Commentary: the pharmacological antioxidant amifostine -- implications of recent research for integrative cancer care

Amifostine is a pharmacological antioxidant used as a cytoprotectant in cancer chemotherapy and radiotherapy. It is thought to protect normal tissues relative to tumor tissue against oxidative damage inflicted by cancer therapies by becoming concentrated at higher levels in normal tissues. The degree to which amifostine nevertheless accumulates in tumors and protects them against cancer therapies has been debated. Guidelines have been published that direct its use in chemotherapy and radiation, taking into consideration the concerns of tumor protection. In this article, clinical studies of amifostine appearing since the publication of the most recent set of guidelines are reviewed. Randomized and nonrandomized trials of regimens involving chemo-therapeutic agents (chemotherapy, chemoradiation, conditioning regimens for bone marrow transplant) are discussed. Nineteen studies showed positive effects for amifostine reducing the level of side effects of these regimens, while 9 showed no effect and 1 had a questionable result. Clinically relevant levels of amifostine toxicity were observed in several studies, but subcutaneous administration may reduce such toxicity. Amifostine showed protection against mucositis, esophagitis, neuropathy, and other side effects, although protection against cisplatin-induced ototoxicity was not observed. No evidence of tumor protection was observed. Amifostine may enable populations unable to tolerate conventional cancer therapy to receive treatment of their cancers, even if some degree of tumor protection is eventually discovered. The authors discuss the implications of this research for patient populations seen in integrative cancer care centers and for research on phytochemical antioxidants such as vitamins and carotenoids.     

Radioprotectants: current status and new directions

The ability to prevent radiotherapy-induced toxicity without affecting antitumor efficacy has the potential to enhance the therapeutic benefit for cancer patients without increasing their risk of serious adverse effects. Among the currently available cytoprotective agents capable of protecting normal tissue against damage caused by either chemo- or radiotherapy, only amifostine has been shown in clinical trials to reduce radiation-induced toxicity. Most notably, it reduces the incidence of xerostomia, which is a clinically significant long-term toxicity arising in patients undergoing irradiation of head and neck cancers. In vitro studies with the active metabolite of amifostine (WR-1065) have shown it to prevent both radiation-induced cell death and radiation-induced mutagenesis. The potential of this agent to prevent secondary tumors, as well as other radiation-induced toxicities is now the focus of ongoing research. Among other novel approaches to radioprotection being explored are methods to increase levels of the antioxidant mitochondrial enzyme manganese superoxide dismutase (MnSOD). In addition, the use of epoetin alfa, alone or in combination with cytoprotectants (e.g., amifostine), to treat radiation-induced anemia is also being investigated. The objective of developing newer cytoprotective therapies is to improve the therapeutic ratio by reducing the acute and chronic toxicities associated with more intensive and more effective anticancer therapies.     

Amifostine: the first selective-target and broad-spectrum radioprotector

After several decades of preclinical and clinical research, the first approved radioprotective drug, amifostine, is being used in clinical practice. Amifostine has been shown to specifically protect normal tissues from damage caused by radiation and chemotherapy. An inactive prodrug, amifostine is converted to an active thiol by dephosphorylation by alkaline phosphatase in the normal endothelium. The hypovascularity and acidity of the tumor environment and the differential expression of alkaline phosphatase in normal and neoplastic tissues contribute to its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free-radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. The U.S. Food and Drug Administration has approved the i.v. use of amifostine to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and to reduce the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. Nonetheless, amifostine has potential applications in many other oncologic settings. Novel schedules and routes of administration are under investigation and may further simplify the use of amifostine, reduce any undesired effects, and considerably broaden its applications. This review summarizes the clinical experience with amifostine and provides insight into future clinical directions.     

Costs of treatment intensification for head and neck cancer: concomitant chemoradiation randomised for radioprotection with amifostine

This study presents an overview of costs of a chemoradiation protocol in head and neck cancer patients and an analysis of whether prevention of acute toxicity with amifostine results in a reduction to costs. Fifty-four patients treated with weekly paclitaxel concomitant with radiation were randomised for treatment with subcutaneously administered amifostine (500 mg) and analysed with respect to costs of treatment. Total costs for work-up, treatment and toxicity were calculated per treatment arm. No significant differences were found between treatment arms in preliminary results regarding response (98%), toxicity and 2-year survival (77%). Average costs for toxicity were Euro 3.789, largely influenced by hospital admissions (Euro 3.013). Total costs for amifostine administration amounted to Euro 6.495 per patient. The average total costs of treatment were Euro 19.647 versus Euro 13.592 with or without amifostine, respectively. The applied (subcutaneous) dose of amifostine appeared to be insufficient for radioprotection and reduction of related costs in the concomitant chemoradiation scheme, whereas total costs increased remarkably. Although it would be accompanied by a further cost raise, applying a higher amifostine dose might reduce (mucosal) toxicity and therefore in the long run lower related costs for hospital admission and tube feeding.     

The radioprotectors amifostine and sodium selenite do not modify the radiosensitivity of rat rhabdomyosarcomas

BACKGROUND: Radiotherapy of head and neck tumors often leads to acute reactions of the adjacent normal tissues resulting e.g. in mucositis and xerostomia. Therefore, radioprotective drugs have been developed to reduce these effects. Studies on a tumor model using amifostine and sodium selenite adjuvant to fractionated irradiation should show whether the radioprotective effect on normal tissue leads to an increase of radioresistance in the tumor and its metastatic potential. METHODS: Rhabdomyosarcomas R1H of the rat growing subcutaneously in the right flank of male adult WAG/RijH rats were irradiated with 60Co-gamma rays (60 Gy/30 fractions/6 weeks). Amifostine (375 mg/m(2)), sodium selenite (15 microg/kg), and equivalent volumes of 0.9% saline were administered intraperitoneally 30 min before each irradiation. Tumor response was determined. Statistical analysis was performed using the post-hoc-test. RESULTS: Irradiation alone inhibited R1H tumor growth (AUC 86.8+/-18.3). The efficacy of irradiation during radiotherapy was significantly improved by amifostine (AUC 63.1+/-15.8) in comparison to the irradiated controls. The radiosensitizing effect of sodium selenite (AUC 73.6+/-21.3) as well as irradiation and amifostine plus sodium selenite (AUC 68.3+/-7.8) was less compared to the irradiated controls and not statistically significant. However, tumor growth delay and metastasis rate were not changed by the radioprotective drugs. Further, the administration of amifostine and amifostine plus sodium selenite induced an enhanced decrease of animal body weight except for sodium selenite in comparison to the controls. CONCLUSIONS: The application of amifostine and sodium selenite to conventionally fractionated irradiation have no influence on the radiosensitivity of the rhabdomyosarcoma R1H. The systemic toxicity of amifostine might be of importance for the radiation treatment of a patient.     

Oral complications of radiotherapy in head and neck cancer

Radiotherapy in the head and neck region constitutes a major therapeutic challenge. Tumors and elective nodal areas are often in close proximity to radiosensitive normal tissues, a factor which often limits the success of radiotherapy. Acute radiation-induced adverse effects such as mucositis and skin reactions occur during the course of treatment. They are generally reversible and patients normally recover from these adverse effects within 3 months. Late radiation reactions such as fibrosis and osteoradionecrosis occur more than 3 months after treatment. Such reactions are characterized by their gradual progression. Xerostomia is the single most important factor leading to chronic loss of quality of life in head and neck cancer patients. Oral complications can be prevented or modified by altered fractionation, by reducing the irradiated volume, or by pharmacologic intervention. Altered fractionation in the form of acceleration or hyperfractionation has improved the therapeutic ratio in several large clinical studies and a recent meta-analysis. Reducing the high-dose volume, and especially avoiding irradiating sensitive structures, is the basis for the increasing use of conformal and intensity-modulated radiotherapy. Such techniques may eventually allow dose escalation in tumor areas leading to increased local tumor control while keeping morbidity at an acceptable level. Numerous pharmacologic agents have been evaluated for the prevention and management of both acute and late complications. The only agent with documented radioprotective activity is amifostine, which can reduce late xerostomia. However, it is still unclear whether amifostine also protects tumor cells. Pilocarpine may relieve late xerostomia in some patients with remaining functional salivary gland reserve. Apart from this limited Indication, pharmacologic agents against oral complications should not be used outside of clinical trials.     

Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: pulmonary function, prediction, and prevention

Although radiotherapy improves locoregional control and survival in patients with non-small-cell lung cancer, radiation pneumonitis is a common treatment-related toxicity. Many pulmonary function tests are not significantly altered by pulmonary toxicity of irradiation, but reductions in D(L(CO)), the diffusing capacity of carbon monoxide, are more commonly associated with pneumonitis. Several patient-specific factors (e.g. age, smoking history, tumor location, performance score, gender) and treatment-specific factors (e.g. chemotherapy regimen and dose) have been proposed as potential predictors of the risk of radiation pneumonitis, but these have not been consistently demonstrated across different studies. The risk of radiation pneumonitis also seems to increase as the cumulative dose of radiation to normal lung tissue increases, as measured by dose-volume histograms. However, controversy persists about which dosimetric parameter optimally predicts the risk of radiation pneumonitis, and whether the volume of lung or the dose of radiation is more important. Radiation oncologists ought to consider these dosimetric factors when designing radiation treatment plans for all patients who receive thoracic radiotherapy. Newer radiotherapy techniques and technologies may reduce the exposure of normal lung to irradiation. Several medications have also been evaluated for their ability to reduce radiation pneumonitis in animals and humans, including corticosteroids, amifostine, ACE inhibitors or angiotensin II type 1 receptor blockers, pentoxifylline, melatonin, carvedilol, and manganese superoxide dismutase-plasmid/liposome. Additional research is warranted to determine the efficacy of these medications and identify nonpharmacologic strategies to predict and prevent radiation pneumonitis.     

Has the outlook improved for amifostine as a clinical radioprotector?

Amifostine has recently been approved for clinical radiotherapy as a protector against irradiation-induced xerostomia. It is our aim to review the outlook for using amifostine as a general clinical radioprotector.Protection against X-rays is mainly obtained by the scavenging of free radicals. The degree of protection is therefore highly dependent on oxygen tension, with protection factors ranging from 1 to 3. Maximal protection is observed at physiological levels of oxygenation. A great variability in protection has also been observed between different normal tissues. Some tissue, like brain, is not protected while salivary glands and bone marrow may exhibit a three-fold increase in radiation tolerance. Amifostine is dephosphorylized to its active metabolite by a process involving alkaline phosphatase. Due to lower levels of alkaline phosphatase in tumor vessels, amifostine is marketed as a selective protector of normal tissue and not tumors. However, the preclinical investigations concerning the selectivity of amifostine are controversial and the clinical studies are sparse and do not have the power to evaluate the influence of amifostine on the therapeutic index. Conclusion: based on the present knowledge amifostine should only be used in experimental protocols and not in routine practice.     

Radiation and third-generation chemotherapy

All of the third-generation chemotherapeutic agents reviewed in this article are independently active against NSCLC, although the agents differ significantly in their cellular and molecular mechanisms of cytotoxicity. All have also been shown to potentiate radiation effects, and thus are promising in exerting further cytotoxicity when used in combination chemoradiation therapy for locally advanced NSCLC. Although the toxicity to normal tissue varies among these agents when used alone, phase I/II clinical results consistently demonstrated higher risk and severity of esophagitis and pneumonitis when these agents were administered concurrently with thoracic radiation. These results were consistent with the radiosensitization properties of all these agents. Nonetheless, most chemoradiation combinations have been made feasible through careful phase I studies that establish safe doses of these agents given concurrently with radiation. Indeed, phase I outcomes consistently have demonstrated the need for dose reduction compared with doses applied in the stage IV, metastatic disease setting (see Tables 1 and 2). There have been many different dose schedules in phase I/II studies for stage III NSCLC, and most have yielded improved response rates with these agents. For all these agents discussed, multiagent chemoradiation increased toxicity when compared with single agent chemoradiation, particularly in the risk of neutropenia, and the tumor response rates were no better than single-agent chemoradiation. Most studies have not reached an adequate interval for survival endpoint to assess the impact on survival using multiagent chemoradiation. A few earlier studies using paclitaxel chemoradiation, in fact, showed that the significant improvement in tumor response rate resulted in only a small gain in survival outcome. Despite much preclinical research conducted with these agents, the optimal sequence and dose of drug and the optimal schedule for combining the two modalities remain unknown. Optimal sequencing of the chemoradiation regimens may improve distant disease control and primary tumor control, as was seen in studies that administered both full-dose induction chemotherapy and concurrent chemoradiation at reduced drug dose and in studies that administered consolidative, full-dose chemotherapy after chemoradiation. Strategically altering the treatment schedule may also enhance the radiosensitizing effects while keeping toxicity low, such as was seen in the pulsed low-dose paclitaxel chemoradiation reported by Chen et al . This pulsed low-dose schedule resulted in superior tumor response (100%) and durable primary tumor control while keeping the toxicity low. Other methods to minimize normal tissue injury and to deliver higher radiation doses, such as conformal three-dimensional radiotherapy that excludes nontarget tissues from the radiation field, are under investigation. Marks and colleagues were able to deliver radiation to 80 Gy using accelerated hyperfractionation radiation after induction chemotherapy. Intensity-modulated radiotherapy is expected to revolutionize the targeting of tumor and exclusion of normal tissues from the high-dose radiation volume in the future. Integrating biologic response modifiers, radioprotectors, and molecular targeting strategies also are being investigated. It remains unclear which agent among the third-generation drugs performs better for combination chemoradiation. The CALGB 9431 study reported by Vokes et al provided some preliminary information, in that it was a randomized phase II study of a three-arm comparison of cisplatin-containing, two-drug combination chemoradiation with one of the third-generation agents. Although direct statistical comparison between the treatment arms was not valid for a phase II setting, such an analysis did indeed reveal similar overall response rates for these three arms. Chemoradiation using third-generation chemotherapeutic agents has improved local tumor response rates, with enhanced radiation toxicity such as esophagitis and pneumonitis. The challenge of targeting distant disease control for locally advanced NSCLC continues.     

Prevention of radiation-induced central nervous system toxicity: a role for amifostine?

PURPOSE: To review the role of amifostine (WR-2721) in ameliorating radiation-induced central nervous system (CNS) toxicity. MATERIALS AND METHODS: Literature review and presentation of preliminary animal experiments designed to test the efficacy of both intrathecal and subcutaneous application of amifostine. RESULTS: Despite its inability to cross the blood-brain barrier, amifostine appears promising because it protects blood vessels against radiation-induced damage. Vascular damage is one of the most important components in the development of CNS toxicity after radiotherapy. Furthermore, the increased permeability of the blood-brain barrier during fractionated radiotherapy might allow penetration of amifostine. Three animal studies with systemic administration found positive results after brain irradiation with different fractionation schedules, total doses and amifostine doses. One study where amifostine was given after radiotherapy showed no protection, suggesting that the timing of the drug application is crucial. Further data suggest that either intrathecal or systemic administration might protect the spinal cord as well. In our experience with spinal cord irradiation, systemic administration was more effective than intrathecal. Regarding CNS protection, the optimum dose of amifostine has yet to be determined. CONCLUSION: Several independent experiments provided preliminary evidence that modulation of the radiation response of the CNS in vivo by systemic administration of amifostine is possible and feasible. Additional studies are warranted to investigate the protective effect with differing regimens of administration, more clinically relevant fractionation regimens and longer follow-up.     

Protective effect of amifostine on dental health after radiotherapy of the head and neck

Purpose: The cytoprotective agent amifostine has been shown to reduce the radiation-induced acute and chronic xerostomia in head and neck cancer patients. The purpose of this study was to evaluate whether or not amifostine also reduces the incidence of dental caries associated with the radiation-induced xerostomia.

Methods and Materials: The dental status before and 1 year after radiotherapy was retrospectively compared in 35 unselected patients treated as part of the prospective randomized and multicenter open-label Phase III study (WR-38) at the University Hospitals of Heidelberg, Freiburg, and Erlangen. The WR-38 study compared radiotherapy in head and neck cancer with and without concomitant administration of amifostine.

Results: Patient and treatment characteristics (particularly the radiation dose and percentage of parotids included in the treatment volume) were equally distributed between the patients who received (n = 17) or did not receive (n = 18) amifostine. Fifteen patients of the amifostine group showed no deterioration of the dental status 1 year after radiotherapy as compared to 7 patients who did not receive the cytoprotector (p = 0.015, two-tailed Fisher exact test).

Conclusion: Our data suggest a protective effect of amifostine on the dental health after radiotherapy of the head and neck. The dental status should be used as a primary endpoint in future studies on amifostine.     

Amifostine (ETHYOL) protects rats from mucositis resulting from fractionated or hyperfractionated radiation exposure

PURPOSE: The cytoprotective drug amifostine (Ethyol) protects rats from oral mucositis resulting from a single dose of gamma-irradiation. We expanded earlier studies to determine whether multiple doses of amifostine protect against fractionated or hyperfractionated radiation and whether the active metabolite of amifostine (WR-1065) accumulates in tissues upon repeated administration. METHODS AND MATERIALS: Rats received amifostine daily for 5 days in conjunction with a 1-week fractionated radiation schedule and were evaluated for oral mucositis. Rats also received amifostine before the am or pm exposure or b.i.d. in conjunction with hyperfractionated radiation. To determine the pharmacokinetics of WR-1065 after repeated dosing, amifostine was given 5 days a week for 1 or 3 weeks, and rat tissue and plasma were collected at intervals during and after treatment and analyzed for WR-1065. RESULTS: Amifostine protected rats from mucositis resulting from fractionated or hyperfractionated radiation. When the number of days of amifostine administration was reduced, protection was diminished. A dose of 100 mg/kg given in the morning or 2 doses at 50 mg/kg provided the best protection against hyperfractionated radiation. WR-1065 did not accumulate in tissues or tumor upon repeated administration. CONCLUSIONS: Amifostine prevented radiation-induced mucositis in a rat model; protection was dose and schedule dependent.     

Cytoprotective effect of amifostine in radiation-induced acute mucositis - a retrospective analysis

PURPOSE: To study the cytoprotective impact of amifostine against acute radiation mucositis. PATIENTS AND METHODS: A total of 117 cancer patients with carcinomas localized in pelvic organs, lung and head and neck were entered into this study. In a retrospective way, and in order to minimize the bias related to the investigator, 138 patients as historical controls were randomly selected from a database in our hospital. Acute radiation-induced gastrointestinal mucositis, esophagitis and stomatitis were assessed using the common toxicity criteria scale. The most severe grade recorded was evaluated as the final morbidity score for this patient. Mean toxicity score (MTS) was the mean value of recorded acute radiation toxicity. Mean interruption time (MIT) was the mean value of recorded interruption time due to radiation toxicity. RESULTS: A significantly reduced severity of symptomatology related to oral, esophageal and rectal mucosa was noted in the amifostine group (group A) (p < 0.05, chi-square test). Furthermore, a significant reduction of MTS as well as MIT was observed in group A versus the historical controls (group B) (p < 0.05, Mann-Whitney U test). CONCLUSION: The administration of amifostine seems to protect patients against radiation-induced mucositis, but further investigation with randomized trials is needed.     

Does amifostine have a role in chemoradiation treatment?

For many years, scientists have been investigating use of drugs to protect normal tissue from injury during radiation therapy, thereby increasing the amount of radiation that can be safely administered to patients. Despite the introduction of modern shielding techniques, dose modulation, and tissue-volume mapping, a small amount of normal tissue surrounding the target volume is inevitably irradiated during treatment, which can lead to severe side-effects. The most recent chemical radioprotector to become available clinically is amifostine. On the basis of efficacy data from a phase III randomised trial in patients with head and neck cancer, which showed reduced acute and chronic xerostomia with preserved antitumour response, some institutions are now adding amifostine to their chemoradiation regimens. However, much controversy surrounds the use of this drug. Some investigators are worried that radioprotectors may stop tumour tissue responding to radiation and therefore reduce treatment effectiveness. Moreover, amifostine opponents argue that the evidence is insufficient to justify routine use of this drug. In this Debate, David Brizel, who worked on the phase III amifostine efficacy study, and Jens Overgaard, a vehement opponent of amifostine therapy, provide thought-provoking arguments for two opposing perspectives on this contentious issue.     

Protection of normal tissues from radiation and cytotoxic therapy: the development of amifostine.

Much effort is being made to reduce the iatrogenic toxicity of antineoplastic treatments in order to improve the quality of life of cancer patients. Cytoprotection of healthy tissue by thiol group donors is one of the most promising lines of research. Amifostine is the most extensively studied drug in the category. We reviewed the extensive medical literature on amifostine. The protective effect of amifostine has been demonstrated for cisplatin-induced toxicity in lung and ovarian cancer, with particular regard to nephrotoxicity, neurotoxicity and neutropenia. No protective effect has been seen for tumor cells owing to a selective action of amifostine on healthy tissues. A frequent side effect of amifostine is a transient decreases in blood pressure; it is usually asymptomatic if an easily handled premedication is given. Cytoprotection by amifostine is also well known for alkylating drugs and radiation therapy, whereas it is still the object of study for new drugs, especially taxanes. The present work also includes a cost-benefit analysis and a prospective view on the most promising research lines.     

Impact on cytoprotective efficacy of intermediate interval between amifostine administration and radiotherapy: a retrospective analysis

PURPOSE: To evaluate the cytoprotective impact of the interval between amifostine administration and radiotherapy (RT). METHODS AND MATERIALS: In a nonrandomized study, we reviewed the records of 177 patients with tumors localized in the pelvis (prostate, bladder, or gynecologic cancer), upper abdomen (pancreas, stomach, kidney), thorax (lung and breast cancer), head and neck (nasopharynx), soft tissue (sarcomas), and central nervous system. The patient records were stratified according to whether the patients had undergone RT either 25-40 min (Group 1, 96 subjects) or 10-15 min (Group 2, 81 subjects) after i.v. amifostine administration. The mean toxicity score was the mean value of recorded acute radiation toxicity. The mean interruption time was the mean value of the recorded interruption time due to radiation toxicity. RESULTS: A significantly reduced severity of symptoms related to oral (p = 0.023), esophageal (p = 0.05) and rectal (p = 0.015) mucosa was noted in Group 2. A statistically significant reduction in the mean toxicity score (p <0.001) and mean interruption time (p = 0.001) was observed in Group 2 vs. Group 1. In terms of the incidence of radiation-induced dermatitis and alopecia, multivariate logistic analysis revealed only the total dose (p = 0.018) and the amifostine-RT interval (p = 0.002) as independent factors. CONCLUSION: A significantly better cytoprotective effect of amifostine against radiation-induced mucositis, dermatitis, and alopecia was noted if RT was administered no later than 15 min after i.v. amifostine infusion. The results presented here need additional investigation with randomized prospective trials.     

Pharmacological strategies to spare normal tissues from radiation damage: useless or overlooked therapeutics?

Half of all the patients with a solid malignant tumor will receive radiation therapy (RT) with a curative or palliative intent during the course of their treatment. Deleterious effects may result in acute and chronic toxicities that reduce the long-term health-related quality of life of these patients. High-tech RT enables precise beam delivery that conforms closely to the shape of tumors yielding an improved efficacy/toxicity ratio. However, sophisticated RT will not completely prevent toxicity in the irradiated field, especially as normal tissue constraints are offset by dose escalation or concurrent chemotherapy. Pharmacological agents can be used before or after RT to reduce side effects and are classified based on the timing of RT delivery. “Radioprotectors,” used as a molecular prophylactic strategy before RT, are mostly based on antioxidant properties. Currently, amifostine is the only radioprotector approved for use in the clinic. “Mitigators,” given during or shortly after RT, reduce the action of cellular ionizing radiation on normal tissues before the emergence of symptoms. Lastly, a “treatment” is the administration of an agent once symptoms have developed in order to reverse those that are mostly due to fibrosis. This review presents the major known physiopathological mechanisms involved in radiation response and tissue damage for which potential pharmacological candidates are emerging. We discuss the potential clinical relevance of such therapeutics in the era of high-precision radiotherapy.     

How to reduce radiation-related toxicity in patients with cancer of the head and neck

Radiation for head and neck cancers is often curative, but high doses are used. Normal tissues, including mucosa, salivary glands, and muscles, are exposed to these high doses, resulting in severe mucositis, xerostomia, and dysphagia. Efforts to minimize toxicity have involved advances in radiation physics and development of pharmacologic agents. Radiation techniques include conformal and intensity-modulated therapy, which minimizes dose to normal tissues while delivering high doses to tumor targets. Drugs used to prevent mucositis have targeted infection, but recently interest has been shown in the use of growth factors. Cholinergic agonists and cytoprotective agents, specifically amifostine, can address xerostomia. Involvement of speech pathologists in evaluation and treatment of patients with dysphagia can minimize swallowing difficulties and identify the tissues most responsible for swallowing. Minimizing radiation dose to these tissues may lower the incidence of radiation-induced dysphagia.     

The role of saliva in oral health: strategies for prevention and management of xerostomia

Oral complications are the most frequent and debilitating sequelae of radiation treatment for patients with head and neck cancer. Impaired salivary function and consequent xerostomia can persist for years after radiation treatment, significantly increasing the risk of oral and dental disease and negatively affecting patients' quality of life. Current evidence indicates that many patients undergoing radiation treatment do not receive adequate oral and dental care and follow-up and that patients' compliance with oral care recommendations is frequently poor. Topical lubricants, coating agents,and saliva substitutes or lozenges may provide transient relief from xerostomia. Cholinergic stimulants such as pilocarpine improve salivary flow but have had mixed results in improving patients' assessments of symptoms or other quality-of-life measures. Advances in radiotherapy techniques, such as intensity-modulated radiation therapy, have enabled increased delivery of therapeutic doses of radiation to tumors while limiting exposure to normal tissues, thereby reducing the incidence, duration, and severity of xerostomia in some patients with head and neck cancers. Additionally, radioprotective agents such as amifostine have been shown to reduce radiation-induced toxicity to normal tissues within the radiation field. Studies are ongoing to determine the optimal approaches for these techniques and agents to maximize clinical response while improving the overall quality of life for patients with head and neck cancer.