Biology in the News Explained

Why chemotherapy doesn’t work

The last Bioblog article explained that a strong immune system is necessary to suppress and even eliminate cancer successfully. If this is your treatment goal, then the “standard of care” for metastatic cancer patients, chemotherapy, is exactly the wrong tool with which to achieve it.

Why is this? There are three main strikes against chemotherapy as a cancer treatment.

1. Chemotherapy kills immune cells
First, most people know that chemotherapy drugs suppress the immune system. In fact, two of the most common chemotherapy drugs, cyclophosphamide (Cytoxan) and methotrexate, are used as immunosuppressants in people with autoimmune diseases (Zitvogel et al., 2008). A primary reason for this is that chemo drugs are designed to target proliferating cells, because of the general but crude idea that tumor cells are dividing much more at any given time than normal cells. The immune system depends on rapid proliferation to be effective, so we are immediately undermining it with chemotherapy. (Sometimes this is done to the point at which the compromised immune system is what actually kills a cancer patient, rather than the cancer itself.)

It isn’t just the primary chemo drugs themselves that suppress the immune system. The common use of drugs called glucocorticoids (e.g. prednisone) as part of chemotherapeutical regimes is a typical example of the fairly indiscriminate use of drugs without consideration of all their potential effects. Prednisone has been used in combination with other drugs to treat lymphoma, leukemia, and breast cancer. The added benefit appears essentially to be in reduction of side effects, so that patients can be treated with a higher dose of poison. Hence, there is sometimes a better tumor reduction associated with its use — but only temporarily (Kufe et al., 2003).

The problem with using prednisone is that this class of drugs has a strong immunosuppressive effect — something anyone who has taken them for a severe allergy outbreak can already tell you. So, in the case of both standard chemo drugs and glucocorticoids, to obtain a short-term gain in tumor suppression, a drug is administered which greatly reduces the body’s ability to achieve long term control of cancer through a healthy immune system (Zitvogel et al., 2008).

2. The way chemotherapy kills cells keeps them invisible to the immune system
Second, a huge reason why chemotherapy does not, most of the time, help stimulate the immune system is because of the way in which it kills cells. There are two main ways that cells in the body experience death. The first is called apoptosis, or programmed cell death, where the cell essentially commits suicide by winding down in a predictable manner. The second is called necrosis, and this can be thought of as more of a violent death against the cell’s will. One might assume that poisoning through chemotherapy would result in necrosis, but as it turns out, the majority of chemo drugs disrupt a cell process during division that causes a cascade resulting in apoptosis.

The reason this is important is due to the way our immune systems work. It should make sense that we do not want our disease-attacking killer T cells on the scene every time a cell dies, because cell death is a normal part of an organism’s life. Cells undergoing apoptosis essentially just call for the cleaning crew: macrophages, or white blood cells that engulf and remove dead cell parts. This is why apoptosis is considered a non-immunogenic process, or one that does not stimulate the immune system to attack. Necrosis, however, stimulates a quick immune response.

Necrosis can be caused by a sudden injury, such as a cut. In this case part of the immune response is inflammation, which helps the healing process, and alerts the immune system against the possibility of invading bacteria. Necrosis can occur internally as well. For instance, when a virus injects itself in our cells, it multiplies and the many virus particles lyse, or break up, the cell, so that they can go infect other cells. The uncontrolled release of cell proteins out of the dying cell alerts the immune system to a potential problem, and kicks the T cells into high gear, seeking out infected cells and killing them before the virus can multiply and spread.

T cells attack tumors as well. Normally, immune cell scouts, known as “antigen presenting cells” (including dendritic cells, which are more commonly being used in cancer immunotherapy), are circulating around all the time, ready to activate a process which alerts the killer T cells to abnormal tumor cells. This is known as “immunosurveillance” and is the reason we don’t all have invasive cancer all the time: although cancer cells are continually forming in our bodies, our immune system usually recognizes them and kills them without us even knowing that they were there.

It is unclear why some cancer cells escape this process and are allowed to form tumors; probably there are different reasons in different people. Unfortunately, once there are invasive tumors, cancer cells end up with lots of mechanisms for hiding from the immune system. So the ideal cancer treatment is not only one that helps strengthen a patient’s immune system, but one that also takes aim at the immune defenses thrown up by tumors. Unfortunately, by the very mechanism by which it causes cell death, chemotherapy usually does nothing to help our immune systems find and destroy cancer cells.

3. Systemic chemo is not likely any more effective than targeted chemo
The third main reason why chemotherapy treatment is making life worse for cancer patients is mainly due to how we deliver it, which is systemically. This means that most of the time, chemo drugs are not injected into tumors to kill them; they are delivered directly into the blood stream, which is why people on chemo get sick all over.

This is done because of the still-mistaken idea that chemo can cure cancer by killing all the cancer cells in your body (including those forming tiny tumors that we can’t see, and those just circulating around your lymphatic system or blood stream). Except perhaps in the occasional case of dose-dense adjuvant chemotherapy (which is designed to hit the cancer with as many poisons as possible as once without killing the host), even when chemotherapy appears to cure cancer, it almost certainly isn’t the chemotherapy that did it, but rather the immune system which somehow got stimulated along the way. This has been borne out by studies in which the tiny percentage of mice that were cured with chemo later had tumor cells injected back into them: even though tumors easily established in these mice before treatment, they would not grow back in the cured mice (Lake and Robinson, 2005).

When an immune response is properly provoked, it happens itself on a systemic level. This means that when necrosis occurs in one tumor, if this succeeds in recruiting killer T cells, those cells will attack all tumor cells in the body, not just those in the specifically injured tumor (Tanaka et al., 2002 [yes, this effect has been known for at least ten years]).

All of this should make it clear that if one’s goal is to cure cancer, a systemic dose of chemotherapy is not only completely unnecessary, but ineffective and in many cases more liable to kill sooner than the cancer itself.

Naturally, there are some gray areas here, some of which suggest that it’s not quite time to toss all chemotherapy entirely, but rather, try to mitigate the immunosuppressive effects somewhat by adjusting dosage levels. In fact, there is a lot of evidence that when chemo works to induce an immune response, it does it through the mechanism of secondary necrosis. This can happen if so much apoptosis occurs at once (due to sensitivity to a chemo drug) that it overwhelms the body’s macrophages (the cleaning crew) which can’t get to all the cells before they start to fall apart from decay (Lake and Robinson, 2005). But this doesn’t change the fact that primary necrosis is much easier to achieve (for example through physical damage to tumors such as with local heat treatments) than getting there by hoping to induce apoptosis on a large scale through chemotherapy (which won’t work for most people on most drugs).

This all begs the question, of course: if chemotherapy is no good, why does it shrink tumors and appear to extend the lives of at least some people? This is the crux of the matter, because if chemo never did anything more than induce immune-mediated remission in 5% of cancer patients, these dozens of drugs never would have been approved in the first place. Unfortunately, it works just often enough in the short term to have gotten these drugs approved, and to keep the clinical oncological community in their treatment boxes, unwilling to face head on the fact that chemo is nearly inevitably useless over the long term, because tumors will nearly always grow back, stronger than before. Why chemo works this way will be the topic of my next article.




Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Corticosteroids in the Treatment of Neoplasms. Available from:

Lake RA, Robinson BW, 2005. Immunotherapy and chemotherapy–a practical partnership. Nat Rev Cancer. 5(5):397-405.

Tanaka F, Yamaguchi H, Ohta M, Mashino K, Sonoda H, Sadanaga N, Inoue H, Mori M, 2002. Intratumoral injection of dendritic cells after treatment of anticancer drugs induces tumor-specific antitumor effect in vivo. Int J Cancer. 101(3):265-9.

Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G., 2008. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 8(1):59-73.


3 Responses to “Why chemotherapy doesn’t work”

  1. Trish says:

    A possible reason chemotherapy appears to work is the improvements in detecting cancers increasing the amount of time that the presence of the cancer is known (this is one reason why cancer “survival times” appear to lengthen – the younger a tumor is when discovered, the longer the time one knows of its existence, the longer period of tie one is ‘surviving”). Perhaps, like so many other illnesses, tumors can wax & wane in size.

  2. Trish, you are absolutely right. The “early detection” mantra has inflated survival rates (as I talk about in earlier posts about mammograms and PSA tests) and the main problem with adjuvant chemotherapy is that there is no way to know if it is working. If you are young especially they poison you with everything they’ve got based on a few percentage-point statistical justification from the literature — it has nothing to do with your own specific pathology or situation — which is a hideous amount, all to “kill” something we can’t see. It comes back anyway in a lot of us, and for those it does not, you have no idea whether it was ever there to kill in the first place. Making an immune-based treatment available in the adjuvant setting would do a lot to alleviate a lot of suffering and in the long run is likely to show much better numbers for preventing recurrence. We have the tools now, we just have to start using them and stop poisoning people wantonly.

  3. Cancer Treatment says:

    Please write an article about this:



  1. “Why chemotherapy doesn’t work “ | All around - [...] immune system is what actually kills a cancer patient, rather than the cancer itself.)“ “Cancer – ...

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