Heidi Fritz; Deborah Kennedy; Dean Fergusson; Rochelle Fernandes; Steve Doucette; Kieran Cooley; Andrew Seely; Stephen Sagar; Raimond Wong; Dugald Seely

“ It is possible that beta carotene had an overall adverse effect on disease risk, thereby producing a falsely positive effect for retinol in comparison, however, this is impossible to determine.
Strengths of this analysis include a comprehensive and systematic survey of the literature with a clear focus on lung cancers. All levels of evidence, human, observational, and preclinical were included to achieve a broad analysis of anticancer activity of vitamin A/retinoids in lung cancers, and any possible interactions with chemotherapy and/or radiation therapy to assess safety alongside efficacy. ”

“ The absorption and conversion of beta carotene to retinol is limited by several factors, including dose administered, with enzymatic saturation occurring at higher doses; the surrounding food matrix; the antagonistic effect of other carotenoids and vitamin A in the diet; and the vitamin A status of the individual [18] , [21] . Beta carotene can correct vitamin A deficiency but it does not achieve the supraphysiological serum retinol levels attained by direct vitamin A supplementation. As such it does not possess the toxicity characteristic of high dose vitamin A supplementation ”

“ Provitamin A carotenoids are found in highly pigmented vegetables such as carrots, squash, yams, and green leafy vegetables [14] . Once in the body, retinol is ultimately converted into retinoic acid and its isoforms, collectively known as retinoids [14] . Vitamin A is responsible for the maintenance of epithelial tissues such as skin, mucus membranes, and lung tissue; it supports immune function; and plays a key role in mediating vision [16] , [17] .
Provitamin A carotenoids, particularly beta carotene, have also been studied for the prevention of lung cancers. ”

“ Modest but encouraging results have been found in the treatment of other cancer types including: head and neck cancer, cutaneous T-cell lymphoma, and neuroblastoma [39] , [40] , with increased survival (p<0.01) and reduced rates of second primary tumors (p = 0.005) demonstrated in some studies [41] , [42] . The utilization of retinoids for the chemoprevention of lung cancers has been controversial, however, exemplified in the findings of the large CARET trial (Beta Carotene and Retinol Efficacy Trial) [43] . ”

“ Additionally, out of ten natural health products (NHPs) assessed during an initial scoping review of the literature for this project, vitamin A had the greatest volume and quality of evidence around its use in lung cancers.
The body obtains vitamin A from two sources: preformed vitamin A (retinol and retinal in the form of retinyl esters) , and provitamin A carotenoids (beta carotene, alpha carotene, beta cryptoxanthin) [14] , [15] . Preformed vitamin A is found in cod liver oil, butter, eggs, animal products, and fortified grains [14] . ”

“ Alternately, novel synthetics that do not exist naturally have been designed for use in cancer (bexarotene and fenretinide) and other proliferative conditions (etretinate) [26] , [27] . The two most common supplemental forms of vitamin A are retinyl palmitate and retinyl acetate [14] . Table 1 outlines the classification of major retinoids and their primary clinical uses [16] , [28] , [29] , [30] , [31] . ”

“ Historically, natural retinoids have been used in the treatment of lung cancers since the late 70's when the first human trials were conducted [4] , [5] , [6] , [7] on the basis of antiproliferative effects specific to epithelial tissues and tumors [8] , [9] , [10] , [11] . The development of synthetic retinoids occurred subsequently in an attempt to retain vitamin A's antiproliferative effects specific to epithelial tissue while avoiding dose limiting side effects such as skin and liver toxicity [4] , [12] . ”

“ Emphasis is placed here on the pharmacokinetics changes and adverse events reported in the literature of the various vitamin A forms and the chemotherapy drugs used in the treatment of lung cancer. Case reports were also reviewed however, no relevant information could be garnered on interactions and these did not enhance the results, and thus are not reported. ”

“ This hypothesis is supported by similar findings from the large Finnish Alpha Tocopherol Beta Carotene (ATBC) trial, conducted in 29,133 male smokers for 5 to 8 years. Investigators found that supplementation of 20 mg beta carotene without vitamin A increased incidence of lung cancers by 16% compared to those not receiving beta carotene, RR 1.16 (95% CI 1.02 – 1.33) [82] . Serum retinol levels rose only 6% compared to placebo in those receiving beta carotene supplementation (p = 0.03) [83] . ”

“ Meta analysis of three trials measuring response rates found no significant effect overall, relative risk RR 0.84, (95% CI 0.68–1.03, I2 = 40.4%) . For one study that reported response rates in terms of complete response, partial response, progressive disease, or disease stabilization, the response rate was calculated based on the number of complete and partial responses [58] . See Figure 2.
Forest Plots: Pooled Results of RCTs for the Treatment or Prevention of Lung Cancer. ”

“ Conversely, one study suggested a co-carcinogenic activity for supplemental retinyl palmitate when combined with 20-methylcholanthrene (20-MCA) [46] and one study showed a potential pro-angiogenic effect with increased VEGF levels [47] . Refer to Table S2 for a detailed summary of preclinical evidence.
Biomarker Trials
In humans, retinoids may modulate mediators of proliferation and some that are associated with lung cancer progression. ”

“ Lippman found no significant effects overall, however, lung cancer recurrence and all cause mortality were significantly increased in current smokers receiving isotretinoin compared to placebo, HR 3.11 (95% CI 1.00–9.71) and 4.39 (1.11–17.29) respectively [61] . Meta analysis of these three RCTs for secondary prevention showed no significant effects for vitamin A on second primary tumor (RR 1.18, 95% CI 0.72–1.94, I2 = 78.7%) , recurrence (RR 0.94, 95% CI 0.74–1.20, I2 = 47.1%) , 5-year survival (RR 1.00, 95% 0.97–1.02, I2 = 0%) , and death (RR 0.94, 95% CI 0.78–1.15, I2 = 0%) . ”

“ Hypertriglyceridemia was usually manageable with antilipid therapy, however in some cases dose reduction was necessary to prevent patient withdrawal from the study due to toxicity (up to 18%) [56] . Up to 24% of patients treated with bexarotene developed hypothyroidism manageable by thyroid hormone replacement therapy [56] .
In the Phase I/II trials, the most common side effects observed were mucocutaneous symptoms (occurring amongst most patients in some of the trials) ; hyperlipidemia, in particular hypertriglyceridemia, ranging from under 44 to 86% in frequency ”

“ These phase I/II trials were conducted in patients with advanced stages of lung cancers, and in most cases, retinoids were used in conjunction with various chemotherapies including: docetaxel and capecitabine, cisplatin, etoposide, vindesine, mitomycin-C, carboplatin, gemcitabine, vinorelbine, 5-fluorouracil, interferon, and interleukin-2. Conversely, chemotherapy was rarely used in the trials showing no significant effects. None of the trials demonstrated disease exacerbation when vitamin A or retinoids were employed for treatment. ”

“ Gatzemeier, U & Miller, WH, “Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy –naïve patients with advanced or metastatic non-small cell lung cancer: SPIRIT II.”, J Clin Oncol 26: 1879–1885, pmid:18398153 1 2 Rizvi, N; Hawkins, MJ; Eisenberg, PD; Yocum, RC & Reich, SD, “Placebo-controlled trial of bexarotene, a retinoid X receptor agonist, as maintenance therapy for patients treated with chemotherapy for advanced non-small-cell lung cancer.”, Clinical Lung Cancer 2: 210–215, pmid:14700480 1 2 3 Ruotsalainen, T ”

“ Linkov, I & Dmitrovsky, E, “Aberrant expression of p53 or the epidermal growth factor receptor is frequent in early bronchial neoplasia and coexpression precedes squamous cell carcinoma development.”, Cancer Res 55: 1365–1372, pmid:7882337 ↑ Ayoub, J ”

“ Chung, JS & Clever, SL, “Effect of supplementation with beta-carotene and vitamin A on lung nutrient levels.”, Cancer Epidemiol Biomarkers Prev 7: 211–214, pmid:9521435 ↑ Goodman, GE; Omenn, GS; Thornquist, MD; Lund, B & Metch, B, “The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with cigarette smokers.”, Cancer Epidemiol Biomarkers Prev 2: 389–396, pmid:8348063 ↑ Albanes, D ”