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
Background of the study:
Cisplatin (CDDP) is a major compound in 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 neurotoxicity during treatment with cisplatin. Recent
studies have shown that the association of anti-oxidants to the 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 efficacy and of side-effects) 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.
Objective of the study:
- 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. If peripheral neuropathy can't be measured,
neuropathy will be assessed as ototoxicity through measuring audiograms.
- 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 (Karnofsky performance index) and
quality of life.
Monocenter, non-academical teaching hospital, double-blind randomized placebo-controlled
50 Consecutive patients, who will receive at least 4 cycles of cisplatin in the treatment of
NSCLC, SCLC and malignant mesothelioma, will be admitted, irrespective of the disease stage.
Patients will be randomized in a placebo-arm and a NAC-arm. They will receive
study-medication (NAC or placebo) intravenously every 3 weeks, each time 6 hours after the
completion of the cisplatin-infusion.
Nature and extent of the burden and risks associated with participation, benefit and group
- Burdens: Patients will have to undergo three electromyographic (EMG) tests, which will
normally take place 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. When EMG's can not be measured, audiograms
will be used, these audiograms are also part of the routines of treatment, so are not
considered an extra burden. Patients will have to fill in Quality of Life
- Risks: NAC is a well known drug, used for over thirty years, that is well tolerated.
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 appropriate 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
preterm arrest of treatment.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
The occurrence of peripheral neuropathy: with the peripheral neuropathy score (PNP-score) and the electrophysiological measurements. If no EMG is available, then audiometric measurements will be taken into account.
Idris Bahce, MD
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)