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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

ABSTRACT: Advances in diagnostic and therapeutic radiology and a better understanding of cell biology are being applied in practical ways to modulate treatment morbidity. Conformal radiotherapy targets the cancer precisely and can be combined with new systemically administered radiosensitizers. The successes of conventional chemoradiation programs support continued study of newer ways to deliver systemic radiosensitizing chemotherapy. However, chemoradiation creates a narrower therapeutic window compared to irradiation alone and increased treatment intensity, even with conformal chemoradiation techniques, can potentially result in frequent complications, detrimental treatment delays, and decreased quality of life. Treatment schedules employing a "best tolerated time" model for systemic administration of radiosensitizing chemotherapy, based on the concept of chronotolerance, offer attractive ways to address the challenging problem of normal tissue toxicity associated with conformal chemoradiation. This approach may be beneficial in the elderly and those medically unfit to tolerate traditional dose-intense combined-modality schedules. Further evaluation of this concept is warranted, based on existing data. [ONCOLOGY 15:1603-1622, 2001]

Treatment advances in upper aerodigestive tract cancers using altered
radiotherapy fractionation in multiple daily vs once daily doses underscores the
importance of the temporal pattern of dose administration. Accelerated or
hyperfractionated irradiation schedules result in improved survival and local
tumor control in patients with head and neck and esophageal cancers.[1-3] This
finding supports further evaluation of compressed treatment schedules to attack
accelerating repopulating tumor cells,[4,5] or "regenerative
resistance."[6] Schedules that provide higher dose intensity (accelerated
irradiation) or higher dose density (sequential chemotherapy delivered in short
overall time spans) are associated with successes in radiation and medical
oncology, respectively. These intense weekly or high total doses can increase
the incidence of acute complications, however, as predicted by laboratory and
clinical models.[7]

A parallel exists between this increased morbidity and the morbidity
associated with chemoradiation, where concurrent irradiation is combined with
simultaneous anti-S-phase radiosensitizing chemotherapy[8] (frequently
fluorouracil [5-FU]-based), and cure rates in gastrointestinal (GI) cancers have
increased (esophageal, gastric, pancreaticobiliary, rectal, and anal).[9-11] One
underutilized approach to better leverage outcomes for these cancers is to
identify ways in which to widen the therapeutic window by reducing acute

This review discusses several of these methods, focusing on the temporal
pattern of radiosensitizing chemotherapy administration during radiotherapy, so
as to ameliorate the GI toxicity of aggressive chemoradiation by exploiting the
differential temporal sensitivity of normal tissues to cytotoxic insult (Figure

New Radiotherapy:
‘Find the Tumor, Hide the Dose’

Better local cure is being attempted through improved tumor definition
coupled with altered fractionation (thereby increasing radiotherapy dose
intensity), or by the delivery of ultrahigh total doses through computer-
controlled treatment approaches.[12] Computerized tomography (CT), magnetic
resonance imaging (MRI), and positron-emission tomography (PET) are used to
delineate precisely the extent of local and regional disease.[13] These
diagnostic radiology approaches are used with three-dimensional (3D) treatment
planning systems to allow dose "sculpting" or isodose
"painting" and tightly conform treatment to the anatomic disease
process. Until prospective randomized trials are conducted, the full value of
these new technical approaches in terms of improved tumor control rates, with or
without acceptable normal tissue toxicity, will remain unknown.

Nevertheless, early results with conformal therapy (including
intensity-modulated radiation therapy) suggest that morbidity is decreased,
compared to standard treatment. For example, with CT treatment planning,
radiation dose distributions can be designed that envelop a head and neck cancer
while transit doses avoid the parotid glands, thereby reducing xerostomia.[14]
For prostate cancer, where the use of total doses of 80 Gy or more suggest better local
control in nonrandomized studies, the anterior rectal wall can be spared acute
damage with similar techniques.[15] For tumors of the upper GI tract, doses of
60 to 72 Gy have been used for hepatic[16,17] and pancreatic cancers[18] without
incurring excessive morbidity. One drawback associated with the use of these
techniques, especially in the chest and abdomen, is that breathing may cause
unwanted movement of the target, and without sophisticated gated
radiotherapy,[19] a portion of the target area may be underdosed.

Despite this problem and other hurdles, the potential benefits of conformal
radiotherapy include increased local cure rates, better control of regional
micrometastatic disease (so-called oligometastasis), and better local symptom
control because of tighter isodose distributions. Preventing acute normal tissue
reactions could, in turn, allow more intense or dose-escalated concomitant
radiosensitizing chemotherapy with less chance of a detrimental interruption in
treatment.[20] Conformal treatment also requires more time for planning and
implementation and can be more expensive than standard treatment, thus adding
another question to be addressed in prospective trials.[21]

Protecting Against Acute Reactions

Acute reactions in the rapidly dividing tissue compartments of the
aerodigestive tract mucosa or the parotid gland can also be protected from
radiotherapy with chemical radioprotectors. The incidence of stomatitis and
xerostomia can be reduced with the use of amifostine (Ethyol), a sulfhydryl
radioprotector that acts to scavenge free radicals, and thereby, preferentially
reduce the amount of initial radiation damage in normal tissue.[22] Although
tumor protection has been a concern, clinical trials to date have not
demonstrated any evidence in support of this activity. Another agent used
successfully to ameliorate xerostomia is pilocarpine (Salagen), which is
administered orally during and after irradiation.[23]

A third means of protecting normal tissues is with biomolecularly designed
growth factors that alter mucosal proliferation (eg, keratinocyte growth
factors).[24] These molecules have been evaluated in preclinical models, and
clinical data should become available soon. One drawback to using chemical and
biomolecular protection of normal tissues is the need to administer these agents
with each radiation treatment, thus requiring technical staff to coordinate
administration of additional treatments in conjunction with irradiation.

Controlling Toxicity

Increased toxicity has also been observed in the GI tract and bone marrow
with chemoradiation compared to radiotherapy alone in gastric, pancreatic,
biliary, rectal, and anal cancer.[25] Within this framework, when
radiosensitizing chemotherapy is administered as a protracted venous infusion,
compared to a rapid (bolus) injection, such treatment results in a different
array and intensity of acute toxicities that can be exploited therapeutically (Figure
). For example, myelosuppression is generally absent with protracted
venous infusion of 5-FU chemoradiation but diarrhea is more common, partly
because of the high cumulative doses administered during a course of pelvic
irradiation.[26] Late morbidity is not increased, however, resulting in an
overall therapeutic gain.[27]

To increase cure rates further among GI cancer patients will likely require
the use of combinations of irradiation with newer systemic chemotherapeutic
radiation sensitizers. There have already been reports of increased acute
morbidity with taxanes,[28] gemcitabine (Gemzar),[29] and irinotecan (CPT-11,
Camptosar)[30] combined with irradiation. These combinations may increase tumor
cure but at the price of increased toxicity, because cellular damage in the
highly proliferative GI tract can result from overlapping toxicity.
Chemoradiation is similar to accelerated treatment in that the increased dose
intensity[8] causes acute reactions to be more severe and appear sooner,[31]
compared to irradiation alone.[32]


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