PRELIMINARY RESULTS OF HELICAL TOMOTHERAPY IN PATIENTS WITH COMPLEX-SHAPED MENINGIOMAS CLOSE TO THE OPTIC PATHWAY

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1 Medical Dosimetry, Vol. 36, No. 4, pp , 2011 Copyright 2011 American Association of Medical Dosimetrists Printed in the USA. All rights reserved /11/$ see front matter doi: /j.meddos PRELIMINARY RESULTS OF HELICAL TOMOTHERAPY IN PATIENTS WITH COMPLEX-SHAPED MENINGIOMAS CLOSE TO THE OPTIC PATHWAY LUIS SCHIAPPACASSE, M.D., RICARDO CENDALES, M.D., KITA SALLABANDA, PH.D., FRANCO SCHNITMAN, M.D., and JOSE SAMBLAS, M.D. Neuro-Oncology Unit, Tomotherapy Department, Clinica La Milagrosa, IMO Group (Instituto Madrileno de Oncologia), Madrid, Spain (Received 13 August 2010; accepted 21 October 2010) Abstract Meningiomas are the most common benign intracranial tumor. Meningiomas close to the optic pathway represent a treatment challenge both for surgery and radiotherapy. The aim of this article is to describe early results of helical tomotherapy treatment in complex-shaped meningiomas close to the optic pathway. Twenty-eight patients were consecutively treated. All patients were immobilized with a thermoplastic head mask and planned with the aid of a magnetic resonance imaging computed tomography fusion. All treatments included daily image guidance. Pretreatment symptoms and acute toxicity were recorded. Median age was 57.5 years, and 92.8% patients had Eastern Cooperative Oncology Group performance status scale <1. The most common localizations were the sella turcica, followed by the cavernous sinus and the sphenoid. The most common symptoms were derived from cranial nerve deficits. Tomotherapy was administered as primary treatment in 35.7% of patients, as an adjuvant treatment in 32.4%, and as a rescue treatment after postsurgical progression in 32.1% patients. Most patients were either inoperable or Simpson IV. Total dose varied between 5000 and 5400 cgy; fractionation varied between 180 and 200 cgy. Median dose to the planning target volume was 51.7 Gy (range, Gy). Median coverage index was 0.89 (range, ). Median homogeneity index was 1.05 (range, ). Acute transient toxicity was grade 1 and included headache in 35.7% patients, ocular pain/ dryness in 28.5%, and radiation dermatitis in 25%. Thus far, with a maximal follow-up of 3 years, no late effects have been seen and all patients have a radiological stabilization of the disease. Helical tomotherapy offered a safe and effective therapeutic alternative for patients with inoperable or subtotally resected complex-shaped meningiomas close to the optic pathway. Acceptable coverage and homogeneity indexes were achieved with appropriate values for maximal doses delivered to the eyes, lenses, and chiasm, despite the proximity of the tumor to these structures American Association of Medical Dosimetrists. Key Words: Meningioma, Visual pathways, Radiotherapy, Intensity-modulated, Tomotherapy. INTRODUCTION Meningiomas are the most common benign intracranial tumor; they account for 15% of all primary intracranial tumors. Approximately 90% are benign tumors, and they occur more frequently in females than in males, with a 2:1 ratio. 1 Although the preferred first treatment alternative is surgery, it is not always possible because of tumor localization or the clinical conditions of the patient. Radiotherapy is effective as primary or adjuvant treatment in surgically inaccessible, recurrent, subtotally excised tumors, or in postsurgical relapses. 2 Tumors close to the optic pathway represent a surgical challenge because they are in contact with critical structures, have a complex shape, and can be moderately large in volume. These difficulties also represent a challenge for the radiotherapy treatment, because it can be difficult to shape Presented as an abstract at the TomoTherapy EMEA User Symposium held in Marbella (Malaga), Spain, May 6 8, Reprint requests to: Luis Schiappacasse, M.D., Tomotherapy Department, Clinica La Milagrosa, Modesto Lafuente 14, Madrid, Spain, lschiap@gmail.com the dose distribution to the tumor while adequately sparing the organs at risk. Radiotherapy techniques for the treatment of meningiomas include radiosurgery, conformal radiotherapy, and intensity-modulated radiotherapy (IMRT). IMRT has shown to be a safe and effective technology in the treatment of intracranial meningioma, with results comparable with those observed in conformal radiotherapy, both in the short 3,4 and the intermediate term, 5 with some dosimetric advantages regarding to planning target volume (PTV) coverage and sparing of organs at risk, even in complex-shaped tumors. 6 Tomotherapy is a helicoidal IMRT treatment with higher modulation capabilities when compared with conventional IMRT, and the advantage of having an on-board megavoltage computed tomography (CT) imaging system capable of performing online image-guided radiotherapy. 7 Tomotherapy has shown discrete dosimetric advantages over some other modern techniques of IMRT in terms of coverage and sparing of organs at risk in the treatment of benign intracranial tumors 8 and greater dose uniformity in small brain tumors. 9 Further 416

2 Meningiomas close to the optic pathway L. SCHIAPPACASSE et al. 417 clinical research has been recommended to validate these preclinical, dosimetric findings. In Spain, tomotherapy was first implemented at the Instituto Madrileno de Oncologia (IMO), in IMO has accumulated an important number of patients with complex-shaped meningiomas close to or in direct contact with the optic pathway with indication of external beam radiotherapy treatment. This retrospective study describes our early treatment experience with tomotherapy in this group of patients. METHODS AND MATERIALS Study design and patients A descriptive, retrospective study was designed. All patients with complex-shaped meningiomas close to or in direct contact with the optic pathway treated with helical tomotherapy between January 2006 and March 2009 at the Tomotherapy Unit, Clinica La Milagrosa, in Madrid, Spain, were included. The subset of eligible patients was identified from records of newly treated patients. Patients with multiple meningiomatosis or preexistent or concomitant malignant diseases were excluded. Tomotherapy treatment All patients were immobilized with a three-point fixation thermoplastic head mask and planned using a computed tomography MRI (CT MRI) fusion for the definition of tumor and organ at risk volumes. The CT axial slice thickness was 3 mm; all CT and MRI images were imported into the Pinnacle treatment planning system (Philips Radiation Oncology Systems, Fitchburg, WI). Register and fusion were performed through the normalized mutual information algorithm. Gross tumor volume (GTV) was defined as the contrast-enhancing area volume on MRI; PTV was defined as the GTV or the tumor bed plus a 2 3-mm margin. Areas of the PTV that were outside the skull were trimmed with a 0.3-cm inner margin to the body contour. Organs at risk included but were not limited to the optic nerves, chiasm, lenses, eyes, brain, and brainstem. Datasets and structures were transferred to the tomotherapy treatment planning software (TomoTherapy, Inc., Madison, WI) and an inverse treatment planning was performed. The helical tomotherapy parameters definitions were between 1 and 2.5 cm for the field size, for pitch, and a planning modulation factor of 2 3. All treatments had a delivery quality assurance previous to treatment initiation. For PTV, the planning treatment objectives were to cover at least 95% of the PTV with the 95% isodose, to have a minimum PTV dose of 90%, and a to have a maximum PTV dose of 105%. For organs at risk, the planning objectives were maximal doses of 50 Gy for optic nerves, 52 Gy for chiasm, 7 Gy for lenses, 30 Gy for eyes, V-40 30% for brain, and 52 Gy for brainstem. All treatments were delivered through a 6-MV photons helical TomoTherapy HiArt II system unit. Patients were positioned by aligning the treatment room s lasers with the marks drawn on the thermoplastic mask. Megavoltage/CT images of the entire length of the PTV were acquired before each fraction and co-registered with the planning images based on bone anatomy. Patient setup before treatment was verified through the system s software and according to the criteria of the radiation therapist. Patient setup deviations were detected in the medial-lateral, cranial-caudal, and anterior-posterior directions. Rotational deviations in the cranial-caudal axis (roll), anterior-posterior axis (pitch), and medial-lateral axis (yaw) were also identified. Daily setup corrections for nonrotational deviations and roll were performed for all patients; rotational deviations for pitch and yaw were taken into account only when subjectively considered important. Follow-up Follow-up with clinical examination was performed weekly during the whole treatment and 3 months after finishing. MRI and clinical examination were performed every 6 months during the remaining first year, and yearly thereafter. Clinical characteristics, pretreatment symptoms, and follow-up information were collected from the clinical charts; acute neurological toxicity (until 4 weeks after finishing treatment) was recorded according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Dose-volume histograms for PTV, optic nerves, chiasm, lenses, eyes, brain, and brainstem were recorded from the dosimetric charts. Homogeneity index was calculated dividing the maximal PTV dose by the prescription dose; the coverage index was calculated dividing the minimum PTV dose by the prescription dose. Both indexes were calculated accordingly to the recommendations established for evaluating tomotherapy treatment plans. 10 Statistical methods Measures of central tendency and dispersion were used for numerical variables; simple frequencies and percentages were used for categorical variables. Normality assumptions were verified through the Shapiro-Wilk test. Exploration of factors associated with toxicity was performed by a traditional means comparison using the independent-sample t-test or the Mann-Whitney U test according to the distributional assumptions. Two-tailed tests were always used and p values less than 0.05 were considered statistically significant. All statistical analyses were performed using the SPSS version 12.0 software (SPSS, Inc., Chicago, IL). Ethical considerations This study was classified as low risk; hence, informed consent was not required. All procedures followed were in accordance with good clinical prac-

3 418 Medical Dosimetry Volume 36, Number 4, 2011 Table 1. Clinical characteristics Variable Variable Levels n % Sex Male Female ECOG ECOG ECOG ECOG Tumor location Silla turcica Cavernous sinus Sphenoid Clivus Other Affected cranial nerves I II III IV V VI VII VII IX X XI XII Neurological symptoms Cranial nerves related Headache Sensitive symptoms Seizures Histology Benign Atypical-malignant No histology Surgical classification of the meningioma Simpson II Simpson III Simpson IV/unresectable ECOG Eastern Cooperative Oncology Group performance status scale. tices in clinical research, the institutional ethics committee standards, and the principles of the Helsinki Declaration. RESULTS From January 2006 to March 2009, 28 patients at our center were treated for complex-shaped meningiomas close to or in direct contact with the optic pathway with helical tomotherapy. Median age was 57.5 years (range, 40 78); most patients were female, with Eastern Cooperative Oncology Group performance status scale 1. Most tumors were located at the sella turcica, followed by the cavernous sinus and the sphenoid; most patients were either inoperable or Simpson IV. The most frequently affected cranial nerve was the II pair. The most common symptoms were derived from compromise of the cranial nerves. Among patients with histologic diagnosis, the most frequent classification was WHO I (Table 1). Radiotherapy was administered as primary treatment in most patients, although it was also frequently used as an adjuvant delayed treatment or as a rescue treatment after postsurgical progression. Three patients had received radiotherapy previously. Total dose varied between 5000 and 5400 cgy, and fractionation varied between 180 and 200 cgy. Target volumes ranged from ml (median, 43.3 ml). Median dose to the PTV was 51.7 (range, ). Median coverage index was 0.89 (range, ) and median homogeneity index was 1.05 (range, ). The aim of covering at least 95% of the PTV with the 95% isodose was accomplished in all patients; however, the intention of achieving a minimum PTV dose of 90% and a maximum PTV dose of 105% were not accomplished for 46.4% and 50% of the patients, respectively. Median maximal dose to the brain was 54.8 Gy, brainstem 48.7 Gy, chiasm 47.1 Gy, right optic nerve 43.1 Gy, left optic nerve 44.1 Gy, right eye 18.6 Gy, left eye 19.0 Gy, right lens 5.8 Gy, and left lens 5.7 Gy (Table 2). Representative axial, coronal, and sagittal images for typically treated patients included in this series are shown in Figs 1 and 2. Acute transient toxicity was limited to grade 1 in all patients and included headache, ocular pain/dryness, radiation dermatitis, and somnolence. Preexisting headache improved in 2 patients. Preexisting cranial nerve symptoms improved in 3 patients, whereas Table 2. Dosimetric characteristics Variable Mean Median Minimum Maximum Percentile 25 Percentile 75 PTV total volume (cc) Maximal dose received in the PTV (Gy) Minimal dose received in the PTV (Gy) Median dose received in the PTV (Gy) Monitor units Homogeneity index Conformity index Maximal dose to brain (Gy) Maximal dose to brainstem (Gy) Maximal dose to chiasm (Gy) Maximal dose to right optic nerve (Gy) Maximal dose to left optic nerve (Gy) Maximal dose to right eye (Gy) Maximal dose to left eye (Gy) Maximal dose to right lens (Gy) Maximal dose to left lens (Gy)

4 Meningiomas close to the optic pathway L. SCHIAPPACASSE et al. 419 Fig. 1. Representative dosimetry in the axial, coronal, and sagittal views, showing a meningioma located in the sphenoidal wing, in close contact with the eye, optic nerve, and chiasm. they worsened in 1 patient (Table 3). The median follow-up was 7.5 months (range, ). One patient had a radiological partial response, and the remaining 27 patients showed radiological stabilization of the disease. The maximal radiation dose among patients with acute ocular pain/dryness was significantly higher than in patients without ocular pain/dryness: left eye 31.5 Gy vs 13.6 Gy, respectively (Mann-Whitney p-value 0.013) and right eye 25.6 Gy vs 15.6 Gy, respectively (Mann- Whitney p-value 0.034). Headache as acute toxicity was not associated with coverage index, homogeneity index, or maximal doses to the brain or brainstem. DISCUSSION Clinical characteristics of this group of patients are similar to some other groups of patients with complexshaped meningiomas of the skull base, cavernous sinus, or surgically inaccessible meningiomas in regard to female:male ratio, mean age, functional status, and tumor grade. Tumor characteristics are also similar, with great variability in tumor volume, high use of radiotherapy as a primary treatment, and the presence of cranial nerve symptoms or headache as the most frequently observed symptomatology. 6,11,12 Total dose and fraction size were within the therapeutic range. An IMRT approach tends to administer doses to the PTV somewhat higher than prescribed in conformal radiotherapy, with a median dose to the PTV of 51.7 Gy. Although fractionation for meningiomas can be of Gy daily, in this group of patients given the proximity to the optic structures, a 1.8-Gy fraction size is preferred to diminish toxicity to critical structures. 13 Acute toxicity was lower than reported in other series of conventional IMRT for ocular pain/dryness

5 420 Medical Dosimetry Volume 36, Number 4, 2011 described with doses between 30 and 40 Gy, but most patients tolerate doses between 30 and 40 Gy in the whole orbit without developing a chronic severe dry eye syndrome. 16 Although a chronic severe dry eye syndrome is improbable with the doses obtained with tomotherapy, we believe that a further dose reduction could be accomplished if lacrimal glands were considered as organs at risk and included in the cost function, translating in a reduction of acute dry eye and chronic nonsevere dry eye. Therefore, in future treatments, we will include the lacrimal gland and the ocular surface as organs at risk, considering 36 Gy as maximal dose both for ocular surface 17 and for lacrimal gland. We suggest this dose constraint from data derived of radiobiological 18 and clinical models, 15 even though a mean dose inferior to 45 Gy was recently published as a constraint for lacrimal glands using tomotherapy. 19 Our suggestion is aimed to reduce acute eye toxicity and chronic nonsevere dry eye. We believe that the suggested constraints can be easily achieved with tomotherapy for tumors in this anatomical location. Corticosteroid use in our series was relatively low, which is in accordance with the low values of acute toxicity. Clinical response was lower than observed in other series of stereotactic fractionated radiotherapy 20,21 and IMRT series 4 ; however our series has a shorter follow-up period, hence, further improvement could be expected. Because of the short Fig. 2. Representative dosimetry in the axial, coronal, and sagittal views, showing a meningioma located in the sella turcica, with compromise of the sphenoidal wing, and a close location to the eye, optic nerve, and chiasm. (28.6% vs 50%), nausea (0% vs 50%), and emesis (0% vs 10%). 4 We did not evaluate the impact of the doses administered to the lacrimal glands or ocular surface because we did not consider them primarily as organs at risk, and we could not estimate the values retrospectively, because the tomotherapy planning software does not allow further modifications of approved plans. However, we subjectively reviewed the isodoses curves on the treatment planning, and we found that for most patients, the lacrimal glands were located near to the isodose curves of Gy, but in affected patients the lacrimal gland/ocular surface was close to the Gy isodose curves. The incidence of xerophthalmia has been reported with doses to the lacrimal gland as low as 24 Gy, 14 although the incidence of chronic dry eye increases steeply with doses 40 Gy. 15 The TD 5/50 defined as the radiation dose that would result in a 50% probability of developing severe complications within 5 years after treatment, for severe dry eye for the lacrimal gland is Gy. Acute effects have been Table 3. Treatment characteristics Variable Variable Levels n % Treatment indication Primary treatment Adjuvant immediate ( mo post surgery) Adjuvant delayed ( 6 mo post surgery) Rescue after postsurgical relapse Rescue after postsurgical radiotherapy relapse Initial radiotherapy 2D treatment technique 3D Tomotherapy total dose (cgy) Radiosurgery Tomotherapy fraction size (cgy) Corticosteroids use during Yes treatment No Acute symptomatology Headache Somnolence Functional status deterioration Ocular pain/dryness Skin Symptomatic improvement Headache Cranial nerves symptoms Symptomatic worsening Cranial nerves symptoms 1 3.6

6 Meningiomas close to the optic pathway L. SCHIAPPACASSE et al. 421 follow-up period, the report of late morbidity is limited on this series. The lack of accomplishment of the planning objectives reflects the balance we had to deal with to achieve the constraints for the organs at risk while trying to keep the prescription in the PTV in a group of patients with tumors located very closely or even invading the organs at risk. Homogeneity index was very close to the ideal value (1), expressing a homogeneous dose with low incidence of hot spots in the irradiated area. Excepting one previously irradiated patient, with a very complex volume and a coverage index of 0.18, the coverage index was close to the unit for most of the remaining patients, expressing a homogeneous dose with low incidence of cold spots in the treatment area. After excluding this value, the mean coverage index increased from , although the median value for coverage index remained unchanged at Meningioma treatment requires a multidisciplinary team approach, including neurosurgeons, radiologists, and radiation oncologists. Surgery is the preferred treatment, but when a complete resection is unfeasible, there is a high recurrence risk 22 ; therefore, radiotherapy becomes an option as primary or adjuvant treatment. Although radiosurgery is the preferred radiotherapy treatment technique, in cases of tumors located in the proximity of the optic pathway, it becomes impractical as a result of limiting doses of these visual structures added to the fact of maximal tumor volume constraints of the technique. Our study demonstrates that tomotherapy is a technique with high capabilities of intensity modulation, despite the complexity of the tumor shape, with higher coverage and homogeneity indexes than those observed in conformal treatments 23 and high capabilities for sparing the organs at risk. Daily image guidance with megavoltage CT guarantees an accurate and precise treatment delivery, providing a safe and effective alternative in this group of therapeutically challenging patients in whom, despite the facial mask use, it has been proved that setup variations range from 1 2 mm in translational errors and up to 1 degree in rotational errors. 24,25 Technology advances have represented an improvement in the treatment of meningiomas since the use of CT and MRI for volume definition, enhanced conformal capabilities using conformal radiotherapy and IMRT, and, finally, tomotherapy as a technique merging advances in modulation capabilities and image guidance as an important component of a highly conformal IMRT treatment administered in a critical anatomical area. CONCLUSION Tomotherapy is a technique capable of delivering a well-tolerated treatment with high homogeneity and coverage indexes and high capabilities for sparing the organs at risk in patients with meningiomas close to the optic pathway. Tomotherapy can be used as a primary or adjuvant treatment when surgery or radiosurgery are not feasible. A longer follow-up is required to appropriately evaluate late toxicity and tumoral response. This study was supported by the Instituto Madrileno de Oncologia (IMO) Foundation Group. REFERENCES 1. Bondy, M.; Ligon, B.L. Epidemiology and etiology of intracranial meningiomas: a review. J. Neurol. Oncol. 29: ; Whittle, I.R.; Smith, C.; Navoo, P.; et al. Meningiomas. Lancet. 363: ; Uy, N.W.; Woo, S.Y.; Teh, B.S.; et al. Intensity-modulated radiation therapy (IMRT) for meningioma. Int. J. Radiat. Oncol. Biol. Phys. 53: ; Pirzkall, A.; Debus, J.; Haering, P.; et al. 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7 422 Medical Dosimetry Volume 36, Number 4, Chen, A.M.; Sreeraman, R.; Mathai, M.; et al. Potential of helical Tomotherapy to reduce dose to the ocular structures for patients treated for unresectable sinonasal cancer. Am. J. Clin. Oncol.; 2010 May 3 [Epub ahead of print]. 20. Brell, M.; Villà, S.; Teixidor, P.; et al. Fractionated stereotactic radiotherapy in the treatment of exclusive cavernous sinus meningioma: functional outcome, local control, and tolerance. Surg. Neurol. 65:28 33, discussion 33 4; Milker-Zabel, S.; Zabel-du Bois, A.; Huber, P.; et al. Fractionated stereotactic radiation therapy in the management of benign cavernous sinus meningiomas: long-term experience and review of the literature. Strahlenther. Onkol. 182:635 40; Simpson, D. The recurrence of intracranial meningiomas after surgical treatment. J. Neurol. Neurosurg. Psychiatry. 20:22 39; Selch, M.T.; Ahn, E.; Laskari, A.; et al. Stereotactic radiotherapy for treatment of cavernous sinus meningiomas. Int. J. Radiat. Oncol. Biol. Phys. 59:101 11; Vaandering, A.; Lee, J.A.; Renard, L.; et al. Evaluation of MVCT protocols for brain and head and neck tumor patients treated with helical Tomotherapy. Radiother. Oncol. 93:50 6; Schubert, L.K.; Westerly, D.C.; Tomé, W.A.; et al. A comprehensive assessment by tumor site of patient setup using daily MVCT imaging from more than 3,800 helical Tomotherapy treatments. Int. J. Radiat. Oncol. Biol. Phys. 73:1260 9; 2009.