Int. J. Radiation Oncology Biol. Phys., Vol. 76, No. 1, pp. 146–153, 2010Copyright � 2010 Elsevier Inc.

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jrobp.2009.01.060

doi:10.1016/j.i

CLINICAL INVESTIGATION Head and Neck

SELECTIVE NODAL IRRADIATION FOR HEAD AND NECK CANCER USINGINTENSITY-MODULATED RADIOTHERAPY: APPLICATION OF RTOG CONSENSUS

GUIDELINES IN ROUTINE CLINICAL PRACTICE

SAPNA NANGIA, M.D.,* KUNDAN S. CHUFAL, M.D.,* ATUL TYAGI, M.SC.(PHY.), D.R.P.,*z

ANSHUL BHATNAGAR, M.B.B.S.,* MANINDRA MISHRA, D.R.P.,* AND D. GHOSH, M.B.B.S., M.D.*

*Batra Hospital and Medical Research Centre, New Delhi, India; and zMMH College, Ghaziabad, Uttar Pradesh, India

Reprintogy, BatrInstitutionFax: 9111

Purpose: We have been using intensity-modulated radiotherapy (IMRT) for selective neck irradiation. This articlepresents an analysis of patterns of failure and their dosimetric correlation.Methods and Materials: Between October 2003 and January 2008, 83 patients with head-and-neck cancer weretreated with IMRT. Nodal levels were contoured as per the Radiation Therapy Oncology Group (RTOG) consensusguidelines.Results: There were 32 relapses with 23 local relapses (21 local relapses alone and 2 local and regional relapses,simultaneously), 9 regional relapses (including 2 simultaneous local and regional relapses), and 5 distant relapses,of which 2 patients had local relapses. At 2 and 3 years, the locoregional relapse-free survival rates were was 68.3%and 60.8%, respectively, while the overall survival rates were 84.1% and 81.7%, respectively. Subgroup analysesrevealed significant differences in locoregional relapse-free survival rates for total treatment times of <53 days vs.>53 days, a volume of CTV1PTV (i.e., the volume prescribed 70 Gy) <177 cc vs. >177 cc, a V100 for CTV1PTV of<91% vs. >91%, and a minimum dose to CTV1PTV of <54 Gy vs. >54 Gy. There were no failures in the electivenodal volume, substantiating both the nodal selection criteria and the RTOG consensus guidelines for delineationof neck node levels.Conclusions: IMRT for head–neck cancer is feasible, using elective nodal selection criteria along with RTOGconsensus guidelines for the radiological boundaries of levels of neck nodes. � 2010 Elsevier Inc.

IMRT, Locally advanced head and neck cancer, RTOG, Target definition, Pattern of failure.

INTRODUCTION

Intensity-modulated radiotherapy (IMRT) is capable of pre-

cisely conforming the dose around the target and thus helps

in reducing the dose to critical organs. In order to accurately

utilize the full potential of this conformal radiotherapy tech-

nique, detailed knowledge of radiological anatomy of the tu-

mor and its lymphatic drainage is a must. Different guidelines

addressing selection of nodal levels as per the primary tumor

are present (1, 2) besides the RTOG consensus guidelines (3),

which describe radiological boundaries of these nodal levels.

We have been using IMRT based on these guidelines since

2003 and have already published our preliminary dosimetric

and clinical results (4, 5). Although selective neck irradiation

using IMRT is feasible for parotid sparing and target cover-

age, how safe is the approach of migrating from comprehen-

sive neck irradiation to selective neck irradiation with regard

to locoregional control? We present our results with special

emphasis on the pattern of failure and its correlation with do-

simetric parameters. In addition, we validate our nodal selec-

requests to: Sapna Nangia, M.D., Department of Oncol-a Hospital and Medical Research Centre, 1, Tughlakabadal Area, New Delhi 110062, India. Tel: 919891010390;29957661; E-mail: sapna_nangia@hotmail.com

146

tion criteria and the RTOG consensus target delineation

guidelines.

METHODS AND MATERIALS

Our clinical IMRT program started from October 2003. Patients

were required to have pathology confirmed squamous cell carci-

noma of the head and neck. Prior permission was granted by the in-

stitutional review board and ethics committee.

Target selection, delineation, and dose prescriptionDelineation of gross tumor volume (GTV) was done as per clin-

ical findings and radiological imaging. We defined clinical target

volume 1 (CTV1) as a high-risk volume with a margin of 1.5 cm

around the GTV. This margin was flexible, depending upon the

presence or absence of an anatomical barrier; for example, the

CTV was not extended into the mandible in the case of carcinoma

at the base of tongue, while for supraglotic carcinoma involving

the base of tongue, the entire base of the tongue was included in

the CTV1, in addition to the portion within the 1.5-cm margin

around the GTV. The planning target volume (PTV) margin of 3

Conflict of interest: none.Received Sept 23, 2008, and in revised form Jan 14, 2009.

Accepted for publication Jan 20, 2009.

Table 1. Dosimetric parotid and tumor coverage parameters

Parameter Coverage Average dose (Gy) V95% V93%

Target coverage Ideal >3 Gy of the prescribed dose >98 >99Acceptable >5 Gy of prescribed dose >95 >98

Parotid volume sparing Ideal sparing dose <30% Gy Volume of 30 Gy #50%Acceptable <32% Gy Volume of 30 Gy #50%

Critical structure Ideal sparing dose <1%* <10%y 0%z

Acceptable <5%* <15%y <1%z

Abbreviations: Vn% = percentage of the volume of target receiving n% of the prescribed dose; Vn Gy = percentage of the volume of the organreceiving $n Gy of the dose.

* Critical structures include the spine (V45 Gy).y mandible (V60 Gy).z brainstem (V54 Gy).

Selective neck irradiation with IMRT d S. NANGIA et al. 147

mm was taken around the CTV1, and the structure was defined as

CTV1PTV. CTV2 was defined as the low-risk volume and included

uninvolved neck node levels selected on the basis of the primary site

and status of the neck. Selection of nodal levels is described in detail

by Eisbruch et al. (2) and Gregoire et al. (1), and we followed the

same guidelines, with minor modifications. Eisbruch et al. (2) advo-

cated inclusion of the ipsilateral lymph node levels for T2 tonsillar

primary, while we treated the neck bilaterally. All nodal levels

which carried a metastatic disease risk of >5 % were included in

CTV2. The probability of involvement was computed as described

for the data compiled by Gregoire et al. (1). Details of uninvolved

nodal level inclusion criteria in our study are given below.

(1) Oropharynx (N0): bilateral Levels II to IV. Oropharynx (N+):

for N+ neck level IB to V plus retropharyngeal lymph nodes, while

for contralateral N0 neck levels II to IV. In the case of lesions ex-

tending from the base of the tongue to the anterior tongue, level

IB was also included for the N0 neck.

(2) Supraglottic larynx (N0): bilateral levels II to IV and VI.

Supraglottic larynx (N+): level II to VI plus retropharyngeal lymph

nodes, while levels II to IV for contralateral N0 neck. In the case of

glottic larynx, stages T3 to T4 were treated as a supraglottic larynx,

while for T2N0 glottic lesions with impaired cord mobility, nodal

levels II to IV bilaterally were included in CTV2. Subglottic prima-

ries were treated like a supraglottic larynx, with the exception of

level VI which was included bilaterally.

(3) Hypopharynx (N0): bilateral levels II to IV and retropharyng-

eal lymph nodes. Hypopharynx (N+): for N+ neck level II to VI plus

retropharyngeal lymph nodes, while for contralateral N0 neck levels

II to IV. In cases of postcricoid lesions, level VI was always in-

cluded.

(4) Oral cavity (excluding buccal mucosa, alveolus and retromo-

lar trigone lesions): N0 neck, bilateral levels IB to IV. Oral Cavity

(N+): for N+ neck level IA to V, while for contralateral N0 neck

levels IB to IV for lesions that warranted contralateral neck irradia-

tion. If the lesion extended anteriorly to the floor of mouth or lip,

level IA was always treated. In the case of buccal mucosa and retro-

molar trigone lesions with N+ neck ipsilateral level IA to V and con-

tralateral level IA to IV was treated.

(5) Postoperative cases. In postoperative cases where the neck

was positive, all nodal levels on the ipsilateral side and selective

contralateral nodal levels, depending on the primary site, were in-

cluded in CTV2, while the tumor bed was taken as CTV1. The af-

fected nodal level was included in the CTV1 volume.

Neck nodes were contoured using the RTOG guidelines for the

N0 neck (3). In all cases where the neck was clinically or patholog-

ically positive, comprehensive nodal irradiation, including retro-

pharyngeal nodes, as explained above, was carried out. If a node

abutted the sternocleidomastoid, the muscle was included along

the course of that node or nodal level, whichever was larger. Level

II was drawn up to the base of the skull and level IV up to the sternal

notch. Boundaries for levels IV and V were modified, and the whole

supraclavicular fossa was included in the CTV2 for the N+ neck. A

PTV of 3 mm was generated around the CTV2, and the structure was

labeled the target. The spinal cord, parotid, mandible, larynx, oral

cavity, cochlea, and brainstem were marked as organs at risk. A

planning risk volume of 3 mm was generated around the spinal

cord and the structure called the planning risk volume spine.

IMRT with simultaneous integrated boost was used. The dose pre-

scription for CTV1PTV was 70 Gy in 35 fractions, while for post-

operative cases, it was 66 Gy in 33 fractions. At the same time,

the target in radical cases received 56 Gy in 35 fractions, whereas

54 Gy in 33 fractions was administered to targets in postoperative

cases. The lower anterior neck was treated with a conventional direct

anterior supraclavicular field, in cases of oral cavity and oropharynx

primaries with no gross primary and/or nodal disease extending to

the lower neck. In the rest of the cases, the lower neck was included

within the IMRT field. If dose constraints could not be met for both

parotids, only the contralateral parotid was spared.

Treatment planning and optimizationThe patient’s neck and shoulder were immobilized with the help

of a thermoplastic cast (Orfit, Belgium) with the head in a neutral

position. Simulation was done with a Verasim simulator (GE Med-

ical Systems, France). The probable isocenter was marked with

radiopaque markers. Treatment planning helical computed tomogra-

phy (CT) with contrast was carried out with a Prospeed SX Advan-

tage unit (GE Medical Systems, WI). Helical CT 2.5-mm slice scans

were obtained from the head down through the clavicle and trans-

ferred to the planning system. Targe delineation was done according

to the above-mentioned methods. The IMRT plans were generated

to achieve the dosimetric parameters as mentioned in Table 1. Plan-

ning details and quality assurance procedures and results have been

reported previously (4, 5, 6). Treatment was delivered using an MD2

linear accelerator (Siemens Medical Systems, Inc., Concord, NH).

Concurrent chemotherapy consisting of cisplatin, 30 mg/m2 or car-

boplatin according to the area under the curve (AUC) at AUC 1 once

per week was administered, where applicable.

Statistical analysis and follow-upAll statistical analyses were done with SPSS software version 15.

Descriptive statistics were calculated for mean, median, proportions,

and standard deviations. The Independent T test was carried out to

highlight the differences within each group. Significant differences

Table 2. Details of pattern of relapses

Patient Treatment Primary site Biopsy T stage N stage TTR (months)* Recurrence Recurrence volume

1 Definitive Tonsil MDSCC T2 N0 21 LRy CTV1PTV2 Definitive Larynx WDSCC T3 N0 17 LR CTV1PTV3 Definitive Tongue WDSCC T4 N0 45 LR CTV1PTV4 Definitive Larynx WDSCC T2 N2b 2 LR CTV1PTV5 Definitive Tonsil MDSCC T2 N0 10 LR CTV1PTV6 Definitive Larynx PDSCC T3 N2b 16 LR CTV1PTV7 Postoperative Oral cavity WDSCC T3 N0 2 LR CTV1PTV8 Definitive Tonsil WDSCC T3 N0 3 LR CTV1PTV9 Definitive Base of tongue WDSCC T4 N2 9 LR CTV1PTV

10 Definitive Hypopharynx WDSCC T2 N0 30 LR CTV1PTV11 Definitive Hypopharynx MDSCC T3 N0 8 LR CTV1PTV12 Definitive Base of tongue PDSCC T4 N2 6 LR CTV1PTV13 Definitive Base of tongue WDSCC T2 N2 19 LR CTV1PTV14 Definitive Tonsil PDSCC T3 N1 2 LR CTV1PTV15 Definitive Base of tongue MDSCC T2 N1 29 LR CTV1PTV16 Definitive Larynx PDSCC T2 N0 21 LR Just outside CTV1PTV17 Definitive Base of tongue WDSCC T3 N2 2 LR CTV1PTV18 Definitive Base of tongue WDSCC T3 N2 25 Ryy CTV1PTV19 Definitive Hypopharynx PDSCC T3 N2b 2 LR CTV1PTV20 Definitive Base of tongue MDSCC T3 N0 11 LR+DMx CTV1PTV plus distant metastases

(lung)21 Definitive Larynx PDSCC T3 N2 17 R CTV1PTV and mediastinal nodes22 Definitive Tonsil UDSCC T3 N2b 7 R CTV1PTV23 Definitive Base of tongue WDSCC T3 N3 6 R CTV1PTV24 Definitive Larynx MDSCC T3 N3 9 R Soft Tissue of neck outside of

CTV1PTV and the target25 Postoperative Larynx MDSCC T4 N2 2 R CTV1PTV26 Definitive Hypopharynx PDSCC T2 N2c 7 LR+R CTV1PTV27 Postoperative Larynx PDSCC T4 N1 5 R CTV1PTV28 Definitive Hypopharynx SCCNOS T2 N1 4 LR+R CTV1PTV29 Definitive Base of tongue PDSCC T4 N2b 5 DM+LR CTV1PTV and distant metastases

(Lung and bone)30 Postoperative Tongue WDSCC T3 N0 14 DM Distant metastases (lung, liver, and

bone)31 Definitive Base of tongue WDSCC T3 N0 8 DM Distant metastases (lung)32 Postoperative Oral cavity WDSCC T4 N0 3 DM+LR Extensive local recurrence with

metastatic nodules over the facialscar and coccyx

Abbreviations: TTR = time to recurrence; LR = local recurrence; R = regional recurrence; DM = distant metastases; T = tumor; N = node;WDSCC = well differentiated squamous cell carcinoma; MDSCC = moderately differentiated squamous cell carcinoma; PDSCC = poorlydifferentiated squamous cell carcinoma.

148 I. J. Radiation Oncology d Biology d Physics Volume 76, Number 1, 2010

(an alpha value of #0.05) were further tested for power (should be

>0.80). Correlation between different variables was tested with the

Pearson correlation coefficient (PCC). The time for endpoints was

calculated from the date of registration. Time-dependent variables

were analyzed using Kaplan-Meier methods. The first recurrence

of disease at a local or regional site or persistent disease was treated

as an event for locoregional relapse-free survival (LRFS). Persistent

disease was regarded as a failure on the last day of radiotherapy.

Events for calculating overall survival (OS) included all deaths

and loss to follow-up. All patients lost to follow-up, with or without

disease, were counted as events, and the time to event was their last

follow-up visit. Differences between various subgroups in terms of

survival functions were identified by using the log rank test and the

value of #0.05 was considered significant. A model was built to

compute the risk of relapse for all the significant variables, using

the Cox regression hazard model with the forward stepwise (likeli-

hood ratio) method.

All patients had follow-up scans. The diagnostic CT scans of

patients for whom therapy failed were visually analyzed by two

authors to delineate the region of relapse, which was visually

matched with the planning CT scans. In the absence of the fusion

of the planning and posttreatment scans, the failures were identified

as being within the CTV1PTV/target rather than infield or marginal

recurrence.

RESULTS

Patient and tumor characteristicsA total of 83 patients were treated with IMRT for head and

neck cancer from October 2003 to January 2008. There were

69 male and 14 female patients with a mean age of 59.6

(�10) years. The distribution of patients according to site

was larynx, 35; hypopharynx, 13; tonsil, 7; base of tongue,

17; anterior tongue, 6; oral cavity, 2; and secondary neck pri-

mary unknown, 3. Forty- seven patients had positive neck

nodes, and the N stage distribution was N0:N1:N2:N3 =

36:10:32:5 patients, respectively. The T stage distribution

was T0:T2:T3:T4 = 3:29:37:14 patients, respectively. Sixty-

six patients were treated definitively, while 17 patients were

Fig. 1. Kaplan-Meier curve representing locoregional relapse-freesurvival.

Table 3. Details of dosimetric parameters achieved

Parameter DoseMean (%)

or Gy SD 95% CI

CTV1PTV V100% 91.2 4.0 90.3, 92.1V95% 97.6 1.4 97.3, 97.9V93% 98.6 0.9 98.4, 98.8V110% 28.2 15.5 24.7, 31.6Minimum (R) 53.7 Gy 6.8 52.1, 55.4Minimum (P) 49.6 Gy 7.9 45.4, 53.8Average (R) 74.4 Gy 1.8 74.9, 74.8Average (P) 71.0 Gy 0.9 70.5, 71.5

Target V100% 92.8 4.1 91.9, 93.7V95% 96.5 2.5 95.9, 97.0V93% 97.6 1.9 97.2, 98.0Minimum 31.4 Gy 10.3 29.2, 33.7

Ipsilateralparotid

V28Gy 85.6 20.5 81.1, 90.1

V30Gy 81.0 22.5 76.1, 85.9V35Gy 72.0 26.4 66.3, 77.8Average 44.1 Gy 12.5 41.3, 46.8

Contralateralparotid

V28Gy 64.4 19.8 64.4, 60.1

V30Gy 56.6 20.0 52.2, 60.9V35Gy 38.6 16.6 34.9, 42.2Average 31.5 Gy 6.5 30.2, 32.9

PRVspine(spinal cord)

Maximum 51.2 Gy 3.7 50.4, 52.0

Brainstem Maximum 47.2 Gy 13.3 44.3, 50.1

Abbreviations: Vn% = percentage of volume of the target receiv-ing n% of the prescribed dose; VnGy = percentage of volume of theorgan receiving a dose $n Gy; R = radical patients; P = postopera-tive patients; SD = standard deviation; CI = confidence interval.

Selective neck irradiation with IMRT d S. NANGIA et al. 149

treated in a postoperative setting, of which 15 cases had unilat-

eral radical neck dissection, 1 had bilateral neck dissection, and

1 had no neck dissection. In all 15 cases the contralateral intact

neck was treated electively and was included in the target vol-

ume. Median average weekly hemoglobin level and follow-up

time for the whole group was 12.5 (�1.25) mg/dl and 33 (�5)

months. Median total treatment time (TTT) for definitive pa-

tients was 53 (�6.3) days, and for postoperative patients, was

50 (�5.1) days . The median volumes of CTV1PTV for post-

operative and radical patients were 177.1 (�66.4) and 187.1

(�108.1) cc, respectively. Concurrent chemotherapy along

with radiation was given to 71 (81.55%) patients, while 12

(14.5%) patients did not receive it.

Pattern of relapseOverall there were 32 relapses. Four patients had residual

neck nodes and underwent neck dissection. Two of these pa-

tients were histopathologically negative and were not consid-

Fig. 2. Kaplan-Meier curve representing overall survival.

ered treatment failures, while the other two were positive.

There were 23 local relapses (21 local relapses alone and 2 lo-

cal and regional relapses simultaneously), 9 regional relapses

(including 2 simultaneous local and regional relapses), and 5

distant relapses, of which 2 patients had local relapses. Details

of relapses are given in Table 2. No patient failed within the

CTV2 volume (defined as the elective nodal volume), while

there was one recurrence at the margin of CTV1 and another

recurrence near the paraspinal muscles of the neck. The first re-

lapse of the two outside the high-dose target volume was a case

of carcinoma supraglottic larynx with T2 N0 disease. The site

of failure was the posterior pharyngeal wall just superior to the

epiglottis and vallecula. This patient subsequently underwent

brachytherapy with an interstitial implant and at present dis-

ease free. The second relapse occurred in a case of carcinoma

larynx T3N3 in the region of the paraspinal muscles from C5 to

C6. Contrast-enhanced CT scans and contrast-enhanced mag-

netic resonance imaging revealed a soft tissue mass with ver-

tebral destruction and cord compression. The patient

presented with stridor and worsening powers in the upper

and lower limbs. Flexible laryngoscopy revealed extensive la-

ryngeal edema that compromised the airway, with no evidence

of disease. The patient underwent cervical laminectomy to re-

lieve the cord compression and tracheostomy for laryngeal

edema, followed by targeted therapy with oral gefitinib. This

patient is presently alive with stable disease. The distribution

of relapses according to the primary site was 5, 7, 2 and 9

Table 4. Comparison of parameters among patients with recurrence vs. patient without recurrence

Parameter Recurrence values � SD (n = 32) No recurrence values � SD (n = 51) p value Power

Total treatment time 56.7 � 5.8 days 52.3 � 6.0 days 0.002 0.95Age 56.9 � 9.1 y 61.2 � 11.8 y 0.087 Not appliedAverage weekly

hemoglobin level12.4 � 1.29 mg/dl 12.4 � 1.23 mg/dl 0.933 Not applied

CTV1PTV volume 233.5 � 117.6 cc 166.2 � 80.2 cc 0.003 0.87V100% for CTV1PTV 89.7% � 3.9% 92.1% � 3.9% 0.008 0.84V95% for CTV1PTV 97.2% � 1.5% 97.8% � 1.3% 0.059 0.51V93% for CTV1PTV 98.3% � 0.9% 98.8% � 0.8% 0.032 0.71Minimum dose

to CTV1PTV51.08 � 5.82 Gy 54.11 � 7.7 Gy 0.047 0.62

Abbreviations: Vn% = percentage of volume of the target receiving n% of the prescribed dose; SD = standard deviation.

150 I. J. Radiation Oncology d Biology d Physics Volume 76, Number 1, 2010

patients for tonsillar, base of tongue, primary tongue, and la-

ryngeal primaries, respectively.

ToxicityAcute toxicity was present in the form of Grade III mucositis

for 55 (66.3%) patients, Grade III dysphagia for 29 (34.9%)

patients, Grades II to III skin toxicity for 16 (19.3%) patients,

and hematological toxicity for 34 (40.9%) patients. Hemato-

logical toxicity was present in the form of Grades II to III

neutropenia for 18 (21.7%) patients and Grades I to II throm-

bocytopenia for 17 (20.5%) patients. Nasogastric (NG) tube

feeding was required for 31 (37.3%) patients, while the rest

of the patients were managed with oral or intravenous nutri-

tional support. The mean duration of NG tube feeding in these

31 patients was 29.3 days (95% confidence interval [CI], 21.1,

37.6). Four patients required NG tube intubation for 3 months

because of severe odynophagia with swallowing dysfunction.

One patient developed a local recurrence and is permanently

on NG tube feeding. Among the 5 patients who presented

with tracheostomy prior to starting radiation, 2 underwent

tracheostomy closure. Postradiation, 8 patients required tra-

cheostomy, 3 as a part of surgery for local recurrence (laryn-

geal, 1; and oropharynx, 2) and 5 patients for laryngeal

edema (base of tongue, 1; and larynx, 4). Of these 5 patients,

3 underwent tracheostomy closure (base of tongue, 1; and lar-

ynx, 2), while 2 patients are presently dependent on tracheos-

tomy. Xerostomia was assessed subjectively for all the patients

at their last follow-up and was assessed as Grade 0 to 1 in 53

(63.9%) patients and Grade II in 30 (36.1%) patients. Compli-

ance to chemotherapy was excellent as 69 (97.2%) patients out

of 71 completed 5 or more than 5 cycles.

Table 5. Comparison of parameters among patients w

Parameter Without xerostomia (n = 53)

CTV1PTV volume 174.7 � 93.2 ccV28Gy CLP 60.5% � 20.2%V30Gy CLP 52.9% � 20.2%V35Gy CLP 34.2% � 14.4%Average dose CLP 29.96 � 5.76 Gy

Abbreviations: VnGy = percentage of the volume of the organ receiving $

Survival dataLRFS and OS rates at 3 years were 60.8% and 81.7%, re-

spectively, with median LRFS and OS times not reached

(Fig. 1). Separate analyses for radical, i.e., definitively

treated, patients (n = 66) revealed 3-year LRFS and OS rates

of 70.6% and 80%, respectively, while rates were 54.5% and

81.9%, respectively, for postoperative cases (n = 17), with no

significant statistical differences. Subgroups were defined on

the basis of median values for continuous variables. LRFS for

patients with TTT of #53 days vs. those with more than 53

days, a CTV1PTV volume of #177 cc vs. more than 177

cc, a V100 for CTV1PTV of #91% vs. more than 91%,

and a minimum dose to CTV1PTV of #54 Gy vs. more

than 54 Gy was 73.1% vs. 39.1% (p = 0.037), 74.8% vs.

32.9% (p = 0.001), 40.9% vs. 67.3% (p = 0.001), and

31.8% vs. 74.3% (p = 0.0003), respectively (Fig. 2). In terms

of OS, this difference was only significant for the volume of

CTV1PTV (93.5% vs. 65.8% [p = 0.028]) and the minimum

dose to CTV1PTV (66.3% vs. 93.1% [p = 0.042]).

Dosimetric details in relation to clinical outcomeResults of dosimetric analyses for the target and critical

structures are presented in Table 3. CTV1PTV was under-

dosed 0.4% and 0.4% in terms of V95% and V93%, respec-

tively. The target was underdosed 1.5% and 1.4% in terms of

V95% and V93%, respectively. V100%, V95%, and V93%

for CTV1PTV among patients treated with radical intent

was 91.3%, 97.8%, and 98.7%, respectively, while for post-

operative cases it was 90.8%, 96.9%, and 98.2%, respec-

tively. Target coverage in terms of V100%, V95%, and

V93% was 92.9%, 96.4%, and 97.5%, respectively, while

ith xerostomia vs. patients without xerostomia

With xerostomia (n = 30) p value Power

222.9 � 108.7 cc 0.036 0.8971.3% � 17.4% 0.016 0.7262.9% � 18.3% 0.028 0.6346.3% � 17.7% 0.001 0.8934.26 � 5.92 Gy 0.002 0.89

n Gy of dose; SD = standard deviation; CLP = contralateral parotid.

Table 6. Comparison of different studies reporting results for IMRT with regard to locoregional control

Study, year (ref.)No. ofpatients Site(s)

No. of patientsreceiving

chemotherapy(% of total)

Operative status,no. of patients

(% of total)

No. of patientswith Stage T3–T4

disease (% of total)Locoregional

control rate (%)

Dawson et al., 2000 (13) 58 OC, OP, HP, L, UP 16 (27.6) PORT, 41 (82.0) 23 (39.6) 2 y, 79%Definitive, 17 (34.0) 3 y, 75%

Chao et al., 2003 (15) 126 NP, PNS, OC, OP, 35 (27.8) PORT, 74 (58.8) 65 (51.6) 2 y, 85%HP, L, UP, Others Definitive, 52 (41.2)

Eisbruch et al., 2004 (9) 133 OC, OP, HP, L, UP 43 (32.3) PORT, 73 (54.9) 51 (38.3) 3 y, 82%Definitive, 60 (45.1)

Arruda et al., 2006 (14) 50 Oropharynx 43 (86.0) All definitive 17 (34.0) 2 y regionalprogression-free, 88%

This study 83 OC, OP, HP, L, UP 71 (85.5%) PORT, 17 (20.5) 51 (63.7) 3 y, 60.1%Definitive, 66 (79.5) 2 y, 68.3%

Abbreviations: HP = hypopharynx; L = larynx; NP = nasopharynx; OC = oral cavity; OP = oropharynx; PNS = paranasal sinus; PORT =postoperative radiotherapy; UP = neck node metastases from unknown primary.

Selective neck irradiation with IMRT d S. NANGIA et al. 151

for postoperative cases it was 92.6%, 96.9%, and 97.9%, re-

spectively. Detailed analyses of factors for patients experi-

encing locoregional relapse are presented in Table 4.

Patients with and without xerostomia had significant differ-

ences in term of various dose volume parameters (Table 5).

Multivariate analysis revealed that TTT, volume of

CTV1PTV, and V100 for CTV1PTV were significant pre-

dictors for locoregional relapse. Correlation between the

variables found to be significant by PCC were excluded

from the final Cox regression hazard model. There was sig-

nificant correlation between TTT and volume of CTV1PTV

(p = 0.000, PCC = 0.548), TTT and minimum dose to

CTV1PTV (p = 0.049; PCC = �0.243), volume of

CTV1PTV and minimum dose to CTV1PTV (p = 0.000;

PCC = �0.455), volume of CTV1PTV and V100% for

CTV1PTV (p = 0.027; PCC = �0.273), minimum dose to

CTV1PTV and V100% for CTV1PTV (p = 0.001; PCC =

0.394). There was no significant correlation between TTT

and V100% for CTV1PTV (p = 0.627; PCC = �0.061),

and these variables were used in the final model for predict-

ing the hazard for locoregional relapse. There was a 9% de-

crease in hazard for locoregional relapse for each percent

increase in coverage by prescription dose, as measured by

V100 for CTV1PTV. Conversely, each day’s increase in

TTT was associated with a 7% increase in hazard of locore-

gional relapse. Combining these two variables, a predictive

model has been built which can compute the change in haz-

ard according to the changes in the values of these two vari-

ables, using the equation, hazard = [100 � (1.07x X 100)] +

[100 � (0.91Y X 100)]. In this formula, x is the change in

total treatment time, while y is change in coverage for

V100% for CTV1PTV; for example, in the case of

a 1-day increase in TTT and a 1% increase in V100%, the

hazard from the above equation can be calculated as [100

� (1.07x X 100)] + [100 � (0.91Y X 100)] = [100 � 107]

+ [100 � 91] = �7 + 9 = 2%; i.e., there will be 2 % decrease

in hazard for LRFS by incorporating the changes in the

equation as described above.

DISCUSSION

Detailed anatomical knowledge of local tumor extension,

local lymphatic drainage, and normal critical structures is

a must for the success of an IMRT program. Selective neck

dissection has been successfully used and validated by head

and neck surgeons (7), allowing radiation oncologists to con-

sider selective neck treatment by irradiation. Gregoire et al.(1) comprehensively reviewed the literature and compiled

data with regard to the pattern of nodal metastases. In the

node-positive neck, target volumes were drawn up to the

base of skull in view of the patterns of failure noted by Eis-

bruch et al. (8) who found recurrences near the base of the

skull and advocated contouring level II nodes up to the base

of skull for the node-positive neck. In their series, Eisbruch

et al. (8) found 21 locoregional recurrences in 133 patients,

with 6 local, 9 regional, and 6 simultaneous locoregional re-

currences. In the present study, there were 30 locoregional re-

currences in 83 patients, with 23 local, 2 simultaneous local

and regional, and 9 regional recurrences. There was no recur-

rence in the region of the neck that was treated for occult met-

astatic disease. No effort was made to spare the ipsilateral

parotid in patients with oropharyngeal or oral cavity cancers

or lesions in close proximity to the ipsilateral parotid, thus

avoiding a cold spot adjacent to the high-dose volume,

CTV1PTV. Periparotid recurrences, reported recently by

Cannon et al. (9), have not been encountered so far.

All locoregional recurrences, except two, were in the

CTV1PTV volume covered by 95% of the prescription

dose. Therapy for 1 patient with a supraglottic primary

(T2N0) lesion failed in the posterior pharyngeal wall just out-

side the CTV1PTV, probably representing a skip metastasis,

thus underlining the importance of generous margins in areas

devoid of an obvious anatomical barrier. The second failure

outside the high-dose region also occurred in a patient with

a supraglottic primary (T4N2c) lesion and was in the soft tis-

sues of the neck, in the region of the paraspinal muscles

anterior to the fifth and sixth cervical vertebrae. This

Fig. 3. The log rank test was used to determine differences in locoregional relapse-free survival in terms of total treatmenttime (upper left panel), volume of CTV1PTV (upper right panel), V100% for CTV1PTV (lower left panel), and minimumdose to CTV1PTV (lower right panel).

152 I. J. Radiation Oncology d Biology d Physics Volume 76, Number 1, 2010

emphasizes the challenge of target delineation in a patient

with locoregionally advanced disease with bilateral nodal

metastases; in the era of conventional radiotherapy the region

of paraspinal muscles would have received a dose sufficient

to control occult metastatic disease.

In our series, V110% of 28.2% for CTV1PTV was high.

The probable reason for this is large tumor volumes and

the use of compensator based IMRT where optimization is

limited by the thickness of the compensator. A study by Ar-

ruda et al. (10) reported mean 70-Gy volume of 126 cc, while

it was 266 cc in this study. On subgroup analysis for V70 Gy

of <150 cc vs. V70 Gy of $150 cc, V110% is 13% vs. 29%,

respectively, with a p value of 0.0034. This clearly indicates

that larger volumes and compensator-based IMRT result in

inhomogeneous dose distribution.

Lee et al. (11) compared IMRT with conventional con-

comitant boost radiotherapy in the setting of concurrent che-

motherapy and found a substantial decrease in toxicity as

defined by pecutaneous endoscopic gastrostomy dependency

(4% vs. 21%) and xerostomia (12% vs. 67%), with no com-

promise of locoregional progression-free survival (82% vs.

92%). In our study, 68 (82%) patients had Stage III and IV

disease, and 71 (85%) patients received concurrent chemo-

therapy. Acute toxicity, grade III mucositis in 55 (66.3%) pa-

tients and odynophagia in 29 (35%) patients occurred in

a substantial number of patients, but nasogastric feeding

was required by only 37.3% of the patients during treatment.

Long-term dependency on nasogastric tube feeding was pres-

ent in only 4 (4.8%) patients. Grade III xerostomia was not

present; grade II xerostomia was present in 36.1% of patients,

while grade 0 or I xerostomia was present in 63.9% of pa-

tients. It would be prudent to compare our results with those

of the studies reporting the use of concurrent chemoradio-

therapy (CCRT) approaches for treating locally advanced

Selective neck irradiation with IMRT d S. NANGIA et al. 153

head–neck cancer. Invariably, results for locally advanced

head–neck cancer with CCRT reveal a 3-year LRFS in the

range of 50 to 70% (12, 13). Single-institution reports using

IMRT and CCRT have shown locoregional control in the

range of 80 to 90% (8, 10, 11, 14, 15). In this study, 3-year

LRFS was 60.1% and was comparable to the published

data pertaining to CCRT and locally advanced head–neck

cancer. Dawson et al. (16) reported a 79% 2-year locore-

gional control rate. In their study, the majority of patients

(82%) received postoperative radiation, and 39.6% of pa-

tients had T3 or T4 lesions. There is only one study, by Ar-

ruda et al. (12), that reports the volumes of PTV; their

mean 70-Gy PTV volume was 126.65 cc, while in this study,

the mean 70-Gy PTV volume in radically treated patients was

188.20 cc. In the patient group reported by Aruda et al. (12),

34% of patients had T3 or T4 lesions, while in this study

63.7% of the patients had T3 or T4 lesions. Studies reporting

results of IMRT for head–neck cancer differ in terms of op-

erative status, primary site, and the proportion of patients

with T3 and T4 lesions (Table 6). This may explain the infe-

rior locoregional control in this patient population compared

to these studies. We had nine regional relapses, and seven of

nine relapses were in patients with N2 or N3 neck disease, in-

dicating poor regional control among the patients who pres-

ent with advanced regional disease. Recurrences within the

high-dose volume represent the importance of intrinsic fac-

tors like hypoxia that make the tumor radioresistant, and ef-

forts to address these issues may improve locoregional

control (16).

CONCLUSIONS

(1) Our target (elective neck node irradiation) selection and

delineation approaches are validated in this analysis with

no recurrences in this volume. This is probably the larg-

est series representing the experience of a community-

based hospital using the RTOG guidelines for nodal

volume delineation for head–neck cancer for IMRT.

(2) Total treatment time and V100% for CTV1PTV are sig-

nificant independent predictors of locoregional relapse

and can be fitted into a model to predict the decrease in

hazard for failure. A larger dataset and longer follow-

up are required to validate these results.

(3) With 61.4% of the patients having T3 or T4 lesions, the

majority of failures in this study lie within the CTV1PTV

volumes. The locoregional control rate of 60.1% at 3

years can possibly be improved by addressing tumor

biology. Hypoxia imaging and targeting is an interesting

future prospect (16).

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