Optimize and refine therapeutic index in radiation therapy: Overview of a century

In 1936, Holthusen theorized the probability of achieving tumor control and of developing normal tissue complications after radiotherapy as a function of radiation dose. This concept was formalized and further developed in 1975. Several concepts for improving the therapeutic gain had been anticipated, including the possibility of modulating the tumor/normal tissue differential response. Eight decades later, it is possible to review and analyze progress achieved in the knowledge of radiation-induced toxicity. The clinical developments using new technologies and biological modulators of radiation response have corroborated a posteriori this model, however, many questions remain unanswered. A few randomized trials have validated the benefit of modern irradiation techniques for improving the therapeutic index; but the level I evidence of a survival improvement is still lacking. In the field of bio-modulation, large meta-analyses have shown that concurrent chemotherapy improves local control in many cancer types. Clinical investigations using molecularly targeted therapies have been rather disappointing, with only one exception: head and neck squamous cell carcinoma. Numerous recent biological findings question the possibility to target tumor tissue without impacting normal tissue response. Moreover, the abscopal and bystander effects suggest that normal tissue irradiation should not be perceived only as a source of toxicity, but may also result in downstream therapeutic effects. This paper reexamines the multiple efforts made to modulate the tumor versus normal tissue differential response, which have translated into incremental therapeutic gain and highlights the ongoing effort to better understand the optimal integration of radiation biology, chemotherapeutic, novel drugs and novel technologies.