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pen Label Multicenter Trial of Subcutaneousmifostine (Ethyol) in the Preventionf Radiation Induced Esophagitis andneumonitis in Patients With Measurable,nresectable Non–Small Cell Lung Cancer

ivek Mehta

While concurrent delivery of chemotherapy and radiotherapy (RT) has a synergistic effecton tumor control and improves the median and overall survival in patients with locallyadvanced non–small cell lung cancer, appreciable acute and late morbidity occur to theesophagus and the lung during treatment (ie, acute radiation esophagitis, pulmonarytoxicity). Emerging evidence suggests that the volume of normal lung exposed to certainthreshold doses of RT might predict for the incidence of pneumonitis. Clinical data alsoindicate that amifostine (Ethyol; Medimmune Inc, Gaithersburg, MD), an organic thiophos-phate, acts as a selective cytoprotective agent for normal tissues against the toxicities ofchemotherapy and RT. Moreover, preclinical and clinical data suggest that subcutaneousadministration of amifostine may be better tolerated with similar efficacy to that of theintravenous route. We are conducting an open-label trial that is accruing patients withlocally advanced non–small cell lung cancer, who will receive concurrent chemoradiother-apy (cisplatin/etoposide or carboplatin/paclitaxel plus RT delivered using 3-dimensionalconformal radiotherapy treatment planning) and amifostine 500 mg before RT. Incidenceand severity of acute radiation esophagitis, acute radiation pneumonitis, chronic radiationpneumonitis, and changes in pulmonary function will be recorded, as will elements of theRT treatment planning (eg, dose volume histogram data for the lung and esophagus). Pre-and post-therapy pulmonary function is a primary endpoint, and others include generalsafety assessments of subcutaneous amifostine administration.Semin Oncol 31(suppl 18):42-46 © 2004 Elsevier Inc. All rights reserved.

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ung cancer is a leading cause worldwide of cancer-relateddeath, with 157,200 projected cases in the United States

lone in 2003.1 More than 80% of newly diagnosed lungancers are non–small cell lung cancer (NSCLC), with theast majority of patients presenting with either metastatic orocally advanced disease. Approximately 40% of NSCLC pa-ients present with locally advanced disease.2 The medianurvival of patients receiving best supportive care is approx-mately 5 months.3 Thoracic radiation alone achieves localesponses, and the median survival improves to 9 to 10onths.4,5 Dilman et al6 and The Cancer and Leukemia

wedish Cancer Institute, Seattle, WA.r Mehta has received research grant support from MedImmune Inc.ddress reprint requests to Vivek Mehta, MD, Swedish Cancer Institute,

o1221-1225 Madison St, First Floor, Seattle, WA 98104.

2 0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved.doi:10.1053/j.seminoncol.2004.12.011

roup B showed that sequential chemotherapy and radio-herapy (RT) improved median survival by 4.1 months overT alone.6 The Radiation Therapy Oncology Group (RTOG)410 trial compared conventional RT with concurrent che-otherapy, induction chemotherapy followed by RT and hy-erfractionated RT.7 In this study, concurrent chemoradio-herapy (chemoRT) showed an improvement in medianurvival. Although a variety of agents have been combinedith RT, the doublets of paclitaxel/carboplatin and cisplatin/

toposide, when administered concurrently with RT, haveeen demonstrated in multiple studies to be well tolerated byatients, result in significant tumor responses, and improvedurvival.8-11

While concurrent delivery of chemotherapy and RT has aynergistic effect on tumor control and improves median and

verall survival in patients with locally advanced NSCLC,

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Amifostine in the prevention of esophagitis 43

his aggressive approach can produce appreciable acute andate morbidity. The toxicity to the esophagus and the lunguring treatment can be particularly debilitating to pa-ients.12,13 Acute radiation esophagitis typically manifests asain with swallowing. Esophagitis tends to start toward theiddle or end of the radiation course, and may last for severaleeks following completion of treatment.14,15 Patients suffer-

ng from the effects of acute radiation esophagitis may be-ome dehydrated or malnourished. Often, patients will re-uire aggressive symptom management with analgesics,

ntravenous (IV) hydration, and parenteral alimentation. Be-ause the mucosal lining is temporarily altered, patients are atisk for developing bacterial or fungal superinfections thatequire treatment.

Severe acute radiation esophagitis may result in treatmentreaks or dose reductions that may limit the success of ther-py.16-18 Werner-Wasik et al19 conducted a multivariate anal-sis of the RTOG database to investigate the time course,redisposing factors, and correlation between the acute radi-tion esophagitis and late radiation pneumonitis in patientsith locally advanced NSCLC receiving concurrent RT and

hemotherapy. A total of 585 patients from four RTOG trialsere analyzed.19 Thoracic RT was either conventionally frac-

ionated (60 Gy) or hyperfractionated (69.6 Gy); chemother-py was cisplatin-based. Grade 2 or higher acute radiationsophagitis developed in 76% of patients, and grade 3 origher acute radiation esophagitis developed in 37%. Radia-ion esophagitis grade peaked in the first month in 38% ofatients, the second month in 49%, and the third month in%. No factors predicted severe radiation esophagitis. Choyt al11 reported a 46% incidence of grade 3 or higher acuteadiation esophagitis in patients receiving weekly paclitaxel0 mg/m2 IV and carboplatin at an area under the curveAUC) of 2 plus concurrent RT (66 Gy) followed by twoycles of consolidation chemotherapy with full-dose pacli-axel 200 mg/m2 IV and carboplatin AUC 6. Additional stud-es using paclitaxel � carboplatin plus concurrent RT reportn incidence of 38% of grade 3 or higher acute radiationsophagitis.20-24

Pulmonary toxicity (ie, radiation pneumonitis) is anotheromplication of combined modality therapy, and may resultn chronic pulmonary dysfunction, such as fibrosis.19,25

cute radiation pneumonitis occurs within 1 to 3 monthsollowing RT, and symptoms can include low-grade fever,ough, and fullness in the chest. There are changes that cane seen on x-ray or computed tomography scan, and typicalhanges include a patchy or hazy infiltrate in the radiationreatment field. Chronic radiation pneumonitis or fibrosisccurs 3 to 12 months following RT, and is considered per-anent. Severe reactions can result in dyspnea, pleuritic

hest pain, hemoptysis, acute respiratory distress, and death.s discussed above in the multivariate analysis of the RTOGatabase, Werner-Wasik et al19 also investigated the timeourse, predisposing factors, and clinical factors that corre-ated with the development of late radiation pneumonitis inatients with locally advanced NSCLC receiving concurrentT and chemotherapy.19 Grade 2 or higher radiation pneu-

onitis developed in 43% of patients (38% by 12 months) h

nd grade 3 or higher radiation pneumonitis in 44% of pa-ients by 6 months, between 6 and 12 months in 14%, andetween 12 and 18 months in 4%. In the same trial discussedbove, Choy et al11 also reported a 22% incidence of grade 3r higher radiation pulmonary toxicity. Additional studies us-

ng paclitaxel with or without carboplatin plus concurrent RTeport an incidence of up to 17% of grade 3 or higher radiationulmonary toxicity (ie, radiation pneumonitis).7,20-24

There is recently emerging evidence suggesting that theolume of normal lung exposed to certain threshold doses ofT can predict for the incidence of pneumonitis. Reviews byeveral centers have suggested that as the volume of normalung receiving over 20 Gy (V20) increases, the chance devel-ping symptomatic radiation pneumonitis goes up in a step-ise manner.26 Other investigators have reported similar ob-

ervations with V30.27

Amifostine (Ethyol; Medimmune Inc, Gaithersburg, MD)s an organic thiophosphate in clinical use as a selective cy-oprotective agent for normal tissues against the toxicities ofhemotherapy and RT. In 1995, the US Food and Drug Ad-inistration (FDA) approved amifostine, given as an IV in-

usion, for the reduction of cumulative renal toxicity associ-ted with the repeated administration of cisplatin in patientsith advanced ovarian cancer. In March 1996, the FDA ex-anded this use to include patients with NSCLC, and in June999, they approved amifostine to reduce the incidence ofoderate to severe xerostomia in patients undergoing post-

perative radiation treatment for head and neck cancerwhere the radiation port includes a substantial portion of thearotid glands). Amifostine is approved in over 60 countriesor similar or extended indications.

The approval and use of amifostine as a radioprotectantepresents a significant advance in the treatment of patientsith head and neck cancer because no other approved ther-

py is available to reduce the incidence and severity of radi-tion-induced acute and late xerostomia. The basis for theerostomia indication was the phase III randomized trial ofrizel et al25 using amifostine in squamous cell carcinoma ofhe head and neck patients treated with conventionally frac-ionated radiation (WR-0038). In this study, 315 patientsere randomized to receive RT with daily fractions of 1.8 to.0 Gy to a total dose of 50 to 70 Gy � amifostine adminis-ered daily at an IV dose of 200 mg/m2, 15 to 30 minutesefore RT. Acute and late radiation toxicity was graded ac-ording to RTOG Acute/Late Radiation Morbidity Scoringriteria, respectively. On an intent-to-treat basis, the inci-ence of grade 2 or greater acute xerostomia was significantlyeduced in those patients treated with amifostine 51% v 78%,�.0001), and the mean cumulative radiation dose received

t onset of grade 2 or greater acute xerostomia increased (6042 Gy, P � .0001). Grade 2 or greater late-effect xerostomiaccurred in 57% of patients in the control arm and 31% ofatients in the amifostine arm (P � .002). However, no dif-erence was apparent in the incidence of grade 3 or greaterucositis between the amifostine (35%) and control (38%)

rms.Five phase III randomized, controlled studies of amifostine

ave been completed to date, and accrued 1,326 patients

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ith various cancers, including head and neck, rectal, ovar-an, and NSCLC. Common adverse events include nausea,omiting, and hypotension, which can usually be treated orrevented by antiemetics and hydration. Other notable ad-erse events included flushing or feeling of warmth, sneezingcaptured under rhinitis), dizziness, somnolence, rigors,ash, and hiccups. In addition, none of these trials have pro-ided definitive evidence suggesting an effect of amifostinen the antitumor efficacy of cytotoxic therapy.Recently, clinical data has emerged to suggest that amifos-

ine has potential radioprotective activity against acute radi-tion esophagitis and radiation pneumonitis (acute andhronic) in NSCLC patients treated with RT with or withoutoncurrent chemotherapy. Antonadou et al28 and the Clinicaladiation Oncology Hellenic Group conducted a multicenter

rial to evaluate whether pretreatment with amifostine couldeduce the incidence of esophagitis, and acute and late lungoxicity associated with RT alone in patients with advancedung cancer. One hundred forty-six patients received RT with2-Gy daily fractions 5 days/week to a total of 55 to 60 Gy �mifostine 340 mg/m2 administered daily, 15 minutes beforeT. Ninety-seven patients were evaluated 2 months post-RT

or the incidence of pneumonitis; 43% (23/53) of patients inhe radiation arm and 9% (4/44) in the amifostine plus radi-tion arm showed changes representative of grade 2 orreater lung damage (P �.001). Pulmonary fibrosis wasresent in 53% (19/36) of patients receiving RT alone versus8% (9/32) receiving radiation plus amifostine. The inci-ence of grade 2 or greater esophagitis during week 4 was2% (31/73) in the radiation alone group compared with 4%3/73) in the group that also received amifostine (P �.001).

Werner-Wasik et al conducted a study (n � 24) in whichatients with locally advanced NSCLC were concurrentlyreated with paclitaxel and thoracic irradiation.20 Patientsere treated with two cycles of induction chemotherapy with

arboplatin at AUC 6 and paclitaxel 225 mg/m2 every 3eeks, followed by concurrent standard thoracic irradiation

up to 62.4 Gy), with weekly paclitaxel 60 mg/m2. After therst 12 patients experienced a high rate of grade 3 or greatersophagitis, amifostine 500 mg IV twice weekly was added tohe regimen. Acute esophagitis was scored on a weekly basis.n esophagitis index was calculated for each patient as anUC showing changing esophagitis severity over the dura-

ion of the thoracic radiation course. The incidence of grade 3r greater esophagitis was 18% in the first 11 patients and 9%n the patients treated with amifostine (P� NS). Althoughmifostine administered twice a week decreased the inci-ence of esophagitis, more frequent dosing might have beenequired.

Komaki et al29 conducted a prospective randomized studyas conducted at the University of Texas M. D. Andersonancer Center (Houston, TX) to determine whether amifos-

ine might reduce the rate of severe esophagitis, hematologicoxicity, and pulmonary toxicity associated with chemoRTor NSCLC. Patients received hyperfractionated RT (1.2 Gy/raction, 2 fractions per day for a total of 69.6 Gy), oraltoposide 50 mg, given twice a day, 30 minutes before RT for

0 days and repeated on day 29, and cisplatin 50 mg/m2 IV 2

n days 1, 8, 29, and 36. Patients in the study group receivedmifostine 500 mg twice a week before chemoRT (n � 27). Aomplete response occurred in seven of 27 patients (26%) inhe amifostine group and two of 26 patients (7%) who didot receive amifostine (P � .07). Morphine intake to reduceevere esophagitis was significantly lower in the amifostineroup (7.4%, 2/27) compared with the control group (31%,/26; P � .03). Acute pneumonitis was also significantly

ower in the amifostine group (3.7%, 1/27) than in the con-rol group (23%, 6/26; P � .037). The median survival timeas 20 months in patients receiving chemoRT plus amifos-

ine and 19 months in controls receiving chemoRT.Gopal et al30 conducted a study of 101 patients with

SCLC treated with radiation therapy and chemotherapy,reradiation and postradiation therapy pulmonary tests wereonducted. Pulmonary function tests were analyzed forhanges in measures of obstruction, restriction, and diffusingapacity. In a subset of 23 patients treated with concurrenthemotherapy and hyperfractionated radiation with or with-ut amifostine, patients receiving amifostine showed aost-RT diffusion capacity decrease of 24% compared with2% in the control group (P � .004).The RTOG recently reported in abstract form a study that

as designed to build on the M. D. Anderson Cancer Centerxperience. In RTOG 9801, all patients were treated withnduction chemotherapy consisting of paclitaxel and carbo-latin, and following induction therapy, they received con-urrent hyperfractionated RT, paclitaxel, and carboplatin.atients were randomly assigned to receive the above regi-en with or without amifostine. However, unlike data fromrevious studies, patients assigned to treatment with amifos-ine did not experience less grade 3 or greater esophagitis.

any potential explanations have been forwarded to explainhe failure of this study to show the effectiveness of amifos-ine in reducing esophagitis. First, patients were treated withwice-a-day RT, and the amifostine was administered onlyefore the afternoon fraction. Second, because these patientsad received neoadjuvant chemotherapy, the pre-existingamage and heightened sensitivity to RT may have been tooreat for the amifostine to overcome.

The FDA initially approved amifostine as a radiation pro-ectant when administered by the IV route; however, thisoute can be particularly challenging for patients receivingmifostine. For example, hypotension and nausea and vom-ting can lead to poor patient compliance. In an effort tomprove patient compliance, studies have been undertakeno explore new ways of administering amifostine that aressociated with fewer acute toxicities. Preclinical and clinicaltudies suggest that subcutaneous (SC) administration ofmifostine may be better tolerated.

Preclinical studies have shown that IV and SC administra-ion of amifostine results in comparable tissue concentrationsf WR-1065 (the active metabolite of amifostine). Cassattt al31 investigated the radioprotective effects and pharmaco-inetics of SC amifostine in animal studies. In single-dosexperiments, Sprague-Dawley rats (5/group) were pretreatedith either IV or SC amifostine (50, 100, or 200 mg/kg) 0.5,

, 4, and 8 hours before receiving a single fraction of gamma

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Amifostine in the prevention of esophagitis 45

rradiation (15.3 Gy) to their head and neck regions. A dose-ependent radioprotective effect was observed in rats pre-reated with IV amifostine up to 4 hours before irradiationnd with SC amifostine up to 8 hours before irradiation.issue studies showed higher levels of WR-1065 in the pa-otid glands, small intestines, and spleen of rats given SCmifostine than of rats given IV amifostine. Only the kidneyhowed higher levels of WR-1065 following IV amifostineersus SC amifostine. In addition, tissue levels of WR-1065n the parotid correlated well with the radioprotective effecteen in the animals. Multiple-dose experiments with IV andC amifostine (50 or 100 mg/kg) showed comparable radio-rotection against mucositis. In tissue studies, no accumula-ion of WR-1065 was seen in any of the tissues following SCr IV amifostine. The pharmacokinetics of WR-1065 follow-ng IV and SC administration of amifostine was also investi-ated in cynomolgus monkeys. The pharmacokinetic profilesf WR-1065 after SC and IV administration in monkeys ap-ear similar to those in humans32 and are comparable to aingle-compartment model (SC administration) or a two-ompartment model (IV administration).

The relative bioavailability of SC amifostine comparedith IV amifostine was 40% at 30 minutes, 67% at 60 min-tes, and 97% at 240 minutes. Preliminary data from mon-ey tissue studies indicated that WR-1065 in lung, kidney,nd parotid gland tissue were slightly higher 30 minutes afterC amifostine than after IV amifostine but were generallyomparable after 60 minutes.

In the rat model of Cassatt et al,31 equal doses of amifostineollowing SC or IV administration were shown to be equallyrotective against radiation-induced oral mucositis, andchieved approximately equal levels of WR-1065 in targetissues. Studies in cynomolgus monkeys showed equal tissueevels of WR-1065 in lung, kidney, and parotid gland tissuesollected 30 and 60 minutes after administration of equaloses of IV and SC amifostine.Recent clinical studies have shown that SC amifostine may

ave equivalent bioavailability, with improved safety profile.randomized phase II study of Koukourakis et al33 that

valuated the feasibility, tolerance, and cytoprotective effectf SC amifostine given during fractionated RT was conductedn 140 patients with locally advanced cancers (60 lung, 40ead and neck, 40 pelvic). Patients with NSCLC received aotal dose of 50 to 60 Gy depending on their previous re-ponse to chemotherapy. Patients were randomized to RTlone, or RT with SC amifostine given 20 minutes before eachT fraction. A significantly reduced severity of symptomatol-gy related to oral, esophageal, and rectal mucosa was seen inhe groups of patients in the SC amifostine arm comparedith the control groups (P �.05). This resulted in signifi-

antly fewer RT delays overall in the amifostine arm (P �.05).dditionally, a subgroup analysis for NSCLC patientshowed a statistically significant benefit with amifostine ineducing mucosal toxicity (P � .02) and treatment delaysP � .02). Moreover, the investigators did not report anyignificant difference in response rates between the two treat-ent groups.

Our investigative group is conducting an open label trial

esigned to build on the clinical experiences to date. Patientsith locally advanced NSCLC will receive concurrent che-oRT and a 500 mg SC/IV daily dose of amifostine beforeT. Patients will be followed to assess the incidence andeverity of acute radiation esophagitis, acute radiation pneu-onitis, chronic radiation pneumonitis, and changes in pul-onary function. The chemotherapy regimens allowed in

his study are widely used regimens (cisplatin/etoposide orarboplatin/paclitaxel). All radiation treatment will be deliv-red using 3-dimensional conformal RT treatment planning.areful elements of the RT treatment planning will be cap-

ured and reviewed including dose volume histogram dataor the lung and esophagus. The study will capture importantbjective measures of pulmonary function (pulmonary func-ion tests, and diffusing capacity of the lung for carbon mon-xide) before, and at regular intervals following completionf therapy. Other endpoints include general safety assess-ents of the SC amifostine. The study is currently enrollingatients.

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