The antidepressant duloxetine was unable to prevent sensory oxaliplatin-induced peripheral neuropathy more significantly than placebo in patients with colorectal cancer receiving chemotherapy, according to the results of the Alliance A221805 trial published in JCO Oncology Advances.
“Since we know duloxetine is effective at treating painful neuropathy caused by neurotoxic chemotherapy drugs, we wanted to see if the medication could also prevent the side effect from developing in the first place,” said study chair for the Alliance A221805 trial Ellen M. Lavoie Smith, PhD, MSN, Interim Associate Dean of Research and Scholarship at the University of Alabama at Birmingham School of Nursing. “The results show that duloxetine is not more effective than a placebo at preventing neuropathy caused by chemotherapy in patients with colorectal cancer.”
Background and Study Methods
Duloxetine is a seotonin and norephinephrine reuptake inhibitor that has been used to treat established neuropathy.
The randomized, double-blind, placebo-controlled, multicenter phase II Alliance A221805 trial explored the use of duloxetine at two doses to see if it could prevent sensory oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer receiving chemotherapy.
A total of 199 patients were randomly assigned 1:1:1 to receive once-daily duloxetine at 30 mg or 60 mg, or placebo. All participants had stage II to III colorectal cancer and no neuropathy at baseline. Patients received oxaliplatin chemotherapy at 85 mg/m2 every 2 weeks (6 or 12 doses) or 130 mg/m2 every 3 weeks (4 doses). Duloxetine or placebo was administered starting on day 1 of the first cycle and continuously thereafter for 17 weeks.
The primary endpoint was a composite response onset and symptom severity of sensory oxaliplatin-induced peripheral neuropathy. This was measured in weeks 19 to 21 using patient-reported surveys focused on extremity numbness, tingling, and pain.
Key Findings
Only 143 patients were evaluable for the primary endpoint analysis due to modified intention-to-treat criteria.
Adherence rates were below 75% in all study arms.
There was no statistically or clinically meaningful difference between the treatment arms, so the study did not meet its primary endpoint. In the 30-mg duloxetine arm, the response rate was 65.2% of evaluable patients (n = 46), which meant that they had a highest sensory oxaliplatin-induced peripheral neuropathy score of two or less and did not withdraw from the study due to neuropathy; the response rate was 66% in the 60-mg duloxetine arm and 68% in the placebo arm.
About 27% to 30% of patients in each arm had sensory oxaliplatin-induced peripheral neuropathy scores above two.
Grade 3 or higher adverse events were reported in 30.2% of patients in the 30-mg duloxetine arm, 36.1% in the 60-mg duloxetine arm, and 31.3% in the placebo arm. The most common grade 3 or higher event was diarrhea.
Two participants in the study died, but only one of these events was considered possibly related to treatment–grade 4 hypokalemia in the 60-mg duloxetine arm.
“While duloxetine remains an important option for managing painful chemotherapy‑induced neuropathy once it develops, this trial confirms that it should not be used for prevention,” Dr. Smith said.
DISCLOSURES: This trial was supported by the National Cancer Institute of the National Institutes of Health. For full disclosures of the study authors, visit ascopubs.org.
