INVITED LECTURE

Esophagus (2003) 1:5–15 © Japan Esophageal Society and Springer-Verlag 2003DOI 10.1007/s10388-003-0007-8

Bruce D. Minsky

The role of radiation therapy in the treatment of esophagus cancer

Received: September 1, 2003

B.D. Minsky (*)Department of Radiation Oncology, Memorial Sloan KetteringCancer Center, 1275 York Avenue, New York, NY 10021, USATel. �1-212-639-6817; Fax �1-212-639-8876e-mail: minskyb@mskcc.org

Abstract Historical series of external beam radiationtherapy alone report 5-year survival rates of 0%–10%. Ingeneral, radiation therapy alone should be reserved for pal-liation or for patients who are medically unable to receivechemotherapy. In the RTOG 85-01 randomized trial, pa-tients with T1–4 primarily squamous cell cancers received 5-FU, cisplatin, and concurrent 50Gy. The control arm wasradiation therapy alone (64Gy). Patients who receivedcombined modality therapy (CMT) had a significant im-provement in both median (14 months vs 9 months), and 5-year survival (27% vs 0%). With a minimum follow-up of 5years, the 8-year survival was 22%. The incidence of localfailure and/or persistence was also lower in the CMT arm(47% vs 65%). INT 0123 was the follow-up trial to RTOG85-01 to test if higher doses of radiation were helpful. Pa-tients were randomized to a slightly modified RTOG 85-01CMT regimen with 50.4Gy versus the same chemotherapywith a higher dose of radiation (64.8Gy). For the 218 eli-gible patients, there was no significant difference in mediansurvival (13.0 vs 18.1 months), 2-year survival (31% vs40%), or local/regional failure and/or local/regional persis-tence of disease (56% vs 52%) between the high-dose andstandard-dose arms. Recent trials have used more novelagents such as paclitaxel, docetaxel, or irinotecan-basedchemotherapy. Brachytherapy alone is as a palliative mo-dality and results in a local control rate of 25%–35% and amedian survival of approximately 5 months. In the RTOG92-07 trial, 75 patients received the RTOG 85-01 CMTregimen followed by a intraluminal boost. Local failurewas 27%, the cumulative incidence of fistula was 18%/year,and the crude incidence was 14%. Therefore, the additionalbenefit of adding intraluminal brachytherapy to radiation orcombined modality therapy, although reasonable, remainsunclear. In the adjuvant setting, one randomized trial

reveals a survival advantage with postoperative CMT. Ameta-analysis from the Oesphageal Cancer CollaborativeGroup also showed no clear evidence of a survival advan-tage with preoperative radiation. There are four random-ized trials comparing preoperative CMT with surgery alonein patients with clinically resectable disease; the results areconflicting. Although this approach is reasonable, it remainsinvestigational.

Key words Esophageal cancer · Combined modalitytherapy · Adjuvant therapy

Introduction

There is considerable controversy as to the ideal therapeu-tic approach for esophageal cancer. The 1992–1994 Patternsof Care study examined 400 patients treated at 61 academicand nonacademic radiation oncology practices to determinepractice patterns in the United States [1]. During thatperiod, treatment approaches included primary chemo-radiation, 54%; radiation alone, 20%; preoperative chemo-radiation, 13%; postoperative combined modality therapy,8%; postoperative radiation, 4%; and preoperative radia-tion, 1%. In a more recent Patterns of Care analysis from1996 to 1999, 414 patients who received radiation therapy aspart of definitive or adjuvant management at 59 institutionswere surveyed [2]. Compared with the 1992–1994 survey,more patients underwent esophageal ultrasound staging(18% vs 2%, P � 0.0001) and received preoperativechemoradiation (27% vs 10%, P � 0.007), preoperativechemoradiation was used more frequently in the subset ofpatients with adenocarcinoma (46% vs 19%, P � 0.0002),and the use of paclitaxel-based chemotherapy increased(22% vs 0.2%, P � 0.001) Brachytherapy was used in 6% ofpatients. In a similar Patterns of Care study of 767 patientstreated in Japan from 1998 to 2001, 220 (28%) receivedeither preoperative and/or postoperative radiation with or

6

without chemotherapy [3]. Various oncology groups havepublished treatment guidelines; however, there is still noconsensus [4–6].

Primary therapy

Primary therapy of esophageal cancer is either surgicalor nonsurgical. Although the overall results of these ap-proaches are similar, the patient population selected fortreatment with each modality is usually different. For sev-eral reasons, this results in a selection bias against nonsurgi-cal therapy. First, patients with poor prognostic features aremore commonly selected for treatment with nonsurgicaltherapy. These features include patients who are not surgi-cal candidates due to medical contraindications or who haveprimary unresectable or metastatic disease. Second, surgicalseries report results based on pathologically staged patientswhereas nonsurgical series report results based on clinicallystaged patients. Third, since some patients treated withoutsurgery may be approached in a palliative rather than acurative fashion, the intensity of chemotherapy and thedoses and techniques of radiation therapy, in many histori-cal series, were suboptimal.

It is difficult to accurately stage esophageal cancer with-out surgery. In addition to the use of computed tomography(CT) and endoscopic ultrasound, the efficacy of 18FDG-positron emission tomography (PET) must be emphasized.Recent studies have examined the effectiveness of PET inthe staging of esophageal cancer. Following standard stag-ing for esophageal cancer (including CT and endoscopy)undetected metastatic disease was detected by PET in 15%of patients in the series by Flamen et al. [7] and 20% in theseries by Downey and associates [8]. Although it is investi-gational, PET is highly encouraged for all patients who areselected for a nonoperative approach.

Nonsurgical therapy

Radiation therapy alone

Many historical series have reported results of externalbeam radiation therapy alone. Most include patients withunfavorable features such as clinical T4 disease. Overall, the5-year survival rate for patients treated with conventionaldoses of radiation therapy alone is 0%–10% [9–11]. Shi andcolleagues reported a 33% 5-year survival rate with the useof late-course accelerated fractionation to a total dose of68.4Gy [12]. However, in the radiation therapy alone armof the Radiation Therapy Oncology Group (RTOG) 85-01trial, in which patients received 64Gy at 2Gy/day with con-ventional techniques, all patients had died of the diseasewithin 3 years [13, 14].

There is limited experience using radiation therapyalone for patients with superficial [15] or clinical T1 disease[16]. The trial by Sykes et al was limited to 101 patients(90% with squamous cell carcinoma) with tumors less than

5cm who received 45–52.5 Gy in 15–16 fractions. The 5-yearsurvival was 20% [17].

In general, radiation therapy alone should be reservedfor palliation or for patients who are medically unable toreceive chemotherapy. As will be discussed later, the resultsof combined modality therapy are more favorable and it isthe standard of care.

Combined modality therapy

There are six randomized trials comparing radiation therapyalone with combined modality therapy [13, 18–24]. Of the sixtrials, five used suboptimal doses of radiation and three usedinadequate doses of systemic chemotherapy. The only trialwhich was designed to deliver adequate doses of systemicchemotherapy with concurrent radiation therapy was theRTOG 85-01 trial reported by Herskovic et al [13, 18, 24].This Intergroup trial primarily included patients with squa-mous cell carcinoma. Patients received four cycles of con-tinuous infusion 5-FU (1000 mg/m2 every 24h for 4 days) andcisplatin (75mg/m2, day 1). Radiation therapy (50Gy at 2Gy/day) was given concurrently with day 1 of chemotherapy.Curiously, cycles 3 and 4 of chemotherapy were deliveredevery 3 weeks (weeks 8 and 11) rather than every 4 weeks(weeks 9 and 13). This intensification may explain, in part,why only 50% of the patients finished all four cycles of thechemotherapy. The control arm was radiation therapy alone,albeit a higher dose (64Gy) than the combined modalitytherapy arm.

Patients who were randomized to receive combinedmodality therapy had a significant improvement in bothmedian (14 months vs 9 months), and 5-year survival (27%vs 0%, P � 0.0001) [21]. With a minimum follow-up of5 years, the 8-year survival was 22% [24]. Histology didnot significantly influence the results with 21% of the 107patients with squamous cell carcinomas alive at 5 yearscompared with 13% of the 23 patients with adenocarci-noma, (P � n.s.). The incidence of local failure as the firstsite of failure (defined as local persistence plus recurrence)was also lower in the combined modality arm (47% vs65%). The protocol was closed early due to the positiveresults. Although African Americans had larger primarytumors, of which all were squamous cell cancers, therewas no difference in survival compared with Caucasians[25].

Based on the positive results from the RTOG 85-01 trial,the conventional non-surgical treatment for esophagealcarcinoma is combined modality therapy. Notwithstanding,the local failure rate in the combined modality therapy armwas 45% and there is room for improvement. Therefore,new approaches such as escalation of the radiation dosewere developed in an attempt to help improve these results.

The standard radiation dose for patients selected forcombined modality therapy is 50.4Gy at 1.8Gy per day(fraction) [26]. Randomized data from France reveal ahigher local control (57% vs 29%) and 2-year survival rate(37% vs 23%) with continuous course compared with splitcourse radiation [27].

7

Intensification of the radiation dose

Two methods have been used to increase the radiation doseto the esophagus: brachytherapy and external beam.

Brachytherapy. Brachytherapy has been used both as pri-mary therapy (usually as a palliative modality) [28–32] aswell as a boost following external beam radiation therapy orcombined modality therapy [28, 33–36]. It can be deliveredby high-dose rate or low-dose rate [37]. Although there aretechnical and radiobiological differences between the twodose rates, there are no clear therapeutic advantages.

Brachytherapy alone is as a palliative modality andresults in a local control rate of 25%–35% and a mediansurvival of approximately 5 months [28–31]. In the random-ized trial from Sur et al, there was no significant differencein local control or survival with high-dose-rate brachy-therapy compared with external beam [29].

A major limitation of brachytherapy is the effectivetreatment distance. The primary isotope is 192Ir, which isusually prescribed to treat at a distance of 1cm from thesource. Therefore, any portion of the tumor which is morethan 1cm from the source will receive a suboptimal radia-tion dose. This limitation has been confirmed by pathologicanalysis of treated specimens [38].

Series which combine brachytherapy with external beamor combined-modality therapy report similar results to con-ventional combined modality therapy. Calais et al reporteda local failure rate of 43% and a 5-year actuarial survival of18% [33]. Even with the more favorable subset of patientswith clinical T1–2 disease Yorozu et al reported a localfailure rate of 44% and a 5-year survival of 26% [39].

In the RTOG 92-07 trial, 75 patients with squamous cellcancers (92%) or adenocarcinomas (8%) of the thoracicesophagus received the RTOG 85-01 combined modalityregimen (5-FU/cisplatin/50Gy) followed by a boost duringcycle 3 of chemotherapy with either low-dose-rate or high-dose-rate intraluminal brachytherapy [40]. The choice ofthe dose rate was at the discretion of the investigator. Dueto low accrual the low-dose-rate option was discontinuedand the analysis was limited to patients who received thehigh-dose-rate treatment. High-dose-rate brachytherapywas delivered in weekly fractions of 5Gy during weeks 8, 9,and 10. Following the development of several fistulas, thefraction delivered at week 10 was discontinued.

Although the complete response rate was 73%, with amedian follow-up of only 11 months, local failure as the firstsite of failure was 27%. Acute toxicity included 58% grade3, 26% grade 4, and 8% grade 5 (treatment-related death).The cumulative incidence of fistula was 18%/year and thecrude incidence was 14%. Of the six treatment related fistu-las, three were fatal. Given the significant toxicity this treat-ment approach should be used with caution. The AmericanBrachytherapy Society has developed guidelines for esoph-ageal brachytherapy [41].

In summary, in the palliative setting, intraluminalbrachytherapy is an effective modality for decreasing symp-toms such as dysphagia and bleeding. In patients treated inthe curative setting, the addition of brachytherapy does not

appear to improve the results compared with radiationtherapy or combined modality therapy alone. Therefore,the additional benefit of adding intraluminal brachytherapyto radiation or combined modality therapy, although rea-sonable, remains unclear.

External beam. A number of investigators have used higherdoses of external beam radiation. For example, Ishikuraet al treated 139 with squamous cell cancers with 5-FU,cisplatin, and 60Gy [42]. Based on the tolerability of higherdoses of external beam radiation (64.8Gy) in the Inter-group 0122 trial, this dose was used in the experimental armof the Intergroup esophageal trial INT 0123 (RTOG 9405)[26]. INT 0123 was the follow-up trial to RTOG 8501. In thistrial, patients with either squamous cell (85%) or adenocar-cinomas (15%) selected for a nonsurgical approach wererandomized to a slightly modified RTOG 85-01 combinedmodality regimen with 50.4Gy versus the same chemo-therapy with 64.8Gy.

The modifications to the original RTOG 85-01 combinedmodality therapy arm included: (1) using 1.8Gy fractions to50.4Gy rather than 2Gy fractions to 50Gy, (2) treating with5-cm proximal and distal margins for 50.4Gy rather thantreating the whole esophagus for the first 30Gy followed bya cone down with 5-cm margins to 50Gy, (3) cycle 3 of5-FU/cisplatin did not begin until 4 weeks following thecompletion of radiation therapy rather than 3 weeks, and(4) cycles 3 and 4 of chemotherapy were delivered every 4weeks rather than every 3 weeks. The trial opened in late1994 and was closed to accrual in 1999 when an interimanalysis revealed that it was unlikely that the high dose armwould achieve a superior survival compared to the standarddose arm.

For the 218 eligible patients, there was no significantdifference in median survival (13.0 months vs 18.1 months),2-year survival (31% vs 40%), or local/regional failure and/or local/regional persistence of disease (56% vs 52%) be-tween the high-dose and standard-dose arms [26]. Although11 treatment-related deaths occurred in the high-dose armcompared with 2 in the standard-dose arm, 7 of the 11occurred in patients who had received 50.4Gy or less.

In addition to increasing the total dose, radiation can beintensified by accelerated or hyperfractionation. Selectedseries using this approach as primary treatment (withoutsurgery) are seen in Table 1 [43–45]. Wang et al randomized101 patients with squamous cell cancer to continuousaccelerated hyperfractionated radiation (66Gy) versus late-course accelerated hyperfractionated radiation (68.4Gy)[45]. Compared with patients who received late-courseaccelerated hyperfractionated radiation, those treatedwith continuous accelerated hyperfractionated radiationhad a significantly higher incidence of grade 3� esophagitis(61% vs 10%, P � 0.001) but showed no benefit in localcontrol or survival. Although these approaches are reason-able, most series report an increase in acute toxicity withoutany clear therapeutic benefit. These regimens remaininvestigational.

In summary, regardless of the technique (brachytherapyor external beam), intensification of the radiation dose

8

beyond 50.4Gy does not improve the results of combinedmodality therapy.

Acute and long-term toxicity of radiation therapy

The toxicity of radiation therapy is a function of the totaldose, technique, and whether the patient has received che-motherapy. During treatment all patients will experienceerythema, lethargy, and esophagitis. These begin 2–3 weeksafter the start of radiation and start to resolve 1 week fol-lowing the completion of therapy.

The most carefully documented acute radiation-relatedtoxicity data are from the control arm of RTOG 85-01where patients received radiation therapy alone to a dose of64Gy [13, 21]. The incidence of acute grade 3 toxicity was25% and grade 4 toxicity was 3%. There were no treatment-related deaths. The incidence of long-term grade 3� toxic-ity was 23% and grade 4� was 2% [24]. In the control armof INT 0123 (which was similar to the combined modalitytherapy arm of RTOG 85-01) the incidence of acute grade 3toxicity was 43% and grade 4 toxicity was 26%. There wereno treatment-related deaths. The incidence of long-termgrade 3� toxicity was 24% and grade 4� was 13% [26]. Aswith surgery, radiation therapy can produce esophagealstrictures. The incidence of benign stricture (in the absenceof local recurrence) is 12% [46].

The high incidence of fistula reported in the RTOG 92-07 trial of combined modality therapy plus intraluminalbrachytherapy (18% actuarial, 14% crude) has not beenseen in series using radiation therapy or combined modalitytherapy without intraluminal brachytherapy.

The incidence of treatment-related death with moderncombined modality therapy was only 2% in RTOG 8501[13] and INT 0123 trials [26]. This compares favorably withthe 6% reported for the surgery alone control arm in INT0113 [47].

Comparison of radiation and surgical therapies

There is one randomized trial addressing the issue of surgi-cal versus non-surgical therapy. However, the randomiza-

tion was limited to patients who responded to initial com-bined modality therapy. The FFCD 9102 trial, reported inabstract form by Bedenne et al., included a total of 445patients with squamous cell cancer who initially receivedtwo cycles of 5-FU, cisplatin, and concurrent radiation(either 46Gy at 2Gy/day or split course 15Gy weeks 1 and3) [48]. The 259 patients who had at least a partial responsewere then randomized to surgery versus additional com-bined modality therapy which included three cycles of 5-FU, cisplatin, and concurrent radiation (either 20 Gy at2Gy/day or split course 15Gy). There was no significantdifference in 2-year survival (34% vs 40%, P � 0.56) ormedian survival (18 months vs 19 months) in patients whounderwent surgery versus additional combined modalitytherapy.

Nonrandomized comparison of surgical versus nonsurgi-cal therapy from the Intergroup trials reveals that the non-surgical approaches (RTOG 85-01 and INT 0123) offer asurvival rate the same if not better than surgery (INT 0113).Although the results are comparable, it is clear that both thenonsurgical and surgical approaches have limited success.Therefore, trials that have combined the two approaches(surgery plus preoperative or postoperative adjuvanttherapy) have been developed.

Adjuvant therapy

Adjuvant radiation therapy without chemotherapy

Preoperative radiation therapy

There are six randomized trials of preoperative radiationtherapy for patients with clinically resectable disease[20, 49–53]. Overall, preoperative radiation therapy didnot increase the resectability rate. The only series toshow a significant improvement in survival was fromNygaard and associates; however, patients also receivedchemotherapy [20]. A recent meta-analysis from theOesphageal Cancer Collaborative Group also showed noclear evidence of a survival advantage with preoperativeradiation [54].

Table 1. High-dose accelerated fractionation/hyperfractionated combined modality therapy: selected series

Series No. of Histology Treatment Local Survival (%) Grade �patients control (%) toxicity (%)

Girinsky [43] 88 – 65 Gy (2 Gy b.i.d.) � 48 3-year 12 3-year 135-FU/CDDPbefore radiation

Jeremic [44] 28 Squamous 54 Gy (1.5 Gy b.i.d.) � 71 29 5-year 505-FU/CDDP four times

Wang [45] 101 Squamous 66 Gy (1.5 Gy b.i.d.) � 56 3-year 38 3-year 61 Esophagitis(randomized) versus

68.4 Gy total: 57 3-year 41 3-year 10 Esophagitis41.4 Gy (1.8 Gy/d) then27 Gy (1.5 Gy b.i.d.)

b.i.d., twice daily; 5-FU, 5 fluorouracil; CDDP, cisplatin

9

Postoperative radiation therapy

Several nonrandomized reports have suggested that post-operative radiation therapy may be effective in followingesophagectomy. Yamamoto and associates reported a 94%2-year local control rate in node positive patients [55]. Inpatients who underwent a three-field dissection, Hosokawaand associates added intraoperative radiation followed by45Gy postoperatively. The 5-year survival was 34% [56]. Inpatients who received the highest dose of intraoperativeradiation (25Gy), 22% developed fatal tracheal ulceration.No treatment-related deaths were seen with doses less than20Gy.

There have been three randomized trials limited to pa-tients treated in the adjuvant setting (Table 2). Teniere andcolleagues [57] reported the results of 221 patients withsquamous cell carcinoma randomized to surgery alone ver-sus postoperative radiation therapy (45 to 55Gy at 1.8Gy/fraction). With a minimum follow-up of 3 years, post-operative radiation therapy had no significant impact onsurvival. In the series by Fok et al [58] patients with bothsquamous cell and adenocarcinomas receiving eithercurative or palliative resections were evaluated; althoughthe total dose of radiation therapy was conventional, thedose per fraction (3.5Gy/fraction) was unconventional.No significant decrease in local failure, distant failure, orimprovement in the median survival was achieved with theaddition of postoperative radiation therapy.

The third trial is the Intergroup trial INT 0116 [59].Although the goal of this trial was to examine the role ofpostoperative adjuvant chemoradiation in gastric cancer,20% of patients had adenocarcinoma of the gastro-esophageal junction. Eligibility included patients withstages IB, II, IIIA, IIIB, and IV nonmetastatic adenocarci-noma of the stomach or gastroesophageal junction. Follow-ing an en bloc resection with negative margins, patientswere randomized to either observation alone or postopera-tive chemoradiation consisting of four monthly cycles ofbolus 5-FU/ leucovorin with 45Gy concurrent with cycle 2.A total of 603 patients were registered. Pretreatment char-acteristics were similar in both arms and most patients had

locally advanced disease. Approximately two-thirds had T3or T4 tumors and approximately 85% had positive local/regional nodes.

Patients randomized to receive postoperative combinedmodality therapy had a significant decrease in local failureas the first site of failure (19% vs 29%) and an increase inmedian survival (36 months vs 27 months), 3-year relapsefree survival (48% vs 31%), and overall survival (50% vs41%, P � 0.005). The most common acute toxicities werehematological and gastrointestinal, and the incidence ofgrade 4 toxicity was higher with combined modality therapy(41% vs 32%). Although 17% could not complete alltherapy as planned there was only one treatment-relateddeath.

Individual grade 3� toxicities included 54% hematologi-cal, 33% gastrointestinal, 6% infection, and 4% neurologi-cal. In order to minimize radiation related toxicity, carefulpretreatment review of the simulation films was performed.This frequently resulted in the recommendation to thetreating radiation oncologist to modify the design and/orvolume of the radiation fields. Based on the positive resultsof the Intergroup 0116 trial, the standard of care for patientswith T3 and/or node positive gastric cancer following acomplete resection with negative margins is postoperativechemoradiation. Since 20% had adenocarcinoma of the gas-troesophageal junction, those patients should also receivethis treatment if they have not received preoperativetherapy.

In summary, the role of postoperative chemoradiation iscontroversial. Because the INT 0116 trial reveals a survivaladvantage with postoperative chemoradiation and patientswith adenocarcinoma of the gastroesophageal junctionwere entered on that trial, it is reasonable to offer postop-erative chemoradiation to patients with stages T3 and/orN1–2 disease.

The other role for postoperative radiation therapy isfor patients with positive margins. Based on the positivesurvival results from chemoradiation trials such as RTOG85-01, patients selected for treated with postoperativeradiation should receive systemic chemotherapy withradiation [13, 14].

Table 2. Postoperative radiation therapy for esophageal cancer: randomized trials

Series No. of Median Survival (%) Local failure (%) Distantpatients survival (months)

LN� LN� OverallFailure (%)

Teniere [57]Radiation 119 – 19 30 10** – –Surgery 102 – 19 38 35 – –

Fok [58]Radiation 30 15 – – – 10 40Surgery 30 21 – – – 13 30

MacDonald [59]Chemoradiation 281 36 50 3-year** – – 19** –Surgery 275 27 41 3-year – – 29 –

The MacDonald trial (INT 0116) primarily included patients with stages IB–IIIB gastric cancer. However, 20% of patients enrolled on the trialhad adenocarcinoma of the gastroesophageal junctionLN�, lymph node positive; LN�, lymph node negative** statistically significant

10

Preoperative combined modality therapy

Nonrandomized trials

In general, the nonrandomized series of preoperativecombined modality therapy have used two treatment ap-proaches. Patients either undergo a planned operation or,for a variety of reasons, are selected for an operation. Mostof the trials use 5-FU/cisplatin-based chemotherapy. Re-cent trials have used more novel agents such as paclitaxel[60–63], docetaxel [64], or irinotecan-based [65] chemo-therapy. Radiation is delivered either once or twice (b.i.d.)daily. In addition to the different treatment schedules, thereis also variability of surgical techniques among the trials.The investigators from the University of Michigan usetranshiatal esophagectomy whereas most others advocatethe Ivor-Lewis approach. The transhiatal esophagectomy isa more conservative approach compared with the morecommonly used Ivor-Lewis procedure since the thorax isnot entered. There is much debate in the surgical literatureas to the relative benefits and risks of these two approaches.

Most of the trials report pathological complete responserates of approximately 25%. Some report higher rates aswell as 3-year survival rates superior to surgery. The 1992–1994 United States Patterns of Care survey study reported asignificant improvement in survival in patients selected toreceived preoperative combined modality therapy com-pared with combined modality therapy alone [66]. Despitethese encouraging results, this approach needs to be con-firmed in randomized trials.

Randomized trials

There are four randomized trials comparing preoperativecombined modality therapy with surgery alone in patientswith clinically resectable disease (Table 3) [67–70]. The se-ries from Le Prise et al is not included because patientsreceived sequential rather than concurrent chemotherapyplus radiation [71].

Urba and associates from the University of Michiganrandomized 100 patients (75% with adenocarcinoma) topreoperative cisplatin, vinblastine, 5-FU, and concurrentradiation therapy (1.5Gy b.i.d. to 45Gy) followed on day 42

by a transhiatal esophagectomy versus surgery alone. In themost recent update there was a significant decrease in localrecurrence (19% vs 42%), however, the survival advantageat 3 years (30% vs 15%) did not reach statistical significance[69].

In the series from Walsh et al, 113 patients with adeno-carcinoma of the mid or distal esophagus (including thecardia) were randomized to two cycles 5-FU/cisplatin plusconcurrent preoperative radiation therapy (2.67 Gy/day to40Gy) versus surgery alone [67]. There was a significantimprovement in both median survival (16 months vs 11months, P � 0.01) and 3-year survival (32% vs 6%, P �0.01). The major criticism of this trial is the high operativemortality rate of 9% and the low 3-year survival (6%) in thesurgical control arm.

Bosset et al. reported the results of an EORTC trial of atotal of 282 patients with clinically resectable squamous cellcarcinomas who were randomized to preoperative com-bined modality therapy versus surgery alone [68]. The un-conventional preoperative regimen included 3.7Gy for 5days followed by a 2-week rest (split course) and another3.7 Gy/day for 5 days. Chemotherapy was limited to low-dose cisplatin 0–2 days prior to (not concurrent with) radia-tion therapy. Patients who received preoperative combinedmodality therapy had a significantly greater 3-year disease-free survival (40% vs 28%) and local disease-free survivalrates (relative risk 0.6) but had no improvement in mediansurvival (19 months) or overall 3-year survival (36%) com-pared with surgery alone.

The last trial has been reported in abstract form. TheAustralasian GI Trials Group randomized 256 patients(61% with adenocarcinoma) to preoperative cisplatin day 1,followed by 5-FU days 2–5 with concurrent 35Gy (at2.33Gy/day) versus surgery alone. Comparing preoperativecombined modality therapy versus surgery alone, themedian overall survival was 22 months versus 19 months(P � 0.38). For patients with squamous cell cancer therewas a significant increase in relapse-free survival but thatdid not translate into a survival advantage. There was noadvantage for adenocarcinomas.

Given the substantial limitations and criticisms of therandomized trials, the Intergroup developed a randomizedtrial of preoperative combined modality therapy (CALGB

Table 3. Randomized trials of preoperative combined modality therapy for esophageal cancer

Series No. of Histology Treatment CR (%) Survival Localpatents

Median (months) 3-year (%)failure (%)

Urba [69] 100 75% Ad Preop CMT 28 17 30* 19**25% Sq Surgery 0 17 15 42

Walsh [67] 113 100% Ad Preop CMT 25 16** 32** –Surgery 0 11 6 –

Bosset [68] 282 100% Sq Preop CMT 26 19 36 –Surgery 0 19 36 –

Burmeister [70] 256 61% Ad Preop CMT 15 22 – –Surgery 0 19 – –

Preop CMT, Preoperative combined modality therapy; Sq, squamous cell carcinoma; Ad, adenocarcinoma; CR, complete esponse* P � n.s.; ** P � 0.05

11

C9781). Unfortunately it was closed prematurely due tolack of accrual. Therefore, it is unlikely that the question ofthe efficacy of preoperative combined modality therapy willever be clearly answered.

Neoadjuvant chemotherapy followed by chemoradiation

Recent trials using taxol/cisplatin- [63, 72] or CPT-11/cisplatin-based [73] neoadjuvant chemotherapy prior to thestart of chemoradiation have reported favorable results.Bains and associates reported that of 38 patients whopresented with dysphagia, 92% had relief following thecompletion of two cycles (weeks 1 and 4) of neoadjuvantpaclitaxel (175mg/m2, 3-h infusion) and cisplatin (75mg/m2

bolus) [72]. Similar results have been reported by Ilson et alin 19 patients who received two cycles neoadjuvant CPT-11(65mg/m2) plus cisplatin (30mg/m2) weeks 1, 2, 4, 5 prior tothe start of chemoradiation [73]. Treatment was well toler-ated with no grade 3� nonhematological toxicity and only5% of patients required a feeding tube. Of the 16 patientswho presented with dysphagia, 81% had dysphagia relieffollowing the completion of neoadjuvant chemotherapy.

Another potential advantage of neoadjuvant chemo-therapy is the early identification of those patients who mayor may not respond to the chemotherapeutic regimen beingdelivered. Ott et al found that the response to a FDG-PETscan 2 weeks after the start of cisplatin/5-FU/leucovorinneoadjuvant chemotherapy followed by surgery in 35 pa-tients with adenocarcinoma of the gastroesophageal (GE)junction or stomach was able to predict patients who re-sponded, based on the surgical specimens, to the full courseof chemotherapy [74]. Although investigational, if thenonresponders can be identified early, changing the chemo-therapeutic regimen may be helpful.

In summary, although the early trials primarily using 5-FU/cisplatin-based neoadjuvant regimens did not suggest abenefit, more recent trials using taxol and CPT-11-basedregimens reveal more favorable response rates and im-provement of dysphagia.

Is surgery necessary after chemoradiation?

Two trials examine whether surgery is necessary afterchemoradiation. The French FFCD 9102 trial addresses theissue of whether patients who respond midway throughchemoradiation should continue with the treatment orundergo surgery [48, 75]. The German OesophagealCancer Study Group addresses the question of whetherchemoradiation followed by surgery is equivalent to non-operative chemoradiation [76].

In the FFCD 9102 trial, all 445 patients with clinicallyresectable T3–4N0–1M0 squamous cell or adenocarcinomaof the esophagus received chemoradiation, however, therandomization was limited to patients who responded toinitial chemoradiation. Patients initially received two cyclesof 5-FU, cisplatin, and concurrent radiation (either 46Gy at2Gy/day or split course 15Gy weeks 1 and 3) [48]. The 259

patients who had at least a partial response were then ran-domized to surgery versus additional chemoradiation whichincluded three cycles of 5-FU, cisplatin, and concurrentradiation (either 20Gy at 2Gy/day or split course 15Gy).There was no significant difference in 2-year survival (34%vs 40%, P � 0.56) or median survival (18 months vs 19months) in patients who underwent surgery versus addi-tional chemoradiation. The data suggest that for patientswho initially respond to nonoperative chemoradiation,patients should complete chemoradiation rather than stopand undergo surgery. Using the Spitzer index, there wasno difference in global quality of life, (QOL) however,a significantly greater decrease in QOL was observed inthe postoperative period in the surgery arm (7.52 vs 8.45,P � 0.01, respectively) [75].

The German Oesophageal Cancer Study Group com-pared preoperative chemoradiation followed by surgeryversus chemoradiation alone [76]. In this trial, 177 patientswith uT3–4N0–1M0 squamous cell cancers of the esophaguswere randomized to preoperative therapy (three cycles of5-FU, leucovorin, etoposide, and cisplatin, followed by con-current etoposide, cisplatin, plus 40Gy) followed by surgeryversus chemoradiation alone (the same chemotherapy butthe radiation dose was increased to 60Gy). Despite animprovement in local control for those who were rando-mized to preoperative therapy followed by surgeryversus chemoradiation alone (81% vs 64%) there was nosignificant difference in 3-year survival (28% vs 20%). Al-though the difference in the radiation dose between the twoarms makes the interpretation of the data difficult, theredoes not appear to be a benefit to surgery followingnonoperative chemoradiation.

Tumor markers and predictors ofresponse to chemoradiation

It would be helpful to be able to predict tumors whichhave a higher likelihood of responding to radiation orchemoradiation. In 38 patients with squamous cell carci-noma who received chemoradiation with or without sur-gery, tumors without p53 expression and tumors with weakBcl-XL expression showed a higher response to chemo-therapy (56% and 53%, respectively) than tumors positivefor p53 or with strong Bcl-XL expression (30% and 32%,respectively, P � n.s.) [77]. Following preoperativechemoradiation, p53-negative tumors had a significantlybetter mean survival compared with p53-positive tumors(31 months vs 11 months, P � 0.0378). There was no prog-nostic impact with the expression of apoptosis-regulatinggenes. By multivariate analysis, Pomp et al. found that overexpression of p53 resulted in a decrease in survival in 69patients with squamous or adenocarcinomas treated withradiation alone [78]. In one study, there was a correlationbetween decreasing levels of four phospholipids and in-creasing T stage and grade [79].

Kishi and associates reported that in 77 patients treatedwith chemoradiation for squamous cell cancer, p53-

12

and metallothionen-positive tumors had a poor responseto treatment, whereas those with strong expression ofCDC25B were associated with a good response [80]. In 73patients with T2–4M0 esophageal cancer treated with 60Gyplus 5-FU and cisplatin, Hironaka examined pretreatmentbiopsies for a variety of markers including p53, Ki-67,EGFR, cyclin D1, VEGF, microvessel density (MVD),thymidylate synthase, dihydropyrimidine dehydrogenase,and glutathione s-transferase [81]. By multivariate analysisMVD, T stage, and performance status were independentprognostic variables (P � 0.002, 0.02, and 0.02, respec-tively). Patients with high MVD tumors had improved 3-year survival compared with those with low MVD tumors(61% vs 33%, P � 0.02). Morita et al. found that the pres-ence of lymphocyte infiltration around the tumor was asso-ciated with 5-year survival of 46%–76% compared with28% (P � 0.05) in patients whose tumors did not havelymphocytic infiltration [82]. With the further discovery andunderstanding of various tumor suppressor genes, thesedata may be used to help select patients for chemoradiation.

Novel chemotheraputic agents

Since 75%–80% of patients die of metastatic disease,advances in systemic therapies are necessary for furtherimprovement of results. The most widely used chemother-apeutic regimen combined with radiation for the treatmentof esophageal cancer is 5-FU and cisplatin. There are newchemotherapeutic agents in both current practice and de-velopment for esophageal cancer. Most are being devel-oped as preoperative regimens and are combined withradiation doses of 45–50.4 Gy. These include both cytotoxicand targeted small molecules. Paclitaxel [63,72,83] anddocetaxel [64] based chemoradiation regimens have shownencouraging results. The RTOG randomized phase II trialE-0113 compares paclitaxel plus cisplatin, with or without5-FU. The ECF (epirubicin, cisplatin, and 5-FU) regimenhas been combined with postoperative radiation [84] andwill serve as the experimental arm of the Intergroup post-operative adjuvant trial for gastric and GE junctioncancers (CALGB 80101). Other agents such as irinotecan[73,85,86], herceptin [87], oxaliplatin [88], and celecoxib[89] are being used as platforms for new regimens. Whetherthese investigational approaches offer improved resultscompared to conventional 5-FU/cisplatin-based chemo-radiation regimens is not known. The development of theideal regimens and schedules remains an active area ofclinical investigation.

Radiation treatment techniques and regimens

Similar to the expert surgical skills required for a successfulesophagectomy, radiation field design for esophageal can-cer requires careful techniques [90]. There are a number ofsensitive organs which, depending on the location of the

primary tumor, will be in the radiation field. These includebut are not limited to skin, spinal cord, lung, heart, intestine,stomach, kidney, and liver. Minimizing the dose to thesestructures while delivering an adequate dose to the primarytumor and local/regional lymph nodes requires patient im-mobilization and CT-based treatment planning for organidentification, lung correction, and development of dose–volume histograms.

Although CT can identify adjacent organs and struc-tures, it may be limited in defining the extent of the primarytumor. To assess the consistency of target volume delinea-tion, Tai and colleagues sent sample cases with CT scansto 48 radiation oncologists throughout Canada and askedthem to fill out questionnaires regarding treatment tech-niques as well as outline the boost target volumes [91].There was substantial inconsistency in defining the planningtarget volume, both in the transverse and longitudinal di-mensions. Therefore, in addition to a CT scan, it is helpfulto obtain a barium swallow at the time of radiation therapysimulation. The integration of other imaging modalities inradiation treatment planning, such as esophageal ultra-sound, PET scan, and magnetic resonance imaging (MRI)are under active investigation.

In a separate study, Tai et al reported the results of 12Canadian radiation oncologists’ cervical esophagus targetvolumes based on the RTOG 94–05 protocol design bothbefore and after a one-on-one training session [92]. A pre-and post-training session survey revealed less variability inthe longitudinal positions of the target volumes, therebyillustrating the importance of specialized training.

Nutting and colleagues compared two–phase conformalradiotherapy with intensity modulated radiation (IMRT) infive patients who received 55Gy plus concurrent chemo-therapy [83]. Treatment plans using both techniques wereperformed and compared using dose-volume histogramsand normal tissue complication probabilities. The IMRTfield using nine equispaced fields provided no improvementover conformal radiation since the larger number of fields inthe IMRT plan distributed a low dose over the entire lung.In contrast, IMRT using four fields equal to the conformalfields offered an improvement in lung sparing.

References

1. Coia LR, Minsky BD, John MJ, Haller DG, Landry J, PisanskyTM, et al. The evaluation and treatment of patients receiving radia-tion therapy for carcinoma of the esophagus. Results of the 1992–1994 patterns of care study. Cancer 1999;85:2499–505.

2. Suntharalingam M, Moughhan J, Coia LR, Krasna MJ, Kachnic L,Haller DG, et al. The national practice for patients receiving radia-tion therapy for carcinoma of the esophagus: results of the 1996–1999 Patterns of Care Study. Int J Radiat Oncol Biol Phys2003;56:981–7.

3. Gomi K, Oguchi M, Hirokawa Y, Kenjo M, Ogata T, Takahashi Y,et al. Process and preliminary outcome of a patterns of care studyof esophageal cancer in Japan: patients treated with surgery andradiotherapy. Int J Radiat Oncol Biol Phys 2003;56:813–22.

4. Coia LR, Minsky BD, John MJ, Haller D, Landry J, Pisansky TM,et al. Patterns of care study decision tree and management guide-lines for esophageal cancer. Radiat Med 1998;16:321–7.

13

5. Wong RKS, Malthaner RA, Zuraw L, Rumble RB. Combinedmodality radiotherapy and chemotherapy in nonsurgical manage-ment of localized carcinoma of the esophagus: a practice guideline.Int J Radiat Oncol Biol Phys 2003;55:930–42.

6. National Comprehensive Cancer Network Panel Members. Esoph-ageal Cancer – Clinical practice guidelines in oncology. J NatlComp Cancer Network 2003;1:14–27.

7. Flamen P, van Cutsem E, Lerut T, Cambier JP, Hustermans K,Bormans G, et al. Positron emission tomography for assessment ofthe response to induction radiochemotherapy in locally advancedoesphageal cancer. Ann Oncol 2002;13:361–8.

8. Downey RJ, Akhurst T, Ilson D, Ginsberg R, Bains MS, Gonen M,et al. Whole body 18FDG-PET and the response of esophagealcancer to induction therapy: results of a prospective trial. J ClinOncol 2003;21:428–32.

9. De-Ren S. Ten-year follow-up of esophageal cancer treated byradical radiation therapy: analysis of 869 patients. Int J RadiatOncol Biol Phys 1989;16:329–34.

10. Newaishy GA, Read GA, Duncan W, Kerr GR. Results of radicalradiotherapy of squamous cell carcinoma of the esophagus. ClinRadiol 1982;33:347–52.

11. Okawa T, Kita M, Tanaka M, Ikeda M. Results of radiotherapy forinoperable locally advanced esophageal cancer. Int J Radiat OncolBiol Phys 1989;17:49–54.

12. Shi X, Yao W, Liu T. Late course accelerated fractionation inradiotherapy of esophageal carcinoma. Radiother Oncol 1999;51:21–6.

13. Herskovic A, Martz LK, Al-Sarraf M, Leichman L, Brindle J,Vaitkevicius V, et al. Combined chemotherapy and radiotherapycompared with radiotherapy alone in patients with cancer of theesophagus. New Engl J Med 1992;326:1593–8.

14. Al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle J,Vaitkevivius J, et al. Superiority of chemo-radiotherapy (CT-RT)vs radiotherapy (RT) in patients with esophageal cancer. Finalreport of an Intergroup randomized and confirmed study [ab-stract]. Proc ASCO 1996;15:206.

15. Seki K, Karasawa K, Kohno M, Hanyuu N, Isobe M, Mitsuhashi N.The treatment result of definitive radiotherapy for superficialesophageal cancer [abstract]. Int J Radiat Oncol Biol Phys 2001;51:264.

16. Nemoto K, Yamada S, Hareyama M, Nagakura H, Hirokawa Y.Radiation therapy for superficial esophageal cancer: a comparisonof radiotherapy methods. Int J Radiat Oncol Biol Phys 2001;50:639–44.

17. Sykes AJ, Burt PA, Slevin NJ, Stout R, Marrs JE. Radical radio-therapy for carcinoma of the oesophagus: an effective alternativeto surgery. Radiother Oncol 1998;48:15–21.

18. Araujo CMM, Souhami L, Gil RA, Carvalho R, Garcia JA,Froimtchuk MJ, et al. A randomized trial comparing radiationtherapy versus concomitant radiation therapy and chemotherapyin carcinoma of the thoracic esophagus. Cancer 1991;67:2258–61.

19. Roussel A, Jacob JH, Jung GM. Controlled Clinical Trial for theTreatment of Patients with Inoperable Esophageal Carcinoma: AStudy of the EORTC Gastrointestinal Tract Cancer CooperativeGroup. In: Schlag P, Hohenberger P, Metzger U, editors. Recentresults in cancer research. Berlin: Springer; 1988. p. 21–30.

20. Nygaard K, Hagen S, Hansen HS, Hatlevoll R, Hultborn R,Jakobsen A, et al. Pre-operative radiotherapy prolongs survival inoperable esophageal carcinoma: A randomized, multicenter studyof pre-operative radiotherapy and chemotherapy. The secondScandinavian trial in esophageal cancer. World J Surg 1992;16:1104–10.

21. Al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS,Vaitkevicius VK, et al. Progress report of combined chemo-radiotherapy versus radiotherapy alone in patients with esoph-ageal cancer: An intergroup study. J Clin Oncol 1997;15:277–84.

22. Slabber CF, Nel JS, Schoeman L, Burger W, Falkson G, FalksonCI. A randomized study of radiotherapy alone versus radiotherapyplus 5-fluorouracil and platinum in patients with inoperable, locallyadvanced squamous cell cancer of the esophagus. Am J Clin Oncol(CCT) 1998;21:462–5.

23. Smith TJ, Ryan LM, Douglass HO, Haller DG, Dayal Y,Kirkwood J, et al. Combined chemoradiotherapy vs. radiotherapyalone for early stage squamous cell carcinoma of the esophagus: a

study of the Eastern Cooperative Oncology Group. Int J RadiatOncol Biol Phys 1998;42:269–76.

24. Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA,Al-Sarraf M, et al. Chemoradiotherapy of locally advanced esoph-ageal cancer. Long-term follow-up of a prospective randomizedtrial (RTOG 85-01). JAMA 1999;281:1623–7.

25. Streeter OE, Martz KL, Gaspar LE, Delrowe JD, Asbell SO,Salter MM, et al. Does race influence survival for esophagealcancer patients treated on the radiation and chemotherapyarm of RTOG 85-01? Int J Radiat Oncol Biol Phys 1999;44:1047–52.

26. Minsky BD, Pajak T, Ginsberg RJ, Pisansky TM, Martenson JA,Komaki R, et al. INT 0123 (RTOG 94-05) phase III trial of com-bined modality therapy for esophageal cancer: high dose (64.8 Gy)vs. standard dose (50.4 Gy) radiation therapy. J Clin Oncol2002;20:1167–74.

27. Jacob JH, Seitz JF, Langlois C, Raoul JL, Bardet E, Bouche O, etal. Definitive concurrent chemo-radiation therapy (CRT) in squa-mous cell carcinoma of the esophagus (SCCE): preliminary resultsof a French randomized trial comparing standard vs. split courseirradiation (FNCLCC-FFCD 9305) [abstract]. Proc ASCO 1999;18:270a.

28. Moni J, Armstrong JG, Minsky BD, Bains MS, Harrison LB. Highdose rate intraluminal brachytherapy for carcinoma of the esopha-gus. Dis Esophagus 1996;9:123–7.

29. Sur RK, Singh DP, Sharma SC. Radiation therapy of esophagealcancer: role of high dose rate brachytherapy. Int J Radiat OncolBiol Phys 1992;22:1043–6.

30. Jager J, Langendijk H, Pannebakker M, Rijken J, Jong J. A singlesession of intraluminal brachytherapy in palliation of esophagealcancer. Radiother Oncol 1995;37:237–40.

31. Sur RK, Donde B, Levin VC, Rad FF, Mannell A. Fractionatedhigh dose rate intraluminal brachytherapy in palliation of ad-vanced esophageal cancer. Int J Radiat Oncol Biol Phys 1998;40:447–53.

32. Maingon P, d’Hombres A, Truc G, Barillot I, Michiels C, BedenneL, et al. High dose rate brachytherapy for superficial cancer of theesophagus. Int J Radiat Oncol Biol Phys 2000;46:71–6.

33. Calais G, Dorval E, Louisot P, Bourlie P, Klein V, Chapet S, et al.Radiotherapy with high dose rate brachytherapy boost and con-comitant chemotherapy for stages IIB and III esophageal carci-noma: results of a pilot study. Int J Radiat Oncol Biol Phys1997;38:769–75.

34. Akagi Y, Hirokawa Y, Kagemoto M, Matsuura K, Ito A, Fujita K,et al. Optimum fractionation for high-dose-rate endoesophagealbrachytherapy following external irradiation of early stage esoph-ageal cancer. Int J Radiat Oncol Biol Phys 1999;43:525–30.

35. Schraube P, Fritz P, Wannenmacher MF. Combined endoluminaland external irradiation of inoperable oesophageal carcinoma.Radiother Oncol 1997;44:45–51.

36. Okawa T, Dokiya T, Nishio M, Hishikawa Y, Morita K. Multi-institutional randomized trial of external radiotherapy with andwithout intraluminal brachytherapy for esophageal cancer inJapan. Int J Radiat Oncol Biol Phys 1999;45:623–8.

37. Caspers RJL, Zwinderman AH, Griffioen G, Welvaart K,Sewsingh EN, Davelaar J, et al. Combined external beam and lowdose rate intraluminal radiotherapy in oesophageal cancer.Radiother Oncol 1993;27:7–12.

38. Sur M, Sur R, Cooper K, Levin V, Bizos D, Dubazana N. Morpho-logic alterations in esophageal squamous cell carcinoma afterpreoperative high dose rate intraluminal brachytherapy. Cancer1996;77:2200–5.

39. Yorozu A, Dokiya T, Oki Y, Suzuki T. Curative radiotherapy withhigh-dose-rate brachytherapy boost for localized esophageal carci-noma: dose-effect relationship of brachytherapy with the balloontype applicator system. Radiother Oncol 1999;51:133–9.

40. Gaspar LE, Qian C, Kocha WI, Coia LR, Herskovic A, Graham M.A phase I/II study of external beam radiation, brachytherapy andconcurrent chemotherapy in localized cancer of the esophagus(RTOG 92-07): preliminary toxicity report. Int J Radiat Oncol BiolPhys 1997;37:593–9.

41. Gaspar LE, Nag S, Herskovic A, Mantravadi R, Speiser B. Ameri-can Brachytherapy Society (ABS) consensus guidelines forbrachytherapy of esophageal cancer. Int J Radiat Oncol Biol Phys1997;38:127–32.

14

42. Ishikura S, Nihei K, Ohtsu A, Boku N, Hironaka S, Mera K, et al.Long-term toxicity after definitive chemoradiotherapy for squa-mous cell carcinoma of the thoracic esophagus. J Clin Oncol2003;21:2697–702.

43. Girinsky T, Auperin A, Marsiglia H, Dhermain F, RandrianariveloH, Kac J, et al. Accelerated fractionation in esophageal cancers: amultivariate analysis on 88 patients. Int J Radiat Oncol Biol Phys1997;38:1013–8.

44. Jeremic B, Shibamoto Y, Acimovic L, Matovic Z, Milicic B,Milisavljevic S, et al. Accelerated hyperfractionated radiationtherapy and concurrent 5-fluorouracil/cisplatin chemotherapy forlocoregional squamous cell carcinoma of the thoracic esophagus: aphase II study. Int J Radiat Oncol Biol Phys 1998;40:1061–6.

45. Wang Y, Shi XH, He SQ, Yao WQ, Wang Y, Guo XM, et al.Comparison between continuous accelerated hyperfractionatedand late-course accelerated hyperfractionated radiotherapy foresophageal carcinoma. Int J Radiat Oncol Biol Phys 2002;54:131–6.

46. Coia LR, Soffen EM, Schultheiss TE, Martin EE, Hanks GE.Swallowing function in patients with esophageal cancer treatedwith concurrent radiation and chemotherapy. Cancer 1993;71:281–6.

47. Kelsen DP, Ginsberg R, Pajak T, Sheahan DG, Gunderson L,Mortimer J, et al. Chemotherapy followed by surgery comparedwith surgery alone for localized esophageal cancer. New Engl JMed 1998;339:1979–84.

48. Bedenne L, Michel P, Bouche O, Triboulet JP, Conroy T, Pezet D,et al. Randomized phase III trial in locally advanced esophagealcancer: radiochemotherapy followed by surgery versus radio-chemotherapy alone (FFCD 9102) [abstract]. Proc ASCO 2002;21:130a.

49. Launois B, Delarue D, Campion JP, Kerbaol M. Preoperativeradiotherapy for carcinoma of the esophagus. Surg Gynecol Obstet1981;153:690–2.

50. Arnott SJ, Duncan W, Kerr GR, Walbaum PR, Cameron E, JackWJL, et al. Low dose preoperative radiotherapy for carcinoma ofthe oesophagus: results of a randomized clinical trial. RadiotherOncol 1993;24:108–13.

51. Huang GJ, Gu XZ, Wang LJ. Combined preoperative irradiationand surgery for esophageal carcinoma. In: Delarue NC, editor.International trends in general thoracic surgery. St. Louis: C.V.Mosby; 1988. p. 315–8.

52. Mei W, Xian-Zhi G, Weibo Y, Guojun H, Liang-Jun W, Da-Wei Z.Randomized clinical trial on the combination of preoperative irra-diation and surgery in the treatment of esophageal carcinoma:Report on 206 patients. Int J Radiat Oncol Biol Phys 1989;16:325–7.

53. Gignoux M, Roussel A, Paillot B, Gillet M, DSchlag P, Favre J-P,et al. The value of preoperative radiotherapy in esophageal cancer:Results of a study of the E.O.R.T.C. World J Surg 1987;11:426–32.

54. Arnott SJ, Duncan W, Gignoux M, Girling DJ, Hansen HS,Launois B, et al. Preoperative radiotherapy in esophageal carci-noma: a meta-analysis using individual patient data (oesophagealcancer collaborative group). Int J Radiat Oncol Biol Phys1998;41:579–83.

55. Yamamoto M, Yamashita T, Matsubara T, Kitahara T, SekiguchiK, Furukawa M, et al. Reevaluation of postoperative radiotherapyfor thoracic esophageal carcinoma. Int J Radiat Oncol Biol Phys1997;37:75–8.

56. Hosokawa M, Shirato H, Ohara K, Hashimoto K, Nishino S,Takamura A, et al. Intraoperative radiation therapy to the uppermediastinum and nerve-sparing three-field lymphadenectomy fol-lowed by external beam radiotherapy for patients with thoracicesophageal carcinoma. Cancer 1999;86:6–13.

57. Teniere P, Hay J-M, Fingerhut A, Fagniez P-L. Postoperative ra-diation therapy does not increase survival after curative resectionfor squamous cell carcinoma of the middle and lower esophagus asshown by a multicenter controlled trial. Surg Gynecol Obstet1991;173:123–30.

58. Fok M, Sham JST, Choy D, Cheng SWK, Wong JW. Postoperativeradiotherapy for carcinoma of the esophagus: A prospective, ran-domized controlled trial. Surgery 1993;113:138–47.

59. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC,Stemmermann GN, et al. Chemoradiotherapy after surgery com-pared with surgery alone for adenocarcinoma of the stomach orgastroesophageal junction. New Engl J Med 2001;345:725–30.

60. Safran H, Gaissert H, Akerman P, Hesketh PJ, Chen MH, MooreT, et al. Paclitaxel, cisplatin, and concurrent radiation for esoph-ageal cancer. Cancer Invest 2001;19:1–7.

61. Ajani JA, Komaki R, Putnam J, Walsh G, Nesbitt J, Pisters PW,et al. A three-step strategy of induction chemotherapy thenchemoradiation followed by surgery in patients with potentiallyresectable carcinoma of the esophagus or gastroesophageal junc-tion. Cancer 2001;92:279–86.

62. Safran HS, Akerman P, Cioffi W, Gaissert H, Joseph P, King T,et al. Paclitaxel and concurrent radiation therapy for locally ad-vanced adenocarcinomas of the pancreas, stomach, and gastroe-sophageal junction. Sem Radiat Oncol 1999;9(2 Suppl 1):53–7.

63. Goldberg M, Lampert C, Colarusso P, Coia L, Farma J, Frucht H,et al. Survival following intensive preoperative combined modalitytherapy with paclitaxel, cisplatin, 5-fluorouracil, and radiation inresectable esophageal carcinoma: a phase I report [abstract]. ProcASCO 2002;21:154.

64. Font A, Garcia-Alfonso P, Arellano A, Molina M, Fernandez-Llamazares J, Munoz-Sanchez M, et al. Preoperative combinedmultimodal therapy with docetaxel plus 5-fluorouracil and concur-rent hyperfractionated radiotherapy for locally advanced esoph-ageal cancer [abstract]. Proc ASCO 2002;21:128b.

65. Anderson S, Ilson D, Bains M, Karpeh MS, O’Reilly E, Kelsen D,et al. Phase I trial of cisplatin and escalating dose irinotecan givenweekly with concurrent radiation in locally advanced esophagealcancer [abstract]. Proc ASCO 2001;20:158a.

66. Coia L, Minsky B, John M, Haller D, Landry J, Pisansky T, et al.Outcome of patients receiving radiation for cancer of the esopha-gus: results of the 1992–1994 patterns of care study [abstract]. ProcASCO 1998;17:258a.

67. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N,Hennessy TPJ. A comparison of multimodal therapy and surgeryfor esophageal adenocarcinoma. New Engl J Med 1996;335:462–7.

68. Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D,et al. Chemoradiotherapy followed by surgery compared with sur-gery alone in squamous cell cancer of the esophagus. New Engl JMed 1997;337:161–7.

69. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A,Strawderman M. Randomized trial of preoperative chemo-radiation versus surgery alone in patients with locoregional esoph-ageal carcinoma. J Clin Oncol 2001;19:305–13.

70. Burmeister BH, Smithers BM, Fitzgerald L, Gebski V, Devitt S,Ackland S, et al. A randomized phase III trial of preoperativechemoradiation followed by surgery (CR-S) versus surgery alone(S) for localized resectable cancer of the esophagus [abstract].Proc ASCO 2002;21:130a.

71. Le Prise E, Etienne PL, Meunier B, Maddern G, Ben Hassel M,Gedouin D, et al. A randomized study of chemotherapy, radiationtherapy, and surgery versus surgery for localized squamous cellcarcinoma of the esophagus. Cancer 1994;73:1779–84.

72. Bains MS, Stojadinovic A, Minsky B, Rusch V, Turnbull A, KorstR, et al. A phase II trial of preoperative combined-modalitytherapy for localized esophageal carcinoma: initial results. JThorac Cardiovasc Surg 2002;124:270–7.

73. Ilson DH, Bains M, Kelsen DP, O’Reilly E, Karpeh M, Coit D,et al. Phase I trial of escalating-dose irinotecan given weekly withcisplatin and concurrent radiotherapy in locally advanced esoph-ageal cancer. J Clin Oncol 2003;21:2926–32.

74. Ott K, Fink U, Becker K. Prediction of response to preoperativechemotherapy in gastric carcinoma by metabolic imaging: resultsof a prospective trial. J Clin Oncol. In press 2003.

75. Bonnetain F, Bedenne L, Michel P, Bouche O, Triboulet JP,Conroy T, et al. Definitive results of a comparative longitudinalquality of life study using the Spitzer index in the randomizedmulticentric phase III trial FFCD 9102 (surgery vs. radio-chemotherapy in patients with locally advanced esophagealcancer) [abstract]. Proc ASCO 2003;22:250.

76. Stahl M, Wilke H, Walz MK, Seeber S, Klump B, Budach W, et al.Randomized phase III trial in locally advanced squamous cell car-cinoma (SCC) of the esophagus: chemoradiation with and withoutsurgery [abstract]. Proc ASCO 2003;22:250.

77. Sarbia M, Stahl M, Fink U, Willers R, Seeber S, Gabbert HE.Expression of apoptosis-regulating proteins and outcome of esoph-ageal cancer patients treated by combined therapy modalities. ClinCancer Res 1998;4:2991–7.

15

78. Pomp J, Davelaar J, Blom J, van Krimpen C, Zwinderman A,Quint W, et al. Radiotherapy for oesophagus carcinoma: the im-pact of p53 on treatment outcome. Radiother Oncol 1998;46:179–84.

79. Merchant TE, Minsky BD, Lauwers GY, Diamantis PM, Haida T,Glonek T. Esophageal cancer phospholipids correlated with histo-pathologic findings: a 31P NMR study. NMR Biomed 1999;12:184–8.

80. Kishi K, Doki Y, Miyata H, Yano M, Yasuda T, Monden M.Prediction of the response to chemoradiation and prognosis inoesophageal squamous cancer. Br J Surg 2002;89:597–603.

81. Hironaka S, Hasebe T, Kamijo T, Ohtsu A, Boku N, Yoshida S,et al. Biopsy specimen microvessel density is a useful prognosticmarker in patients with T2-4M0 esophageal cancer treated withchemoradiotherapy. Clin Cancer Res 2002;8:124–30.

82. Morita M, Kuwano H, Araki K, Egashira A, Kawaguchi H, SaekiH, et al. Prognostic significance of lymphocytic infiltration follow-ing preoperative chemoradiotherapy and hyperthermia for esoph-ageal cancer. Int J Radiat Oncol Biol Phys 2001;49:1259–66.

83. Nutting CM, Bedford JL, Cosgrove VP, Tait DM, Dearnaley DP,Webb S. A comparison of conformal and intensity-modulatedtechniques for oesophageal radiotherapy. Radiother Oncol2001;61:157–63.

84. Fuchs C, Fitzgerald T, Mamon H, Haller DG, Venook A, EnzingerP, et al. Postoperative adjuvant chemoradiation for gastric orgastroesophageal adenocarcinoma using epirubicin, cisplatin, andinfusional (CI) 5-FU (ECF) before and after CI 5-FU and radio-therapy (RT): a multicenter study [abstract]. Proc ASCO 2003;22:257.

85. Ilson DH, Minsky B, Kelsen D. Irinotecan cisplatin and radiationin esophageal cancer. Oncology 2002;16(5 Suppl 5):11–5.

86. D’Adamo DR, Bains M, Minsky B, Kelsen D, Rusch V, Karpeh M,et al. A phase I trial of paclitaxel, cisplatin, irinotecan, and concur-rent radiation therapy in locally advanced esophageal cancer[abstract]. Proc ASCO 2003;22:349.

87. Safran H, DiPetrillo T, Nadeem A, Rathmore R, Constantino M,Ramdin N, et al. Neoadjuvant herceptin, paclitaxel, cisplatin, andradiation for adenocarcinoma of esophagus: a phase I study[abstract]. Proc ASCO 2002;21:141a.

88. Khushalani KI, Leichman CG, Proulx G, Nava H, Bodnar L,Klippenstein D, et al. Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trialfor patients with esophageal cancer. J Clin Oncol 2002;20:2844–50.

89. Enzinger PC, Mamon H, Bueno R, Choi N, Fidias P, Kulke M,et al. Phase II cisplatin, irinotecan, celecoxib and concurrent radia-tion therapy followed by surgery for locally advanced esophagealcancer [abstract]. Proc ASCO 2003;22:361.

90. Phillips TL, Minsky BD, Dicker A. Cancer of the Esophagus. In:Leibel S, Phillips TL, editors. Textbook of radiation oncology.Philadelphia: W.B. Saunders; 1998. p. 601–23.

91. Tai P, van Dyk J, Yu E, Battista J, Stitt L, Coad T. Variability oftarget volume delineation in cervical esophageal cancer. Int JRadiat Oncol Biol Phys 1998;42:277–88.

92. Tai P, van Dyk J, Battista J, Yu E, Stitt L, Tonita J, et al. Improvingthe consistency in cervical esophageal target volume definitionby special training. Int J Radiat Oncol Biol Phys 2002;53:766–74.