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." 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.
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 (frequently fluorouracil(Drug information on 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 complications.
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 1).
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. Computerized tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) are used to delineate precisely the extent of local and regional disease. 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. 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. For tumors of the upper GI tract, doses of 60 to 72 Gy have been used for hepatic[16,17] and pancreatic cancers 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, 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. 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.
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(Drug information on amifostine) (Ethyol), a sulfhydryl radioprotector that acts to scavenge free radicals, and thereby, preferentially reduce the amount of initial radiation damage in normal tissue. 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(Drug information on pilocarpine) (Salagen), which is administered orally during and after irradiation.
A third means of protecting normal tissues is with biomolecularly designed growth factors that alter mucosal proliferation (eg, keratinocyte growth factors). 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.
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. 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 1). 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. Late morbidity is not increased, however, resulting in an overall therapeutic gain.
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, gemcitabine(Drug information on gemcitabine) (Gemzar), and irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) 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 causes acute reactions to be more severe and appear sooner, compared to irradiation alone.