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INTRODUCTION |
Ifosfamide, a structural analogue of cyclophosphamide,
is widely used as a first-line agent in the treatment of a variety of
solid tumors in the pediatric age group.1 Although its
early use was limited by severe hemorrhagic cystitis, the introduction of sodium 2-mercaptoethanesulphonate in the 1980s has provided bladder
protection, enabling ifosfamide to be used in higher and more
frequent dosing.2
Preclinical toxicologic studies of ifosfamide failed to detect any
significant nephrotoxicity.3 However, with the extended use
of this agent, evidence for nephrotoxicity in children has been
accumulated. Although ifosfamide-induced renal toxicity can involve
each segment of the nephron, proximal tubulopathy characterized by
tubular wasting of glucose, phosphate bicarbonate amino acids, and
protein is the most common pattern of toxicity.4
As the survival rate of children with cancer improves, both the short-
and the long-term toxicity of chemotherapy is receiving greater
attention. The importance of long-term ifosfamide-induced renal damage
is emphasized further by some reports that have demonstrated persistent
renal Fanconi syndrome in up to 5% of ifosfamide-treated patients over
a 2-year follow-up period.5,6 Many risk factors have been
proposed to play a role in the development of nephrotoxicity in
children receiving ifosfamide, including patient's age, cumulative dose of ifosfamide, method of its administration, previous or concurrent administration of platinums or other nephrotoxic agents, radiation, and unilateral nephrectomy.
Presently, the literature is far from consistent regarding the weight
of each risk factor. Complicating the issue further, the large
interindividual differences in the occurrence and severity of
ifosfamide-induced nephrotoxicity in children of similar ages receiving
similar doses of the drug may limit the generalization of the
predictive value of each risk factor for all ifosfamide-treated patients.
The objectives of this work were to review critically the evidence for
each of the different risk factors and to examine the relative
importance of each of them in predicting the development and severity
of this side effect.
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CUMULATIVE IFOSFAMIDE DOSE |
As with many other adverse drug reactions, ifosfamide-induced
nephrotoxicity was claimed to be dose-dependent. Skinner et al recently
studied 23 children who had received ifosfamide for various
cancers.5 None of the children had received cisplatin or undergone nephrectomy, two important confounders. In a multiple regression analysis, only the total ifosfamide dose was associated significantly with proximal tubulopathy. Moreover, this study has
demonstrated a significant linear correlation between the cumulative
dose of ifosfamide and the different markers of tubulopathy (serum
phosphate, serum bicarbonate. and renal tubular threshold for
phosphate). This report also indicated that a cumulative ifosfamide dose of 100 g/m2 should be avoided in an attempt to reduce the severity and frequency of nephrotoxicity induced by ifosfamide. This recommendation arises from the observation that among the 10 children who had received <100 g/m2, only 2 developed
moderate toxicity compared with 6 of 10 children who had received 
100 g/m2 who developed moderate to severe tubulopathy. Many
other studies have independently supported the observation of
dose-dependency of ifosfamide-induced nephrotoxicity. However, most
studies have indicated a total dose of 60 g/m2 as the
cutoff cumulative dose that represents a higher risk for
nephrotoxicity.7,8 Clearly, Skinner's study has a very
limited sample size to allow definite delineation of 100 g/m2 as a cutoff point.
Ifosfamide is metabolized to 4-hydroxyifosfamide, chloroacetaldehyde,
and acrolein, all reactive metabolites that have been demonstrated to
induce oxidative stress by depleting lymphocytes glutathione.2,9 Although renal tubular cells contain
relatively high concentrations of glutathione, these may be subject to
a degree of depletion, especially during high individual and cumulative doses of ifosfamide.
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AGE |
Data on age-dependent differences in ifosfamide-induced
nephrotoxicity have emerged from different studies; we analyzed rates of nephrotoxicity among 102 children who received the drug between 1984 and 1989 in Toronto, Canada, and who had sufficient tests performed.10 The 25 children exhibiting nephrotoxicity
were younger (78.1 ± 64.1 months) than those without
nephrotoxicity (104 ± 67 months) (P < .05). The two groups did not differ in their numbers of ifosfamide
cycles or its cumulative dose, or dose of sodium
2-mercaptoethanesulphonate per cycle. However, the children exhibiting
nephrotoxicity had been more likely exposed to cisplatin (40% vs 18%)
(P < .05) and had significantly larger decreases in their height percentile, suggesting that more severe renal
changes may result in stunted growth.
These data were confirmed independently by Skinner and
colleagues,11 who have shown that in children treated with
ifosfamide, those <5 years of age had significantly lower plasma
phosphate concentrations (0.69 ± 0.17 mmol/L) than those >5
years of age (1.17 ± 0.9 mmol/L) (P = .03). The researchers noted that younger children generally should have
higher plasma phosphate concentrations, further emphasizing the
differences. In this study, children exposed to ifosfamide were not
treated with cisplatin, thus correcting for the potential confounder in
our larger study.
A total of 74 children with malignant mesenchymal tumors who have all
received the same ifosfamide chemotherapy protocol were studied 1 year after the completion of treatment.12 None of the
children had received cisplatin chemotherapy, and all of them were in
complete remission correcting for these two important risk factors.
Severe toxicity resulting in Fanconi syndrome was correlated with both
younger age (<30 months) and higher cumulative dose of ifosfamide (60 g/m2). Lower rates and mild forms (mild generalized
aminoaciduria only) of tubulopathy were noted after a relatively high
total dose of ifosfamide (72 g/m2) in an older cohort of
patients (age range, 7-20 years) to further support younger age as an
important risk factor especially for the severe forms of
tubulopathy.13
Compared with tubulopathy, ifosfamide-induced glomerular toxicity
commonly affects older children, probably reflecting the late onset of
this problem.14
That ifosfamide tends to be more nephrotoxic in the young is in
contrast to the pathology seen with aminoglycosides and cisplatin and
suggests a very different mechanism of renal damage. A previous report,15 together with preliminary data from our
laboratory (C. Woodland, S. Ito, J. Klein, personal communication),
suggests renal capacity to metabolize ifosfamide as the mechanism
of renal damage. Whether age-dependent differences in renal drug
metabolism or active metabolites detoxification play a role in
ifosfamide renal toxicity is currently under investigation.
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CONCURRENT AND/OR PREVIOUS PLATINUMS THERAPY |
Among all nephrotoxic agents, cisplatinum and carboplatinum had
received the greatest attention as potential risk factors for
ifosfamide-induced renal toxicity. Rossi and coworkers studied 120 children and adolescents 3 or more months after completion of
chemotherapy including treatment with ifosfamide.6
Using the different nephrotoxic agents (cisplatin, methotrexate,
gentamycin) as independent variables in a stepwise regression model
proved a highly significant influence, with a calculated odds ratio of 6.4 of concomitant cisplatin therapy on ifosfamide nephrotoxicity. Interestingly, neither gentamycin nor methotrexate had any influence on
the incidence or severity of ifosfamide-induced tubulopathy. Goren et
al evaluated the influence of previous therapies with three
tubular nephrotoxins (cisplatin, high-dose methotrexate, and
aminoglycosides), lower abdominal irradiation, and unilateral nephrectomy on ifosfamide-related tubulopathy in 36 patients with solid
tumors.16 A multiple linear regression analysis showed the
number of previous cisplatin doses (90 to 100 mg/m2 per dose) to be the factor related most closely to the total urinary protein excretion. This analysis indicated that patients who had received at least three doses of cisplatin had significantly higher levels of urinary protein excretion, compared with those who had received three or fewer doses. Because all of the other agents were
distributed evenly between the two groups, it is probably the cisplatin
that potentiates ifosfamide toxicity. However, it is noteworthy that
urinary protein excretion is a nonspecific indicator of renal damage in
general rather than a specific indicator of either ifosfamide or
proximal tubular damage. Moreover, there are no data to relate the
magnitude of urinary protein excretion to the severity of
nephrotoxicity induced by ifosfamide. Our study10 further
supports concurrent platinum treatment as a significant risk factor by
showing that among the 25 children with ifosfamide-induced tubulopathy,
40% had received previous cisplatin therapy, compared with 18% in
those with normal renal function (P < .05).
Importantly, ifosfamide-induced tubulopathy was detected in the same
range of incidences (16% to 30%) and severity in studies that
controlled for platinums therapy.5,11 This fact indicates that concurrent and/or previous cis/carboplatinum administration probably is not a major single predictive risk factor.
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UNILATERAL NEPHRECTOMY |
Among a cohort of 120 children studied by Rossi and
colleagues,6 10 had undergone unilateral nephrectomy.
Subanalysis of these patients revealed that 3 of them developed the
full Fanconi syndrome and another 3 generalized tubulopathy, whereas
only 4 remained with normal renal functions. Comparison of the
nephrectomized versus the nonnephrectomized patients showed a relative
risk of 11.4 to develop renal Fanconi syndrome among the former.
Despite the small sample size, these data raise concerns that
nephrectomy might be an important risk factor for ifosfamide
tubulopathy.
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METHOD OF ADMINISTRATION |
There are no convincing data from clinical studies that the method
of intravenous ifosfamide administration (bolus vs short infusion vs
continuous infusion) affects the risk of nephrotoxicity. Although
continuous infusion of ifosfamide over 5 days (an extreme dose
fractionation) had been reported to increase the maximal tolerated
dose,17 a recent study reported a lower response rate after 2 g/m2/day of ifosfamide administered as a continuous infusion for 4 days, compared with that seen after the same total dose
administered as a daily 4-hour infusion on 4 consecutive days in adults
with soft tissue sarcomas.18 Moreover, there are several
reports of severe forms of tubulopathy with either forms of
administration.19-21
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SUMMARY |
Taken together, the data appear to indicate that the most
consistent predictive risk factor for renal toxicity is the cumulative dose of ifosfamide. This factor is proved to be related to both the
incidence and the severity of proximal tubulopathy in almost all of the
studies that have analyzed the different risk factors.
It is unclear whether there is a safe threshold above which the risk of
developing renal toxicity increases significantly. Although many
studies indicate a cumulative dose of 60 g/m2 as the
cutoff point, a recent publication suggested a less conservative cumulative dose of 100 g/m2 as the dose that should not be exceeded. It is important, however, to realize that avoidance of
cumulative doses of either 60 g/m2 or 100 g/m2
will probably lead to reduced frequency and severity of nephrotoxicity
rather prevent it altogether. This is primarily attributable to the
large interindividual variability in ifosfamide-induced nephrotoxicity, which can be explained in part by the interindividual differences in
the extent and rate of ifosfamide metabolism.
Both concurrent cisplatinum administration and a single functioning
kidney probably potentiate renal damage induced by ifosfamide. However,
studies that controlled for cisplatinum administration and the small
number of nephrectomized patients who were analyzed exclude these
factors as major independent predictive determinants.
As opposed to many other agents, ifosfamide appears to be related to
younger age in induced renal toxicity, and especially to more severe
forms of proximal tubulopathy. Presently, almost nothing is known
about the renal handling of ifosfamide and its metabolites. Any attempt
to explain age- dependent changes must await detailed characterization
of the renal handling of the drug and its metabolites. Subsequently, it
may be possible to try to develop approaches to protect the developing
kidney while allowing the benefits of this important agent.
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Abstract
Introduction
