Trial design
This study was a double-blind, parallel randomized placebo-controlled clinical trial to assess lithium’s efficacy and safety for CIPN prevention in breast cancer patients undergoing chemotherapy. The method of assigning individuals to groups was randomized blocks of four. Patients were randomly assigned to the drug (n=18) or the placebo (n=19) groups by a ratio of 1:1. The study was approved by the Ethics Committee of the Islamic Azad University of Pharmaceutical Sciences (IAUPS), Tehran, Iran (No: 374).
Participants
The inclusion criteria were having a breast cancer diagnosis, aged between 18 and 60 years old, undergoing chemotherapy, and agreement for participation by signing informed consent. The chemotherapy regimen consisted of four courses of Adriamycin-cyclophosphamide with four courses of taxanes-based medicines (AC4*T4). The exclusion criteria consisted of lack of interest to participate; comorbidities such as diabetes, cardiovascular disorders, renal disorders, bipolar, and thyroid disorders; the presence of peripheral nerve damage due to another illness and/or medication; pregnant or breastfeeding status; planning to become pregnant; opium addiction; lithium intoxication; and manifesting dangerous complications.
Intervention
Interested eligible patients were enrolled randomly by the blinded researcher from November 2017 to June 2019 at the Breast Clinic of Motamed Cancer Institute in Tehran, Iran. After obtaining written consent, patients were randomly assigned to one of the drug or placebo groups.
The placebo group patients were given one placebo tablet 1 day before initiating each chemotherapy cycle and continuing 4 days (5 days-one tablets per day). The placebo tablets were manufactured at the Industrial Laboratory of Islamic Azad University of Pharmaceutical Sciences Branch, Tehran, Iran. The placebo tablets’ main ingredients included starch, lactose, Avicel (microcrystalline cellulose), and PVP (polyvinyl pyrrolidone).
The drug group patients were given 300 mg lithium carbonate tablets, production of Tehran Darou Pharmaceutical Co. Tehran, Iran, for five consecutive days, starting 1 day before each chemotherapy cycle. Lithium is a well-known drug that is used as a mood stabilizer medicine among bipolar patients. We applied an intervention with a low dose of lithium carbonate due to the lack of human studies, ethical issues, and lithium interference with the Adriamycin-cyclophosphamide regimen. Carbonate salt is the only salt of lithium that exists in the Iranian pharmaceutical market. It is completely absorbed within 6–8 h, with plasma peak levels in 30 min to 2 h. Lithium is distributed in total body water and intracellular compartment slowly. Its initial volume of distribution is 0.5 L/kg, then rising to 0.7–0.9 L/kg. It has some sequestration in bone without protein binding. Lithium excretion is in the urine with a plasma half-life of about 20 h. According to the Nice guideline, lithium carbonate dosage is different in patients with a bodyweight of < 50 and > 50 kg. It can be prescribed up to 400 mg in a bodyweight of > 50 kg. Since most participants were > 50 kg, a daily dose of 300 mg was used to prevent side effects [22]. The placebo tablets and lithium carbonate tablets had a round, white, and striped appearance and thickness.
At the start of the study, participants’ demographic and clinical characteristics were recorded in a checklist. EMG-NCV tests in four limbs and neurologic signs and symptoms were measured before starting chemotherapy, 3 and 9 months after it. They were compared and evaluated in each group and between the two groups. Figure 1 shows a summary of the study design.
Outcome
-
1)
Signs and symptoms: these included numbness, tingling, freezing, sensitivity to touch, muscle weakness, and knee and elbow reflexes and were measured before chemotherapy, 3 and 9 months after starting chemotherapy by a blinded oncologist through examination.
-
2)
EMG-NCV: these tests were taken by a blinded neurologist before chemotherapy, 3 and 9 months after starting chemotherapy.
Instrument
Demographic and clinical characteristics such as age, reproductive status, stage of disease, lymph node number, tumor size, and hormone therapy were recorded by a checklist. During the 9 months of study, all patients’ signs and symptoms were recorded in a clinical registry form by the physician’s examination. The data of EMG-NCV indices were extracted from the neurologist’s report.
Sample size
The required sample size was calculated according to an animal study. In that study, sensory-motor activity was evaluated by the rotarod instrument. The length of time on the rotarod for the paclitaxel-saline-treated and paclitaxel-lithium-treated mice dropped to 67 + 6% and 5 + 9%, respectively, compared to vehicle-saline-treated mice. Considering the power of 0.8, significant level α=0.05, and a 10% dropout rate, the final sample size was estimated to be twenty patients in each group. So, forty patients were included in the study.
Randomization
In this study, a random block of four was provided in closed envelopes by a statistician. Letters A and B were considered intervention (chemotherapy + lithium) and placebo (chemotherapy + placebo) groups. The blocks consisted of equal numbers of A and B drugs with a random arrangement. Each eligible patient was enrolled in one of the two groups randomly through the available sampling method by a trained researcher. All the information about the type of intervention was confidential, and patients and investigators were not aware of the allocated groups. The tablets and the packs containing them were identical in appearance, size, and color to achieve this goal.
Statistical analysis
Results were analyzed using the Statistical Package for Social Sciences (SPSS) version 22. Considering the small sample size (less than 30 patients in each group), we used nonparametric tests despite the normal distribution of variables to increase this study’s power.
The chi-square test evaluated the frequency difference of the clinical and demographical variables between groups. Changes of EMG_NCV over the study time were assessed by the Friedman test. The generalized estimating equations (GEE) tests were performed to evaluate three-time spans’ interaction effect (before starting chemotherapy, 3 and 9 months after it) and two groups on the EMG_NCV changes. The interaction of time and group effect on symptom score was studied by GEE, too.