When I discuss with patients how we treat cancer, I usually divide treatments into three groups of treatments; surgery, radiotherapy, and “chemotherapy”. I use this term quite broadly at this stage, and every time I say it, my conscience taps me on the shoulder and says “you know it’s more complicated than that.” My conscience is annoyingly right.
Chemotherapy in its literal meaning, is chemical therapy, so I guess I’m technically right; almost all of the treatments I use are chemicals. The ways in which all of the different chemicals we use is vastly different and worthy of explaining in a bit more detail than “Cancer = Bad. Chemotherapy = Good.”
It is important that a person receiving cancer therapies understands what treatment they’re receiving. Firstly because I think it’s their right to be aware of what’s going into their bodies. Secondly, patients can be empowered to be on the look-out for specific side effects of the treatment that they’re getting if they’ve been educated appropriately. Thirdly, if a patient ends up in an Emergency Department, it is vital that the Emergency doctors know exactly what they’re facing. If they think that a patient is on standard chemotherapy (cytotoxic chemotherapy, explained more below), they will think along the lines of the patient’s immune system being impaired from the chemo, and that they likely have an infection. If the Emergency Doctors are aware that the patient is on immune therapy or targeted therapy, they may think more along the lines of an overactive immune system and not infection. Both of these are treated completely differently and can be time-critical in terms of starting on the right treatment.
Almost all of the cells in our bodies are constantly dividing. When a cell divides, its DNA is copied, the cellular components all reproduce, and cellular machinery then drag the duplicated components to opposite ends of the cell before the cell divides down the middle and two cells are created.
Classical chemotherapy is what we as Oncologists refer to as cytotoxics; these interfere with dividing cells. We have drugs that interfere with almost all of these phases of cellular reproduction. Because cancer cells divide more than normal cells, they tend to be more sensitive to cytotoxic chemicals.
Not all of our cytotoxic chemicals work for all cancer types, and historically, our specialty has centred around matching a cytotoxic drug that has been proven to work on a patient’s specific cancer, and choosing a dose and frequency of drug administration that causes enough damage to a cancer cell to kill it, or to make the immune system recognise a cancer cell as “broken” enough to destroy it itself. The cytotoxic sweet spot is where we give enough drugs to kill or damage the cancer, but not too much that it affects too many normal cells.
We have equations that take into account gender, kidney function, and body size, that we use to help us estimate how much chemotherapy should be effective for any given person, but there is a lot of individual variation in sensitivity to drugs, in metabolism of the drugs we give, and many other factors that often mean that our equations can be wrong, and side effects can occur. We use our experience to apply what we often refer to as the “Art of Oncology” to the way we prescribe to minimise the risk of side effects, but there will always be elements that we can’t predict or account for.
The side effects of cytotoxic chemotherapy can mostly be explained by thinking about which normal cells turn over frequently – they are the most at-risk of being affected by cytotoxic treatments. Normal cells that turn over quickly include the lining of the mouth, hair follicles, and white blood cells – this leads to fairly common side effects of mouth ulcers, hair loss (or thinning, depending on the chemotherapy drug), and low white blood cell count. White blood cells fight off infection and without them, patients are at risk of any infection that they contract becoming severe and even potentially life-threatening. There are medications we can use in some situations to prevent the white blood cell count from dropping (a condition called neutropenia), however what I refer to as the “Golden Rule of Chemotherapy” is that if you’ve had cytotoxic chemotherapy in the last month, and you develop a fever, do not pass Go, do not collect $200; go to your nearest Emergency Department – have a low threshold for calling an ambulance if you feel bad enough. The ambulance officers and Emergency Department nurses and doctors will check for signs of severe infection by taking your blood pressure, heart rate, temperature, and try to find out where any potential infection might be coming from by doing blood tests, a chest X-ray, and sending a urine sample to the lab. They will check your white blood cell count in that set of blood tests and usually call your Oncologist for guidance.
Control over the rate of cell growth and the rate of division is tightly regulated under normal conditions, but it isn’t constant. Sometimes cell turnover needs to speed up (for example, in response to damage in order to heal), and sometimes it needs to slow down (once healing has occurred). The body regulates cellular growth through chemicals and hormones that are detected by the cell and trigger a chain reaction of signals that eventually reach the cell nucleus and triggers it to divide.
An important concept when understanding cellular messaging and activating mutations is the way that proteins are formed. DNA (yours and that of your cancer) is made up of nucleotides; the simplest way that we know that the body codes its information – a complex type of Morse Code, if you will. Those nucleotides are read in strings of three and that combination of three nucleotides tells the cellular machinery which amino acid to add next in its line of creating a string of amino acids. This string of amino acids eventually forms a protein and the protein then performs a function in the cell to play a role in cellular signalling and cell cycling, or to form the structure of the cell, or to attach to foreign particles to flag down the immune system to keep the place clean, you name it. All cellular functions involve proteins, and when the proteins that are created are incorrect, things go wrong.
Every time something is copied, be it a recipe, or a photocopy, or a cell, there is a chance of error. Errors in cellular reproduction often result in the cell being unable to survive. Sometimes those errors are detected by the immune system that recognises an error and attacks the cell. Sometimes however, like the background to many superhero movies, those mutations enable the cell to survive, even when it would be better for the organism if the cell was sacrificed. These mutations can result in uncontrolled growth, resistance to normal cell death processes, or even the ability to spread to distant sites (what we call metastasize). These abilities acquired by cancer cells are what we call the Hallmarks of Cancer, and were first outlined by Hanahan and Weinberg in 2000, and then updated in 2011 (fantastic, but complicated article can be found here), and are displayed in Figure 1.
Science’s understanding of these specific signalling pathways has come a long way in recent years and has led to the development of drugs that target proteins to counteract the abilities that these mutations have given the cancer cells.
Examples of targeted therapies include:
There is more than one way that these proteins can be mutated. Some mutations seem to be just bystanders and don’t drive cancer forward at all (so targeting them with a drug does nothing to slow the cancer). Some mutations do drive the cancer, but the drugs we have for them only work when the protein has been mutated in a specific way. For example, a lung cancer with a mutation in the epithelial growth factor receptor (EGFR; a protein that triggers cell growth) may respond to drugs that we have to target that mutation. The most common way that that protein is mutated is that it has some deleted code in what we call exon 19 (shorthand: exon19del), and those types of mutations are sensitive to the drugs we use. Lung cancers with a T790M mutation of their EGFR (a substitution of the amino acid threonine (T) at position 790, for what should normally be methionine (M)), do not respond to the first-generation drugs that were developed (but don’t worry, we have a drug for that mutation now too).
Mutations can also tell us when to not use a drug. If a cancer has a mutation “downstream” of where our drugs are known to work, blocking that upstream mutation will not turn off the signal to the cell to divide. For example, bowel cancers with a RAS-mutation do not respond to the drugs we have that target EGFR as EGFR is upstream of RAS (Figure 2). Turning off EGFR would still leave the RAS signalling pathway turned on and the cancer would still be driven to grow. This is getting a bit complicated, but I hope you follow.
What makes some of our work even more frustrating is that mutations in the same protein in different cancers won’t necessarily respond to the same drugs. There are many possible reasons for this, including different ways in which that protein is mutated, and the ability of the drug to get to the cells (what we call “penetrance”, which is often a problem when we’re trying to attack cancer cells in the brain).
The side effects of these targeted drugs often depend on where else the targets are. As an example, epithelial growth factor receptor (EGFR) is a receptor that we often target in bowel cancers. As the name suggests, the receptor also exists in normal epithelial cells (including skin cells). The most well-known side effect of the medications we use to turn off EGFR is a rash. Vascular endothelial growth factor receptor (VEGFR) is a target we use in several cancers, and by turning it off, we are impairing the cancer’s ability to signal for more blood vessels to form to feed it. The effect of blocking VEGFR often leads to raised blood pressure. The specific target of our therapies often dictates the side effects, but there are certain side effects that are common across different types of targeted therapy, such as liver impairment and inflammation in the lungs. For a patient on a targeted therapy, we often keep an eye on both the non-specific side effects, and the specific side effects of the drug we’ve given you.
The benefit of targeted (and immunotherapies), is that they generally do not cause low white blood cell count (neutropenia), although it is possible. They also generally have a short time to effect in terms of the benefit they have on cancer. And, most importantly, they’re not chemotherapy!
New targets are constantly being identified and drug trials are underway in many of these areas to see if targeting specific mutations can offer benefit to patients with specific mutations. Drug trials sometimes pay for mutational testing to identify patients for their clinical trials, but these mutation tests are also available privately – I often have patients asking about sending their biopsies off for mutational testing, and I thought I’d explain a little bit more about it here also.
These tests are often several thousand dollars to have done. I recommend only doing this if the testing will lead to something (ie another treatment). The problems we often face with the results of these tests is that we find many mutations that we think are just bystander mutations (targeting them with drugs won’t result in improved quality or quantity of life). We may find a mutation that we know does drive cancers forward, but we might not have a drug for it in development yet. There may be a drug in development, but if you’re not fit enough, or have other medical problems that mean you can’t get on the clinical trial to get access to it anyway, then it still won’t have helped you to have the test done. And finally, we may have a drug available for a mutation that we find that we suspect might help, but there might not be enough evidence out there to have satisfied the government to pay for the medication for you. In this case, if you want the drug, you may have to pay many thousands of dollars every month for a drug that we only suspect might help you. If you know that spending that much on a hunch isn’t possible, then we need to have a chat about whether doing the test in the first place is worth it.
Sometimes we talk about genetic testing to help give family members an idea of whether they may be at risk of developing the same, or related cancers, and this is a very different outcome and a completely different discussion. Many of these genetic tests are funded by the government, but there are some others that do cost, and I’m happy to investigate these for you if it’s something we agree on being worthwhile.
Immunotherapies are everywhere in the news lately. Cancers are sneaky; they know that they look different to normal cells and that there are immune cells circulating to try and find and kill them. Many cancers have adapted to express a “don’t kill me” signal that confuses these circulating immune cells, making them think they are normal cells. This can be seen back in the Hallmarks of Cancer diagram in Figure 1 in the top right of the diagram referred to as “Avoiding immune destruction”.
Immunotherapies work in one of two ways; they either block this “don’t eat me” signal (more common), or they try to make the cancer cells express an “eat me” signal. We are using combination immunotherapies in more and more cancers, and are also looking at using immunotherapies alongside chemotherapy and targeted therapies, or as a maintenance treatment after chemotherapy and radiotherapy. The research ongoing in this field is immense.
Immunotherapies are exciting, and when they work have the potential to work really well. The problem from my point of view is that firstly, they don’t work for all types of cancer. Often patients come to clinic asking about immunotherapies and we have to unfortunately explain that although we are seeing absolutely remarkable responses to immune therapy in some melanomas or lung cancers, we are not seeing nearly the same responses to immunotherapy in other cancers such as prostate cancer, pancreatic cancer, or glioblastoma.
Some cancers, even when you point the immune system directly at the cancer cells and take away their “don’t eat me” signal, just don’t seem that appealing to the immune system and it therefore doesn’t result in the immune system attacking the cancer. Additionally, the side effects, although less common than chemotherapy, can be severe. Especially when using combination immunotherapy – there can be upwards of a 60% chance of a patient ending up being admitted to hospital with a side effect of their immunotherapy that they may or may not fully recover from. The side effects of immunotherapy stem from the fact that the immune system can get confused and attack good tissues like lungs, liver, bowel, the thyroid gland, pancreas, and many others. We can cause people to be insulin-dependent or require hormone supplements for the rest of their lives, or severely and permanently damage their lungs to the point where they need oxygen at home, or even die. It’s sometimes very hard to balance the benefits and the risks with the severity of the side effects that we have seen. We have to pick which cancers are likely to respond to immunotherapy, and which patients could tolerate severe immune-related side effects of their treatment, if they occur) and balance this risk:benefit ratio to see if we think it’s a good idea to use immunotherapy.
This is not to say that immune therapies are anything other than complete game changers. In the field of melanoma, for example, historically we used chemotherapy that was honestly not thought to have much benefit (it does have a chance of helping, or else we wouldn’t offer it at all, but not much). Now we are seeing many patients with dramatic responses to immune therapies and have seen expected survival times improve from being measured in months, to being measured in years in many cases.