Efficacy and Safety of Subcutaneous Amifostine in Minimizing Radiation-Induced Toxicities in Patients Receiving Combined-Modality Treatment for Squamous Cell Carcinoma of the Head and Neck

Int. J. Radiation Oncology Biol. Phys., Vol. 69, No. 5, pp. 1361–1368, 2007 Copyright Ó 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter

doi:10.1016/j.ijrobp.2007.05.052

CLINICAL INVESTIGATION

Head and Neck

EFFICACY AND SAFETY OF SUBCUTANEOUS AMIFOSTINE IN MINIMIZING RADIATION-INDUCED TOXICITIES IN PATIENTS RECEIVING COMBINED-MODALITY TREATMENT FOR SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK AMY LAW, M.D.,* THOMAS KENNEDY, M.D., F.A.C.S.,y PHILLIP PELLITTERI, D.O., F.A.C.S.,y CRAIG WOOD, M.S.,* DOUGLAS CHRISTIE, M.D.,z AND OMAR YUMEN, M.D.z Departments of *Hematology/Oncology, y ENT, Head and Neck Surgery, and z Radiation Oncology, Geisinger Medical Center, Danville, PA Purpose: To report long-term data from a prospective trial of subcutaneous (s.c.) amifostine in patients who received chemoradiotherapy for squamous cell carcinoma of the head and neck (SCCHN). Methods and Materials: Patients $18 years of age with previously untreated Stage III/IV SCCHN received fractionated radiotherapy, 1.8–2.0 Gy/day, 5 days per week, to a total dose of 70–72 Gy, plus weekly paclitaxel (40 mg/ m2) and carboplatin (100 mg/m2) administered intravenously (i.v.) for 6 weeks. All patients received 500 mg s.c. amifostine 30–60 min before radiotherapy with antihistamine and antiemetic prophylaxis. Results: Twenty patients were evaluable (median age, 55 years). The incidence of Grade 2 xerostomia was 42% and 29% at 12 and 18 months, respectively; there were no reports of Grade $3 xerostomia. Grade $3 mucositis occurred in 30% of patients, with median time to resolution of 12.5 weeks (range, 5–17 weeks). Survival estimates at 1 and 2 years were 95% and 71%, respectively. All patients experienced Grade 2 weight loss; 7 patients (35%) experienced Grade #2 nausea/vomiting. There were no reports of Grade $3 amifostine-related adverse events. Conclusions: Subcutaneous amifostine was well tolerated by patients receiving chemoradiotherapy for SCCHN, with lower rates of nausea/vomiting than reported in trials with i.v. amifostine. Xerostomia and mucositis rates were similar to those reported in trials with i.v. amifostine. Ó 2007 Elsevier Inc. Subcutaneous, Amifostine, Head and neck cancer, Chemoradiotherapy, Cutaneous reactions.

Locoregional relapse and distant metastases are frequent after radiotherapy (RT) treatment of advanced Stage III or IV squamous cell carcinoma of the head and neck (SCCHN) (1). In patients with locally advanced resectable tumor, surgery is usually followed by postoperative RT (2). In patients with advanced tumor that is not amenable to surgery, concurrent treatment with RT and chemotherapy (CRT) is a promising approach (3, 4). Meta-analyses have reported the impact of concurrent CRT on survival (5, 6). Concurrent CRT provided an absolute benefit on 5-year survival of approximately 10%. Several studies have demonstrated that locally advanced tumors, particularly at nasopharynx and oropharynx,

respond better to concurrent CRT than to RT alone (7–11). However, CRT is associated with increased acute adverse effects. The primary nonhematologic toxicities are mucositis and xerostomia. In a recent report, 36% of patients who received RT for head and neck cancer continued to experience moderate to severe xerostomia 24 months after completion of treatment (12). Dry mouth was cited as the most debilitating effect of radiation treatment in a survey of head-and-neck cancer patients (13). Hence, efforts in reducing toxicities associated with CRT may improve the efficacy of treatment. Amifostine is an aminothiol prodrug that protects normal tissues from the effects of radiation or chemotherapy. Intravenous amifostine (200 mg/m2) is approved to reduce the incidence of moderate to severe xerostomia in patients

Reprint requests to: Amy Law, M.D., Department of Hematology/Oncology, Geisinger Medical Center, 100 North Academy Ave., Danville, PA 17822. Tel: (570) 271-6045; Fax: (570) 2716542; E-mail: [email protected] Supported by a grant from MedImmune Oncology Inc., a subsidiary of MedImmune, Inc., Gaithersburg, MD, manufacturer of amifostine. Presented in abstract form at the 2004 Annual Meeting of the American Society for Clinical Oncology, June 5–8, 2004, New

Orleans, LA (Abstract 5564) and at the 2005 Annual Meeting of the American Society for Clinical Oncology, May 13–17, 2005, Orlando, FL (Abstract 5576). Conflict of interest: none. Acknowledgment—The authors thank Catherine Grillo, M.S., Gerard P. Johnson, Ph.D., and Janet E. Stead, B.M., B.S., who provided medical writing and editorial assistance. Received Oct 20, 2006, and in revised form May 4, 2007. Accepted for publication May 8, 2007.

INTRODUCTION

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undergoing RT for head and neck cancer for whom the radiation port includes a substantial portion of the parotid glands (12, 14, 15). Intravenous (i.v.) administration of amifostine is associated with reversible hypotension and dose-limiting nausea and vomiting. Patients receiving i.v. amifostine require adequate hydration, blood pressure monitoring throughout the infusion period, and premedication with antiemetic medication. Daily i.v. administration of amifostine is time consuming and can present logistic difficulties in a busy radiation oncology setting. This has prompted interest in subcutaneous (s.c.) administration of amifostine. A recent phase III study reported similar efficacy in the reduction of acute xerostomia and mucositis between i.v. and s.c. administration of amifostine for head-and-neck tumors treated by RT (17). Furthermore, two phase II studies in the RT setting demonstrated a decreased incidence of hypotension and nausea/ vomiting with s.c. administration of amifostine (16, 18). The purpose of this phase II study was to evaluate the efficacy and safety of s.c. amifostine in decreasing acute and chronic treatment-related toxicities in patients receiving CRT for SCCHN. Although the s.c. administration route of amifostine is not approved by the U.S. Food and Drug Administration, on the basis of clinical experience, this route of administration was used because it was considered to improve the logistics of administering amifostine. METHODS AND MATERIALS Study design and eligibility criteria This open-label, nonrandomized, prospective phase II study was conducted at a single center (Geisinger Medical Center, Danville, PA). The study was conducted in accordance with the principles of the Declaration of Helsinki. The protocol was approved by the Geisinger Institutional Review Board, and all patients provided written informed consent. Treatment-naive patients aged $18 years with histologically confirmed Stage III/IV SCCHN and no evidence of distant metastases were eligible for inclusion. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1; a life expectancy of $12 months; and adequate function of the bone marrow (white blood cell count $3000/mL, platelet count $100,000/mL, hemoglobin $9 g/dL), liver (total bilirubin <2.0 mg/dL, aspartate aminotransferase/alanine aminotransferase ratio less than three times the upper limit of normal), and kidneys (serum creatine <2.0 mg/dL). Women of childbearing potential were required to use an effective method of birth control throughout their participation in this study. Excluded from the study were patients with a primary lesion of the parotid gland, patients receiving amifostine or who had received amifostine within 6 months of study entry, patients treated with any investigational drugs within 4 weeks of study entry, patients with a history of poorly controlled cardiovascular disorders (hypertension, angina, arrhythmias), and patients with medical or psychological conditions that would impair their ability to complete the study or provide informed consent.

Treatment regimen All patients had a percutaneous endoscopic gastrostomy (PEG) tube inserted before starting treatment. Dental and nutritional support was provided throughout the treatment period.

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Chemotherapy Paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) 40 mg/ m2 was administered as a weekly i.v. infusion over 1 h for 6 cycles. All patients received pretreatment with ondansetron 24 mg p.o., ranitidine 50 mg i.v. push, diphenhydramine 25 mg p.o., and dexamethasone 10 mg per os (p.o.) before each dose of paclitaxel. Carboplatin (Paraplatin; Bristol-Myers Squibb) 100 mg/m2 was administered weekly as a continuous i.v. infusion over 30 min for a 6-week cycle. Patients unable to tolerate carboplatin received 30 mg/m2 cisplatin weekly as a continuous i.v. infusion. Platinum treatment was administered after paclitaxel. Chemotherapy was withheld if patients developed Grade 3 mucositis and was reinstituted when mucositis was less than Grade 2.

Radiotherapy Radiation therapy consisted of once-daily megavoltage radiation (6 MV), given at 1.8–2.0 Gy per fraction, 5 days per week, for a total dose of 70–72 Gy over 35–39 fractions to areas of gross disease. Computed tomography (CT) scans were used for the assessment of the primary tumor and the involved lymph nodes and also for the treatment planning. Initial treatment fields encompassed the primary tumor plus a 2-cm margin, clinically and radiographically involved nodal disease, and lymphatics thought to be at risk of harboring microscopic disease. The primary tumor and neck were treated with parallel opposed lateral photon fields and an anteroposterior bilateral supraclavicular field with a midline block. Lateral photon fields were reduced to exclude the spinal cord at 39.6–40 Gy and the posterior necks boosted with electrons to a dose of 50–50.4 Gy. After receiving 50–50.4 Gy in the initial opposed lateral photon fields, the primary tumor and clinically and radiographically involved nodes and a 2-cm margin were boosted with an additional 20–22 Gy at 1.8–2.0-Gy daily fractions. The boost treatments were delivered by conformal 6-MV photon fields. The patients entered in our study had extensive primary tumors of the oral cavity or oropharynx, which obliged us to include $75% of the parotid glands in the treatment fields.

Amifostine administration Amifostine (Ethyol; MedImmune Oncology, a subsidiary of MedImmune, Gaithersburg, MD) is available in single-use vials containing 500 mg amifostine as the anhydrous base. Amifostine was reconstituted with 2.5 mL sodium chloride and administered in two 250-mg s.c. injections 30–60 min before each RT session on Days 1 through 5 of each week. Injection sites were rotated daily and recorded on each patient’s case report form. To minimize amifostine-related adverse events (AEs), patients were pretreated with diphenhydramine 25 mg p.o., dexamethasone 4 mg p.o., ondansetron 8 mg p.o., and acetaminophen 1000 mg p.o. 30 min before amifostine. Patients were adequately hydrated before receiving amifostine.

Study evaluations All patients underwent a baseline CT scan. Scans of soft-tissue neck and chest were repeated within 2 months of completion of treatment. Weekly complete blood counts, electrolytes, blood urea nitrogen, and creatinine were monitored during treatment. No blood tests were performed after completion of treatment unless clinically indicated. The incidence, severity, and duration of cutaneous reactions, xerostomia, and mucositis were assessed weekly and graded according to the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria. All other toxicities and AEs were graded according to the National Cancer Institute Common Toxicity

Subcutaneous amifostine with CRT in SCCHN d A. LAW et al.

Criteria version 2.0 (NCI CTC v2). Local and generalized cutaneous reactions were managed according to predefined treatment protocols (Fig. 1). Adverse events were recorded on the clinical report form. Weight loss was graded as the percentage loss from baseline according to NCI CTC v2; Grade 1 weight loss was defined as 5% to <10% weight loss, and Grade 2 was a loss of 10% to <20%. Serious AEs were defined as any AE that resulted in death, was life threatening, required hospitalization or prolonged an existing hospitalization, caused significant disability or incapacity, or any other important medical event considered serious upon medical judgement that required medical or surgical intervention to prevent one of the above outcomes, and were reported within 24 h to MedWatch and the study sponsor.

Study endpoints The primary study endpoints were the incidence of Grade $2 acute and chronic xerostomia and Grade $3 acute oral mucositis. Secondary endpoints included the incidence of RT interruptions and the frequency and severity of cutaneous reactions. Overall survival, disease-free survival, weight loss, PEG dependence, and response rate were also evaluated. Disease-free survival was defined as the interval from the time of diagnosis to first onset of disease recurrence or development of a second primary cancer. Complete response was defined as disappearance of all tumor lesions for at least 1 month. A partial response required a $50% decrease in the diameter of measured lesions for at least 1 month without the simultaneous increase in the size of any lesion or the appearance of new lesions.

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Statistical analysis Overall survival and disease-free survival were analyzed by calculating nonparametric estimates of the survival function using the Kaplan-Meier method. Survival point estimates and their 95% confidence intervals were reported at 6, 12, 18, 24, and 30 months of follow-up. The survival analysis and Kaplan-Meier curves were created using S-PLUS 2000 (Mathsoft, Cambridge, MA).

RESULTS Patients Twenty-two patients were enrolled between November 2002 and February 2004. Two patients withdrew from the study after a single chemotherapy treatment, 1 patient decided against chemotherapy, and 1 patient withdrew from the study after developing Grade 1 asthenia. Both patients tolerated the chemotherapy. Twenty patients completed all planned chemotherapy and radiation treatments and were evaluable for efficacy and safety. Baseline data for this population are presented in Table 1. The primary tumor site was the oropharynx in 17 patients (85%); the primary tumor was in the oral cavity in the remaining 3 patients. Median followup was 23 months (range, 9–36 months). Treatments The mean ( standard deviation) total RT dose was 70  3.6 Gy (Table 2). The mean total doses of carboplatin and paclitaxel were 906.3  273.5 mg and 357.5  103.5 mg, Table 1. Baseline characteristics (N = 20) Age (y) Median Range Sex Men Women Race/ethnicity White/non-Hispanic Other Disease stage at enrollment* T1 N2a N2b T2 N2a N3 T3 N0 N2b N2c T4 N1 N2c Tx N2ay Performance status 0 1

Fig. 1. Management algorithm for cutaneous reactions. (a) Local reactions. (b) Generalized reactions. IV = intravenous; PO = per os.

55 41–72 19 1 20 0 3 1 4 2 3 1 1 1 2 2 13 7

* American Joint Committee on Cancer staging system. y Insufficient tissue for confirmatory diagnosis, suspected base of tongue.

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Table 2. Treatment protocols

Table 3. Amifostine dosing

2

Carboplatin (100 mg/m ) (mg) Mean  SD Median Range Paclitaxel (40 mg/m2) (mg) Mean  SD Median Range Cisplatin (40 mg/m2) (mg)* Mean  SD Median Range Radiotherapy (Gy) Mean total dose  SD Median total dose Range

No. of amifostine doses per patient Mean  SD Median Range Cumulative dose (mg) Mean  SD Median Range Average daily dose (mg) Mean  SD Median Range

906.25  273.5 900 540–1400 357.5  103.5 360 180–560 380  20 380 360–400 70  3.6 70 56–74

31.65  7.5 35 5–35 15,825  3776 17,500 2500–17,500 500  0 500 500

Grade 3 acute oral mucositis was reported in 6 (30%) patients; there were no reports of Grade 4 mucositis (Table 4). Median time to resolution of mucositis was 12.5 weeks (range, 5–17 weeks). The mean and median times to PEG tube independence were 7 and 4.5 months, respectively (range, 0–30 months). At the time of current follow-up, 3 patients (15%) continue to experience dysphagia after cessation of treatment and remain PEG tube dependent at 34, 36, and 36 months; all 3 have oropharyngeal cancer. All patients experienced Grade 2 weight loss based on the need to maintain nutritional support (Table 5); 75% of patients experienced Grade 1 or 2 weight loss determined by the percentage loss. Median weight loss was 12 lb (range, 0–35 lb). Mean weight loss was 14 lb. Grade $3 hematologic toxicities reported were neutropenia (10%) and thrombocytopenia (10%).

* n = 4 patients who did not tolerate carboplatin.

respectively. Four patients did not tolerate carboplatin and received cisplatin to a mean dose of 380  20 mg. Patients received a mean of 31.65  7.5 doses of amifostine, with a mean cumulative dose of 15,825  3776 mg (Table 3). Of the 20 patients, 18 completed planned amifostine treatment. Two patients did not complete the planned amifostine treatment and had RT treatment interruptions: 1 with hepatic encephalopathy and another with myocardial infarction. These events were considered by the investigators to be unrelated to amifostine treatment, and both patients completed 75% of planned amifostine doses. One additional patient who experienced neutropenic fever had 1 dose of RT held, and another patient had 4 doses interrupted because of dehydration.

Amifostine-related adverse events There were no reports of Grade $3 AEs considered by the treating physician to be possibly or probably amifostine related (Table 6). A total of 7 patients (35%) experienced nausea and vomiting; all but one of these events was Grade 1. Six patients experienced Grade 1 or 2 cutaneous reactions that were confined to the injection site area (2–3-cm diameter) and were possibly attributable to amifostine treatment. One patient developed Grade 1 generalized cutaneous rash at Week 7 of his treatment. There were no treatment-related deaths or serious AEs during the study.

Chemoradiotherapy-related toxicities Ten patients (50%) experienced Grade 2 acute xerostomia; there were no reports of Grade $3 xerostomia at any time during the study (Table 4). Grade 2 xerostomia was first documented at 30 Gy in 2 patients, 50 Gy in 4 patients, and 60 Gy in 4 patients. The median cumulative RT dose to onset of xerostomia was 58 Gy. At 12 months, the incidence of Grade 2 xerostomia was 42%; by 18 months the incidence had decreased to 29%.

Table 4. Incidence of xerostomia and mucositis Grade Event Xerostomia End of treatment 12-mo follow-up 18-mo follow-up Mucositis* End of treatment 12-mo follow-up 18-mo follow-up

No. of evaluable patients

1

2

3

4

Total

20 19 17

10 (50) 11 (58) 12 (71)

10 (50) 8 (42) 5 (29)

0 0 0

0 0 0

20 (100) 19 (100) 17 (100)

20 19 16

0 0 0

14 (70) 0 0

6 (30) 0 0

0 0 0

20 (100) 0 0

Values in parentheses are percentages. * Median time to resolution: 12.5 weeks. All cases resolved within 17 weeks.

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Table 5. Chemoradiotherapy-related toxicities Grade Event

1

2

Weight loss (based on need 0 20 (100) of nutritional support) Weight loss (based on 8 (40) 7 (35) percentage loss) Anemia 1 (5) 5 (25) Neutropenia 1 (5) 1 (5) Febrile neutropenia 0 1 (5) Thrombocytopenia 0 0 Hepatic encephalopathy 0 0 (unrelated to treatment) Myocardial infarction 0 0 (unrelated to treatment)

3

4

Total

0

0 20 (100)

0

0 15 (75)

0 2 (10) 2 (10) 2 (10) 1 (5)

0 0 0 0 0

6 (30) 4 (20) 3 (15) 2 (10) 1 (5)

1 (5)

0

1 (5) Fig. 2. Overall survival.

Values in parentheses are percentages.

Antitumor efficacy The overall survival rates at 1 and 2 years were 95% and 71%, respectively (Fig. 2). Disease-free survival rates were 90% and 74% at 1 and 2 years, respectively (Fig. 3). The overall clinical response rate was 100%: 14 patients (70%) exhibited a complete clinical response, and 6 patients (30%) had a partial response. After a median follow-up of 23 months, 13 patients were alive with no evidence of disease. Locoregional tumor control rates were 95% and 88% at 12 and 18 months, respectively. Three patients died of disease progression at 13, 18, and 24 months, 1 with local disease and 2 with distant metastases. Two patients with no evidence of disease died of unrelated causes at 9 and 18 months. At the 12-month follow-up, 1 patient developed distant metastases to lung and bone and another developed local recurrence. Two patients developed distant metastases, 1 each to the lung and bone at 14 and 18 months, respectively. At 16 months, 1 patient developed a second primary malignancy, was successfully treated, and remained disease free from both primaries at 36 months. DISCUSSION Concomitant CRT demonstrates an improvement in the clinical outcome in the treatment of locally advanced SCCHN compared with RT alone in both definitive and postoperative settings (8–11, 19, 20). However, concurrent CRT causes more intense toxicity-related side effects. In Calais’ phase III study comparing definitive RT and concomitant CRT in patients with advanced oropharynx cancer, patients

in the CRT group experienced a prolongation of overall survival and an improvement in locoregional control rate (8). Three cycles of a 4-day regimen with carboplatin (70 mg/ m2/day) and 5-fluorouracil (600 mg/m2/day) by continuous infusion was administered during standard RT. The acute toxicity was significantly increased. In particular, the incidence of Grades 3 and 4 mucositis was nearly twofold higher among CRT recipients (71% vs. 39%) than patients treated with RT alone. In the ORO 93-01 trial, 15% of patients with locoregionally advanced carcinoma of the oropharynx who received CRT or accelerated hyperfractionated RT had almost three times more frequent Grade $3 mucositis in the CRT group (44%) than in the RT group (15%) (11). These differences persisted over time; 67% of patients who received CRT continued to report Grade $2 xerostomia after 24 months, compared with 43% of patients treated with conventional fractionated RT (11, 21). Two phase III studies of postoperative concurrent administration of high-dose cisplatin and RT for high-risk SCCHN, by Cooper et al. (19) and Bernier et al. (20), reported improved locoregional control rate and disease-free survival. The combined treatment was associated with a significant increase in adverse effects. In Cooper’s study, patients treated with CRT had a near twofold increase in the incidence of

Table 6. Amifostine-related adverse events Grade Event

1

2

3

4

Total

Nausea Vomiting Injection-site cutaneous reaction

6 (30) 6 (30) 5 (25)

1 (5) 1 (5) 1 (5)

0 0 0

0 0 0

7 (35) 7 (35) 6 (30)

Values in parentheses are percentages.

Fig. 3. Disease-free survival (DFS).

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acute adverse effects of Grade 3 or greater compared with those treated with RT alone (77% vs. 34%, p < 0.001) (19). Bernier et al. (20) reported a similar twofold increase in incidence of Grade 3 or higher acute functional mucosal adverse effects (41% vs. 21%, p = 0.001) in the group receiving CRT. The types of severe mucosal adverse effects were similar in both CRT and RT groups, as was the incidence of late adverse effects. Therefore, strategies that would reduce the incidence and severity of CRT side effects may enhance treatment efficacy. Intensity-modulated radiotherapy (IMRT) and amifostine have been used independently by various investigators to decrease radiation-induced acute and chronic toxicities in patients with head-and-neck cancer. Intensity-modulated radiotherapy is the most advanced form of RT that delivers a highly conformal dose to the target while sparing normal critical tissues. In Chao’s prospective study of salivary function sparing in patients with head-and-neck cancer receiving IMRT, there was a reduction of late xerostomia at 6 months with IMRT (22). Twenty-seven patients were treated with inverse planning IMRT and 14 patients with forward-planning three-dimensional conformal RT. Attempts were made to spare only superficial lobes of parotid glands to avoid underdosing tumor targets in the parapharyngeal space. Mean parotid dose was lower in patients receiving IMRT vs. three-dimensional conformal RT. There was a correlation between mean parotid dose and the fractional reduction of stimulated saliva output at 6 months after radiation. A 50% or greater preservation of salivary function was achieved by limiting the mean dose to both parotids to <16 Gy: a mean dose <32 Gy afforded $25% preservation of salivary function. Amifostine is an aminothiol prodrug that is rapidly taken up by tissues in which it is dephosphorylated to the free thiol WR-1065 by cellular alkaline phosphatase in the plasma membrane (23–25). Uptake of WR-1065 is up to 100 times greater in healthy cells than in neoplastic tissues because neoplastic cells are deficient in membrane-bound alkaline phosphatase, and the hypoxic-acidic environment of cancer cells impedes uptake and activation of amifostine (26, 27). In normal cells, WR-1065 protects against chemotherapy- and radiation-induced damage by scavenging free radicals, depleting oxygen, donating hydrogen ions to free radicals, and directly binding and inactivating the reactive metabolites of cytotoxic drugs. Pretreatment with i.v. amifostine has been shown to significantly reduce the incidence of Grade $2 acute and chronic xerostomia in patients with head-and-neck cancer receiving RT (14, 15) or CRT (28). In the pivotal phase III trial that supported the indication for radioprotection in head-and-neck cancer, amifostine reduced the incidence of acute Grade $2 xerostomia from 78% to 51% (p < 0.001) and chronic (24 months after treatment) xerostomia from 36% to 20% (p = 0.002) (15). A clinical trial of i.v. amifostine in patients treated with CRT consisted of conventional RT and weekly carboplatin (90 mg/m2) by Antonadau et al. (28) reported a lower incidence of mucositis in the amifostine-treated

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patients, with 77.2% of patients treated with amifostine showing no signs of mucositis by Week 8 of follow-up, compared with only 47% of the patients not treated with amifostine. Intravenous amifostine (300 mg/m2) was administered 15–30 min before RT. Amifostine delayed the onset of acute mucositis and reduced its rate of progression. Amifostine administration significantly reduced the duration of CRT treatment compared with the control group (p = 0.0127). At 3 months of follow-up, only 27% of patients treated with amifostine experience Grade 2 xerostomia, compared with 73.9% in the control group (p = 0.0001). Eighteen months after cessation of therapy, the proportion of patients with Grade 2 xerosomia was 4.5% in the amifostine treatment group. Furthermore, cytoprotection with amifostine did not affect treatment outcome, with 90.9% complete responses in the amifostine-treatment group compared with 78.3% in the control group. Recently, a phase III trial comparing i.v. (200 mg/m2) and s.c. (500 mg) amifostine in patients receiving RT for headand-neck cancer reported similar incidence of acute Grade $2 xerostomia and mucositis in both i.v. and s.c. treatment groups (xerostomia: 39% vs. 40%; mucositis: 80% vs. 80%). The rates of Grade $2 nausea/vomiting were also similar with i.v. and s.c. amifostine (16% vs. 14%), and there were few reports of hypotension (3% and 1%). A higher incidence of cutaneous rash (11% vs. 22%, p = 0.02) and local pain (0 vs. 9%, p = 0.0008) was reported in patients receiving s.c. amifostine (17, 29). Two phase II studies showed that administration of s.c. amifostine before each RT session is well tolerated, effectively reduces early toxicities of RT, and prevents treatment delays (16, 18). Koukourakis et al. (16) conducted a randomized phase II study of the feasibility, tolerance, and cytoprotective efficacy of s.c. amifostine administered during fractionated RT in patients receiving RT for a range of pelvic, thoracic, or head-and-neck cancers. A flat dose of 500 mg, diluted in 2.5 mL of normal saline, was injected s.c. 20 min before each RT fraction. Amifostine was well tolerated by 85% of patients. Amifostine therapy was interrupted in approximately 5% of patients because of cumulative asthenia and in 10% because of a fever/rash reaction. Hypotension was not observed, whereas nausea was frequent. A significant reduction of pharyngeal, esophageal, and rectal mucositis was noted in the amifostine arm (p < 0.04). The delays in RT because of Grade 3 mucositis were significantly longer in the group of patients treated with RT alone (p < 0.04). In the phase II study of s.c. amifostine in head-and-neck cancer, Anne et al. (18) used the same study eligibility criteria as that of the phase III randomized trial reported by Brizel et al. (15). Fifty-four patients received 500 mg amifostine s.c. approximately 60 min before RT. The total dose was 50–70 Gy at 1.8–2.0 Gy per fraction. The 56% incidence of acute Grade 2 xerostomia and 45% incidence of late Grade 2 xerostomia reported in the Anne study are comparable to the 51% and 34% incidence of acute and late Grade 2 xerostomia reported in the phase III randomized study by Brizel et al. (15). Overall 35% of patients in the phase II trial

Subcutaneous amifostine with CRT in SCCHN d A. LAW et al.

discontinued amifostine before completing treatment, but 74% of patients received $75% of the planned amifostine dose. Nausea was a prevalent side effect associated with s.c. amifostine. In the study of s.c. amifostine in patients undergoing postoperative IMRT, Thorstad et al. (30) reported a reduction in the incidence of Grade 2/3 nausea with appropriate antiemetic prophylaxis. Of 6 initial patients, 4 discontinued amifostine because of Grade 2/3 nausea. An antiemetic prophylaxis regimen, consisting of 5–10 mg of oral prochlorperazine administered 1 h before radiation or administration of 8 mg of oral ondansetron when prochlorperazine was effective, reduced the incidence of Grade 2/3 nausea to 19% in the subsequent 21 patients enrolled on the study. Grade 1 nausea was observed in 52% of patients. Therefore, although more data are needed, s.c. amifostine may represent a more convenient way to deliver amifostine with rigorous antiemetic prophylaxis. The study reported herein provides data on a cohort of 20 patients with SCCHN who received amifostine with concomitant RT and CT (paclitaxel and carboplatin). There were no reports of Grade $3 xerostomia at any point during the study or follow-up period. At treatment completion, approximately half of the patients were experiencing Grade 2 xerostomia, with no reports of Grade $3 xerostomia. This rate is similar to those from previous studies with s.c. (18) and i.v. (15) amifostine in patients receiving RT alone, and considerably lower than rates reported in patients receiving RT without amifostine (18). At 18 months, the incidence of Grade 2 xerostomia had decreased to 29%, similar to the incidence of chronic xerostomia seen in trials with i.v. amifostine (15). Although all patients experienced Grade 2 or 3 mucositis during treatment, this resolved within 17 weeks in all cases, such that at the 12-month follow-up no mucositis was reported. This rapid resolution of mucositis is also consistent with an earlier study with i.v. amifostine (28). This protection was provided without evidence of loss of tumor control: disease-free and progression-free survival rates were similar to

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those previously reported in studies of CRT without amifostine (28). In the present study, no hypotensive episodes attributable to amifostine administration were reported. This is consistent with observations from previous studies that hypotension is less frequent in patients receiving s.c. amifostine compared with i.v. amifostine (16, 18). Furthermore, the incidence and severity of nausea and vomiting seemed to be lower than reported in previous studies of i.v. and s.c. amifostine, despite administration of potentially emetogenic chemotherapeutic agents. These findings may reflect the consistent use of rigorous pretreatment antiemetic protocols. The low incidence of hypotension and nausea/vomiting seen in this study may also explain the high compliance with amifostine treatment. Because rare but severe cutaneous reactions have been reported in patients treated with amifostine (31), all patients in this study were administered prophylactic diphenhydramine and were carefully monitored for cutaneous reactions throughout the treatment period. The absence of Grade $3 amifostine-associated cutaneous toxicity and rare incidence of Grade 1 general cutaneous reactions are encouraging. Because this phase II study had a relatively small patient population, it compared results with the i.v. and s.c. control groups from separate studies. The study analyzed locoregional control and survival for only 2 years. A larger clinical study is needed to confirm the efficacy and safety of s.c. dosing of amifostine in minimizing radiation-induced toxicities in patients receiving CRT for SCCHN. Our study demonstrates that the incidence and severity of nausea and vomiting, as well as the severe cutaneous reactions associated with s.c. amifostine, can be lowered with rigorous pretreatment antiemetic protocols and prophylactic administration of diphenhydramine, respectively. The relative ease of s.c. administration, coupled with the favorable safety and tolerability profile of s.c. amifostine, suggests potential advantages in the s.c. administration of amifostine in clinical practice.

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