We assessed the effects of two different chemotherapy regimens on cytokine IL-6 and chemokines MCP-1 and IL-8 to understand possible effects of chemotherapy regimens on inflammatory processes that may be implicated in chemotherapy-related cognitive difficulties. To our knowledge, this is the first study to compare the effects of two different chemotherapy regimens on these three cytokines in breast cancer patients undergoing chemotherapy. We observed that MCP-1, IL-6, and IL-8 all increased in the doxorubicin-based chemotherapy group but decreased in the CMF group over two cycles of treatment.
Both chemotherapy regimens included cyclophosphamide with or without fluorouracil. The major difference between our chemotherapy groups was adriamycin in the AC/CAF group and methotrexate in the CMF group. Therefore, differences in cytokine/chemokine responses are likely due to these specific agents.
Adriamycin, an anthracycline that intercalates DNA preventing cell replication, is associated with an increase in cytokine IL-1β in Hodgkin’s patients receiving chemotherapy regimens containing this agent (18
). More specific evidence that adriamycin directly contributes to an inflammatory response comes from an animal study, in which adriamycin was given to non-tumor-bearing mice. Peripheral and brain-inherent levels of cytokine TNF-α were increased (23
) even though adriamycin was not found to cross the blood brain barrier. The peripheral increase in TNF-α was also associated with an increase in brain reactive oxygen species suggesting damage; when a TNF-α blocking antibody was given, adriamycin-induced brain oxidation levels were decreased. Overall, this study suggests that the inflammatory reponses following adriamycin directly led to an elevation in brain oxidation which could result in cognitive difficulties. In fact, other animal studies have shown that adriamycin leads to impairment in performing cognitive tasks (24
Unlike adriamycin, methotrexate, an anti-metabolite that inhibits the synthesis of purine and pyrimidine precursors, appears to have anti-inflammatory properties (25
). Specifically, methotrexate can inhibit growth of monocytes and macrophages (26
)—cells which can produce the cytokines and chemokines assessed in this paper. For example, IL-6 expression by human monocytes is reduced following exposure to methotrexate (27
It is difficult to interpret the inverse but significant relationships between changes in MCP-1 levels and changes in difficulty thinking, difficulty with concentration, and forgetfulness in those receiving AC/CAF. One explanation from our results is that changes leading to reduced MCP-1 levels are associated with cognitive decline and vice versa. However, since serum cytokine levels fluctuate over time, this observation could be incomplete. It is also possible that MCP-1, which is an early-stage mediator of inflammation, could have led to signaling via other inflammatory pathways that are more indicative of cognitive difficulties at the cycle 2 to cycle 4 time-points. For example, a recent study investigated serum MCP-1 levels in those who had a diagnosis of MCI and Alzheimer’s disease. Those with MCI had high levels of MCP-1 compared to healthy controls; however, Alzheimer’s cases had decreased levels of MCP-1 compared to both MCI and healthy controls (13
). This result could explain our findings if more severe cognitive difficulties are associated with reductions in MCP-1 but perhaps increases in other inflammatory molecules.
The main strength of this study was our measurement of cytokines and chemokines in patients treated with two distinct chemotherapy regimens over two cycles of treatment; therefore, we could assess changes in levels of these molecules over the two cycles of chemotherapy and determine whether those changes differed by regimen. The study would have been strengthened with biomarker measurements prior to any treatment, and prior to and after each cycle of chemotherapy. The assessment of additional inflammatory mediators and their specific signaling pathways could have provided a greater understanding of the complexity of inflammatory responses following administration of various chemotherapy regimens.
We are limited in our interpretation of the cytokine/chemokine results as they relate to cognitive difficulties in these cancer patients. First, our cytokine/chemokine measurements were done prior to chemotherapy and our cognitive assessment was performed after chemotherapy. Secondly, our cognitive questions were taken from the FSCL, which is a measure designed to assess fatigue. Additionally, our study was not adequately powered to address the relationship between cytokine/chemokine levels and cognitive function. Therefore, it is difficult to explain the significant relationships between lower MCP-1 levels (prior to chemotherapy) and greater difficulty with thinking, concentration, and forgetfulness (memory) in those receiving AC/CAF. Lastly, we did not have information on stage of disease or other treatment information (e.g. corticosteroid, hormone treatments) that may have affected cytokine levels in these patients.
Nonetheless, this study revealed that specific chemotherapy regimens can lead to different responses in chemokine/cytokine levels. The results of this study are preliminary and hypothesis-generating and need to be confirmed in larger studies that specifically evaluate multiple inflammatory mediators at multiple time-points with concurrent neuropsychological assessments and/or validated cognitive questionnaires. These studies will clarify the influence of specific chemotherapy regimens on distinct inflammatory pathways and the effects of those pathways on the development and progression of cognitive impairment in cancer patients. In this study, patients had similar levels of self-reported cognitive complaints, however, cytokines increased over time in the adriamycin-based chemotherapy group but decreased over time in those receiving CMF. Only a greater-powered study can address whether there may be multiple inflammatory mechanisms involved, and/or other contributing pathways (e.g. endocrine), in the development of chemotherapy-related cognitive difficulties. Identifying all of these related pathways may allow for the development of tailored interventions in patients with cognitive impairments.