Possible acceleration of aging by adjuvant chemotherapy: a cause of early onset frailty?

Cancer chemotherapy has three main applications. It is curative for a small number of malignancies including childhood leukemia, Hodgkin's and non-Hodgkin's lymphoma, and germ cell malignancies. It has a palliative role for most metastatic epithelial malignancies. Finally, it has an adjuvant role in several types of resected epithelial malignancies particularly breast cancer. First successfully employed in the mid 1970s, adjuvant chemotherapy is associated with up to a 30% relative improvement in long-term overall survival in high risk breast cancer but demonstrates significantly less absolute improvement. Now that adjuvant chemotherapy is being used in lower risk disease, both the relative and absolute improvement in overall survival is even less impressive. With a growing number of long-term survivors, we are only now able to define the delayed implications of adjuvant chemotherapy. These long-term side effects include acceleration of neurocognitive decline, musculoskeletal complications such as early onset osteoporosis, premature skin and ocular changes and the most common long-term complaint; mild to profound fatigue. This complex of problems is suggestive of early onset frailty. This paper explores various potential mechanisms of aging including accumulation of free-radical damage, accumulation of DNA damage, telomere shortening with accompanying decline in telomerase activity and finally a decline in neuroendocrine/immune function. The impact of chemotherapy, particularly those agents used in the adjuvant setting, in relationship to these aging mechanisms is explored. There is good evidence that chemotherapy can effect all these aging mechanisms leading to early onset frailty. The implications of this hypothesis are quite profound. Whereas short-term toxicity of chemotherapy can usually be considered acceptable even for a small improvement in survival, long-term toxicity such as early onset frailty can have an impact on quality of life that could last for years. This possible effect on aging could have implications on the decision to take adjuvant chemo, what agents to use, means to minimize the aging effect and the need to monitor for early onset frailty.