfamide-containing combination [71].

Because, thereafter, concerns were raised on whether or not the lack of superiority for the combinations was a result of less than optimal doses in these combinations, the EORTC initiated a randomized phase III study assigning patients to either doxorubicin (75 mg/m²) or doxorubicin (75 mg/m²) combined with ifosfamide (10 g/m² per cycle). That study is still in progress.

Although evidence of superior efficacy of doxorubicin- plus ifosfamide-based combinations over doxorubicin alone is currently lacking, whereas greater toxicity using the combination is evident, high doses of ifosfamide in combination with doxorubicin in the treatment of younger patients with aggressive tumors is frequently applied, especially if the chemotherapy is administered in a neoadjuvant or preoperative setting [6, 71–73].

	FUTURE PERSPECTIVES AND CONCLUSIONS

Top Learning Objectives Abstract Introduction Ifosfamide Metabolism Clinical Pharmacology Side Effects of Ifosfamide Ifosfamide in Soft Tissue... Future Perspectives and... References

 
It is clear that ifosfamide exhibits activity in advanced and metastatic soft tissue sarcomas to a similar extent as doxorubicin. Nevertheless, the overall survival of this patient group remains poor. One way to improve survival outcomes is through paying more attention to factors that may influence susceptibility to specific antitumor treatments. Unfortunately, such factors enabling the identification of patients who are likely to respond to ifosfamide have not been revealed yet. This is in contrast to doxorubicin-based therapies for which such factors have been elucidated. A large study showed that, in a multivariate analysis, the absence of liver metastasis, young age, and a high histopathological grade were associated with a favorable response [74]. In the same study, good performance status, young age, no liver involvement, a low histopathological grade, and a long time between the primary diagnosis and start of treatment were independently associated with a longer overall survival time. A similar analysis to identify factors predicting outcome to ifosfamide is clearly warranted.

There are evident indications that the distinct sarcoma subtypes differ in their susceptibility to certain drugs and that treatment strategies should therefore be tailored according to subtype. This holds true for angiosarcomas of the scull and myxoid/round cell liposarcomas, in which paclitaxel and trabectedin, respectively, induce response rates that are higher than those seen using other compounds. The combination of gemcitabine and docetaxel exhibits antitumor activity against metastatic leiomyosarcomas and undifferentiated high-grade pleiomorphic sarcomas [75]. With respect to ifosfamide, synovial sarcoma in particular is thought to be highly sensitive to this drug, but this is merely based on small series of patients while randomized data are lacking [4, 6, 69, 76, 77]. Better characterization and understanding of the molecular biology and the pathogenesis of the different subtypes of sarcomas is needed in order to engineer and develop more specific treatments. This may also lead to identification of subtypes or gene-expression profiles of tumors likely to respond to ifosfamide.

In recent years, several new compounds with promising antitumor activity in early clinical trials have been identified. ET-743 (ecteinascidin-743, trabectedin, Yondelis®; PharmaMar, Madrid, Spain) is a new compound that exerts its antitumor activity through binding to the minor groove of DNA [78]. It has demonstrated activity as a first-line or second-line treatment for advanced sarcomas, following doxorubicin and ifosfamide [79, 80], in particular against myxoid/round cell liposarcomas. This drug was recently registered in Europe. The mammalian target of rapamycin (mTOR) inhibitors mediate their activity by binding to the intracellular protein FKBP-12 (FK506 binding protein) and subsequently inhibiting the protein kinase of mTOR, finally leading to cell cycle arrest and apoptosis [81]. AP23573, an mTOR-inhibitor, yielded promising results in patients with advanced sarcomas in phase II studies and will be assessed in the context of randomized studies shortly [82]. Furthermore, the process of tumor angiogenesis is a potential target, because new blood vessel formation is one of the prerequisites for growth and dissemination of tumors in general, including soft tissue sarcomas. The use of drugs targeting angiogenesis, including monoclonal antibodies and TKIs, is therefore rapidly increasing in oncology. Very recently, sorafenib and pazopanib, TKIs targeting VEGFR, yielded strong hints of antitumor activity in particular tumor subtypes, prompting the initiation of randomized studies [83, 84].

Next to their application as single agents, there is a strong rationale to explore these compounds in combination regimens. Preferably, there are several conditions that have to be met when agents are combined in cancer treatment, with single-agent activity of both agents, different mechanisms of action, nonoverlapping toxicity profiles, and synergistic antitumor activity being the most important ones. Because several of these criteria have already been met, it is attractive to combine the above-mentioned novel drugs with either doxorubicin or ifosfamide. In particular for agents that may exaggerate doxorubicin-induced cardiomyopathy, as, for example, has been shown for inhibitors of the VEGF-mediated pathway, ifosfamide is the preferred agent [15]. However, it should be emphasized that whether these new drug combinations indeed improve antitumor activity can only be settled after results from well-designed, randomized studies are known. The same holds true for other combinations, including doxorubicin and ifosfamide, for which no robust data currently exist indicating that they outperform single-agent regimens in terms of longer overall survival times. Therefore, the results from the randomized EORTC study comparing this combination with single-agent doxorubicin, all given at doses considered optimal, are eagerly awaited.

It is clear that, in the era of targeted drug therapy and tumor type–specific treatments, the old drug ifosfamide still has an important role in the treatment of soft tissue sarcoma that is likely to increase in the near future.

	REFERENCES

Top Learning Objectives Abstract Introduction Ifosfamide Metabolism Clinical Pharmacology Side Effects of Ifosfamide Ifosfamide in Soft Tissue... Future Perspectives and... References

 

1. Enzinger FM, Weiss SW. In: Enzinger FM, Weiss SW, eds. Soft tissue Tumors. General considerations. Third Edition. St. Louis: Mosby, 1995:1-16.
2. Sarcoma Meta-Analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: Meta-analysis of individual data. Lancet 1997;350:1647–1654.[CrossRef][Medline]
3. Schoenfeld DA, Rosenbaum C, Horton J et al. A comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide versus vincristine, actinomycin-D, and cyclophosphamide for advanced sarcoma. Cancer 1982;50:2757–2762.[CrossRef][Medline]
4. Borden EC, Amato DA, Rosenbaum C et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 1987;5:840–850.[Abstract/Free Full Text]
5. Omura GA, Major FJ, Blessing JA et al. A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer 1983;52:626–632.[CrossRef][Medline]
6. Edmonson JH, Ryan LM, Blum RH et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 1993;11:1269–1275.[Abstract/Free Full Text]
7. Sleijfer S, Seynaeve C, Verweij J. Using single-agent therapy in adult patients with advanced soft tissue sarcoma can still be considered standard care. The Oncologist 2005;10:833–841.[Abstract/Free Full Text]
8. O'Bryan RM, Baker LH, Gottlieb JE et al. Dose response evaluation of adriamycin in human neoplasia. Cancer 1977;39:1940–1948.[CrossRef][Medline]
9. Benjamin RS, Legha SS, Patel SR et al. Single-agent ifosfamide studies in sarcomas of soft tissue and bone: The M.D. Anderson experience. Cancer Chemother Pharmacol 1993;31(suppl 2):S174–S179.[Medline]
10. Nielsen OS, Judson I, van Hoesel Q et al. Effect of high-dose ifosfamide in advanced soft tissue sarcomas. A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2000;36:61–67.[Medline]
11. Stuart-Harris RC, Harper PG, Parsons CA et al. High-dose alkylation therapy using ifosfamide infusion with mesna in the treatment of adult advanced soft-tissue sarcoma. Cancer Chemother Pharmacol 1983;11:69–72.[Medline]
12. van Oosterom AT, Mouridsen HT, Nielsen OS et al. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer 2002;38:2397–2406.[CrossRef][Medline]
13. Bramwell VH, Mouridsen HT, Santoro A et al. Cyclophosphamide versus ifosfamide: Final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 1987;23:311–321.[CrossRef][Medline]
14. Lorigan P, Verweij J, Papai Z et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group study. J Clin Oncol 2007;25:3144–3150.[Abstract/Free Full Text]
15. D'Adamo DR, Anderson SE, Albritton K et al. Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas. J Clin Oncol 2005;23:7135–7142.[Abstract/Free Full Text]
16. Tran J, Master Z, Yu JL et al. A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci U S A 2002;99:4349–4354.[Abstract/Free Full Text]
17. Riedel F, Götte K, Goessler U et al. Targeting chemotherapy-induced VEGF up-regulation by VEGF antisense oligonucleotides in HNSCC cell lines. Anticancer Res 2004;24:2179–2183.[Medline]
18. Toi M, Matsumoto T, Bando H. Vascular endothelial growth factor: Its prognostic, predictive, and therapeutic implications. Lancet Oncol 2001;2:667–673.[CrossRef][Medline]
19. Zhang L, Hannay JA, Liu J et al. Vascular endothelial growth factor overexpression by soft tissue sarcoma cells: Implications for tumor growth, metastasis, and chemoresistance. Cancer Res 2006;66:8770–8778.[Abstract/Free Full Text]
20. Willett CG, Boucher Y, di Tomaso E et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145–147.[CrossRef][Medline]
21. Heldin CH, Rubin K, Pietras K et al. High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 2004;4:806–813.[CrossRef][Medline]
22. Vlahovic G, Ponce AM, Rabbani Z et al. Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts. Br J Cancer 2007;97:735–740.[CrossRef][Medline]
23. Pietras K, Ostman A, Sjoquist M et al. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 2001;61:2929–2934.[Abstract/Free Full Text]
24. Connelly EF, Budd GT. Ifosfamide in the treatment of soft tissue sarcomas. Semin Oncol 1996;23(suppl 6):16–21.[Medline]
25. Brade W, Seeber S, Herdrich K. Comparative activity of ifosfamide and cyclophosphamide. Cancer Chemother Pharmacol 1986;18(suppl 2):S1–S9.[CrossRef]
26. Kerbusch T, de Kraker J, Keizer HJ et al. Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites. Clin Pharmacokinet 2001;40:41–62.[CrossRef][Medline]
27. Kaijser GP, Korst A, Beijnen JH et al. The analysis of ifosfamide and its metabolites (review). Anticancer Res 1993;13:1311–1324.[Medline]
28. Boddy AV, Yule SM. Metabolism and pharmacokinetics of oxazaphosphorines. Clin Pharmacokinet 2000;38:291–304.[CrossRef][Medline]
29. Sladek NE. Metabolism of oxazaphosphorines. Pharmacol Ther 1988;37:301–355.[CrossRef][Medline]
30. Bruggemann SK, Radike K, Braasch K et al. Chloroacetaldehyde: Mode of antitumor action of the ifosfamide metabolite. Cancer Chemother Pharmacol 2006;57:349–356.[CrossRef][Medline]
31. Zhang J, Tian Q, Yung Chan S et al. Metabolism and transport of oxazaphosphorines and the clinical implications. Drug Metab Rev 2005;37:611–703.[CrossRef][Medline]
32. Shaw IC, Graham MI. Mesna—a short review. Cancer Treat Rev 1987;14:67–86.[CrossRef][Medline]
33. Boddy AV, Cole M, Pearson ADR et al. The kinetics of the auto-induction of ifosfamide metabolism during continuous infusion. Cancer Chemother Pharmacol 1995;36:53–60.[CrossRef][Medline]
34. Lewis LD. A study of 5 day fractionated ifosfamide pharmacokinetics in consecutive treatment cycles. Br J Clin Pharmacol 1996;42:179–186.[CrossRef][Medline]
35. Kerbusch T, Mathot RA, Keizer HJ et al. Influence of dose and infusion duration on pharmacokinetics of ifosfamide and metabolites. Drug Metab Dispos 2001;29:967–975.[Abstract/Free Full Text]
36. Brain EGC, Rezai K, Weill S et al. Variations in schedules of ifosfamide administration: A better understanding of its implications on pharmacokinetics through a randomized cross-over study. Cancer Chemother Pharmacol 2007;60:375–381.[CrossRef][Medline]
37. Kerbusch T, Jansen RL, Mathot RA et al. Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin. Clin Pharmacol Ther 2001;70:132–141.[CrossRef][Medline]
38. Singer JM, Hartley JM, Brennan C et al. The pharmacokinetics and metabolism of ifosfamide during bolus and infusional administration: A randomized cross-over study. Br J Cancer 1998;77:978–984.[Medline]
39. Yu L, Waxman DJ. Role of cytochrome P450 in oxazaphosphorine metabolism. Deactivation via N-dechloroethylation and activation via 4-hydroxylation catalyzed by distinct subsets of rat liver cytochromes P450. Drug Metab Dispos 1996;24:1254–1262.[Abstract]
40. Code EL, Crespi CL, Penman BW et al. Human cytochrome P4502B6: Interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metab Dispos 1997;25:985–993.[Abstract/Free Full Text]
41. Stresser DM, Kupfer D. Monospecific antipeptide antibody to cytochrome P-450 2B6. Drug Metab Dispos 1999;27:517–525.[Abstract/Free Full Text]
42. Huang Z, Roy P, Waxman DJ. Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol 2000;59:961–972.[CrossRef][Medline]
43. Roy P, Tretyakov O, Wright J et al. Stereoselective metabolism of ifosfamide by human P-450s 3A4 and 2B6. Favorable metabolic properties of R-enantiomer. Drug Metab Dispos 1999;27:1309–1318.[Abstract/Free Full Text]
44. Larrey D, Pageaux GP. Genetic predisposition to drug-induced hepatotoxicity. J Hepatol 1997;26(suppl 2):12–21.[CrossRef][Medline]
45. Cerny T, Kupfer A, Zeugin T et al. Bioavailability of subcutaneous ifosfamide and feasibility of continuous outpatient application in cancer patients. Ann Oncol 1990;1:365–368.[Abstract/Free Full Text]
46. Keizer HJ, Ouwerkerk J, Welvaart K et al. Ifosfamide treatment as a 10-day continuous intravenous infusion. J Cancer Res Clin Oncol 1995;121:297–302.[CrossRef][Medline]
47. Lokich I, Anderson N, Bern M et al. Ifosfamide continuous infusion without mesna. A phase I trial of a 14-day cycle. Cancer 1991;67:883–885.[CrossRef][Medline]
48. Antman KH, Ryan L, Elias A et al. Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 1989;7:126–131.[Abstract]
49. Cerny T, Castiglione M, Brunner K et al. Ifosfamide by continuous infusion to prevent encephalopathy. Lancet 1990;335:175.[Medline]
50. Patel SR, Vadhan-Raj S, Papadopoulos N et al. High-dose ifosfamide in bone and soft tissue sarcomas: Results of phase II and pilot studies—dose-response and schedule dependence. J Clin Oncol 1997;15:2378–2384.[Abstract/Free Full Text]
51. Cerny T, Leyvraz S, von Briel T et al. Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: A pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 1999;10:1087–1094.[Abstract/Free Full Text]
52. Schoenike SE, Dana WJ. Ifosfamide and mesna. Clin Pharm 1990;9:179–191.[Medline]
53. Rossi R. Nephrotoxicity of ifosfamide—moving towards understanding the molecular mechanisms. Nephrol Dial Transplant 1997;12:1091–1092.[Free Full Text]
54. Ho PT, Zimmerman K, Wexler LH et al. A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults. Cancer 1995;76:2557–2564.[CrossRef][Medline]
55. Marina NM, Poquette CA, Cain AM et al. Comparative renal tubular toxicity of chemotherapy regimens including ifosfamide in patients with newly diagnosed sarcomas. J Pediatr Hematol Oncol 2000;22:112–118.[CrossRef][Medline]
56. Nicolao P, Giometto B. Neurological toxicity of ifosfamide. Oncology 2003;65(suppl 2):11–16.[CrossRef][Medline]
57. Lokiec F. Ifosfamide: Pharmacokinetic properties for central nervous system metastasis prevention. Ann Oncol 2006;17(suppl 4):iv33–iv36.[Abstract/Free Full Text]
58. Lind MJ, Roberts HL, Thatcher N et al. The effect of route of administration and fractionation of dose on the metabolism of ifosfamide. Cancer Chemother Pharmacol 1990;26:105–111.[Medline]
59. DeVita VT, Hellman S, Rosenberg SA et al, eds. Cancer: Principles & Practice of Oncology. Seventh Edition. Philadelphia: Lippincott Williams & Wilkins, 2005:1-2898.
60. Tursz T. High-dose ifosfamide in the treatment of advanced soft tissue sarcomas. Semin Oncol 1996;23(suppl 7):34–39.[Medline]
61. Gullu I, Yalcin S, Tekuzman G et al. High-dose ifosfamide by infusion with mesna in advanced refractory sarcomas. Cancer Invest 1996;14:239–242.[Medline]
62. Palumbo R, Palmeri S, Antimi M et al. Phase II study of continuous-infusion high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas. Ann Oncol 1997;8:1159–1162.[Abstract/Free Full Text]
63. Yalcin B, Pamir A, Buyukcelik A et al. High-dose ifosfamide with hematopoietic growth factor support in advanced bone and soft tissue sarcomas. Exp Oncol 2004;26:320–325.[Medline]
64. Le Cesne A, Antoine E, Spielmann M et al. High-dose ifosfamide: Circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas. J Clin Oncol 1995;13:1600–1608.[Abstract/Free Full Text]
65. Buesa JM, Lopez-Pousa A, Martin J et al. Phase II trial of first-line high-dose ifosfamide in advanced soft tissue sarcomas of the adult: A study of the Spanish Group for Research on Sarcomas (GEIS). Ann Oncol 1998;9:871–876.[Abstract/Free Full Text]
66. Schutte J, Mouridsen HT, Stewart W et al. Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma. The EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 1990;26:558–561.[Medline]
67. Patel SR, Vadhan-Raj S, Burgess MA et al. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol 1998;21:317–321.[CrossRef][Medline]
68. Leyvraz S, Bacchi M, Cerny T et al. Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK). Ann Oncol 1998;9:877–884.[Abstract/Free Full Text]
69. Reichardt P, Tilgner J, Hohenberger P et al. Dose-intensive chemotherapy with ifosfamide, epirubicin, and filgrastim for adult patients with metastatic or locally advanced soft tissue sarcoma: A phase II study. J Clin Oncol 1998;16:1438–1443.[Abstract/Free Full Text]
70. Santoro A, Tursz T, Mouridsen H et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcoma: A randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995;13:1537–1545.[Abstract/Free Full Text]
71. Antman K, Crowley J, Balcerzak SP et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 1993;11:1276–1285.[Abstract/Free Full Text]
72. Keohan ML, Taub RN. Chemotherapy for advanced sarcoma: Therapeutic decisions and modalities. Semin Oncol 1997;24:572–579.[Medline]
73. Papai Z, Bodoky G, Szanto J et al. The efficacy of a combination of etoposide, ifosfamide, and cisplatin in the treatment of patients with soft tissue sarcoma. Cancer 2000;89:177–180.[CrossRef][Medline]
74. Van Glabbeke M, van Oosterom AT, Oosterhuis JW et al. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: An analysis of 2,185 patients treated with anthracycline-containing first-line regimens—a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group study. J Clin Oncol 1999;17:150–157.[Abstract/Free Full Text]
75. Maki RG. Gemcitabine and docetaxel in metastatic sarcoma: Past, present, and future. The Oncologist 2007;12:999–1006.[Abstract/Free Full Text]
76. Baker LH, Frank J, Fine G et al. Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: A randomized comparative trial. A phase III, Southwest Oncology Group Study (7613). J Clin Oncol 1987;5:851–861.[Abstract/Free Full Text]
77. Rosen G, Forscher C, Lowenbraun S et al. Synovial sarcoma. Uniform response of metastases to high dose ifosfamide. Cancer 1994;73:2506–2511.[CrossRef][Medline]
78. Pommier Y, Kohlhagen G, Bailly C et al. DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 1996;35:13303–13309.[CrossRef][Medline]
79. Garcia-Carbonero R, Supko JG, Maki RG et al. Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: Multicenter phase II and pharmacokinetic study. J Clin Oncol 2005;23:5484–5492.[Abstract/Free Full Text]
80. Le Cesne A, Blay JY, Judson I et al. Phase II study of ET-743 in advanced soft tissue sarcomas: A European Organisation for the Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group trial. J Clin Oncol 2005;23:576–584.[Abstract/Free Full Text]
81. Janus A, Robak T, Smolewski P. The mammalian target of the rapamycin (mTOR) kinase pathway: Its role in tumourigenesis and targeted antitumour therapy. Cell Mol Biol Lett 2005;10:479–498.[Medline]
82. Chawla AP, Tolcher AW, Staddon AP et al. Updated results of phase II trial of AP23573, a novel mTOR inhibitor, in patients with advanced soft tissue or bone sarcomas. J Clin Oncol 2006;24:521S.
83. Sleijfer S, Papai Z, Le Cesne A et al. Phase II study of pazopanib (GW786034) in patients (pts) with relapsed or refractory soft tissue sarcoma (STS): EORTC 62043. J Clin Oncol 2007;25:552S.
84. D'Adamo DR, Keohan M, Schuetze S et al. Clinical results of a phase II study of sorafenib in patients with non-GIST sarcomas (CTEP study#7060). J Clin Oncol 2007;25:545S.

This Article Abstract Full Text (PDF) CME: Take the course for this article: The Pharmacologic Basis of Ifosfamide Use in Adult Patients with Advanced S... eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tascilar, M. Articles by Sleijfer, S. Search for Related Content PubMed PubMed Citation Articles by Tascilar, M. Articles by Sleijfer, S.