Int. J. Radiation Oncology Biol. Phys., Vol. 78, No. 5, pp. 1407–1412, 2010Copyright � 2010 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/$–see front matter

jrobp.2009.10.012

doi:10.1016/j.i

CLINICAL INVESTIGATION Esophagus

PHASE II STUDY OF CONCURRENT CHEMORADIATION IN COMBINATION WITHERLOTINIB FOR LOCALLY ADVANCED ESOPHAGEAL CARCINOMA

GANG LI, M.D.,* WEI HU, M.D.,y JIANHUA WANG, M.D.,y XIA DENG, M.D.,* PING ZHANG, M.D.,*

XUEBANG ZHANG, M.D.,* CONGYIN XIE, M.D.,* AND SHIXIU WU, M.D.*

*Department of Radiation Oncology, The first affiliated hospital of Wenzhou Medical College, WenZhou, ZheJiang, People’s Republicof China; and yDepartment of Radiation Oncology, Taizhou Hospital, Wenzhou Medical College, Taizhou, Zhejiang, People’s Republic

of China

ReprinMedical Cince, P.R88069372

Purpose: To investigate the feasibility and efficacy of concurrent chemoradiation in combination with erlotinib forlocally advanced esophageal carcinoma.Methods and Materials: Twenty-four patients with locally advanced esophageal carcinoma were treated with con-current chemoradiotherapy. A daily fraction of 2.0 Gy was prescribed to a total dose of 60 Gy over 6 weeks. Con-current paclitaxel (135 mg/m2, d1) and cisplatin (20 mg/m2, d1-3) were administered on Day 1 and Day 29 of theradiotherapy. Erlotinib, an oral epidermal growth factor receptor–tyrosine kinase inhibitor, was taken by everypatient at the dose of 150 mg daily during the chemoradiotherapy.Results: The median follow-up of the 24 patients was 18.6 months (range, 7.1–29.6 months). The 2-year overallsurvival, local-regional control, and relapse-free survival were 70.1% (95% CI, 50.4–90%), 87.5% (95% CI,73.5–100%), and 57.4% (95% CI, 36.3–78.7%), respectively. During the chemoradiotheapy, the incidences of acutetoxicities of Grade 3 or greater, such as leucopenia and thrombocytopenia, were 16.7 % (4/24) and 8.3% (2/24).Conclusions: Application of concurrent chemoradiotherapy in combination with erlotinib for locally advancedesophageal carcinoma yielded satisfactory 2-year overall survival and local-regional control. The toxicities werewell tolerated. � 2010 Elsevier Inc.

Chemoradiation, Esophageal carcinoma, EGFR inhibition, Radiosensitization.

INTRODUCTION

Esophageal carcinoma is the sixth most common cause of

cancer-related death, and 462,000 new cases were diagnosed

during 2002 (1, 2). However, the optimal treatment approach

for esophageal carcinoma still needs to be elucidated. Surgery

is the cornerstone in treatment for esophageal carcinoma. Data

fromtwocontemporary randomizedstudies indicatedamedian

survival ranged from 13.6 to 16 months and 2-year survival of

34% to 37% (3, 4). In these two trials, nearly half of the patients

could not achieve R0 resection. After resection alone, approx-

imately 58% of patients experienced local-regional recur-

rence. It is unknown whether surgery after neoadjuvant

chemoradiation is of benefit, although improvement in

survival was reported in several series (5, 6).

Concurrent chemoradiation has been widely recognized as

a viable option for locally advanced esophageal carcinoma.

The Radiation Therapy Oncology Group (RTOG) 8501 trial

showed that concurrent chemoradiation is superior to radiation

alone as primary therapy (7). The combination of radiotherapy

t requests to: Shixiu Wu, M.D., First hospital,Wenzhouollege, No.2 Fuxue Lane, WenZhou City, ZheJiang prov-

.China, 325000. Tel: +86-577-88069372; Fax: +86-577-; E-mail: wushixiu@medmail.com.cn

1407

and concurrent chemotherapy with cisplatin and fluorouracil

has led to a long-term survival rate of approximately 25%,

an outcome similar to that associated with surgery alone.

The patterns of failure observed after definitive chemoradia-

tion showed that local-regional control is poor, with approxi-

mately 52% patients in the RTOG 8501 study experiencing

local failure. Local-regional recurrence of cancer after surgery

or radiotherapy alone remains a common problem.

The epidermal growth factor receptor (EGFR) is a member

of the erb-B family of receptors with intrinsic tyrosine kinase

activity. The EGFR is activated on binding of ligand to its

extracellular domain, resulting in autophosphorylation and

activation of downstream molecules, such as Ras, ErK,

PI3K, and Akt. In tumorigenesis EGFR plays an important

role in that it promotes growth of cells and is highly expressed

in a variety of solid tumors, with overexpression observed in

29% to 90% of esophageal cancers, which may be correlated

with poor prognosis and inferior response to therapy (8).

Oral tyrosine kinase inhibitors (TKIs) compete with adenosine

triphosphate for binding to the receptors of tyrosine kinase

Presented in part at the 44th American Society of Clinical Oncol-ogy Annual Meeting, May 30–June 3, 2008, Chicago, IL.

Conflict of interest: none.Received March 26, 2009, and in revised form Sept 10, 2009.

Accepted for publication Oct 7, 2009.

1408 I. J. Radiation Oncology d Biology d Physics Volume 78, Number 5, 2010

domain, inhibit the enzyme’s ability to autophosphorylate, and

block the receptor-dependent signaling cascade (9).

Early preclinical work showed that radiation-induced EGFR

phosphorylation and tumor proliferation could be effectively

blocked by the addition of an EGFR-signaling inhibitor (10).

Further work in cell culture and xenograft models showed the

capacity of EGFR inhibition to enhance radiation response in

several tumor types (11). Bonner et al. demonstrated that radio-

therapy plus cetuximab improved median and overall survival

and significantly enhanced local tumor control in squamous-

cell carcinoma of the head and neck (12). Dobelbower et al.reported safety and tolerability of erlotinib delivered at

150 mg/day with concurrent 5-FU, cisplatin, and thoracic

radiation in a Phase I study of esophageal carcinoma (13).

Currently, preclinical and limited clinical data suggest that

there may be significant potential for epidermal receptor

inhibitors to enhance the effectiveness of radiation. The

EGFR inhibitors are among the most promising molecular

targeting agents in combination with radiotherapy. The

potential advantage of EGFR-TKIs includes ease of adminis-

tration and no issues with infusion reactions. The aim of our

study was to evaluate the feasibility and efficacy of erlotinib

added to concurrent chemoradiation in patients with locally

advanced esophageal squamous cell carcinoma.

METHODS AND MATERIALS

PatientsTwenty-four patients with squamous cell carcinoma of the esoph-

agus between January 1, 2007, and October 31, 2008, were enrolled

in this trial. All patients had pathologically confirmed esophageal

squamous cell carcinoma. The 24 patients were staged according

to the International Union Against Cancer (UICC, 2002)TNM stage

criteria. Patients were clinically staged T1–4 Nx, M0–1a excluding

patients with a tracheoesophageal fistula.

Pre-entry computed tomography (CT) of the thorax and abdomen

with transesophageal ultrasound (EUS) was required for accurate

staging. Patients were to be of $18 years of age with a Karnofsky

Performance Status $60. White blood cell counts had to be

$3,000/mm, platelet counts $100,000/mm, hemoglobin $10 g%,

serum creatinine at or less than the institutional upper limit of

normal, and/or creatinine clearance $50 cc/min.

Bronchoscopy was required for patients with T3 or T4 lesions near

the carina, to exclude tracheoesophageal fistula. Patients must not

have had a second malignancy, other than curable nonmelanoma

skin cancer or cervical cancer in situ, unless they were disease free

for $5 years. No prior chest radiation or chemotherapy was allowed.

Informed consent was signed before enrollment. This study and col-

lateral translational research were approved by the institutional re-

view board at the first hospital of Wenzhou Medical College.

ChemotherapyPaclitaxel 135 mg/m2 was administered intravenously over

3 hours on Day 1 and Day 29 with standard premedications. Cis-

platin 20 mg/m2 was administered as an i.v. infusion on Days 1,

2, and 3 and Days 29, 30, and 31. Chemotherapy was given concur-

rently with radiation for two cycles. The drug dosage was adjusted

according to the acute toxicities occurring in the first cycle. Erlotinib

was administrated at the beginning of chemoradiation with 150 mg/

d from Day 1 to Day 42.

RadiotherapyRadiotherapy started on the first day of the first cycle of chemo-

therapy; 6 MV of X-ray energy was used. Before the start of the

irradiation, a planning CT scan was made from the cricoid to L1

vertebra with a slice thickness of 5 mm, with the patient in treatment

position. The gross tumor volume (GTV) was defined as the primary

tumor and any enlarged regional lymph nodes as defined by transe-

sophageal ultrasound, esophagram, or CT scan (whichever was

larger). The planning target volume (PTV) provided a 2-cm radial

margin and a proximal and distal margin of 5 cm around the

GTV. A barium swallow was obtained at the time of simulation to

confirm the location of the esophagus. If the primary tumor was

above the carina (proximal esophagus), the supraclavicular nodes

were included in the initial field (40 Gy). If the primary was in the

lower third of the esophagus, the celiac nodes were included in

the initial field (40 Gy). Initially 40 Gy (20 fractions at 2 Gy per frac-

tion) was given in the anteroposterior fields over 4 weeks. A 20-Gy

boost was then delivered through parallel opposed lateral or oblique

portals. However, the superior and inferior fields were decreased to

2 cm beyond the tumor. The maximum dose to the spinal cord was

limited to 40 to 45 Gy. A total of 60 Gy of radiation delivered over

30 fractions in 6 weeks. The prescription dose was specified at the

International Commissions of Radiation Units and Measurements

(ICRU) 50/62 reference point. The daily prescription dose was

2 Gy at the ICRU reference point, and the 95% isodose had to

encompass the entire planning target volume (PTV). For the upper

thoracic and cervical esophageal carcinoma, a three-dimensional

conformal radiation technique was adopted in the boost phase.

Follow-UpAll of the patients were monitored weekly during the treatment

for acute treatment toxicity. At completion of treatment, patients

underwent CT, endoscopy, and biopsy to evaluate response to treat-

ment. The follow-up was carried out at 3-monthly intervals in the

first 2 years and at 6-monthly interval after 2 years.

Evaluation of early treatment efficacyPatients were required to have bidimensionally measurable or

assessable disease. Bidimensionally measurable disease was defined

as tumor masses that could be evaluated by radiography, CT, or

physical examination in which two perpendicular dimensions could

be obtained and monitored serially. A complete response required

disappearance of all evidence of tumor, and for patients with the pri-

mary tumor in place, endoscopic confirmation of a complete

response with normal endoscopic biopsy specimens or brushings

was required. A partial response was defined as a greater than

50% reduction in the sum of the products of the longest perpendic-

ular diameters of indicator lesions. A minor response was defined as

a greater than 25% but less than 50% reduction in measurable tumor

area. Assessable disease was defined as radiographically distinct,

unidimensional tumor that could be evaluated serially by radio-

graphic studies (i.e., the primary tumor evaluated by double-contrast

barium esophagram). Response in assessable disease was defined as

a more than 50% improvement in unidimensional disease as

determined by at least 2 observers (14).

Statistical analysisAll of the statistical analyses were performed using SPSS version

10.0 software (SPSS Inc., Chicago, IL). Toxicity was graded using

the National Cancer Institute Common Toxicity Criteria 3.0. Overall

survival was determined as the time (in months) between the first

day of therapy and the date of death.

Table 1. Patient characteristics

Characteristic n %

Age (y)$60 13 54.2<60 11 45.8

PathologySquamous 24 100Adenocarcinoma 0 0

Primary tumorCervical 1 4.2Upper thoracic 8 33.3Middle thoracic 12 50Lower thoracic 3 12.5

TNM classificationStage I–II 7 29.2Stage III–IV 17 70.8

Pretreatment weight lossNormal 15 62.5<10% 7 29.2>10% 2 8.3

Chemoradiotherapy plus Erlotinib for esophageal carcinoma d G. LI et al. 1409

Local-regional control survival was calculated as the time (in

months) from the date of therapy to the date of local-regional recur-

rence as the first site of recurrence (radiologic or pathologic). Overall

survival, local-regional control survival, and relapse-free survival

were calculated using the Kaplan-Meier method (15), and patients

of different stages were compared with the log-rank test. Our previ-

ous study indicated the incidence of persistent disease was 35.7% in

101 patients of esophageal cancer treated by radiotherapy with con-

current chemotherapy containing paclitaxel and cisplatin (16). When

the same chemoradiotherapy regimen was added with erlotinib we

hope the incidence of persistent disease can be decreased to 10%.

The statistical design was intended to allow us to detect a response

percentage of at least 20%, it was calculated that a sample size of

24 patients was needed.The primary end point of this study was lo-

cal-regional control survival and overall survival. The secondary ob-

jectives included response rate, toxicit,y and tolerability.

RESULTS

Patient characteristicsTwenty-four patients were enrolled, with a median age of

61 years (range, 40–72 years) and median Karnofsky Perfor-

mance Status of 90 (range, 80–90). One patient had T2, 17

had T3, and 6 had T4 disease diagnosed by EUS with refer-

ence of CT and MRI scans. Sixteen patients had N0, 8 had

N1, and 8 had M1a. One patient’s lesion was in cervical,

8 in upper, 12 in mid, and 3 in lower locations. Among these

24 patients, 7 had pretreatment weight loss of less than 10%,

and 2 of more than 10% (Table 1).

ToxicitiesIn all, 83% (20/24) of patients completed both cycles of

chemotherapy. In the first cycle of chemotherapy, 4 patients

had Grade 3 or greater leucopenia. The second cycle of che-

motherapy was held in 3 patients for severe depression of

bone marrow function and impairment of liver function.

The other patient required dose reduction by 25% in the

second cycle of chemotherapy for hematological toxicities.

All patients completed radiation on schedule except

1 patient who had a radiation delay for 7 days. Acute esoph-

agitis in Grade 1, Grade 2, and Grade 3 occurred in 9, 10, and

5 patients, respectively. Among the 24 patients, 54.2% (13/

24) had acute tracheitis with 12 in Grade 1 and 1 patient in

Grade 2, and none had acute tracheitis of Grade 3 or more.

During the chemoradiation, 21 patients developed skin rash

on the face and chest, with 1 patient in Grade 3, 8 in Grade

2, and 12 in Grade 1. The other 3 patients had no rash until

the end of chemoradiotherapy (Table 2).

Treatment resultsThe last date of follow-up was August 31, 2009. The median

follow-up of the 24 patients was 18.7 months (range, 7.1–29.6

months). Of the 24 patients, 11 (45.8%) attained a partial re-

sponse, and 11 (45.8%) attained a complete response as con-

firmed by chest CT scan and barium swallow. All patients

underwent upper endoscopy and biopsy. Two patients (8.3%)

had persistent disease after completion of chemoradiotherapy.

Until the date of analysis, 8 patients had distant recurrence,

1 in the bone, 3 in the liver, and 4 in lung. Among them,

1 patient also experienced failure at the site of the original le-

sion. Kaplan-Meier analysis showed that 2-year local-regional

control in the 24 patients was 87.5% (95% CI, 73.5–100%)

(Fig. 1), and the 2-year disease-free survival was 57.4%

(95% CI, 36.2–78.7%). At the time of analysis, 7 patients

had died. One patient, who had persistent disease at the comple-

tion of chemoradiothrepy, died of hemorrhage of esophagus,

and the other 6 patients died of tumor recurrence. The 2-year

survival was calculated as 70.1% (95% CI, 50.4–90 %) (Fig. 2).

DISCUSSION

Radiotherapy or chemoradiotherapy, in combination with

target therapy, had been tried in limited fashion. The intro-

duction of targeted agents against the EGFR pathway has

been shown to improve overall survival in locally advanced

head and neck carcinomas. The results of the first randomized

clinical Phase III trial on simultaneous fractionated irradia-

tion and EGFR inhibition by the monoclonal antibody

(mAb) cetuximab (Erbitux) were promising. The landmark

study demonstrated the application of cetuximab during

primary radiotherapy of patients with head and neck squa-

mous cell carcinoma led to a significant improvement of local

tumor control and survival compared with radiotherapy

alone. The median survival was 28 months for the radiation

alone vs. 54 months for the cohort receiving cetuximab.

Three-year overall survival was also significantly improved

by the addition of cetuximab (44 vs. 57%, respectively).

The treatment was well tolerated with minimal enhancement

in the toxicity profile associated with radiotherapy. However,

it is notable that the addition of cetuximab to radiation ther-

apy had not reduced the risk of distant metastases compared

to radiotherapy alone (12). These data support the incorpora-

tion of chemotherapy into radiotherapy plus target therapy

when applied in locally advanced esophageal carcinoma,

which will facilitate further decrease of distant metastases.

Pfister et al. tested it in a Phase II trial. The results observed

that addition of cetuximab to cisplatin-based

Table 2. Acute toxicities during chemoradiation

Grade 0 1 2 3 4

Leucopenia 0 5 (20.8%) 15 (62.5%) 4 (16.7%) 0Hemoglobin 16 (66.7%) 5 (20.8%) 3 (12.5%) 0 0Platelets 17 (70.8%) 4 (16.7%) 1 (4.2%) 2 (8.3%) 0Vomiting 0 17 (70.8%) 7 (29.2%) 0 0Alopecia 3 (12.5%) 7 (29.2%) 14 (58.3%) 0 0Esophagitis 0 9 (37.5%) 10 (41.2%) 5 (20.8%) 0Tracheitis 11 (45.8%) 12 (50.0%) 1 (4.2%) 0 0Skin rash 3 (12.5%) 12 (50.0%) 8 (33.3%) 1 (4.2%) 0

1410 I. J. Radiation Oncology d Biology d Physics Volume 78, Number 5, 2010

radiochemotherpy in head and neck carcinoma patients

achieved promising overall survival rates of 76% and local

tumor control rates of 71% after 3 years (17). However, it

cannot be taken for granted that addition of EGFR inhibitors

to combined chemoradiotherapy will necessarily further im-

prove treatment outcomes. A Phase I/II trial on neoadjuvant

radiochemotherapy with capecitabine/oxaliplatin combined

with cetuximab in patients with rectal carcinoma showed

complete tumor response rates of only 9% in the pathohisto-

logical specimens, which was less than in historical data on

radiochemotherapy without cetuximab (18).

Our data showed the addition of erlotinib to radiation with

concurrent chemotherapy containing paclitaxel and cisplatin

was effective in locally advanced esophageal carcinoma.

Although most of patients were in Stage III to IV, the

2-year overall survival and 2-year disease-free survival

were 70.1% and 57.4%, respectively. The clinical outcomes

were comparable to latest results of surgical series (3). In con-

trast to the results of the RTOG 8501 study (7), the 2-year

local control in our series was excellent, reaching 87.5%.

Our previous study indicated the incidence of persistent

disease was 35.7% in 101 patients of esophageal carcinoma

treated by radiotherapy with concurrent chemotherapy con-

taining paclitaxel and cisplatin. Although it is sometimes mis-

Fig. 1. Kaplan-Meier plots of local-regional control survival rate of24 patients with esophageal squamous cell carcinoma.

leading in the assessment of the presence of residual

carcinoma, the incidence of persistent disease significantly

decreased from 35.7% to the present 8.3% as evaluated by en-

doscopic biopsy in combination with fluorography (16). The

protocol design, including radiation dose, field arrangements,

and chemotherapy regimen, was as same as in our present trial

except for the addition of erlotinib. The results suggested that

erlotinib in addition to chemoradiation may significantly en-

hance the local control in esophageal carcinoma.

With the addition of synchronous chemotherapy to radio-

therapy, acute treatment-related toxicity is significantly

increased. In the RTOG 8501 trial (7), 29% of patients ran-

domized to the chemoradiation arm experienced Grade 3 or

4 toxicity, primarily with esophagitis, myelosuppression,

and pneumonitis. The profile of acute toxicity during concur-

rent erlotinib and chemoradiotherapy was consistent with

that reported in our previous chemoradiotherapy trials (16).

The most frequent Grade 3 to 4 toxicities in the regimen

were leucopenia, esophagitis, and skin rash. The incidences

of leucopenia and thrombocytopenia of Grade 3 or more

were 16.7% (4/24) and 8.3% (2/24), respectively. The pa-

tients tolerated the treatment well. Erlotinib does not seem

to increase chemoradiotherapy-induced acute toxicities, in-

cluding mucositis and skin reactions. However the effect of

Fig. 2. Kaplan-Meier plots of overall survival rate of 24 patientswith esophageal squamous cell carcinoma.

Chemoradiotherapy plus Erlotinib for esophageal carcinoma d G. LI et al. 1411

erlotinib combined with cisplatin and concurrent radiother-

apy in locally advanced head-and-neck carcinomas was re-

ported in a Phase II study with a high incidence (45%) of

Grade 3 to 4 in-field dermatitis (19). An interim analysis of

the Tarceva Lung Cancer Survival Treatment(TRUST) study

for patients with advanced non–small-cell lung cancer

showed that of 4,965 patients for whom safety data were

available, erlotinib-related rash was observed in 70% of pa-

tients, and 16% of these cases were Grade 3 or 4. Although

erlotinib-related rash was observed in 82% of patients in

a Chinese series, only 10% of these cases were Grade 3 or

4 (20). A retrospective case-control study has compared ge-

fitinib vs. platinum-containing doublet chemotherapy as

a first-line treatment in clinically selected non-small cell

lung cancer(NSCLC) patients (Stage IIIB or IV adenocarci-

noma) in China. The most commonly recorded adverse event

in the gefitinib arm was rash or acne (9.1%), which was lower

than in other gefitinib studies recruiting patients of different

origins: 49.4% in an Iressa Non-Small Cell Lung Cancer

Trial Evaluating Responses & Survival against Taxotere(IN-

TEREST) study, 37.0% in an IRESSA Survival Evaluation

in Lung Cancer (ISEL) study, and even 66.1% in an IRESSA

Pan-ASia Study (IPASS) in Asia (21). Rudin et al. conducted

a prospective study of 80 patients with lung, head and neck,

and ovarian cancer receiving standard dose (150 mg daily) er-

lotinib to assess the pharmacogenomic and pharmacokinetic

determinants of skin rash and diarrhea, the two major adverse

reactions associated with erlotinib. The results demonstrated

that some gene polymorphisms may be involved in the mech-

anism underlying development of skin rashes. The genotype

of these genes may affect the incidence of skin rashes among

patients of different racial/ethnic backgrounds (22).

The EGFR is overexpressed in approximately 80% of

esophageal carcinoma (23). Studies have also shown overex-

pression of EGFR in up to 88% of lymph node metastases

(24). Overexpression of EGFR has been correlated with

poor prognosis in esophageal carcinoma patients (25–29);

however, not all studies have found such a connection (30).

In NSCLC, there is strong evidence supporting the presence

of mutations in the catalytic domain of EGFR with sensitivity

to EGFR-directed therapy. The finding that EGFR kinase do-

main mutations were not detected in esophageal squmaous

cell carcinoma may be a result of the low frequency of

EGFR mutations detected in tumors other than NSCLC. In

this setting we did not consider it necessary to detect expres-

sion or mutation of EGFR in enrollment of patients. Cis-

platin-based concurrent chemoradiotherapy was the

standard regimen as established in the RTOG 8501 trial

(7). Paclitaxel had significant antineoplastic activity in the

treatment of advanced, unresectable esophageal carcinoma

(31). Response rates of up to 100% have been reported for

paclitaxel-based combination chemotherapy regimens (32,

33). Paclitaxel was prescribed in weekly regimen instead of

in full dose in most of studies of concurrent radiochemother-

apy (34, 35). The toxicities were of major concern. However,

the efficacy of weekly vs. full-dose regimen had never been

compared. Chemoradiotherapy with low-dose weekly carbo-

platin and paclitaxel, as widely adopted, may not be optimal

and may be inferior to regimens using systemic doses of che-

motherapy. The results of concurrent chemoradiotherapy con-

taining full doses of paclitaxel in esophageal carcinoma were

encouraging (16). We found that toxicities associated with

therapy were significant but manageable. The rationale for

the choice of a full dose of paclitaxel was based on the follow-

ing: first, it is helpful for maintaining adequate systemic cyto-

toxic effect compared to weekly dosage; and second, daily oral

erlotinib can result in a better radiosensitization effect.

Given promising results in NSCLC, single-agent TKIs

have been studied in several different pretreated carcinoma

types, including esophageal carcinoma. Tew et al. demon-

strated a disease control rate of 54.5% (partial response

(PR), 9%; stable disease(SD), 45.5%) with erlotinib in a 22-

patient cohort with metastatic, pretreated esophageal squa-

mous cell carcinoma or adenocarcinoma. Both patients with

PRs had squamous cell histology and EGFR overexpression

(36). Ferry et al. reported on a Phase II trial of gefitinib in ad-

vanced adenocarcinoma of the esophagus, revealing that gefi-

tinib is an active treatment with a disease control rate (PR or

SD) of 58% (37).There was no correlation found between re-

sponse to gefitinib and the level of EGFR expression (38).

These studies described similar modest response rates with ei-

ther erlotonib or gefitinib in esophageal squamous cell carci-

noma. The TKIs were well tolerated, with the most common

side effects being Grade 1 to 2 (skin rash and diarrhea). De-

spite the relatively poor activity in esophageal carcinoma

treated by TKIs alone, EGFR inhibitors have demonstrated ra-

diosensitizing effects in head and neck carcinomas, suggest-

ing that these may interact with intracellular pathways in

ways that are significant only in the context of concurrent ad-

ministration of radiotherapy.

CONCLUSION

Chemoradiotherapy in combination with erlotinib can be

safely delivered in esophageal carcinoma. It has potential

to enhance local control and to improve 2-year overall sur-

vival in esophageal carcinoma. The toxicities associated

with therapy, although manageable, were significant.

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