Dr. Rich and colleagues present a compelling argument for the manipulation of temporal and spatial treatment parameters in chemoradiation programs. In essence, the authors address the shielding of normal tissues from the effects of cytotoxic agents. With respect to radiotherapy, this can be achieved via physical shielding by computer-generated dose algorithms using elaborate new planning technology (eg, intensity-modulated radiation therapy [IMRT]), chemical shielding with radioprotectants (eg, amifostine(Drug information on amifostine) [Ethyol]), or temporal shielding by altered-fractionation schemes that exploit the differential alpha/beta ratios between tumor and normal tissue (eg, hyperfractionation).
With regard to chemotherapy, the authors explore the concept of temporally shielding normal tissue by chronomodulation of administration schedules based on circadian cell-cycle rhythms. Potential benefits include dose escalation and a corresponding reduction in acute and late side effects by maximizing the tolerance of normal tissues to antineoplastic agents. As the authors point out, chronomodulated intravenous infusion of fluorouracil(Drug information on fluorouracil) (5-FU) has been used in the treatment of various gastrointestinal malignancies for some time.
Further exploitation of this principle to incorporate other cytotoxic agents and tumor sites carries the potential for significant gain, and continued investigation is certainly warranted. As Rich et al have noted, the prospect becomes even more attractive when cost is considered, especially compared with the exorbitant price tags associated with cutting-edge refinements in diagnostic and therapeutic radiology.
Hyperfractionated Radiation Schedules
Alterations in temporal dose sequencing have been explored in detail for radiation therapy fractionation schemes.[1-9] At the University of Florida, hyperfractionated radiation schedules have been used since 1978 to treat malignancies of the head and neck and other sites.[10-14] Advances in physical shielding have moved away from traditional parallel-opposed blocked fields to noncoplanar stereotactic setups using sophisticated planning software. We have also gradually shifted to ipsilateral wedge-pair setups for certain lateralized head and neck malignancies, with a resultant sparing of contralateral salivary tissues.
Patient selection for this method continues to evolve, the critical concept being that normal tissue excluded from the treatment volume is at low risk of harboring subclinical disease. More recently, IMRT has been used for selected lesions. Tumor volumes are carefully outlined using three-dimensional (3D) computed tomography (CT) planning with intravenous contrast. Typically, the clinical tumor volumes for 50 Gy and 70 Gy are defined with selective sparing of the spinal cord, salivary glands, and any other critical structures in which a high radiation dose is undesirable.