Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 5, pp. 1398–1404, 2011Copyright � 2011 Elsevier Inc.

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

jrobp.2010.04.048

doi:10.1016/j.i

CLINICAL INVESTIGATION Head and Neck

CONFORMAL RADIOTHERAPY IN THE TREATMENT OF ADVANCED JUVENILENASOPHARYNGEAL ANGIOFIBROMA WITH INTRACRANIAL EXTENSION: AN

INSTITUTIONAL EXPERIENCE

SANTAM CHAKRABORTY, M.D., SUSHMITA GHOSHAL, M.D., VIJAY MARUTI PATIL, M.D.,ARUN SINGH OINAM, M.SC., AND SURESH C. SHARMA, M.D.

Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh, India

ReprinRadiotherResearch,4345249;

Purpose: To describe the results of conformal radiotherapy in advanced juvenile nasopharyngeal angiofibroma ina tertiary care institution.Methods and Materials: Retrospective chart review was conducted for 8 patients treated with conformal radiother-apy between 2006 and 2009. The median follow-up was 17 months. All patients had Stage IIIB disease with intracranialextension. Radiotherapy was considered as treatment because patients were deemed inoperable owing to extensiveintracranial/intraorbital extension or proximity to optic nerve. All but 1 patient were treated with intensity-modulated radiotherapy using seven coplanar fields. Median (range) dose prescribed was 39.6 (30–46) Gy. Actuarialanalysis of local control and descriptive analysis of toxicity profile was conducted.Results: Despite the large and complex target volume (median planning target volume, 292 cm3), intensity-modulated radiotherapy achieved conformal dose distributions (median van’t Reit index, 0.66). Significant sparingof the surrounding organs at risk was obtained. No significant Grade 3/4 toxicities were experienced during or aftertreatment. Actual local control at 2 years was 87.5%. One patient died 1 month after radiotherapy secondary tomassive epistaxis. The remaining 7 patients had progressive resolution of disease and were symptom-free at lastfollow-up. Persistent rhinitis was the only significant toxicity, seen in 1 patient.Conclusions: Conformal radiotherapy results in good local control with minimal acute and late side effects in ju-venile nasopharyngeal angiofibromas, even in the presence of advanced disease. � 2011 Elsevier Inc.

Nasopharyngeal neoplasms, Angiofibroma, Radiation, Dose–response relationship, Intensity-modulated radio-therapy.

INTRODUCTION

Juvenile nasopharyngeal angiofibromas are rare benign tu-

mors seen mostly in adolescent boys. The classic description

given by Martin et al. (1) of ‘‘a specific highly vascular, non

infiltrating, essentially benign neoplasm occurring in the na-

sopharynx or posterior nasal cavity of pubescent males’’ still

holds true. Classically the neoplasm is believed to originate

from the sphenopalatine foramen and has the unfortunate ten-

dency to spread through the foramina in the base of skull into

the cranium. Surgery is the mainstay of treatment, but intra-

cranial extension and encasement of the cavernous sinus can

render surgical extirpation fraught with complications (2).

Radiotherapy has been used in the management of these

tumors from the radium era and has shown good control rates

in various series (3, 4). Recent advances in conformal

radiotherapy have allowed the oncologist to conform the

dose to the target volume with ever-increasing accuracy. Ad-

vanced angiofibromas with extensive intracranial extensions

t requests to: Santam Chakraborty, M.D., Department ofapy, Post Graduate Institute of Medical Education and

Chandigarh UT 160012, India. Tel: (+91) 172; E-mail: drsantam@gmail.com

1398

are in close relationship with various critical structures like

temporal lobes, pituitary gland, hypothalamus, optic nerve,

and chiasma. However, as has been shown in several surgical

series, tumor invasion of these structures is rare, and in the

majority a plane exists between the mass and the intracranial

contents (5). In such a situation use of intensity-modulated ra-

diotherapy (IMRT) may prove to be beneficial in achieving

dose reduction to these critical structures because extensive

margins for microscopic extension are not necessary. The

present study reviews the institutional experience with the

use of conformal radiotherapy in the treatment of these

tumors with extensive intracranial extension.

METHODS AND MATERIALS

A retrospective chart review of all patients with juvenile nasopha-

ryngeal angiofibroma referred to the radiotherapy department of our

institution was performed. Patients treated with three-dimensional

conformal radiotherapy (3D-CRT) or IMRT only were selected

Conflict of interest: none.Received Feb 17, 2010, and in revised form March 29, 2010.

Accepted for publication April 3, 2010.

Conformal RT in juvenile nasopharyngeal angiofibroma d S. CHAKRABORTY et al. 1399

for the purpose of the present study. All patients had a volumetric

contrast-enhanced planning CT acquired as a part of the treatment

planning process. The findings in this imaging study along with

other studies obtained before radiotherapy were used to delineate

the target volume as well as to report the areas involved in the pres-

ent study. In our institution the standard approach is to operate on all

patients with juvenile nasopharyngeal angiofibromas, except those

with extensive intracranial or cavernous sinus involvement, who

are treated with definitive radiotherapy. A total of 10 patients

were identified for the period 2006–2009; of these, 2 patients

were excluded because 3D-CRT/IMRT was not performed. All pa-

tients were boys, aged 10–16 years. The majority of patients pre-

sented with nasal obstruction (n = 4), swelling (n = 3), and

epistaxis (n = 1) as the initial presenting features. Presenting symp-

toms were present for a median of 27 months (range, 6–60 months)

before referral to radiotherapy.

Patients underwent endoscopy and contrast-enhanced CT scans

of the nasal cavity, nasophayrnx, and paranasal sinuses to delineate

the extent of the tumor. Patients referred for definitive external radi-

ation are not required to have a biopsy if the imaging features are

sufficiently diagnostic. Preradiotherapy embolization was not per-

formed in any patient. Pretreatment staging was done using Rad-

kowski’s staging system (Table 1) (6). As per this staging system,

all 8 patients had Stage IIIB disease at presentation, with gross intra-

cranial extension. Four patients had orbital involvement, and 5 had

tumors in proximity to the optic nerve and pituitary fossa (Fig. 1).

In the 2 patients who had surgical excision done before radiother-

apy, 1 had recurred 14 months after surgery by a Weber-Ferguson

approach before referral for radiotherapy. The second patient had

undergone four excisions over the space of 2 years, and the last

surgery was performed by a combined endoscopic and Weber-

Ferguson approach 10 days before referral for gross intracranial

extension, which could not be removed. Patients were referred for

radiotherapy because they were deemed to be inoperable.

After providing written informed consent, patients were planned

with a custom-made thermoplastic cast covering the head. A cus-

tomized bite block was prepared and attached to the thermoplastic

cast in all patients to improve reproducibility.

Image segmentation and treatment planning was done on the

Eclipse Treatment Planning System (Varian Medical Systems,

Palo Alto, CA). Gross tumor volume included the homogenously

enhancing tumor on contrast-enhanced planning CT scans and

was expanded by 4 to 5 mm isotropically to obtain the planning tar-

get volume (PTV). The eyes, optic nerve, temporal lobes, pituitary,

Table 1. Radkowski’s staging system (1996)

IA Limited to the nose or the nasopharynxIB Extension into one or more paranasal sinusIIA Minimal extension through sphenopalatine foramen into and

including a minimal part of the medial-most part ofpterygomaxillary fossa

IIB Full involvement of the pterygomaxillary fossa, displacingposterior wall of maxillary antrum forward. Lateral oranterior displacement of the branches of maxillary artery.

Superior extension may occur, eroding the orbital bonesIIC Extension through the pterygomaxillary fossa into the cheek

and temporal fossa or posterior to the pterygoid platesIIIA Erosion of the skull base with minimal intracranial extensionIIIB Erosion of skull base with extensive intracranial involvement

with or without cavernous sinus involvement

See reference 6.

internal ear, parotid, brainstem, and oral cavity were contoured as

organs at risk. One patient was treated with four-field 3D-CRT tech-

nique, and 7 patients were treated with IMRT and were planned us-

ing seven equispaced coplanar beams. The use of IMRT was

prompted by the proximity of the target volume in these patients

to the organs at risk outlined above.

Inverse planning was done using Helios IMRT software (Varian

Medical Systems) with the help of the Dose Volume Optimizer al-

gorithm, version 7.3.10. A dynamic sliding leaf movement tech-

nique was used for delivery of IMRT. Biweekly portal imaging

was done for verification of setup, and errors >3 mm in any direction

were corrected. The dose prescribed ranged from 30 to 46 Gy in 1.5

to 2 Gy per fraction. The median dose prescribed was 39.6 Gy, and

a dose of 46 Gy was prescribed for 2 patients. The median biologi-

cally equivalent dose was 46.73 Gy10 (range, 34.5–55.2 Gy10).

Plan evaluation included evaluation of dose–volume histograms

for target volume and organs at risk. The van’t Reit index was

used to calculate the conformity index because it gave the best pos-

sible indication of the dose conformity and the spillage into the sur-

rounding normal tissues using a single number (7).

Patients were assessed biweekly for toxicities using the National

Cancer Institute Common Terminology Criteria for Adverse Events

(NCI-CTCAE), version 3.0 grading scheme (8). Posttreatment

follow-up was done at 3-month intervals for the first year and at

6-month intervals thereafter. At each follow-up, patients were eval-

uated clinically, and CT scans were requested at 6 months and there-

after as clinically indicated. Endoscopic evaluation was done in the

first two visits and annually thereafter. Late toxicities were assessed

using the NCI-CTCAE version 3.0 grading scheme (8). The median

duration of follow-up was 17 months (range, 2–47 months).

Statistical analysis was done using SPSS 15.0 software (SPSS,

Chicago, IL). Local control was defined as absence of any radio-

graphic or endoscopic abnormalities. In addition, patients with re-

sidual static or resolving abnormalities over repeated imaging

were considered to be locally controlled. The Kaplan-Meier method

was used for evaluation of local control. Duration of local control

was calculated from date of registration, and locally controlled pa-

tients were censored on the date of last follow-up for actuarial anal-

ysis of local control.

RESULTS

The median volume of the contoured tumor was 174.4 cm3

(range, 94.95–751.55 cm3), whereas median PTV volume

was 292 cm3 (range, 216.64–1001.41 cm3). Target volume

coverage and normal organ sparing were evaluated using

multiple dosimetric parameters (Table 2). The Dmax to the

PTV ranged from 109% to 120% (median, 119%) of the pre-

scribed dose. The median van’t Reit conformation number

for the PTV coverage was 0.66 (range, 0.51–0.77). All but

1 patient had a van’t Reit conformation number greater

than 0.6, indicating conformal treatment (7). Brainstem

dose was well below the tolerance level, with a median

Dmax of 40 Gy in the patient population. The median average

dose to the oral cavity was 18.17 Gy (range, 13.16–30.38

Gy), whereas that for the pituitary gland was 34.54 Gy

(range, 20.31–48.09 Gy). Figure 2 shows an example target

volume and dose coverage with this technique.

Radiation was delivered without serious Grade 3/4 toxic-

ities. All patients tolerated radiation well and completed it

without any gaps. Grade 1 and Grade 2 mucositis was seen

Fig. 1. Axial (A) and coronal (B) reconstructed CT images showing outlines of target volumes of the 8 patients superim-posed on each other. Note the extensive intracranial disease with involvement of orbit, middle cranial fossa, infratemporalfossa, and buccal space and proximity to optic nerve, temporal lobe, parotid gland, and other organs at risk.

1400 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 5, 2011

in 2 patients, and in each it resolved spontaneously within 2

weeks of completion of radiotherapy. This was primarily no-

ticed in the hard and soft palate mucosa, which were part of

the target volume in all patients. In patients with buccal space

involvement, mucositis was noted in the region of the ipsilat-

eral retromolar trigone and buccal mucosa. Unlike experi-

ence with treatment of other head-and-neck malignancies,

mucositis at atypical sites in the anterior oral cavity were

not noticed in this series (9, 10). Other toxicities

experienced in this series included Grade 2 vomiting in 1

patient (12.5%), Grade 1 fatigue in 4 patients (50%), and

Grade 2 anorexia in 1 patient (12.5%). No Grade 3

toxicities were seen during the period of treatment.

Of 8 patients, 7 were symptomatically improved after ra-

diotherapy and had a radiologic response. A complete re-

sponse was obtained in 5 of 8 patients at 6 months after

radiotherapy. In 2 patients there was persistent regression

of the enhancing abnormality to last follow-up. One patient

had only minimal regression in the mass lesion. This patient

had an episode of fatal epistaxis 1 month after completion of

radiotherapy and died at home. The actuarial local control at

Table 2. Sample dosimetric pa

Eye Internal ear O

Parameter Ipsi Contra Ipsi Contra Ipsi

Dmax (Gy) 33.10 31.14 33.78 31.63 38.60D33 (Gy) 29.05 17.80 30.55 23.75 36.70Dmean (Gy) 27.31 16.59 31.61 22.08 34.66

Abbreviations: Ipsi = ipsilateral organ at risk; Contra = contralateral orceived by 33% volume; Dmean = mean dose.

2 years was 87.5%. No recurrences were seen in the 7 surviv-

ing patients during the follow-up. Patients with regression of

the lesion and no clinical symptoms were kept on close

follow-up. Computed tomography scans were acquired dur-

ing follow-up and images registered with planning CT to

evaluate whether the residual abnormality was in the area en-

compassed by the prescribed dose. In both patients the area of

abnormality was encompassed by the 95% isodose. Figure 3

shows an example of a residual soft-tissue abnormality in

a patient at 17 months’ follow-up, with superimposed 95%

isodose of the planning CT scan.

The 10-year-old child who died from massive epistaxis 1

month after completion of radiotherapy had extensive disease

involving the infratemporal fossa and masticator space, in ad-

dition to large-volume intracranial disease (Fig. 4). He had

presented with nasal obstruction for 18 months along with

epistaxis for 6 months. Except for these symptoms he had

good general condition and had a normal coagulogram. He

had three episodes of epistaxis with blood loss exceeding

50 mL in the 2 months preceding radiotherapy, but none

during radiotherapy, and had completed the planned course

rameters for the patients

ptic nerve Temporal lobe Parotid gland

Contra Ipsi Contra Ipsi Contra

36.82 43.69 42.54 40.39 23.5731.70 30.60 21.65 27.49 12.8030.31 22.94 18.81 24.80 10.85

gan at risk; Dmax = maximum point dose; D33 = minimum dose re-

Fig. 2. Example target volume coverage (A) and dose–volume histogram (B) for a patient treated with intensity-modulatedradiotherapy. All the curves for organs at risk are for the ipsilateral organs. Note the relative sparing of the opposite eyedespite the proximity to the target volume as a result of use of intensity-modulated radiotherapy.

Conformal RT in juvenile nasopharyngeal angiofibroma d S. CHAKRABORTY et al. 1401

of 40 Gy in 20 fractions uneventfully. Although a malignant

process cannot definitely be ruled out because biopsy was not

obtained from the growth, the natural history and tempo of

disease did not suggest a malignant process. In addition,

the imaging was very classic for benign angiofibroma. The

child hailed from a distant province and did not return for

follow-up after completion of radiotherapy. The news of

his death was obtained by telephone, so the exact cause of ep-

istaxis could not be ascertained. However, during discharge

Fig. 3. Patient with residual disease on CT at 15 months’ follow-up,showing coverage of residual disease with 95% dose coverage afterimage fusion with the pretreatment CT scan.

after completion of radiotherapy, the authors had noted that

the visible mass lesion had not shrunk appreciably in size,

and he was advised to come for follow-up early for evalua-

tion for surgery.

No major later-term toxicities were experienced in the co-

hort over the duration of follow-up. None of the patients had

developed cataract, visual deficits, hearing difficulties, or

growth disturbances over the period of follow-up. One pa-

tient had Grade 1 persistent rhinitis, which resolved with

symptomatic treatment.

DISCUSSION

Intracranial spread in juvenile nasopharyngeal angiofi-

broma has been described in various series to vary from

6% to 37.5% (11–13). The incidence of intracranial

extensions is more in some Indian series as compared with

Western series, primarily owing to delays in referral and

poorer health care available at the primary health care

facilities (13–15). As shown by Mistry et al. (13) in a tertiary

care referral institute in India, almost 90% of patients had

Stage III/IV disease. In the present series all patients were

deemed unresectable before referral owing to intracranial

extension and proximity to optic nerve and cavernous sinus.

The use of IMRT/3D-CRT in juvenile nasopharyngeal an-

giofibroma could be started only in the year 2006 because the

linear accelerator capable of delivering this was acquired in

the later part of 2005. Before this, as part of institutional pol-

icy, these rare benign tumors were treated with staged exci-

sions and embolization of residual disease. Radiotherapy

was reserved only for those patients who did not have sal-

vageable recurrences, to avoid late radiation-induced toxicity

to the neuroendocrine structures. In fact, during the period

2000–2005, only 1 patient received external radiation for

this indication, with parallel-opposed portals to a dose of

36 Gy in 20 fractions. After 2006, a gradual shift in practice

Fig. 4. Axial, coronal, and sagittal representative sections with isodose curves superimposed on the planning target volumefor the patient who died 1 month after radiotherapy due to massive epistaxis.

1402 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 5, 2011

pattern resulted from departmental efforts to promote the ad-

vantages of IMRT/3D-CRT in these advanced tumors, which

resulted in referrals.

In contrast to extracranial tumors, for which surgery re-

mains the treatment of choice, the management decision is

complex in patients with intracranial extension. Classically,

excision of tumors with extensive spread and intracranial ex-

tension is associated with high recurrence rates (approaching

50%) and perioperative morbidity (2). In a large Indian series

reported by Tyagi (12), 80% of patients (8 of 10) had local

residual after surgery for Stage IV tumors. In these patients

a local recurrence rate of 30% (3 of 10) was found during

follow-up, and it is noteworthy that none of the patients

had received adjuvant radiotherapy. Fagan et al. (16) showed

a recurrence rate of 37.5% in these tumors and correlated

poor outcomes with skull base invasion. Postoperative mor-

bidity includes complications like mid-facial growth distur-

bance, which has been reported in the majority of patients

with extensive craniofacial resection (16). Using modified re-

section techniques, other complications like secretory otitis

media may supervene (12). Tumors with extensive intracra-

nial extension often necessitate a staged excision to avoid

the complications secondary to prolonged surgery, blood

loss, cerebrospinal fluid leak, and risk of infections (17). In

addition, removal of tumors with extensive intracranial ex-

tension can cause further deformities due to use of the tempo-

ralis muscle in the operative repair of the large surgical

defects from the lateral approach needed in these situations

(18). Keeping these disadvantages in mind, radiotherapy is

considered the treatment option of choice in these patients

at our institution.

Table 3 summarizes the results of some series in which ra-

diotherapy was used as the primary mode of treatment (3, 4,

14, 19–21). These series have shown that the control rates in

this tumor with the use of radiotherapy range from 73% to

100%. Despite long follow-up, only few cases of second ma-

lignancies have been described (3, 19). Late-term complica-

tions are primarily in the form of cataract (3, 4, 19, 20), dental

caries secondary to xerostomia (14), nasal dryness and crust-

ing, and hypopituitarism (4, 19). It is noteworthy that 1

patient in the University of California, Los Angeles series,

who had developed temporal lobe necrosis and

endophthalmitis, had received a cumulative dose of 75 Gy

using 60Co over a time span of 3 years, along with staged

intracranial excision for an aggressive, recurrent tumor (4).

Thus, radiation provides equivalent or better control in ad-

vanced juvenile angiofibromas, with morbidity comparable

to that with surgical approaches (4, 14, 19).

Juvenile nasopharyngeal angiofibromas require moderate

doses of radiotherapy for durable control and cure, with

a dose range of 35–46 Gy being used in various series. At

these doses there is risk of significant toxicities, particularly

to the parotid gland, optic nerve, pituitary gland, temporal

lobe, and eye with long-term follow-up. This is true in pa-

tients with extensive intracranial extension as in this series,

with median gross tumor volume in excess of 170 cm3. In

particular, the volume of intracranial disease in our patients

was large (Fig. 1). Conformal radiotherapy can potentially re-

duce complications in this scenario with significant dose re-

ductions to the normal organs. As highlighted by Beriwal

et al. (22) in their series, none of the patients had serious com-

plications in the follow-up period, which ranged from 26 to

48 months. Significant dose reductions could be obtained,

and no marginal recurrences were observed during this pe-

riod. Kuppersmith et al. (23) have presented a series of pa-

tients treated with IMRT in which they could reduce the

dose to the critical organs even further while maintaining lo-

cal control in all patients. In their series, the follow-up ranged

from 6 months to 40 months and showed progressive resolu-

tion of tumor, with control of local symptoms in all. The au-

thors highlighted the excellent critical organ sparing

produced by using IMRT with mean doses to 24–28 Gy to

optic nerve (53–82% of prescribed dose) (23). In the present

series the mean doses to optic nerve ranged from 63% to

Table 3. Literature review of series reporting on patients of juvenile nasopharyngeal angiofibromas treated with external radiotherapy(Stage IIIB by Radkowski’s staging system)

Authors, year(reference) N

StageIIIB (%)

XRT dose (Gy)(fractions)

Localcontrol (%) Comments

Cummings et al.,1984 (19)

55 17 30–35 (21) 80 Relapse correlated with smaller field size, highlighting importance of targetvolume delineation. Cataract (3.6%), hypopitutarism (1.8%), secondcancer (3.6%)

Robinson et al.,1989 (20)

10 30 30–40 (15–20) 100 (4 y) 30% Stage IV patients. All patients controlled at time of last follow-up.One patient had cataract (10%)

McGahan et al.,1989 (21)

15 100 32–46 (16–23) 73.33 All recurrences with lower dose of 32 Gy (4/5 patients). All recurrenceswithin 2 y. No serious complications

Fields et al.,1990 (14)

13 15 36.6–52 (21–26) 85 (11.3 y) Both relapses in patients with extensive disease. Dental caries (15%), andmost patients had nasal dryness. One patient required treatmentinterruption

Reddy et al.,2001 (3)

15 67 30–35 (17–22) 85 (5 y) Two relapsed patients had successful surgical salvage. 40% residual after24 mo. Cataracts (20%). Delayed transient CNS syndrome in 1 patient.Basal cell cancer (in-field) in 1 patient

Lee et al.,2002 (4)

27 85 30–55 85 Cataract (4%), hypopitutarism (4%), 1 temporal lobe necrosis and growthretardation (4%)

Abbreviation: XRT = external-beam radiotherapy; CNS = central nervous system.

Conformal RT in juvenile nasopharyngeal angiofibroma d S. CHAKRABORTY et al. 1403

100% of the prescribed dose, which can be explained by the

larger target volume and higher incidence of proximity to op-

tic nerve in this series. Another advantage of the conformal

volume–based technique may be reduced risk of failure sec-

ondary to geographical miss, which was attributed to be the

cause of failure in the series by Cummings et al. (19).

The lack of late complications is heartening; however, the

duration of follow-up is short. Even in the patient with 47

months’ follow-up no ocular or neurologic complications

have been noted. It is also noteworthy that none of the pa-

tients had xerostomia at late follow-up, which can be attrib-

uted to the excellent sparing of both parotid glands due to

use of IMRT. As a consequence, secondary complications

like dental caries were notably absent in the follow-up. A

similar experience is seen in the conformal radiotherapy se-

ries mentioned above (22, 23). Thus, morbidity as

compared with the older radiotherapy series is considerably

reduced, which is an important consideration in these

patients who are young and expected to live an active life

without impairment caused by late radiation toxicity.

Like other series treating angiofibromas with radiotherapy,

we have also observed a proportion of patients with persistent

residual abnormalities on CT scan without symptoms (4, 19).

This pattern of slow involution of the tumor is well described

in the literature, and we also keep these patients on close

clinical and radiologic follow-up. One patient in the series

died of epistaxis after radiotherapy, and he was thought to

have died from residual local disease.

The major limitation of the present study is the retrospec-

tive nature of the analysis, which brings into question various

sources of bias. However, it should be noted that as part of

institutional policy we treat only those patients who are

deemed inoperable with radiotherapy. Thus, invariably pa-

tients with the most advanced disease are taken up for radio-

therapy. The short follow-up is another major shortcoming;

however, the lack of late complications and good control

rates are encouraging. Further, the rarity of the tumor makes

any prospective randomized trial difficult to implement.

CONCLUSIONS

Excellent local control approaching 85% can be obtained

for advanced juvenile nasopharyngeal angiofibromas with

the use of IMRT. The moderate doses required can be deliv-

ered with minimal acute and almost no late-term complica-

tions. Further evaluation of the patients and longer follow-up

can help clarify the issues of local control in the long term

and delayed toxicity.

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