A randomized double-blind study of N-Acetylcysteine vs. placebo to Prevent Neurotoxicity induced by Platinum containing chemotherapy in patients treated for (Non)Small Cell Lung Cancer and Malignant Mesothelioma.

Cisplatin (CDDP) and carboplatin are major compounds of chemotherapy in
patients with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC)
and malignant mesothelioma. Cisplatin is associated with a number of
side-effects, one of which is neurotoxicity. For a number of patients this
neurotoxicity is a dose-limiting side-effect. At this point no measures are
taken to prevent the occurrence of this neurotoxicity during treatment with
cisplatin. Recent studies have shown that the association of anti-oxidants to
treatment with cisplatin has a neuroprotective effect without loss of
anti-tumour efficacy of cisplatin. One of these anti-oxidants is glutathione
(GSH), this is a natural anti-oxidant that is synthesized in all cells, mainly
in the liver and the muscles. This GSH plays a central role in the
pathophysiology of cisplatin. We want to investigate the efficacy of
N-acetylcysteine (NAC), which serves as a substrate for the synthesis of GSH,
in the prevention of cisplatin-induced neurotoxicity. NAC has been shown to
increase the GSH levels in the serum, it is also according to this principle
that NAC is currently used in the treatment of
acetaminophen-(paracetamol)-intoxications, where it replenishes the
GSH-depletion of the liver.

The primary objective is to establish the neuroprotective efficacy of NAC
against cisplatin-induced neurotoxicity. Mainly the sensory neuronal guidance
will be assessed before and after treatment with cisplatin in a group of
patients receiving NAC compared to a control-group receiving placebo. The
secondary objectives are establishing the protective effect of NAC regarding
other cisplatin-induced side-effects such as haematological pathology (anaemia,
leucopenia, thrombopenia, febrile neutropenia), loss of creatinine clearance
and occurrence of liver-chemistry abnormalities. Secondary objectives include
also establishing the effect on tumour response, clinical performance
(Karnofski performance index) and quality of life.

Monocenter, non-academical teaching hospital, double-blind randomized
placebo-controlled study.

Patients will be randomized in a placebo-arm and a NAC-arm. They will receive
intravenous study-medication every 3 weeks, each time 6 hours after the
completion of the cisplatin-infusion.

Burdens: The most important burden is the electromyographic (EMG) testing,
which will normally take place 3 times during the course of the whole
treatment, therefore patients will have to visit the hospital to be measured.
To minimize this burden, the EMG-measurements will be planned on the same day,
the patient has to visit the hospital for reasons regarding his/her regular
chemotherapy-treatment. Only surface patch electrodes will be used (no needle
electrodes). All other information will be obtained from the patients* files
(blood samples, physic evaluations, etc) these are considered to be part of the
routines of treatment. Patients will have to fill in Quality of Life
questionnaires.
Risks: For intravenous NAC, allergic reactions have been reported. There is
also a theoretical risk, that NAC may reduce anti-tumour efficacy of cisplatin,
this risk will be theoretically ruled out by appropiate dosing of NAC. After
inclusion of the first 30 patients an interim analysis will be performed
regarding the tumour response.
Benefits: NAC will possibly prevent the occurrence of neurotoxicity, improving
quality of life. This may, in turn, result in less probability of
dose-reductions and of pre-term arrest of treatment.