Common wisdom is that vitamin in fruits and vegetables prevent cancer. However, trials of supplementing vitamins like vitamin A analogues (retinoids: beta-carotene, retinol, retinyl palmitate, or isotretinoin) or vitamin E (alpha-tocopherol), did not prevent lung cancer in smokers. Randomised trials in all the three settings: primary (healthy high-risk e.g. smokers), secondary (pre-malignant lesions), and tertiary (prevention of second primary tumours in previously treated patients), have produced negative results (either neutral or harmful).

Chemoprevention trials were prompted by relationship between diet and lung cancer. Diet rich in foliage vitamins was protective against lung cancer – as demonstrated in a recent Dutch study of 939 patients. Similarly, higher blood level of ß-carotene is linked to a lower risk of lung cancer. Nonetheless, intervention trials failed to show a reduced risk in lung cancer by consuming ß-carotene. A phase III trial, the Alpha-Tocopherol, Beta-Carotene (ATBC) [beta-carotene (20 mg/d), alpha-tocopherol (50mg/d)] indicated significant increases in lung cancer incidence (18%) and no effect on lung cancer mortality (risk ratio, 0.99). Another study, CARET, had a 28% increase in lung cancer with vitamin treatment. Similarly, in both Euro-scan and the US-Lung Intergroup Trial (both testing retinoids in tertiary prevention), results were neutral.

Despite definitive positive trials of isotretinoin in non-smokers and former smokers in head and neck squamous cell carcinoma (HNSCC), and alpha-tocopherol in prostate cancer prevention, findings in lung cancer emphasise a need for further trials and that empirical use of innocuous substances like vitamins can be harmful.

The cause of this paradox has incited close scrutiny. Lung carcinogenesis is intensified when high tissue concentrations of beta-carotene interacts with oxidative tobacco smoke. In a recent study Wang et al, confirmed these findings in animal model. Smoking-related modification of molecular machinery includes a loss of retinoic acid receptor that explains the inability of retinoids to arrest lung pre-malignancy.

The future of lung cancer chemoprevention will rely heavily on molecular studies of carcinogenesis and drug mechanisms to develop novel chemopreventive targets, drugs, risk markers, and surrogate end point biomarkers. Also, pre-clinical drug testing is ongoing with other natural molecules in fruits and vegetables like lycopene and curcumurin.