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Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 1, pp. 126–135, 2007Copyright © 2007 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/07/$–see front matter

doi:10.1016/j.ijrobp.2006.12.070

LINICAL INVESTIGATION Head and Neck

POSITRON EMISSION TOMOGRAPHY-GUIDED, FOCAL-DOSE ESCALATIONUSING INTENSITY-MODULATED RADIOTHERAPY FOR HEAD AND

NECK CANCER

INDIRA MADANI, M.D.,* WIM DUTHOY, M.D., PH.D.,* CRISTINA DERIE, R.N.,*WERNER DE GERSEM, IR.,* TOM BOTERBERG, M.D., PH.D.,* MICKY SAERENS,*

FILIP JACOBS, IR., PH.D.,* VINCENT GRÉGOIRE, M.D., PH.D.,† MAX LONNEUX, M.D., PH.D.,†

LUC VAKAET, M.D., PH.D.,* BARBARA VANDERSTRAETEN, IR.,*‡ WOUTER BAUTERS, M.D., PH.D.,§

KATRIEN BONTE, M.D.,� HUBERT THIERENS, PH.D.,‡ AND WILFRIED DE NEVE, M.D., PH.D.*

*Department of Radiotherapy, Ghent University Hospital, Ghent; †Department of Radiation Oncology and Center for MolecularImaging and Experimental Radiotherapy, Université Catholique de Louvain, St.-Luc University Hospital, Brussels;

‡Department of Medical Physics, Ghent University; §Department of Radiology, and �Department of Head and Neck Surgery,Ghent University Hospital, Ghent, Belgium

Purpose: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomog-raphy (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer.Methods and Materials: A Phase I clinical trial was designed to escalate the dose limited to the [18-F]fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET)-delineated subvolume within the gross tumor volume.Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapywith an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30Gy (level II), delivered in 10 fractions. Standard IMRT was applied for the remaining 22 fractions of 2.16 Gy.Results: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two casesof dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16(81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85%and 87% (p � n.s.), and 1-year overall survival at 82% and 54% (p � 0.06), at dose levels I and II, respectively.In 4 of 9 patients, the site of relapse was in the boosted 18F-FDG-PET-delineated region.Conclusions: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximumtolerated dose was not reached at the investigated dose levels. © 2007 Elsevier Inc.

Intensity-modulated radiotherapy, Head and neck cancer, 18F-FDG-PET, Focal-dose escalation.

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INTRODUCTION

t was reported that most failures after conformal radiother-py and intensity-modulated radiotherapy (IMRT) of headnd neck cancer were detected within the regions that re-eived the highest doses (1–3). Homogeneous dose escala-ion in a typically large planning target volume (PTV), asncountered in head and neck cancer, has been limited by

Reprint requests to: Indira Madani, M.D., Department of Ra-iotherapy, Ghent University Hospital, De Pintelaan 185, 9000hent, Belgium. Tel: 0032-9240-30-74; Fax: 0032-9240-38-63;-mail: [email protected] work was presented at the 25th Meeting of the European

ociety for Therapeutic Radiology and Oncology (ESTRO),eipzig, Germany, October 8–12, 2006, and received the ESTRO-iemens Best Poster Award.Conflict of interest: none.I.M. and W.D. contributed equally to this work.
This study was supported by grants from the Belgische Federa-
126

adiation-induced toxicity (4). Disregarding the dogma of ho-ogeneous PTV-irradiation and directing the increased dose to

elapse-prone (i.e., radioresistant) subvolumes may be an al-ernative approach. In this approach, [18-F]fluoro-2-deoxy-D-lucose positron emission tomography (18F-FDG-PET) maye of interest for delineating radioresistant subvolumes.

The evidence that 18F-FDG-avid regions of the tumor aref increased radioresistance was provided by in vitro (5–8)

ie tegen Kanker (51AC8904, FBC2003/2006, and ZKB2747), theesearch Foundation of Flanders (G.0183.03), Ghent University

GOA 12050401, BOF 01112300, 011VO497, and 011B3300),nd the Centrum voor Studie en Behandeling van Gezwelziekten.cknowledgments—B.V. is a research assistant (aspirant) of theesearch Foundation of Flanders. Professor M. Mareel (Ghentniversity Hospital, Ghent, Belgium) is acknowledged for fruitfuliscussions on this and related topics.Received Aug 28, 2006, and in revised form Nov 8, 2006.

ccepted for publication Dec 1, 2006.

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127FDG-PET-guided IMRT for head and neck cancer ● I. MADANI et al.

nd in vivo (9) animal studies that correlated cellular oregional 18F-FDG uptake with hypoxia. In patients, Rajen-ran et al. observed highly significant, positive, pixel-by-ixel correlations between PET images of 18F-FDG uptakend a tracer of hypoxia [18F]fluoromisonidazole; the valuef the correlation coefficient was highest for head and neckumors (10). Tumor hypoxia increases the accumulation of8F-FDG, probably through activation of the glycolyticathway (11), where hypoxia-inducible factor 1-� inducesncreased expression levels of the glucose transporterslut-1, Glut-3, and hexokinase-II that carry 18F-FDG into

he cells (12).For defining the gross tumor volume (GTV) in head and

eck cancer, 18F-FDG-PET was found to be a very accuratemaging modality (13). This approach has been applied inadiotherapy planning of head and neck cancer for contour-ng of the GTV (14–17). However, there are no data onreatment outcomes when 18F-FDG-PET-based target delin-ation is used for dose escalation in head and neck cancer.

Here, we present the results of a Phase I clinical trial thatxplored the feasibility of dose escalation based on 18F-DG-PET. The main goal was to establish the maximum

olerated dose (MTD) when the dose was escalated in 18F-DG-PET-avid foci within the anatomically (based on CT,RI, and clinical examination) documented GTV of head

nd neck cancer. We also report on late toxicity, localontrol, patterns of relapse, survival, and causes of death.

METHODS AND MATERIALS

esign of the trialFocal-dose escalation was performed as an upfront, simulta-

eously integrated boost (SIB) (18) to the 18F-FDG-PET-positiveubvolume within the GTV. The 18F-FDG-PET examination waserformed before the onset of radiotherapy, to obtain optimalmage quality. Radiotherapy tends to decrease the 18F-FDG uptaken the tumor, while radiation-induced inflammation (17) increaseshe background signal in the irradiated volume. With the 18F-FDG-ET examination performed before radiotherapy, we reasoned that

he boost had to be integrated from the start of radiation therapy toecure the fewest possible anatomic and biologic changes betweenhe moment of imaging and the time of radiation delivery. TheMRT was delivered in two phases. During the first phase, the doseas escalated to a focal region defined by 18F-FDG-PET within

he GTV to 25 Gy (dose level I) or 30 Gy (dose level II) in 10ractions. The second phase consisted of standard IMRT applied in2 fractions of 2.16 Gy. This resulted in a total physical dose of2.5 Gy (dose level I) or 77.5 Gy (dose level II) delivered in 32ractions to the 18F-FDG-PET-positive subvolume. The boost vol-me was not limited at dose level I. Based on the experience withdding stereotactic or brachytherapy boosts after high-dose exter-al radiotherapy (19–21), we reasoned that limiting the boostolume could increase safety (i.e., avoidance of radiation necrosisf the SIB procedure). If the boost volume of 18F-FDG-PET-ositive foci at dose level II exceeded 10 cm3, the volume of 10m3 with the highest signal intensity received a daily dose of 3.0y, while the remaining volume received 2.5 Gy. The two phasesf IMRT were delivered using consecutive treatment plans based
n pretreatment imaging. The main goal of the trial was to deter- a
ine the MTD for focal-dose escalation, defined as the maximumose to the 18F-FDG-PET-positive subvolumes that caused dose-imiting toxicity (DLT) in �15% of patients. The DLT was defineds any Grade 4 toxicity observed during radiotherapy and in therst 4 weeks after the end of radiotherapy. Other parameters thatere analyzed included (1) late toxicity, (2) local control, (3) sitef recurrence, (4) overall and cause-specific survival, and (5)auses of death.

nclusion and exclusion criteria, and rules for stoppingPatients were eligible to enroll in the study if they had nonmeta-

tatic, histologically confirmed squamous-cell carcinoma of the oro-harynx, hypopharynx, or larynx (Stage T3–4 N0 or Tany N� foraryngeal cancer according to the TNM classification of Malignantumors of the International Union Against Cancer), for whom theultidisciplinary Head and Neck Cancer Working Group of Ghentniversity Hospital proposed radiotherapy alone or in combinationith chemotherapy, or if patients were considered inoperable or

efused surgery. The Karnofsky performance status was �70. Beforereatment, all patients gave written, informed consent. For staging,atients underwent a detailed clinical examination, pan-endoscopynder anesthesia with biopsy and histologic confirmation of squa-ous-cell carcinoma, CT and/or MRI of the head and neck region,

nd chest CT to exclude pulmonary metastases. Laboratory testsncluded a complete blood count and metabolic panels. Patients withther malignancies, except nonmelanoma skin cancer, and/or previousrradiation of the head and neck region were excluded from the study.his study was approved by the Ethics Committee of Ghent Univer-ity Hospital, and was registered at http://www.clinicaltrials.gov un-er the number NCT00135161. We planned on a minimum of 40atients to enroll in the study: 20 at level I, and 20 at level II. Patientsere continually included in the level I focal-dose escalation studyntil a follow-up of 6 months was achieved for at least 10 patients.nclusion was to be halted if �3 of 20 patients developed Grade �3ate laryngeal, cutaneous, mucosal, or mandibular toxicity at 6 monthsf follow-up or later. Inclusion was also to be stopped if there was aeath due to acute toxicity or if �3 patients developed DLT requiringtreatment break.

maging and target definitionFor planning CT and 18F-FDG-PET imaging, patients were posi-

ioned and immobilized with a thermoplastic mask and neck support.ll images were acquired in the treatment position. Contrast-en-anced CT scanning of the head-and-neck region and thorax waserformed with 2-mm-wide and 5-mm-wide adjacent slices inside andutside the macroscopic tumor region, respectively. The targets andrgans at risk (OARs) were outlined on each CT image. Patientnatomy was assumed to be invariant during treatment. The 18F-DG-PET imaging was performed �1 week after planning CT. The8F-FDG-PET acquisition was performed according to the protocoldapted by Daisne et al. (22) on a Siemens Exact HR� camera (CTI,noxville, TN) operating in three-dimensional mode, using an axialeld of view of 26.675 cm (two bed positions, with a 3.9-cm overlapetween the two bed positions). The PET images were reconstructedith an Ordered Subset Expectation Maximization (OSEM) algo-

ithm after Fourier rebinning.Two GTVs were outlined for radiotherapy planning: the ana-

omic imaging-based GTV (GTVCT), and the biologic imaging-ased GTV (GTVPET). For planning purposes, the GTVCT en-losed the primary tumor and the enlarged lymph nodes separately,
s identified by CT and/or MRI. The anatomic imaging-based
http://www.clinicaltrials.gov

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128 I. J. Radiation Oncology ● Biology ● Physics Volume 68, Number 1, 2007

linical target volume (CTVCT) was a result of three-dimensionalxpansion of the GTVCT by adding a 1.5-cm margin with adjust-ent to exclude uninvolved bones and air cavities. In delineation

f the elective neck CTV, we followed the guidelines proposed byrégoire et al. (23). The 18F-FDG-PET transmission scans wereanually coregistered with planning CT images on a Pinnacle treat-ent planning system, version 6.2b (Philips Medical Systems, An-

over, MA). The GTVPET was the result of automatic segmentationf the 18F-FDG-PET images, based on the source-to-background ratio22). The union GTV (GTVunion) encompassed both the GTVCT andTVPET. In a way similar to the creation of the CTVCT from theTVCT, the CTVunion was created from the GTVunion. A margin of 3m was added to each CTV, to create the respective PTV. Subtrac-

ion of a 6-mm-wide buildup region from the PTV resulted in the PTVithout buildup (PTVwhbu). To create the PTVoptim, a structure used

n optimization, the spinal cord, expanded by a 5-mm margin, as wells all PTVs to which a higher dose was prescribed, were subtractedrom the PTVwhbu. The PET-based PTV (PTVPET) was a result ofxpansion of the GTVPET by a 3-mm margin. The volumes ofontoured structures are shown in Table 1. The following structuresere outlined as OARs: the spinal cord, brainstem, parotid glands,

nd mandible. The spinal cord and the brainstem were expanded by a-mm and 3-mm margin, respectively, to obtain their planning riskolumes (PRVs).

lanning procedure and toolsThe beam configuration was based on a class solution of six

onopposing coplanar beams with a single isocenter (Fig. 1). TheMRT treatment plans were optimized with an in-house-developedxtension of the GRATIS software package (24). For every beam,he in-house-developed, anatomy-based segmentation tool gener-ted initial beam segments based on all PTVs, taking into accounthe presence of the spinal cord and the distance from the targettructures to the skin (25). The parotid gland was included in theool as an organ of avoidance if sparing was considered achievable.egment weight and leaf-position optimization was performedsing the in-house-developed segment outline and weight-adaptingool. The optimization algorithm involved a biophysical objective

Table 1. Volumes of contoured structures as well as D2, D50,and D98 in PTV69 at dose levels I and II

Volumes anddoses Dose level I Dose level II p value

TVPET (cm3) 34.46 � 100.84 23.78 � 32.56 0.32TVPET (cm3) 41.61 � 84.88 53.68 � 49.67 0.85TVunion (cm3) 38.94 � 98.49 39.84 � 42.67 0.6TVunion (cm3) 137.17 � 163.67 188.46 � 93.63 0.992 (Gy) 61.63 � 4.23 59.73 � 5.23 0.5150 (Gy) 69.46 � 0.53 69.54 � 0.61 0.798 (Gy) 72.99 � 0.73 76.76 � 1.09 0.06

Abbreviations: GTVPET � 18F-FDG PET-positive gross tumorolume resulting from automatic segmentation of 18F-FDG PETmages based on source-to-background ratio; PTV69 � PTV re-eiving 69 Gy; PTVPET � PET-based planning target volume;TVunion � combined CT- and PET-based gross tumor volume;TVunion � combined CT- and PET-based clinical target volume.alues are mean � SD (unpaired t-test). D2 and D98 are used as

urrogates for dose maximum and dose minimum, respectively32). D , D , and D are dose levels on the DVHs above which

m2 50 98

ay 2%, 50%, and 98% of the contoured volume, respectively.

unction (26, 27). When the treatment plan fulfilled the acceptanceriteria, the combine, reorder, and step-and-shoot tool resulted in arescription file for the linear accelerator (28).

ose prescription and constraintsThe prescription featured multiple dose levels delivered simul-

aneously (Table 2). A median dose of 69 Gy in 32 fractions of.16 Gy was prescribed to the PTV encompassing the CTVunion,eferred to as PTV69. The PTVPET was the target for focal-dosescalation. The aim was to deliver a dose �65.5 Gy to �95% ofhe volume of the PTV69 minus PTVPET, and to restrict doses

73.8 Gy to �7% of the volume of the PTV69 minus the PTVPET.roportionally similar dose-volume constraints were applied to thether PTVs. Dose inhomogeneity, calculated as (D2–D98)/D50, hado be �12% in the PTV69 and PTVPET. The total physical dose forTVPET was 72.5 Gy or 77.5 Gy for dose levels I and II, respec-

ively (Table 2). A maximum dose of 50, 60, and 70 Gy wasllowed to �5% of the volume of the spinal cord (PRV), brainstemPRV), and mandible, respectively. Median doses should not ex-eed 45, 50, and 27 Gy to the spinal cord, brainstem, and thepared parotid gland, respectively. The D2, D50, and D98 are doseevels on the dose-volume histograms (DVHs) above which lay%, 50%, and 98% of the contoured volume, respectively.

reatment deliveryThe IMRT treatment was delivered with a step-and-shoot tech-

ique, using 6-MV photons of an Elekta Sli 18 linear acceleratorElekta, Crawley, UK). To reduce systematic errors, portal imageswith an Elekta electronic portal imaging device) were acquireduring the first 4 days of treatment. The average setup error wasorrected, with weekly use of the Elekta electronic portal imagingevice.

valuation during treatmentPatients were examined weekly during the course of treatment.onitoring ensured supportive care, including pain and nutrition

ig. 1. Class solution set of six coplanar nonopposing isocentriceams used for intensity-modulated radiotherapy of head and neckancer at Ghent University Hospital. The set consists of beams withantry (G) angles of 45°, 75°, 165°, 195°, 285°, and 315°, respectively.

anagement, antimycotic and topical treatment, and referral for

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ercutaneous gastrostomy if needed. Acute mucosal and skin re-ctions, dysphagia, and weight loss were recorded weekly duringadiotherapy and at 4 weeks after the end of radiotherapy, using theommon Toxicity Criteria, version 2.0 (29).

ollow-upFollow-up was performed during the multidisciplinary consul-

ation of radiation oncologists and head-and-neck surgeons. Forssessment of tumor response and late toxicity, patients underwentclinical examination, conventional contrast-enhanced CT scan-

ing of the head and neck region, and endoscopy at month 3 andhen at 6-month intervals. The Response Evaluation Criteria inolid Tumors (RECIST) were used to score tumor response atonth 3 (30). Documented recurrence was classified as local,

egional, or distant. To relate the site of relapse to sites of therimary tumor and elective lymph nodes, the locoregional relapsesere contoured as rGTVs (recurrent GTVs) on the follow-up CT

nd/or MRI images, which were then fused with the PET-CT usedor treatment planning. A radiologist who specialized in head-and-eck pathology, and who was not involved in the original treat-ent planning, delineated the rGTV(s) of local and regional re-

urrence on the control images for each patient. The midpoint ofGTV was considered the site of relapse. Late toxicity was scoredccording to the LENT/SOMA (Late Effects on Normal Tissues—ubjective, Objective, Management, Analytic) scale (31), 6onths after the end of radiotherapy and then twice a year.valuation of late toxicity included mucosal and skin toxicity,ysphagia, trismus, and laryngeal pain. Overall survival was com-uted from day 1 of radiotherapy to day of death from any cause.ocal control was determined from day 1 of radiotherapy to day of

ocal disease recurrence. Disease-specific survival was estimatedrom day 1 of radiotherapy to day of death due to cancer progres-ion. Patients who were free from cancer recurrence and for whomhe cause of death was precisely known were censored at time ofeath. For all other patients, the cause of death was assumed to beancer progression.

tatistical analysisComparison of the volumes of contoured structures was made

y unpaired t-test. Acute toxicity was scored as incidence of aertain grade of toxicity according to the Common Toxicity Cri-eria, version 2.0 (29). The relationship between severe acuteoxicity and chemotherapy, as well as between acute and late

Table 2. Prescriptio

PTV Frac

TVPET � level I of dose escalationTVPET � level II of dose escalationTV69 � macroscopic tumor � enlarged lymph nodesTV66 � resected lymph nodes with capsule ruptureTV62 � resected lymph nodes without capsule ruptureTV56 � elective lymph nodes

Abbreviations: PTV � planning target volume; PTVPET � PET6 Gy; PTV62 � PTV receiving 62 Gy; PTV56 � PTV receivinelivered in 2.0-Gy fractions based on a linear-quadratic equationays.* The dose of 3 Gy was only delivered to a 10-cm3 subvolume

ysphagia, was evaluated using the chi-square test. Overall sur- o

ival, disease-free survival, and local control were estimated withaplan-Meier techniques. The difference in survival and local con-

rol between the two dose levels was assessed by log-rank statistics. Aalue of p � 0.05 was considered statistically significant. Statisticalnalysis was performed using the Statistical Package for the Socialciences, version 12.0 (SPSS, Inc., Chicago, IL).

RESULTS

Between September 2003 and May 2005, 41 patients withead and neck cancer were treated according to the protocol.he patient characteristics are summarized in Table 3.wenty-three patients were enrolled at level I, and 18 pa-

ients at level II. Most patients fell into Stages T3 and N2.ne patient at level II presented with two primary tumors,

ocated in both the oral cavity and the hypopharynx. Nineatients at level I and 14 at level II received concomitantisplatin-based chemotherapy. Lymph-node dissection waserformed in 12 patients at each dose level. Distribution ofumor site and treatment with chemotherapy were not equaletween both dose levels. Dose level I included more pa-ients with laryngeal cancer (39%), and chemotherapy wasiven to 39% of the patients. At dose level II, 53% patientsad oropharyngeal carcinoma, and 78% patients received che-otherapy. All patients were treated with curative intent.Thirty-nine patients completed the treatment. The median

uration of treatment was 45 days (range, 34–54 days). Therescription dose was not achieved in 2 patients because ofiver metastasis diagnosed in one during radiotherapy (doseevel I), and toxic death in another (dose level II). Twoatients required respective treatment interruptions of 5ays because of Grade 4 skin toxicity (dose level I), and 10ays because of stridor and Grade 3 dysphagia requiringracheotomy and percutaneous gastrostomy (dose level II).he D2, D50, and D98 in the PTV69 did not differ statisticallyetween the two dose levels (Table 1).

cute toxicityThe incidence of acute toxicity, stratified according to

ose level, is presented in Table 4 as the highest scores

levels to the PTVs

e per fraction (Gy)

Total dose (Gy) NID2Gy (Gy)–10 Fractions 11–32

2.16 72.5 78.22.16 77.5 86.72.16 69.1 72.52.06 65.9 67.21.94 62.1 60.91.75 56.0 51.1

PTV; PTV69 � PTV receiving 69 Gy; PTV66 � PTV receivingy; NID2Gy � normalized isoeffective dose, equivalent to dose

where �/� � 10, � � 0.035, with a potential doubling time of 4

rest of the PTVPET received 2.5 Gy.

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reatment, and was scored as an acute toxic reaction. The

Table 3. Patient a

CharacteristicD

Median age (range) in years 60Gender

MaleFemale

Karnofsky performance status90%80%70%

Tumor locationOropharynxHypopharynxLarynxOral cavity

Squamous-cell carcinomaGrade 1 (well-differentiated)Grade 2 (moderately differentiated)Grade 3 (poorly differentiated)Grade unspecified

T-stageT1T2T3T4

N-stageN0N1N2N3

ChemotherapyYesNo

Lymph-node dissectionYesNo

Abbreviation: n.s. � no significance.* One patient had two primary tumors.† Trend test was used for T-stage and N-sta

Table 4. Incide

Dose level n �G3 dysphagia G3

Dose level ICRT 9 8* (89%)RT 14 5 (36%)All 23 13 (57%)

Dose level IICRT 14 8 (57%)RT 4 2 (50%)All 18 10 (56%)

Abbreviations: n � number of patients; Gtoxicity; CRT � chemoradiotherapy; RT � ra

* Includes one patient with Grade 4 dysphradiotherapy.

† Includes one patient with Grade 4 skin toxicity.

ost problematic acute toxicity was caused by dysphagiand mucositis. More than half of the patients at both doseevels (13 of 23 [57%] and 10 of 18 [56%] at dose levels I

or characteristics

vel I23)

Dose level II(n � 18)

Chi-squarep value†

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acute toxicity

sitis �G3 skin toxicity G2 weight loss

) 5† (56%) 4 (44%)) 8 (57%) 1 (7%)) 13 (57%) 5 (22%)

) 5 (36%) 3 (21%)) 0 (0%) 1 (25%)) 5 (28%) 4 (22%)

rade 2 acute toxicity; G3 � Grade 3 acuterapy alone.hich developed at month 3 after the end of

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nd II, respectively) developed Grade �3 dysphagia. Of 23atients receiving chemoradiotherapy (both dose levels), 1670%) and 8 (35%) patients had Grade 3 dysphagia anducositis, respectively. In the 18 patients who received

adiotherapy alone, 7 (39%) patients developed Grade 3ysphagia, and 6 (33%) patients developed Grade 3 mucosi-is. The differences between radiochemotherapy and radio-herapy alone for causing Grade 3 dysphagia or mucositisere not statistically significant (p � 0.5 and p � 1.0,

espectively).Percutaneous gastrostomy was performed in 10 patients

43%) at dose level I and 13 patients (72%) at dose level II,ncluding a gastrostomy placed during treatment in 4 and 6atients at dose levels I and II, respectively. Weight loss of20% was not observed. Grade �2 skin toxicity was theost common toxic reaction. It occurred in 21 of 23 patients

91%) at dose level I, and in 13 of 18 patients (72%) at doseevel II. Grade �3 skin toxicity was observed in 10 of 2343%) patients and 8 of 18 (44%) patients, respectively,eceiving chemoradiotherapy and radiotherapy only (p �.80). Weight loss of Grade 2 (�10%) was observed in 5 of3 (22%) patients at dose level I, and in 4 of 18 (22%)atients at dose level II. Six patients (26%) at dose level I,nd 10 patients (56%) at dose level II, required hospitaliza-ion because of toxicity.

ose-limiting toxicityThere were two events of DLT at dose level I. Grade 4

kin toxicity developed at a cumulative radiation dose of9.6 Gy. Radiotherapy was interrupted for symptomaticreatment, and was completed without any consequentialate effects. Another patient developed Grade 4 dysphagia 3onths after the end of radiotherapy followed by tracheot-

my and laryngectomy. At dose level II, a 51-year-old manith cT3cN3 oropharyngeal cancer developed sepsis and

espiratory and prerenal insufficiency shortly after the endf the second cycle of concomitant chemotherapy (doserescription of cisplatin was 100 mg/m2/3 weeks). The totaladiation dose at that moment was 53 Gy. This patient diedoon afterwards, and his death was attributed to sepsis and

Table 5. Late toxicity measured

Dose level n

DysphagiaLa

G1–2 G3

Dose level ICRT 8 4 (50%) 2 (25%)RT 12 3 (25%) 1 (8%)All 20 7 (35%) 3 (15%)

Dose level IICRT 7 6 (86%) 1 (14%) 1RT 3 2 (67%)All 10 8 (80%) 1 (10%) 1

Abbreviations: n � number of patients; G1
toxicity; CRT � chemoradiotherapy; RT � radiothe
enal failure. The study accrual was stopped because of thisoxic event, as per our protocol.

ate toxicityEvaluation of late toxicity was performed at a minimum

f 6 months after the end of radiotherapy. Eleven patientsere not available for late-toxicity evaluation: one patientid not complete treatment, one patient died during theourse of treatment, one moved abroad, 7 died �6 monthsfter the end of radiotherapy, and one patient with oropha-yngeal carcinoma developed a second primary tumor in thesophagus �6 months after the end of treatment. The datan late toxicity are summarized in Table 5. Twenty patientsere evaluated at dose level I, and 10 patients at dose level

I. No patient developed any Grade 4 late toxic reactions.ysphagia and fibrosis were the predominant toxicities: 10f 20 (50%) and 9 of 10 (90%) patients presented dysphagiaf Grades 1–3 at dose levels I and II, respectively. Thereas no statistically significant relationship between the oc-

urrence of acute and late dysphagia. One patient presentedrade 3 mucosal toxicity at dose level II, located at the

egion of dose escalation. We observed the onset of fibrosisGrades 1–2) in 9 patients in the entire cohort: in 5 of 2025%) patients at level I, and 4 of 10 (40%) patients at levelI (p � 0.8).

umor responseTumor response by dose level is presented in Table 6.

wo patients were not evaluated for response, because deathccurred during radiotherapy or �3 months after the end ofreatment; another 2 patients were lost to follow-up. Theverall tumor-response rate in evaluated patients complet-ng therapy was 90% (19 of 21 patients) and 94% (15 of 16atients) at dose levels I and II, respectively. Clinical com-lete response was observed in 18 of 21 patients (86%) atose level I vs. 13 of 16 patients (81%) at dose level IIp � 0.93). No locoregional progression was observed atither dose level.

nths after last day of treatment

l Mucosal pain andintegrity Fibrosis Trismus

G1 G3 G1–2 G1

1 (13%) 2 (25%)3 (25%)

1 (5%) 0 5 (25%) 0

1 (14%) 3 (43%) 2 (29%)1 (33%)

0 1 (10%) 4 (40%) 2 (20%)

Grade 1–2 late toxicity; G3 � Grade 3 late

�6 mo

ryngeapain

G1

0

(14%)

(10%)

–2 �
rapy alone.

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atterns of failurePatterns of failure are presented in Table 7 and Fig. 2.

he results should be interpreted with caution, consideringhe short follow-up of patients at dose level II. Figure 2ahows that distant metastases were observed in 9 of 1464%) relapsing patients. Isolated regional relapse was ob-erved in 1 of 14 (7%) relapsing patients. Isolated localelapse was observed in 3 of 14 (21%) relapsing patients.using the CT and/or MRI images with the planningET-CT images showed the pattern of locoregional relapseiven in Fig. 2b. Of 9 locoregional recurrences, 2 wereocated in the volume that received 56 Gy of electiverradiation (CTV56). In one patient, the tumor recurred both atTV56 and at CTV69, the volume that received 69 Gy for aross primary tumor and enlarged lymph nodes. One patientelapsed inside the CTV69 but outside the GTVPET. One patientelapsed at the border of the CTV69 and GTVPET; in 4 patients,he site of relapse was the GTVPET.

ocoregional control, and disease-specific andverall survivalThe median follow-up of surviving patients was 14onths (dose level I, 19 months; dose level II, 11 months).he actuarial rate of local control (Fig. 3) at 1 year was 85%t dose level I, and 87% at dose level II (p � 0.82). Thectuarial 1-year rate of overall survival (Fig. 4) was 82% at

Table 6. Tu

Dose level I(n � 23) Percent

Complete response 18 85.7Partial response 1 4.8Stable disease 2 9.5ProgressionNot evaluated 2

Table 7. Clinical charact

Tumor site T N Chemotherapy

ose level IHypopharynx 2 1 NoOropharynx 4 2 YesLarynx 3 1 NoLarynx 3 1 NoLarynx 3 0 NoOropharynx 3 3 YesHypopharynx 4 2 YesHypopharynx 3 3 NoLarynx 2 2 NoOropharynx 4 3 YesHypopharynx 2 2 No

ose level IIOropharynx 4 3 YesOropharynx 4 2 YesOropharynx 2 3 Yes

* Diagnosed during radiotherapy.

ose level I, and 54% at dose level II (p � 0.06). The causef death at dose level I was cancer progression in 7 patients,ntercurrent in 2 patients (one patient died from new cancer,nd another from intercurrent bilateral pneumonia). At doseevel II, causes of death were treatment-related in one pa-ient, cancer progression in 3 patients, intercurrent in 2atients, and unknown (one patient moved abroad). Actu-rial disease-specific survival at 1 year was 82% at doseevel I and 64% at dose level II (p � 0.2) (Fig. 5).

DISCUSSION

Modern imaging techniques may provide spatial informa-ion on radiobiologically relevant parameters inside tumorsr normal tissues that can be directly utilized in radiother-py planning. Using IMRT, intentionally inhomogeneousose distributions can be designed to deliver increasedoses to intratumor regions of higher radioresistance. Al-hough this paradigm has received much attention in theiterature, the results of prospective, clinical validation trialsre scarce. In this prospective dose-escalation trial, 41 pa-ients were included before the trial was stopped by a fataloxic event that seems unrelated to the specific design of therial, i.e., testing focal radiation-dose escalation based on8F-FDG PET imaging. As a result of the early stop, the trialould not be amended to allow further dose escalation, and

sponse rate

e level II� 18) Percent

All patients(n � 41) Percent

13 81.2 31 83.82 12.5 3 8.11 6.3 3 8.1

2 4

and patterns of failures

recurrenceonths)

Regional recurrence(months)

Distant metastases(months)

15 1413117 114 5

6 62*

1113

12

4 45

5

mor re

Dos(n

eristics

Local(m

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he MTD could not be reached. Regarding the main objec-ive of the trial, we can conclude that a boost-dose of 3.0y/fraction to �10 cm3 of the 18F-FDG-PET-avid regions

an be safely integrated in conventionally fractionatedMRT during the first 2 weeks of treatment. The observationhat 39 of 41 patients could finish the prescribed treatment,nd that only 2 of 39 patients required a treatment break,eads us to conclude that the schedule was feasible, evenhen combined with concurrent cisplatin. Grade 3 dyspha-ia, occurring in 57% (dose level I) and 56% (dose level II)f patients, was the most disturbing acute side effect. Con-idering the brief follow-up, the already high incidence ofate dysphagia and fibrosis (Table 7) deserves attention.ariables that could contribute to late toxicity include: (1)

he fraction size of 2.16 Gy to relatively large CTV volumesncompassing the GTV with a 1.5-cm margin; (2) highrescription doses of 56–66 Gy to elective nodal sites; (3)pplication of the guidelines of Grégoire et al. (23) forelineation of elective nodal regions, which leads to largeolumes of elective irradiation; (4) the use of chemotherapyn �50% of patients; and (5) focused dose escalation withraction sizes of 2.5–3.0 Gy. In one patient treated at doseevel II, a poorly healing ulceration of the pharyngeal mu-osa coincided with the region of focal-dose escalation.

ig. 2. Patterns of failure: (a) types of failure and (b) sites of failuren target volumes. Numerals within circles indicate the number ofatients with a failure depending on the type and the site of theailure. GTVPET � PET-based gross tumor volume; CTV69 �TVPET � clinical target volume receiving 69 Gy minus the

8F-FDG-PET-delineated subvolume of the GTV; CTV � clin-
56
cal target volume receiving 56 Gy. l

In 9 of 14 (64%) patients with recurrence, distant metas-ases were detected. Four of these patients received concur-ent chemotherapy but developed metastatic disease at 2, 5,

ig. 3. Kaplan-Meier estimates of local control by dose levels.ecurrence inside CTVPET and/or CTV69 was scored as an event.

ncomplete observations or deaths by any cause were censored onast day of follow-up or on day of death, respectively. CTV69 �linical target volume receiving 69 Gy.

ig. 4. Kaplan-Meier estimates of overall survival by dose
evels.

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Fl


, and 13 months of follow-up. Locoregional recurrence,ith or without distant metastasis, was observed in 9 pa-

ients, in whom 5 had the 18F-FDG-avid region or its borders site of relapse. In 4 patients, the 18F-FDG-avid regionas the sole site of recurrence. These observations suggest

hat 18F-FDG might be a useful tracer for detecting intratu-or regions of increased radiation resistance. Plans of fo-

used dose escalation based on 18F-FDG-PET imaging cane designed for the initial phase of fractionated radiother-py. Given the association of high 18F-FDG-uptake withypoxic regions and inflammation, 18F-FDG-PET may be

ig. 5. Kaplan-Meier estimates of disease-specific survival by doseevels.

ess useful later during fractionated radiotherapy, when r

REFEREN

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1

1

1

eoxygenation and inflammation occur. During the mid- andate stages of proliferation, focused dose escalation, basedn tracers that image proliferation or intrinsic radiosensitiv-ty, seems a more logical approach. The use of consecutiveracers for adapting plans of focused dose escalation duringcourse of fractionated radiotherapy seems self-evident, but

he technical challenges are far from resolved. It seems thatodels for geometrical image deformation will be needed,

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adiotherapy, the anatomy of the patient as well as theiological signal distribution may have changed.A strong tendency toward worse survival and cause-

pecific survival was observed in patients included at doseevel II of this study. This difference cannot be explained byifferences in tumor response or local failure rates, whicheem to be equal at both dose levels. For patients includedt dose level II, the GTV tended to be larger, and relativelyore pharyngeal than laryngeal tumors were included. Of

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A randomized Phase II trial comparing the dose prescrip-ion at dose level II with standard IMRT (i.e., no foci ofose escalation inside the GTV) is planned, with localontrol as the primary endpoint.

CONCLUSIONS

Focused dose escalation using 18F-FDG-PET imaging iseasible in head and neck cancer. An upfront SIB of 3.0y/fraction during 10 fractions is below the MTD, andigher or prolonged dose-escalation studies should be ini-iated. More than half of the local relapses occurred insidehe 18F-FDG-avid region, which received the highest dose,hich suggests the ability of 18F-FDG-PET to detect

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