Retinoids in lung cancer chemoprevention and treatment

Our plain-English summary of Retinoids in lung cancer chemoprevention and treatment, by S. Toma, P. Raffo, L. Isnardi, et al (Annals of Oncology, 1999).

The study

• Authors: S. Toma, P. Raffo, L. Isnardi, R. Palumbo
• Journal: Annals of Oncology
• Published: 1999;10 Suppl 5:S95-102
• Type of article: Review
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

In this review, we aim to synthesize the emerging picture of retinoids in lung cancer through a summary of ongoing investigations in biology, chemoprevention and therapy settings, in an attempt to clarify the possible role of these agents in such a disease. Early work in head and neck cancer has evidenced the capability of retinoids to interrupt field carcinogenesis by reversing premalignant lesions and decreasing the incidence of second primary tumors (SPTs). At this time, the completed randomized trials in lung cancer have failed to demonstrate an evident chemopreventive effect of the tested agents on different study end points, although both a marginally significant benefit of retinol palmitate in time-to-development rates for smoke-related SPTs and a potential preventive effect of retinol supplementation against mesothelioma in selected populations of asbestos-exposed workers have been recently reported. Concerning the role of retinoids in lung cancer treatment, a moderate activity of 13-cis-retinoic acid (13cRA) or all-transretinoic acid (ATRA) as single agents has been reported in small series of advanced, mostly pretreated lung cancer patients. More encouraging findings derive from combination studies, in which retinoids, especially ATRA, are added to either alpha-interferon or chemotherapy and radiotherapy. Major recent advances have been made towards the understanding of retinoids mechanisms of action; at this regard, the role of RAR-beta basal or treatment-induced levels seems to be of particular interest as intermediate end point and/or independent prognostic factor, besides their known importance in lung carcinogenesis. Future research for chemopreventive and therapeutic programs with retinoids in lung cancer should be focused on the investigation of new generation compounds with a specificity for individual retinoid nuclear receptors. Such selective molecules may have a greater activity against lung cancer, with a more favourable toxicity profile, as recently suggested by our preliminary data on Ro 41-5253.

In plain English

This was a review, not a new trial. The authors summarized laboratory and clinical research on retinoids (vitamin A and related compounds) in lung cancer. They drew on a Medline search in February 1998 and on hand-searched journals and conference reports. They also added preliminary laboratory results of their own on a compound called Ro 41-5253 in lung cancer cell lines. Two of the reviewed trials included asbestos-exposed workers. In the first, by De Klerk and colleagues (1998), retinol and beta-carotene were compared. Neither protected against lung cancer, but the retinol group had a significantly lower rate of mesothelioma: 3 cases on retinol against 12 on beta-carotene. In the second, the CARET study of smokers and asbestos-exposed workers, the treated group had 28% more lung cancers and 17% more deaths. Across the treatment studies the authors tabulated, 22 of 173 evaluable patients, mostly with advanced lung cancer, had an objective response. The authors concluded there was a suggestion that retinol may protect against mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published laboratory and clinical studies, with some preliminary cell-line results from the authors' own laboratory
• Who was studied: Published retinoid studies in lung cancer: five completed randomized prevention trials with about 20,000 participants, two ongoing prevention trials, and small treatment studies in patients with mostly advanced lung cancer. Two of the prevention trials (CARET, and De Klerk et al. 1998, 1990-1995) included asbestos-exposed workers.
• Exposure: Retinoids given as prevention or treatment: etretinate, isotretinoin (13-cis-retinoic acid), retinol, retinol/retinyl palmitate, all-trans-retinoic acid (ATRA) and the experimental compound Ro 41-5253, plus beta-carotene (pro-vitamin A). Asbestos exposure was a characteristic of some trial populations, not an exposure the authors studied.
• Main results:
  • In the reviewed De Klerk et al. trial in asbestos-exposed workers, retinol (25,000 IU/day) and beta-carotene (30 mg/day) gave no protection against lung cancer. The retinol group had a significantly lower rate of mesothelioma.
  • In that trial, the retinol group had 4 lung cancer cases and 3 mesothelioma cases.
  • In that trial, the beta-carotene group had 6 lung cancer cases and 12 mesothelioma cases.
  • In the reviewed CARET study (Omenn et al. 1996) of smokers and asbestos-exposed workers, the group given retinyl palmitate and beta-carotene had more lung cancers and more deaths than the placebo group.
  • In the reviewed adjuvant trial of retinyl palmitate in patients with resected stage I non-small-cell lung cancer (Pastorino et al.), five-year survival did not differ significantly between groups. A subset analysis of time to smoking-related second primary tumors reached statistical significance.
  • Across the treatment studies the authors tabulated, mostly in advanced and/or previously treated lung cancer, 22 of 173 evaluable patients (13%) had an objective response. Only 2 of these were complete remissions.
  • In the authors' own preliminary laboratory work, Ro 41-5253 inhibited proliferation and induced apoptosis (cell death) in an adenocarcinoma lung cancer cell line (A549). In a squamous carcinoma cell line (SK.Mes.1), effects appeared only at high concentrations.
• The authors' conclusion: The authors concluded that there was a suggestion that retinol may have a protective effect on mesothelioma, while no benefit could be gained from beta-carotene supplementation.
• Limitations the authors state:
  • The authors stated that using sputum atypia or bronchial metaplasia as end points in some controlled trials may partly explain why positive pilot results were not confirmed.
  • The authors stated that the best agent, dose and duration for long-term lung cancer prevention trials had not yet been defined.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Carcinogenesis, Mesothelioma, Chemotherapy.

Related studies

• The role of intervention studies in ascertaining the contribution of dietary factors in lung cancer. The Seattle chemoprevention trial of retinoids in asbestos-exposed workers — G.S. Omenn, G.E. Goodman, et al. (1988)
• Mailing strategies and costs of recruiting heavy smokers in CARET, a large chemoprevention trial — B. Valanis, J. Blank, et al. (1998)
• Chemoprevention of cancer: lessons to be learned from beta-carotene trials — H. Vainio (2000)
• Inflammation as a chemoprevention target in asbestos-induced malignant mesothelioma — Y. Kadariya, E. Sementino, et al. (2022)
• microRNAs in Cancer Chemoprevention: Method to Isolate Them from Fresh Tissues — F. Ganci, G. Blandino (2016)
• Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke — X.D. Wang, C. Liu, et al. (1999)

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