Lymphoma & leukemia: data for foods & supplements
Introduction
Vegetables & Fruit
Vegetables & Fruit
Vegetables & Fruit
Vegetables & Fruit
Vegetables & Fruit
Soluble Fiber
Vegetables & Fruit
Soluble Fiber
Anti-oxidants
Folic acid & Vitamin B12
Soluble Fiber
Vitamin D
Folic acid & Vitamin B12
Folic acid & Vitamin B12
Folic acid & Vitamin B12
Folic acid & Vitamin B12
Folic acid & Vitamin B12
Zinc, Selenium, & Copper
Zinc, Selenium, & Copper
Zinc, Selenium, & Copper
Vitamin C
Zinc, Selenium, & Copper
Zinc, Selenium, & Copper
Curcumin
Zinc, Selenium, & Copper
Curcumin
Biotin
Gluten-free Diet
Curcumin
Gluten-free Diet
Gluten-free Diet
Gluten-free Diet
leukemia & lymphoma: Foods with Neutral Cancer risk
Carbonated Beverages
Carbonated Beverages
Carbonated Beverages
Vitamin A, C, E
Carbonated Beverages
Carbonated Beverages
lymphoma & leukemia: introduction
Introduction
For the patient, among the fundamental health changes one can make is diet modification. This is also one of the few aspects of health the individual can control. A number of foods, food extracts, and vitamin supplements have been explored in lymphoma, and multiple key scientific publications are detailed below. Among the key foods and supplements with data include vegetable intake, Vitamin D, zinc, and vitamin B12. With this burgeoning field, we believe in being data-driven, and special attention is paid to human trials, the methodology of the individual studies, and the external generalizability of a given set of data.
Vegetables & fruit
Vegetables & Fruit
Study 1
A case-control study published from Oman in 2013, analyzing 43 non-Hodgkin lymphoma cases. (6) A 117-item semi-quantitative food frequency questionnaire was administered to each patient. In addition to vegetables, the risk of carbohydrates and meat was also reported.
Results demonstrated that firstly, a marked reduction in risk was associated with higher consumption of vegetables, with an odds ratio = 0.24 [95%CI: 0.07 – 0.82]. Multiple food items were found to confer increased risk for lymphoma, including consumption of carbohydrates, with an odds ratio = 5.32 [95%CI: 1.78-15.86]. Meat overall also was associated with increased risk, with odds ratio = 1.55 [95%CI: 0.58-4.15).
Study 2
The large prospective European Prospective Investigation into Cancer and Nutrition (EPIC) study included over 500,000 subjects from 10 European countries. (2) Fourteen body sites were examined in this analysis. No statistically significant associations of risk or benefit with intakes of fruit, vegetables, or fiber was observed.
Study 3
In the Nurses' Health Study, which comprised 88,410 United States subjects, a total of 199 incident cases of non-Hodgkin's lymphoma were found over 14 years of follow up. (10) The data was analyzed risk/benefit with consumption of fruit, vegetables, as well as a few subtypes.
In this study it was found that higher intake of fruits and vegetables was associated with a lower risk of non-Hodgkin's lymphoma, in a statistically significant fashion (p = 0.02). The relative risk based on consumption (fruits + vegetables) was 0.62 [95% CI: 0.38-1.02] in comparing intake of > 6 servings per day versus intake of < 3 servings per day.
Examination of the differential risk between fruits and vegetables, it was seen that vegetables had a more clear link for benefit (p for trend = 0.02 for vegetables; P for trend = 0.16 for fruits). The data also revealed that higher intake of cruciferous vegetables was associated with a decreased risk (P for trend = 0.03).
Overall, the body of literature shows a likely benefit of fruit and vegetable intake in reducing the risk for lymphoma. The link is stronger statistically in vegetables offering a protective effect, as evidenced by data the above studies (6, 10). Furthermore, the Nurses' Health Study showed an association of benefit with cruciferous vegetable intake specifically.
soluble fiber
Soluble Fiber
The Nurses' Health Study also collected data on fiber intake. (10) In this dataset, 88,410 women were followed over 14 years. A total of 199 cases of non-Hodgkin's lymphoma occurred during follow up.
In comparing the highest quintile of intake versus the lowest, dietary fiber from vegetable sources was correlated with a reduced risk for lymphoma, with relative risk = 0.54 [95% CI: 0.34-0.87; p = 0.01].
However, the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) study, with over 500,000 subjects from 10 European countries, did not find an association for risk or benefit with fiber intake.
The data from fiber intake shows mixed results. This may be partly due to different populations studied in both of these large datasets, with one being an American and the other European. As the Nurses' Health Study examined fiber intake from vegetable sources, and as vegetables do have evidence for lymphoma risk reduction, this could be a confounding variable.
anti-oxidants
Anti-oxidants
Antioxidants have purported benefits in numerous body processes. Whether antioxidants can confer benefit with lymphoma was explored in the California Teacher's Study. (7) In this large cohort of patients, a total of 110,215 were followed, and 536 women developed incident B-cell non-Hodgkin lymphona (NHL), 104 with multiple myeloma, and 34 developed Hodgkin lymphoma. Multiple phytocompounds and antioxidants were tracked, including isoflavones, lignans, and isothiocyanates.
Results revealed that there were two weak associations, for isothiocyanates and an antioxidant index, were observed, with trends towards a protective effect. Other associations were negative for benefit or risk. Specifically, a protective effect of isothiocyanates versus diffuse large B-cell lymphoma (an aggressive NHL) was observed with relative risk = 0.67 [95% CI: 0.43-1.05], when comparing intake of ≥12.1 vs. <2.7 mcM/day. For the antioxidant index, which quantifies hydroxyl radical absorbance capacity, the relative risk = 0.68 [95% CI: 0.42-1.10; p = 0.08.
In both of these trends, the confidence interval crossed 1.0, and therefore these associations can only be deemed trends, and more study is needed to confirm this benefit.
Vitamin D
Vitamin D
Study 1
A meta-analysis published in the Journal of Clinical Endocrinology & Metabolism in 2014 explored the association of Vitamin D levels (25-hydroxy Vitamin D) with lymphoma mortality. (3) In aggregate, 25 studies with 17,332 lymphoma cases were included in this analysis.
Results demonstrated that when comparing the highest vs. lowest quartile of 25-hydroxy Vitamin D levels, the OS was found to be 0.48 [95% CI: 0.36-0.64]. Secondly, higher Vitamin D levels reduced lymphoma-related mortality (p < 0.001), and prolonged disease-free survival (DFS) (p < 0.05).
The risk was further quantified based on blood 25-hydroxy-Vitamin D level. For each 10-nmol/L increase, there was a hazard ratio for benefit of 0.96 [95% CI: 0.95-0.97], for overall survival of lymphoma patients.
Study 2
Data from the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) trial studied the association of a patient's pre-diagnosis 25-hydroxy-Vitamin D level and lymphoma risk. (4) A case-control analysis was conducted, with 1,127 lymphoma cases and 1,127 matched controls. The mean follow-up time was 7.1 years. In comparing quartiles of 25-hydroxy-Vitamin D levels, levels were standardized by season.
This analysis revealed that there was not a statistically significant association of Vitamin D level and overall lymphoma risk. However, when a diagnosis was made during the first 2 years of follow up, an association was observed (of deficient Vitamin D and increased chance of lymphoma diagnosis).
For patients who had at least 2 years of follow up, there was a statistically significant association of a protective effect for higher Vitamin D level and chronic lymphocytic leukemia (which is in the same spectrum and can also often be called small lymphocytic lymphoma, a type of non-Hodgkin lymphoma). In comparing the top versus the bottom quartile of season-specific Vitamin D level, the hazard ratio for benefit was 0.31 [95% CI: 0.13-0.76; p = 0.03). When this was correlated with dietary Vitamin D intake, the risk ratio also showed a consistent protective effect, with RR = 0.33 [95% CI: 0.12-0.89; p = 0.006].
The data for Vitamin D shows a consistent story both in a large meta-analysis, as well as a large prospective European trial. The meta-analysis publication reported an overall survival and lymphoma-specific survival advantage with higher Vitamin D levels (25-hydroxy-Vitamin D). The European EPIC study showed the strongest link for chronic lymphocytic leukemia (in the spectrum of small lymphocytic lymphoma, a type of non-Hodgkin lymphoma). (4)
folic acid and vitamin b12
Folic Acid and Vitamin B12
One of the key clinical concerns after a patient with acute leukemia undergoes chemotherapy, to kill leukemia cells, is the length of recovery of the normal blood cells. If normal cells remain at low levels for too long, there is an increasing probability of medical complications such as serious infection and bleeding.
To this end, a study of the potential benefit of adequate Vitamin B12 and folic acid levels prior to chemotherapy for acute lymphoblastic leukemia (ALL) was undertaken. (5) 50 cases of ALL were enrolled in a study from India. Baseline deficiency was observed as folows: folate deficiency in 41.3% and B12 deficiency in 36.9%.
During chemotherapy, folate and Vitamin B12 levels were monitored. Physiologically, folic acid stores in the body have a shorter lifespan than Vitamin B12. Folate levels further declined significantly on serial measurements during chemotherapy (P=0.001).
In assessment of bone marrow recovery (and therefore recovery of normal blood cells), those with folate deficiency at baseline had a higher risk for delayed bone marrow recovery after leukemia chemotherapy. Furthermore, B12 deficiency (p = 0.001) and folate deficiency (p = 0.03) were associated with toxic deaths during induction. Hypoalbuminemia (low blood albumin levels, a marker of protein nourishment status and overall nutrition), was also associated with death when deficient (p = 0.04).
This compelling data underscores the importance of maintaining adequate, physiologic doses of Vitamin B12 and folic acid for patients undergoing chemotherapy for leukemia. Not only was delayed blood cell recovery observed among these 50 patients, but a statistically significant increase in deaths as well. As there are multiple similar medications used for leukemia and lymphoma, this principle could be reasonably applied to lymphoma as well.
zinc, selenium, & copper
Zinc, Selenium, & Copper
Deficiency of zinc, selenium, and copper have been researched as to their link with risk of lymphoma.
Study 1
One such study was an analysis from a Turkish population of Hodgkin’s disease and Burkitt’s lymphoma. (11) In this analysis, zinc status & risk was assessed for 81 patients with Hodgkin's disease, and 15 with Burkitt's lymphoma. 21 of these patients also had selenium status recorded. Plasma and hair levels of both zinc and selenium were available, and measured by atomic absorption spectrophotometry.
Outcomes from this study demonstrated that patients with deficiencies of both zinc and selenium had a higher risk for Hodgkin lymphoma and Burkitt's lymphoma.
Study 2
Another investigation looked at hair selenium status in children with newly diagnosed lymphoid malignancies, as well as the relation between malnutrition and selenium deficiency. (13) In this study, published in the Journal of Pediatric Hematology Oncology in 2007, Thirty total patients were enrolled: 17 with leukemia and 13 with lymphoma. 25 healthy controls served as the comparator arm.
Results revealed that hair selenium levels of the patients with lymphoma/leukemia were significantly lower than those of the healthy control group [666.96 ng/g vs. 1019.22, (p < 0.001)]. This difference was more marked in the malnourished subset of patients, with selenium level in hair of 483.51 ng/g (p = 0.036).
Study 3
A Brazilian cross-sectional study investigated nutritional status, and serum zinc and copper levels of children with newly diagnosed leukemia. (18) 23 children with newly diagnosed acute lymphocytic leukemia or acute non-lymphocytic leukemia between the ages of 1 and 10 years were enrolled. The control subjects were 31 healthy school children of similar age from local schools. Both food intake and serum levels of zinc and copper were measured in participants.
Review of the data showed that the children were not malnourished at baseline, but the serum zinc levels were significantly lower in the leukemic group of patients compared to the healthy comparator arm. However, serum copper levels were significantly higher among the leukemia patients.
The data for zinc, copper, and selenium is mixed. In Turkish and Brazilian populations, selenium has the most consistent association with blood system cancers including leukemia and lymphoma. Zinc deficiency also has been found to have an association with both lymphoma and leukemia compared to appropriate healthy control populations. Copper, however, was not found to be more deficient amongst these patients; in fact copper levels were higher among the leukemia patients in the Brazilian study (18), of which the significance is not clear.
vitamin c
Vitamin C
Vitamin C has antioxidant properties, and was explored in leukemia patients has to possible higher risk for malignancy. In a study of Iranian children, vitamin C status and total antioxidant capacity (TAC) in children with acute lymphoblastic leukemia (ALL) was measured in 28 patients and 30 healthy subjects. (14)
Results revealed that vitamin C intake in patients with ALL was more than twice as much compared to healthy subjects. However, in spite of this excess intake, plasma and urinary concentrations of vitamin C were more than 10 times and 2.5 times higher, respectively, than healthy controls (p < 0.001).
This study, in a pediatric population in Iran, was striking in that Vitamin C intake was twice as much among the leukemia patients, and yet their plasma level of Vitamin C was 10 times lower than controls. The exact mechanism or implication for this discordance is not clear, though it is possible that Vitamin C is being utilized by the body in an attempt to combat leukemia, but these reserves of the body are quickly depleted.
curcumin
Curcumin (turmeric)
The effect of curcumin, which has been used in food and ayurvedic medicine in India for hundreds of years, was explored as to its effect on Hodgkin lymphoma cells. (12)
In this laboratory effort, curcumin treatment of cells led to curcumin being incorporated into Reed-Sternberg cells (the key lymphoma cell in Hodgkin disease). It was observed that curcumin worked to inhibit to cancer pathways: NF-kappaB and STAT3 activation. Furthermore, curcumin led to a significant decrease in Reed-Sternberg cell viability, with a reduction of 80-97%. Cell cycle arrest in the G2-M phase of the cell cycle was seen in this experiment, with apoptosis being the driving mechanism. Activation of apoptosis proteins caspase-3 and caspase-9 were found, as were changes in nuclear morphology (cell nucleus shape & form).
This laboratory data is compelling in that treatment with curcumin alone led to a dramatic reduction in cell viability of up to 97%. The mechanism seen is that of inducing apoptosis and resultant cell death.
biotin
Biotin
There is evidence that biotin deficiency can stimulate lymphoma survival. A laboratory study from the University of Nebraska-Lincoln tested whether biotin deficiency stimulates NF-kappaB-dependent survival pathways in human lymphoma cells. (16) This may in turn make lymphoma cells more resistant to chemotherapy.
Cell lines were tested in both biotin-deficient (0.025 nmol/L) and biotin-supplemented (10 nmol/L) media for growth. These cells were then treated with chemotherapy agents including doxorubicin and vinblastine, which are commonly used in lymphoma therapy. After this treatment, NF-kappaB proteins (p50 and p65) were able to get into the nucleus of lymphoma cells over 25% greater in biotin-deficient compared with biotin-supplemented cells. In other words, such an increase can promote lymphoma survival more readily in the face of chemotherapy. Therefore activation of lymphoma survival pathways in biotin-deficient lymphoma cells was seen.
This intriguing laboratory study provides evidence that biotin-deficiency promotes NF-kappaB mediated survival pathways to increase, allowing lymphoma cells to survive. This survival advantage is even in spite of treatment with typical lymphoma chemotherapy medications. Conversely the biotin-supplemented cells did not have such an increase in NF-kappaB signaling. This could be of utility in both lymphoma prevention and during treatment of lymphoma.
gluten-free diet
Gluten-free Diet
One non-Hodgkin lymphoma subtype, enteropathy-associated T-cell lymphoma, is seen more prevalently with celiac disease. A study of an Italian patient population examined whether or not a gluten-free diet is protective for this form of lymphoma. (9) In total, 1,757 celiac patients for a total period of 31,801 person-years cumulatively among the patients. Data was gathered about the frequency of gluten intake, and the incidence of the enteropathy-associated T-cell lymphoma cases was recorded.
Data revealed that nine celiac patients developed enteropathy-associated T-cell lymphoma, with a standard morbidity ratio of 6.42 to develop lymphoma [95% CI: 2.9-12.2; p < 0.001]. Of these 9 patients, only 2 had maintained a gluten-free diet after the diagnosis of celiac disease. With this data and comparing the rate (with standard morbidity ratio) of developing the malignancy based on gluten-free diet adherence, the authors of the study reported that a protective effect of a gluten-free diet was observed.
The overall numbers of cases are small (9 cases developed in over 31,000 person-years), but enteropathy-associated T-cell lymphoma is a rare condition. This type of study is the one of the most practical ways to get a large number of patients, and trying to associate risk. The methodology is sound, and this study does provide evidence for a protective effect from lymphoma among those with celiac disease.
carbonated beverages
Carbonated Beverages
Cases were reviewed from the Cancer Prevention Study-II Nutrition Cohort data to see if there was an association of either sugar-sweetened or artificially sweetened carbonated beverages with non-Hodgkin lymphoma. (1) In total 100,442 adults were in the data set, and among these, 1,196 non-Hodgkin lymphoma cases were found over 10 years.
The data revealed that, compared to no consumption, neither sugar-sweetened nor artificially sweetened carbonated beverages had an increase in non-Hodgkin lymphoma risk. Specifically, for artificially sweetened beverages, the RR = 0.92 (95% CI: 0.73 - 1.17; p = 0.14), and for sugar-sweetened beverages, the RR = 1.10 (95% CI: 0.77 - 1.58; p = 0.62). The data was analyzed by lymphoma subtype as well, and no trend towards any increased risk for a particular subtype was found.
This large data set showed that there is no statistically significant link of either sugar-sweetened or artificially sweetened carbonated beverages for lymphoma risk.
Vitamin A, C, E
Vitamin A, C, E
Employing data from a large prospective mortality study of Americans, consumption of Vitamin A, C, and E (as well as multivitamin intake) was analyzed for a connection with death from lymphoma. (17) 1,571 non-Hodgkin's lymphoma deaths among 508,351 men and 1,398 non-Hodgkin's lymphoma deaths among 676,306 women were documented over 14 years of follow up.
This large dataset showed no connection of either the three individual supplements or multivitamins with risk of death from lymphoma. Results for men were: Vitamin A had a RR = 1.03, Vitamin C RR = 1.04, Vitamin E RR = 1.06, and multivitamin RR = 1.14. All confidence intervals crossed 1.0, and therefore there was no statistically significant connection between the consumption of these specific vitamins and lymphoma-related mortality. The relative risk values were similar among women, and again all confidence intervals crossed 1.0.
This large prospective US dataset therefore does not support any mortality effect of oral intake of Vitamin A, C, or E and non-Hodgkin lymphoma mortality. However, it is possible that whatever effect, if any, that is present for these vitamins, it may more likely confer a risk (or protective effect) for developing non-Hodgkin lymphoma, rather than the level of oral intake ultimately affecting mortality.
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