Vitamin A Derivative Does Not Prevent Second Primary Tumors in Head and Neck Cancer Patients

Chemoprevention with low-dose 13-Cis retinoic acid (13-CRA; isotretinoin), a synthetic vitamin A derivative, did not lower the incidence of second primary tumors in patients with squamous cell cancer of the head and neck (SCCHN), according to long-term results of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590) trial published in Cancer.

These data are the longest follow-up to date showing the effects of a retinoid in preventing second primary tumors in patients with SCCHN.

Aarti K. Bhatia, MD, MPH, of the department of medical oncology at Yale University School of Medicine and Yale Cancer Center in New Haven, Connecticut, and colleagues, wrote that these results combined with those of a similar study at MD Anderson Cancer Center “conclusively rest this question of low-dose vitamin A analogs having a substantive chemopreventive role in patients with early-stage SCCHN.”

The trial included 176 patients with stage I/II SCCHN who were randomly assigned to either low-dose 13-CRA or placebo for 2 years. The median follow-up was 16.1 years. During follow-up, 108 patients died. More than three-quarters of patients received 13-CRA for 1 year; 52% received 2 years of treatment.

Forty-five patients had second primary tumors, most commonly in the head and neck (n = 11) and lungs (n = 10). At 2 years, treatment with 13-CRA did not significantly reduce the incidence of second primary tumor or the time to second primary tumor compared with placebo.

Data showed a trend toward improved survival with 13-CRA, particularly in patients whose index tumor was surgically excised (hazard ratio [HR], 0.50; P = .057), women (HR, 0.44; P = .065), and never/former smokers (HR, 0.61; P = .055).

According to the researchers, these results did not confirm benefits seen in the MD Anderson trial in which high-dose, short-term 13-CRA was received by patients with stage I to IV SCCHN.

“It is possible that the lower dose of isotretinoin used in the C0590 trial diminished the benefit previously observed with higher doses of the drug, either when used alone or when used in combination with interferon alpha and vitamin E in patients with locally advanced SCCHN,” they wrote. “It is also possible that excluding the locally advanced subgroup of patients mitigated a likely benefit, because this would be the subset with the highest risk of recurrence.”

The researchers noted that the lack of molecular characterization of tumors was a limitation to the study design, and that future studies of prevention in SCCHN should “factor in both prognostic and predictive molecular markers to optimize responses and resources.”