Integrating chemoradiation and molecularly targeted therapy

While the advent of combined chemoradiation has improved outcomes for innumerable patients with locally advanced cancers, further improvements are urgently needed. Escalation of either chemotherapy or radiotherapy is associated with unacceptable toxicity. An alternative strategy is the integration of chemoradiation and molecularly targeted therapies, which exploits biological differences between cancer and normal tissue and should therefore increase efficacy while maintaining tolerable toxicity. Combining chemoradiation with agents that modulate tumor-specific pathways such as cell cycle checkpoints, PARP signaling, EGFR signaling, the PI3K/AKT/mTOR axis and androgen signaling has shown immense promise in preclinical and clinical studies, as have combinations with environmentally-targeted agents against the immune system and angiogenesis. The optimal application of these strategies will likely require consideration of molecular heterogeneity between patients and within individual tumors.