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Clinical Experience With Radiation Therapy in the Management of Neurofibromatosis-Associated Central Nervous System Tumors
Int. J. Radiation Oncology Biol. Phys., Vol. 73, No. 1, pp. 208–213, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.03.073
CLINICAL INVESTIGATION
Brain
CLINICAL EXPERIENCE WITH RADIATION THERAPY IN THE MANAGEMENT OF NEUROFIBROMATOSIS-ASSOCIATED CENTRAL NERVOUS SYSTEM TUMORS STACY WENTWORTH, M.D.,* MELVA PINN, M.D.,y J. DANIEL BOURLAND, PH.D.,* ALLAN F. DEGUZMAN, PH.D.,* KENNETH EKSTRAND, PH.D.,* THOMAS L. ELLIS, M.D.,z STEVEN S. GLAZIER, M.D.,z KEVIN P. MCMULLEN, M.D.,* MICHAEL MUNLEY, PH.D.,* VOLKER W. STIEBER, M.D.,* STEPHEN B. TATTER, M.D., PH.D.,z AND EDWARD G. SHAW, M.D.* Departments of * Radiation Oncology and z Neurosurgery, Wake Forest University School of Medicine, Winston Salem, NC; and y Department of Internal Medicine, Brody School of Medicine, Greenville, NC Purpose: Patients with neurofibromatosis (NF) develop tumors of the central nervous system (CNS). Radiation therapy (RT) is used to treat these lesions. To better define the efficacy of RT in these patients, we reviewed our 20-year experience. Methods and Materials: Eighteen patients with NF with CNS tumors were treated from 1986 to 2007. Median follow-up was 48 months. Progression was defined as growth or recurrence of an irradiated tumor on serial imaging. Progression-free survival (PFS) was measured from the date of RT completion to the date of last follow-up imaging study. Actuarial rates of overall survival (OS) and PFS were calculated according to the Kaplan-Meier method. Results: Eighty-two tumors in 18 patients were irradiated, with an average of five tumors/patient. Median age at treatment was 25 years (range, 4.3–64 years). Tumor types included acoustic neuroma (16%), ependymoma (6%), low-grade glioma (11%), meningioma (60%), and schwanomma/neurofibroma (7%). The most common indication for treatment was growth on serial imaging. Most patients (67%) received stereotactic radiosurgery (median dose, 1,200 cGy; range, 1,000–2,400 cGy). The OS rate at 5 years was 94%. Five-year PFS rates were 75% (acoustic neuroma), 100% (ependymoma), 75% (low-grade glioma), 86% (meningioma), and 100% (schwanomma/neurofibroma). Thirteen acoustic neuromas had a local control rate of 94% with a 50% hearing preservation rate. Conclusions: RT provided local control, OS, and PFS rates similar to or better than published data for tumors in non-NF patients. Radiation therapy should be considered in NF patients with imaging progression of CNS tumors. Ó 2009 Elsevier Inc. Neurofibromatosis, Radiation therapy, Acoustic neuroma, Meningioma, Radiosurgery.
INTRODUCTION
cord, and peripheral nerves can lead to tumor-associated morbidity. Prior studies have shown lower than expected rates of tumor control and hearing preservation in patients with NF treated with single-fraction stereotactic radiosurgery (SRS) for acoustic neuroma (5–7). There is a paucity of data regarding the treatment of patients with NF-associated tumors in other CNS sites. To clarify the role of RT in patients with NF, we reviewed the records of NF patients treated with RT in our department during the last 20 years.
Neurofibromatosis (NF) type 1 (NF1) and type 2 (NF2) are inherited genetic disorders that predispose affected individuals to benign and malignant neoplasms. Both NF1 and NF2 are also associated with a wide variety of other clinical manifestations, including loss of vision and hearing, learning disabilities, and skeletal disorders. Table 1 lists the National Institutes of Health diagnostic criteria for NF1 and NF2 (1). Patients with NF1 and NF2 are predisposed to central nervous system (CNS) tumors, including optic nerve gliomas (NF1 > NF2), acoustic neuromas (NF2), meningiomas, and schwanommas (1–4). Treatment is individualized and options include observation with serial scans, surgery, radiation therapy (RT), radiosurgery, chemotherapy, or combinations of these modalities. The presence of these tumors in or around many eloquent structures in the brain, spinal
METHODS AND MATERIALS Patient population We retrospectively analyzed the data for patients with NF1 and NF2 treated with RT in the Department of Radiation Oncology at the Wake Forest University School of Medicine (Winston-Salem,
Reprint requests to: Edward G. Shaw, M.D., Ph.D., Professor and Chairman, Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157. Tel: (336) 713-3600; Fax: (336) 713-6622; E-mail: [email protected]
Conflict of interest: none. Received Jan 3, 2008, and in revised form March 25, 2008. Accepted for publication March 27, 2008. 208
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Table 1. National Institutes of Health Consensus Development Conference Criteria for Diagnosis of NF1 and NF2 NF1 $2 of the following: $6 Cafe´-au-lait spots $1.5 cm in postpubertal individuals, $0.5 cm in prepubertal individuals $2 Neurofibromas of any type or $1 plexiform neurofibroma Freckling in the axilla or groin Optic glioma (tumor of the optic pathway) $2 Lisch nodules (benign iris hamartomas) A distinctive bony lesion: dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex A first-degree relative with NF1 NF2 Bilateral vestibular schwannomas Presumptive (probable) NF2: family history of NF2 (first-degree family relative) plus unilateral VS or any 2 of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, juvenile cortical cataract Individuals with the following clinical features should be evaluated for NF2: Unilateral vestibular schwannoma plus at least 2 of any of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract Multiple meningiomas ($2) plus unilateral vestibular schwannoma or any 2 of the following: glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract Abbreviations: NF1 = neurofibromatosis type 1; NF2 = neurofibromatosis type 2; VS = vestibular schwannoma. Data from Gutmann et al. (1). NC) between 1986 and 2007. The school’s Institutional Review Board reviewed and approved this study. Twenty-five patients with NF1- or NF2-associated CNS tumors were evaluated in our department during the 20-year period between 1986 and 2007. Radiation therapy was recommended and received in 18 of these patients. Eighty-two tumors in these 18 patients were treated with definitive RT. After treatment, patients were followed up with serial magnetic resonance imaging studies at 3–6-month intervals.
Statistical Analysis Progression was defined as growth or recurrence of an irradiated tumor on serial imaging studies. The progression-free survival (PFS) rate was measured from the date RT was completed to the date of the last follow-up imaging study. Patients without followup imaging studies were censored at the RT completion date and not considered treatment failures. The PFS rates were measured from the date RT was completed to the date of the last follow-up imaging study. Actuarial rates of overall survival (OS) and PFS were calculated according to the Kaplan-Meier method. Comparisons were made by using log-rank test.
RESULTS Table 2 lists patient characteristics of this cohort. Median age at treatment was 25 years. Six patients had NF1, whereas the other 12 had NF2. Seventy-two percent of patients were females. The average number of tumors treated was five (range, 1–27). Most patients (84%) did not have histologic confirmation of disease and were treated based on imaging findings alone. The most commonly treated tumor type was meningioma (60%). The most common indication for treatment was progressive growth on serial imaging studies, although many patients presented with symptoms. Fifty-five lesions were treated with single-fraction SRS using Gamma Knife– or linear accelerator–based systems (median dose, 1,200 cGy; range, 1,000–2,400 cGy). Radiosurgery dose typically was prescribed to the 50% isodose line. Twenty-seven lesions
were treated with fractionated external beam RT (median dose, 4,500 cGy; median dose/fraction, 180 cGy; range: 3,420–6,040 cGy). Patients with low-grade gliomas included World Health Organization (WHO) Grade I tumors (juvenile pilocytic astrocytoma; three tumors), WHO Grade II astrocytoma (three tumors), and unbiopsied optic nerve gliomas (three tumors). The majority of patients with low-grade gliomas were treated with external beam RT to the primary site with margin to a total dose of 4,500–6,040 cGy. One patient underwent Gamma Knife radiosurgery (12 Gy to the 50% isodose line). Two patients with pilocytic astrocytomas had prior subtotal resection, and the third had prior vincristine/carboplatin chemotherapy. Regarding patients with optic nerve glioma, 1 adult patient was treated for bilateral optic nerve gliomas. Table 2. Patient characteristics Median age at treatment (y) NF1 NF2 Gender Male Female Histologic confirmation of disease Average no. of treated tumors Treatment modality External beam radiation therapy Gamma Knife SRS Linear accelerator–based SRS Tumor type of treated tumors Acoustic neuroma Ependymoma Low-grade glioma Meningioma Neurofibroma/nonacoustic schwanomma Total tumors:
25 (4.3–64) 6 (33) 12 (67) 5 (28) 13 (72) 13 (16) 5 (1–27) 27 (33) 50 (61) 5 (6) 13 (16) 5 (6) 9 (11) 49 (60) 6 (7) 82
Abbreviations: NF1 = neurofibromatosis type 1; NF2 = neurofibromatosis type 2; SRS = stereotactic radiosurgery. Values expressed as median (range) or number (percent).
I. J. Radiation Oncology d Biology d Physics
Her total dose was 5,040 cGy at 180 cGy/fraction to both areas. Because she was an adult, no prior treatments had been attempted. At 7 years of follow-up, vision was completely preserved in her left eye and useful vision (i.e., ability to count fingers) was preserved in the right eye. The second patient, a 2-year-old child, had an optic chiasm glioma. She was initially treated with vincristine/carboplatin chemotherapy for 1 year, then developed imaging progression worrisome for malignant transformation and received 5,400 cGy at 180 cGy/fraction. Vision was preserved in the left eye, but lost in the right. Two patients who underwent RT for low-grade gliomas experienced transformation to malignant gliomas and eventually died. Five patients were treated in our department for ependymoma. Three patients received treatment with external RT to the primary site with margin to a total dose of 45–54 Gy. One patient did not finish treatment and another underwent Gamma Knife radiosurgery. Only 1 patient had previously undergone subtotal resection, and no patient received craniospinal RT. Twelve of the 13 patients with vestibular schwannoma underwent SRS and 1 underwent fractionated external beam RT. Useful hearing was present in 6 of the 12 patients with radiosurgically treated acoustic neuromas before treatment. After SRS, useful hearing was preserved in three acoustic neuromas (two in the same patient, who received 12 Gy to each tumor; the other patient’s tumor received 10 Gy) and lost in the other 3 patients with acoustic neuromas (tumor dose 12 Gy in all 3 patients). Facial weakness was present before SRS in 1 patient (postoperative complication). Four of 12 patients with acoustic neuromas (33%) developed facial weakness after SRS. The 1 patient treated with fractionated RT (5,040 cGy) lost useful hearing and had local control and no cranial nerve complications. Local control was achieved in all except one acoustic neuroma (94%). Most patients treated for meningiomas presented with asymptomatic lesions that showed growth on serial imaging and were in eloquent locations in which further growth could lead to morbidity. Most lesions were treated using Gamma Knife radiosurgery (12–14 Gy to the 50% isodose line) with a 5-year PFS rate of 86%. Several patients had multiple lesions treated and tolerated therapy well. Patients who received fractionated RT had similar PFS. Six neurofibromas/nonacoustic schwanommas were treated with RT. Three lesions were recurrences in previously resected areas and all lesions were symptomatic, including extremity weakness, numbness, or incontinence. All six lesions were treated with external beam RT with an average dose of 4,500 cGy. One patient had five tumors treated during the course of 3 years, including tumors on the right brachial plexus, left sacral nerve plexus, and nerve roots of the cervical, thoracic, and lumbar spine. This patient had no new symptoms for almost 2 years after treatment until new tumors grew outside the treated areas. With a median follow-up of 48 months (range, 0–199 months), the 5-year OS rate for all patients was 94%
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Fig. 1. Overall survival rate of all patients.
(Fig. 1). There was no difference in OS between tumor types (p = 0.34). The 5-year PFS rates for patients with acoustic neuroma, ependymoma, low-grade glioma, meningioma, and neurofibroma/nonacoustic schwanomma were 75%, 100%, 75%, 86%, and 100%, respectively. Figure 2 shows PFS rates by tumor type. There was no significant difference in outcomes by tumor type. Six tumors (7%) showed imaging progression after RT, including one of 13 acoustic neuromas (8%), two of nine (22%) low-grade gliomas, and three of 49 meningiomas (6%). There were no RT failures in the treated ependymomas (five tumors) or neurofibroma/nonacoustic schwanommas (six tumors). DISCUSSION NF1 NF1 has a prevalence of 1:3,500 persons worldwide. Patients with NF1 are predisposed to developing low-grade gliomas, including optic nerve gliomas, neurofibromas, and nonacoustic schwannomas. Optic nerve gliomas Ten percent to 20% of patients with NF1 develop optic nerve gliomas, including tumors of the optic nerve, chiasm, and optic tracts, usually by the age of 6 years (8). These lesions are WHO Grade I pilocytic astrocytomas. Growth in these locations can lead to severe visual loss and/or hypothalamic dysfunction. Therapeutic options include surgical debulking, chemotherapy, and fractionated external beam RT. The overall rarity of optic nerve gliomas combined with the variable rate of progression have made it difficult to determine the optimal time to intervene in these patients. Visual loss can occur in up to 20% of patients, but spontaneous regression of tumors also has been noted (8, 9). Although screening of patients with NF1 for optic nerve glioma is controversial, the literature suggests that tumors rarely progress after the age of 6 years. Treatment generally is indicated in children presenting with significant visual loss or signs of intracranial pressure and/or imaging evidence of tumor progression (10).
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% Patients Free of Progression
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25
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Fig. 2. Progression-free survival by tumor type: (solid line) acoustic neuroma, (red line) ependymoma, (long-short dash) low-grade glioma, (short dash) meningioma, and (long dash) neurofibroma/nonacoustic schwanomma.
Chemotherapy has been used to delay progression of disease, but most patients eventually require definitive treatment (11). Both RT and surgery provide durable local control of disease; however, complete surgical excision of tumors in this area is difficult (12, 13). Two patients in our series were treated with RT for optic nerve gliomas, 1 with prior chemotherapy. Vision was ultimately preserved in three of four treated eyes. Other low-grade gliomas Five patients with NF1 in our department were treated for other low-grade gliomas. Three had prior therapy, including surgical resection and chemotherapy. Several investigators recently reported their outcomes in treating low-grade glioma in children with fractionated external beam RT using stereotactic techniques with smaller than usual margins (0.5–1 vs. 2 cm) (14–16). Both reported 80– 90% local control rates, and local failures tended to be in the radiated field, rather than marginal failures, which supports the use of narrow margins and sparing dose to normal structures. Local control was achieved in 3 of 5 patients in our series, with 2 patients converting to higher grade gliomas in the treated field. Ependymoma There are currently no randomized prospective multi-institutional trials establishing the standard of care in patients with ependymoma. Moreover, there are no recommendations specifically for patients with NF. The results of Phase II trials and retrospective reviews have provided the basis of treatment for these patients (17, 18). In general, local fractionated external beam RT is recommended for patients with low-grade epen-
dymomas without evidence of cranial or spinal leptomeningeal dissemination. The 5 patients with NF1 treated with RT for ependymoma in our series had local control. This control rate is similar to local control rates observed in the literature for patients with low-grade nondisseminated ependymomas (19, 20). NF2 NF2 has an incidence of 1:40,000–50,000. Adult patients with NF2 usually present with auditory or vestibular symptoms as a result of the characteristic bilateral vestibular schwannomas. Children with NF2 often present as a result of genetic testing or non-cranial nerve VIII–related tumors. The majority of patients treated in our department presented with meningiomas or acoustic neuromas. Treatment options for patients with vestibular schwanommas include surgery, SRS, and active surveillance (21, 22). Acoustic neuromas Numerous institutions have published their experiences in managing patients with NF2-associated bilateral acoustic neuromas (Table 3). The decision for when to intervene and on which side can be complex. Local control rates greater than 90% with SRS compare favorably with reported data in patients with non-NF. However, hearing preservation rates are much lower compared with patients with non-NF. Rowe et al. (6) reported on the largest experience of treating acoustic neuromas in patients with NF2 with Gamma Knife SRS. These investigators reported that 79% of patients treated with Gamma Knife radiosurgery were able to avoid surgery, with a 40% hearing preservation rate (6). In our series, useful hearing was preserved in 3 of 6 patients by using
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Table 3. Results of stereotactic radiosurgery for acoustic neuroma in patients with neurofibromatosis Institution (reference)
No. of patients
Margin dose (Gy)
Local control rate (%)
Hearing preservation rate (%)
Incidence of facial weakness (%)
University of Pittsburgh (5) Royal Hallamashire Hospital, UK (6) Komaki City Hospital, Japan (7) Wake Forest (current series)
74 92 20 12
14 13.4 13 12
88 79 100 94
42 40 33 25
8 5 10 42
SRS. Although the rate of hearing preservation is low, it must be interpreted in the context of the natural history of NF2 in which 100% of these patients will eventually progress to bilateral loss of hearing if left untreated. Moreover, brain stem auditory implants after radiosurgery in patients with NF2 have the potential to restore some useful hearing (23). Meningiomas To our knowledge, this is the largest reported experience of patients with NF-associated meningiomas treated with RT. Control rates with fractionated radiotherapy or SRS in patients with non-NF are well reported and approach 80– 90% (24, 25). The majority of our patients presented with asymptomatic lesions that showed growth on serial imaging and were in eloquent locations in which further growth would lead to morbidity. Given the propensity of these patients to develop multiple tumors over time, repeat craniotomies usually are not appropriate and instead, given the high rate of local control, patients can be treated with less invasive radiotherapeutic approaches. Recent publications have raised concerns over radiationinduced malignancies in pediatric patients undergoing treatment for CNS tumors (26, 27). The incidence of second malignancies is low (<1%), but benign and malignant tumors continue to appear decades after treatment for the primary tumor. In one study including patients with NF and non-NF, children who received higher doses of RT were at higher risk of developing a CNS tumor (benign or malignant) later in life. Another concern when offering RT to patients with NF is the transformation to malignant tumors, including malignant peripheral nerve sheath tumors. Some investigators reported this to be as high as a 10-fold increased risk of malignant transformation in patients with NF undergoing RT vs. unirradiated patients (28). Two patients who underwent external beam RT for low-grade gliomas experienced transformation to a more malignant glioma and eventually died of disease. However, this occurs in approximately half the patients with non-NF, with low-grade glioma as part of the natural history of their disease (29). We did not observe malignant transformation of any other treated lesions. No malignant peripheral-nerve sheath tumors were seen in our patient population, although these have been reported in patients with NF (30). Neurofibromas/nonacoustic schwannomas Neurofibromas are benign peripheral-nerve sheath tumors consisting of Schwann cells often found in patients with NF1.
The most common neurofibroma found in patients with NF1 is a localized cutaneous type that usually is slow growing and painless tumors found on the skin that can number in the thousands on some patients. The second most common type of neurofibroma is the localized intraneural neurofibroma. These tumors are found on peripheral nerves from the spinal and cranial nerve roots to their most distal branches. Their growth within the nerve itself can lead to symptoms because of disruption of axonal communication pathways. These tumors can grow up to several centimeters in diameter and can cause a significant amount of mass effect (e.g., on the bladder in the pelvis). Surgical resection is performed in a majority of these patients, and with microsurgical techniques, preservation of nerve signaling is possible. Subtotally resected tumors have up to a 45% recurrence rate (31). Reports of the treatment of patients with these tumors with definitive or adjuvant RT are rare, but report good local control (32–34). The 1 patient treated with RT for five neurofibromas at our institution has durable local control in the treated areas, but continued morbidity secondary to the growth of neurofibromas distal to the treated areas. The systemic nature of NF lends itself well to chemotherapeutic or molecularly targeted agents. The genes involved in these diseases, as well as their protein products, neurofibromin and schwannomin, have been identified and act as tumor-suppressor genes (35–37). Pharmacologic strategies, including targeting the fibroblast pathway, have shown promise in Phase I and II studies. In a recently reported Phase II study, pirfenidone, an antifibroblastic agent, was administered to patients with NF1 with symptomatic or surgically unresectable plexiform neurofibromas or paraspinal neurofibromas. The majority of patients showed stable disease, with 15% of patients showing tumor shrinkage on follow-up imaging (38). Other agents under investigation include thalidomide and inhibitors of the Ras signal transduction pathway (39, 40). CONCLUSIONS Patients with NF-associated CNS tumors present a unique management dilemma. The toxicities of therapy must be balanced with the morbidity of progressive disease. Multidisciplinary evaluation of these patients is crucial to optimal care. Radiation therapy, either fractionated external beam RT or SRS, provides an effective and safe method of local tumor control for patients with most NF-associated CNS tumors and should be considered in patients with symptoms and/or progression.
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doi:10.1016/j.ijrobp.2008.03.073
CLINICAL INVESTIGATION
Brain
CLINICAL EXPERIENCE WITH RADIATION THERAPY IN THE MANAGEMENT OF NEUROFIBROMATOSIS-ASSOCIATED CENTRAL NERVOUS SYSTEM TUMORS STACY WENTWORTH, M.D.,* MELVA PINN, M.D.,y J. DANIEL BOURLAND, PH.D.,* ALLAN F. DEGUZMAN, PH.D.,* KENNETH EKSTRAND, PH.D.,* THOMAS L. ELLIS, M.D.,z STEVEN S. GLAZIER, M.D.,z KEVIN P. MCMULLEN, M.D.,* MICHAEL MUNLEY, PH.D.,* VOLKER W. STIEBER, M.D.,* STEPHEN B. TATTER, M.D., PH.D.,z AND EDWARD G. SHAW, M.D.* Departments of * Radiation Oncology and z Neurosurgery, Wake Forest University School of Medicine, Winston Salem, NC; and y Department of Internal Medicine, Brody School of Medicine, Greenville, NC Purpose: Patients with neurofibromatosis (NF) develop tumors of the central nervous system (CNS). Radiation therapy (RT) is used to treat these lesions. To better define the efficacy of RT in these patients, we reviewed our 20-year experience. Methods and Materials: Eighteen patients with NF with CNS tumors were treated from 1986 to 2007. Median follow-up was 48 months. Progression was defined as growth or recurrence of an irradiated tumor on serial imaging. Progression-free survival (PFS) was measured from the date of RT completion to the date of last follow-up imaging study. Actuarial rates of overall survival (OS) and PFS were calculated according to the Kaplan-Meier method. Results: Eighty-two tumors in 18 patients were irradiated, with an average of five tumors/patient. Median age at treatment was 25 years (range, 4.3–64 years). Tumor types included acoustic neuroma (16%), ependymoma (6%), low-grade glioma (11%), meningioma (60%), and schwanomma/neurofibroma (7%). The most common indication for treatment was growth on serial imaging. Most patients (67%) received stereotactic radiosurgery (median dose, 1,200 cGy; range, 1,000–2,400 cGy). The OS rate at 5 years was 94%. Five-year PFS rates were 75% (acoustic neuroma), 100% (ependymoma), 75% (low-grade glioma), 86% (meningioma), and 100% (schwanomma/neurofibroma). Thirteen acoustic neuromas had a local control rate of 94% with a 50% hearing preservation rate. Conclusions: RT provided local control, OS, and PFS rates similar to or better than published data for tumors in non-NF patients. Radiation therapy should be considered in NF patients with imaging progression of CNS tumors. Ó 2009 Elsevier Inc. Neurofibromatosis, Radiation therapy, Acoustic neuroma, Meningioma, Radiosurgery.
INTRODUCTION
cord, and peripheral nerves can lead to tumor-associated morbidity. Prior studies have shown lower than expected rates of tumor control and hearing preservation in patients with NF treated with single-fraction stereotactic radiosurgery (SRS) for acoustic neuroma (5–7). There is a paucity of data regarding the treatment of patients with NF-associated tumors in other CNS sites. To clarify the role of RT in patients with NF, we reviewed the records of NF patients treated with RT in our department during the last 20 years.
Neurofibromatosis (NF) type 1 (NF1) and type 2 (NF2) are inherited genetic disorders that predispose affected individuals to benign and malignant neoplasms. Both NF1 and NF2 are also associated with a wide variety of other clinical manifestations, including loss of vision and hearing, learning disabilities, and skeletal disorders. Table 1 lists the National Institutes of Health diagnostic criteria for NF1 and NF2 (1). Patients with NF1 and NF2 are predisposed to central nervous system (CNS) tumors, including optic nerve gliomas (NF1 > NF2), acoustic neuromas (NF2), meningiomas, and schwanommas (1–4). Treatment is individualized and options include observation with serial scans, surgery, radiation therapy (RT), radiosurgery, chemotherapy, or combinations of these modalities. The presence of these tumors in or around many eloquent structures in the brain, spinal
METHODS AND MATERIALS Patient population We retrospectively analyzed the data for patients with NF1 and NF2 treated with RT in the Department of Radiation Oncology at the Wake Forest University School of Medicine (Winston-Salem,
Reprint requests to: Edward G. Shaw, M.D., Ph.D., Professor and Chairman, Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157. Tel: (336) 713-3600; Fax: (336) 713-6622; E-mail: [email protected]
Conflict of interest: none. Received Jan 3, 2008, and in revised form March 25, 2008. Accepted for publication March 27, 2008. 208
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Table 1. National Institutes of Health Consensus Development Conference Criteria for Diagnosis of NF1 and NF2 NF1 $2 of the following: $6 Cafe´-au-lait spots $1.5 cm in postpubertal individuals, $0.5 cm in prepubertal individuals $2 Neurofibromas of any type or $1 plexiform neurofibroma Freckling in the axilla or groin Optic glioma (tumor of the optic pathway) $2 Lisch nodules (benign iris hamartomas) A distinctive bony lesion: dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex A first-degree relative with NF1 NF2 Bilateral vestibular schwannomas Presumptive (probable) NF2: family history of NF2 (first-degree family relative) plus unilateral VS or any 2 of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, juvenile cortical cataract Individuals with the following clinical features should be evaluated for NF2: Unilateral vestibular schwannoma plus at least 2 of any of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract Multiple meningiomas ($2) plus unilateral vestibular schwannoma or any 2 of the following: glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract Abbreviations: NF1 = neurofibromatosis type 1; NF2 = neurofibromatosis type 2; VS = vestibular schwannoma. Data from Gutmann et al. (1). NC) between 1986 and 2007. The school’s Institutional Review Board reviewed and approved this study. Twenty-five patients with NF1- or NF2-associated CNS tumors were evaluated in our department during the 20-year period between 1986 and 2007. Radiation therapy was recommended and received in 18 of these patients. Eighty-two tumors in these 18 patients were treated with definitive RT. After treatment, patients were followed up with serial magnetic resonance imaging studies at 3–6-month intervals.
Statistical Analysis Progression was defined as growth or recurrence of an irradiated tumor on serial imaging studies. The progression-free survival (PFS) rate was measured from the date RT was completed to the date of the last follow-up imaging study. Patients without followup imaging studies were censored at the RT completion date and not considered treatment failures. The PFS rates were measured from the date RT was completed to the date of the last follow-up imaging study. Actuarial rates of overall survival (OS) and PFS were calculated according to the Kaplan-Meier method. Comparisons were made by using log-rank test.
RESULTS Table 2 lists patient characteristics of this cohort. Median age at treatment was 25 years. Six patients had NF1, whereas the other 12 had NF2. Seventy-two percent of patients were females. The average number of tumors treated was five (range, 1–27). Most patients (84%) did not have histologic confirmation of disease and were treated based on imaging findings alone. The most commonly treated tumor type was meningioma (60%). The most common indication for treatment was progressive growth on serial imaging studies, although many patients presented with symptoms. Fifty-five lesions were treated with single-fraction SRS using Gamma Knife– or linear accelerator–based systems (median dose, 1,200 cGy; range, 1,000–2,400 cGy). Radiosurgery dose typically was prescribed to the 50% isodose line. Twenty-seven lesions
were treated with fractionated external beam RT (median dose, 4,500 cGy; median dose/fraction, 180 cGy; range: 3,420–6,040 cGy). Patients with low-grade gliomas included World Health Organization (WHO) Grade I tumors (juvenile pilocytic astrocytoma; three tumors), WHO Grade II astrocytoma (three tumors), and unbiopsied optic nerve gliomas (three tumors). The majority of patients with low-grade gliomas were treated with external beam RT to the primary site with margin to a total dose of 4,500–6,040 cGy. One patient underwent Gamma Knife radiosurgery (12 Gy to the 50% isodose line). Two patients with pilocytic astrocytomas had prior subtotal resection, and the third had prior vincristine/carboplatin chemotherapy. Regarding patients with optic nerve glioma, 1 adult patient was treated for bilateral optic nerve gliomas. Table 2. Patient characteristics Median age at treatment (y) NF1 NF2 Gender Male Female Histologic confirmation of disease Average no. of treated tumors Treatment modality External beam radiation therapy Gamma Knife SRS Linear accelerator–based SRS Tumor type of treated tumors Acoustic neuroma Ependymoma Low-grade glioma Meningioma Neurofibroma/nonacoustic schwanomma Total tumors:
25 (4.3–64) 6 (33) 12 (67) 5 (28) 13 (72) 13 (16) 5 (1–27) 27 (33) 50 (61) 5 (6) 13 (16) 5 (6) 9 (11) 49 (60) 6 (7) 82
Abbreviations: NF1 = neurofibromatosis type 1; NF2 = neurofibromatosis type 2; SRS = stereotactic radiosurgery. Values expressed as median (range) or number (percent).
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Her total dose was 5,040 cGy at 180 cGy/fraction to both areas. Because she was an adult, no prior treatments had been attempted. At 7 years of follow-up, vision was completely preserved in her left eye and useful vision (i.e., ability to count fingers) was preserved in the right eye. The second patient, a 2-year-old child, had an optic chiasm glioma. She was initially treated with vincristine/carboplatin chemotherapy for 1 year, then developed imaging progression worrisome for malignant transformation and received 5,400 cGy at 180 cGy/fraction. Vision was preserved in the left eye, but lost in the right. Two patients who underwent RT for low-grade gliomas experienced transformation to malignant gliomas and eventually died. Five patients were treated in our department for ependymoma. Three patients received treatment with external RT to the primary site with margin to a total dose of 45–54 Gy. One patient did not finish treatment and another underwent Gamma Knife radiosurgery. Only 1 patient had previously undergone subtotal resection, and no patient received craniospinal RT. Twelve of the 13 patients with vestibular schwannoma underwent SRS and 1 underwent fractionated external beam RT. Useful hearing was present in 6 of the 12 patients with radiosurgically treated acoustic neuromas before treatment. After SRS, useful hearing was preserved in three acoustic neuromas (two in the same patient, who received 12 Gy to each tumor; the other patient’s tumor received 10 Gy) and lost in the other 3 patients with acoustic neuromas (tumor dose 12 Gy in all 3 patients). Facial weakness was present before SRS in 1 patient (postoperative complication). Four of 12 patients with acoustic neuromas (33%) developed facial weakness after SRS. The 1 patient treated with fractionated RT (5,040 cGy) lost useful hearing and had local control and no cranial nerve complications. Local control was achieved in all except one acoustic neuroma (94%). Most patients treated for meningiomas presented with asymptomatic lesions that showed growth on serial imaging and were in eloquent locations in which further growth could lead to morbidity. Most lesions were treated using Gamma Knife radiosurgery (12–14 Gy to the 50% isodose line) with a 5-year PFS rate of 86%. Several patients had multiple lesions treated and tolerated therapy well. Patients who received fractionated RT had similar PFS. Six neurofibromas/nonacoustic schwanommas were treated with RT. Three lesions were recurrences in previously resected areas and all lesions were symptomatic, including extremity weakness, numbness, or incontinence. All six lesions were treated with external beam RT with an average dose of 4,500 cGy. One patient had five tumors treated during the course of 3 years, including tumors on the right brachial plexus, left sacral nerve plexus, and nerve roots of the cervical, thoracic, and lumbar spine. This patient had no new symptoms for almost 2 years after treatment until new tumors grew outside the treated areas. With a median follow-up of 48 months (range, 0–199 months), the 5-year OS rate for all patients was 94%
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Fig. 1. Overall survival rate of all patients.
(Fig. 1). There was no difference in OS between tumor types (p = 0.34). The 5-year PFS rates for patients with acoustic neuroma, ependymoma, low-grade glioma, meningioma, and neurofibroma/nonacoustic schwanomma were 75%, 100%, 75%, 86%, and 100%, respectively. Figure 2 shows PFS rates by tumor type. There was no significant difference in outcomes by tumor type. Six tumors (7%) showed imaging progression after RT, including one of 13 acoustic neuromas (8%), two of nine (22%) low-grade gliomas, and three of 49 meningiomas (6%). There were no RT failures in the treated ependymomas (five tumors) or neurofibroma/nonacoustic schwanommas (six tumors). DISCUSSION NF1 NF1 has a prevalence of 1:3,500 persons worldwide. Patients with NF1 are predisposed to developing low-grade gliomas, including optic nerve gliomas, neurofibromas, and nonacoustic schwannomas. Optic nerve gliomas Ten percent to 20% of patients with NF1 develop optic nerve gliomas, including tumors of the optic nerve, chiasm, and optic tracts, usually by the age of 6 years (8). These lesions are WHO Grade I pilocytic astrocytomas. Growth in these locations can lead to severe visual loss and/or hypothalamic dysfunction. Therapeutic options include surgical debulking, chemotherapy, and fractionated external beam RT. The overall rarity of optic nerve gliomas combined with the variable rate of progression have made it difficult to determine the optimal time to intervene in these patients. Visual loss can occur in up to 20% of patients, but spontaneous regression of tumors also has been noted (8, 9). Although screening of patients with NF1 for optic nerve glioma is controversial, the literature suggests that tumors rarely progress after the age of 6 years. Treatment generally is indicated in children presenting with significant visual loss or signs of intracranial pressure and/or imaging evidence of tumor progression (10).
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% Patients Free of Progression
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25
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Fig. 2. Progression-free survival by tumor type: (solid line) acoustic neuroma, (red line) ependymoma, (long-short dash) low-grade glioma, (short dash) meningioma, and (long dash) neurofibroma/nonacoustic schwanomma.
Chemotherapy has been used to delay progression of disease, but most patients eventually require definitive treatment (11). Both RT and surgery provide durable local control of disease; however, complete surgical excision of tumors in this area is difficult (12, 13). Two patients in our series were treated with RT for optic nerve gliomas, 1 with prior chemotherapy. Vision was ultimately preserved in three of four treated eyes. Other low-grade gliomas Five patients with NF1 in our department were treated for other low-grade gliomas. Three had prior therapy, including surgical resection and chemotherapy. Several investigators recently reported their outcomes in treating low-grade glioma in children with fractionated external beam RT using stereotactic techniques with smaller than usual margins (0.5–1 vs. 2 cm) (14–16). Both reported 80– 90% local control rates, and local failures tended to be in the radiated field, rather than marginal failures, which supports the use of narrow margins and sparing dose to normal structures. Local control was achieved in 3 of 5 patients in our series, with 2 patients converting to higher grade gliomas in the treated field. Ependymoma There are currently no randomized prospective multi-institutional trials establishing the standard of care in patients with ependymoma. Moreover, there are no recommendations specifically for patients with NF. The results of Phase II trials and retrospective reviews have provided the basis of treatment for these patients (17, 18). In general, local fractionated external beam RT is recommended for patients with low-grade epen-
dymomas without evidence of cranial or spinal leptomeningeal dissemination. The 5 patients with NF1 treated with RT for ependymoma in our series had local control. This control rate is similar to local control rates observed in the literature for patients with low-grade nondisseminated ependymomas (19, 20). NF2 NF2 has an incidence of 1:40,000–50,000. Adult patients with NF2 usually present with auditory or vestibular symptoms as a result of the characteristic bilateral vestibular schwannomas. Children with NF2 often present as a result of genetic testing or non-cranial nerve VIII–related tumors. The majority of patients treated in our department presented with meningiomas or acoustic neuromas. Treatment options for patients with vestibular schwanommas include surgery, SRS, and active surveillance (21, 22). Acoustic neuromas Numerous institutions have published their experiences in managing patients with NF2-associated bilateral acoustic neuromas (Table 3). The decision for when to intervene and on which side can be complex. Local control rates greater than 90% with SRS compare favorably with reported data in patients with non-NF. However, hearing preservation rates are much lower compared with patients with non-NF. Rowe et al. (6) reported on the largest experience of treating acoustic neuromas in patients with NF2 with Gamma Knife SRS. These investigators reported that 79% of patients treated with Gamma Knife radiosurgery were able to avoid surgery, with a 40% hearing preservation rate (6). In our series, useful hearing was preserved in 3 of 6 patients by using
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Table 3. Results of stereotactic radiosurgery for acoustic neuroma in patients with neurofibromatosis Institution (reference)
No. of patients
Margin dose (Gy)
Local control rate (%)
Hearing preservation rate (%)
Incidence of facial weakness (%)
University of Pittsburgh (5) Royal Hallamashire Hospital, UK (6) Komaki City Hospital, Japan (7) Wake Forest (current series)
74 92 20 12
14 13.4 13 12
88 79 100 94
42 40 33 25
8 5 10 42
SRS. Although the rate of hearing preservation is low, it must be interpreted in the context of the natural history of NF2 in which 100% of these patients will eventually progress to bilateral loss of hearing if left untreated. Moreover, brain stem auditory implants after radiosurgery in patients with NF2 have the potential to restore some useful hearing (23). Meningiomas To our knowledge, this is the largest reported experience of patients with NF-associated meningiomas treated with RT. Control rates with fractionated radiotherapy or SRS in patients with non-NF are well reported and approach 80– 90% (24, 25). The majority of our patients presented with asymptomatic lesions that showed growth on serial imaging and were in eloquent locations in which further growth would lead to morbidity. Given the propensity of these patients to develop multiple tumors over time, repeat craniotomies usually are not appropriate and instead, given the high rate of local control, patients can be treated with less invasive radiotherapeutic approaches. Recent publications have raised concerns over radiationinduced malignancies in pediatric patients undergoing treatment for CNS tumors (26, 27). The incidence of second malignancies is low (<1%), but benign and malignant tumors continue to appear decades after treatment for the primary tumor. In one study including patients with NF and non-NF, children who received higher doses of RT were at higher risk of developing a CNS tumor (benign or malignant) later in life. Another concern when offering RT to patients with NF is the transformation to malignant tumors, including malignant peripheral nerve sheath tumors. Some investigators reported this to be as high as a 10-fold increased risk of malignant transformation in patients with NF undergoing RT vs. unirradiated patients (28). Two patients who underwent external beam RT for low-grade gliomas experienced transformation to a more malignant glioma and eventually died of disease. However, this occurs in approximately half the patients with non-NF, with low-grade glioma as part of the natural history of their disease (29). We did not observe malignant transformation of any other treated lesions. No malignant peripheral-nerve sheath tumors were seen in our patient population, although these have been reported in patients with NF (30). Neurofibromas/nonacoustic schwannomas Neurofibromas are benign peripheral-nerve sheath tumors consisting of Schwann cells often found in patients with NF1.
The most common neurofibroma found in patients with NF1 is a localized cutaneous type that usually is slow growing and painless tumors found on the skin that can number in the thousands on some patients. The second most common type of neurofibroma is the localized intraneural neurofibroma. These tumors are found on peripheral nerves from the spinal and cranial nerve roots to their most distal branches. Their growth within the nerve itself can lead to symptoms because of disruption of axonal communication pathways. These tumors can grow up to several centimeters in diameter and can cause a significant amount of mass effect (e.g., on the bladder in the pelvis). Surgical resection is performed in a majority of these patients, and with microsurgical techniques, preservation of nerve signaling is possible. Subtotally resected tumors have up to a 45% recurrence rate (31). Reports of the treatment of patients with these tumors with definitive or adjuvant RT are rare, but report good local control (32–34). The 1 patient treated with RT for five neurofibromas at our institution has durable local control in the treated areas, but continued morbidity secondary to the growth of neurofibromas distal to the treated areas. The systemic nature of NF lends itself well to chemotherapeutic or molecularly targeted agents. The genes involved in these diseases, as well as their protein products, neurofibromin and schwannomin, have been identified and act as tumor-suppressor genes (35–37). Pharmacologic strategies, including targeting the fibroblast pathway, have shown promise in Phase I and II studies. In a recently reported Phase II study, pirfenidone, an antifibroblastic agent, was administered to patients with NF1 with symptomatic or surgically unresectable plexiform neurofibromas or paraspinal neurofibromas. The majority of patients showed stable disease, with 15% of patients showing tumor shrinkage on follow-up imaging (38). Other agents under investigation include thalidomide and inhibitors of the Ras signal transduction pathway (39, 40). CONCLUSIONS Patients with NF-associated CNS tumors present a unique management dilemma. The toxicities of therapy must be balanced with the morbidity of progressive disease. Multidisciplinary evaluation of these patients is crucial to optimal care. Radiation therapy, either fractionated external beam RT or SRS, provides an effective and safe method of local tumor control for patients with most NF-associated CNS tumors and should be considered in patients with symptoms and/or progression.
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