New Drugs Hold Real Promise for Metastatic Melanoma

I'm going to show you a survival curve for metastatic melanoma.

This data was analyzed in 2001, but sadly, even current 5 year-survival for metastatic melanoma sits around 15%. But some new drugs might change this.

For the video version of this post, click here.

Here's a chart examining Melanoma-associated mortality rates over time:

Compare that to breast cancer, which has seen some dramatic therapeutic advances over the past few decades:

But melanoma is riding a wave of novel immunotherapies that hold promise to change the treatment landscape substantially.

Appearing in the Journal of the American Medical Association is a type of study we don't see too much of these days.  It's not really a clinical trial. It's not really a meta-analysis.  Frankly, I'm not sure what to call it – an aggregate analysis perhaps?

The study examines 655 patients treated with the PD-1 inhibitor pembrolizumab from 2011 to 2013. Yup, that's the same pembrolizumab which was used so successfully to treat this charming former president:

A brief aside here. Pembrolizumab is a monoclonal antibody directed towards programmed cell death protein 1, PD-1. PD-1 acts to prevent immune cells from attacking your own cells – it's an immune "checkpoint" making pembrolizumab one in a class of "checkpoint inhibitors".  Basically, by blocking PD-1, pembrolizumab allows your immune system to attack your own cells. Not something you want under ordinary circumstances, but perhaps beneficial when your own cells have turned against you.

Merck has bet big on pembrolizumab, with clinical trials ongoing or planned in melanoma, non-small-cell lung cancer, small-cell lung cancer, ovarian cancer, glioma, colorectal cancer, and on and on. What happens when a company is doing so many trials like this is a kind of fractionation, where you lose the aggregate knowledge of patient experiences because they are spread out across so many trials.

So I was gratified to see this aggregate analysis which examined patients with advanced melanoma receiving pembrolizumab across four different trials. See, if you do four trials, and one is nice and positive, and the others are equivocal, and you are a for-profit drug company, maybe you're more likely to try to get that positive trial into some high-profile journal, and let the others either languish in peer-review hell or get published in an out-of-the-way rag.

What we get in JAMA, though, is a study with adequate power to demonstrate that pembrolizumab might make a difference.

Among all the patients treated with pembrolizumab (and yes, there is no control group reported here), the objective response rate was 33%. The median overall survival was 23 months, and 31 months among those for whom pembrolizumab was the first systemic cancer therapy.  Compared to the historical median survival of under a year, this represents a substantial improvement.

Interestingly, among those who responded to the drug initially, the duration of response was fairly long. In fact, at 2 years, around 70% of people who initially responded to the drug were still responding.  This is a good thing, as it demonstrates that development of resistance to therapy might be limited.

Now, before we bestow too many accolades on Merck for giving us this aggregate data, we might ask whether they would have been as forthcoming if the trials weren't quite as successful. But, placing cynicism aside for the moment, it seems that this drug, or one of its competitors will have a place at the table in the treatment of advanced melanoma.

Bitter news: citrus fruits linked to higher rates of melanoma.

For the video version of this article, click here.

Browsing through article titles this week, my eye caught one from the Journal of Clinical Oncology with the words “melanoma” and “citrus fruit”.  Not worth looking at I thought, clearly a study linking citrus intake with melanoma is hopelessly confounded.  People who eat citrus fruits are probably healthier in general, have better access to care, etc - clearly they’ll have lower melanoma rates.

But then I read the abstract, and, go figure - people consuming more citrus fruits had higher rates of melanoma. This was worth a deeper dive.

The background here is that all citrus fruits contain compounds called “psoralens”. Psoralens are photo-reactive chemicals and, in pharmacologic doses, are used to sensitize the skin to UVA radiation in the treatment of psoriasis, for example. When exposed to UV light, these compounds can intercalate into DNA, causing mutations, so there might be some biologic plausibility here.

That said, the dose you take as part of PUVA therapy is the equivalent to what you’d find in about 10,000 liters of grapefruit juice…

But let’s push on. Here are the details:

Harvard researchers used two large, prospective databases: the Nurse’s Health Study and the Health Professionals follow-up study.  Combined, these studies comprised about 170,000 people, but after applying various exclusion criteria (including excluding anyone who wasn’t white), they had around 105,000 individuals to study. After a whopping 25 years of follow-up there were about 2000 cases of melanoma. They correlated answers from a food frequency questionnaire with subsequent melanoma incidence. Bottom line? A dose-response relationship, with the highest category of citrus eaters (>1.6 times per day) having a roughly 50% increase in the rate of melanoma.

Surprisingly, the annual UV exposure and number of sunburns weren’t different among the citrus consumption groups - so we’re not seeing a “Florida effect” here.

The authors strengthened their findings by looking at the association of other fruits and fruit juices to melanoma (none found), and looking at the association between citrus fruits and other types of cancer (none found), but there were still a couple of odd findings.

When they broke down the citrus fruits, they found that grapefruit, but not grapefruit juice, was associated with melanoma. Conversely, orange juice, but not oranges, were associated with melanoma. They argue that orange intake in it’s non-juice form was so rare that they didn’t have power to detect a link, but we don’t get numbers to support that, and frankly, I’d be surprised if grapefruits are getting eaten more than oranges in this country.

Now, if you want to throw out a study, you can always argue (as many have) that food frequency questionnaires are terrible instruments. But even taking the study at its face-value, let me give you some data the authors don’t include directly.  The incidence of melanoma in this study was 7 cases per 10,000 individuals per year. To prevent one of those cases, you’d need to convince around 2500 people who eat a lot of citrus to stop, whereas you’d only need to convince 140 people to wear sunscreen. My advice?  Keep your grapefruit juice, and wear a hat.

If drugs for erectile dysfunction cause cancer, would you want to know?

If this is one of those "ignorance is bliss" situations, read no further...

With that in mind, I present to you a study linking erectile dysfunction drugs to malignant melanoma.

For the video version of this post, click here.

The background here is that ED drugs work by inhibiting phosphodiesterase-5, and the down-regulation of that enzyme also occurs in some biochemical pathways that lead to melanoma, so we can put a check mark next to biologic plausibility. Human evidence of the link, prior to this week, involves a cohort study in the US which suggested that men taking sildenafil had a nearly two-fold increase in melanoma risk (but of the melanoma cases, only 14 had been taking sildenafil).

This week, appearing in the Journal of the American Medical Association we get the results of a Swedish study that examined over 5000 cases of melanoma in an effort to put this issue to bed.

The researchers used a preexisting cohort of around 600,000 Swedish men.  In that group, there were roughly 4000 cases of melanoma, which they matched (based on year of birth) to 20,000 controls.

In unadjusted analyses, the PDE-5 inhibitors were associated with about a 30% increase in melanoma. This persisted after adjusting for a smattering of confounders such as income and comorbidity scores, but the authors state that they believed their adjustments were incomplete. If the association were causal, it would mean an additional 7 cases of melanoma out of every 100,000 men taking ED drugs.

But despite the association, two major findings make the link hard to believe. First, the relationship between ED drugs and melanoma was only seen in those who had a one-time prescription for the drug. If the drugs were causal, we’d expect an increase in risk among those who got more prescriptions.  In addition, the researchers found a link between ED drug use and basal-cell carcinoma, a malignancy that doesn’t have a known PDE5 link.  This all suggests that men who take ED drugs might also engage in other behaviors that increase the risk of melanoma - like taking vacations in sunny places.

Just to make it clear that we’re not totally out of the woods here, I should note that this PDE5 pathway only appears to be relevant in the roughly 50% of melanoma cases that have a BRAF mutation - it’s conceivable that if the researchers could stratify by BRAF status, they may have found a link. For now, though, we can rest easy - data linking ED drugs and melanoma is simply not that firm.

Does coffee stave off melanoma? The answer won't surprise you.

A recent study appearing in the Journal of the National Cancer Institute claims that coffee might prevent melanoma.  Watch the following video to see what other hoops this poor data set has had to jump through.

Click below to view the video:

Analysis: Can Coffee Prevent Melanoma? | Medpage Today.