Conformal Radiotherapy in the Treatment of Advanced Juvenile Nasopharyngeal Angiofibroma With Intracranial Extension: An Institutional Experience

Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 5, pp. 1398–1404, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter

doi:10.1016/j.ijrobp.2010.04.048

CLINICAL INVESTIGATION

Head and Neck

CONFORMAL RADIOTHERAPY IN THE TREATMENT OF ADVANCED JUVENILE NASOPHARYNGEAL 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 Purpose: To describe the results of conformal radiotherapy in advanced juvenile nasopharyngeal angiofibroma in a tertiary care institution. Methods and Materials: Retrospective chart review was conducted for 8 patients treated with conformal radiotherapy between 2006 and 2009. The median follow-up was 17 months. All patients had Stage IIIB disease with intracranial extension. Radiotherapy was considered as treatment because patients were deemed inoperable owing to extensive intracranial/intraorbital extension or proximity to optic nerve. All but 1 patient were treated with intensitymodulated radiotherapy using seven coplanar fields. Median (range) dose prescribed was 39.6 (30–46) Gy. Actuarial analysis 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), intensitymodulated radiotherapy achieved conformal dose distributions (median van’t Reit index, 0.66). Significant sparing of the surrounding organs at risk was obtained. No significant Grade 3/4 toxicities were experienced during or after treatment. Actual local control at 2 years was 87.5%. One patient died 1 month after radiotherapy secondary to massive epistaxis. The remaining 7 patients had progressive resolution of disease and were symptom-free at last follow-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 juvenile nasopharyngeal angiofibromas, even in the presence of advanced disease. Ó 2011 Elsevier Inc. Nasopharyngeal neoplasms, Angiofibroma, Radiation, Dose–response relationship, Intensity-modulated radiotherapy.

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 radiotherapy (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.

INTRODUCTION Juvenile nasopharyngeal angiofibromas are rare benign tumors 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 nasopharynx 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 tendency to spread through the foramina in the base of skull into the cranium. Surgery is the mainstay of treatment, but intracranial 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. Advanced angiofibromas with extensive intracranial extensions

METHODS AND MATERIALS A retrospective chart review of all patients with juvenile nasopharyngeal 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

Reprint requests to: Santam Chakraborty, M.D., Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh UT 160012, India. Tel: (+91) 172 4345249;; E-mail: [email protected]

Conflict of interest: none. Received Feb 17, 2010, and in revised form March 29, 2010. Accepted for publication April 3, 2010. 1398

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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 present 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 patients were boys, aged 10–16 years. The majority of patients presented with nasal obstruction (n = 4), swelling (n = 3), and epistaxis (n = 1) as the initial presenting features. Presenting symptoms 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 radiation are not required to have a biopsy if the imaging features are sufficiently diagnostic. Preradiotherapy embolization was not performed in any patient. Pretreatment staging was done using Radkowski’s staging system (Table 1) (6). As per this staging system, all 8 patients had Stage IIIB disease at presentation, with gross intracranial 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 radiotherapy, 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 WeberFerguson 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 customized 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 target volume (PTV). The eyes, optic nerve, temporal lobes, pituitary,

Table 1. Radkowski’s staging system (1996) IA IB IIA

Limited to the nose or the nasopharynx Extension into one or more paranasal sinus Minimal extension through sphenopalatine foramen into and including a minimal part of the medial-most part of pterygomaxillary fossa IIB Full involvement of the pterygomaxillary fossa, displacing posterior wall of maxillary antrum forward. Lateral or anterior displacement of the branches of maxillary artery. Superior extension may occur, eroding the orbital bones IIC Extension through the pterygomaxillary fossa into the cheek and temporal fossa or posterior to the pterygoid plates IIIA Erosion of the skull base with minimal intracranial extension IIIB Erosion of skull base with extensive intracranial involvement with or without cavernous sinus involvement See reference 6.

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internal ear, parotid, brainstem, and oral cavity were contoured as organs at risk. One patient was treated with four-field 3D-CRT technique, and 7 patients were treated with IMRT and were planned using 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 algorithm, version 7.3.10. A dynamic sliding leaf movement technique 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 biologically 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 possible indication of the dose conformity and the spillage into the surrounding 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 evaluated clinically, and CT scans were requested at 6 months and thereafter 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 radiographic or endoscopic abnormalities. In addition, patients with residual 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 patients were censored on the date of last follow-up for actuarial analysis 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 prescribed 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 toxicities. All patients tolerated radiation well and completed it without any gaps. Grade 1 and Grade 2 mucositis was seen

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

2 years was 87.5%. No recurrences were seen in the 7 surviving 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 during follow-up and images registered with planning CT to evaluate whether the residual abnormality was in the area encompassed 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 addition 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

in 2 patients, and in each it resolved spontaneously within 2 weeks of completion of radiotherapy. This was primarily noticed 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 ipsilateral retromolar trigone and buccal mucosa. Unlike experience 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 radiotherapy and had a radiologic response. A complete response 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 parameters for the patients Eye

Internal ear

Optic nerve

Temporal lobe

Parotid gland

Parameter

Ipsi

Contra

Ipsi

Contra

Ipsi

Contra

Ipsi

Contra

Ipsi

Contra

Dmax (Gy) D33 (Gy) Dmean (Gy)

33.10 29.05 27.31

31.14 17.80 16.59

33.78 30.55 31.61

31.63 23.75 22.08

38.60 36.70 34.66

36.82 31.70 30.31

43.69 30.60 22.94

42.54 21.65 18.81

40.39 27.49 24.80

23.57 12.80 10.85

Abbreviations: Ipsi = ipsilateral organ at risk; Contra = contralateral organ at risk; Dmax = maximum point dose; D33 = minimum dose received by 33% volume; Dmean = mean dose.

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

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 epistaxis could not be ascertained. However, during discharge

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 evaluation for surgery. No major later-term toxicities were experienced in the cohort 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 patient had Grade 1 persistent rhinitis, which resolved with symptomatic treatment. DISCUSSION

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

Intracranial spread in juvenile nasopharyngeal angiofibroma 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 angiofibroma 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 policy, these rare benign tumors were treated with staged excisions and embolization of residual disease. Radiotherapy was reserved only for those patients who did not have salvageable 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

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

pattern resulted from departmental efforts to promote the advantages of IMRT/3D-CRT in these advanced tumors, which resulted in referrals. In contrast to extracranial tumors, for which surgery remains the treatment of choice, the management decision is complex in patients with intracranial extension. Classically, excision of tumors with extensive spread and intracranial extension 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 morbidity includes complications like mid-facial growth disturbance, which has been reported in the majority of patients with extensive craniofacial resection (16). Using modified resection techniques, other complications like secretory otitis media may supervene (12). Tumors with extensive intracranial 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 extension can cause further deformities due to use of the temporalis 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 radiotherapy 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 malignancies 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 crusting, 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 advanced 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 patients 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 reduce complications in this scenario with significant dose reductions to the normal organs. As highlighted by Beriwal et al. (22) in their series, none of the patients had serious complications 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 period. Kuppersmith et al. (23) have presented a series of patients treated with IMRT in which they could reduce the dose to the critical organs even further while maintaining local control in all patients. In their series, the follow-up ranged from 6 months to 40 months and showed progressive resolution of tumor, with control of local symptoms in all. The authors 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

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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)

Stage XRT dose (Gy) N IIIB (%) (fractions)

Cummings et al., 55 1984 (19)

17

30–35 (21)

Robinson et al., 1989 (20) McGahan et al., 1989 (21) Fields et al., 1990 (14)

10

30

30–40 (15–20)

15

100

32–46 (16–23)

13

15

36.6–52 (21–26)

Reddy et al., 2001 (3)

15

67

30–35 (17–22)

Lee et al., 2002 (4)

27

85

30–55

Local control (%)

Comments

80

Relapse correlated with smaller field size, highlighting importance of target volume delineation. Cataract (3.6%), hypopitutarism (1.8%), second cancer (3.6%) 100 (4 y) 30% Stage IV patients. All patients controlled at time of last follow-up. One patient had cataract (10%) 73.33 All recurrences with lower dose of 32 Gy (4/5 patients). All recurrences within 2 y. No serious complications 85 (11.3 y) Both relapses in patients with extensive disease. Dental caries (15%), and most patients had nasal dryness. One patient required treatment interruption 85 (5 y) Two relapsed patients had successful surgical salvage. 40% residual after 24 mo. Cataracts (20%). Delayed transient CNS syndrome in 1 patient. Basal cell cancer (in-field) in 1 patient 85 Cataract (4%), hypopitutarism (4%), 1 temporal lobe necrosis and growth retardation (4%)

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

100% of the prescribed dose, which can be explained by the larger target volume and higher incidence of proximity to optic nerve in this series. Another advantage of the conformal volume–based technique may be reduced risk of failure secondary 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 patients had xerostomia at late follow-up, which can be attributed 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 series 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 retrospective 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 patients with the most advanced disease are taken up for radiotherapy. 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 delivered with minimal acute and almost no late-term complications. 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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16. Fagan JJ, Snyderman CH, Carrau RL, et al. Nasopharyngeal angiofibromas: Selecting a surgical approach. Head Neck 1997; 19:391–399. 17. Gill G, Rice DH, Ritter FN, et al. Intracranial and extracranial nasopharyngeal angiofibroma. A surgical approach. Arch Otolaryngol 1976;102:371–373. 18. Zhang M, Garvis W, Linder T, et al. Update on the infratemporal fossa approaches to nasopharyngeal angiofibroma. Laryngoscope 1998;108:1717–1723. 19. Cummings BJ, Blend R, Keane T, et al. Primary radiation therapy for juvenile nasopharyngeal angiofibroma. Laryngoscope 1984;94:1599–1605. 20. Robinson AC, Khoury GG, Ash DV, et al. Evaluation of response following irradiation of juvenile angiofibromas. Br J Radiol 1989;62:245–247. 21. McGahan RA, Durrance FY, Parke RB, et al. The treatment of advanced juvenile nasopharyngeal angiofibroma. Int J Radiat Oncol Biol Phys 1989;17:1067–1072. 22. Beriwal S, Eidelman A, Micaily B. Three-dimensional conformal radiotherapy for treatment of extensive juvenile angiofibroma: Report on two cases. ORL J Otorhinolaryngol Relat Spec 2003;65:238–241. 23. Kuppersmith RB, Teh BS, Donovan DT, et al. The use of intensity modulated radiotherapy for the treatment of extensive and recurrent juvenile angiofibroma. Int J Pediatr Otorhinolaryngol 2000;52:261–268.