Friday Favorites: How Effective Is Chemotherapy? And How Much Does It Improve Survival?

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

Intro: Chemotherapy is one of the most common treatments for cancer. How effective is it for improving survival and quality of life? This video, and the next, will answer those questions.

Over the next few decades, the number of new cancer cases will continue to skyrocket. Are we winning the war on cancer? Sadly, in general, no––this despite the introduction of hundreds of new anticancer drugs.

The war on cancer has been likened to the war on terror. No matter how many drone strikes you do, it’s nearly impossible to kill all the bad guys, and no matter how precise the bombing, one must always consider the collateral damage. The toxicity from cancer therapy can be debilitating, and not just health-wise. There’s also the “financial toxicity.”

Patented anticancer drugs are priced at up to nearly a thousand dollars a day. Even with health insurance, the average cost to patients for stage IV breast cancer, for example, can run $190,000. It’s bad enough to be fighting for your life without bankrupting your family at the same time; it’s a problem still common to this day.

Who can forget the apocryphal story of Walter White, working two jobs with health insurance, and still couldn’t afford his cancer care. Now, not everyone is willing to start their own meth lab, but many are willing to go for broke. A large proportion of cancer patients reported their willingness to declare bankruptcy or sell their homes to pay for treatment. I mean, look, aren’t the high prices justified if new and innovative treatments offer significant benefits to patients? But you may be shocked to find out that many FDA-approved cancer drugs might lack clinical benefit.

Wait, then how did they become FDA-approved? “Most approvals of cancer drugs are based on flimsy or untested surrogate endpoints, and postmarketing studies rarely validate the efficacy and safety of these drugs on patient-centered endpoints.” Let me explain what that means. New chemo drugs are increasingly approved just based on so-called surrogate endpoints, which means instead of looking at what we really care about—survival or quality of life—they approve drugs based on things like “response rate” or tumor shrinkage. But who cares if the tumor shrinks, if it doesn’t actually extend your quantity or quality of life? It’s kind of counterintuitive, but just seeing a tumor shrink on a CT scan or MRI is not necessarily correlated with improvements in survival or symptoms. In fact, most studies that have actually followed people out found low correlations with survival. The most recent comprehensive analysis found 90 percent of studies of such validation trials found little correlation with overall survival.

Of 36 new chemo drugs approved by the FDA based on these kinds of surrogate endpoints, once they were actually put to the test in the real world, only one in seven was actually shown to extend life, and half explicitly flopped. And the rest remain untested, revealing “that most cancer drug approvals have not been shown to, or do not, improve clinically relevant endpoints.” “Exorbitant drug prices are bad enough for treatments that work, but charging vulnerable patients for drugs without evidence that they actually improve patients’ survival and quality of life is unconscionable.”

Why doesn’t the FDA require proof that chemo drugs actually benefit patients before approving them? Drug companies say that requiring randomized, controlled trials with meaningful measures would take too long, but the study time reduction using surrogate endpoints rather than overall survival is estimated at just 11 months. So, instead of it taking 7.3 years to come to market, on average, it would take 8.2 years. Yes, we want to get these drugs out as soon as possible, but only if they’re actually going to help people.

Do cancer drugs improve survival or quality of life? “You don’t need to know, according to our broken regulatory system.” And things aren’t much better over in Europe. A systematic evaluation of chemo drug approvals showed that most entered the market without evidence of benefit on survival or quality of life. And even years later, there was still no conclusive evidence that these drugs offered any benefit, and when they did, the gains were often marginal.

That’s why you see editorials in the Journal of the National Cancer Institute referencing Hans Christian Andersen, the author of the tale of The Emperor’s New Clothes. “These studies all converge on a singular conclusion: only a minority of new cancer drugs approved by US and European regulatory authorities in recent years deliver clinically meaningful benefits to patients.” In fact, some cancer-related deaths may be hastened, or even caused, by the toxic effects of chemotherapy rather than the cancer itself. Based on a review of tens of thousands of cancer patients, in as many as 27 percent of cases, the cancer treatment itself caused or hastened death. Okay, but it might be worth that risk if the potential benefit is large enough. And that’s the subject of my next video: How Much Does Chemotherapy Improve Survival?

Though we often hear new cancer drugs described as game-changing breakthroughs, most afford much more modest benefits. In my last video, I quoted a recent editorial in the Journal of the National Cancer Institute suggesting that the majority of new cancer drugs don’t deliver clinically meaningful benefits at all. At least when they are later proven to be ineffective, they’re pulled from the market, right? No. Even when postmarket studies show the new drugs to have no clinically meaningful benefit compared to not just older drugs, but compared to nothing—compared to a sugar pill—most chemo drugs retain FDA approval, and remain on the market, even at the same ridiculous prices. In fact, the most expensive drug they looked at, the one costing $169,836 a year, did not improve overall survival at all, and actually worsened quality of life. That’s $169,000 just to make you feel worse with no benefit. Why pay a penny for a treatment that doesn’t actually help?

And even when they do improve survival, what does that actually mean? Currently, the trend is for Big Pharma to design large trials that may detect statistically significant, but often trivial, differences in survival endpoints. For example, check out this famous trial. Adding this second drug, erlotinib, to gemcitabine for advanced pancreatic cancer significantly prolonged overall survival. Yeah, they suffered more side effects, but we’re not just talking about tumor shrinkage—they lived significantly longer. The placebo group only lived 5.91 months, whereas the added drug group survived all the way to…6.24 months. Wait a second. They only lived a third of a month longer; that’s just 10 days. All the side effects and expense for an average of just 10 days? That’s why doctors shouldn’t use the statistical jargon—”significant improvement in survival”—while informing patients about benefits of a new treatment. When patients hear the word “survival,” they’re not thinking about a week and a half.

If you put all the new chemo drugs together approved over a dozen years, the average overall survival benefit is 2.1 months. Now look, two months is two months, I don’t want to downplay that. But time and again, surveys have indicated that patients expect much more. Incredibly, about three-quarters of patients with metastatic lung or colorectal cancer did not report understanding that their chemo was not at all likely to cure their cancer. I mean, that’s the primary treatment, but the chemo is not curative; it’s just eking out a few extra weeks or months. Why weren’t the majority of patients told that? It’s not that they were being over-optimistic, explained the researcher. They were under the mistaken belief that the treatment offered a chance of cure, when it in fact didn’t. That deprives patients of the opportunity to weigh the risks and benefits and make their own decisions about their own body.

If you ask cancer patients, most want at least half a year to stomach the side effects, which suggests that most cancer patients might not choose chemotherapy if they knew how little they’d actually benefit. But look, everyone’s different. One patient they interviewed said living even one week longer would be worth it; whereas another said they wouldn’t even want to do chemo for two extra years of life since they wouldn’t want anything to interfere with the quality of time they had left. Either way, people deserve to know the truth. I find it telling that oncologists and cancer nurses themselves express less willingness to accept intensive chemotherapy, given the associated toxicities. Most chemo drugs are cytotoxic, meaning they work by killing off cancer cells, but they also kill off some healthy cells as collateral damage, which is why they can damage our nerves, cause irreversible heart failure, slough off the linings of our gut, or damage our immune system.

Drug companies frequently downplay the risks, though––for example, describing this breast cancer drug as having “acceptable” side-effect profiles for most patients, or this pancreatic cancer drug as having a “manageable and mostly reversible safety profile.” These were studies published in top medical journals. Naturally, readers would take these statements to be true. However, if you actually look at the data, the number of serious, even life-threatening side effects was double, or even five times higher, on the new breast cancer drug. And the “manageable and mostly reversible” side effects evidently weren’t referring to those who were killed by the drug. I like how they even included something like a cheat sheet. Acceptable toxicity? Acceptable to whom? Manageable? Serious events and deaths can never be considered manageable. And feasible? Who would sign up for a drug whose toxicity could only be described as feasible? Favorable? Compared to what? Tolerable? That’s for the patient to decide. And any drug that kills people can hardly be considered safe.

Still, patients may very well consider it worth the risk. For some cancers, we’ve made tremendous strides. Testicular cancer, for example. There is greater than a one in three chance that chemotherapy would enable you to survive at least to the five-year mark. It’s the same with Hodgkin’s disease, a relatively rare form of lymphoma. But even when researchers tried to err on the side of overestimating the benefit, for our most common cancers—colon, lung, breast, and prostate—the chances that chemo would enable survival to the five-year mark appear to be more like 1 or 2 percent.

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