This module on chemotherapy and molecular-targeted therapies answers these questions:
How does chemo work?
What are molecular targeted therapies?
How can you reduce the side effects?
How can you make chemo more effective?
This is the fifth module of the Make Cancer History course, and it is all about chemotherapy and molecular targeted therapy.
Chemotherapy is really the backbone of cancer treatment, unfortunately. I think most people or most cancer patients know that chemotherapy came from chemical weapons – a mustard gas in World War One. From your history lessons, you may remember that mustard gas has a high vapor pressure. That means it hangs around waist height or chest height, and attacks the body, particularly the lungs. It was observed in World War I that soldiers who had lesions and wounds – some of those shrunk a bit when exposed to mustard gas. Particularly it was also observed that their white blood cell counts were low, so there was a hint that this might be good for treating the blood cancers, which are cancers of the white blood cells (leukemias).
This came up again in World War II rather interestingly, although chemical weapons were banned after World War One. The US had quite a stock of mustard gas and there was an accident on a U.S warship in Italy and a bunch of mustard gas got out ,and a lot of the US Navy were exposed to this mustard gas. Again you saw low white blood cell counts, and from this was developed chemotherapy.
The word chemotherapy just means treating cancer with chemicals essentially. But when people talk about chemotherapy, what we generally mean is essentially the use of poisons that interrupt the cell division and growth cycle – that cycle that we probably all learned about in school. I can’t remember the basic science, but the nucleus where the DNA gets a bit bigger and divides, and the cell divides. Where you had one cell, you now have two and then four and eight and sixteen. It keeps going with those powers of two.
With mustard gas, there is a problem. It’s a deadly poison, and that was really no good as a medicine. But it was possible to make a modified version. That was the first chemo.
We really think about chemotherapy as drugs that damage the cell growth cycle, and we often think of one of the definitions of cancer, is this idea of unregulated cell division. When we’re growing as kids, cells are dividing a lot. That means, there are big issues with using chemotherapy for children who are growing. But as adults, we’re not growing generally, but we do have a lot of cells dividing. Our skin is getting replenished all the time, also the lining of our GI tract (stomach lining and intestines or whatever), so that’s why chemotherapy causes us all those problems with digestion, and all that wonderful constipation and diarrhea that we get from chemo – that’s why that happens.
Also skin and of course hair follicles. That’s why our hair falls out. I didn’t have a lot of hair anyway, so that was okay. But it’s obviously a classic side effect of chemo.
Also things like the nail beds, around where your toenails and fingernails are growing, that can be a really tough side effect to deal with. At points during my treatments, it was really difficult to walk because of the damage of those drugs attacking around my toenails, it was very unpleasant.
Chemotherapy generally does not cure cancer. It’s generally not a curative treatment, at least superficially. Chemo is really used in three ways. For early stage cancer, often a single chemo drug is used, and I guess that could be curative. Although presumably what’s happening is the chemo is killing a lot of the cancer, and the immune system is recognizing these dying cancer cells, and then taking care of the rest.
Then in late stage cancer, chemo is usually used as a combination, possibly with other chemos. Of course now with molecular targeted therapy as well, which I’ll talk about later. That’s called Adjuvant chemotherapy. Adjuvant chemotherapy is a third way which is used, particularly after surgery. Chemo seems to work better when there’s not so much tumor burden, so physically not so much cancer in the body, so used after surgery to hopefully prevent the cancer coming back.
Although again we must be a bit careful, because it’s not really going away, and coming back. It’s more like there are probably cancer stem cells hanging around, and it recurs.
Chemo dosage is generally based on the surface area of your skin, because that is a good proxy of how much blood is in the body. When you see chemo dosing, it will be a certain number of mms or mgs per square meter of patient skin. It’s a little bit weird, but that’s how they do it.
Chemo is often taken as an IV drip (intravenous drip) and often if you’re having a lot of chemo, like I was, you’ll get a chemo port. I had a chemo Port- it’s been removed now. I’m not sure if I can show you the scar, but somewhere around here was where my chemo port was. It’s sometimes called a Picc line – there are various brands and various kinds. Essentially it’s a chunk of plastic that’s put under the skin with a tube leading from it towards the heart. That makes it convenient for putting needles in, particularly if (like me), you have narrow blood vessels.
About half of all people have quite narrow blood vessels, so it can be quite difficult to put in an IV drip. But also a chemo port is useful, because with many chemo drugs, the side effects at the point of where it’s put in, are less with a chemo port. The chemo that I did originally (FOLFOX – a combination chemo of 5FU with oxaliplatin), that’s one where if you don’t have a chemo port and it’s just put directly in your arm, there’s a bit more risk of trouble around the injection site.
A third reason for a chemo port is that some chemotherapies are given as a very slow infusion, a few mls/ hr. For people with colorectal cancer – many of us are familiar with the slow infusion for 46 hours of 5FU. There is a little device with it, essentially a balloon of chemotherapy drug inside. The atmospheric pressure pushes on that balloon, the balloon slowly deflates, dripping the chemo into your body. For that, you really would want a chemo port.
Chemo can also be taken orally. In that case, it doesn’t usually have the chemo drugs in the medicine, but it’s got what’s called a “pro-drug”. A pro-drug is a drug that turns into the final drug in your liver. Xeloader would be a famous example of that, which contains pro drugs to 5FU. You take that – it’s a load of tablets and they turn into chemotherapy in your liver.
That has advantages and disadvantages. It’s nice to take some tablets instead of going to hospital for a day of drips and then doing a slow infusion. But what happens when you take the tablets, is that you get a peak of chemo drug in your body, and then a sharp decrease. That means it can’t be used in certain combination treatments. Specifically with Xeloader, it doesn’t work well with Erbitux, which is a molecular targeted therapy, often used with 5FU for colorectal cancers. For that to get a good result from Erbitux, you need the slow infusion.
On the subject of drugs, one thing we need to be a bit careful of, particularly when we see reports of new drugs in the media, or if people are trying to sell us miracle cures, is that lots of things kill cancer very effectively in the lab, and it’s very different from them being a viable cancer drug. Part of the reason for that, as I’ve just said, is that the liver is in the way. When you take a chemo tablet that contains a pro-drug, it’s being metabolized in your liver, turning into the chemo drug. So there are plenty of things that will kill cancer in the lab, but your body’s got a lot of defenses against toxins. Our liver is very effective at detoxifying our body. It’s one of the many roles of the liver.
So we need to be a bit skeptical. You’ll sometimes hear in the media, a game-changing drug has just been developed and is in pre-clinical trials with a 100% success rate. All that means is that they found something that killed cancer in mice in the lab, of which there are thousands and thousands of things. Very few of those become viable drugs, because they might not work in humans, or they may have side effects that can’t be tolerated, or they may have unforeseen consequences when they may do damage to you that can’t heal. So please be very skeptical when you see these media reports of new game changing cancer drugs.
Basically for research scientists, unless they say something is revolutionary and game changing, the media just don’t want to know. You don’t even get a mention. Media are not interested in the reality of slow drug discovery over many years. It’s interesting that chemo came from chemical weapons, and the chemo worked and then later it was found why it works. In the case of those mustard gas-derived ones, the chemo makes links across the DNA, so the DNA can’t divide and the DNA can’t do its job of making RNA and building proteins and expressing itself as the scientists say. The drug was discovered, it worked and the mechanism was discovered later. After World War II in the 1950s, that’s when DNA was discovered. In 1953, the double helix structure was discovered. So people could work out, this is how it’s working.
Now of course, drug discovery is moving a lot in the other direction of binding mechanisms, and then making drugs that work with those. Particularly with the molecular targeted drugs, where there are targets on the cancer cell, and then drugs that can be made to work with those.
One other way that chemo is sometimes taken for skin cancer, is by a chemo cream.
As I mentioned, boring old 5FU is available as a cream as well for skin cancer.
One way that chemotherapy can be made more effective, is by using something called hyperthermia therapy- heating up tumors or areas of the body. For some cancer patients, we’ve heard of this thing called HIPEC, which is a heated chemotherapy procedure. For some kinds of gynecological cancers that have spread to the abdominal membrane, colorectal cancer that’s spread to the membrane, asbestosis which is a lung cancer you get from exposure to asbestos, that was how HIPEC was first developed.
But there are other forms of hyperthermia therapy as well. One that’s used quite a lot in Japan and also in Germany, is a regional hypothermia therapy, where you lie in a machine for about 40 minutes, and a region of your body is heated up. In the one I did, the machine heats a 30 cm section of your body. In my case, I had the machine targeted at my liver and the abdominal membrane, and it heats up that part of your body to a fever range of temperature (~41 degrees). That kind of temperature is maintained for half an hour- 40 minutes. One of the consequences of that is you get more blood flow in there. When you’re hot, blood rushes to the hot places, so you can lose heat that way. Of course the opposite happens when you’re cold – the blood goes into your core and your skin turns paler, particularly fingertips, and you get cold toes.
So hyperthermia therapy is heating up the tumors to increase the blood flow, so you get more chemo in. That was particularly important for me, because the cancer spread to the abdominal membrane, and not much chemo gets into the abdominal membrane, because there’s the membrane and the tumors – they also have a poor blood supply. So heating them up is a good way to make chemo more effective. The effect is probably not massive, but it’s a safe, cheap treatment if you can access it, with no side effects really. It’s very uncomfortable, but when they turn the machine off, the heating stops immediately and you’re fine. It’s uncomfortable for the 40 minutes lying there, although I did eventually get so used to it, that I could read a book while doing it, sweating profusely as my tumors heated up. But if it makes a few % difference, it’s potentially worthwhile.
This brings me very neatly on to something I hadn’t considered, which is that one use of chemotherapy can be to make other treatments possible. Particularly shrinking tumors so that you can do surgery for example, Or if you have several tumors – if you have 5 tumors and 2 are small – maybe chemotherapy could shrink them enough so that the 2 small tumors almost disappear, then you can have radiotherapy for the other 3. Without doing chemotherapy, the radiotherapist may say, “I can’t treat 5 tumors, it’ll be too much radiation for you”, so you get no radiotherapy.
Sometimes chemotherapy can be a good way to get to another treatment, and can make surgery possible. If you have lots of liver tumors and maybe they’re spread throughout the liver, it’s too dangerous to do one-step liver surgery. But chemo might be enough to get rid of some of the tumors or shrink them enough that you could then do your liver surgery.
There are lots of different mechanisms for chemo. There are 5 kinds of chemos that work in different ways. Some of them cause the DNA to fuse together, like I mentioned the mustard gas-derived ones. Some suppress enzymes that are used to prevent mutations happening, so the results are too mutated and die.
There are various mechanisms but from a patient’s point of view, chemo is unpleasant and is something that we tend to do a lot as cancer patients. There are lots and lots of different combinations of chemos at the moment (70+ combinations). Typically chemotherapy does seem to work better as combination treatments, particularly in those ones with molecular targeted treatment as well.
If you are a cancer patient yourself and you’ve done chemo, then you’re very familiar with the side effects of fatigue, skin trouble, hair trouble and nerve damage. For me, the toughest to deal with was the nerve damage which can be quite scary. You get damage in the peripheral nerves (those long nerves in your arms and legs). You keep dropping stuff which is scary, and doesn’t seem to be much you can really do.
If you’re suffering a lot with that, something worth looking into though is called Scrambler therapy. This has been done as trials in the US, maybe the Cleveland Clinic was one of them. Scrambler therapy is using electrostimulation. It’s a bit like those TENS machines that some people use if they have paralysis problems. In the case of Scrambler therapy, it causes a lot of nervous stimulation, and for some reason that seems to reverse the damage pretty effectively. So that’s one thing you can look into.
For skin trouble, the really important thing seems to be early intervention. When you’re going to start chemo, typically the nurses and maybe the doctors as well, will tell you to start your skin treatment before you do the chemo, and it’s very good advice to already be doing the moisturizing to strengthen up the skin barrier.
For a lot of chemos and some molecular targeted therapies, you’ll be given a 3-step skin care, which will be a moisturizer, some kind of antibiotics (it might be a skin cream or tablets), and then a steroid as well, to calm down the skin rashes.
For hair, in the UK, for some reason a lot of emphasis is put on Cold Caps. The idea is the opposite of what I explained about hypothermia. The cold cap goes on and stops the chemo getting into the hair follicles and seems to work a bit. I don’t know why it’s pushed so much in the UK, but whenever I look into hair loss, particularly for those gynecological cancers, in the UK they seem to emphasize that cap a lot.
Fatigue is a really serious issue, because it has such an impact on your daily life. The only thing that I personally found that could help with the fatigue, was gentle exercise. I certainly did not want to do exercise of any kind when I was on chemo, but that’s all I found.
When you go to hospital to get your chemo, it will usually be a cocktail with various chemos, molecular targeted therapy, some anti-vomit drug, often an anti-allergy drug (that’s for safety to stop you having an allergic reaction), and then also steroids.
Steroids are obviously extreme drugs as we all know. I found that for the first 2 – 2.5 – 3 days after chemo, I had a lot of energy because of the steroids. But it caused a lot of problems, because one thing is some of those steroids boost your appetite so you feel hungry, but you don’t want to eat because you’re feeling sick. Steroids tend to interfere a lot with sleep. I was given steroids as part of the drip, and then I was given a steroid to take – I think I was given dexamethasone. Dexamethasone (also called Decadron) is a steroid that is very flexible as an oral steroid, because it typically comes in very small tablets, so you can adjust it very well.
I really struggled with it because it made me too hungry, stopped me sleeping, also caused me to sneeze a lot for hours at a time, which just after surgery was really unpleasant because I had pains from the stitches. So good luck with the steroids – I didn’t find them particularly useful. Gentle exercise was the only thing that worked.
A big thing for controlling side effects is dose reduction and having the chemo less frequently. The problem with that is if you’re having chemotherapy with molecular targeted therapy, some of those don’t work at reduced dose. Also, I just can’t find any serious research about dose reduction and about the chemo holidays, when your oncologist says skip this cycle or put more time between the cycles. I just couldn’t find really good convincing research of how safe it is. Sometimes you have to miss chemo because white blood cell count is too low, or you’ve got an infection. Because chemo wipes out our white blood cells, it makes us more open to infection, which is a problem.
There’s another side effect that all chemo patients are familiar with, that we don’t really get any help with at all, and that’s called “chemo brain”. The “chemo brain” is this mental fog that makes it hard to think and do stuff. I found it very hard to take any action. I’d be sat on a chair or lying in bed, knowing I had to do something and wanting to do something, and time would just be passing and I couldn’t do it. This is one of those examples of something that’s very complex, and therefore the medical world just doesn’t acknowledge it. You may be told “that’s just fatigue”. You may be told “there’s no clinical evidence for human brain fog”. But I’ve talked to enough patients over the past six years, and I’ve experienced chemo brain myself, to know it’s absolutely real. Yes, it may be that there are a whole bunch of mechanisms there, and maybe a really big one is just fatigue. I should say that chemotherapy-induced fatigue is very different from exercise-induced fatigue. Exercise-induced fatigue is when you’re tired from exertion, and then you rest and then you’re okay. With chemotherapy fatigue, it seems that when you rest, you’re not okay afterwards, so resting doesn’t seem to help. It’s the same for people that have chronic fatigue syndrome (like ME).
That’s kind of a bit about chemo. Very briefly, I’ll talk about the next targeted therapies which are often confused with chemo.
Very crudely there’s two types, two families. There’s the monoclonal antibodies, that basically attack the cell from the outside, or label the cell, and it’s attacked by the body, and then there’s the small molecule inhibitors that go into the cells and do damage in the cell, stop the cancer cells doing what cancer cells want to do, like dividing and that kind of thing.
Often I think people confuse monoclonal antibodies with immunotherapy or immunotherapies. In the UK, oncologists often confuse these and say “You can do this immunotherapy”. People excitedly write in the Facebook groups that they are starting an immunotherapy drug, thinking it’s going to have the amazing results of what they’ve read about in the media, when you hear about CAR-T cell therapy or something. Then someone like me has to gently break it to them that they’re just getting standard molecular targeted treatment that the rest of the world has been using for decades.
A really important thing to understand about monoclonal antibodies is that there are 3 kinds. There are ones that come from animals – I’m pretty sure they’re all mouse derived, maybe a couple are pig derived. There’s partially humanized ones, and then fully humanized ones.
The examples I’m most familiar with, are these molecular targeted therapies called Vectibix and Erbitux. Vectibix is fully human. If you’re someone in the UK, you’ll probably know that as panitumumab (Vectibix is the commercial name, panitumumab is the generic name; Erbitux – the generic name for that is cetuximab). If something ends with “-mab”, that’s going to be a monoclonal antibody, hence “-mab”. Cetuximab is animal derived. You’d think that you’d want fully humanized ones. Pharmaceutical companies may say “fully humanized is better because maybe less chance of an allergic reaction, maybe less severe side effects”. But particularly if you’re having immunotherapy, it can be better to have the partial humanized one or the animal ones.
In the case of Erbitux against Vectibix – for example, Erbitux seems to be able to label the cancer cells as cancer cells. Because it’s an animal derived drug, your immune system recognizes that and thinks, “this is something a bit odd, I’ll attack it”. So it can be a way, particularly if you’re having immunotherapy, it can help the immunotherapy work a bit better.
I should say at this point, I’m not a doctor, I’m not giving any medical advice. I do however have some very strong opinions on cancer treatments, and I’ll say something that oncologists probably won’t say, which is that molecular targeted therapies, if they’re narrow (a specific or quite a narrow target), they seem to work for about 12 months, and if they’re broad ( if they’re multi-targets – you may have heard of multi-kinase Inhibitors, which is a type of molecular targeted therapy that attacks kinase which is a type of enzyme – if you remember enzymes are biological catalysts) – so if you have a something like that, a multi-target one it’s harder to get treatment resistance. So you potentially can get a good response for a lot longer. But because it’s multi-target, their side effects are much worse, because far more healthy cells are going to be hit.
So this is the big problem with molecular targeted therapy. The drug companies are really pushing them, particularly in conjunction with what’s called a “liquid biopsy” or sometimes “Next Generation Sequencing” – this idea that you can read the genetics of the cancer, so you can you can check out the genome of the cancer, and find the targets and match it up to the drugs.
What the drug companies don’t tell you is that the business implications of that are very good. Because if the patient gets a good response, that response may last 6, 8, 12 months or whatever. Then the cancer is resistant to that targeted drug, so you then do another genome test and maybe new mutations are developed in the cancer, then you can do another molecular targeted therapy. So from a business point of view that’s fantastic, because you can use these very expensive drugs for maybe 12 months at a time, and switch the patient. I guess you could say it’s great, because you get to live hopefully, but that’s treating cancer as a chronic disease or a series of chronic diseases. So I don’t think that’s a winning strategy for dealing with cancer.
Some molecular targeted therapies only work for people with certain mutations. For example, the drugs I mentioned (Erbitux,Vectibix), they work for mutations where the cancer cells are producing too much of this thing called Epidermal Growth Factor Receptor. Epidermal reminds us that it’s something to do with the skin, and this of course means that those two drugs have horrific skin side effects. I haven’t had Erbitux now for a couple of years, but there’s permanent damage all over my face, which you can see, where I had a really terrible skin rash for a couple of years while I was on those treatments, and all the blood vessels in my face got destroyed. So now I look like someone who’s been drinking whiskey since a young age, which is certainly not me.
Other molecular targeted drugs don’t rely on mutations. A good example of that would be AAvastin (the generic name for that is bevacizumab). Avastin is an angiogenesis inhibitor, which means it prevents cells from growing new blood supplies. Every cell in your body has to be within a few cells from a blood supply. If you think about a cancer tumor, it’s growing and growing, so it needs some blood vessels in there, it needs some blood supplies. That’s why when you see cancer on a scan, it’s got that very characteristic kind of ragged edge.
Non-cancerous tumors (like cysts) are often very rounded, and the jaggedy ones are the cancer, because the cancer’s growing, searching for blood supply. It’s spreading out, growing in a jaggedy way.
Avastin stops cancer making new blood supplies. However, it also stops your healthy tissue from not making new blood supplies, which means you do get a lot of problems with wound healing. This is why if you’re on Avastin and you’re going to have surgery, you’ll be told to stop the Avastin for 4 weeks before surgery. After the surgery, you’ll be told you can’t restart it for quite a few weeks as well.
Interestingly, Avastin seems to have another mechanism as well. Even though it was invented as an angiogenesis inhibitor, it also seems to perforate cancer cells, which is why Avastin works so well with chemotherapies. Because imagine Avastin can make holes in the cancer cells, and more chemo drugs can get in and damage it. In late stage cancer ( stage 4), it seems that Avastin doesn’t have so much ability to stop new blood supplies forming, but it still has this ability to perforate cancer cells. So despite what the oncologist may tell you, Avastin still is very useful for stage 4 patients. It may be your oncologist is just confused, because when Avastin was first trialed as a monotherapy, (that means just by itself), it was found it didn’t stop cancer going into stage 4. But actually, with other treatments, it then has that other role of perforating the cell wall.
Avastin has some nasty side effects. It interferes with wound healing. It causes a lot of nasal bleeding, so you get used to daily nosebleeds. It can cause holes to appear in your body, which is of course incredibly serious. That seems to be very rare, but if you have holes in your body (maybe from surgery or from some other problem from a cancer treatment), then you wouldn’t be able to take Avastin. It would not be available to you.
Avastin is expensive. There is a biosimilar drug, which means there’s a drug that is exactly the same as Avastin except it’s been changed enough that the drug company doesn’t have to pay Merck who owns it. So depending on where you are, you may be able to get Avastin as a biosimilar, which can be a lot cheaper.
Avastin is a very standard cancer drug in almost every country in the world, or every country that has a developed health system. If you’re in the UK, it’s currently not standard for most cancer types. So you’d have to get it from the “Cancer Drug Fund”. Sometimes they change the name of the Cancer Drug Fund. I think it’s changed back to the Cancer Drug Fund at the moment, but that basically means your oncologist has to fight and apply to get the drug for you. The Cancer Drug Fund lets you access drugs that are not standard treatment.
I’m not a doctor, however if you wanted to say what is a game changing cancer medicine, Avastin would certainly be it, because it seems to help across so many different kinds of cancers, making the chemo work better.
Another side effect of Avastin is you get high blood pressure. So if you already have high blood pressure, that again may be a reason why you would be told you couldn’t have Avastin.
There are a whole bunch of other molecular targeted treatments, like MEK Inhibitors, PARP Inhibitors which stop cancer repairing well. So if you’re told that a drug won’t work for you, it’s always worth seeing if there’s a trial of that drug with another molecular targeted therapy.
Actually that goes not just for drugs, but for other treatments as well.For example, the PARPInhibitors might be good for radiotherapy, because if you can imagine the radiotherapy is damaging the cancer cells, damaging the DNA and then the PARP inhibitor stops the cells from self-repairing. This is a really huge area for clinical trials.
So if you’ve been told a certain immunotherapy isn’t an option for you, then you want to search online for that immunotherapy to see if there’s a trial of it, maybe with another drug.
A specific example recently, is there have been trials of checkpoint inhibitors,with patients who shouldn’t respond well to checkpoint inhibitors, but combining them with other drugs to try and get a response. For example, for me, my cancer is MSI low (microsatellite instability low) so I’ve been told checkpoint inhibitors shouldn’t work for me. But there are trials using them with another drug. So if and when my cancer comes back, that might be something I’ll look into.
I’ve just given you an overview of the delights of chemotherapy and molecular targeted therapies, and I hope it has been useful.