Taking a vitamin A derivative called isotretinoin did not reduce the risk of second primary tumors or improve survival in patients with stage I or II head and neck squamous cell cancers (HNSCC), according to a study in the April 5 issue of the Journal of the National Cancer Institute. In addition, current smokers had an increased risk of second primary cancers and death.
HNSCCs are the fifth most common cancers and sixth leading cause of cancer related death today. In 2002, there were 600,000 new cases diagnosed worldwide. Some studies have suggested that vitamin A derivatives called retinoids may halt or even reverse growth of head and neck tumors. A clinical trial of high doses of a retinoid called isotretinoin, widely used to treat cystic acne, in patients with HNSCC found that those receiving isotretinoin developed fewer second primary tumors, particularly smoking-related tumors. However, there were substantial side effects among those who received the high-dose isotretinoin, and subsequent studies of the compound have shown mixed results.
To assess the effect of lower, more tolerable doses of isotretinoin on the development of second primary tumors and survival among patients with early-stage HNSCC, Fadlo R. Khuri, MD, associate director of the Emory Winship Cancer Institute, and colleagues conducted a randomized clinical trial of 1,190 patients diagnosed with stage I or II HNSCC. Patients were randomly assigned to receive low-dose isotretinoin (30 mg/day) or a placebo for 3 years. They continued to monitor the patients for 4 or more years after treatment. This clinical trial is the largest chemoprevention study to date to examine the use of retinoids in patients with early-stage HNSCC.
The study found that low-dose isotretinoin did not reduce the rate of second primary tumors or improve overall survival compared with a placebo. Current smokers in both the treatment and placebo groups had an increased rate of second primary tumors and death. The authors conclude that the study provides substantial evidence that doctors should work with patients on smoking cessation, and they do not recommend isotretinoin monotherapy as a preventive agent for second primary tumors in people with stage I or II HNSCC.
"After two decades of research that has drastically changed the principles and practice of cancer chemoprevention, the present chapter on translational cancer chemoprevention with retinoid monotherapy in HNSCC closes with this definitive report," said Khuri. "A tolerable dose of isotretinoin was ineffective in preventing the development of second primary tumors in this phase III trial, further reinforcing results from two other negative phase III retinoid trials in lung and aerodigestive cancer chemoprevention."
In an accompanying editorial, Sarah J. Freemantle, PhD, of Dartmouth Medical School, and colleagues discuss the role of retinoids in chemoprevention, calling KhuriÕs findings "definitive" and consistent with past findings in similar trials. The authors suggest that further evaluation of other classical and nonclassical retinoids and of combination regimens should continue. They write, "It is now important to uncover the basis for this paradoxical lack of isotretinoin clinical chemoprevention activity."