
Chemotherapy, Then and Now - apsec112
https://www.sarah-constantin.org/blog/2018/1/14/chemotherapy-then-and-now
======
iskander
>Targeted chemotherapy consists of drugs that are meant to specifically kill
cancer cells and not healthy cells.

Putting immunotherapies (like nivolumab) under this category I think will only
confuse the reader about the state (and direction) of oncology.

Nivolumab doesn't target cancer cells, it blocks an inhibitory receptor on
T-cells, which then kill cancer cells more readily. It's been approved for a
wide range of cancer types since it's really a treatment of the immune system:

[https://www.drugs.com/history/opdivo.html](https://www.drugs.com/history/opdivo.html)

Approvals to date: melanoma, lung cancer, kidney cancer, hodgkin lymphoma,
head and neck cancer, bladder cancer, MSI-H colorectal cancer.

The distinction between targeted therapies and immunotherapies is very
important since, aside from different mechanism, they also tend to have very
different trajectories of relapse/resistance. Any metastatic cancer is
essentially guaranteed to become resistant to a targeted therapy within 6-18
months. Drugs like nivolumab, on the other hand, offer a minority of patients
(10-40% depending on the cancer) a chance at durable responses (cancers either
cured or prevented from spreading by immune surveillance).

~~~
adrianm
I am being treated with pembrolizumab for metastatic MSI-H CRC (I'm in my late
20s). Last year the cancer rapidly metastasized further, covering my abdomen
in tumors. Prognosis was not good to say the least.

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.

~~~
victor106
Congratulations on your recovery!!!

Death is so final, yet life is full of possibilities. – Tyrion Lannister /
Game of Thrones

------
sgt101
The obvious question is : given all of the facts presented why is a multi-
billion industry stuffed with the finest minds and equipment that can be
bought or found carry on in apparent defiance of reason?

I see three explanations. First the pharma/cancer industry is a giant
conspiracy working against the health and needs of cancer patients everywhere.
Second, for some dreadful reason none of the brilliant minds working
ceaselessly day and night have noticed these facts so far. They haven't read
the studies and have been unable to parse the evidence, data science
(counting) to the rescue. Third, there are other facts and knowledge which the
author and readers external to the industry are not privy to, possibly because
acquiring them required seven years of medical school followed by twenty years
of biomedical research.

~~~
iskander
The premise of this blog post is flawed. Despite the madness of the
pharmaceutical industry, we are currently experiencing a revolutionary
improvement in treatment.

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...

~~~
dekhn
I used to work in cancer research and I don't think it's fair to say that
we're experiencing a revolutionary improvement. It looks pretty marginal to
me. Sure, some cancers (the "easy" ones) are making significant improvements
and grinding down on death and recurrence rates.

But most of what you are describing is forward-thinking, not an accurate
description of today.

~~~
iskander
Were metastatic melanoma and NSCLC considered "easy" before immunotherapy? My
understanding is that they were near certain death sentences.

I think that the progress so far certainly looks revolutionary compared with
the previous few decades. I also agree though that a lot of excitement is
related to perceived future benefits.

~~~
dekhn
are you ignoring all the major (incremental) advances made in the previous few
decades? Like adjuvant chemotherapy?

You are also ignoring the immense dollar cost we had to make to have these
achievements- not really justified by the massive expenditures required.

~~~
iskander
I'm relatively new to cancer research (start 4 years ago), so I might be
ignorant of significant advances.

Did adjuvant chemo improve long term survival for any disseminated cancers?

------
mitchtbaum
> Its results are distinctly unimpressive... So far as I can tell, where there
> has been improvement in cancer mortality since the 1970’s, it is mostly due
> to people smoking less, early detection of some kinds of cancer, and
> adjuvant (cytotoxic) chemotherapy, not to targeted chemotherapies.

I'll just add this quote for a starting point from such abject failure, "The
first step towards wisdom is to call things by their right name." -Confucius

"what's cancer?", "how do you fix it?", don't ask them.

------
legulere
The article sounds pretty negative, but if you look at 5 year survival rates
for cancer you see slow but steady progress:
[https://pancreaticcanceraction.org/wp-
content/uploads/2012/1...](https://pancreaticcanceraction.org/wp-
content/uploads/2012/10/Trends-in-cancer-survival-by-tumour-
site-1971_2011-1000x570.png)

~~~
dennis_jeeves
The steady 'progress' is not what it seems. Improved and earlier detection of
cancer means that a patient will survive for significantly longer after the
detection past the 5 year mark. Several decades ago the patient would die
relatively quickly between the period of detection and within the 5 year
period. As one of the posters ( reasonattlm )pointed out,cancer can be
regarded as one of the diseases of aging. To kill cancer cells will not
improve things beyond a point because the body will produce more. I would
speculate if detection methods we sufficiently sensitive, we would _all_ have
some cancer cells within us. It is a matter of degree. Summary: Except of a
few types of cancer, the treatment has not improved the outcome for cancer
patience during the past few decades. Also remember: lies, damn lies and
statistics. My sources: A non-mainstream cancer doctor ( but is a conventional
MD ) who was widely regarded as a quack, by the mainstream medical community.
Heresy is not tolerated well.

------
beefman
> Part of this is due to the fact that many of these are drugs for refractory
> or late-stage cancer; this in turn may be due to regulatory or medical-
> ethics issues that make it hard to directly compare a new drug to the
> standard-of-care old drugs.

My best friend's younger brother is currently dying of sarcoma. I think it
should be illegal to give therapies (and false hope) which are proven to
extend agony and proven not to extend overall survival. Meanwhile, studies of
new therapies must be performed on relapsed patients with hardened cancers. As
long as this is true, the rate of discovery of effective therapies will remain
staggeringly low, and the rate of human suffering from cancer staggeringly
high.

It's easy to blame regulations, but in my opinion they are ultimately a
consequence of our inability to speak honestly. People I've known all my life,
through thick and thin... yet it seems impossible for us to acknowledge the
truth of his treatment: progressively increasing suffering and death, at
tremendous financial cost to his family and society.

I recently forced myself to break the ice a bit in a conversation with a
mutual friend. It was harder than I imagined but went better than I thought it
would. Paul Erdos had a way of talking extremely honestly about things... I
tried to channel him a bit. I encourage everything to think hard about
breaking the status quo of discourse about cancer.

I'm left wondering whether, if I get cancer, I will have the ability to choose
experimental treatment in lieu of "protocols" which are proven to be unsafe
and ineffective. (If anyone has advice on that, I'd like to start getting a
plan together.)

Background: My parents were both pharmaceutical chemists. My father is named
on over 40 patents. I invest in pharmaceutical and "biotech" companies with a
focus on new cancer therapies.

~~~
specialist
_" I think it should be illegal to give therapies (and false hope) which are
proven to extend agony and proven not to extend overall survival."_

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.

~~~
beefman
Thanks for sharing your story. BMT is a surgery though, and surgery is always
experimental in a sense, and has been improving at a satisfactory rate in
general. Drugs are a little different. Great to hear about your friend. A
close friend of mine died last year of cancer while enrolled in an
immunotherapy trial. He wasn't enrolled until after he'd failed two rounds of
conventional treatment, and I wonder if it might have been better to do things
in a different order.

Edit: Completely wrong; thanks maxerickson.

~~~
maxerickson
Bone marrow transplants are chemotherapy (and maybe radiation treatments) to
kill existing bone marrow and then infusion of new cells into the bloodstream.
It's not a surgery as such.

[https://bethematch.org/patients-and-families/about-
transplan...](https://bethematch.org/patients-and-families/about-
transplant/what-is-a-bone-marrow-transplant-/)

~~~
beefman
Thanks. I've invested in a new ablation agent for BMT but I never knew the
second step was nonsurgical.

------
dm319
Here is a nice figure on cancer survival changes from 1971 to 2011[1]. The
writer is correct that not all of this improvement is down to newer drugs - a
lot of it is down to better 'supportive' management - recognising side effects
of chemo, keeping on top of transfusions, having cancer centres where all of
this can be coordinated, having specialists (oncologists) managing the disease
etc etc. For example, the survival of acute myeloid leukaemia has improved
dramatically since then, but our treatment has remained the same two old-
fashioned drugs.

Also the writer lumps chemo drugs into two categories - cancer chemotherapy,
and targeted therapies. That is probably not a good way to look at it as
iskander has already mentioned re: immune checkpoint therapy, which is quite
different. Other categories include:

* small molecule drugs (not antibodies, target a cell metabolic pathway) * adoptive cell therapy - grafting antibodies to killer immune cells etc etc...

Progression-free survival isn't as good a metric as overall survival - that is
true. It was brought in as a replacement for some other indicators, such as
relapse-free survival, which ignored everything (including death due to
treatment) except relapse. Progression free survival doesn't let you get away
with that. Some diseases have been changed massively by treatment. CML used to
have an overall survival of around 5-7 years, it's now so long we can't really
measure it since imatinib was brought it. Obviously people do die of the
disease, but we don't know what the average life expectancy is because they
are doing pretty well. To introduce new treatments in this disease you're
going to have to use another metric apart from overall survival.

[1]
[http://www.cancerresearchuk.org/sites/default/files/styles/c...](http://www.cancerresearchuk.org/sites/default/files/styles/cruk_wide_resp_breakpoint_one/public/cs_surv_trends.png?itok=0LfcIZ84)

------
liveoneggs
this is strange since I watched my mother take medicine and survive (trial-to-
trial) for over ten years without any traditional chemotherapy, which she
wanted to avoid at all costs. A clerical error meant she missed the next trial
and.. anyway that was that.

A friend's dad currently has stage 4 lung cancer and has been taking a daily
pill for over two years now and just surviving without any of the traditional
chemotherapy issues.

These pills are amazing but I guess your luck eventually runs out.

------
scythe
I'm a bit surprised that we're only looking at the results of targeted therapy
in _late-stage_ cancer. It seemed apparent to me from the name that targeted
therapies were supposed to be less toxic, so they could be used in patients
who weren't effectively dead, i.e., in earlier-stage cancers. Late-stage
malaria and tuberculosis have terrible survival rates, and those are diseases
we're supposed to be _good_ at treating.

------
lr4444lr
Enjoyable read. Anyone know if she did a similar research review of
concomitant temporary fasting during the pre-application and treatment periods
of chemotherapy? Her blog is not searchable and a domain-specific Google
search for relevant terms didn't turn up anything.

~~~
ezekg
Luckily, most WordPress/SquareSpace blogs give you a link to a search page, or
a search bar directly, on the 404 page: [https://www.sarah-
constantin.org/search](https://www.sarah-constantin.org/search).

------
dnautics
> (Normally we associate decentralization with freedom; but consolidating
> authority in a small number of people rather than a bureaucratic process can
> make it easier to get things done quickly and iterate.)

I would hardly call 'bureaucratic process' decentralization.

------
paulie_a
I have a close friend's mother with lung cancer that is currently being
treated with an experimental drug. After reading the "no difference" multiple
times I am not too optimistic. I do not know which drug she is taking but :(

------
kyberias
I think the text contrast couldn't be any worse.

------
sowbug
Why do so many modern cancer drug names end with the letter B?

~~~
IvyMike
[https://en.wikipedia.org/wiki/Drug_nomenclature](https://en.wikipedia.org/wiki/Drug_nomenclature),
[https://www.medscape.com/viewarticle/867446_3](https://www.medscape.com/viewarticle/867446_3)

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

