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Fractionated Stereotactic Radiotherapy of Vestibular Schwannomas Accelerates Hearing Loss
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Central Nervous System Tumor
Fractionated Stereotactic Radiotherapy of Vestibular Schwannomas Accelerates Hearing Loss Rune Rasmussen, MD,* Magnus Claesson, MD,* Sven-Eric Stangerup, MD,y Henrik Roed, MD, DMSc,z Ib Jarle Christensen, MSc,x Per Caye´-Thomasen, MD, DMSc,y and Marianne Juhler, MD, DMSc, Professor * *Department of Neurosurgery, yEar, Nose, and Throat Department, zDepartment of Radiation Oncology, and xThe Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark Received Nov 28, 2011, and in revised form Jan 24, 2012. Accepted for publication Jan 25, 2012
Summary In this study of 42 patients with vestibular schwannoma (VS) treated with fractionated stereotactic radiotherapy (FSRT), we describe the long-term outcome in a subgroup of 21 patients with functional hearing and compare the hearing preservation rates to an untreated control group. Our results show that FSRT accelerates the naturally occurring hearing loss in patients with VS and thus call into question the value of fractionation to reduce hearing loss.
Objective: To evaluate long-term tumor control and hearing preservation rates in patients with vestibular schwannoma treated with fractionated stereotactic radiotherapy (FSRT), comparing hearing preservation rates to an untreated control group. The relationship between radiation dose to the cochlea and hearing preservation was also investigated. Methods and Materials: Forty-two patients receiving FSRT between 1997 and 2008 with a minimum follow-up of 2 years were included. All patients received 54 Gy in 27-30 fractions during 5.5-6.0 weeks. Clinical and audiometry data were collected prospectively. From a “waitand-scan” group, 409 patients were selected as control subjects, matched by initial audiometric parameters. Radiation dose to the cochlea was measured using the original treatment plan and then related to changes in acoustic parameters. Results: Actuarial 2-, 4-, and 10-year tumor control rates were 100%, 91.5%, and 85.0%, respectively. Twenty-one patients had serviceable hearing before FSRT, 8 of whom (38%) retained serviceable hearing at 2 years after FSRT. No patients retained serviceable hearing after 10 years. At 2 years, hearing preservation rates in the control group were 1.8 times higher compared with the group receiving FSRT (PZ.007). Radiation dose to the cochlea was significantly correlated to deterioration of the speech reception threshold (PZ.03) but not to discrimination loss. Conclusion: FSRT accelerates the naturally occurring hearing loss in patients with vestibular schwannoma. Our findings, using fractionation of radiotherapy, parallel results using singledose radiation. The radiation dose to the cochlea is correlated to hearing loss measured as the speech reception threshold. Ó 2012 Elsevier Inc. Keywords: Frationated stereotactic radiotherapy, Hearing preservation, Vestibular schwannoma
Reprint requests to: Rune Rasmussen, MD, Department of Neurosurgery, Rigshospitalet, 2093, Blegdamsvej 9, 2100 Copenhagen, Denmark. Tel: (þ45) 20157524; E-mail: [email protected] Conflict of interest: none. Int J Radiation Oncol Biol Phys, Vol. 83, No. 5, pp. e607ee611, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2012.01.078
AcknowledgmentsdWe thank Lars Holme Nielsen for initial support and guidance and Steen Østergaard Olsen for assistance in management of audiometric data. We also thank Niels Rasmussen for critically revising the manuscript for important intellectual content.
e608 Rasmussen et al.
International Journal of Radiation Oncology Biology Physics
Introduction
treatment. Serviceable hearing was defined as Gardner-Robertson class 1 or 2 hearing, which included a speech reception threshold (SRT) of <50 dB and a discrimination loss (DL) <50% (10). Since the establishment of the stereotactic radiotherapy unit in 1996-1997, all patients have been consecutively registered with diagnosis, date of treatment, dose, and number of stereotactic radiation fractions.
Vestibular schwannomas (VS) are benign, slow-growing tumors that arise from the Schwann cell sheath. Surgery remains the gold standard for treating VS. However, increasing knowledge about the natural history of VS in combination with advancements in stereotactic radiotherapy and imaging has made way for other treatment options. The treatment options for newly diagnosed VS are currently microsurgery, including hearing preservation surgery; stereotactic radiotherapy; or a “wait-and-scan” strategy. Linear accelerator-based (LINAC) stereotactic radiotherapy has been used for treatment of medium-sized VS for more than 2 decades. Radiotherapy has been given as fractionated stereotactic radiotherapy (FSRT) or in a single dose (stereotactic radiosurgery, SRS). Most LINAC treatment has been fractionated. The rationale behind FSRT is the biological advantage of fractionation, thereby reducing radiation-induced toxicity in adjacent normal tissue, mainly brainstem and cranial nerves. Tumor control rates after FSRT have been reported to be >95% (1-7). Hearing preservation rates have been reported from 63% to 94%, suggesting hearing preservation to be superior following FSRT than after both microsurgery and SRS (1, 3-5, 7, 8). However, only a few studies are based on full audiological examinations (9), and many include postoperatively radiated tumors, patients with neurofibromatosis (NF-2), and patients with short follow-up. In this study, we describe the long-term outcome of hearing and tumor control with at least 2 years’ follow-up in a selected population with full audiological examination at prospectively determined intervals. We compare hearing preservation after FSRT to a “waitand-scan” control group. We also investigate the relation between radiation dose to the cochlea and hearing preservation because this was a significant predictor for outcome in a previous study (8).
Methods and Materials
Indications for radiotherapy All patients with newly diagnosed VS in Denmark are referred to our institution and evaluated by a team of neurosurgeons and otolaryngologist. Large tumors and tumors with progressive clinical symptoms from the brainstem or hydrocephalus are removed surgically shortly after diagnosis. Small and mediumsized VS are enrolled in the wait-and-scan group and followed with MRI and audiological examinations every year. All patients with significant tumor growth (>2 mm) on 2 successive MRI scans are offered treatment by either surgery or SRS. No patients were offered FSRT without significant tumor growth or only based on progressive hearing loss, tinnitus or vertigo. The treatment modality is decided individually, with the patient’s preference taken into account.
Control group Between 1980 and 2008, 810 patients in the wait-and-scan group had a follow-up of at least 2 years. Because pretreatment DL has been shown to be the most significant prognostic factor for degree of hearing preservation (11, 12), the control group was matched solely by initial DL. Given the range of initial DL of 4-30 in the 21 patients with serviceable hearing before FSRT, we selected all of the 810 wait-and-scan patients within this range (n Z 409) as control subjects. Median initial DL in the control group was 15.2 (range, 4-30) compared with the median initial DL in the FSRT group of 16.3 (range, 4-30).
Study design Follow-up This study was performed as a single-institution study. Patients were prospectively followed radiologically and clinically at intervals according to a predetermined protocol. The data were then collected and analyzed retrospectively. The inclusion criteria were patients with VS receiving FSRT with a minimum follow-up of 2 years. Exclusion criteria were NF-2 and previous surgery.
All patients in the treatment group were followed prospectively with MRI and audiological examinations 1, 2, 3.5, 5, 7, and 10 years after radiotherapy. The largest tumor diameter, intrameatal as well as extrameatal, was assessed by a neuroradiologist. The audiological examination was performed by an otolaryngologist and included assessment of pure tone audiometry, SRT, and DL.
Patient population Radiotherapy Between 1996 and 2008, 68 patients with VS were treated. Ten patients were diagnosed with NF-2, and 8 patients had previous surgery. Seven patients received single-dose treatment, and 1 immigrated shortly after treatment, leaving 42 patients with unilateral VS receiving FSRT. All 42 patients (20 men, 22 women) subjected to FSRT were analyzed and followed for tumor control. Median age at diagnosis was 57 years (range, 35-82 years), mean tumor size was 20 mm (range, 11-32), and location distribution was 25 left and 17 right. Of the 42 patients, 21 had serviceable hearing before FSRT. We only included these patients for further hearing analysis because we do not consider it meaningful to study “hearing preservation” in patients with severe hearing impediment before
The treatment equipment is a 6-MV linear accelerator dedicated to cranial stereotactic radiotherapy (Clinac 600SR, Varian, Palo Alto, CA). Initially, we used circular collimators, 0.5-3.5 cm diameter with 0.5-cm increments between sizes. Since August 2000, collimation and field shaping has been provided by micro-multileaf collimators after upgrading to the Novalis planning and treatment system (BrainLab/Iplan, Munich, Germany). Both conformal arc therapy and intensity-modulated radiation therapy have been used. An individual mask of the head was made during the planning process and was used during all the treatments. The mask was fixed to the board during the radiation, providing immobilization.
Volume 83 Number 5 2012 A fusion of MR and CT scans was used as a visual treatment plan in which the gross target volume was estimated. A 2-mm margin was added to account for setup uncertainties and penumbra. All patients were treated with 54 Gy in 27-30 fractions prescribed to the periphery of the gross target volume during 5.5-6.0 weeks.
Measurement of radiation doses to the cochlea Only patients treated after 2000 could be analyzed for this part of the project because of software changes that year. The location of the cochlea was determined on bone window CT scans. Using BrainLAB software, dose-volume histograms of the cochlea were measured using the original treatment plan. The percentage of cochlea receiving a minimum of 90% of the total radiation dose (V90%) was measured in all patients.
FSRT accelerates hearing loss e609 after treatment (incapability to cope with fear of tumor growth) and was excluded from further analysis. The remaining 5 patients demonstrated increasing tumor size (>3 mm) on MRI and were operated after 2, 2.5, 3, 4, and 11 years, respectively (Fig 1). The patient undergoing surgery after 11 years had demonstrated stable tumor size for 10 years on 5 successive MRI scans before significant growth of 5 mm was observed over 6 months.
Cranial nerve toxicity After FSRT, 2 patients developed facial weakness (HouseBrackmann grade 2), recorded at 2 and 5 years, respectively, with both patients having stable tumors. No patients experienced deterioration in trigeminal function after FSRT.
Noncranial nerve toxicity Statistics Statistical analysis of DSRT and DDL and their association to radiation dose was performed using a linear model. Results are presented with 95% confidence intervals. Estimates of overall resection-free survival probabilities were obtained using the Kaplan-Meier method. Analysis of time to loss of hearing was performed using the actuarial method. P values <5% were considered significant. Calculations were performed using SAS (v9.2, SAS Institute, Cary, NC).
Results Follow-up Five patients in the cohort died of causes not associated with VS. One patient was lost to follow-up. Median follow-up was 5 years (range, 2-12 years).
Tumor control Tumor control was defined as resection-free survival. Treatment failure was seen in 6 of the 42 patients after FSRT. However, 1 patient underwent surgery for psychological reasons 19 months
Fig. 1.
One patient developed hemiparesis within the first 6 months following FSRT. MRI showed changes in the brainstem compatible with radiation-induced damage. One patient required a shunt at 5 months after radiation because of hydrocephalus.
Tumor growth and hearing deterioration in the control group Of the 409 control subjects, 48 had significant tumor growth (>2 mm) but declined treatment. Of these, 29 (60%) maintained Gardner-Robertson class 1 hearing after 2 years. In the remaining 361 with no tumor growth, 213 (59%) maintained GardnerRobertson class 1 hearing. Thus, hearing deterioration in the control group is not likely to be dependent on tumor growth (PZ.85).
Hearing preservation Hearing preservation was defined as preservation of serviceable hearing. All of the 21 patients with serviceable hearing before FSRT were in Gardner-Robertson class 1. Two years after FSRT, only 3 patients remained in class 1, and 5 patients had dropped to class 2. The remaining 13 patients had all lost serviceable hearing.
Kaplan-Meier plot of resection-free survival in 41 patients treated with fractionated stereotactic radiotherapy.
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International Journal of Radiation Oncology Biology Physics
Hearing loss was reflected in equal deterioration of DL and SRT after FSRT (Fig 2). None of the 7 patients followed for a minimum of 10 years retained serviceable hearing. Fig 3 shows the time course of hearing loss in patients subjected to FSRT compared with patients in the wait-and-scan control group. Two years after FSRT, the hearing preservation rate in the FSRT group had dropped to 38%, compared with 67% in control group. The difference (29%) was significant (confidence interval 21.4%, PZ.007). Difference in hearing preservation beyond 6 years did not reach statistic significance because population size decreased markedly after this point.
Radiation dose to the cochlea Radiation dose to the cochlea could be measured in 15 of the 21 patients with serviceable hearing before FSRT. The percentage of the cochlea receiving a minimum of 90% of total radiation dose (v90%) was measured in these 15 patients. Median v90% was 18.8% (range, 0%-54.2%). The deterioration of DL (DDL) and SRT (DSRT) at 2 years (values at 2 years minus baseline values) was calculated for each patient and compared with v90%. A significant association between loss of SRT and v90% was found (PZ.03, Fig 4). No significant association was found between DL and v90% (PZ.24).
Discussion The tumor control rate in our study defined as resection-free survival compares unfavorably to many previously published studies (1e7). However, in our study, all patients with radiological progression underwent surgery. This is in contrast to a recent study of 385 patients receiving FSRT in which a radiological progression rate of 21%, identical to ours, was found, but only a small proportion underwent salvage surgery (13). Radiological progression could occur at any time throughout the observation period. One tumor demonstrated shrinkage (from 40 mm to 25 mm) during the first 2 years and then remained stable for 8 years, before significant growth (>6 mm) occurred at 10 years post-FSRT. This case illustrates the need for radiological follow-up for more than 10 years. The high rates of hearing preservation, from 63% to 94%, reported in previous studies (1, 3-5, 7, 8), are superior even to the natural history of the disease (11, 12). Our data suggest a significantly lower preservation rate because only 38% retained
Fig. 2. Mean speech reception threshold (SRT) and mean discrimination loss (DL) just before and 2 years after fractionated stereotactic radiotherapy (FSRT).
Fig. 3. Hearing preservation rates after fractionated stereotactic radiotherapy (FSRT) compared with a “wait-and-scan” control group with 95% confidence interval. The P value for log-rank test comparing the 2 curves was .008. serviceable hearing at 2 years. One other report from 2005 found poor hearing preservation after FSRT in a small group of patients (14) with only 1 of 11 patients retaining serviceable hearing after FSRT. Similar to our study, the data were also based on full audiometric follow-up. The number of long-term studies with full audiometric follow-up are limited, and controversy exists regarding degree of hearing preservation after FSRT (9). The rationale behind FSRT is to minimize tissue toxicity to achieve better hearing preservation rates than with SRS. Because hearing preservation rates after SRS have been reported to be from 32% to 71% (9), the present study does not support that FSRT is superior to SRS. Furthermore, our results suggest that not only is FSRT incapable of preventing hearing loss, it also accelerates it significantly. All patients in our study with initial serviceable hearing were Gardner-Robertson class 1, which further emphasizes the hearing loss to be important and significant. However, the limited number of patients in this study does not allow for conclusions to be made regarding the development of hearing loss after 6 years. In agreement with Thomas et al (8) we found a significant positive correlation between radiation dose to the cochlea and
Fig. 4. Association between radiation dose to the cochlea and deterioration of speech reception threshold (SRT) 2 years after fractionated stereotactic radiotherapy. Regression line with 95% confidence interval.
Volume 83 Number 5 2012 increased SRT after FSRT but no correlation between radiation dose to the cochlea and DL. Even though DL is considered the more important acoustic parameter, our findings support that the cochlea should be defined as an organ at risk in the planning of the radiation field.
Conclusion This is the first study of hearing prognosis after FSRT for VS compared with an untreated control group and clearly demonstrates that FSRT accelerates the naturally occurring progression of hearing loss in patients with VS. Our findings, using fractionation of radiotherapy, are comparable to results using single-dose radiation. Because the rationale for fractionation is to reduce radiation damage to healthy tissue, the question can be raised whether single-dose SRS should replace FSRT in LINAC-based treatment. To clarify this question, similar long-term follow-up studies comparing the risks of facial nerve and brainstem dysfunction are needed. The radiation dose to the cochlea is correlated to hearing loss measured as SRT. To achieve more favorable hearing preservation rates, we suggest that the cochlea be defined as an organ at risk when planning FSRT.
References 1. Fuss M, Debus J, Lohr F, et al. Conventionally fractionated stereotactic radiotherapy (FSRT) for acoustic neuromas. Int J Radiat Oncol Biol Phys 2000;48:1381-1387. 2. Meijer OW, Vandertop WP, Baayen JC, et al. Single-fraction vs. fractionated linac-based stereotactic radiosurgery for vestibular schwannoma: a single-institution study. Int J Radiat Oncol Biol Phys 2003;56:1390-1396.
FSRT accelerates hearing loss e611 3. Sawamura Y, Shirato H, Sakamoto T, et al. Management of vestibular schwannoma by fractionated stereotactic radiotherapy and associated cerebrospinal fluid malabsorption. J Neurosurg 2003;99:6856-6892. 4. Shirato H, Sakamoto T, Takeichi N, et al. Fractionated stereotactic radiotherapy for vestibular schwannoma (VS): comparison between cystic-type and solid-type VS. Int J Radiat Oncol Biol Phys 2000;48: 1395-1401. 5. Combs SE, Volk S, Schulz-Ertner D, et al. Management of acoustic neuromas with fractionated stereotactic radiotherapy (FSRT): longterm results in 106 patients treated in a single institution. Int J Radiat Oncol Biol Phys 2005;63:75-81. 6. Maire JP, Huchet A, Milbeo Y, et al. Twenty years’ experience in the treatment of acoustic neuromas with fractionated radiotherapy: a review of 45 cases. Int J Radiat Oncol Biol Phys 2006;66:170-178. 7. Koh ES, Millar BA, Me´nard C, et al. Fractionated stereotactic radiotherapy for acoustic neuroma: single-institution experience at the Princess Margaret Hospital. Cancer 2007;109:1203-1210. 8. Thomas C, Di MS, Ma R, et al. Hearing preservation following fractionated stereotactic radiotherapy for vestibular schwannomas: prognostic implications of cochlear dose. J Neurosurg 2007;107: 917-926. 9. Murphy ES, Suh JH. Radiotherapy for vestibular schwannomas: a critical review. Int J Radiat Oncol Biol Phys 2011;79:985-997. 10. Gardner G, Robertson JH. Hearing preservation in unilateral acoustic neuroma surgery. Ann Otol Rhinol Laryngol 1988;97:55-66. 11. Stangerup SE, Thomsen J, Tos M, et al. Long-term hearing preservation in vestibular schwannoma. Otol Neurotol 2010;31:271-275. 12. Stangerup SE, Caye-Thomasen P, Tos M, et al. Change in hearing during “wait and scan” management of patients with vestibular schwannoma. J Laryngol Otol 2008;122:673-681. 13. Kapoor S, Batra S, Carson K, et al. Long-term outcomes of vestibular schwannomas treated with fractionated stereotactic radiotherapy: an institutional experience. Int J Radiat Oncol Biol Phys 2011;81:647-653. 14. Lin VY, Stewart C, Grebenyuk J, et al. Unilateral acoustic neuromas: long-term hearing results in patients managed with fractionated stereotactic radiotherapy, hearing preservation surgery, and expectantly. Laryngoscope 2005;115:292-296.
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Central Nervous System Tumor
Fractionated Stereotactic Radiotherapy of Vestibular Schwannomas Accelerates Hearing Loss Rune Rasmussen, MD,* Magnus Claesson, MD,* Sven-Eric Stangerup, MD,y Henrik Roed, MD, DMSc,z Ib Jarle Christensen, MSc,x Per Caye´-Thomasen, MD, DMSc,y and Marianne Juhler, MD, DMSc, Professor * *Department of Neurosurgery, yEar, Nose, and Throat Department, zDepartment of Radiation Oncology, and xThe Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark Received Nov 28, 2011, and in revised form Jan 24, 2012. Accepted for publication Jan 25, 2012
Summary In this study of 42 patients with vestibular schwannoma (VS) treated with fractionated stereotactic radiotherapy (FSRT), we describe the long-term outcome in a subgroup of 21 patients with functional hearing and compare the hearing preservation rates to an untreated control group. Our results show that FSRT accelerates the naturally occurring hearing loss in patients with VS and thus call into question the value of fractionation to reduce hearing loss.
Objective: To evaluate long-term tumor control and hearing preservation rates in patients with vestibular schwannoma treated with fractionated stereotactic radiotherapy (FSRT), comparing hearing preservation rates to an untreated control group. The relationship between radiation dose to the cochlea and hearing preservation was also investigated. Methods and Materials: Forty-two patients receiving FSRT between 1997 and 2008 with a minimum follow-up of 2 years were included. All patients received 54 Gy in 27-30 fractions during 5.5-6.0 weeks. Clinical and audiometry data were collected prospectively. From a “waitand-scan” group, 409 patients were selected as control subjects, matched by initial audiometric parameters. Radiation dose to the cochlea was measured using the original treatment plan and then related to changes in acoustic parameters. Results: Actuarial 2-, 4-, and 10-year tumor control rates were 100%, 91.5%, and 85.0%, respectively. Twenty-one patients had serviceable hearing before FSRT, 8 of whom (38%) retained serviceable hearing at 2 years after FSRT. No patients retained serviceable hearing after 10 years. At 2 years, hearing preservation rates in the control group were 1.8 times higher compared with the group receiving FSRT (PZ.007). Radiation dose to the cochlea was significantly correlated to deterioration of the speech reception threshold (PZ.03) but not to discrimination loss. Conclusion: FSRT accelerates the naturally occurring hearing loss in patients with vestibular schwannoma. Our findings, using fractionation of radiotherapy, parallel results using singledose radiation. The radiation dose to the cochlea is correlated to hearing loss measured as the speech reception threshold. Ó 2012 Elsevier Inc. Keywords: Frationated stereotactic radiotherapy, Hearing preservation, Vestibular schwannoma
Reprint requests to: Rune Rasmussen, MD, Department of Neurosurgery, Rigshospitalet, 2093, Blegdamsvej 9, 2100 Copenhagen, Denmark. Tel: (þ45) 20157524; E-mail: [email protected] Conflict of interest: none. Int J Radiation Oncol Biol Phys, Vol. 83, No. 5, pp. e607ee611, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2012.01.078
AcknowledgmentsdWe thank Lars Holme Nielsen for initial support and guidance and Steen Østergaard Olsen for assistance in management of audiometric data. We also thank Niels Rasmussen for critically revising the manuscript for important intellectual content.
e608 Rasmussen et al.
International Journal of Radiation Oncology Biology Physics
Introduction
treatment. Serviceable hearing was defined as Gardner-Robertson class 1 or 2 hearing, which included a speech reception threshold (SRT) of <50 dB and a discrimination loss (DL) <50% (10). Since the establishment of the stereotactic radiotherapy unit in 1996-1997, all patients have been consecutively registered with diagnosis, date of treatment, dose, and number of stereotactic radiation fractions.
Vestibular schwannomas (VS) are benign, slow-growing tumors that arise from the Schwann cell sheath. Surgery remains the gold standard for treating VS. However, increasing knowledge about the natural history of VS in combination with advancements in stereotactic radiotherapy and imaging has made way for other treatment options. The treatment options for newly diagnosed VS are currently microsurgery, including hearing preservation surgery; stereotactic radiotherapy; or a “wait-and-scan” strategy. Linear accelerator-based (LINAC) stereotactic radiotherapy has been used for treatment of medium-sized VS for more than 2 decades. Radiotherapy has been given as fractionated stereotactic radiotherapy (FSRT) or in a single dose (stereotactic radiosurgery, SRS). Most LINAC treatment has been fractionated. The rationale behind FSRT is the biological advantage of fractionation, thereby reducing radiation-induced toxicity in adjacent normal tissue, mainly brainstem and cranial nerves. Tumor control rates after FSRT have been reported to be >95% (1-7). Hearing preservation rates have been reported from 63% to 94%, suggesting hearing preservation to be superior following FSRT than after both microsurgery and SRS (1, 3-5, 7, 8). However, only a few studies are based on full audiological examinations (9), and many include postoperatively radiated tumors, patients with neurofibromatosis (NF-2), and patients with short follow-up. In this study, we describe the long-term outcome of hearing and tumor control with at least 2 years’ follow-up in a selected population with full audiological examination at prospectively determined intervals. We compare hearing preservation after FSRT to a “waitand-scan” control group. We also investigate the relation between radiation dose to the cochlea and hearing preservation because this was a significant predictor for outcome in a previous study (8).
Methods and Materials
Indications for radiotherapy All patients with newly diagnosed VS in Denmark are referred to our institution and evaluated by a team of neurosurgeons and otolaryngologist. Large tumors and tumors with progressive clinical symptoms from the brainstem or hydrocephalus are removed surgically shortly after diagnosis. Small and mediumsized VS are enrolled in the wait-and-scan group and followed with MRI and audiological examinations every year. All patients with significant tumor growth (>2 mm) on 2 successive MRI scans are offered treatment by either surgery or SRS. No patients were offered FSRT without significant tumor growth or only based on progressive hearing loss, tinnitus or vertigo. The treatment modality is decided individually, with the patient’s preference taken into account.
Control group Between 1980 and 2008, 810 patients in the wait-and-scan group had a follow-up of at least 2 years. Because pretreatment DL has been shown to be the most significant prognostic factor for degree of hearing preservation (11, 12), the control group was matched solely by initial DL. Given the range of initial DL of 4-30 in the 21 patients with serviceable hearing before FSRT, we selected all of the 810 wait-and-scan patients within this range (n Z 409) as control subjects. Median initial DL in the control group was 15.2 (range, 4-30) compared with the median initial DL in the FSRT group of 16.3 (range, 4-30).
Study design Follow-up This study was performed as a single-institution study. Patients were prospectively followed radiologically and clinically at intervals according to a predetermined protocol. The data were then collected and analyzed retrospectively. The inclusion criteria were patients with VS receiving FSRT with a minimum follow-up of 2 years. Exclusion criteria were NF-2 and previous surgery.
All patients in the treatment group were followed prospectively with MRI and audiological examinations 1, 2, 3.5, 5, 7, and 10 years after radiotherapy. The largest tumor diameter, intrameatal as well as extrameatal, was assessed by a neuroradiologist. The audiological examination was performed by an otolaryngologist and included assessment of pure tone audiometry, SRT, and DL.
Patient population Radiotherapy Between 1996 and 2008, 68 patients with VS were treated. Ten patients were diagnosed with NF-2, and 8 patients had previous surgery. Seven patients received single-dose treatment, and 1 immigrated shortly after treatment, leaving 42 patients with unilateral VS receiving FSRT. All 42 patients (20 men, 22 women) subjected to FSRT were analyzed and followed for tumor control. Median age at diagnosis was 57 years (range, 35-82 years), mean tumor size was 20 mm (range, 11-32), and location distribution was 25 left and 17 right. Of the 42 patients, 21 had serviceable hearing before FSRT. We only included these patients for further hearing analysis because we do not consider it meaningful to study “hearing preservation” in patients with severe hearing impediment before
The treatment equipment is a 6-MV linear accelerator dedicated to cranial stereotactic radiotherapy (Clinac 600SR, Varian, Palo Alto, CA). Initially, we used circular collimators, 0.5-3.5 cm diameter with 0.5-cm increments between sizes. Since August 2000, collimation and field shaping has been provided by micro-multileaf collimators after upgrading to the Novalis planning and treatment system (BrainLab/Iplan, Munich, Germany). Both conformal arc therapy and intensity-modulated radiation therapy have been used. An individual mask of the head was made during the planning process and was used during all the treatments. The mask was fixed to the board during the radiation, providing immobilization.
Volume 83 Number 5 2012 A fusion of MR and CT scans was used as a visual treatment plan in which the gross target volume was estimated. A 2-mm margin was added to account for setup uncertainties and penumbra. All patients were treated with 54 Gy in 27-30 fractions prescribed to the periphery of the gross target volume during 5.5-6.0 weeks.
Measurement of radiation doses to the cochlea Only patients treated after 2000 could be analyzed for this part of the project because of software changes that year. The location of the cochlea was determined on bone window CT scans. Using BrainLAB software, dose-volume histograms of the cochlea were measured using the original treatment plan. The percentage of cochlea receiving a minimum of 90% of the total radiation dose (V90%) was measured in all patients.
FSRT accelerates hearing loss e609 after treatment (incapability to cope with fear of tumor growth) and was excluded from further analysis. The remaining 5 patients demonstrated increasing tumor size (>3 mm) on MRI and were operated after 2, 2.5, 3, 4, and 11 years, respectively (Fig 1). The patient undergoing surgery after 11 years had demonstrated stable tumor size for 10 years on 5 successive MRI scans before significant growth of 5 mm was observed over 6 months.
Cranial nerve toxicity After FSRT, 2 patients developed facial weakness (HouseBrackmann grade 2), recorded at 2 and 5 years, respectively, with both patients having stable tumors. No patients experienced deterioration in trigeminal function after FSRT.
Noncranial nerve toxicity Statistics Statistical analysis of DSRT and DDL and their association to radiation dose was performed using a linear model. Results are presented with 95% confidence intervals. Estimates of overall resection-free survival probabilities were obtained using the Kaplan-Meier method. Analysis of time to loss of hearing was performed using the actuarial method. P values <5% were considered significant. Calculations were performed using SAS (v9.2, SAS Institute, Cary, NC).
Results Follow-up Five patients in the cohort died of causes not associated with VS. One patient was lost to follow-up. Median follow-up was 5 years (range, 2-12 years).
Tumor control Tumor control was defined as resection-free survival. Treatment failure was seen in 6 of the 42 patients after FSRT. However, 1 patient underwent surgery for psychological reasons 19 months
Fig. 1.
One patient developed hemiparesis within the first 6 months following FSRT. MRI showed changes in the brainstem compatible with radiation-induced damage. One patient required a shunt at 5 months after radiation because of hydrocephalus.
Tumor growth and hearing deterioration in the control group Of the 409 control subjects, 48 had significant tumor growth (>2 mm) but declined treatment. Of these, 29 (60%) maintained Gardner-Robertson class 1 hearing after 2 years. In the remaining 361 with no tumor growth, 213 (59%) maintained GardnerRobertson class 1 hearing. Thus, hearing deterioration in the control group is not likely to be dependent on tumor growth (PZ.85).
Hearing preservation Hearing preservation was defined as preservation of serviceable hearing. All of the 21 patients with serviceable hearing before FSRT were in Gardner-Robertson class 1. Two years after FSRT, only 3 patients remained in class 1, and 5 patients had dropped to class 2. The remaining 13 patients had all lost serviceable hearing.
Kaplan-Meier plot of resection-free survival in 41 patients treated with fractionated stereotactic radiotherapy.
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International Journal of Radiation Oncology Biology Physics
Hearing loss was reflected in equal deterioration of DL and SRT after FSRT (Fig 2). None of the 7 patients followed for a minimum of 10 years retained serviceable hearing. Fig 3 shows the time course of hearing loss in patients subjected to FSRT compared with patients in the wait-and-scan control group. Two years after FSRT, the hearing preservation rate in the FSRT group had dropped to 38%, compared with 67% in control group. The difference (29%) was significant (confidence interval 21.4%, PZ.007). Difference in hearing preservation beyond 6 years did not reach statistic significance because population size decreased markedly after this point.
Radiation dose to the cochlea Radiation dose to the cochlea could be measured in 15 of the 21 patients with serviceable hearing before FSRT. The percentage of the cochlea receiving a minimum of 90% of total radiation dose (v90%) was measured in these 15 patients. Median v90% was 18.8% (range, 0%-54.2%). The deterioration of DL (DDL) and SRT (DSRT) at 2 years (values at 2 years minus baseline values) was calculated for each patient and compared with v90%. A significant association between loss of SRT and v90% was found (PZ.03, Fig 4). No significant association was found between DL and v90% (PZ.24).
Discussion The tumor control rate in our study defined as resection-free survival compares unfavorably to many previously published studies (1e7). However, in our study, all patients with radiological progression underwent surgery. This is in contrast to a recent study of 385 patients receiving FSRT in which a radiological progression rate of 21%, identical to ours, was found, but only a small proportion underwent salvage surgery (13). Radiological progression could occur at any time throughout the observation period. One tumor demonstrated shrinkage (from 40 mm to 25 mm) during the first 2 years and then remained stable for 8 years, before significant growth (>6 mm) occurred at 10 years post-FSRT. This case illustrates the need for radiological follow-up for more than 10 years. The high rates of hearing preservation, from 63% to 94%, reported in previous studies (1, 3-5, 7, 8), are superior even to the natural history of the disease (11, 12). Our data suggest a significantly lower preservation rate because only 38% retained
Fig. 2. Mean speech reception threshold (SRT) and mean discrimination loss (DL) just before and 2 years after fractionated stereotactic radiotherapy (FSRT).
Fig. 3. Hearing preservation rates after fractionated stereotactic radiotherapy (FSRT) compared with a “wait-and-scan” control group with 95% confidence interval. The P value for log-rank test comparing the 2 curves was .008. serviceable hearing at 2 years. One other report from 2005 found poor hearing preservation after FSRT in a small group of patients (14) with only 1 of 11 patients retaining serviceable hearing after FSRT. Similar to our study, the data were also based on full audiometric follow-up. The number of long-term studies with full audiometric follow-up are limited, and controversy exists regarding degree of hearing preservation after FSRT (9). The rationale behind FSRT is to minimize tissue toxicity to achieve better hearing preservation rates than with SRS. Because hearing preservation rates after SRS have been reported to be from 32% to 71% (9), the present study does not support that FSRT is superior to SRS. Furthermore, our results suggest that not only is FSRT incapable of preventing hearing loss, it also accelerates it significantly. All patients in our study with initial serviceable hearing were Gardner-Robertson class 1, which further emphasizes the hearing loss to be important and significant. However, the limited number of patients in this study does not allow for conclusions to be made regarding the development of hearing loss after 6 years. In agreement with Thomas et al (8) we found a significant positive correlation between radiation dose to the cochlea and
Fig. 4. Association between radiation dose to the cochlea and deterioration of speech reception threshold (SRT) 2 years after fractionated stereotactic radiotherapy. Regression line with 95% confidence interval.
Volume 83 Number 5 2012 increased SRT after FSRT but no correlation between radiation dose to the cochlea and DL. Even though DL is considered the more important acoustic parameter, our findings support that the cochlea should be defined as an organ at risk in the planning of the radiation field.
Conclusion This is the first study of hearing prognosis after FSRT for VS compared with an untreated control group and clearly demonstrates that FSRT accelerates the naturally occurring progression of hearing loss in patients with VS. Our findings, using fractionation of radiotherapy, are comparable to results using single-dose radiation. Because the rationale for fractionation is to reduce radiation damage to healthy tissue, the question can be raised whether single-dose SRS should replace FSRT in LINAC-based treatment. To clarify this question, similar long-term follow-up studies comparing the risks of facial nerve and brainstem dysfunction are needed. The radiation dose to the cochlea is correlated to hearing loss measured as SRT. To achieve more favorable hearing preservation rates, we suggest that the cochlea be defined as an organ at risk when planning FSRT.
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