Dangling the carrot of improved survival in non-Hodgkin lymphoma: does carotenoid consumption make a difference?

In 2012, there were an estimated 18 940 deaths from non-Hodgkin lymphoma (NHL) in the USA [1]. While the addition of rituximab to traditional therapies has improved survival [2], determining lifestyle factors that can reduce the effects of chemotherapy-related toxicities and influence survival in patients with NHL is needed. Fruits and vegetables are high in natural antioxidants, which help prevent cellular damage induced by oxidative stress [3]. Fruit and vegetable consumption has not only been associated with decreased risk of developing NHL [4], it has also been linked to improved survival for a number of malignancies, including bladder cancer [5], postmenopausal breast cancer [6] and NHL [7]. The one prior study assessing fruit and vegetable intake in relation to NHL survival by Han et al. reported an association between higher intake of fruits and vegetables, particularly green leafy vegetables, 1 year prior to diagnosis and overall survival (OS) in patients with NHL [7].

In the study presented in this issue of Leukemia and Lymphoma, Ollberding and colleagues also address the same question, as well as how specific nutrients in these foods impact OS in patients with NHL [8]. In their cohort of 301 newly diagnosed patients with NHL from Nebraska enrolled in the study from January 1999 to December 2002, the frequency and amount of food intake in the year prior to diagnosis was assessed by a food frequency questionnaire, and patients were followed for a median of 8.2 years. The authors did not find any associations between fruit and vegetable or specific nutrient intake and all NHL, follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL) survival, although numbers were quite small for the subtype analyses. In an exploratory analysis stratified by smoking status, better OS was observed among ever smokers when comparing highest to lowest tertiles of consumption of carotene-rich vegetables (hazard ratio [HR] = 0.4, 95% confidence interval [CI] 0.2–1.0) and α-carotene (HR = 0.4, 95% CI 0.2–0.9).

Strengths of the study include the evaluation of associations between OS in NHL and specific nutrients found in fruits and vegetables as well as assessment of interactions with lifestyle variables. Treatment and clinical prognostic variables were not included in the main analysis, as they were only available for ˜ 52.5% of the patients. However, the authors did perform a sensitivity analysis incorporating these variables, and reported no substantial changes to the survival estimates. The limitations of this study include a small sample size and number of events, particularly to assess subtype specific associations. Given that this study contains just over half the number in the Han study, it is possible that lack of associations are simply due to lack of power. In addition, considering the number of comparisons in this study, the associations found in the smoking status stratified analysis may be due to chance. Another concern is that pre-diagnostic intake does not take into account changes to dietary habits that may have taken place following diagnosis, which could be more influential in survival. As pointed out previously by Thompson et al. [9], the most relevant question may be whether fruit and vegetable intake after diagnosis improves survival, a question best answered in a controlled trial.

Prior experimental results support the biological plausibility of the anti-tumor effects of α-carotene. For example, using mouse models of spontaneous liver, 4-nitroquinoline 1-oxide induced lung and 7,12-dimethylbenz[α]anthracene induced skin tumors, Murakoshi et al. found that α-carotene supplemented mice had significantly lower numbers of tumors for all three tumor types, compared to control mice assessed at the same time point [10]. A recent observational study also supports α-carotene's role in improved outcomes in human populations; α-carotene concentrations in serum from 15 318 National Health and Nutrition Examination Survey (NHANES) III participants were inversely associated with risk of death from cancer, as well as death from cardiovascular disease and all causes [11]. Thus, a controlled trial of α-carotene supplementation in patients with NHL, particularly those with a history of smoking based on the present findings, might be informative. However, caution should be used in over-interpreting the importance of specific nutrients, especially when their intake values were derived from the consumption of whole foods. Furthermore, establishing the optimal dose is critical, as we have learned from β-carotene supplementation trials [12]. We must also consider that α-carotene may simply act as a surrogate for other nutrients that are truly responsible for the survival effects, or that it acts in conjunction with other components of carotene rich foods to achieve survival benefits. While the impact of fruit and vegetable intake may be unclear for NHL survival at this point, given the well-established positive effects on overall health, consuming more fruits and vegetables still seems advisable.

Potential conflict of interest:

A disclosure form provided by the author is available with the full text of this article at www.informahealthcare.com/lal.

The author was funded by grant number R25 CA92049.