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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)


Clinical Trial Focus: ECOG 5597 & Selenium Supplementation for Prevention?
Howard (Jack) West, MD

In addition to risk for having a recurrence of a lung cancer that has been surgically removed, patients with a history of early NSCLC are also at risk for a second primary (unrelated to the first) lung cancer. In other words, having had a lung cancer, even if it was cured, means that a person remains at higher risk for a new lung cancer than people who never had a lung cancer. That risk is in the general range of about 1-1.5% per year, so patients who are around four years out from diagnosis and treatment for lung cancer are getting to a point where the risk of a recurrence is getting lower than the risk of a new cancer. Fortunately, that's a low likelihood for both, but it's why I and others in the lung cancer field want to continue to do approximately yearly visits and CT scans for long-term survivors of lung cancer on a chronic basis (iin addition to the surveillance function, we often genuinely LIKE the patients and are only to happy to share a hopefully upbeat, congratulatory experience). We'd all like to reduce that risk of a new lung cancer as low as possible, to get that 1-1.5% yearly risk as close to 0 as possible. But because this is a chronic, ongoing risk, any intervention/treatment that we might consider needs to have little or no toxicity if it is going to be given chronically.

Selenium is an essential (not made by the body, but needs to be consumed from the outside world) trace element in humans, which does have toxic forms, but which has been shown in some animal models to reduce the risk of some chemically-induced cancers, and it has been demonstrated to enhance immune stimulatory function in humans (reference article here). It is an essential component of the antioxidant enzyme glutathione peroxidase, which protects against oxidative damage and may possibly help stimulate the process of apoptosis (AY-pah-TOH-sis: the second p is supposed to be silent, but many people do pronounce it as AY-pop-TOH-sis), a fancy word that means "programmed cell death", an auto-destruct mechanism that cells have built into them when they recognize that they are not functioning properly, or sometimes in normal development. One of the ways that cancers are able to succeed is that cancer cells can evade this auto-destruct mechanism.

Some studies of broad populations have shown associations of lower selenium concentrations and lung cancer risk (reference article here). Rates of cancer throughout the US are (modestly) correlated with lower soil levels of selenium, map here or stylized here:

Selenium Stylized Map (click to enlarge)

So there's some evidence that low levels of selenium are correlated with lung cancer risk. A few studies have suggested that adding selenium MAY be associated with lower risk of cancer death. One study done by Clark and colleagues (abstract here) gave 200 micrograms of selenium vs. placebo for an average of over 4 years to over 1300 patients between 1983 and 1991, looking for a potential improvement in rates of skin cancer. THey didn't find that, but they did see a halving of the total cancer mortality rate and a significant reduction in cases of lung, prostate, and colorectal cancers. Mortality secondary to lung cancer was significantly reduced, with a hazard ratio of 0.47 (remember, with hazard ratios, lower is better, and 0.47 is a 53% reduction in lung cancer death rates compared to placebo).

Lab studies have suggested that selenium may possibly act as a chemopreventive agent (a medication to prevent disease, not necessarily chemotherapy) by several different mechanisms. The leading possibilities are as follows:

Selenium proposed MOA

I'm not going to go into these issues because

1) they're proposed ideas, which means that we really don't have a good idea which, if any, of these mechanisms is really important

2) they're all complicated enough to be the subject of separate posts

3) they're the kind of things science PhDs are working on, and many of the rest of us don't need to burden ourserves with the headache-inducing details.

The study, which is known as ECOG 5597, is enrolling over 1700 patients who have undergone surgery but no chemo or radiation afterward to receive either selenium at 200 micrograms per day (two-thirds) or a placebo (one-third) for four years. Patients must be at least 6 months but no more than 3 years out from surgery. Remember, stage I NSCLC patients may be considered for post-operative chemo, but these patients are the ones with more marginal evidence supporting it and the best prognosis after surgery alone. So the trial is asking the primary question of whether selenium supplementation reduces the risk of second lung cancers in these patients who have a good prognosis from their treated lung cancer but who need to continue to be watched closely due to concern for either a recurrence of the prior cancer or a new one developing. It will also carefully assess the safety of long-term administration of selenium, since it can have side effects that range from skin changes (skin irritation, itching, hair loss) to gastrointestinal problems (nausea, vomiting, constipation, metallic taste, belching) to general ones like weakness, irritability, and a garlic odor to breath and sweat (which may be appealing if your friends and family like garlic as much as I do). The trial also builds in tissue collection from as many patients as possible, in order to find genes associated with better or worse survival, and those that may predict response to a chemopreventive agent. There are also detailed questionnaires about dietary intake and smoking to help clarify the relationship of survival and effects of selenium with these factors. Importantly, smoking cessation interventions are also offered to patients who continue to smoke.

One of the potential concerns with a trial like this is that there is a placebo arm, so patients may be reluctant to be randomized to what they perceive as something vs. nothing. But the trial includes detailed and close follow-up for everyone, and there is also a possibility of selenium conferring no benefit and just side effects to recipients. We have also learned from a similar chemoprevention trial with a vitamin A derivative called 13-cis retinoic acid, or isotretinoin, that supplements thought to be potentially helpful may even significantly INCREASE the risk of cancer, as was seen in that large trial (full article here). So we don't know if the placebo arm may fare better, and we are therefore reluctant to recommend people take selenium without evidence available from this study. We also can't say anything about whether selenium has any impact on survival or other clinical variables in patients who already have lung cancer or any other cancer.

The ECOG 5597 trial is available not only through the sites working with ECOG all around the US, but also through many other cooperative groups like SWOG, the CALGB, RTOG, and others. If you are interested in participating, please talk with your physician about whether this trial is available where you are treated and is an appropriate option for you.

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