Carmustine (BCNU)
BiCNU · Nitrosourea alkylator
Delayed interstitial fibrosis with high cumulative dose.
CINTMA
ModerateOpen →
Nitrosourea (alkylating)
Fotemustine
Muphoran · FTM
A lipophilic nitrosourea for melanoma and glioma whose class carries delayed, cumulative tubulointerstitial kidney injury — usually mild, but occasionally consequential.
ModerateLate-1980s nitrosourea · approved 1989
Disseminated malignant melanoma, including cerebral metastasesRecurrent high-grade glioma / glioblastoma (often after temozolomide)
Signature kidney injury
Chronic Interstitial Nephropathy
Renal toxicity is generally reported as mild within fotemustine regimens, but, consistent with the nitrosourea class, delayed tubulointerstitial injury/ATN can occur; in one combination study renal toxicity was mild yet possibly contributed to two deaths. Drug-specific incidence is not well quantified and is often confounded by co-administered cisplatin.
Source: Semb et al., Melanoma Res 1998
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityModerate
ReversibilityPartially reversible
Evidence0 refs
Nephron map
Proximal Tubule
Distal Tubule / Collecting Duct
InterstitiumSupporting tissue around the tubules
Chronic Interstitial Nephropathy
Slow, cumulative tubulointerstitial scarring — fibrosis, tubular atrophy and glomerulosclerosis with no discrete acute phase. The nitrosourea (carmustine/lomustine) lesion and delayed radioligand (radiation) nephropathy; often irreversible and detected only as a creeping creatinine months to years later.
Mechanism of kidney injury
As a chloroethyl-nitrosourea, fotemustine and its reactive metabolites can alkylate and carbamoylate renal tubular and interstitial proteins, producing the class-typical pattern of cumulative, dose-related tubulointerstitial nephritis and tubular (ATN-type) injury seen with other nitrosoureas (e.g., carmustine, lomustine, semustine). Injury is delayed and dose-dependent. Direct mechanistic data specific to fotemustine are limited; the profile is largely inferred at the class level.
Clinical presentation
Typically an insidious rise in serum creatinine, sometimes with tubular dysfunction; overt AKI is uncommon at standard exposure. With high cumulative nitrosourea dosing the class can progress to chronic interstitial fibrosis and CKD. In combination regimens, acute renal events are often driven by accompanying cisplatin.
Onset
Delayed — weeks to months, and cumulative with repeated cycles; chronic interstitial injury may appear after prolonged exposure.
Reversibility
Partially reversible
Anticancer mechanism
Fotemustine is a chloroethyl-nitrosourea alkylating agent. Its high lipophilicity allows central-nervous-system penetration; it alkylates and cross-links DNA (chloroethylation at the O6 position of guanine), causing interstrand cross-links and cytotoxicity independent of cell cycle. It is used for disseminated malignant melanoma (including cerebral metastases) and recurrent high-grade glioma.
Management
No specific antidote. Hold or discontinue with significant or progressive renal dysfunction, provide supportive care and volume repletion, and manage as drug-induced tubulointerstitial injury. Given the delayed/cumulative nature, monitor renal function beyond the active treatment window.
Risk factors
- High cumulative nitrosourea dose
- Pre-existing renal impairment
- Concurrent nephrotoxins (notably cisplatin in melanoma regimens)
- Volume depletion from nausea/vomiting
Prevention
- Track and cap cumulative nitrosourea dose
- Baseline and serial renal function and urinalysis
- Maintain hydration
- Avoid stacking nephrotoxins where feasible
Note · Single-drug glioma series (e.g., GEINOFOTE; Scoccianti second-line) report predominantly hematologic toxicity with renal function generally preserved; the clearest renal signal arises in cisplatin-containing melanoma combinations, complicating attribution.
Clinical depth
Renal dose adjustment
Use caution and consider dose reduction or avoidance in significant renal impairment; specific renal dosing thresholds are not well established for fotemustine. Withhold for evolving renal dysfunction and reassess cumulative exposure.
Dialyzability & ESKD dosing
Dialyzability is not well characterized; nitrosoureas are lipophilic and rapidly metabolized, so dialysis is not a relied-upon removal strategy. Manage by dose limitation and monitoring rather than dialysis timing.
Differential diagnosis
Distinguish delayed nitrosourea tubulointerstitial injury from cisplatin ATN/electrolyte wasting in combination regimens, prerenal azotemia, and tumor- or contrast-related causes. The hallmark of nitrosourea nephrotoxicity is its delayed, cumulative, dose-related interstitial pattern.
Monitoring
- Serum creatinine / eGFR at baseline and before cycles, with delayed-onset surveillance
- Urinalysis for tubular markers
- Electrolytes
- CBC (thrombocytopenia/leukopenia are dominant, often delayed)
Key trials & series
- Semb et al. 1998 — FCT (fotemustine, cisplatin, tamoxifen) in metastatic melanoma; renal toxicity generally mild but possibly contributed to two deaths
- Scoccianti et al. 2008 — second-line single-agent fotemustine in temozolomide-pretreated glioblastoma (toxicity mainly hematologic)
- Perez-Segura et al. 2015 (GEINOFOTE) — fotemustine in recurrent high-grade glioma with poor performance status (renal function part of safety assessment)
Clinical pearls
- Nitrosourea kidney injury is characteristically delayed and cumulative — monitor renal function beyond the end of treatment.
- In fotemustine melanoma combinations, much of the acute renal signal is really cisplatin.
- Renal toxicity is usually mild but is not zero — it possibly contributed to deaths in the FCT regimen.
- Glioma monotherapy series show predominantly hematologic, not renal, dose-limiting toxicity.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Interstitium
Supporting tissue around the tubules
Injury signatures
Acute Tubular NecrosisChronic Interstitial NephropathyElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of nitrosourea (alkylating)s.
Ophthalmic
Keratopathy, uveitis, retinopathy
- Visual disturbance (crizotinib)
Hepatic / Liver
Transaminitis, hepatitis, VOD/SOS
- Transaminitis
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- CNS effects (lorlatinib)
Evidence
4 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkClinical experience of fotemustine, cisplatin and high dose tamoxifen in patients with metastatic malignant melanoma.Semb KA et al. · Melanoma Res 1998 · PMID 9918419Reports that renal toxicity with the FCT regimen was generally mild but possibly contributed to two deaths — the clearest fotemustine-associated renal signal.PMIDSecond-line chemotherapy with fotemustine in temozolomide-pretreated patients with relapsing glioblastoma: a single institution experience.Scoccianti S et al. · Anticancer Drugs 2008 · PMID 18525321Single-agent fotemustine glioblastoma series requiring adequate renal function; toxicity was mainly hematologic, contextualizing the modest direct renal risk.PMIDGEINOFOTE: efficacy and safety of fotemustine in patients with high-grade recurrent gliomas and poor performance status.Perez-Segura P et al. · Clin Transl Oncol 2015 · PMID 26542177Safety study of fotemustine in real-world high-grade glioma patients in whom renal function was part of eligibility and monitoring.PMID[Renal complications of anti-cancer treatments].Kessler M et al. · Rev Med Interne 1991 · PMID 1771317Class-level review identifying nitrosoureas among cytotoxics whose nephrotoxicity is frequent and dose-limiting, supporting the tubulointerstitial framing for fotemustine.
Related agents
Other agents sharing the same signature kidney injury.
Profile
Lomustine (CCNU)
Gleostine · Nitrosourea alkylator
Cumulative interstitial nephritis and CKD.
CIN
ModerateOpen →
Lutetium-177 Dotatate
Lutathera · Radioligand therapy (PRRT)
Peptide receptor radionuclide therapy; proximal tubular radiation nephropathy is dose-limiting — amino-acid co-infusion is renoprotective.
CINTMA
ModerateOpen →