A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients vom (Mai 2005)
Isabelle Bairati et al.
J. Nat. Cancer Inst. 97, 481-88, 2005
Objective
Primary objective: to assess whether the intervention would reduce the incidence of second primary cancers.
Second objective: to assess whether the intervention would reduce the adverse effects of radiation therapy without compromising treatment efficacy.
Third objective: to assess whether the intervention would improve cancer-free survival.
Methodology
Multicenter, double-blind, placebo-controlled, randomized chemoprevention trial among 540 patients with stage I or II head and neck cancer treated by radiation therapy between 1994 and 2000. Supplementation: alpha-tocopherol (400 IU/day) and beta-carotene (30 mg/day); began on the first day of radiation therapy and continued for 3 years after the end of radiation therapy. Beta-carotene supplementation was discontinued after 156 patients had enrolled because of ethical concerns. The remaining patients received alpha-tocopherol or placebo only. Survival was evaluated by Kaplan-Meier analysis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
Results
After a median follow-up of 52 months, second primary cancers and recurrences of the first tumor were diagnosed in 113 and 119 participants, respectively. The effect of supplementation on the incidence of second primary cancers varied over time. Compared with patients receiving placebo, patients receiving alpha-tocopherol supplements had a higher rate of second primary cancers during the supplementation period (HR = 2.88, 95% CI = 1.56 to 5.31) but a lower rate after supplementation was discontinued (HR = 0.41, 95% CI = 0.16 to 1.03). Similarly, the rate of having a recurrence or second primary cancer was higher during (HR = 1.86, 95% CI = 1.27 to 2.72) but lower after (HR = 0.71, 95% CI = 0.33 to 1.53) supplementation with alpha-tocopherol. Overall, after eight years, the proportion of patients who were free of a second primary cancer was similar in both groups.
Conclusions
Unexpectedly, patients who received vitamin E supplements were at greater risk of developing a second primary cancer while receiving supplementation, as well as a lower risk of a second primary cancer after the end of supplementation (compared with placebo patients).
Comment
General Comment
All of the 540 subjects had been previously treated for head and neck cancer and were at high risk of developing another cancer. The authors of the study admitted that there is concern about the generalization of the study results on individuals in the general population who are at low risk of a first cancer.
At the end of the eight-year study, the percentage of patients who developed cancer was the same in the vitamin E and placebo groups. It is therefore misleading to conclude that the results seen in this study would translate to the general population.
As the authors stated, in recent years, there has been much debate regarding the use of antioxidants during cancer therapy. Although some suggest that antioxidants can reduce the toxic side effects of therapy without compromising treatment efficacy, others argue that they interfere with treatment. This controversy shows that still more research is needed to come to a final conclusion.
Unfortunately, the vitamin C plasma levels of the patients have not been measured. Vitamin C is necessary to neutralize the tocopheroxyl radicals1. In the case that only vitamin E levels are high and the levels of vitamin C are low, this recycling process of vitamin E is not possible. Due to the fact that the nutritional data of the subjects have not been recorded, the different nutrition habits and thus the corresponding vitamin C status may be also of importance regarding the results of the study.
The theory by the authors that antioxidant vitamin supplementation may accelerate the progression of cancers and leads to earlier clinical diagnosis of more advanced latent tumors is speculative and in contradiction to similar intervention trials with positive results (see chapter “Other clinical trials with vitamin E and cancer”)
Statistics
A major protocol change occurred in the course of the trial with the cessation of the supplementation with β-carotene. After excluding the first 156 patients, the trial power was only 75.5%.
Serious diseases as cancer are influenced by many factors. In this study, different types of neck cancer at different stages and sites are complicating the situation. So there is also a statistical distribution of these factors between the both study arms that may be not fully identical. May be the vitamin E group had more patients with latent tumors? After a median follow-up of 52 months, second primary cancers were diagnosed in 113 patients out of 540, 63 (11.6%) in the supplemented arm and 50 (9.3%) in the placebo arm, respectively. Considering the high degree of biological variability of the examined cancers, these results may also be a matter of chance.
The authors stated that the increased risk of tumor recurrences was also only of borderline statistical significance.
Other clinical trials with vitamin E and cancer
Antioxidants including vitamin E are believed to help protect cell membranes against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. Many types of cancer are thought to result from oxidative damage to DNA caused by free radicals. Vitamin E also may block the formation of nitrosamines, which are carcinogens formed in the stomach from nitrites consumed in the diet. It also may protect against the development of cancers by enhancing immune function.
In the recently published results of the HOPE-TOO study2 carried out with over 9000 high risk cardiovascular subjects partially treated also with 400 IU of vitamin E it was shown that there was no significant differences in cancers (552 (11.6%) in the vitamin E group vs. 586 (12.3%) in the placebo group (relative risk 0.94; 95% confidence interval, 0.84-1.06; p = 0.30) and cancer deaths 156 (3.3%) vs. 178 (3.7%) (relative risk 0.88, 95% confidence interval 0.79-1.09; p=0.23). Furthermore, a reduction in lung cancers with vitamin E was observed (relative risk 0.72, 95% confidence interval 0.53-0.98; p=0.04). However, this did not reach the predefined level of statistical significance.
In the ATBC study a significant risk reduction of 34% was found for incidence of prostate cancer. It also reduced the risk of prostate cancer mortality3. Because of these findings a randomized, placebo-controlled intervention study (SELECT) that involves more than 34,000 men is currently being conducted to examine the effect of alpha-tocopherol supplementation on prostate cancer risk4.
In the recently published SU.VI.MAX trial low-dose of vitamin E in combination with other antioxidants lowered significantly total cancer incidence in men5.
The American Cancer society recently released the results of a long-term study that evaluated the effect of regular use of vitamin C and vitamin E supplements on bladder cancer mortality in almost 1,000,000 adults in the U.S. The study, conducted between the years 1982 to 1998, found that subjects who regularly consumed a vitamin E supplement for longer than 10 years had a reduced risk of death from bladder cancer6.
The Iowa women study provided evidence that an increased dietary intake of vitamin E may decrease the risk of colon cancer, especially in women under 65 years of age7.
Some other studies failed to support the theory that an increased dietary intake of vitamin E may decrease the risk of cancer. This means that still more research is needed to handle the complexity of vitamin E and its effect on cancer.
Vitamin E and proven health benefits
Vitamin E has shown to provide health benefits and to play an essential role in the whole body, important for several functions including risk reduction for chronic diseases and /or age related diseases such as:
Immune response: most recently researchers from the Tufts University published that elderly given vitamin E had reduced incidence of upper respiratory tract infection8.
Eye Health: the AREDS study9 (2001) has shown reduced progression of advanced age-related macular degeneration and the REACT study revealed reduced occurrence of cataract10.
Cognitive Impairment: the ADCS study has shown that vitamin E significantly delayed the onset of Alzheimer’s disease11. Furthermore, a number of important prospective epidemiologic studies have pointed to a possible benefits of vitamin E.
Conclusion
Study results in the literature on vitamin E and cancer are controversy. Fact is that cancer is a serious and multifactorial disease with many different faces and stages and that the influence of a nutrient such as vitamin E is not yet elucidated. On the other hand it is well known that vitamin E is an essential antioxidant and it is difficult to obtain adequate vitamin E from our diets, particularly while following the American Heart Association’s guideline for low fat intake. Thus, in addition to healthy lifestyle and good diet, vitamin E supplementation may be prudent. Furthermore, it has been shown, that vitamin E is safe across a broad range of intake levels. This topic has been summarized recently showing clear evidence from animal and human data12.
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