Monday, September 2, 2019

Chemotherapy: A Pervasive and Misunderstood Treatment Option

One of the worst diagnoses a person thinks they can get is that dreaded "c" word: cancer.  When people imagine cancer, they imagine a very specific future.  Chemotherapy, hair loss, weight loss, a slow wasting peppered with bouts of nausea.  People's understanding of cancer, and chemotherapy, is largely informed by the cultural zeitgeist.  When we see people in movies with cancer, we see a rather specific interpretation.  Rarely, for example, do we see anyone who is chubby from taking steroids; rather, we always see someone pale and hollow-cheeked.

 There's not really anything funny about cancer so here's a meta-meme.

Though everyone today is familiar with cancer as a concept, few know much about it.  We probably think we know more than we do.  For chemotherapy, this is even more true.  People have a vague notion of what chemotherapy is: it's an IV drug that somehow kills cancer and makes you sick.

Beside that, the internet is rampant with misinformation.  If you've ever been on Facebook for more than two seconds you've probably seen all sorts of bogus conspiracy theories that revolve madly around cancer treatment, everything from the idea that it can be cured using crystals and sound frequencies (looking at you, Amanda) to the notion that a cure exists and is being hidden from us by doctors who are profiting off of the treatment of cancer.

It was one such Facebook post that inspired me to write this post.

As usual, this post cites no source.  One thing I've always told people on Facebook and other social media is, get the source.  That includes news articles.  If no primary source or study is linked, don't trust what you're reading.  This is an easy way to bullshit-check medical claims, even if you're not a scientist.

As a skeptic, I tend to go searching for the sources of claims such as these myself.  Most of the time, of course, it's total bunk.  But once in a while I stumble onto a half-truth that startles me.  (One time, a yoga-obsessed friend posted a link to an article stating that yoga can be used to treat scoliosis.  It's legit.)

I plunged down a rabbit-hole of chemotherapy research, curious about its true origins, and found that at least one part of the little meme was correct.  Chemotherapy was, in fact, actually developed from mustard gas.

Today's post is a brief overview of the history of chemotherapy, a thing most people only learn about in earnest once they have to deal with it on their own.  Hopefully, reader, you and I won't have to confront that from a personal standpoint for a long while yet, if at all. But nonetheless, it's not a bad thing to have a broad overview of the facts while emotionally distanced from them.  I will not be speaking much about cancer itself, because that's too broad of a topic.

However, I do want to explain at least one exceedingly common misconception about cancer.

The windmill thing.

That misconception is that it is a single disease.  People talk about the "cure for cancer" the way that they talk about the "cure" for the common cold.  But like the common cold, cancer isn't so much a single disease as it is a series of diseases.  Cancer comes from abnormal or uncontrolled cell growth or propagation, but it has a broad range of causes and manifestations.  Conspiracy theories who claim that scientists secretly have the cure for cancer are partially right.  There are forms of cancer we have effectively cured.  Skin melanoma, for example, has a 99% survivability rate.  And Hodgkin's lymphoma has an 86% survivability rate five years after diagnosis.

And it's with Hodgkin's lymphoma that we will begin, because this cancer, perhaps more than any other, is the one whose patients have benefited the most from chemotherapy.

First described in 1832 after the titular Thomas Hodgkin, Hodgkin's lymphoma is a cancer that affects the white blood cells known as lymphocytes.  It's often detected when people notice a swelling in the lymph nodes, something that occurs due to over-production of these cells.  Unfortunately it can also be easily missed because your lymph nodes also swell for most minor infections in which your body would produce extra lymphocytes to ward off bacteria.

 I am so sorry.

In 1915, the first effective use of mustard gas came into play.  Mustard gas (sulfur mustard) was designed by chemist Fritz Haber, inventor of the Haber process and strong proponent of chemical warfare.  Ironically carcinogenic, mustard gas, in its purest form, is both colorless and odorless.  But the type deployed on WWI battlefields was low-grade mustard gas.  Yellowish-brown and reeking of peppery horseradish, soldiers were not inclined to worry much about the carcinogenic properties, as contact with the gas caused immediate skin blistering, blindness, and, in large amounts, suffocation.  It was a terrible way to die and the use of mustard gas in warfare was banned by the Geneva Convention in 1925.  Hitler was famously against the use of chemical warfare after being hit in 1918.  (This dislike of chemical warfare did not extend to the Jews and political prisoners he gassed in the camps using Zyklon B, a chemical developed by, you guessed it, Fritz Haber, who was Jewish and whose whole family was ironically killed by his own invention.)

Soldiers who survived exposure to mustard gas suffered ill effects, including anemia and low white blood cell counts.  Clearly, the gas suppressed the development of some of the components of the blood.

Fast-forward to 1942.  Sulfur gas wasn't being used in WWII, but two scientists from Yale Louis Goodman and Alfred Gilman were nonetheless interested in the effects.  They had ample data from all of the WWI soldiers who had been hit and the idea that mustard gas suppressed white blood cell propagation intrigued them.  After injecting a ton of animals bearing lymph tumors with sulfur-nitrogen compounds, they observed that the tumors stopped growing and even got smaller.

Armed with the no-fucks-given attitude of medical testing in the '40s that gave us Captain America, they found themselves a human test subject, listed in the records as "J.D."  J.D. was suffering from massive tumors in his mouth, armpits, and groin; his prognosis was bad.  With no other option, in severe pain and desperate for relief, he agreed to be injected with "substance X."  Two months later, his tumors were receding and he reported feeling a lot better.

I wish I could give J.D. a happy ending but, alas, this earliest form of chemotherapy failed to target only the lymphocytes.  It wiped out J.D. bone marrow and platelets, and he ended up dying from internal bleeding as a result.  By some accounts, he "passed peacefully."  You can be the judge of whether or not you believe that to be true.

Who the fuck knows how the human body works, really.

Regardless, Goodman and Gilman published an article with their results in 1946.  On its heels followed Alexander Haddow's 1948 paper in Nature that determined which parts of the nitrogen molecule were actually needed and how they worked.  (Spoiler: it's the chlorine atoms.)  Later papers expanded on this, determining causality; the nitrogen molecule worked by linking to DNA within the cell and prompting it to "commit suicide."  Instead of multiplying endlessly, cancer cells were being triggered to self-destruct by the mutagenic properties of "mustine," the first chemical used specifically as chemotherapy to treat cancer.

The struggle of most scientists.
Haddow, happily, got to see the fruits of his labor in his own time.

Following Alexander Haddow's paper, researchers began synthesizing new molecules that were structurally similar to mustine but might better cure patients without killing them.  They came up with chlorambubil, put into use in the 1970s and used today to treat several types of white blood cell cancer, including leukemia and non-Hodgkin's lymphoma.  Since its use in the 1970s, survival from non-Hodgkin's lymphoma has tripled.

Haddow's paper describing the mechanism by which mustard gas actually worked meant that people were no longer being treated with mustine, but other chemicals, ones with fewer side effects.  These chemicals were calls "alkylating agents" because they worked by alkylating organic molecules such as DNA (rendering them useless, and unable to replicate, which in turn triggers cell death, or apoptosis).  Alkylating agents include chemicals not derived from nitrogen mustard at all, such as tetrazines.

One thing worth noting here is that chemotherapy targets living, multiplying cells.  In particular, modern chemotherapy tries to target cells that are actively or rapidly multiplying.  This includes not only cancer cells, but also hair follicles, which divide rapidly, which is why your hair grows so quickly.  This is why many chemo patients lose their hair and why their skin looks unhealthy; hair, fingernails, and skin have some of the fastest-multiplying cells in the body.  Chemotherapy isn't like antibiotics, capable of targeting "other" or "non-self" cells.  Cancer is, by definition, your cells that have gone bonkers.  Although modern chemotherapy can target specific kinds of cells (for example, ones that are multiplying rapidly), it's impossible with our current technology to separate cancerous vs. non-cancerous cells.  Cancer isn't a viral or bacterial infection; it's you.  Chemotherapy is often demonized as "poison."  This is correct.  It is literally an attempt to poison the bad cells in you, and regrettably, there is no way to separate "good" from "bad" cells, because all of them are yours, and contain your DNA.  Unfortunately, people who are suspicious of or don't understand chemistry tend to point to the vicious side effects of chemo as "evidence" that it's bad for you.  Yes, of course it's bad for you.  It's also bad for the cancer, which is also you.

Haddow wasn't the only one who had stumbled across something remarkable.  In Boston, Sidney Farber was toying around with aminopterin, a chemical that blocked DNA replication.  This was the precursr to methotrexate, a modern chemotherapy drug.  Using aminopterin, Farber got ten children with leukemia into remission, earning him the title of Father of Modern Chemotherapy.

The first "cures for cancer" had been found.  (The first cure for a metastatic cancer is widely said to be via the use of methotrexate, in 1956.)

In the 1950s, pharmaceutical giant Eli Lilly announced that plant alkaloids would be used as cancer drugs.  These weren't chemicals synthesized in a lab;  vinca alkaloids (like vinblastine and vincristine) were extracted from Vinca rosea.  Though they were using the research done on alkaloids that originally came out of the mustard gas era, these new compounds were naturally occurring.

Note that nearly all chemicals occur in nature 
and that "natural" does not inherently mean "safe" nor "effective."

The 1950s marked the beginning of "combination chemotherapy," in which multiple drugs would be used to try to target cancer from multiple angles while minimizing the effects on healthy cells.  In some cases, chemo was used to get rid of remaining cancer cells after the surgical removal of a tumor.  This is called adjuvant chemo and dramatically increased the remission rates of localized cancers like breast cancer and testicular cancer by ensuring the cancer couldn't return after the removal of the tumor.

Prior to the 1940s, cancer wasn't a big concern in the minds of most Americans.  Half of all mortalities were from infectious diseases.

You can look up the statistics yourself but I liked this graph in particular.  
Less than 4% of people died of cancer in 1900.  Less than 4%!  
By the 1940s, that figure would leap to over 10%.

It was only with the rise of antibiotics that cancer was noticed; people were living longer and actually developing it, instead of succumbing to something else, and in the 1940s and 1950s, a series of PSAs were put out declaring "war on cancer."


Many of these PSAs had to explain what the hell cancer was.  It was simply not part of the public knowledge back then.  (I have some vague memory of a cartoon by Disney or Looney Tunes explaining cancer using old timey speech, but could not find it and wonder now if I dreamed it up.)

Many of the things we take for granted now (like germ theory and antibiotics) are only recent medical discoveries.  Yet people have a tendency to pick and choose which types of medicines they deem "safe."  Chemotherapy is a pretty easy one to demonize, not only because of its history but also because of its nasty side effects.

But it works.

To those who think that chemotherapy is merely a conspiracy by evil doctors who are profit-driven, I have some bad news (that is, in fact, great news).  The passage of the Cancer Act of 1971 earmarked 85% of money spent in the "war against cancer" toward investigator-initiated research projects.  In other words, scientists, not doctors.  A sizeable portion of the remaining money was put into adjuvant chemo programs.  "But why chemo?" you ask.  Well, for one thing, chemo works.  Is it horrible?  Oh, yes.  But it works.  Alternative therapies don't; a massive study of cancer patients who refused recommended treatment in lieu of alternative therapies found that, universally, alternative therapies don't work in treating cancer.  Not in any form of cancer.  Not a one.

On the other hand, Hodgkin's lymphoma now has a 2/3 remission rate.  That is, people whose cancer is cured; 60% of those who undergo chemotherapy can now achieve complete remission without ever relapsing, allowing them to die from something else (if they're very unlucky, another form of cancer).  If you click on no other link in this post, please do click on this one, which links to a very well-written article on the history of chemotherapy and addresses many of the fringe anti-scientific criticisms of it.

Chemotherapy has a long and storied history, but this doesn't mean it doesn't work or is part of some vast network of doctors conspiring to profit.  There are plenty of instances in history that we stumbled across something wonderful while actively doing something horrible (or, more often, bone-headed).  The question isn't really how we discovered it, but how we can apply it now, and what good it can do us.  More importantly, we need to understand that the origin of a thing isn't the same as the thing itself.  Modern chemotherapy isn't the same as getting hit with mustard gas in WWI.  For many, it's their best shot at survival.  And demonizing it to push a pro-hemp agenda is staggeringly irresponsible. Chemotherapy is saving lives.  Does a better treatment option exist?  Maybe.  But we haven't yet discovered it.  And sometimes, as chemotherapy has shown us, life-saving discoveries can come from the unlikeliest of places.

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