Venlafaxine for prevention of oxaliplatin-induced peripheral neuropathy - A randomised clinical trial

Oxaliplatin is a third generation platinum based cytotoxic agent that is widely
used for the treatment of colorectal cancer, in adjuvant and metastatic
setting. In addition, oxaliplatin is also used in the treatment of other forms
of digestive cancer. The mechanism of action of oxaliplatin is not entirely
clear but it is hypothesized that oxaliplatin causes DNA damage which leads to
apoptosis of cancer cells.
When compared to its platinum-analogue cisplatin, oxaliplatin causes little or
no nephrotoxicity, less haematological toxicity and less gastrointestinal side
effects. Peripheral neuropathy is a side effect very commonly observed with all
platina-analogues, but the oxaliplatin-induced peripheral neuropathy (OIPN) has
its unique spectrum and is associated with dose-limiting toxicity. Peripheral
neuropathy is a painful disorder characterised by pain due to dysfunction or
disease of the nervous system at a peripheral level, a complex entity with many
symptoms and signs that fluctuate in number and intensity over time. Important
components of neuropathy are steady and neuralgic pain and hypersensitivity.
Neuropathic pain can be very disabling, severe and intractable, causing
distress and suffering for individuals, including dysesthesia and paresthesia.
Sensory deficits, such as partial or complex loss of sensation, are also
commonly seen. In addition, there are significant psychological and social
consequences linked to chronic neuropathic pain, which contribute to a
reduction in quality of life.
In OIPN, two different types of neuropathy are commonly observed: the acute and
more chronic form. Acute neuropathy occurs in approximately 60% of patients and
manifest itself particularly as intolerance to cold, paresthesia and
dysesthesia in the extremities and the perioral region, and an uncomfortable
feeling in the throat. These side effects occur mostly within hours after
infusion up till 1-2 days after first treatment. Acute neuropathy is generally
reversible and disappears within 7-14 days. The mechanism behind acute
neuropathy is unclear but experimental data suggest it is caused by oxaliplatin
affecting the axonal sodium channel function through damaging of microtubules.
The chronic form of neuropathy lasts longer and is associated with cumulative
doses and a significant reduction in quality of life. It is characterized by
distal dysesthesia and paresthesia that increase in intensity and duration with
the cumulative dose. Many patients experience effects still after 12 months
after cessation of chemotherapy. The mechanism that is most accepted to be the
cause of chronic neuropathy is accumulation of oxaliplatin in the dorsal root
ganglia and subsequent progressive loss of function. OIPN symptoms can be so
severe, that chemotherapy regimens have to be adjusted by treatment delays,
dose reductions or early discontinuations, which may affect cancer treatment
outcomes.
Treatment of neuropathy is not easy. Patients with neuropathic pain do not
always respond to standard analgesics such as non-steroidal anti-inflammatory
drugs (NSAIDs) and to some extent neuropathic pain is resistant to opiates. The
pharmacologic agents best studied and longest used for the treatment of
neuropathic pain are antidepressants and anticonvulsants. Several agents have
been examined and tested for the prevention and treatment of neuropathy
resulting from chemotherapy, with varying success. Intravenous calcium and
magnesium infusions have been extensively used for prevention of OIPN, after
earlier suggested beneficial effects, but the latest studies showed that the
effect of the electrolyte combination can not be proven and may even have
negative effects on cancer therapy outcome.
The mechanisms of action of antidepressant drugs in the treatment of
neuropathic pain remain uncertain. Analgesia is often achieved at lower dosage
and faster (usually within a few days) than the onset of any antidepressant
effect which can take up to six weeks. In addition, there is no correlation
between the effect of antidepressants on mood and pain. Furthermore,
antidepressants produce analgesia in patients with and without depression. Two
main groups of antidepressants are in common use. The older tricyclic
antidepressants (TCAs) such as amitriptyline and imipramine, and a newer group
of selective serotonin reuptake inhibitors (SSRIs). The clinical impression was
that TCAs are more effective in treating neuropathic pain. There is no evidence
that antidepressants have a pre-emptive effect in preventing the development of
neuropathic pain. ASCO guidelines describe a literature search to identify
possible preventive and therapeutic measures for chemotherapy induced
peripheral neuropathy. Two agents are proposed to have possible beneficial
effect: duloxetine and venlafaxine. The use of duloxetine, a selective
serotonin- and norepinephrine reuptake inhibitor, is based on a prospective
randomized clinical trial by Smith et al. In this study, duloxetine decreased
neuropathy pain score by 1,06 on a 11-point scale.
Venlafaxine is an antidepressant, a serotonin and, in higher dosages, a
norepinephrine reuptake inhibitor (SNRI); it has shown therapeutic effects for
the management of chronic and neuropathic pain, particularly in patients with
diabetes mellitus. It is suggested that venlafaxine blocks neuronal sodium
channels and thereby can prevent detrimental effect of neurotoxic agents such
as oxaliplatin. The rapid onset of the action of the SNRI is an advantage,
regarding the consideration that dose reduction of oxaliplatin can be prevented
by immediate control of neuropathic symptoms.
Two case reports describe the successful treatment of patients with severe
disabling oxaliplatin-induces neuropathy who greatly benefited from
venlafaxine. A prospective study from this group with venlafaxine showed
promising results for the treatment of acute neuropathy. It gave full relief of
neuropathy in 31,3 % of patients (n=54) versus 5,3% in the placebo group (P =
0.03). Venlafaxine was generally well tolerated as evidenced by the relatively
low incidence of adverse effects. Nausea, dizziness, fatigue, somnolence and
insomnia were the most frequently reported adverse effects, and they were
primarily of grade 1 and 2. These results are promising but due to the small
sample size of the study and the methodological limitations, the use of
venlafaxine is not recommended for routine use in the clinic, and the authors
suggest that additional research is necessary to provide supporting data.
Retrospective research in the Maasstad Hospital showed that in 92% of the
patients, treated with at least three cycles of oxaliplatin, any form of OIPN
occurred. This percentage is comparable to the findings in literature. Dose
reduction is currently the strategy to alleviate symptoms. In patients with
grade 3 or higher, stopping oxaliplatin is mandated, thereby hampering the
success rate of chemotherapy. Some patients are seen by a neurologist.
Electromyograms (EMG) are sometimes performed in these patients to examine the
extent of peripheral nerve damage. For patients with persisting complaints,
either antiepileptic agents (e.g. carbamazepine, pregabalin, gabapentin) or
antidepressants (TCA, venlafaxine) are prescribed. The choice for a specific
drug is made on the basis of the physician*s preference.

Given the significant number of patients with OIPN and the possible
prophylactic properties of venlafaxine, this study is designed. This study will
consist of a randomised placebo-controlled clinical trial to study the
prophylactic effect of venlafaxine on the incidence and severity of OIPN in
patients treated with oxaliplatin.

To determine the effect of venlafaxine versus placebo on the incidence of
patients with chronic OIPN (%) after 3 cycles of oxaliplatin containing
chemotherapy (130 mg/m2 every three weeks regimen). Incidence is defined as the
occurrence of patients with any grade neuropathy symptoms as defined by adverse
event criteria of the US National Cancer Institute (Common Terminology Criteria
for Adverse Events 2010).

Double blind, placebo-controlled phase III clinical trial to evaluate the
efficacy of venlafaxine for prevention of OIPN during treatment with
oxaliplatin. The study will take place in the Maasstad Hospital Rotterdam,
Ikazia Hospital Rotterdam, Spijkenisse Medical Center and Van Weel Bethesda
Hospital in Dirksland. Patients who receive oxaliplatin as part of their
adjuvant or palliative XELOX regimen (iv oxaliplatin 130 mg/m2 every 3 weeks
combined with po capecitabine 1000 mg/m2 bid for 2 weeks, with or without
bevacizumab) for colorectal, oesophageal, pancreatic or stomach cancer will be
asked to participate. A total of 150 patients will be recruited and randomised
to the intervention arm or placebo arm in a 1:1 ratio. Inclusion will take
place over a period of about 2 years.

Patients will be randomly assigned to receive one of the following double-blind
treatments during the course of chemotherapy:

Venlafaxine hydrochloride extended release capsules (XR) or matching placebo
37,5 mg once daily (OD) in week 1 of cycle 1 and twice daily (BID) in week 2
and further. Increase to 75 mg BID is possible (to doctors insight) after cycle
2 if OIPN Grade >=2 occurs. This dose escalation option is based on the data in
neuropathic pain.

Retrospective research in the Maasstad Hospital showed that in 92% of the
patients, treated with oxaliplatin, OIPN occurred. This percentage is
comparable to the findings in literature. Given the significant number of
patients with OIPN and the possible prophylactic properties of venlafaxine this
study is designed. The use of venlafaxine for neuropathy is based on several
preliminary small scale clinical studies. This study attributes additional data
on the use of venlafaxine, and can thereby lead to a recommendation for
venlafaxine in the prevention of OIPN.