Plasmapheresis reverses all side-effects of a cisplatin overdose – a case report and treatment recommendation
© Hofmann et al; licensee BioMed Central Ltd. 2006
Received: 26 July 2005
Accepted: 04 January 2006
Published: 04 January 2006
Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death.
We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m2 of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae.
To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects.
Cisplatin is a widely used antineoplastic agent which is effective against different types of tumours. In addition to its high antitumour activity, cisplatin is a drug with potential side effects including nephro-, neuro-, myelo- and ototoxicity, as well as liver damage and severe emesis. These toxicities are dose-dependent and dose- and therapy-limiting. The maximum tolerated single dose of cisplatin is considered to be 100 to 120 mg/m2 per cycle and should be administered with adequate pre- and posthydration [1, 2]. However, accidental overdose of cisplatin may occur despite all precautions and to date, no general accepted guidelines for the treatment of such cases are available.
GOT = AST (U/l)
GPT = ALT (U/l)
GGT = GGTP (U/l)
laboratory findings demonstrating renal function
day before/after overdose
GFR (ml/min/1.73 m2)
In 1992, the first warning for all physicians and hospital pharmacists regarding erroneous cisplatin dosing was published  after the reporting of several cases of cisplatin overdose to a pharmaceutical company. Three possible mechanisms of errors were identified: total dose of one cycle divided over a period of days was given as a daily dose (as in our case), administration of cisplatin instead of carboplatin, and the prescription and administration of an overdose itself. Due to the fact that no antidote exists for cisplatin, a continuous effort has been made to protect patients from cisplatin induced toxicities since the early 1980's [1, 2, 4, 5]. Besides prevention, a possible treatment option for a cisplatin overdose was identified as to try to directly eliminate cisplatin from body fluids.
Hemodialysis, for example, is able to reduce free cisplatin in plasma, but cisplatin binds to plasma proteins after administration very quickly and therefore cannot be further eliminated by this procedure [6, 7]. In addition, it has been shown that there exists a rebound of cisplatin into plasma from an exchangeable pool shortly after hemodialysis. Plasmapheresis substantially removes plasma with its proteins and therefore the protein-bound fraction of cisplatin (see Figure 3), which seems to be a large part of this exchangeable pool of cisplatin distributed in the body. The same rebound-phenomenon as observed in hemodialysis exists after plasmapheresis (see Figure 1), but due to the better clearance of cisplatin, which is mostly plasma-protein bound in vivo, the platinum-pool is reduced more effectively.
The cisplatin-fraction which is distributed in this exchangeable pool, is mostly responsible for prolonged toxic effects [6, 8]. In addition to our experience, data from the cases reported in literature (Table3) show that only plasmapheresis performed before day 12 after overdose leads to the complete recovery of the patients including hearing loss without sequelae. It seems that the delay in the start of treatment prolonges cisplatin distribution from this exchangeable pool into other body compartments and consequently causes irreversible damage . Plasma exchange started even on day 12 after overdose was still able to reduce plasma platin levels on the one hand and improve clinical symptoms on the other hand . Therefore, plasmapheresis should be performed in any case of a cisplatin overdose regardless of the time elapsed since overdose to at least attempt to improve the patient's condition of the patient. In two other published cases, plasmapheresis was performed together with administration of a chemoprotectant, but the role of the protectant in ameliorating symptoms in this cases remained unclear [9, 10]. Chemoprotection itself is another approach of combatting therapy-induced side effects in general. Several cytoprotective agents have been tested with cisplatin-based therapies and have proven to reduce and even avoid toxic events. They all have the common feature of compounds containing sulfur. Their mechanism of action is thought to be free radical scavenging, covalent binding to the agent or both, but is still not entirely understood [1, 2, 4].
treatment, delay to start of treatment and outcome of published cases
Brivet et al.
alive, CRF, hearing loss
Schiller et al.
Delanian et al.
alive, CRF, hearing loss
Chu et al.
Lagrange et al.
Jung et al.
total 640 mg
Sheik-Hamad et al.
alive, hearing loss
Erdlenbruch et al.
Choi et al.
total 750 mg
HD, NAC, PPH
Charlier et al.
Referring to our case and the cases reported [19, 20], plasmapheresis performed as soon as possible should be considered as integral part of treatment when a cisplatin overdose occurs. Plasmapheresis itself has calculable risks [21–24] and is available in most hospitals with units for hemodialysis. The early administration of chemoprotectants, mainly sodium thiosulfate, should be taken in consideration as well , until the patient can be transferred to a specialised center with the possibility and experience of plasma exchange. However, the best strategy still remains to be the prevention of such errors since even these treatments may be unsuccessful [9, 10]. We therefore recommend to evaluate, establish and implement the best possible and accurate control mechanisms on different levels for prescription, preparation and administration of chemotherapy agents in general and in cisplatin-based regimens in particular.
List of abbreviations used
granulocyte-colony stimulating factor
granulocyte-macrophage-colony stimulating factor
standard operating procedure
Written consent was obtained from the patient's husband for publication of this case.
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