March 30, 2011 — The antidepressant venlafaxine (Effexor, Wyeth) has clinical activity against the most severe and dose-limiting cumulative adverse effect of oxaliplatin chemotherapy — neurotoxicity, according to a new study from France.
The phase 3 trial did not reach its targeted accrual of patients, but did reach its primary end point, with a significant reduction of patients experiencing acute neurologic toxicity in the venlafaxine group, report the authors, led by J.P. Durand, MD, from the Université Paris Descartes in France.
Pain scale scores indicated that "full relief" was more frequent in the venlafaxine group (31.3% vs 5.3%; P = .03).
The findings "may have immediate applications in the management of cancer patients under oxaliplatin-based chemotherapy," say the authors, who add that further study is needed.
The paper was published online March 22 in the Annals of Oncology.
"Even though I do not use venlafaxine in this setting, I would certainly use it based on this study," said Matti S. Aapro, MD, from Doyen IMO Clinique de Genolier in Switzerland, and a European Society of Medical Oncology spokesperson who was approached by Medscape Medical News for comment. He added that he might reduce the high loading dose in the protocol, which was associated with vomiting.
Dr. Aapro currently uses glutathione as an alternative method of reducing the chemotherapy-related neurotoxicity, "but this is not available in most countries," he said.
Explanation About Ending the Trial Early
During the trial, "most clinicians were convinced of the effect of venlafaxine and became reluctant to go on" randomizing patients to placebo, according to the authors.
The trial was slow to accrue patients because exclusions such as no concomitant antidepressant treatment barred many potential participants, they report.
The adverse effects associated with venlafaxine include grade 1/2 nausea (43.1%) and asthenia (39.2%), but there were no grade 3/4 events of any kind.
Venlafaxine is a serotonin/norepinephrine reuptake inhibitor that has shown therapeutic effects in the management of chronic and neuropathic pain, particularly in patients with diabetes mellitus, the authors explain.
They previously reported clinical activity of venlafaxine against acute neurotoxicity in a small series of patients receiving oxaliplatin (Anticancer Drugs 2003;146:423-425).
A potential explanation for the efficacy of venlafaxine is its protective effect against oxidative stress. Preclinical models indicate that venlafaxine modulates the oxidative stress in the nervous system, write the authors. At the same time, "there is growing evidence that oxaliplatin induces oxidative stress," they say.
Oxaliplatin is widely used in colorectal cancer and is an alternative option to cisplatin in various cancers, such as ovarian, gastric, and lung. "Because of its lack of nephrotoxicity, oxaliplatin is of particular interest in the growing population of 'unfit' patients," the authors note.
Study Details
The study was conducted in 6 university hospitals in France. Patients reporting acute neurotoxicity after the administration of their oxaliplatin-based chemotherapy were eligible.
Patients were randomized to placebo or to venlafaxine 50 mg 1 hour before oxaliplatin infusion and venlafaxine extended release 37.5 mg twice a day from day 2 to day 11 of chemotherapy. Study treatment was continued as long as oxaliplatin chemotherapy lasted.
The primary end point was the percentage of patients with 100% relief of acute neuropathy.
To determine this outcome, the investigators had patients who presented with oxaliplatin-induced acute neurotoxicity complete a pretreatment evaluation — the Neuropathic Pain Symptom Inventory (NPSI). The NPSI evaluates spontaneous ongoing pain, spontaneous paroxysmal pain, evoked pain, and paresthesia/dysesthesia.
Once therapy with venlafaxine began, patients rated their pain symptoms with the NPSI; each pain category was measured on a 0 to 10 numeric rating scale.
As noted above, about one third of the patients treated with venlafaxine achieved 100% relief of acute neuropathy. Similarly, there were significantly more patients experiencing a relief of 50% or more in the venlafaxine group (68.8% vs 26.3%; P = .02).
A secondary end point was the occurrence of cumulative permanent neurosensory toxicity. At 3 months after the end of treatment, there were more patients in the venlafaxine group than in the placebo group with grade 0 toxicity (38.5% vs 5.6%; P = .06), and significantly fewer patients with grade 3 toxicity (0% vs 33.3%; P = .03)
The toxicity profile of venlafaxine was "acceptable," with no grade 3/4 adverse events, report the authors. Grade 1/2 vomiting was observed more frequently with venlafaxine. Reducing the 50 mg loading dose of venlafaxine might help with vomiting, suggest the authors.
It is not known whether a pharmacokinetic interaction exists between oxaliplatin and venlafaxine, the authors point out. However, oxaliplatin is mainly eliminated by renal clearance and venlafaxine is primarily metabolized by liver CYP2D6. Thus, "the likelihood of a pharmacokinetic interaction is low," write the authors.
The study was promoted by EUREKA, an academic research association that received funds from Sanofi Aventis France for this trial. The researchers have disclosed no relevant financial relationships.
Ann Oncol. Published online March 22, 2011. Abstract
The phase 3 trial did not reach its targeted accrual of patients, but did reach its primary end point, with a significant reduction of patients experiencing acute neurologic toxicity in the venlafaxine group, report the authors, led by J.P. Durand, MD, from the Université Paris Descartes in France.
Pain scale scores indicated that "full relief" was more frequent in the venlafaxine group (31.3% vs 5.3%; P = .03).
The findings "may have immediate applications in the management of cancer patients under oxaliplatin-based chemotherapy," say the authors, who add that further study is needed.
The paper was published online March 22 in the Annals of Oncology.
"Even though I do not use venlafaxine in this setting, I would certainly use it based on this study," said Matti S. Aapro, MD, from Doyen IMO Clinique de Genolier in Switzerland, and a European Society of Medical Oncology spokesperson who was approached by Medscape Medical News for comment. He added that he might reduce the high loading dose in the protocol, which was associated with vomiting.
Dr. Aapro currently uses glutathione as an alternative method of reducing the chemotherapy-related neurotoxicity, "but this is not available in most countries," he said.
Explanation About Ending the Trial Early
During the trial, "most clinicians were convinced of the effect of venlafaxine and became reluctant to go on" randomizing patients to placebo, according to the authors.
The trial was slow to accrue patients because exclusions such as no concomitant antidepressant treatment barred many potential participants, they report.
The adverse effects associated with venlafaxine include grade 1/2 nausea (43.1%) and asthenia (39.2%), but there were no grade 3/4 events of any kind.
Venlafaxine is a serotonin/norepinephrine reuptake inhibitor that has shown therapeutic effects in the management of chronic and neuropathic pain, particularly in patients with diabetes mellitus, the authors explain.
They previously reported clinical activity of venlafaxine against acute neurotoxicity in a small series of patients receiving oxaliplatin (Anticancer Drugs 2003;146:423-425).
A potential explanation for the efficacy of venlafaxine is its protective effect against oxidative stress. Preclinical models indicate that venlafaxine modulates the oxidative stress in the nervous system, write the authors. At the same time, "there is growing evidence that oxaliplatin induces oxidative stress," they say.
Oxaliplatin is widely used in colorectal cancer and is an alternative option to cisplatin in various cancers, such as ovarian, gastric, and lung. "Because of its lack of nephrotoxicity, oxaliplatin is of particular interest in the growing population of 'unfit' patients," the authors note.
Study Details
The study was conducted in 6 university hospitals in France. Patients reporting acute neurotoxicity after the administration of their oxaliplatin-based chemotherapy were eligible.
Patients were randomized to placebo or to venlafaxine 50 mg 1 hour before oxaliplatin infusion and venlafaxine extended release 37.5 mg twice a day from day 2 to day 11 of chemotherapy. Study treatment was continued as long as oxaliplatin chemotherapy lasted.
The primary end point was the percentage of patients with 100% relief of acute neuropathy.
To determine this outcome, the investigators had patients who presented with oxaliplatin-induced acute neurotoxicity complete a pretreatment evaluation — the Neuropathic Pain Symptom Inventory (NPSI). The NPSI evaluates spontaneous ongoing pain, spontaneous paroxysmal pain, evoked pain, and paresthesia/dysesthesia.
Once therapy with venlafaxine began, patients rated their pain symptoms with the NPSI; each pain category was measured on a 0 to 10 numeric rating scale.
As noted above, about one third of the patients treated with venlafaxine achieved 100% relief of acute neuropathy. Similarly, there were significantly more patients experiencing a relief of 50% or more in the venlafaxine group (68.8% vs 26.3%; P = .02).
A secondary end point was the occurrence of cumulative permanent neurosensory toxicity. At 3 months after the end of treatment, there were more patients in the venlafaxine group than in the placebo group with grade 0 toxicity (38.5% vs 5.6%; P = .06), and significantly fewer patients with grade 3 toxicity (0% vs 33.3%; P = .03)
The toxicity profile of venlafaxine was "acceptable," with no grade 3/4 adverse events, report the authors. Grade 1/2 vomiting was observed more frequently with venlafaxine. Reducing the 50 mg loading dose of venlafaxine might help with vomiting, suggest the authors.
It is not known whether a pharmacokinetic interaction exists between oxaliplatin and venlafaxine, the authors point out. However, oxaliplatin is mainly eliminated by renal clearance and venlafaxine is primarily metabolized by liver CYP2D6. Thus, "the likelihood of a pharmacokinetic interaction is low," write the authors.
The study was promoted by EUREKA, an academic research association that received funds from Sanofi Aventis France for this trial. The researchers have disclosed no relevant financial relationships.
Ann Oncol. Published online March 22, 2011. Abstract
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