Cancer Drugs: How Far We’ve Come

Overlooked in the Covid-19 pandemic has been our failing war against cancer. The breaking of the human genetic code in 2000 set the stage for thinking that a cure for cancer was just around the corner. Unfortunately, it doesn’t appear we are closer to a cure after spending hundreds of billions of dollars on cancer research, new cancer drug development, and TV marketing for these new drugs.

A recent article has exposed the problem (1). This article analyzed all the new cancer drugs developed from 2000 to 2016 and then looked at the gold standard for any cancer trial; overall survival of the patients getting the drugs. Overall survival is the gold standard because it is a very unambiguous clinical endpoint. It also takes into account any unanticipated toxic side effects of the cancer drug. So, what was the median overall survival improvement of all of these breakthrough cancer drugs in the 21st century? It was giving the cancer patients an extra 73 days of life. That doesn’t sound like a breakthrough to me.

The first question to ask is, how do these cancer drugs get approved in the first place? Cancer drug approvals are often based upon surrogate markers that are easier and less costly to track. One of these surrogate markers is progression-free survival or PFS. This marker is defined as how long a person lives without the disease worsening. It is considered a marker of disease control but not of survival. An even better surrogate marker for drug companies is the tumor response. This marker only means the primary tumor has to shrink in size. Since cancer drugs are designed to kill tumor cells in the primary tumor, this surrogate marker of reduced tumor size is a winner for drug companies looking for a quick approval. Unfortunately, most cancer patients usually die from secondary metastases of the tumor, not the primary tumor itself. Not surprisingly, these surrogate markers are often far more impressive than any increase in the overall survival rate. Thus, the use of surrogate markers is the primary selling point used by drug companies to get FDA approval of their new cancer drugs.

So why do these new cancer drugs have such unremarkable results for overall survival? The answers may lie in understanding how most cancer drugs work. While cancer drugs kill cancer cells, they don’t remove the dead tumor cells’ cellular debris from the killing zone. That cellular debris contains survival factors that can awaken other dormant cancer cells in the body to begin to grow (2). When this happens, the cancer is said to metastasize. In essence, the cancer treatment itself is often the cause of these new tumor outbreaks.

Furthermore, because of the survival factors found in the initially killed original cancer cells’ cellular debris, these metastasized cancer cells are resistant to the same cancer drug being used again. Maybe a drug can be used to “take out” the cellular debris from the killed cancer cells? Unfortunately, no such drug exists. However, the body is way ahead of the game by making hormones known as resolvins derived from EPA and DHA that activate specific immune cells (i.e., macrophages) to remove this cellular debris effectively. At the molecular level, resolvins activate macrophages to turn them into highly effective garbage collectors.

I think the focus should shift from the development of new novel cancer drugs that may have limited benefits to ways to make resolvins that work with existing cancer drugs. This can help with the removal of cellular debris. Resolvins can only be made with adequate levels of EPA and DHA in the blood to serve as a reservoir for helping to make resolvins. What’s a sufficient level? The answer is taking enough omega-3 fatty acids to have an AA/EPA ratio between 1.5 and 3. The lower the AA/EPA ratio, the more effective the macrophages’ resolvin activation is to enhance the efficient removal of the cellular debris created by any cancer drug. Since the average AA/EPA ratio in Americans is about 20, this goes a long way to explain why all the new cancer drugs developed in the 21st century have not delivered their promise of a longer overall survival rate for the vast majority of cancer patients who used them. There wasn’t enough EPA and DHA in the patients’ blood to take out the trash the new cancer drugs had created.

 

References

  1. Ladanie A et al. “Clinical trial evidence supporting US Food and Drug Administration approval of novel cancer therapies between 2000 and 2016.” JAMA Network Open 3:e2024406 (2020)
  2. Sulciner ML et al. “Resolvins suppress tumor growth and enhance cancer therapy.” J Exp Med 215:115-140 (2018)
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