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Comment by jackweirdy | Hacker News Reader

> Although the cases drew wide media attention in Britain, some researchers said that because the London team also gave the children standard chemotherapy, they failed to show the cell treatment actually cured the kids.

Could someone explain what the process for proving it would be in this case? I presume some kind of animal testing?

Seems pretty immoral to give someone a wildcard treatment and not back it up with something known to work. Not disparaging this treatment but given we don't know if it works yet (and how aggressive cancer can be) it seems totally fair to administer it alongside chemo.

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Standard approach would likely be to choose a population of patients, randomize them between "chemo" and "chemo+immune" treatment groups, and then test for a significant difference in the metric of choice such as response rate or progression-free survival. The graphical analysis of these data is often done using Kaplan-Meier curves (https://en.wikipedia.org/wiki/Kaplan%E2%80%93Meier_estimator)

So, can't simple take some (or all) other children who are going through "just chemo" in any other hospital, or even in the same hospital? I think there are plenty of children in the world that are doing (suffering?) chemo everyday.

You need a larger sample size than 2 to differentiate between the odds of "success due to just chemo" vs "success due to chemo + x treatment."

No, they can't. To do so would introduce confounding variables in the inevitably unique way they treat their subjects, even if it's just knowing you're part of the experiments.

For maximum assurance of conclusions, such studies need to be double-blind: neither the subjects nor the researches who interact with them are to know who's taking just chemo and who's taking the new treatment.

You'd want to eliminate as many potential confounding variables as possible. If they took the control group from another hospital, maybe that other hospital does something that improves or hurts their chances. Even if you pull from the same hospital, just being in the study might change the treatment they get in subtle ways.

There's also the issue of blinding. If the control group is some outside group, then you know that everyone in the study group is receiving the new treatment. It would be much better if everyone involved didn't know whether any given patient was getting the new treatment or not until after all the results were in. For that, you need to recruit patients into the study, then randomly assign them to the new treatment or the conventional sort.

With something like cancer which has a wide geographical coverage, and more or less standardised treatments, couldn't you get a good result from including everyone in hospital X in a treatment and comparing to the general public?

No, cancer does not have standardized treatments. The remission rates vary greatly depending on the hospital and even on the doctor.

Huh...? There are standard treatment protocols.

The point still stands in practice- it's an interesting sociology of science topic. There are often unwritten rules and protocols that have a huge impact.

Speaking from very recent experience, some things are obviously standard, like "take these pills twice a day" but cancer often comes with lots of ancillary issues, and most treatments come with side effects.

There was a lot of variance in how doctors and nurses treated the side effects, how they spoke to the patient, what other resources they provided, the quality of bedside manner, their attentiveness to lab results and patient health over time, whether they consistently washed their hands, etc.

People don't really die "of cancer" they die of things like blood loss, toxic build up from renal failure, blood clots, or infections acquired in the hospital that attack a weakened immune system, to name a few.

Sure. Anyone with cancer should go to a high volume academic and designated cancer center. The hospital should also rate high in us news and reports and score top marks in nurses, safety and cleanliness. But you can't deviate from FDA guidelines except in very exceptional cases.

What guidelines?

Doctors have tremendous latitude in how they treat patients and, as far as I know, there are no "official" guidelines for most diseases (very communicable diseases might be one major exception).

There are guidelines for developing, manufacturing, advertising, and selling drugs. However, doctors can use them off-label. From the FDA (here: http://www.fda.gov/ForPatients/Other/OffLabel/default.htm ) "From the FDA perspective, once the FDA approves a drug, healthcare providers generally may prescribe the drug for an unapproved use when they judge that it is medically appropriate for their patient. "

That was my experience of variability for a family member treated within a particular high volume academic hospital and designated cancer center.

But my point is in response to the original parent comment. If you give treatment Y at one top hospital and your control group is everyone getting treatment X at all the other top hospitals, you still have basically anecdotal data.

If I'm very sick and the standard treatments aren't working, would I want to try a protocol that was anecdotally very successful in some clinic? Absolutely. Just because it's not scientifically proven to work doesn't mean it doesn't work.

They do run multi center clinical trials... but yes if your current treatment doesn't work or is likely out of date then you should seek another treatment option (usually a phase 1 or 2 trial)

You'd also have a host of confounding factors outside the treatment. Trace minerals in local water, different pollution, different seasons, etc...

You can get A result, but not a good one.

You want to eliminate anything and everything that can (in)directly effect the outcome of treatment in a study. Ideally, the only difference at all would be the variable you are testing, but real life doesn't make things that easy.

You don't need blinding for cancer trials

Its not immoral.

Right now I'm in a cancer treatment study. (my particular study is a "shotgun" type of study. They have a drug that they know works on certain types of cancer, but they have a guess that it might work on my weird/rare type.)

The previous studies on this drug I'm on, were done on patients they had exhausted the conventional treatments, chemo, radiation etc. And they were put on this drug as a last chance after the conventional treatments had failed. I'm lucky in that I'm getting this drug as a first line treatment.

In this case, with these kids, it sounds like they were given the traditional chemo, and when that show results, they tried this. As a result, they don't know if the chemo caused the remission or it was the T-Cells, or the combination.

Give both the normal treatment and (new thing), and compare it to just the normal treatment and see which group has better outcomes. For serious issues you can stop the trial early and give it to everyone if it's shown to be a dramatic improvement.

The full paper states that they did this prior to even phase I of clinical trials:

http://stm.sciencemag.org/content/9/374/eaaj2013.full

Therapy was provided for two infants under the UK. special license arrangements after institutional ethical reviews.

Named-patient, open-label, nonblinded, compassionate therapy was undertaken in two infants ahead of planned phase 1 clinical trials.

I guess the proceedings of the ethical reviews would be quite interesting.

Compassionate therapy basically means "it seemed super likely that these patients are on track to die, so even if this therapy is awful for them, you can't make the situation much worse, and we should take a shot at curing them."

> Could someone explain what the process for proving it would be in this case?

You can have a look at NICE who do the cost:benefit approvals for meds in England.

Here's what they said about Abraxane, a medication for pancreatic cancer. (TL:DR it's not good enough to replace current first treatment, and it has too many side effects to replace current second level treatment. I don't think cost, a bit over £5000 for the average patient, was a factor.)

https://www.nice.org.uk/guidance/ta360

If you walk through the complete document you can see what they think is important; what the manufacturers think is important, and what evidence is used.

It's written for a specific audience, and it's a bit medical, but it's (IMO) very readable.

Animal testing is used for some initial toxicology and indicators that a treatment is worth testing in humans but you can't use animals to "prove" a treatment is effective for people.

Once a treatment is through animal safety trials, they will give it to patients with very advanced stages of cancer, who are considered unlikely to survive very long. This is both to minimize harm, and make it easier and cheaper to tell whether a treatment worked.

> Seems pretty immoral to give someone a wildcard treatment and not back it up with something known to work.

I think they're giving the treatment to patients for whom pretty much all options have already been pursued and they're still terminally ill. Of course that still doesn't "justify" necessarily a wildcard treatment completely, but I guess one last wildcard attempt might be better than nothing.

It depends. If the usual treatment for a terminal disease has big side effects and is unlikely to pay-off it might be more ethical to use a promising treatment whose effects are uncertain.

However, I expect a lot is known about chemo-only survival rates so it may not even be a legit criticism as you can compare the combination survival rate to the baseline. That said, n=2 is too small to draw conclusions.

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