Skin cancer: Half of people surviving advanced melanoma
bbc.co.uk
bbc.co.uk
I was diagnosed with melanoma in 2010. At the time, the standard of care for melanoma was remove it surgically... and then cross your fingers and hope it doesn't come back.
During the 3 month interval between when I was first diagnosed and when we learned that the cancer had spread, that changed. The first paper showing an overall survival benefit for melanoma patients (by dosing them with ipilimumab) was published in the NEJM in June 2010. Although ipilimumab (marketed as Yervoy) wasn't approved by the FDA until the next spring, I was able to get access to a very high dose of the drug through a clinical trial.
The trial was weird in a couple ways. First, I can get on clinicaltrials.gov, pull up the results of my study, and calculate that if I'd been put in the placebo arm of the trial, there's a 25% chance I wouldn't be here to write these words. That's a strange thing to know.
Second, the side effects were really unusual and unpleasant. I didn't have to endure the acute toxicity you get from chemotherapy, so that was a blessing. On the other hand, immunotherapies (like both of the drugs referenced in this study) mess with immune regulation mechanisms that apparently aren't supposed to be messed with. My personal experience ranged from the mundane to the miserable: fatigue, severe acne, absolutely excruciating eye infections, and other stuff I won't get into here. I'm still dealing with some of these issues almost a decade later, but the key point is that I'm here to deal with them!
Ipilimumab was the first step; James Allison recently won a Nobel prize for discovering the protein that it targets. Nivolumab (marketed as Opdivo) actually gives even better performance, so nivo is the standard and is sometimes supplemented with Yervoy (or so I understand; I'm not a physician.) I can only imagine what the side effects of the combination therapy are like. Remarkably, both drugs were developed by Bristol-Myers Squibb.
I think you fared much much better than most. Maybe it's because you received a very high dose of ipilimumab. The people in the article's trial (which I assume wasn't your trial) were less fortunate. Specifically:
The results showed:
26% were still alive on ipilimumab alone
Our immune systems are fantastically complicated, probably more complex a defense system than the entire US military with hundreds of millions of years of evolutionary pressure.
One big advantage of immunotherapy is that the therapy causes a long-term (permanent? I'm not sure anyone knows; the drugs are less than a decade old) change to the immune system - the body continues to attack the cancer even after the drug treatment has ceased.
If you put these two things together, however, you might see why the side effects can be so bizarre. Your immune system might decide that the liver looked at it funny one day, but then decide that the GI tract is actually the real troublemaker a few days later. And since the immune system change persists post-treatment, so do the side effects.
These side effects can (usually) be controlled with corticosteroids (hydrocortisone/prednisone/etc.), which have an immunosuppressant effect. Of course, long-term corticosteroid use has its own severe side effects (plus severe dependency issues). And if you're suppressing the immune system, then you're suppressing the mechanism that the immunotherapy uses to fight the cancer in the first place. The treatment and the side effects are two sides of the same coin.
That sounds like checkpoint inhibitor immunotherapy. Others like CAR-T may have fewer side effects, since they're just augmenting your T cells with a manufactured supply that is primed to attack a specific target.
CAR-T is a lot more expensive for now but over time such "precision" immunotherapies may become mass produced and cheaper and we'll be able to make the immune system do what we want with fewer side effects.
You are correct. That is because the article is about checkpoint inhibitor immunotherapy (specifically yervoy/ipilimumab and opdivo/nivolumab).
I made a similar generalization about dentists a number of years back. I regret making that generalization now.
I wish I had instead decided “that one can’t be trusted, let me try another”.
I also went through that with dentists years back and had several in a row insisting I needed lots of expensive work but I kept spending on more opinions as it was out of line with my historical dental health. I lucked into one that confirmed I did not need any of that, proved why to my satisfaction, and said its a real problem in the business and I have been with them ever since.
“ If it is caught in the early stages then the chances of survival are good, but as the cancer becomes more aggressive and spreads throughout the body (known as metastatic cancer) then survival plummets”
Craig Venter:
All of our early detection tools are pretty terrible and we can't ethically test everyone for everything so it's all about educating the patients to take a proactive role.
This is pretty astounding to me. Where should I read more about this?
In a given mammogram it's more like 7-12%.
The younger you are, the more likely your positive result will be a false positive. And it also varies based on tissue density (women with more dense breasts have higher false positive rates). The higher false positive rate in younger women is of course why they've shifted screening times, pushing back the suggested start age and or doing every other year instead of every year.
If you recall someone from screening for additional diagnostic views, this is not strictly a false positive as the initial evaluation is definitionally incomplete. However, many would argue the additional views result in additional patient stress and anxiety (I personally do not buy this argument especially if you set expectations at the time of initial image acquisition).
Of the patients who are recalled, maybe 20% proceed to biopsy, of which probably 20% have histologic cancer and another percentage have high risk lesions that are not cancerous per se but are often surgically removed as they either cannot be fully sampled using a minimally invasive technique.
Recall rates are tracked and heavily scrutinized at the individual radiologist level. The targeted recall rate is in the range of 5-10% with the assumption that recalling more than this is being too sensitive and less than this is potentially missing cancer.
Mammography performance is often defined in cancers per 1000 screening exams for a given population.
Realistically, someone needs to proceed to all the way to biopsy (and have it come back negative) to have a real false positive.
Someone being recalled from screening for additional views only to be released as “superimposed tissue” or “benign finding” is not a true false positive. To argue so is being a bit disingenuous.
This is a big problem, but it's far from the only problem. The other problem is catching cancers that are destined to stay harmlessly in place. So-called "turtles." They are surprisingly common among the population.
South Korea currently has this problem - 15 years of screening has found a massive amount of thyroid cancer, so much so that thyroid cancer is now the most common cancer in Korea. Yet all these extra cancers discovered and treated early hasn't reduced the death rate at all. That means the cancers being detected and treated are destined to have no negative consequences to the patient.
https://www.npr.org/sections/health-shots/2017/05/09/5275692...
It's been a while since I've been in the field, but at least as of several years ago the oncologists I knew were starting to turn against heavy pushes for early screening for these and similar reasons.
Along with better early detection, aren’t we trying to increase the tests’ accuracy?
If we have 2-3 additional years to monitor and treat a cancer, we have more options.
My feeling is that we’ll be much better off it we detect at a very early stage then learn to monitor it properly.
it almost sounds superstitious that people are afraid to find out sooner.
If you can reliably distinguish between those malignant neoplasms and "any growing neoplasm in the body", collect your Nobel and enjoy your well-earned message board karma from winning this debate. Since you can't, what you're really doing here is begging the question.
EDIT: Just to be clear, the idea of accurate early detection is of course a good one. But as of today it is just not viable.
No one said it’s viable today. The entire point is to do the research so that someday it is viable.
On a population-wide scale, ignorance may be the best option right now.
Often it's impossible to tell right now which asymptotic localised cancers are going to eventually kill the patient if left untreated and which are going to be non-bothersome or even spontaneously regress. They look the same in many cases.
https://www.npr.org/sections/health-shots/2017/05/09/5275692...
You also have to be careful to quantify "useless," "useless" can mean "doesn't work," but if we are objectively detecting cancers it's hard to say it's "useless."
You also may have one person's life saved for every 20 who were harmed by the screening program - it's still useful for those people who benefited. So yeah, that terminology is problematic.
It's more accurately to speak of a bad screening program "causes more harm than good on a population wide scale."
And, of course, it's important to clarify we are talking about screening the general population who is asymptomatic and at average risk. If you've got symptoms then the topic becomes diagnosis, not screening. If you have an increased risk due to genetic factors, family history, or increased exposure to some cancerogenics then then risks of screening for the general population don't apply to you.
Yet when we actually study these things we find out early detection might not be desirable (but also sometimes is). It's complicated and there's a whole lot we don't know.
Also "most cancers" is almost certainly false, more like "some cancers." And at what cost?
https://fivethirtyeight.com/features/the-case-against-early-...
>It’s hard to believe in overdiagnosis and overtreatment if you imagine that cancer behaves in a progressive manner: that is, that it arises from one haywire cell that replicates abnormally before inevitably spreading to other parts of the body, eventually killing the person. Let’s call this way of thinking the relentless progression model. In this model, every cancer cell is destined to spread and become lethal, and that’s how doctors have traditionally been taught to think of cancer’s progression.
>Today, thanks to sophisticated cancer genetics and advances in tumor biology, we know that’s not always how it works. Cancer is not a single disease; it’s many. On one end of the spectrum lie cancers that become aggressive and invasive from the start, and on the other end are cancers that remain non-invasive and therefore harmless. Whether a single rogue cell replicates slowly and stays put or goes wild and spreads is determined by a variety of factors that scientists are still working to understand.
>What’s clear is that cancers fall into a few general behavior patterns, which Welch and others have compared to animals that must be kept in the barnyard to prevent a deadly rampage. Papillary tumors are like turtles — they move very slowly and never pose an escape risk. They don’t need screening, because they will never cause trouble. Then there are rabbits, which are eager to hop away to other parts of the body, but can be confined if they’re found and fenced. These are the cancers that can be helped by early detection and treatment. Birds, on the other hand, are so flighty and quick that they can’t be confined. Screening makes no difference for bird cancers, because they’re so aggressive that they can’t be detected before they’ve begun their deadly course.
>No cancer screening has ever eliminated the majority of cancer deaths. Instead, the best screening can do is reign in the rabbits. Birds remain unstoppable, and they’re the ones responsible for most cancer deaths. This is why, Welch says, three decades of mammography have failed to put a dent in the rate of women presenting with metastatic breast cancer upon their initial diagnosis.
See also:
https://sciencebasedmedicine.org/a-skeptical-look-at-screeni...
https://www.wbur.org/commonhealth/2017/06/08/cancer-diagnosi...
Anyone have a link to a preprint? Can't find one anywhere. Hard to comment without seeing the actual source.
For people without university or other access: https://sci-hub.tw/https://www.nejm.org/doi/full/10.1056/NEJ...
From what I understand, Bristol Myers almost didn't develop the drugs. Back then the idea of targeting the immune system to treat cancer wasn't a mainstream idea. It's a very good thing they moved forward with them!
Edit: also, my buddy was the only guy in the study group who didn't drop out. He just happened to be a massive pill-head(opiates), and smoked a ton of pot, which probably helped get him through the side effects.
Immune therapies are worlds better than traditional chemo/rad, which often ended up giving you an entirely different kind of cancer years later, but they are not without side-effects.
I'd be willing to bet if we made even more aggressive investments in finding treatments and cures, we'd be able to achieve both rapid incremental improvements and a handful of breakthroughs with the net results being a radical decline in suffering and deaths due to cancer (not to mention amazing discoveries in science for the sake of science).
It's a shame we don't do this.
I'm very glad to read this article.