Practical Radiation Oncology (2011) 1, 271–278

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Original Report

Radiotherapy for juvenile nasopharyngeal angiofibroma Robert J. Amdur MD a,⁎, Anamaria R. Yeung MD a , Bridget M. Fitzgerald MSW, LCSW a , Anthony A. Mancuso MD b , John W. Werning MD c , William M. Mendenhall MD a a

Department of Radiation Oncology, College of Medicine of the University of Florida, Gainesville, Florida Department of Radiology, College of Medicine of the University of Florida, Gainesville, Florida c Department of Otolaryngology, College of Medicine of the University of Florida, Gainesville, Florida b

Received 9 March 2011; accepted 5 April 2011

Abstract Purpose: To explain the concepts that radiation oncologists need to understand to manage patients with juvenile nasopharyngeal angiofibroma (JNA). To accomplish this goal we first describe our institution's experience with radiotherapy for JNA and then use this data set as a framework for explaining the role of radiotherapy in the treatment of this uncommon tumor. Methods and Materials: We studied the outcomes of all 24 patients treated with radiotherapy for JNA at our institution. All patients had at least 4 years of follow-up (median follow-up, 18 years). The standard dose in the first half of the series was 30 Gy in 22 treatments (1.43 Gy/treatment). After observing recurrences with this schedule, the prescription was changed to 35 to 36 Gy at 1.8 Gy/treatment. In all cases, the target volume was the primary site without an attempt to cover the regional nodes. Results: All recurrences were at the primary site and presented within 5 years of completing radiotherapy. There appeared to be a dose response for tumor control: 77% with 30 to 32 Gy versus 91% with 35 to 36 Gy. All recurrences following radiotherapy were successfully salvaged with surgery. The only complications from radiotherapy were cataracts in 2 patients. No patient had a significant growth abnormality or second tumor. Conclusions: Surgery is the best treatment for JNA when cure is likely with low morbidity, but the threshold for using radiotherapy should be low because moderate-dose radiotherapy cures about 90% of patients with a low risk of serious complications. We recommend 36 Gy at 1.8 Gy per treatment in most cases. Elective nodal irradiation is not necessary. Radiographic response should be almost complete within a year of radiotherapy. Patients should be followed with cross-sectional imaging every 6 months for at least 5 years. © 2011 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Introduction Juvenile nasopharyngeal angiofibroma (JNA) is a benign tumor that develops from tissue near the Conflicts of interest: None. ⁎ Corresponding author. 2000 SW Archer Rd, PO Box 100385, Gainesville, FL 32610-0385. E-mail address: [email protected] (R.J. Amdur).

nasopharynx in males during puberty.1 The tumor is highly vascular so nasal bleeding is the most common presenting symptom. Surgery results in cure in most patients with early-stage disease, but many patients present with tumor in the base of the skull where resection is difficult and the risk of morbidity is high. Radiotherapy (RT) has a long history in the management of JNA, but the role of RT relative to surgery and the details of RT treatment are controversial.

1879-8500/$ – see front matter © 2011 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.prro.2011.04.002

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Our department has been tracking the outcome of patients treated with RT for JNA for many years, such that we now have the most mature experience in the literature.1,2 The purpose of this paper is to present the latest update of our experience with RT for JNA, and then use this data set as a framework for explaining the management principles that should guide radiation oncologists when evaluating and treating patients with this uncommon tumor.

Methods and materials Data for this study were collected as part of an Institutional Review Board approved protocol and according to the Health Insurance Portability and Accountability Act. Table 1 summarizes the main characteristics of our study population. Most of our patients were not good candidates for surgery. Specifically, most patients (79%) had at least 1 curative-intent operation before RT, and all of the patients had gross tumor at the time of RT that was in an unfavorable stage, with intracranial spread in onethird of the patients. This is a 30-year experience (date range, June 1975 to June 2006) with the last patient treated 4 years before the date of analysis (December 31, 2010). No patient was lost to follow-up, and all patients were alive at last follow-up. In addition to a review of medical records from the time of RT to the present, we evaluated the outcome of every patient with a verbal interview conducted during the year 2010. Imaging follow-up was incomplete in that 4 patients treated over 15 years ago never had an imaging study after RT and 8 additional patients stopped getting imaging studies 4 years after completing RT. The RT dose prescription changed near the middle of the study period. Before about 1995, the standard prescription was 30 Gy at 1.43 Gy per treatment. After several patients recurred with this low-dose schedule, the standard prescription was increased to 35 or 36 Gy at 1.7 to 1.8 Gy per treatment for the remainder of the study period. Information that is not included in Table 1, but may be of interest to some readers, is that the diagnosis of JNA was confirmed via tissue analysis in 71% of patients, diagnostic imaging before RT-involved angiography in 55% of patients, computed tomographic (CT) scan in 88% of patients, and magnetic resonance (MR) scan in 68% of patients. Endovascular embolization of tumor before surgery was performed in the 20 patients who underwent surgical resection before RT, and the carotid artery was ligated to control bleeding before RT in 1 patient who did not have a resection before RT. RT was delivered with photon beams in all cases. The radiation beam was Cobalt-60 in 17% of patients and 6- to 20-MV photons in the remainder. RT simulation involved only orthogonal radiographs (2-dimensional planning) in 12% of patients, CT simulation without MR in 67%, and CT simulation with MR fusion in 21%.

Practical Radiation Oncology: October-December 2011 Table 1

Patient, tumor, and treatment characteristics

Characteristic

Value

30-year study period

January 1, 1975 to December 31, 2006 24, all male

Number of patients Race White Black Hispanic Median age on day 1 of RT (range) No tissue diagnosis Biopsy without attempted resection RT for gross residual immediately following curative-attempt resection RT for recurrence after 1-2 curative-intent resections Gross tumor present at the time of RT Chandler stage at the time of RT Stage 3, ethmoid or orbit Stage 4, intracranial Conventional 2- to 3-field technique Laterals + anterior Laterals only Lateral and anterior Noncoplanar SRT or IMRT (5-6 fields) RT dose 30 Gy at 1.3 to 1.8 Gy per fraction 32 Gy at 1.8 Gy per fraction 35-36 Gy at 1.7 to 1.8 Gy per fraction Follow-up from day 1 of RT Median follow-up (range) N10 years N15 year Median CT or MR scan follow-up in patients without tumor recurrence after RT (range)

22 patients 1 patient 1 patient 17 years (11 to 22) 29% 4% (1 patient) 12% 55% 100% 67% 33% 63% 21% 4% 12%

50% 4% 46% 18 years (4 to 35) 88% 29% 4 years (0 to 31)

CT, computed tomography; IMRT, intensity modulated radiation therapy; JNA, juvenile nasopharyngeal angiofibroma; MR, magnetic resonance; RT, radiotherapy; SRT, stereotactic radiation therapy without intensity modulation.

Complications from RT were graded with the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE, v4.0).3 In this report we did not consider salvage surgery for recurrent tumor following RT, or problems from such surgery, as an RT complication.

Results Figure 1 shows the rate of tumor control and survival in our study population. Overall, 4 of the 24 patients (17%) developed tumor recurrence. All recurrences were at the primary site in areas that received at least 95% of the prescription dose. There appears to be a dose response for

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tumor control. Although the differences were not statistically significant, the control rate was 91% with the higher dose regimen that we used in the second part of the study period compared to 77% with the lower dose regimen. All 24 patients were alive without evidence of tumor at last follow-up in the year 2010. The 4 patients whose tumor recurred following RT underwent a salvage operation involving a base of skull resection and all 4 of these patients are alive without evidence of tumor 11 to 16 years after salvage surgery. The only events that appeared to be related to normaltissue damage from RT were ocular cataracts in 2 patients, neither of whom required salvage surgery for tumor recurrence. In both patients the cataract was unilateral and was treated with surgical therapy with a good visual outcome. The need for surgery defined these events as grade 3 complications. The complication rate was 13% (3 of 24 patients) based on the entire study population and 15% (3 of 20 patients) based on the patients who did not require salvage surgery for recurrent tumor. No patient in this series developed a second tumor, growth abnormalities, or cognitive impairment based on the methods we used to detect such problems. None of the 4 patients who developed tumor recurrence following RT had malignant features in the tissue removed during salvage surgery.

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Figure 1 Actuarial plot of tumor control and survival for the 24 patients in our series. There appears to be a dose response for tumor control, but the differences were not statistically significant. All patients were alive without evidence of tumor at last follow-up in the year 2010 (100% ultimate tumor control and survival). The 4 patients who developed tumor recurrence following radiotherapy (RT) underwent a salvage surgical procedure involving a base of skull resection at a tertiary care medical center. Salvage surgery was successful in all cases with all 4 patients alive without evidence of tumor 11 to 16 years after salvage surgery.

express the vascular endothelial growth factor receptor-2 (VEGFR2), the transforming growth factor beta 1 (TGF beta1), and the insulin-like growth factor 2 (IGF-II).10

Discussion Our group has summarized the major surgery and RT series in a review article published in 2003.1 Since then there have been a few published series sharing short-term results with new technology, which have not affected the basic issues.4-7 The remainder of the Discussion is organized into subsections that explain the concepts and guidelines that radiation oncologists need to manage patients with JNA.

Pathogenesis and epidemiology The pathogenesis of JNA is unknown. Hicks and Nelson describe the 5 main theories.8 Some theories are based on the concept of hormonal stimulation of developing tissue while others suggest that JNA is an inflammatory reaction rather than a true neoplasm. The striking feature of JNA is its epidemiology. This is a tumor that only occurs in males and forms during puberty. The median age in our series was 17 years, which is similar to what other studies report. That JNA only occurs in pubescent males suggests that hormonal changes play a major role in JNA formation and growth. Multiple studies confirm that JNA frequently expresses androgen receptors and at least 1 study suggests that these tumors often express a type of estrogen receptor.9 More recent studies demonstrate that JNA stroma cells

Presentation, diagnostic workup, and differential diagnosis JNA originates in the tissue near the junction of the lateral wall of the nasal cavity and the nasopharynx, near the medial boundary of the pterygopalatine fossa. The main presenting symptom of JNA is epistaxis that is often so severe that carotid ligation or emergent embolization is required. In our series every patient presented with epistaxis. The important point about diagnosis is that tissue is not required to plan treatment if the clinical and radiographic picture is classic for JNA. These are highly vascular tumors and even a small biopsy may cause serious bleeding. In our series one-third of the patients did not have a tissue diagnosis. Historically, diagnosis of JNA required an angiogram. Today a contrast-enhanced CT or MR scan is usually sufficient to make the diagnosis of JNA. In our series about half of the patients did not have an angiogram. The findings that must be present on CT or MR to plan treatment for JNA without a tissue diagnosis are as follows: (1) a highly vascular mass with the epicenter where the posterior wall of the nasal cavity meets the nasopharynx, near the medial boundary of the pterygopalatine fossa; (2) changes in adjacent bone that are characteristic of a benign tumor, meaning

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there is remodeling rather than frank bone destruction; and (3) no evidence of regional or distant metastasis, with the exception of the rare case of positive retropharyngeal nodes.

Staging systems The American Joint Committee on Cancer has not presented a staging system for JNA. Historically, the 3 main staging systems have been those of Sessions, Chandler, and Radkowski but new systems are being proposed in response to the widespread use of endoscopic surgery for tumors near the base of skull.1,11

Natural history without treatment Data are scarce on observation of JNA without resection or RT. Observation is reasonable to consider since there are documented cases of spontaneous resolution of JNA without treatment.12 Spontaneous regression appears to occur after age 25 years, presumably in response to changes in the hormonal environment after puberty. There is no published guideline that recommends observation in a patient with a JNA, but the concept of spontaneous regression after puberty has several implications for treatment decisions in the modern era. First, many patients are being managed surgically even when cure is not likely. The idea behind this approach is that tumor growth can be prevented with repeated endoscopic resections that cause little long-term morbidity. Multiple surgeries may avoid the need for RT if residual tumor is going to spontaneously resolve after puberty. A second rare scenario, a JNA is discovered incidentally in an adult when it is asymptomatic or causing symptoms that are easy to control. In such cases time may be the best treatment in the hopes that the tumor will spontaneously regress in the near future.

Medical treatment There is currently no standard medical therapy for JNA. The recent discovery that many JNAs express receptors for estrogen and VEGF raise the possibility that therapy with agents that specifically target these receptors may be useful.9,10

Embolization Endovascular embolization can control acute bleeding from JNA at presentation and decrease blood loss during surgery. There are various techniques related to embolization, and new agents are being developed that may improve treatment efficacy in the future.6

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There are no data that embolization influences the ability of RT to control a JNA. In our series most patients (79%) had their tumor embolized at some point before RT because embolization was done in all patients who underwent a surgical resection. We have no data to support this bias but our preference is to not embolize a patient who is going to be treated with RT because we are concerned that tumor hypoxia from embolization may cause radioresistance.

Surgery versus radiotherapy as primary treatment Surgery has always been the treatment of choice when complete resection is likely with low morbidity, and the cure rates are high in these situations.1 The debate is about how far to push the indications for surgery to avoid the potential complications of RT. The fatality from extensive surgery in the 2002 University of California-Los Angeles (UCLA) series emphasizes the risk of attempting complete resection in patients with advanced-stage disease. 13 Today, the sophistication of endoscopic surgery for skull base tumors has changed the complexion of the debate so that some recently published papers imply that there is almost no role for RT in JNA.7,11 Our view is that improvements in surgical technique have decreased the morbidity of curative resection in many patients with JNA, so surgery is the best treatment for some patients who we would have treated with RT in the past. But we are skeptical about the advantage of surgery in advanced-stage disease, especially when prior surgery has been unsuccessful. Our series is the most mature RT experience in the literature with 88% of patients having over 10 years of follow-up. Our results are in line with other series that document a tumor control rate of about 85%, with doses in the range of 36 Gy at 1.8 Gy per treatment.1,4 Considering that most patients in our series had advanced-stage disease that recurred following surgical resections, there is no question that RT is a highly effective tool for controlling JNA. The concern lies in the complications that arise from delivering RT to the midface in young patients relative to the complications that will result from surgical resection. The rate of serious complications from RT for JNA is the subject of the next subsection. We do not have a bright-line rule for when to treat a JNA with surgery versus RT. We recommend surgery when resection is likely to be curative with low morbidity. Tumor recurrence is a serious problem such that we do not plan treatment with the idea that multiple resections in the future are better than RT now. We do not use RT before a planned resection to improve the chance of a curative resection. Similarly, we do not advocate RT as part of a plan for subtotal resection followed by RT and we do not add RT following a gross-total resection when the final status of the resection margin is microscopically positive.

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We reserve RT for patients with visible tumor on CT or MR scan that is not amenable to a potentially curative resection with a low risk of morbidity.

Complications of radiotherapy There is no question that RT for JNA causes permanent normal-tissue damage, that retrospective studies will not record most of the low-grade problems, and that the frequency of serious problems will increase with time following treatment. Given these limitations, the available reports suggest that the rate of moderate or serious problems from RT for JNA is low.1,4,13 The only report of brain necrosis is from the 2002 UCLA report in a patient who was treated with 2 courses of RT following intracranial surgery.13 The length of follow-up is critical because many of the problems that we are most concerned about will not be detected on routine exams until several years following treatment. Our series represents the highest quality data on late effects of RT for JNA in the literature because all patients were still alive with a verbal interview during the year 2010, and most of the patients are long-term survivors. In our series we did not find evidence for complications with the exception of cataracts in 2 patients. We suspect that sensitive testing would reveal neurocognitive abnormalities, but the medical records and current interviews suggest that none of our patients developed serious cognitive or memory problems following RT. Similarly, no patient reported cosmetic problems related to abnormal growth of the face and no patient reported uncorrectable vision or hearing problems. The complication that is the focus of many discussions about RT versus surgery for JNA is the risk of RT causing a cancer to develop in the future, either by transforming a benign JNA into a malignant sarcoma or by inducing a malignancy in previously normal tissue. There are publications that report malignant transformation of JNA many years following RT, but we did not observe this in our study.14 Many of our patients do not have a recent head scan but at this time we have no evidence of a second tumor, benign or malignant. We recently published a comprehensive review of our experience with second tumors in all children and young adults who received RT to the brain at our institution.15 From these studies we know that the risk of a second tumor from RT for JNA is likely to be b 10%, and most tumors that will occur will be meningiomas that have a high chance of being cured if they are detected early and treated correctly.15 Understanding that we are underestimating the problems from RT in our study, our conclusion is that the risk of moderate or severe uncorrectable problems from RT for JNA is low, such that we recommend RT over surgery when a potentially curative resection is likely to leave the patient with a serious deficit.

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Radiographic response following radiotherapy Data on time course and degree of radiographic response of JNA to RT are scarce. We did not image our patients at systematic time points, and about 15% of our patients never had a follow-up scan. However, from the scans that we performed we see that the pattern of response of JNA to RT is different than that of other benign tumors such as paraganglioma, schwannoma, or meningioma. JNA responds quickly and almost completely to RT. In all of our patients with follow-up imaging, tumor size decreased by more than 50% within 12 months after RT. The few patients who were imaged between the completion of RT and the time that their tumor recurred responded as well and as quickly as those who remained controlled. We draw 2 conclusions from our observations about radiographic tumor response following RT: (1) A tumor that does not decrease in size by at least 50% within 12 months of completing RT is probably not a JNA. (2) A complete radiographic response soon after RT should not decrease the schedule of follow-up imaging.

Pattern of recurrence and target definition JNA metastasis to a regional node is rare. In our series we did not enlarge the target volume to treat the regional lymphatics, and there were no nodal failures. We do not know of a case with tissue documentation of JNA failing in a regional node. For this reason, elective nodal irradiation is not necessary in JNA. All 4 recurrences in our series were at the primary site and “in field,” meaning the recurrence was confined to an area that received at least 95% of the prescription dose. However, our current policy is to be generous with our clinical target volume (CTV) contour when there is any question about the boundary of the gross tumor volume, especially when the tumor recurs after surgery. At a minimum, we draw the CTV 1.0 cm beyond the gross tumor volume in areas where there is no barrier to tumor spread; we include the entire pterygopalatine fossa and inferior orbital fissure on the ipsilateral side in all cases, the entire sphenoid sinus if there is tumor in any portion of this sinus, and the entire maxillary sinus or ethmoid complex on the ipsilateral side if there is gross tumor in any portion of these structures. We cover the cavernous sinus in our CTV when there is gross tumor in the inferior orbital fissure or if there is intracranial extension. Figure 2 shows selected images of the treatment planning contours on a representative case.

Salvage surgery for recurrent tumor following RT All 4 patients in our series who failed RT were alive without evidence of tumor over a decade after undergoing salvage surgery at a tertiary care medical center.

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Figure 2 Selected images from the radiotherapy planning scans for a patient with a juvenile nasopharyngeal angiofibroma (JNA) that recurred several years following resection. Images (A) and (B) are from the contrast-enhanced, T1-weighted magnetic resonance (MR) scan that we fuse to the simulation computed tomographic (CT) scan. Space does not permit us to show partner CT images. We show the MR images because in most JNA cases it is much easier to see the boundaries of the tumor with MR. In images (A) and (B) the tumor is bright white, indicating that it is highly vascular. In image (A) the tumor (T) involves the right side of the sphenoid sinus and probably involves the posterior portion of the inferior orbital fissure and nasal cavity. In image (B) the tumor (T) epicenter is in the pterygomaxillary fossa and the tumor involves the medial portion of the infratemporal fossa and the posterior portion of the nasal cavity. The white line in images (A) and (B) is the CTV, which puts a margin of a least 1 cm on the gross tumor volume (GTV) in areas where there is no barrier to tumor spread. When tumor involves a portion of the sphenoid sinus we cover the entire sinus in the CTV. Image C is the midline sagittal reconstruction CT image showing the GTV and PTV (CTV + 1 mm).

Some of these patients had residual deficits from their surgery, such as cheek numbness and asymmetry in facial contour, but none had major complications like stroke or blindness. When salvage surgery is likely to be curative with a low risk of major complications, we should not use a primary therapy that is likely to cause major deficits even if it is slightly better at achieving tumor control than a low-toxicity alternative, and we

should follow patients closely after treatment to detect a recurrence as soon as possible.

Radiotherapy dose The RT dose in published series of JNA ranges from 30 to 46 Gy at 1.5 to 2.3 Gy per treatment, with 30 to 35 Gy being most common.1,4 There is no statistically significant

Practical Radiation Oncology: October-December 2011 Table 2

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Treatment guidelines for juvenile nasopharyngeal angiofibroma

Diagnosis

Observation Medical therapy Surgery Indication for RT

RT dose RT technique a RT simulation

Target definition

Target dose constraints

Normal structures

Follow-up

Juvenile nasopharyngeal angiofibroma

CT or MR scan is usually adequate. Angiography is optional. Tissue is not necessary if the clinical picture is classic for JNA: a highly vascular mass with its epicenter where the posterior wall of the nasal cavity meets the nasopharynx, near the medial boundary of the pterygopalatine fossa in a male of age 10 to 20 years with no evidence of regional or distant metastasis. Main differential diagnosis: nasopharyngeal carcinoma, rhabdomyosarcoma, lymphoma, capillary hemangioma, pyogenic granuloma. No standard role but JNA may resolve spontaneously after age 20, so this may be a reasonable option in older patients with small tumors and minimal symptoms. No standard role but agents targeting vascular endothelial growth factor and steroid receptors are likely to be investigated in the near future. Surgery is the treatment of choice when complete resection is likely with low morbidity. There is no role for “debulking” surgery prior to RT. Resection is usually preceded by embolization. Visible tumor on CT or MR scans in a situation where curative resection with low morbidity is unlikely. Positive microscopic margins or history or recurrence in the setting of radiographic complete resection are not indications for RT. 36 Gy at 1.8 Gy per treatment. Consider boosting gross tumor to 45 Gy in selected cases: age greater than 18 years and no gross tumor in the orbit or cavernous sinus. In most cases the optimal photon RT technique will involve multiple non-coplanar fixed beams or segmental arcs. With a fixed-beam approach our standard plan uses 5 angles and intensity modulation. Position is supine with the head extended so that the floor of the orbit is perpendicular to the table and immobilized using a plastic mask or whatever approach optimizes immobilization and setup reproducibility. We use an oral stent to move the tongue inferiorly. CT simulation with fusion to head MR scan, both with intravenous contrast. CT: 3-mm contiguous slices from the skull vertex to the mid neck. MR: 1-mm contiguous slices with a T1-weighted sequence (TR 1720 and TE 3.4 msec). GTV = visible tumor on CT and MR. CTV = the entire pterygopalatine fossa and inferior orbital fissure on the ipsilateral side plus 1.0 cm expansion of the GTV in all directions where there is no barrier to tumor spread. The CTV is not expanded to cover the regional lymphatics. PTV = CTV plus 1 mm because we use daily cone beam CT and a real-time surface image-guided stereotactic positioning system. These are “hard” constraints that must be met at the expense of normal-tissue dose: 95% of the PTV receives 100% of the prescription dose; 99% of the PTV receives 93% of the prescription dose; No more than 20% of the PTV receives 110% of the prescription dose. The main normal structures to contour are lens, retina, optic nerve, optic chiasm, pituitary, hypothalamus, cochlea, brainstem, and spinal cord. Normal structure doses are evaluated for PRV where PRV = normal structure plus 1 mm. The PRV dose goal is “as low as possible” with the requirement that we make the target coverage constraints. The resultant dose to normal structures depends on tumor location. Clinic examination and MR scan b: 3 months after completing RT; then every 6 months for 5 years; and then every 5 years thereafter.

CT, computed tomography; CTV, clinical target volume; JNA, juvenile nasopharyngeal angiofibroma; GTV, gross tumor volume; MR, magnetic resonance, PTV, planning target volume; PRV, planning organs at risk volume; RT, radiotherapy. a RT technique: These guidelines are for photon radiotherapy. The technique will be different with proton beams. b Follow-up: MR preferred over CT to avoid additional ionizing radiation.

comparison that demonstrates a dose-response over this range. We observed a higher recurrence rate with our lowerdose schedule so our bias is to use 36 Gy at 1.8 Gy per treatment (20 treatments) regardless of tumor size, stage, or other factors. Our tumor-control rate is approximately 90% with this schedule, and the tradeoff between improved cure rate and increased complications is unlikely to be favorable from going to a higher dose in most situations. We consider

boosting the gross tumor volume above 36 Gy for rare cases of older patients with all gross disease below the base of skull. In these cases, we consider reducing the treatment volume after 36 Gy to boost the gross tumor to a total dose of 45 Gy at 1.8 Gy per treatment. We are reluctant to use a hypofractionated regimen, as we do in radiosurgery or stereotactic body cases, because of concerns about complications from high-dose treatment in this setting.

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Radiotherapy technique It is unnecessary to discuss the lack of data showing that new technologies will improve outcome following RT for JNA because we are all going to use them if they may be at all beneficial.4 Most of our patients were treated with 2 opposed laterals and 1 anterior field with about 2 cm between the field edge and the gross tumor as seen on a CT or MR scan with intravenous contrast. It is difficult to miss the target with this technique, which may explain why there were no marginal misses in our series and none are reported in the literature. We now treat JNA cases with newer technologies. At our department without a proton beam we treat JNA patients with stereotactic, intensity-modulated radiation therapy with 5 to 7 noncoplanar beam angles and we will soon use noncoplanar dynamic arcs in selected cases. Table 2 summarizes the dosimetric parameters in these cases. At our proton institute, we use noncoplanar proton beams with the number of beams dependent on tumor size and location.

Time course of recurrence after RT and follow-up imaging Few series report information on the time of recurrence following RT. In our series, all 4 recurrences presented within 4 years of completing RT and most presented within 2 years. We find it difficult to use radiographic response to predict tumor control because JNA responds quickly and almost completely to RT. Based on these observations on the timing of recurrence and the success of salvage surgery, we conclude that patients with JNA should be imaged frequently during the first 5 years following RT and surgery. Our preference is to follow patients with MR scan instead of CT to avoid additional ionizing radiation. We recommend follow-up imaging 3 months after completing RT, then every 6 months for 5 years, and then every 5 years for the remainder of the patient's life. The reason behind follow-up after 5 years is the small chance of a second tumor. In our experience, most second tumors following brain RT are usually meningiomas which have an excellent prognosis if they are detected early and treated appropriately.15

Conclusions Table 2 summarizes the concepts radiation oncologists need to understand to manage patients with JNA. Surgery is the best treatment when cure is likely with low morbidity, but the threshold for using RT should be low because moderate dose RT cures about 90% of patients with a low risk of serious complications. We recommend 36 Gy at 1.8 Gy per treatment in most cases. Elective nodal irradiation

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is not necessary. Radiographic response should be almost complete within a year of RT. Patients should be followed with cross-sectional imaging every 6 months for at least 5 years because surgical salvage is highly successful.

Acknowledgments The authors would like to thank the staff in the research office of the Department of Radiation Oncology at the University of Florida for helping prepare the manuscript for publication.

References 1. Mendenhall WM, Werning JW, Hinerman RW, Amdur RJ, Villaret DB. Juvenile nasopharyngeal angiofibroma. J Hong Kong Coll Radiol. 2003;6:15-19. 2. McAfee WJ, Morris CG, Amdur RJ, Werning JW, Mendenhall WM. Definitive radiotherapy for juvenile nasopharyngeal angiofibroma. Am J Clin Oncol. 2006;29:168-170. 3. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v4.0, DCTD, NCI, NIH, DHHS. http://www.ctep. cancer.gov/protocolDevelopment/electronic_applications/docs/ ctcae_index.pdf#search="common terminology". Updated April 15, 2010. Accessed June 4, 2010. 4. Chakraborty S, Ghoshal S, Patil VM, Oinam AS, Sharma SC. Conformal radiotherapy in the treatment of advanced juvenile nasopharyngeal angiofibroma with intracranial extension: an institutional experience. Int J Radiat Oncol Biol Phys. 2010 Jun 30. [Epub ahead of print]. 5. Bleier BS, Kennedy DW, Palmer JN, Chiu AG, Bloom JD, O'Malley BW Jr. Current management of juvenile nasopharyngeal angiofibroma: a tertiary center experience 1999-2007. Am J Rhinol Allergy. 2009;23:328-330. 6. Herman B, Bublik M, Ruiz J, Younis R. Endoscopic embolization with onyx prior to resection of JNA: a new approach. Int J Pediatr Otorhinolaryngol. 2011;75:53-56. 7. Lee JT, Keschner DB, Kennedy DW. Endoscopic resection of juvenile nasopharyngeal angiofibroma. Operative Techniques in Otolaryngology. 2010;21:56-65. 8. Hicks JL, Nelson JF. Juvenile nasopharyngeal angiofibroma. Oral Surg Oral Med Oral Pathol. 1973;35:807-17. 9. Montag AG, Tretiakova M, Richardson M. Steroid hormone receptor expression in nasopharyngeal angiofibromas. Consistent expression of estrogen receptor beta. Am J Clin Pathol. 2006;125:832-37. 10. Coutinho-Camillo CM, Brentani MM, Nagai MA. Genetic alterations in juvenile nasopharyngeal angiofibromas. Head Neck. 2008;30:390-400. 11. Snyderman CH, Pant H, Carrau RL, Gardner P. A new endoscopic staging system for angiofibromas. Arch Otolaryngol Head Neck Surg. 2010;136:588-594. 12. Tosun F, Onerci M, Durmaz A, Ugurel S. Spontaneous involution of nasopharyngeal angiofibroma. J Craniofac Surg. 2008;19:1686-1689. 13. Lee JT, Chen P, Safa A, Juillard G, Calcaterra TC. The role of radiation in the treatment of advanced juvenile angiofibroma. Laryngoscope. 2002;112(7 Pt 1):1213-1220. 14. Makek MS, Andrews JC, Fisch U. Malignant transformation of a nasopharyngeal angiofibroma. Laryngoscope. 1989;99(10 Pt 1): 1088-1092. 15. Galloway TJ, Indelicato DJ, Amdur RJ, Swanson EL, Morris CG, Marcus RB. Favorable outcomes of pediatric patients treated with radiotherapy to the central nervous system who develop radiationinduced meningiomas. Int J Radiat Oncol Biol Phys. 2011;79: 117-120.

Radiotherapy for juvenile nasopharyngeal angiofibroma.

To explain the concepts that radiation oncologists need to understand to manage patients with juvenile nasopharyngeal angiofibroma (JNA). To accomplis...
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