Biomund: A tumor is a mixture of cells that vary in their genetic nastiness. If there are 1000 cells in the tumor, 100 of these have a genetic makeup that will eventually produce the metastatic spread of the original cancer. We treat the 1000 cells with chemotherapy and kill off 500 of the weaker cancer cells (reducing the tumor burden by 50%) but we are also strongly selecting for the resistant cancer cells to proliferate. By killing off the weaker cancer cells, we are actually improving the local environment for the nastiest cells as they are not inhibited by typical cell-cell interactions and there is less competition for blood flow, nutrition and other substrate. Most of the chemotherapies place a strong selection pressure on the worst of the cancer cells and strongly selects for aggressive, chemo resistant clones of cancer. It is these clones that metastasize so rapidly at the end of the patient's illness. They are the result of the artificial selection pressure produced by chemo.
What we see clinically is a short term effect on tumor bulk (reduce the visible amount of cancer by weeding out the weaker cancer cells). This is translated as "an improvement" in progression free survival. Once the weaker cells are killed off, the patient is left with the nastiest of the cells that have been untouched by the chemo except selected for more aggressive traits. These cells are now chemo-resistant and have very well developed growth characteristics. They rapidly overwhelm the patient.
These are common situations. Our treatment kills the weaker cancer cells but is unable to kill the cells that are destined to metastasize. Unwittingly, we provide a better environment for the worst of the cells which then run the show in the second half of treatment. Clinically, things can look quite good as the chemo devastates most of the cancer cells at the beginning of treatment but it is the cells that have metastatic potential that have to be killed. Once the resistant cells get control, the clinical course accelerates to death.
Thus, an improvement in progression-free survival may not be associated with any overall survival benefit. That is not to say that improving the length of time to symptoms is not an important goal but let's not confuse PFS as an accurate surrogate for overall survival.
These types of findings are seen in Radiation therapy and many forms of therapies for solid tumors. Pt therapy for Ovarian cancer is a great example.
cheers, Geneman
AI
