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Modulation of Dose Intensity in Aerodigestive Tract Cancers: Strategies to Reduce Toxicity

Modulation of Dose Intensity in Aerodigestive Tract Cancers: Strategies to Reduce Toxicity

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 [Ethyol]),
or temporal shielding by altered-fractionation schemes that exploit the
differential alpha/beta ratios between tumor and normal tissue (eg,

Chronomodulated Administration

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 (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

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.[15] 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.


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