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onsiderations in Treatmentlanning for Esophageal Cancer

heodore S. Hong, MD,* Elizabeth M. Crowley, MS,* Joseph Killoran, PhD,† andarvey J. Mamon, MD, PhD†

Radiation therapy is an important component of the multidisciplinary management ofesophageal cancer. In this article, we review the current approaches to achieving thedesired dose to the esophagus and regional lymph nodes, with an emphasis on the doseconstraints to adjacent normal structures, particularly the heart and lungs. The applicationof newer technologies such as positron-emission tomography/computed tomography scan-ning and intensity-modulated radiation therapy is also explored.Semin Radiat Oncol 17:53-61 © 2006 Elsevier Inc. All rights reserved.

KEYWORDS esophageal cancer, treatment planning, normal tissue tolerance, PET scanning,IMRT

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sophageal cancer is an increasingly common malignancywith generally poor outcomes.1 It is a cancer that is fre-

uently diagnosed at an advanced stage, rendering a curativeesection impossible for many patients.2-4 Surgery for pa-ients with nonmetastatic disease provides a cure in only 20%o 40% of patients. For this reason, chemoradiation hasmerged as an important part of therapy, both in the preop-rative setting and as an option for definitive therapy.4,5

Because of the advanced presentation of esophageal can-ers, large radiation fields are commonly used. The treatmentolume is further enlarged by the large longitudinal marginsecessary to cover submucosal spread and also the need toover distant nodal basins,6 including celiac nodes for distalumors and supraclavicular nodes for proximal tumors.hese large fields encompass significant volumes of normal

issue including the heart, lungs, and liver. In this review, weill discuss approaches to radiation treatment planning for

sophageal cancer. This will be followed by a discussion ofhe normal tissue tolerances that need to be considered inreatment planning. Lastly, we will introduce the potentialontributions of newer technologies such as positron-emis-ion tomography (PET) imaging for improved determination

Department of Radiation Oncology, Massachusetts General Hospital, Bos-ton, MA.

Department of Radiation Oncology, Dana Farber Cancer Institute, Brighamand Women’s Hospital, Boston, MA.

ddress reprint requests to Harvey J. Mamon, MD, PhD, Department ofRadiation Oncology, Dana Farber Cancer Institute, Brigham and Wom-en’s Hospital, 75 Francis Street, L2, Boston, MA 02115. E-mail:

ihmamon@partners.org

053-4296/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1016/j.semradonc.2006.09.001

f the target volume and intensity-modulated radiation ther-py (IMRT) for increasing the conformality of treatmentlans.

wo- and Three-Dimensionallanning Approaches

here are no randomized data comparing different treatmentelds for radiation therapy of the esophagus. Review of theelds used in a sample of the major trials in the treatment ofsophageal cancer, however, reveals a reasonable consensusmong most investigators regarding the appropriate targetolumes for radiation therapy. The Radiation Therapy On-ology Group (RTOG) 8501 trial established the superiorityf combined modality therapy (CMT), consisting of 50 Gyith cisplatin and 5-FU, compared with radiation alone to 64y.5 For mid- and lower esophageal cancers, the first-course

reatment field (30 Gy for the CMT arm and 50 Gy for theadiation-alone alone arm) extended from the supraclavic-lar region to the gastroesophageal junction, omitting theupraclavicular nodes for tumors in the lower third of thesophagus. The boost field included the tumor with 5-cmranial and caudal margins. Normal tissues constraints in-luded 45 Gy to the spinal cord, 25 Gy to any lung beyond 2m from the tumor, and a maximum of 40 Gy to the wholeeart with no more than 50% of the heart receiving 45 Gy.ultifield techniques were recommended but not specified.

n practice, a common approach is anterior:posterior (AP-A) fields for the first course, and a 3-field approach consist-

ng of an AP and 2 posterior obliques, or opposed obliques,

53

54 T. Hong et al.

Figure 1 (A) First course dose distribution by using AP and PA fields. (B) Cone-down dose distribution by using an APfield and 2 off-cord posterior obliques. (C) Cumulative dose distribution showing that the contribution of the 2posterior oblique fields is approximately 10 Gy, which would not be anticipated to cause a significant risk of normal

tissue complications such as pneumonitis.

Figure 2 CT scan at the level of GE junction and gastric cardia. (A) FDG-PET/CT at the same level, helping to define thelocation of the tumor. (B) A coronal view of the FDG-PET/CT for the same patient showing the utility of FDG-PET in

visualizing the cranial-caudal extent of the tumor.

Figure 6 IMRT dose distributions for a GE-junction carcinoma. Axial, sagittal, and coronal views of an IMRT plan for adistal esophageal tumor involving the GE junction. The red volume represents the GTV and the dark blue volume

represents the boost CTV, which is carried to 50.4 Gy.

Figure 7 Comparison of 3D-CRT (left), IMRT (middle), and combined (right) plan for a distal esophageal tumorinvolving the GE junction. The IMRT plan shows a striking dispersion of the 5 Gy isodose cloud throughout the entire

lung seen at this CT level.

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Treatment planning for esophageal cancer 55

or the cone-down volume (Fig 1). The advantages of thispproach include limiting the lung dose during the AP-PAortion of treatment and then limiting the spinal cord dosey replacing the PA field with off-cord obliques for the coneown, during which the dose to the lungs will remain wellelow tolerance for that organ. A disadvantage, particularlyor distal tumors, is the significant cardiac volume often in-luded in both portions of the treatment course.

The follow-up study to RTOG 8501, Intergroup (INT)122, treated patients to 50.4 Gy followed by a 14.4 Gy coneown.7 The first course was defined to extend 5 cm beyondhe tumor superiorly and inferiorly, with the other marginseing 2 cm. Supraclavicular nodes were only included forumors of the cervical esophagus. The cone-down field in-luded the gross tumor with a 2-cm margin. Because thisegimen had unacceptable toxicity, the successor study, INT123, randomized patients to 50.4 versus. 64.8 Gy with less

ntensive chemotherapy than used in the INT 0122 trial.8 Thearget volumes were the same as in INT 0122, but there wasore emphasis on dose homogeneity. The protocol specified

ess than a 5% dose inhomogeneity within the target volume,nd the dose was prescribed to the isodose line that coveredhe volume at risk. The study concluded that the higher doseid not improve outcomes, and 50.4 Gy should remain thetandard of care.

The most recent RTOG esophageal protocol, 0113, was ahase II comparison of 2 taxane-based chemotherapy regi-ens given concurrently with radiation. This protocol madeore explicit reference to ICRU-50 definitions of gross tumor

olume (GTV), clinical tumor volume (CTV), and planningumor volume (PTV) and also specifically referred to the ap-roach of AP-PA treatment followed by an AP field with 2osterior oblique fields. The CTV was defined to include theTV with 4-cm proximal and distal margins and 1-cm lateralargins. The PTV represented a 1- to 2-cm expansion be-

ond the CTV to allow for variability in setup and patient orrgan motion. Local-regional nodes were considered part ofhe CTV, even if clinically negative. These definitions wereesigned to result in field that would be roughly similar to thearlier studies, in which the superior and inferior borders ofhe radiation field were set at 5 cm above and below the GTVnd 2 cm lateral to the GTV, although larger fields could besed as needed for nodal coverage. Coverage of the supracla-icular nodes was recommended for tumors above the carina,ith inclusion of the celiac nodes for distal tumors, whereaseither nodal group was included for midesophageal can-ers. None of the RTOG protocols allowed corrections forung inhomogeneity.

In addition to the RTOG trials of definitive chemoradia-ion, there have been multiple randomized trials of neoadju-ant chemoradiation versus surgery alone. In general, thesetudies have used a very similar approach to the RTOG stud-es in the choice of radiation treatment fields. For example, inhe trial by Bosset and coworkers,9 in which the fractionationonsisted of two 1-week courses of 3.7 Gy � 5 fractions, theeld included the tumor with 5-cm superior and inferiorargins and 2-cm radial margins. The celiac axis was not

ncluded. Similarly, Urba and coinvestigators10 used 1.5 Gy V

wice-daily fractionation to the same field as in the Bossetttudy, without extending the field to include uninvolvedymph nodes. Walsh and coinvestigators4 treated to a similareld by using a dose of 40 Gy in 2.67-Gy fractions. Theancer and Leukemia Group B 9781 trial11 treated to 50.4y. Radial margins were 2 cm beyond the esophagus; supe-

ior and inferior field borders were 5 cm above and below theross tumor, including the supraclavicular nodes for proxi-al tumors and the celiac axis for distal tumors.This brief sampling of the many published studies of CMT

or esophageal cancer reveals a range of fractionationchemes, with 50.4 Gy commonly used in the United Statesnd lower doses with larger fraction sizes more common inurope. There is a fairly broad consensus extending to bothides of the Atlantic, however, that the radiation field shouldxtend 5 cm above and below the gross tumor, with many butot all investigators extending the field to include supracla-icular or celiac nodal regions for proximal and distal can-ers, respectively.

ormal Tissue Constraintsung Dose and Pulmonary Complicationsadiation pneumonitisatients receiving chemoradiation for esophageal cancerre at risk for developing pulmonary complications be-ause of treatment. Radiation pneumonitis, a commonose-limiting complication of radiation therapy for lungancer, is characterized by persistent cough or shortness ofreath arising 6 weeks to 6 months after therapy withadiologic correlation with the photon-beam path. Thisyndrome can have a significant impact on a patient’s qual-ty of life and in rare instances can be responsible forreatment-related mortality.

Numerous publications have evaluated dose volume his-ogram (DVH) parameters predicting the risk of radiationneumonitis. The largest clinical series, reported by Kwa andolleagues,12 studied 540 patients from 5 institutions whoere pooled to determine the relationship of dose distribu-

ion in the lung and the subsequent development of grade �2adiation pneumonitis. This series included 399 lung pa-ients, 1 esophagus patient, 78 lymphoma patients, and 59reast patients. A combined lung volume was considered,nd differences in fractionation were accounted for by nor-alization of the dose into 2-Gy equivalents (normalized

otal dose) using the linear-quadratic formulation. This anal-sis showed that the risk of grade 2 or greater pneumonitisorrelated with mean lung dose. The authors concluded thatsing a normalized total dose mean of 20 Gy was associatedith a normal tissue complication rate of 13% to 24%, which

he authors deemed acceptable. Others have seen a similarelationship between the mean lung dose and the rate oflinically significant pneumonitis.13-16 Investigators have alsoxamined the concept of choosing specific points on a DVHo predict the risk of pneumonitis. Some DVH points thatave been found to be informative include V20 �40%15 and

30 �18%.16 There remains no evidence that any one of

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hese characteristics is more accurate than another. Furtheromplicating lung DVH analysis is that there may be regionalnatomic difference in lung sensitivity. A study by Yorke andolleagues13 examining DVH predictors of pneumonitisound that the dose received by the contralateral lung and thepper portion of the lungs were not strong predictors ofomplications.

Despite the significant efforts to predict risk using DVHarameters, the concept of using dosimetric parametersas some flaws. First, the lung patients included in thesetudies constitute a heterogeneous population of patientsith respect to lung function and performance status.lso, chemotherapy regimens have evolved over time andemain a confounding variable in any pneumonitistudy.17 Finally, varying definitions of lung have beensed (ipsilateral lung, combined lung, combined lung mi-us PTV, and so on) These factors make it difficult to

dentify a definitive set of DVH parameters that correlateith a low pneumonitis risk.

ostoperative Pulmonary Complicationsostoperative pulmonary complications represent a clini-ally separate entity. These encompass any respiratory orulmonary complications that occur in the postoperativeeriod. In contrast to radiation pneumonitis, postopera-ive pulmonary complications are generally regarded as ancute complication. It represents a serious and perhapsnderappreciated complication. In one large series fromong Kong, pulmonary complications occurred in over5% of patients and accounted for 55% of the hospitaleaths after esophagectomy.18

The correlation between lung radiation and postopera-ive lung complications was studied by Wang and col-eagues19 from MD Anderson Cancer Center. In this study,10 patients who underwent preoperative chemoradiationollowed by esophagectomy were evaluated. The studyndpoint was postoperative lung complication as definedy pneumonia or adult respiratory distress syndrome oc-urring within 30 days of surgery. Eighteen patients de-eloped postoperative pulmonary complications. The onlyndependent predictor associated with postoperative pul-

onary complications was the absolute volume sparedrom 5 Gy. The authors hypothesized that the importancef the volume of lung that received or was spared low-doseadiation was predictive of postoperative lung complica-ions because the physiologic strain of surgery triggersubclinical damage that would not otherwise become clin-cally evident. This observation highlights an emergingheme of intensity-modulated radiation therapy (IMRT)elivery. Often the low-dose isodose cloud is spread outver a large volume and may have important, and cur-ently poorly understood, clinical implications.

Recognizing the importance of the low-dose regions forung complications as well as more classically described val-es such as V20 and mean lung dose, the investigators at MDnderson evaluated whether IMRT could improve lung spar-

ng compared with 3-dimensional (3D) plans.20,21 Optimal t

D plans were compared with IMRT plans using 4 beams, 7eams, and 9 beams. IMRT plans improved lung V10, V20,nd mean lung dose. However, the investigators did not see aignificant difference in dose received by the spinal cord,eart, or liver.

ardiac Dose and Toxicityong-term cardiac morbidity and mortality from esophagealadiation remain largely unknown. This lack of data is likelyaused by the fact that late radiation-induced cardiac eventsay not occur until 10 to 20 years after radiation. Given the

elatively small number of esophageal cancers diagnosed andreated each year and the low cure rate, it is difficult to dis-ern what the risk of cardiovascular disease is specifically insophageal cancer patients. However, data from other dis-ases provide some insight in the importance of cardiac dose.he Early Breast Cancer Trialists’ Collaborative Grouphowed that excess cardiac deaths after 20 years of follow-upn the group receiving radiotherapy.21 Generally, these areatients who received high doses to a small portion of the leftentricle. Similarly, long-term survivors of Hodgkin’s diseasehow an increased risk of heart disease. In an analysis by Ngnd colleagues,22 survivors of Hodgkin’s disease had an ab-olute excess risk (per 10,000 patient-years) of 5 to 7 in theime interval from 0 to 15 years. However, the risk increasedrastically beyond that time period to 13.9 between 15 to 20ears and to 41.1 beyond 20 years. Eriksson and colleagues23

imilarly noted an increased risk of cardiac mortality. In anttempt to correlate these findings with DVH parameters, 3isk groups were identified. The high-risk group received38 Gy to 35% of the cardiac volume. The intermediate

roup received �38 Gy to 35% of volume and �35 Gy to0% of volume. The low-risk group received �35 Gy to 30%f the volume. The excess risk of cardiovascular disease at 15ears was 7.9%, 5.5%, and 3.8% for the high-, intermediate-,nd low-risk groups, respectively. These values had wideonfidence intervals reflecting the relatively limited numbersf patients with long follow-up.Although it may be difficult to show in esophageal cancer

atients, it is likely that patients who are long-term survivorsay see a similarly increased risk of cardiac events. The car-iac dose may become more important as cure rates improve.hus, it is desirable to reduce cardiac dose as much as pos-ible. However, there are few data to describe which dosimet-ic parameters predict for rates of long-term cardiac compli-ations. This paucity of data is largely a function of the needor 15 or more years of follow-up to see a significant rise inardiovascular morbidity. Because 3D planning has been inidespread use for less than 15 years, it is difficult to find aataset with adequate follow-up and complete DVH informa-ion. Furthermore, the anatomic importance of differenttructures of the heart make DVH analysis of the whole heartnherently flawed. Assessment of DVH characteristics for theeft ventricle, different segments of coronary arteries, andndividual valves requires very high-resolution 4-dimen-ional imaging and more importantly deformable registration

o assess the actual delivered dose to these structures. For

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Treatment planning for esophageal cancer 57

ow, it seems that limiting the volume of heart receiving 40y is a reasonable goal, pending further investigations. Asill be described, however, this goal is often not easily

chievable, particularly when treating distal and gastro-sophageal junction tumors. There are no more specific lit-rature-based cardiac dose guidelines for the use of IMRTlanning available.

18F]-fluoro-2-deoxy-D-glucoseositron-Emission Tomographynd FDG-PET/Computed Tomographycans in Esophageal Cancer Planning

n the various trials using CMT for esophageal cancer de-cribed earlier, the GTV was generally determined by a com-ination of barium swallow at the time of simulation, com-uted tomography (CT) scans, and endoscopy reports. It cane difficult, however, to convert distances from the incisorss reported at endoscopy to a location on a planning scan.articularly in the distal esophagus, which has become theost prevalent site for esophageal tumors in many popula-

ions,24 it can be very difficult to distinguish tumor fromormal GE junction and cardia radiographically.The increased sensitivity and specificity of [18F]-fluoro-2-

eoxy-D-glucose positron-emission tomography (FDG-PET)canning compared with standard CT scans in the staging ofsophageal cancer is discussed elsewhere in this issue. Heree will focus specifically on the utility of FDG-PET/CT data

n defining the primary tumor and nodal targets for treatmentlanning. Although several investigators have examined thetility of FDG-PET or FDG-PET/CT scanning in treatmentlanning for lung25 or head and neck cancers,26 there areewer reports regarding the use of FDG-PET scans in treat-

ent planning for esophageal carcinoma. Leong and cowork-rs27 recently reported the results of a study in which 21atients with esophageal cancer underwent treatment plan-ing with and without information from an integrated FDG-ET/CT scanner. Unsuspected regional nodal disease was

dentified in 4 patients, with unsuspected metastatic diseaseetected in 4 additional patients. Of 16 patients who went ono have treatment planning, the GTV based on CT imagesissed FDG-PET–avid disease in 11 (69%) patients; for 5 of

hese (31%), this would have resulted in excluding grossumor from the treatment field. The major benefit identifiedo integrating FDG-PET/CT data into treatment planning wasmproved definition of the longitudinal extent of the tumor,articularly in the region of the gastroesophageal junction.Similarly, Moreau-Zabotto and coworkers28 reported on

heir experience in fusing CT scans to FDG-PET data in 34atients. Two patients were found to have unsuspected dis-ant metastases. In 12 patients, the FDG-PET information ledo a decrease in the size of the PTV, whereas in 7 patients theesult was an increase in size. In 18 of these 19 patients, thehange in size of the GTV was sufficient to affect the planningreatment volume; in the majority of cases, this change had aignificant impact on the lung dose as measured by V20.onski and coworkers,29 in an analysis of 25 patients, com-

ared the length of the primary esophageal tumor in patients (

s measured by FDG-PET (5.4 cm), CT (6.8 cm), and endos-opy (5.1 cm). They concluded that both endoscopic ultra-ound (EUS) and FDG-PET significantly improve the abilityo precisely define the GTV in patients with esophageal can-er. Vrieze and coworkers30 found discordances in the detec-ion of lymph nodes between CT/EUS and FDG-PET in 14 of0 patients analyzed. In 8 patients, nodal involvement wasetected on CT or EUS but not FDG-PET, whereas in 6 pa-ients pathologically confirmed lymph nodes were detectedn FDG-PET despite a normal CT and EUS. The authorsoncluded that the irradiated volume should not be reducedased on FDG-PET findings but that enlarging the volumeased on FDG-PET scan results should be considered.In our institution, we have been routinely fusing FDG-

ET/CT scans done for diagnostic purposes to planning CTcans as an aid to defining the GTV, for both involved pri-ary and nodal areas. Whereas a “light-box” comparison of aT scan to a FDG-PET/CT scan is helpful in determining thextent of disease for treatment planning, we have found com-uter-aided fusion a significant advantage over comparinghe planning CT scans and diagnostic FDG-PET/CT scans byye. Figure 2 shows a patient with a GE junction tumor inhom the extent of disease is difficult to determine from theT scan alone. The fused FDG-PET data provide additionaluidance in locating the GTV. Figure 3 shows a patient whoy EGD and EUS had 2 areas of tumor, one in the midsophagus and the other in the GE junction, the later associ-ted with gastrohepatic lymphadenopathy. Both of these ar-as are well visualized by FDG-PET scan. This figure alsohows a limitation of FDG-PET compared with EUS.

hereas the EUS had the resolution to visualize the primaryumor and adjacent gastrohepatic lymph nodes, on FDG-PETmaging these appear as a contiguous mass. For treatment-lanning purposes, however, this limitation is of limited con-equence because both the primary tumor and adjacentDG-avid lymph nodes will be treated to the same dose.igure 3B shows the finding of a FDG-PET-positive supracla-icular lymph node, which was not appreciated from othertaging studies.

In considering the use of FDG-PET to help define treat-ent volumes, the limitations must be considered along with

he potential advantages. Although most studies agree thatDG-PET or FDG-PET/CT significantly improves the accu-acy of staging compared with endoscopic ultrasound andonventional CT, few of these studies suggest that FDG-ET/CT has a sensitivity or specificity approaching 100%.31

or example, a recent review from the Mayo Clinic found thathe sensitivity and specificity of FDG-PET for nodal stagingere 82% and 60%, respectively.32 Both candidal infection33

nd esophagitis secondary to chemotherapy34 have been re-orted to cause false-positives in FDG-PET evaluation of thesophagus. In our own experience, we have had a patientith sarcoidosis whose FDG-PET/CT scan was read as show-

ng M1 disease because of supraclavicular adenopathy (Fig). On biopsy, the lymph node showed sarcoid.In addition to these false-positives, we have also seen the

pposite phenomenon. At esophagogastroduodenoscopy

EGD), a patient had a circumferential lesion extending from

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58 T. Hong et al.

4 to 42 cm from the incisors, with biopsies taken at 35, 38,nd 40 cm all showing invasive carcinoma. However, theDG-PET/CT imaging revealed an area of increased uptake

imited to the very distal esophagus, measuring only 1 to 2m (Fig 5). Thus, although FDG-PET/CT scans are certainlyseful, they must be interpreted with caution and taken in

Figure 3 Coronal view of a FDG-PET/CT scan of a patienton endoscopy, one in the midesophagus and the other inlocating these 2 regions of tumor involvement. (A) In thunsuspected supraclavicular lymph node. (Color versio

igure 4 False-positive lymph nodes secondary to sarcoidosis.

Color version of figure is available online.) e

he context of other staging studies such as EGD, EUS, andontrast CT scans rather than used in isolation.

It will require larger prospective trials to determinehether any improvements in target definition and treatment

as found to have 2 discrete areas of tumor involvementstal esophagus. The FDG-PET data were very helpful inpatient, the FDG-PET/CT scan identified a previously

ure is available online.)

igure 5 False-negative FDG-PET/CT scan showing a 2-cm area ofnvolvement in a patient with biopsy-proven disease extending overt least 5 cm, with an 8-cm area suspicious for tumor visualized

who wthe die same

ndoscopically. (Color version of figure is available online.)

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Treatment planning for esophageal cancer 59

lanning resulting from incorporation of FDG-PET/CT dataill lead to improved clinical outcomes. Future directions

nclude evaluating the cost-benefit ratio of incorporatingDG-PET/CT scanners into radiation oncology departmentss dedicated simulation scanners, the use of FDG-PET tossess the response to therapy,35-39 and the use of baselineDG-PET studies as a prognostic factor in patient outcome.40

n considering the use of dedicated FDG-PET/CT scannersor simulation, however, the risk of radiation exposure toimulation therapists cannot be ignored because this expo-ure has been estimated at 3.0 to 3.5 �Sv per patient simu-ated.41

MRTMRT affords the potential to shape high-dose radiationround normal structures while fully dosing tumor and othert-risk areas. Conventional radiation techniques for esopha-eal cancer use large static fields that produce generally ho-ogeneous dose distributions and generous field coverage.owever, the heart and lungs frequently will also receive

imilar high doses of radiation therapy. In contrast, IMRT canecrease dose to these structures and potentially decrease thepectrum of late effects that may affect long-term survivors ofsophageal cancer. This potential benefit has led to a veryapid increase in the utilization of IMRT across the Unitedtates, particularly in head and neck (H&N) cancer and pros-ate cancer.42

IMRT has different challenges for different diseases sites.or example, in H&N cancer, the target is in tight proximityo small normal structures and doses of 70 Gy are commonlysed. Thus, functional sparing of normal organs such as sal-

vary glands or cranial nerves requires very steep dose gradi-nts. Similarly for prostate cancer, doses in the mid-70-Gyange to as high as the 80-Gy range are used. Sparing theectal wall, which is in direct contact with the prostate, sim-larly requires a steep dose gradient. In contrast, for esopha-eal cancer, doses of approximately 50 Gy are commonlysed in both the preoperative and definitive setting. Further-ore, improvement in heart and lung DVH parameters isore easily achievable because of their larger size and dis-

ance from the esophageal gross tumor volume. Such steepose gradients in the high isodose regions are likely unnec-ssary to achieve clinical benefit.

In contrast to H&N cancer and prostate cancer, data re-arding the use of IMRT for esophageal cancer remain quiteparse. Further complicating the integration of IMRT in tolinical practice for esophageal cancer is the still evolvingiterature on dose-volume predictors of pulmonary and car-iac complications, as discussed. We will review the ratio-ale, the relevant literature, and the practical issues in usingMRT in esophageal cancer.

ose Reductiono Normal Organsne common use of IMRT is to reduce radiation dose to

djacent normal structures. Organs of particular interest in-

lude the lungs, heart, spinal cord, liver, and kidneys. With aonventional plan, the doses to the spinal cord, liver, andidneys are kept within tolerance with little difficulty. Ofreater interest is the potential of IMRT to reduce lung dosend heart dose. However, as described earlier, the preciseose-volume parameters predicting pulmonary and cardiacoxicity continue to evolve. Furthermore, it is unlikely thatny definitive data will become available soon because lateffect data, by definition, take years to mature. Hence, theenefit of IMRT in esophageal cancer may continue to be

imited until better dosimetric predictors of toxicity are es-ablished.

osimetry Studieso date, there is little literature regarding the use of IMRT insophageal cancer. Most of the published current research toate has evaluated potential dosimetric advantages of IMRTver 3D conformal radiation therapy (3D-CRT). Wu and col-eagues43 compared IMRT plans with forward and inverseD-CRT plans on 15 patients with midesophageal cancers.lans were evaluated for target conformality as well as theose received by heart and lungs. A dose of 60 Gy was pre-cribed to isocenter with 95% of the PTV receiving 58 Gy.he IMRT plans generated the most conformal high-doseistribution around the PTV (P � .008) as well as lower mean

ung dose and mean heart dose. The authors concluded thatMRT may afford better potential for dose escalation. Fu andolleagues44 reached a similar conclusion when comparinghe ability of 3D and IMRT to deliver simultaneous integratedoost dose-escalated plans in which the GTV received 67.22.4 Gy/fraction) and 50.4 (1.8 Gy/fraction) Gy over 28 frac-ions. Upper-esophageal locations were specifically evaluatedn 5 patients. The IMRT appeared to produce lower V20 and30 volumes in the lung. Cardiac dose was not specificallyddressed because of the upper esophageal location.

In contrast to the 2 studies described earlier, the previouslyentioned Chandra study20 specifically addressed the poten-

ial advantage of IMRT in distal esophageal cancers, fittingith the US epidemiology. Furthermore, a standard preop-

rative and definitive dose of 50.4 Gy was evaluated in 1.8y/fraction. Ten patients were analyzed in this study. The

MRT plans showed significant reduction in mean lung dose,s well as V10 and V20. There was no significant reduction inardiac dose from the 3D-CRT plans.

uture Directionsecause of the large volume treated for esophageal cancer asell as the proximity of critical organs, IMRT has attractiveotential in delivering better plans. However, much remainsnknown about the routine use of IMRT for esophageal can-er. First, it is unclear how one should balance dose con-traints for lung and heart. Furthermore, attempts to limitardiac dose or produce greater conformality of the highsodose lines may be associated with a “spraying” of the low-ose isodose cloud into more lung tissue.

To examine this point, we performed a dosimetric study

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ith the goal of decreasing cardiac dose in distal esophagealancers. The CTV was defined by the CT-based GTV with a-cm cranial-caudal and a 2-cm radial expansion. PTV ex-ansions were individualized based on 4-dimensional CT;D-CRT and IMRT plans were created to treat the CTV to0.4-Gy in 1.8-Gy fractions (Fig 6). A “combined” plan waslso created that treated the CTV to 36 Gy in 20 fractionssing 3D, followed by an IMRT boost for the final 14.4 Gy. Inll plans, a cone down was performed after 45 Gy. The treat-ent planning goals were, in order of priority: (1) spinal cordax dose �45 Gy, (2) � 95% of the PTV covered by therescription isodose line, (3) lung dose restricted to a com-ined V20 �30% and a mean lung dose of 20 Gy, (4) heartose restricted to V40 � 20%, and (5) global hotspot of lesshan 15%.

The DVH results for fifteen 3D-CRT, IMRT, and combinedistal esophageal plans are depicted in Table 1, with an ex-mple shown in Figure 7. The treatment plans using full-ourse IMRT plans were best able to reduce dose to the hearts measured by V40 and mean dose but were also associatedith the highest V5 and V20. Plans using 3D-CRT were least

uccessful in achieving the cardiac planning constraint. Theombined plans achieved both cardiac and pulmonary plan-ing dose constraints and displayed a superior lung V20.ean lung doses were not significantly different and equiva-

ent uniform dose analyses on 9 of the plans suggest thatquivalent uniform doses for the high-dose CTV do not differetween plans. In this preliminary analysis for treatment ofistal esophageal cancers, a combined 3D/IMRT plan (in con-rast to full-course IMRT) achieved adequate cardiac sparinghile maintaining lower lung DVH parameters.These studies highlight a fundamental difficulty of the

linical translation of IMRT to clinical practice. An IMRT planan be optimized in any number of ways and can always beade to look superior to a 3D plan for a single-treatmentlanning goal, be it lung sparing or cardiac sparing. However,his “improvement” is frequently at the expense of otherreatment planning goals. This cost of optimizing one treat-ent planning goal may be increased dose or volume irradi-

ted for other organs, degradation of conformality of theigh-dose isodose, or increased dose heterogeneity in the

able 1 Comparative Dosimetry of 3D, IMRT, and Combinedlan for Distal Esophageal Cancer.

3D-CRT IMRT Combined

eartV40 26.0% 10.3% 17.9%Mean Dose 33.0 Gy 23.9 Gy 29.9 Gy

ungV5 56.3% 74.5% 64.9%V20 27.2% 28.1% 22.3%lobal Hot Spot 56.6 Gy 58.1 Gy 56.0 Gy

OTE: Although IMRT was able to meet all planning constraints, itproduced the highest lung V5 and V20. Values are averaged over5 plans.

arget volume. The clinical data required to evaluate the rel-

tive importance of these treatment planning goals do not yetxist.

Although the focus of some the early dosimetry studies haseen the use of IMRT for dose escalation in the definitiveetting, it is important to note that there is no level 1 evidenceo suggest that there is a survival benefit to treating to a dosebove 50.4 Gy (at least as high as 64.8 Gy).8 Although itemains possible that there is a dose-response relationship,his relationship has yet to be defined. Any use of dose esca-ation should be considered investigational and not routinelysed outside a clinical trial.

onclusionsMRT is a promising advance in radiation therapy that affordshe potential of decreased toxicity in the management ofsophageal cancer. However, data are limited and heteroge-eous regarding precisely what dose constraints for pulmo-ary and cardiac toxicity should be used. IMRT brings newhallenges to the radiation oncologist, such as attention to theow-dose isodose cloud and management of hot spots. Ulti-

ately, the utility of IMRT will need to be confirmed basedn clinical data, which has yet to emerge.

eferences1. Jemal A, Tiwari RC, Murray T, et al: Cancer statistics, 2004. CA Cancer

J Clin 54:8-29, 20042. Hulscher JB, van Sandick JW, de Boer AG, et al: Extended transthoracic

resection compared with limited transhiatal resection for adenocarci-noma of the esophagus. N Engl J Med 347:1662-1669, 2002

3. Surgical resection with or without preoperative chemotherapy in oe-sophageal cancer: A randomised controlled trial. Lancet 359:1727-1733, 2002

4. Walsh TN, Noonan N, Hollywood D, et al: A comparison of multimo-dal therapy and surgery for esophageal adenocarcinoma. N Engl J Med335:462-467, 1996

5. Herskovic A, Martz K, al-Sarraf M, et al: Combined chemotherapy andradiotherapy compared with radiotherapy alone in patients with cancerof the esophagus. N Engl J Med 326:1593-1598, 1992

6. Hosch SB, Stoecklein NH, Pichlmeier U, et al: Esophageal cancer: Themode of lymphatic tumor cell spread and its prognostic significance.J Clin Oncol 19:1970-1975, 2001

7. Minsky BD, Neuberg D, Kelsen DP, et al: Final report of IntergroupTrial 0122 (ECOG PE-289, RTOG 90-12): Phase II trial of neoadjuvantchemotherapy plus concurrent chemotherapy and high-dose radiationfor squamous cell carcinoma of the esophagus. Int J Radiat Oncol BiolPhys 43:517-523, 1999

8. Minsky BD, Pajak TF, Ginsberg RJ, et al: INT 0123 (Radiation TherapyOncology Group 94-05) phase III trial of combined-modality therapyfor esophageal cancer: High-dose versus standard-dose radiation ther-apy. J Clin Oncol 20:1167-1174, 2002

9. Bosset JF, Gignoux M, Triboulet JP, et al: Chemoradiotherapy followedby surgery compared with surgery alone in squamous-cell cancer of theesophagus. N Engl J Med 337:161-167, 1997

0. Urba SG, Orringer MB, Turrisi A, et al: Randomized trial of preopera-tive chemoradiation versus surgery alone in patients with locoregionalesophageal carcinoma. J Clin Oncol 19:305-313, 2001

1. Krasna M, Tepper JE, Niedzwiecki D, et al: Trimodality therapy issuperior to surgery alone in esophageal cancer: Results of CALGB 9781.Paper presented at: ASCO 2006 Gastrointestinal Cancers Symposium,San Francisco, California, January 26-28, 2006

2. Kwa SL, Theuws JC, Wagenaar A, et al: Evaluation of two dose-volumehistogram reduction models for the prediction of radiation pneumoni-

tis. Radiother Oncol 48:61-69, 1998

1

1

1

1

1

1

1

2

2

2

2

2

2

2

2

2

2

3

3

3

3

3

3

3

3

3

3

4

4

4

4

4

Treatment planning for esophageal cancer 61

3. Yorke ED, Jackson A, Rosenzweig KE, et al: Dose-volume factors con-tributing to the incidence of radiation pneumonitis in non-small-celllung cancer patients treated with three-dimensional conformal radia-tion therapy. Int J Radiat Oncol Biol Phys 54:329-339, 2002

4. Oetzel D, Schraube P, Hensley F, et al: Estimation of pneumonitis riskin three-dimensional treatment planning using dose-volume histogramanalysis. Int J Radiat Oncol Biol Phys 33:455-460, 1995

5. Graham MV, Purdy JA, Emami B, et al: Clinical dose-volume histogramanalysis for pneumonitis after 3D treatment for non-small cell lungcancer (NSCLC). Int J Radiat Oncol Biol Phys 45:323-329, 1999

6. Hernando ML, Marks LB, Bentel GC, et al: Radiation-induced pulmo-nary toxicity: A dose-volume histogram analysis in 201 patients withlung cancer. Int J Radiat Oncol Biol Phys 51:650-659, 2001

7. Lingos TI, Recht A, Vicini F, et al: Radiation pneumonitis in breastcancer patients treated with conservative surgery and radiation therapy.Int J Radiat Oncol Biol Phys 21:355-360, 1991

8. Law S, Wong KH, Kwok KF, et al: Predictive factors for postoperativepulmonary complications and mortality after esophagectomy for can-cer. Ann Surg 240:791-800, 2004

9. Wang SL, Liao Z, Vaporciyan AA, et al: Investigation of clinical anddosimetric factors associated with postoperative pulmonary complica-tions in esophageal cancer patients treated with concurrent chemora-diotherapy followed by surgery. Int J Radiat Oncol Biol Phys 64:692-699, 2006

0. Chandra A, Guerrero TM, Liu HH, et al: Feasibility of using intensity-modulated radiotherapy to improve lung sparing in treatment planningfor distal esophageal cancer. Radiother Oncol 77:247-253, 2005

1. Favourable and unfavourable effects on long-term survival of radio-therapy for early breast cancer: An overview of the randomised trials.Early Breast Cancer Trialists’ Collaborative Group. Lancet 355:1757-1770, 2000

2. Ng AK, Bernardo MP, Weller E, et al: Long-term survival and compet-ing causes of death in patients with early-stage Hodgkin’s diseasetreated at age 50 or younger. J Clin Oncol 20:2101-2108, 2002

3. Eriksson F, Gagliardi G, Liedberg A, et al: Long-term cardiac mortalityfollowing radiation therapy for Hodgkin’s disease: Analysis with therelative seriality model. Radiother Oncol 55:153-162, 2000

4. Pera M, Manterola C, Vidal O, et al: Epidemiology of esophageal ade-nocarcinoma. J Surg Oncol 92:151-159, 2005

5. Lavrenkov K, Partridge M, Cook G, et al: Positron emission tomogra-phy for target volume definition in the treatment of non-small cell lungcancer. Radiother Oncol 77:1-4, 2005

6. Nishioka T, Shiga T, Shirato H, et al: Image fusion between 18FDG-PET and MRI/CT for radiotherapy planning of oropharyngeal and na-sopharyngeal carcinomas. Int J Radiat Oncol Biol Phys 53:1051-1057,2002

7. Leong T, Everitt C, Yuen K, et al: A prospective study to evaluate theimpact of FDG-PET on CT-based radiotherapy treatment planning foroesophageal cancer. Radiother Oncol 78:254-261, 2006

8. Moureau-Zabotto L, Touboul E, Lerouge D, et al: Impact of CT and18F-deoxyglucose positron emission tomography image fusion forconformal radiotherapy in esophageal carcinoma. Int J Radiat Oncol

Biol Phys 63:340-345, 2005

9. Konski A, Doss M, Milestone B, et al: The integration of 18-fluoro-deoxy-glucose positron emission tomography and endoscopic ultra-sound in the treatment-planning process for esophageal carcinoma. IntJ Radiat Oncol Biol Phys 61:1123-1128, 2005

0. Vrieze O, Haustermans K, De Wever W, et al: Is there a role for FGD-PET in radiotherapy planning in esophageal carcinoma? Radiother On-col 73:269-275, 2004

1. van Westreenen HL, Heeren PA, Jager PL, et al: Pitfalls of positivefindings in staging esophageal cancer with F-18-fluorodeoxyglucosepositron emission tomography. Ann Surg Oncol 10:1100-1105, 2003

2. Lowe VJ, Booya F, Fletcher JG, et al: Comparison of positron emissiontomography, computed tomography, and endoscopic ultrasound in theinitial staging of patients with esophageal cancer. Mol Imaging Biol7:422-430, 2005

3. Shrikanthan S, Aydin A, Dhurairaj T, et al: Intense esophageal FDGactivity caused by Candida infection obscured the concurrent primaryesophageal cancer on PET imaging. Clin Nucl Med 30:695-697, 2005

4. Bural GG, Kumar R, Mavi A, et al: Reflux esophagitis secondary tochemotherapy detected by serial FDG-PET. Clin Nucl Med 30:182-183, 2005

5. Weber WA, Ott K, Becker K, et al: Prediction of response to preopera-tive chemotherapy in adenocarcinomas of the esophagogastric junctionby metabolic imaging. J Clin Oncol 19:3058-3065, 2001

6. Downey RJ, Akhurst T, Ilson D, et al: Whole body 18FDG-PET and theresponse of esophageal cancer to induction therapy: Results of a pro-spective trial. J Clin Oncol 21:428-432, 2003

7. Song SY, Kim JH, Ryu JS, et al: FDG-PET in the prediction of pathologicresponse after neoadjuvant chemoradiotherapy in locally advanced,resectable esophageal cancer. Int J Radiat Oncol Biol Phys 63:1053-1059, 2005

8. Wieder HA, Beer AJ, Lordick F, et al: Comparison of changes in tumormetabolic activity and tumor size during chemotherapy of adenocarci-nomas of the esophagogastric junction. J Nucl Med 46:2029-2034,2005

9. Westerterp M, van Westreenen HL, Reitsma JB, et al: Esophageal can-cer: CT, endoscopic US, and FDG PET for assessment of response toneoadjuvant therapy–systematic review. Radiology 236:841-851, 2005

0. Hong D, Lunagomez S, Kim EE, et al: Value of baseline positron emis-sion tomography for predicting overall survival in patient with non-metastatic esophageal or gastroesophageal junction carcinoma. Cancer104:1620-1626, 15

1. Jarritt P, Hounsell A, Carson K, et al: Use of combined PET/CT imagesfor radiotherapy planning: Initial experiences in lung cancer. Br J Ra-diol 28:S33-S40, 2005 (suppl)

2. Mell LK, Roeske JC, Mundt AJ: A survey of intensity-modulated radia-tion therapy use in the United States. Cancer 98:204-211, 2003

3. Wu Q, Mohan R, Morris M, et al: Simultaneous integrated boost inten-sity-modulated radiotherapy for locally advanced head-and-neck squa-mous cell carcinomas. I: Dosimetric results. Int J Radiat Oncol Biol Phys56:573-585, 2003

4. Fu WH, Wang LH, Zhou ZM, et al: Comparison of conformal andintensity-modulated techniques for simultaneous integrated boost ra-diotherapy of upper esophageal carcinoma. World J Gastroenterol 10:

1098-1102, 2004