Why Do Some Cancers Come Back?

Understanding How and Why Cancer Returns

female physician talking to patient about cancer recurrence
Why do some cancers come back (recur)?. istockphoto.com

Despite treatments such as surgery, chemotherapy, and radiation therapy, too often a cancer comes back. And while many cancers recur in the first 5 years, many of us know of someone who remained cancer free for years and even decades before their cancer returned. Why do some cancers come back, and how does this happen?

Brief Review of Cancer Terminology

When talking about a cancer coming back it helps to define exactly what a recurrence is, as well as a few other terms.

  • Recurrence - A cancer recurrence refers to a cancer that returns (comes back, relapses, or recurs) after a period of time during which a cancer has been remission (usually meaning that there is no evidence of disease (NED) and the cancer is not detected on scans.) While there is not a precise definition of time that must pass during which someone is cancer free and when cancer is considered a recurrence, many oncologists believe that cancers which recur within 3 months are a progression rather than a recurrence.
  • Progression (Progressive Disease - PD) - Cancer progression refers to a cancer that is worsening and has increased at least 20 percent in size or has spread after treatment.
  • Partial Response - A partial response to treatment means that a tumor decreases at least 30 percent in size, but does not go away completely as noted on clinical exam or by scans. This is also called partial regression.
  • Stable Disease - Stable disease, also referred to as ​static disease, means a tumor is not growing or shrinking significantly. It also means that there are no new tumors and that the tumor has not spread to any new regions of the body. The tumor has not increased enough to be called progressive disease (a 20 percent increase or more) or decreased enough to be called a partial response (at least a 30 percent decrease.)
  • Complete Response - Complete response or complete regression means the same thing as a complete remission or NED (no evidence of disease.) This means that no residual tumor can be detected on physical exam, with scans, or with blood tests, but does not mean a cancer is cured.
  • Remission - Remission does not mean a cancer is cured, but instead refers to the absence of disease. There are 2 types of remission. In complete remission, a cancer is unable to be detected through physical examination or through radiological studies. In partial remission, a cancer is still detectable but has decreased in size.
  • No Evidence of Disease (NED) - NED is defined the same way as a complete remission - a cancer cannot be detected by any tests or examination.
  • Relapse - The term relapse is usually used interchangeably with recurrence.

Why Do Some Cancers Come Back?

Since recurrence is a significant cause of morbidity (sickness) and mortality (death) from cancer, understanding why cancers return is critical in improving survival rates for cancer patients.

It's hoped that, as knowledge improves in this area, the survival rate for many cancers will increase.

It's important to begin by saying that it only takes a few cancer cells left over after treatment for that cancer to return. It takes many millions of cancer cells together to form a tumor that can be detected with even the most advanced imaging techniques.

What About Surgery and Radiation Therapy That Seems Successful?

If you have surgery with clear margins on your pathology report, and if a scan shows no evidence of cancer, it can be hard to understand why a cancer would come back. Yet even when no cancerous cells are seen at the edges of a tumor, some cancerous cells may have already spread via the lymphatic system, locally to nearby tissues, or through the bloodstream to other regions of the body. These cancer cells that are undetectable are referred to as micrometastases. 

To learn more, check out this article: How Does Cancer Spread?

Both surgery and radiation therapy are considered "local treatments." As such they do not treat cancer cells that have traveled beyond the treatment region. In addition, radiation therapy may not kill all cancer cells. Radiation works by damaging DNA in both cancer cells and normal cells. Just as normal cells may recover following radiation, some cancer cells may "recover" as well.  The possibility of micrometastases is the reason that some people receive adjuvant chemotherapy - chemotherapy that is given after the completion of the local treatment with surgery or radiotherapy to ensure that micrometastases are eradicated.      

Why Wouldn’t Chemotherapy Kill All Cancer Cells?

Chemotherapy, unlike surgery and radiation therapy, is considered a systemic therapy, designed to treat not just cancer cells near a tumor, but to get rid of cancer cells that have spread beyond the areas of the body that are treated with surgery and radiation. So why wouldn't chemotherapy kill all cancer cells in the body? To understand the answer to this question, it’s important to understand a bit about how chemotherapy works. Most chemotherapy drugs work at some point in the process of cell division. Not all cancer cells are dividing at all times, and cells that are not dividing, or are at a different stage in cell division that a specific chemotherapy drug addresses, may survive.This is one of the reasons that people are often treated with more than one chemotherapy drug (chemotherapy drugs work at different points in the cell division process) and why chemotherapy is usually given in several sessions spaced out over time.

How Can Cancer Cells Hide for Years or Decades?

There are a few theories that have been proposed to account for what seems to be a cancer cell's ability to "hide" for an extended period of time. For example, 20 to 45 percent of estrogen-receptor positive breast cancer recurrences occur years or even decades after the cancer has been successfully treated. 

One is these is the idea of cancer stem cells, a subset of cancer cells. Simplistically, you might think of cancer cells as having a hierarchy.  In this case, cancer stem cells would be the "general" and stronger than other cancer cells (more resistant to treatment such as chemotherapy, perhaps because they divide more slowly than regular cancer cells.) While cancer treatments may kill off many of the soldiers, these higher ranked cells would remain alive, ready to grow again. 

Another concept is that of dormancy.  For some reason, a cancer cell (dormant cells may be cancer stem cells) can lie dormant (like a plant during winter, or a fungal spore) and, given the right circumstances, begin to grow again. These dormant cancer cells may "sleep" for long periods of time before "waking up" and entering a rapid growth phase. They may "go to sleep" due to a good immune system, or a lack of angiogenesis (the ability of a cancer to make blood vessels to feed it and allow it to grow) and then "wake up" if the immune system is not functioning as well (immunosuppression,) if angiogenesis takes place.

What Cancers Don't Come Back (Recur) and Can Be Considered Cured?

Doctors don't usually use the word "cured" because most tumors have the ability to come back. Exceptions include some early stage cancers that have very low risk of coming back (for example early thyroid cancer.)

Is Cancer That Recurs More Aggressive?

Yes, usually it is easier to treat cancer in front line than when it recurs. On the other hand, some forms of cancer may still be curable even after they recur, for example, testicular cancer.

Next Steps

The possibility that a cancer will come back can weigh heavily on the minds of people after cancer treatment. Check out these articles on coping with the fear of recurrence, and well as why doctors rarely will say: "Your cancer is cured."

Sources:

Almog, N. Molecular mechanisms underlying tumor dormancy. Cancer Letters. 2010. 294(2):139-46.

Kleffel, S., and T. Schatton. Tumor dormancy and cancer stem cells: two sides of the same coin?. Advances in Experimental Medicine and Biology. 2013. 734:145-79.

Li, S., et al. Model of Tumor Dormancy/Recurrence after Short-Term Chemotherapy. PLOS One. Published May 20, 2014.

National Cancer Institute. When Cancer Returns. Accessed 03/11/15. https://www.cancer.gov/publications/patient-education/when-cancer-returns.pdf

Wang, Sih-han, and Shiaw-Yih Lin. Tumor dormancy: potential therapeutic target in tumor recurrence and metastasis prevention. Experimental Hematology and Oncology. 2013. 2:29.

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