A hypothesis for the pathogenesis of radiation-induced oral mucositis: when biological challenges exceed physiologic protective mechanisms. Implications for pharmacological prevention and treatment

Abstract

Oral mucositis (OM) remains a significant unmet need for patients being treated with standard concomitant chemoradiation (CRT) regimens for head and neck cancers (HNC). OM's pathogenesis is complex and includes both direct and indirect damage pathways. In this paper, the field is reviewed with emphasis on the initiating and sustaining role of oxidative stress on OM's pathobiology. A hypothesis is presented which suggests that based on OM's clinical and biological trajectory, mucosal damage is largely the consequence of cumulative CRT-induced biological changes overwhelming physiologic self-protective mechanisms. Furthermore, an individual's ability to mount and maintain a protective response is dependent on interacting pathways which are primarily determined by a multiplex consisting of genomics, epigenomics, and microbiomics. Effective biologic or pharmacologic OM interventions are likely to supplement or stimulate existing physiologic damage-control mechanisms.

Keywords: Mucositis; Oxidative stress; Pathobiology; Radiation.

Fig. 1

Differences in the clinical trajectory of oral mucositis between a bolus and fractionated stomatotoxic challenge: one blow from a sledgehammer vs. cumulative hits from a small ball peen hammer. The acuity of SOM development and resolution in patients receiving high-dose chemotherapy such as in conditioning regimens for stem cell transplants contrasts dramatically with the slower onset, duration, and time to resolution observed in patients receiving typical regimens of fractionated doses of radiation for the treatment of head and neck cancers. While there is similarity in the underlying pathogenic mechanisms, the repetitive challenge of multiple radiation doses produces a cumulative biological effect that results in injury, i.e., one blow from a sledgehammer vs. repeated hits with a small hammer

Fig. 2

Fractionated radiated challenge influences biological interactions and phenotype in the development of SOM. The biological sequence which delineates the pathogenesis of mucositis has been described as a linear 5-phase process (5,6): initiation (I), signaling (S), amplification (A), ulceration (U), and healing (H). The concept was originally proposed based on data obtained following challenges with bolus chemotherapy in humans or a single dose of high energy radiation in animals (Panel 1). The sequence also characterizes the biological response and course associated with each daily fraction of radiation experienced by patients being treated for cancers of the head and neck. Critically, however, in cases of fractionated dosing, the net clinical effect is not only a consequence of the linear events initiated by each fraction but more importantly by the vertical crosstalk which recognizes that the biological consequences of each fraction not only affect tissue horizontally but also modifies or is modified by cell function primed by earlier doses (Panel 2)

Fig. 3

Mucositis is the consequence of the cumulative biological effects of the radiation challenge exceeding the intrinsic capacity of physiological protective mechanisms. Increasing the threshold for a gain in biological protection results in consequent increase in the threshold for manifestations of mucosal injury. Interventional strategies that supplement protective mechanisms and pathways or those that stimulate intrinsic mechanisms to optimize their effectiveness have proven to be most effective.