Surviving the Cure: Modeling the Long-Term Consequences of Chemotherapy

Due to advances in treatment protocols, survival rates for childhood cancers have improved significantly over the past several decades, with five-year survival now reaching 85%. However, survivorship often comes at a cost, as exposure to intensive chemotherapy impairs skeletal muscle health, reducing quality of life and increasing the risk of early mortality. The CHOP regimen, comprising cyclophosphamide, doxorubicin, vincristine, and prednisone, is a backbone combination used in the treatment of childhood non-Hodgkin lymphoma. Previous data from our lab demonstrates that CHOP causes acute and reductions in growth and muscle size in juvenile mice, yet data on long-term outcomes remain limited. PURPOSE: To determine if CHOP chemotherapy administered to juvenile mice has long term effects on skeletal muscle into adulthood. METHODS: At 28 days of age, animals were assigned to receive two cycles of either CHOP chemotherapy (n=3) or placebo (n=3). Each CHOP cycle consisted of three chemotherapeutic agents (cyclophosphamide, doxorubicin, and vincristine) administered in combination with prednisone, followed by four additional days of prednisone injections and a five-day recovery period. Placebo-treated animals received equivalent volumes of phosphate-buffered saline (PBS). Mice were then allowed to age until approximately 15 months of age. At that time, animals completed a graded treadmill exercise test to fatigue to assess endurance capacity. Following testing, skeletal muscles were collected, weighed, and processed for histological analysis of muscle fiber cross-sectional area and fiber type distribution. Muscle sections were stained, imaged, and qualitatively assessed. As this was a pilot study, statistical analyses were not performed. RESULTS: CHOP treated animals CHOP had slightly lower body mass (CHOP: 38.49g ± 1.76, Control: 39.66g ± 0.75) and gastrocnemius muscle mass (CHOP: 140mg ± 3.92, Control: 145mg ± 3.70) than control mice. Average gastrocnemius cross-sectional area was also lower in the CHOP animals (CHOP:1600.3 ± 64.1, Control: 1839.3 ± 35.5). The CHOP animals also exhibited lower total work (in kg/m) during the graded exercise test (CHOP: 3.15 ± 0.40, Control: 5.04 ± 0.36). CONCLUSION: These preliminary findings suggest that CHOP treatment causes lasting muscle atrophy and reduced fatigue tolerance in adulthood, mirroring clinical observations in pediatric chemotherapy survivors.