Chemotherapy, Then and Now

It took around 12 weeks for the treatment to "kick in", but at that point tumor regression became rapid. Every CT scan since has shown significant reduction in the abdominal tumors until my last one a few weeks ago; there is no longer any sign of cancer in my abdomen. Overall, it went from "countless" visible tumors ranging from a few mm to several cms each in size, to nothing visible on CT today. o_O

Who knows what the future will bring. I'm trying to be optimistic but I'm also realistic about the statistics here. However, going from my literal death bed where I was in horrible pain suffering for 24 hours a day to quasi-normalcy in a matter of several months blows my mind when I think about it. It did give me horrible colitis (yay for autoimmune side-effects!), but I'll take that over a painful death any day of the week. The colitis is bad enough that they had to discontinue the treatment for a while.

tldr; Science rules. Side effects suck. And a sincere thank you to anyone reading who is or was ever involved in cancer research.

Also, adding 4 months of life when you're talking about something 40% of Americans are going to be diagnosed with really is a huge deal. Adding say 1 extra day of life to every cancer patient in the US would be the equivalent of saving ~25 lives each and every year.

https://en.wikipedia.org/wiki/Cancer_Drugs_Fund#Criticism

Having spent time working in/with the research and clinical trial divisions of large pharmas (and their oncology programs), I don't think there is an actual "conspiracy". However, there are certainly circumstances where incentives align (or misalign) such that the pharma/cancer industry devotes resources/time/energy into relatively futile efforts. As brought up in this article, currently we see a proliferation of cancer therapies that have slim (or debatable) benefit in progression-free survival or overall survival. Crucially, because CMS & insurers will usually reimburse the exorbitant prices for these therapies, the pharmas continue to search for, research, develop, and market them. Simultaneously, pharmas will continue to point to the high costs of R&D to justify the costs of therapy. (In some cases those R&D costs are quite exaggerated, but that is another story.)

Since pharmas are constantly trying to balance exploration vs exploitation (i.e. a multi-armed bandit), when they find a therapeutic paradigm that is profitable, a big chunk of the research enterprise & industry ramps up to it: NIH grants, university research programs, startups, etc all start pumping out research and therapies and such in that area. In the past decade-ish for oncology, it has been targeted antibodies/inhibitors: all these -mib and -mab drugs. As this article points out, sometimes these targeted therapies truly do work for some sets of patients/diseases. The progress has been undeniable. Sure, there are therapies which give a few months of progression-free survival at the rate of $100k+/year, and then we find that overall survival doesn't budge. But there is significant hope that maybe if we look at the right subset of patients which the right type of disease, or develop a more targeted and more specific inhibitor, we will get even better results.

Which points us to where a lot of oncology is going now, which is toward "precision medicine". Some of the new cancer therapies are useful only if your tumor exhibits a specific genetic mutation. That is, it might not matter if you have lung cancer or breast cancer or colon cancer -- if your cancer has a mutation in XYZ gene, you should be on ABC inhibitor.[1] For some patients, the results for some of these therapies have been near miraculous. For some, it has not. But again, it gives us hope that there is a lot to be learned, as uncovering tumor DNA sequences has not been cheap or easy until relatively recently, especially since tumors exhibit heterogeneity in their DNA. Another hot area is personalized immunotherapy, as with CAR T-cell therapies, which harvest your body's immune cells and custom re-engineer them to attack your cancer -- definitely not a cheap prospect currently.

So as therapies get over the hurdles of showing "enough" benefit vs risk to get through the FDA, and as payers agree to reimburse for them, once again the research enterprise will increase its resources to these new paradigms. And with all that inertia behind it, sometimes the research field is over-excited about the uncovering of an previously unknown mechanistic link and the promise of new therapies... and we end up a little blind to the crappiness of the clinical studies and actual outcomes. I believe the system can be better. But as of now, the costs and the incentives and the burdens of heavily regulated R&D and the sick patients combine to make it a challenging landscape to work in, and alas that is currently how it works.

[1] One example is microsatellite instability / mismatch repair & a therapy called pembrolizumab, which was uncovered during a trial of patients with advanced colon cancer that was going very poorly, except for one patient who had an incredible response to the drug. Further investigation and subsequent studies demonstrated a link, reported in NEJM (http://www.nejm.org/doi/full/10.1056/NEJMoa1500596) and elsewhere, leading to eventual FDA approval for that indication.

It's a sort of categorical issue- we've tried inexact, scattershot methods that are just barely controlled enough to be called "medicine" (i.e., cytotoxic chemotherapy.) Now we're trying "targeted" methods which tailor medicines to effect cancer in known ways (i.e., "targeted therapy.") What else is there? Those two categories essentially cover the whole paradigm of "giving medicine to patients."

(Note, incidentally, that there is other work going on in the field- early detection/screening methods, for instance, or tumor-subtype classification methods, either of which could make the available treatments much more effective in practice.)

- investigate the biochemistry of the disease state in a fundamental research paradigm, fairly disconnected from incentive to build treatments, and very distant from root causes. They work backwards from the end state.

- find new discoveries, 99.9% of which can only lead to marginal strategies, because they are working backwards through proximate causes. If you mess with proximate causes, you are not building cures.

- nonetheless, a healthy dose of status arrives from the applicability of findings, so everyone involved is incentivized to oversell applicability. The researchers are usually less guilty, the institutional support network usually much more guilty (but look at David Sinclair as an example of the inverse).

- then the institutional funding for translational development, that really has no capacity to judge expectation value, and is staffed by exceedingly conservative people who are not going to get fired for deploying funding in exactly the same way as their predecessor, deploys money towards marginal strategies that really only arose as a form of status signaling.

So that something effective happens is entirely a happy accident.

As to where most of the blame lies, I'd say the translational research funding institutions. It is their job to pick good projects, and it should be their job to influence earlier parts of the chain towards higher expectation value research and prototyping. Doing that would be vastly cheaper than the present utter waste of value.

what makes you think that type of school had them?

LOL. I worked in pharma/oncology. There are a lot of very smart people, but no risk takers and the smartest people I was schooled with do not work in life sciences research. Research, and by extension pharma, does NOT pay very well compared to most industries. If you are literally 'brilliant' it is a really terrible ROI for you. Additionally, if you are of the type that likes to take moonshots and think outside the box, pharma is not for you (though research in some other areas may be more fitting).

For some reason, every other industry talks about how they need to pay well to attract the best talent. Biotech/pharma/life science researchers talk about how terrible someone must be as a researcher if they care at all about money. It's quite frankly, disgusting.

Essentially nothing interesting, from the patient's perspective, happened between the time that effective chemotherapy combinations were formulated (60s & 70s) and roughly ten years ago.

More recently, however, there have a surge of approvals in immunotherapy which have turned death sentence diagnoses (e.g. metastatic melanoma) into potentially survivable diseases. The 2 year survival rate for stage IV melanoma has increased from ~5-8% to 20-40%. The tools used to achieve this increase in survival are broadly applicable to other cancers and have been achieving gains in survival for lung cancer, bladder cancer, &c. More importantly, immunotherapy research is just getting started and there are lots of promising approaches (personalized vaccines, engineered T-cells, oncolytic viruses, more interesting routes of immune modulation). Many of these approaches seem to synergize. So, treatment has improved dramatically for many indications and looks like it will continue improving. There are some cancers which a patient is still unlikely to survive (pancreatic, GBM), but the industry's output of useful drugs is definitely not stagnant.

Now, the pricing of those drugs once approved is a whole different problem...

as a former insider, i will tell you that this is not the case.

the real case is not nearly as bad:

imagine two therapies that are in prototyping phase, being tested extensively in hundreds or thousands of tumor-prone and heavily irradiated mice, but still not yet ready for clinical trials in humans.

one of the therapies is cheaper to produce, has one or more cousin-drugs that have cleared the trial process and have FDA approval, and does a worse job at treating the mice when they inevitably develop knots of tumors. the mice who get this therapy die faster, and from the looks of it, they suffer horrendously in the meantime. it affects most of the models of mice in the same way; there are populations which suffer slightly less, but it's still awful. there is a 20% minority of mice that don't respond to this treatment at all.

the other therapy is more expensive to produce-- let's say by about 10%-- but there's no precedent for its use in humans, or if there have been trials in cousin drugs, the trials have not panned out for reasons that many say were merely statistical blips. but in the mice, it's a winner-- they die slower, and don't seem to suffer nearly as much. in some of the mouse models, it's an even bigger winner, and can be curative. and in a few of the mice, it doesn't seem to be effective at all, but this is a small minority-- let's say 5%.

which therapy does the pharma company push forward into clinical trials, and which does it shelve?

the answer is that neither are shelved, but the first therapy goes to the clinical pipeline first, which puts the second therapy at least a few years behind it before hitting the market, assuming it clears trials and the FDA, which it might not.

the risk of the superior treatment's failure is only tolerable by the pharmas if there's a recent success in hand.

this is why patients get shafted in the short run; their suffering is irrelevant to the risk of drug development as far as the pharma execs care.

the first drug will clear the clinical trial process more reliably, which means that it'll get busy treating patients faster, which means that it'll be a moneymaker faster-- even if its side effects make it a second or third line of treatment right out of the gate.

this leads to having a lot of shitty drugs that aren't very effective, but they're better than nothing, and they're probably better than what came before.

then, a few years later, we see the wonder cures. the wonder cures exist in the same therapy ecosystem as the shitty drugs, which now have a few more years of familiarity behind them.

there's one more wrinkle: the drug company doesn't want its drugs to be competing with each other. so the original shitty drug goes back to the mice and likely back to the clinical trials for a different use case, which it gets approval for-- viola, a "new drug" for cancer.

so the pharma companies save lives, often miraculously. as a former scientist, i am proud to have contributed to that.

but it is the nature of the pharma companies to serve humanity's purposes very poorly as a result of the financial incentives they face.

I used to agree with you, emphatically. Now I'm not so sure.

I had a bone marrow transplant 30 years ago. At the time, one year mortality was 95%. Let's just say it was hard, both physically and mentally. And the doctors absolutely lied by omission.

I see that look of hopeful desperation in new patients every time I go back for a checkup. No doubt patients (research subjects) are being exploited.

But...

Whereas I was a boy in the bubble, similar treatment today is practically an outpatient therapy.

Like a comment upthread, one of my bffs was diagnosed with terminal cancer, qualified for a clinical trial for immunotherapy, now three years later is "cancer free".

Seeing how far we've progressed, now I think our sacrifices were probably worth it. I'm certainly less angry about it.

TL;DR: -ab is related to antibody, -ib is related to inhibitors.

https://en.wikipedia.org/wiki/Onomastics

https://en.wiktionary.org/wiki/onomatology

https://en.wiktionary.org/wiki/nomen

https://en.wiktionary.org/wiki/-nym

http://messymatters.com/nominology/