Pilot study: Is concomitant administration of lidocaine during oxaliplatin infusion able to prevent pain as a result of oxaliplatin induced acute neuropathy?

Annually, 12700 patients are diagnosed with colon cancer in the Netherlands.
The number of annual colorectal cancer deaths is approximately half the annual
incidence. Colon cancer is after prostate cancer the most common type of cancer
in men. In women, colon cancer takes a second place after breast cancer.
Of these patients, more than 50% will be treated with adjuvant chemotherapy
after an operation in order to reduce the recurrence risk. Despite a curative
treatment intention, an important part of the patients are faced with
metastases, and either in this situation they will receive chemotherapy to
extend life expectancy.
Oxaliplatin is a chemotherapeutic and the treatment of choice for many tumors
of the gastro-intestinal tract. Up to 90% of these patients develop an acute
neuropathy (i.e. a sodium channelopathy) as a result of the treatment with
oxaliplatin. In the acute phase (during oxaliplatin treatment) patients
experience intense pain and paresthesias in throat, face, hands and feet. In
25-30% of the patients, a chronic polyneuropathy (i.e. sensory neuropathy
develops with continuous painful hands and feet leading to discomfort
experienced by walking, holding cold things, or having difficulty with fine
motor skills.
These neuropathic symptoms result in a substantial reduction in quality of
life. The emergence of polyneuropathy seems to depend on the total administered
dose oxaliplatin, severity of acute pain and patient (immunological and
genetic) characteristics.
Medically, neuropathy is a reason to stop or reduce the dose of oxaliplatin.
This can result in a reduced probability of curative adjuvant treatment; and in
a reduced survival rate in case of oxaliplatin treatment for metastatic
disease, because without oxaliplatin treatment options are less.
Despite extensive research, there is still no effective treatment for
oxaliplatin-induced neuropathy; the usual analgesics (acetaminophen, NSAIDS,
morphine) have little or no effect on the symptoms. Additionally, there are no
known treatment options to prevent these symptoms.
Lidocaine is the only local anesthetic agent, considered safe for intravenous
use. It has analgesic, antihyperalgesic and anti-inflammatory properties.
Limited research has revealed lidocaine to reduce pain in patients with chronic
polyneuropathy. Proposed mechanisms are a direct effect of lidocaine on nerve
fibers or/and modulation of the immune system. The pathophysiologic mechanism
of oxaliplatin induced neuropathy are partially mediated via sodium- and
potassium channels and via inflammatory mechanisms, which can be addressed by
lidocaine.
We hypothesize that intravenous lidocaine reduces pain as a result of acute and
subsequently chronic oxaliplatin induced neuropathy when administered
simultaneously with oxaliplatin. Additionally we will investigate the acute
inflammatory response in patients receiving oxaliplatin and lidocaine.
Inflammatory factors play a role in pain transmission, we hypothesize lidocaine
will modulate this.
Intravenous lidocaine administration during oxaliplatin treatment seems to be a
very interesting, safe and low cost therapeutic option in the treatment of
acute chemotherapeutic induced neuropathy, which additionally will lead to an
improved oncologic treatment and improved quality of life of cancer patients.
Moreover, several other chemotherapeutics (paclitaxel, vinca alkaloids,
bortezomib, cisplatin) are known for the development of neuropathy. The
insights this (pilot) study will reveal, can be of particular interest to other
patient groups

Primary objective
To evaluate the efficacy of low dose intravenously lidocaine in comparison with
placebo in terms of pain relief after the first oxaliplatin administration
measured by a numeric rating scale (NRS 0-10).

Secondary objectives
1. Difference in pain scores between placebo and low dose intravenously
lidocaine administered concomitant with oxaliplatin during and after all cycles
of oxaliplatin administration.
2. Does low dose intravenously lidocaine administered concomitant with
oxaliplatin attenuate systemic inflammatory response measured by plasma
cytokine levels of interleukin (IL)-6, IL-8, IL-10, IL-1β, TNF-α and ICAM-1?
3. To evaluate if low dose intravenously lidocaine administered concomitant
with oxaliplatin influences quantative sensory testing (pressure algometry and
ice-bucket).
4. To evaluate if low dose intravenously lidocaine administered concomitant
with oxaliplatin reduces chronic neuropathic changes measured by the clinical
total neuropathy score (TNS), neurophysiologic conductions studies, and
measured by a NCI-CTC and EORTC QLQ-CIPN20 questionnaire.
5. Cumulative oxaliplatin dosage.
6. Cumulative analgesics usage.
7. Other secondary outcomes consists of quality of life improvements measured
by EORTC QLQ-C30 and patient reported outcome variables for sensory function.

On the basis of a review of the literature on pain measures prepared for the
IMMPACT - II consensus meeting and discussions among the participants, an
11-point (ie 0-10) NRS measure of pain intensity is recommended as a core
outcome measure in clinical trials of chronic pain treatments.

Reduction in pain intensity using the NRS is not the only clinical relevant
measurement evaluating efficacy of pain treatment. Severity and consequences of
the oxaliplatin induced neuropathy is another outcome. We propose this will be
measured by the clinical total neuropathy score, quantitative sensory testing
(pressure algometry), NCI-CTC questionnaire, EORTC QLQ-CIPN20 questionnaire,
and neurophysiologic studies (skin wrinkle testing, nerve conduction studies,
surface EMG and needle EMG if necessary), which are commonly used in other
studies. Skin wrinkle testing is a reliable and efficient technique to detect
small fiber neuropathy. Combining different measurements for detecting
neuropathy and grading the severity of chemotherapy induced neuropathy is
advised in literature.

This study will be a single center double blinded randomized placebo controlled
trial

Group I receives 1,5 mg/kg bolus of lidocaine intravenous 30 minutes before
oxaliplatin administration followed by 1,5 mg/kg/h continuous infusion for 3
hours.
Group II receives saline in equivalent volumes.

Subjects will receive every oxaliplatin infusion the same study medication.

Subjects will be asked for NRS scores before, every hour during oxaliplatin
administration and until 5 days after each oxaliplatin infusion (diary; pain
scores of hand/feet, throat discomfort, muscle cramps, sensitivity to
swallowing cold items and sensitivity touching cold items). During oxaliplatin
administration and till 5 days afterwards patients will register sensory
differences as a result of oxaliplatin.
During administration of the study medication subjects will be monitored
respiratory and hemodynamically, to ensure possible side effects of lidocaine
will be captured.
An additional intravenous line will be placed to administer lidocaine.
After the first oxaliplatin administration there will be an extra vena punction
for blood samples to determine cytokine levels and RNA biobanking.
At baseline, before the fourth and eight oxaliplatin infusion and at 3 months
follow up a clinical total neuropathy score and quantative sensory testing will
be examined (30 min)
A NCI-CTC and EORTC QLQ-CIPN20 questionnaire will be performed at baseline,
before each oxaliplatin infusion and at 3 months follow up (15min)
At baseline and at 3 months follow up a EORTC QLQ-C30 will be questioned
(+/-10min).