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© 2000 American Society for Clinical Oncology Phase III Randomized Trial of Amifostine as a Radioprotector in Head and Neck CancerFrom the Department of Radiation Oncology, Duke University Medical Center, Durham, NC; Division of Radiation Oncology, Mallinckrodt Institute of Radiology, St. Louis, MO; Clinic of Radiation Oncology, University of Freiburg, Freiburg; Clinic of Radiation Oncology, Erlangen; Clinic of Radiation Oncology, University of Heidelberg, Heidelberg, Germany; CHG Andre Boulloche, Montebeliard; Department of Radiotherapy, Institute Gustave-Roussy, Villejuif Cedex, France; and Medimmune Oncology, Inc, West Conshohocken, PA. Address reprint requests to David M. Brizel, MD, Department of Radiation Oncology, Box 3085, Duke University Medical Center, Durham, NC 27710; email brizel{at}radonc.duke.edu
PURPOSE: Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands. This randomized trial evaluated whether amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients.
PATIENTS AND METHODS: Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade
RESULTS: Nausea, vomiting, hypotension, and allergic reactions were the most common side effects. Fifty-three percent of the patients receiving amifostine had at least one episode of nausea and/or vomiting, but it only occurred with 233 (5%) of 4,314 doses. Amifostine reduced grade CONCLUSION: Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved.
THE USE OF IONIZING radiation in cancer therapy may lead to transient and/or permanent injury to normal tissues within the treatment field. The magnitude of damage depends both on the volume of tissue irradiated and the dose of radiation delivered. Radiotherapy plays a significant role in the management of head and neck cancer, either as the primary treatment modality or as a postsurgical adjuvant modality. The most common and clinically significant toxicities arising from head and neck irradiation are acute mucositis and acute and chronic xerostomia, the last of these often being lifelong in duration. Xerostomia disrupts normal activities including eating and speaking and may lead to sequelae including dental caries and tooth loss with the secondary risk of osteonecrosis. Oral pilocarpine can palliate xerostomia when used in a postradiotherapy setting.1,2 Unpleasant cholinergic side effects occur in approximately half of the patients using this drug, and lifelong treatment may be required. The benefits from pilocarpine may arise from the hyperstimulation of small residual volumes of unirradiated parotid gland. The usefulness of pilocarpine when the entirety of both parotids have been irradiated to high doses is unclear. Pilocarpine has no role in the management of mucositis. Strategies for the prophylaxis of xerostomia and mucositis are needed. The radioprotective potential of thiol-containing compounds has been recognized for decades.3 The United States Army screened over 4,400 compounds and selected amifostine (WR-2721, Ethyol; Medimmune Oncology, Inc, West Conshohocken, PA) as the most promising of these agents. Amifositine and its active metabolite, WR-1065, accumulate in many epithelial tissues with the highest concentrations found in the salivary glands and kidneys.4,5 Amifostine reduces cisplatin-induced nephrotoxicity.6 Its putative mechanism of radioprotection is through the scavenging of radiation-induced free radicals. Small clinical trials have suggested that amifostine protects against radiation-induced xerostomia and mucositis.7,8 Although amifostine was generally well tolerated in these early trials, nausea, vomiting, and hypotension were the most commonly reported side effects. An inherent risk in any toxicity reduction scheme is that the drug could protect the tumor and reduce treatment efficacy. Such an agent would not be clinically useful. The present study was performed to evaluate whether amifostine could protect against xerostomia and mucositis in head and neck cancer patients receiving radiotherapy without compromising the antitumor efficacy of the radiation.
Patients and Eligibility Criteria Patients with newly diagnosed, previously untreated squamous cell head and neck cancer were eligible for enrollment in this open-label, phase III, multi-institutional (see Appendix A), randomized trial. Inclusion of  75% of both parotid glands within the radiation fields to doses 40 Gy was required. Other inclusion criteria included Karnofsky performance status 60, granulocyte count 2,000/µL, and platelet count 100,000/µL. Prophylactic use of pilocarpine during radiotherapy was prohibited. Patients with T1N0 or T2N0 carcinomas of the true vocal cords were ineligible as were those with tumors of the major or minor salivary glands or with a history of malignancy other than in situ cervix carcinoma within the 5 years preceding diagnosis. Patients could not have previously been treated with radiotherapy or chemotherapy. Pregnant women were ineligible. This protocol was approved by the institutional review board of each participating hospital, and written informed consent was obtained from all patients before enrollment. Tumors were staged according to American Joint Committee on Cancer criteria.9 Staging procedures included history and physical examination, fiberoptic endoscopy, computerized tomography of the head and neck, chest x-ray, and examination under anesthesia. Posttherapy follow-up examinations were obtained every 2 months during the first year and every 6 months during the second year. Computerized tomography was repeated 1 year and 2 years after treatment.
Study End Points Whole saliva production was quantitated (5-minute collection period) before the commencement of radiotherapy and at follow-up 1, 5, 11, 17, and 23 months after treatment. Patients also evaluated their symptoms through the administration of an eight-item Patient Benefit Questionnaire (PBQ) given at baseline, weekly during treatment, and at each follow-up visit.10 Each question was answered on a 10-point scale, where a 10 represented no negative effect from radiotherapy and a 1 signified a severe negative effect. The questions addressed issues including impairment of speaking, taste, and swallowing, need for oral comfort aids, and sensation of mouth dryness. A detailed description of the PBQ will be published elsewhere.
The incidence of Local-regional control was the primary antitumor efficacy end point. Local-regional failures included disease recurrence or persistence at the primary site or neck nodes. Patients whose first site of failure was distant metastases were still followed and considered to be at risk for local-regional failure. Nonetheless, the occurrence of distant relapses or deaths before local failure could have interfered with reliable estimation of local-regional control.12,13 Because of this competing risk problem, disease-free survival and overall survival were used as secondary end points. Each of these parameters was computed from the first day of treatment using the Kaplan-Meier product-limit method14 and performed using intent-to-treat analysis. Survival curves were compared with the log-rank test.
The estimated sample size for this study was 250 assessable patients (125 per treatment arm), based on an anticipated reduction in grade
This study was a multi-institutional, open-label, randomized trial. Treatment assignment was determined by a phone call from the enrolling institution to the protocol sponsor (US Bioscience). Patients were stratified according to the following parameters: treatment center, primary tumor site (nasopharynx, oropharynx, oral cavity, or hypopharynx/larynx), nodal status (N0 v N+), Karnofsky performance status (< 80 v
Radiotherapy and Amifostine The treatment schema is detailed in Fig 1. Treatment consisted of once daily isocentric external-beam megavoltage irradiation given at 1.8 to 2.0 Gy per fraction. Definitive irradiation was prescribed to a total dose of 66 to 70 Gy. Doses of postoperative irradiation were either 60 to 64 Gy (high-risk patients) or 50 to 54 Gy (low-risk patients). The primary tumor and draining lymphatics were treated with parallel opposed lateral fields. Supraclavicular and low neck nodes were treated with a single anterior field of 40 to 44 Gy with midline blocking to prevent spinal cord overlap. The lateral fields were reduced after 40 to 44 Gy to avoid overdosage of the spinal cord. Posterior cervical lymph nodes were boosted with electron-beam irradiation at the discretion of the treating physician. A second field reduction occurred at 54 to 60 Gy. Patients who received amifostine were irradiated in the same fashion as those who did not. Diagnostic radiographic studies, dosimetric records, simulator films, and initial treatment portal films for all patients were submitted to a central office for review at the onset of therapy. Reduced-field portal films were submitted during treatment. At the conclusion of the trial, all records and films were reviewed by two of the principal investigators (D.M.B. and T.H.W.) to assess protocol compliance. Amifostine was delivered 15 to 30 minutes before radiotherapy daily as a 3-minute intravenous (IV) infusion at a dose of 200 mg/m2 dissolved in normal saline at a concentration of 1 mg/mL. Prophylactic antiemetic premedication was recommended. Indwelling peripheral venous access lines were used in many patients to minimize the inconvenience of daily venipuncture. Toxicity of amifostine was graded according to National Cancer Institute common toxicity criteria.
Three hundred fifteen patients were enrolled and randomized from October 1995 to October 1997. Twelve patients were randomized but never received any treatment or follow-up. Table 1 lists the demographics, disease characteristics, and treatment classification of the remaining 303 patients. Approximately two thirds of the patients received postoperative irradiation. Nearly half of all primary tumors originated in the oropharynx. Three patients had less than 75% of their parotids in the treatment fields (amifostine plus irradiation, n =1; radiotherapy alone, n = 2); 22 patients discontinued amifostine before receiving 40 Gy, but 18 still completed their radiation therapy. They were included in the analysis of the efficacy of the drug. All patients were included in the analyses of local-regional control, progression-free survival, survival, and drug toxicity. All patients who received at least one dose of amifostine were assessable for toxicity.
Amifostine Toxicity Amifostine was generally well tolerated. Nausea, vomiting, hypotension, and allergic reactions were the most common side effects (Table 2). A total of 4,314 doses of amifostine were delivered. Fifty-three percent of the patients receiving the drug had at least one episode of nausea and/or vomiting, but it only occurred with 233 (5%) of 4,314 doses. It was severe (grade 3) in 7% of all patients and 13 (< 1%) of 4,314 of all doses. Despite the greater incidence of nausea and vomiting associated with amifostine, median weight loss at the end of treatment was higher in the group of patients treated with radiotherapy alone than those treated with both radiotherapy and amifostine (5.6% v 4.5% of pretreatment weight, respectively; P = .026). Hypotension, usually mild and of short duration, was associated with less than 1% of all amifostine dosages.
Complications caused by venous catheters (ie, catheter infection, catheter malfunction, catheter site drainage, catheter site edema, and IV perfusion infiltrates) and daily IV punctures (injection site pain and injection site red) occurred in seven patients (5%) in the amifostine arm, with no grade 3 or 4 toxicity. Infections (ie, general, fungal, and bacterial) were seen in 21 patients (14%) in both treatment arms, with only three patients (2%) in the amifostine arm reporting grade 3 toxicity. Clotting/vascular disorders (ie, phlebitis, thrombosis, and disseminated intravascular coagulation) occurred in five patients (3%) in the amifostine arm, with one patient (< 1%) reporting a grade 4 toxicity. A total of 35 patients (21%) discontinued amifostine before the completion of the scheduled treatment. Twenty-two patients discontinued amifostine before receiving 40 Gy, and 31 patients discontinued amifostine before receiving 60 Gy. Of the 22 patients who discontinued amifostine before receiving 40 Gy, 16 discontinued amifostine because of adverse events and six patients for other reasons (ie, patient request). Nausea/vomiting (nine patients) and hypotension (two patients) were the most common adverse events that resulted in discontinuation of amifostine. Other adverse events included weakness/anxiety, drowsiness, cachexia, allergic reaction, and erythema/fever. A total of 119 patients were treated with antiemetics prophylactically in this study. The most frequently used antiemetics were oral 5-hydroxytryptamine-3 antagonists. Seventy-four patients (62%) received 5-hydroxytryptamine-3 antagonists, and 45 patients (38%) received phenothiazine and/or metoclopramide. A total of 31 patients received no antiemetics. Side effects definitely or probably reported caused by antiemetics were not reported. However, it cannot be ruled out that antiemetics contributed to some side effects.
Efficacy of Amifostine
Patients’ assessment of their symptoms coincided with the clinical evidence of diminished xerostomia secondary to amifostine. The overall mean score on the PBQ 1 year after treatment was 7.36 versus 6.66 in favor of amifostine (Fig 2; P = .008). Late xerostomia grade 2 was significantly correlated with both saliva production (r = 0.313, P = .0001) and the PBQ mean score (r = 0.455, P = .0001). The PBQ score was also significantly correlated with saliva production (r = 0.304, P = .0001). 
Amifostine did not reduce the incidence of mucositis. Mucositis grade 3 occurred in 35% of the amifostine group and in 39% of the radiotherapy alone patients (P = .48). The median duration of mucositis was also similar in the two groups of patients (41 days v 38 days, respectively; P = .685).
Review of the treatment portals and field sizes demonstrated that smaller quantities of mucosa received the total prescribed dose of irradiation for patients treated in the United States and France than for those treated in Canada, Britain, and Germany. Analysis of this subset revealed that grade
Antitumor Efficacy
This trial is the first large-scale randomized study to report the successful clinical use of a radioprotective agent. Patients who were pretreated daily with amifostine had a significantly lower incidence of acute grade 2 xerostomia than those who received radiotherapy alone. Furthermore, those patients pretreated with amifostine who did develop xerostomia did not do so until higher cumulative doses of irradiation had been delivered. Moderate to severe chronic xerostomia was significantly less prevalent with the use of amifostine. The volume of saliva produced was significantly greater in patients receiving amifostine. Longitudinal posttreatment patient self-assessment showed fewer symptoms in the patients who received amifostine. Most clinical attempts to improve the therapeutic ratio in head and neck cancer have focused on increasing tumor control probabilities. Successful strategies have included hyperfractionated and accelerated fractionation schemes and the integration of radiotherapy and concurrent chemotherapy.21-24 The increased intensity of these programs can increase both acute and chronic treatment-related toxicity, which may partially offset improvements in treatment efficacy.
Xerostomia and mucositis are the most common and severe side effects of radiotherapy for head and neck cancer. The former is often permanent when doses Xerostomia was assessed (1) by the physician using Radiation Therapy Oncology Group criteria, (2) by the quantitation of saliva flow, and (3) by the administration of a validated PBQ. One could argue that in an open-label trial, such as this one, assessment by the treating physician could lead to a bias in favor of the patients receiving amifostine. A placebo-controlled trial would have been ideal, but the potential risks and inconvenience of daily intravenous placebo injections were felt to be unjustified. Likewise, having separate treating and assessing physicians25 would have been desirable but was logistically impractical. Subjective patient assessment of benefit was consistent with the physician assessment, which speaks against the likelihood of any significant bias. Amifostine did not diminish the severity of acute mucositis. The subgroup analysis, however, suggested a mucoprotective benefit in those patients treated with smaller fields. Other studies examining the impact of amifostine on mucositis imply that daily doses more than 300 mg/m2 are desirable.7 The dose of 200 mg/m2/d in this study may have been inadequate to provide full mucosal protection especially when large areas of mucosa were irradiated. Given its impact against xerostomia, further evaluation of the effectiveness of higher daily doses of amifostine against mucositis is warranted. Tumor protection is the greatest potential risk associated with the use of any toxicity modifier. An agent that ameliorated treatment toxicity but that also reduced antitumor efficacy would be unsuitable for clinical use. Local-regional relapses (primary site or nodes) constitute the vast majority of initial recurrences after the treatment of head and neck cancer. Therefore, an increased incidence of local-regional failure would provide strong evidence of tumor protection with the use of a localized treatment modality such as radiotherapy. Actuarial estimates of local-regional control and disease-free survival and overall survival were equivalent among patients who did or did not receive amifostine and argue against any such protection. Moreover, the prognosis of both groups of patients was similar to that of more than 2,000 head and neck cancer patients in the Radiation Therapy Oncology Group database26 (T. Pajak, personal communication, June, 1999). Analysis of the time course of the cumulative frequency of all recurrences reinforces the concept that amifostine did not impair the efficacy of radiotherapy. It is well established that those patients who will recur after treatment of head and neck cancer will do so quickly. Approximately 50% of all recurrences transpire within 6 months of initial treatment, 70% within 1 year, and 80% to 90% within 2 years.27 This same pattern was observed in both cohorts of patients in the current study (data not shown). This trial has demonstrated that daily administration amifostine can successfully reduce the incidence and severity of acute and chronic xerostomia that develops during the radiotherapy of head and neck cancer without compromising the efficacy of the radiation. It has established the proof of principle that lays the foundation for the investigation of normal tissue radioprotection strategies for other types of cancer. Several problems still need to be addressed regarding the use of radioprotectors in general and in head and neck cancer in particular and form the basis of ongoing studies. These include whether or not an administration route more convenient than daily IV injection is possible and associated with less toxicity, understanding the role of this drug in treatment schemes that use modified fractionation schedules and/or concurrent chemotherapy, and more clearly delineating the mucoprotective effects, if any, of amifostine. The answers will help to define the role of this drug in clinical practice.
Supported by Medimmune Oncology, Inc, West Conshohocken, PA.
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Johnson KP, Brooks BR, Cohen JA, et al: Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability: Copolymer 1 Multiple Sclerosis Study Group. Neurol 50: 701-708, 1998 26. Cooper JS, Farnan NC, Asbell SO, et al: Recursive partitioning analysis of 2105 patients treated in Radiation Therapy Oncology Group Studies of head and neck cancer. Cancer 77: 1905-1911, 1996[Medline] 27. Fu KK, Clery M, Ang KK, et al: Randomized phase I/II trial of two variants of accelerated fractionated radiotherapy regimens for advanced head and neck cancer: Results of RTOG 88-09. Int J Radiat Oncol Biol Phys 32: 589-597, 1995[Medline] Submitted October 25, 1999; accepted May 9, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 test. 
= 0.048, with a statistical power greater than 80% adjusted for multiple comparisons. 
