Fruit and vegetable intake and survival from non-Hodgkin lymphoma: does an apple a day keep the doctor away?

In the United States in 2009, an estimated 66 000 people will be diagnosed with non-Hodgkin lymphoma (NHL) and 19 500 will die from this cancer [1]. Fortunately, NHL survival rates have been increasing, and this has led to an expanding number of survivors, currently estimated at over 450 000 people [1]. Thus, identifying new ways to improve the long-term outcomes of NHL patients addresses a major clinical and public-health issue. One of the more consistent epidemiologic findings is a potential protective role of fruits and vegetables against the development of NHL [2,3]. Fruits and vegetables rich in antioxidant nutrients are hypothesized to be chemoprotective against many cancer types, including lymphoma, by several mechanisms including reduction of reactive oxygen species responsible for oxidative DNA damage, regulation of cell survival and apoptosis pathways, and protection of immune homeostasis [4,5]. Intake of fruits and vegetables also decreases the risk of cardiovascular disease, the leading cause of death in the US [6]. In other tumor types (e.g. breast cancer, lung cancer, gastric cancer, and head and neck cancer), intake of fruits and vegetables has been suggested to improve overall survival [7]. However, the association between fruit and vegetable intake and survival from NHL has not been previously studied. In this issue of Leukemia and Lymphoma, Han and colleagues [8] provide the first test of the hypothesis that a higher intake of fruits and vegetables is associated with better NHL survival.

Using a population-based cohort of 568 women with newly diagnosed NHL followed for a median of 7.7 years, they found 32% better overall survival for NHL patients who had higher pre-diagnosis intake of vegetables and fruits (hazard ratio [HR] = 0.68, 95% confidence interval [CI] 0.49–0.95) after adjustment for demographic and clinical variables. Total vegetables (HR = 0.58, 95% CI 0.38–0.89), green leafy vegetables (HR = 0.71, 95% CI 0.51–0.98), and citrus fruits (HR = 0.73, 95% CI 0.54–0.99) showed the strongest associations. In general, all of these associations held for the two most common NHL subtypes (diffuse large B-cell and follicular lymphoma); there were too few cases of other subtypes to make reliable conclusions. Interestingly, all of these associations were attenuated only slightly when the outcome was restricted to deaths due to lymphoma. This raises the hypothesis that intake of fruits and vegetables may impact NHL progression as well as overall health. This will be important to tease out in future studies with assessment of disease progression, particularly within specific NHL subtypes. Further, in the Han et al. study there is a potential for confounding by comorbid health conditions at diagnosis, such that patients who consumed higher amounts of fruits and vegetables could have had fewer comorbidities and therefore they were able to tolerate lymphoma treatment better than others, leading to increased lymphoma-specific survival and decreased deaths due to non-cancer causes. Since there was no comorbid health information available in this study, this remains an open question and needs to be addressed in future studies.

There are several key strengths to this report, including: the comprehensive assessment of diet; ability to crudely adjust for treatment class and clinical variables (stage and B-symptoms); ability to adjust for potentially important confounding factors including smoking; complete and relatively long-term follow-up; and preliminary evaluation of less common NHL subtypes. Another strength is the population-based design using a Surveillance, Epidemiology and End Results (SEER) cancer registry, which enhances generalizability to the community. However, this strength also brings limitations, as treatment details, more traditional clinical variables such as the international prognostic index (IPI) and follicular lymphoma international prognostic index (FLIPI) [9,10], and disease progression and relapse were not available. Not all eligible cases were enrolled, and in particular, early deaths never entered the study, and thus these results cannot address this group of patients. Furthermore, these results may not generalize beyond white women. Finally, cases were enrolled from 1996 to 2000, and thus these results will need to be verified in patients treated in the current era that includes rituximab.

However, the major design limitation that must be recognized is that the study could only address pre-diagnosis fruit and vegetable intake and outcome. Pre-diagnosis diet was collected because the cases were derived from a case–control study and were specifically asked to report on their usual diet 1 year before diagnosis. It is unknown whether patients in the study changed their diet, and more important, whether increasing fruit and vegetable intake would have improved outcome. The latter question is best answered by a randomized clinical trial design. There is evidence that 30–60% of cancer survivors change toward a healthier diet including eating more fruits and vegetables, although recidivism also appears to be high [7]. Such a change would be expected to attenuate the results of this study, perhaps masking stronger effects. Nevertheless, caution is warranted, as a randomized trial among women with breast cancer found that increasing intake of fruits, vegetables, and fiber while decreasing fat did not reduce disease recurrence or mortality [11].

Thus, it would seem important to investigate the question of whether increasing intake of fruits and vegetables after diagnosis impacts lymphoma progression and overall survival in a randomized setting, and this study, particularly if replicated, would support such an investigation. In the meantime, results of this study support current public-health efforts to promote the intake of fruits and vegetables in the general population, as there is growing evidence to suggest that this may not only decrease the risk of developing cancer but also increase the likelihood of surviving cancer. It is sobering to note that only 22% of the patients in this study followed public-health recommendations for the intake of fruits and vegetables, suggesting that the lymphoma diagnosis may be an important ‘teachable’ moment to improve diet and perhaps other health behaviors [7].