Abstract
BACKGROUND: Gamma Knife radiosurgery (GKRS) allows for the treatment of intracranial tumors with a high degree of dose conformality and precision. There are, however, certain situations wherein the dose conformality of GKRS is desired, but single-session treatment is contraindicated. In these situations, a traditional pin-based GKRS head frame cannot be used, because it precludes fractionated treatment.
OBJECTIVE: To report our experience in treating patients with fractionated GKRS using a relocatable, noninvasive immobilization system.
METHODS: Patients were considered candidates for fractionated GKRS if they had 1 or more of the following indications: a benign tumor >10 cc in volume or abutting the optic pathway, a vestibular schwannoma with the intent of hearing preservation, or a tumor previously irradiated with single-fraction GKRS. The immobilization device used for all patients was the Extend system (Leksell Gamma Knife Perfexion, Elekta, Kungstensgatan, Stockholm).
RESULTS: We identified 34 patients treated with fractionated GKRS between August 2013 and February 2015. There were a total of 37 tumors treated including 15 meningiomas, 11 pituitary adenomas, 6 brain metastases, 4 vestibular schwannomas, and 1 hemangioma. At last follow-up, all 21 patients treated for perioptic tumors had stable or improved vision and all 4 patients treated for vestibular schwannoma maintained serviceable hearing. No severe adverse events were reported.
CONCLUSION: Fractionated GKRS was well tolerated in the treatment of large meningiomas, perioptic tumors, vestibular schwannomas with intent of hearing preservation, and reirradiation of previously treated tumors.
Keywords: Gamma Knife radiosurgery, Meningioma, Pituitary adenoma, Radiosurgery, Vestibular schwannoma
ABBREVIATIONS
- CNS
central nervous system
- GKRS
Gamma Knife radiosurgery
- SRS
stereotactic radiosurgery
Gamma Knife radiosurgery (GKRS) is used in the treatment of benign and malignant intracranial tumors and in the treatment of various nonneoplastic conditions including arteriovenous malformation and trigeminal neuralgia. GKRS dose distributions have steep dose gradients and high-dose conformality allowing for excellent target coverage and capabilities for avoidance of nearby structures at risk. Certain clinical situations exist wherein it would be advantageous to exploit GKRS dose conformality in the treatment of a tumor, but a contraindication is present that precludes single-fraction treatment. GKRS has traditionally been delivered by using an invasive, pin-based, rigid head frame system that both defines the stereotactic coordinate system and immobilizes the patient for treatment delivery with high stereotactic precision. One disadvantage of this system is that its relocation is not reproducible once removed, and thus multiple sessions of GKRS are unable to be delivered unless the head frame is kept in place or if the serial head frame placements are performed along with stereotactic imaging for each successive placement.
With the recent development of the Gamma Knife Extend system (Elekta, Stockholm, Sweden), multiple-session GKRS has now become a feasible treatment modality. The Extend system relies upon computed tomo-graphic (CT) imaging and a vacuum-assisted mouthpiece for immobilization, and is reproducible over multiple sessions,1 with a mechanical accuracy on the order of 0.5 mm.2 This has led to the emergence of several new indications for treatment with fractionated GKRS in situations wherein the use of single-fraction GKRS is not ideal or contraindicated. Such indications include the treatment of benign optic pathway-adjacent tumors, tumors >10 cc in volume, and reirradiation of tumors previously treated with stereotactic radiosurgery (SRS). Multisession treatment may also be considered for vestibular schwannoma in patients with useful hearing; although single session SRS is not contraindicated in this scenario, because there is some evidence that hearing preservation rates may be higher with multisession vs single-session SRS.3
The current report represents a single-institution experience with the use of fractionated GKRS with reproducible immobilization. The experience includes patients with meningioma, pituitary adenoma, vestibular schwannoma, hemangioma, and brain metastasis. To our knowledge, this series constitutes the largest reported experience on the use of fractionated GKRS for each of these tumor types.
METHODS
A retrospective review of an institutional review board-approved prospective GKRS database was performed at our institution. Patients were selected for treatment with fractionated GKRS if they had a tumor with volume >10 cc or in close proximity to the optic pathway, a vestibular schwannoma with ipsilateral useful hearing, or a tumor previously treated with single-fraction GKRS.
All patients underwent preliminary evaluation by a radiation oncologist and neurosurgeon after which they were subsequently treated under the care of a neurosurgeon, radiation oncologist, and medical physicist. Nonstereotactic magnetic resonance imaging (MRI) of the head was obtained including high-resolution, postintravenous gadolinium, and volumetric images through the lesion. A stereotactic CT scan was then obtained with the patient immobilized in the Elekta Extend bite-block palatal vacuum immobilization system. Patients were deemed candidates for the bite-block immobilization system only if they had ≥3 maxillary teeth. Details regarding the procedure used to apply the Extend immobilization system are consistent with those previously described in the literature.1 Treatment planning was performed using the GammaPlan Treatment Planning System (Elekta). The CT and magnetic resonance images (MRIs) were transferred to the GammaPlan workstation. The tumor was outlined using the regions and volume tool of the GammaPlan software. The final target volume was represented by the tumor volume, with no additional margin used. Multiple isocenter plans were created for each tumor. The radiation oncologist then prescribed a dose of 16 to 32 Gy to the 50% isodose line to be delivered in 4 to 5 daily fractions. Benign tumors were typically treated to a dose of 20 Gy in 4 fractions prescribed to the 50% isodose line. The total dose of 20 Gy for benign perioptic tumors was chosen based on evidence of efficacy and low toxicity when treating to this dose with SRS in 2 to 5 fractions.4 Malignant tumors were typically treated to a dose of 32 Gy in 4 fractions. The threshold to which the optic apparatus was constrained for each fraction was the 4 Gy line tangential to the tumor.5 Daily repositioning errors were constrained to <1.2 mm, based on the comparison of daily skull radii measurements in comparison with reference skull radii measurements obtained at the time of palatal immobilization and stereotactic CT imaging.
Patients were seen during treatment and clinically evaluated by a radiation oncologist after the third treatment fraction. Follow-up data were collected by review of the patients’ electronic medical records and by telephone interview. Imaging follow-up with MRI was routinely performed 6 months after completion of treatment for benign tumors (<3 months for brain metastasis) and at least yearly thereafter. The initial and posttreatment tumor volumes were determined based upon pretreatment and posttreatment MRI, with tumor volumes volumetrically assessed by using the contouring tools available in MIM Maestro, version 6.4 (MIM Software Inc, Cleveland, Ohio). Toxicities were graded using the Radiation Therapy Oncology Group central nervous system (CNS) toxicity scoring system.
RESULTS
Between August 2013 and February 2015, we identified 41 patients whose tumors were suitable for treatment with fractionated GKRS. Of these 41 patients, 34 were treated with fractionated GKRS, whereas 7 were unable to successfully have an immobilization mouthpiece molded because of either inadequate maxillary dentition or intolerance of the palatal vacuum bite-block assembly. Of these 7 patients, 3 patients were found to have inadequate maxillary dentition before bite-block formation, 3 patients were unable to comply with the use of the bite-block because of psychological factors, and 1 patient died of unrelated causes (aortic dissection) before treatment.
Of the 34 patients treated, 1 patient had 3 brain metastases treated, and another patient had both a meningioma and a vestibular schwannoma treated. All other patients had only a single tumor treated. Therefore, there was a total of 37 tumors treated with GKRS. Of these, 30 were benign tumors, which included 14 meningiomas, 11 pituitary adenomas (1 functioning, 10 nonfunctioning), 4 vestibular schwannomas, and 1 hemangioma. Malignant tumors treated with fractionated GKRS included 6 brain metastases and 1 anaplastic meningioma in a patient with multifocal disease. The indications for treatment and other pretreatment characteristics are summarized in Table 1.
TABLE 1.
Patient Characteristicsa
| No. of patients | 34 |
| Age, mean (range), y | 62 (31-90) |
| Sex, n (%) | |
| Male | 10 (29) |
| Female | 24 (71) |
| Tumor, n (%) | |
| Benign | 30 (81.1) |
| Malignant | 7 (18.9) |
| Tumor histology, n (%) | |
| Meningioma | 15 (40.5) |
| Pituitary adenoma | 11 (29.7) |
| Vestibular schwannoma | 4 (10.8) |
| Hemangioma | 1 (2.7) |
| Metastasis | 6 (16.2) |
| Treatment indication, n (%) | |
| Perioptic location | 21 (56.8) |
| >10 cc tumor volume | 7 (18.9) |
| Reirradiation | 5 (13.5) |
| Vestibular schwannoma | 4 (10.8) |
| Tumor volume, median (range), cc | |
| Meningioma | 11.45 (0.37-51.81) |
| Pituitary adenoma | 5.42 (1.58-9.59) |
| Vestibular schwannoma | 0.37 (0.07-0.89) |
| Hemangioma | 5.95 (5.95) |
| Metastasis | 1.92 (0.72-20.54) |
| Dose/fractionation, benign tumors, n (%) | |
| 20 Gy/4 fractions | 29 (78.4) |
| 16 Gy/4 fractions | 1 (2.7) |
| Dose/fractionation, malignant tumors, n (%) | |
| 32 Gy/4 fractions | 4 (10.8) |
| 24 Gy/4 fractions | 1 (2.7) |
| 22 Gy/4 fractions | 1 (2.7) |
| 20 Gy/5 fractions | 1 (2.7) |
aPatient characteristics for all patients treated with fractionated Gamma Knife radiosurgery (GKRS) using the Extend system.
Optic Pathway-Adjacent Tumors
Twenty-one patients were treated for tumors in close proximity to the optic pathway. Figure 1 reports the composite dose-volume histogram data for all patients with perioptic tumors. Nineteen of the tumors treated were benign, while 2 were malignant. The benign tumors included 11 pituitary adenomas, 7 meningiomas, and 1 cavernous sinus hemangioma, while the malignant tumors included 1 optic nerve metastasis and 1 anaplastic meningioma (in a patient with multifocal, recurrent anaplastic meningioma). Twelve patients (57%) had vision deficits before treatment, including bitemporal hemianopsia (n = 6), ipsilateral temporal field deficits (n = 3), decreased ipsilateral visual acuity (n = 2), and ipsilateral blindness (n = 1). Pretreatment and posttreatment visual field assessment by a neuroophthalmologist was frequently performed for patients with visual field deficits, but was not routinely performed for all patients.
FIGURE 1.
Composite dose-volume histogram for all patients with perioptic tumors. Solid lines represent the mean dose to the given volume, while dashed lines represent the minimum and maximum doses to these volumes.
All 19 benign perioptic tumors were treated with fractionated GKRS to a total dose of 20 Gy in 4 fractions. At the time of the most recent follow-up (median, 7.6 months; range, 4.3-17.2 months), all 19 patients with benign optic pathway-adjacent tumors had either stable or improved vision based on patient reports and confrontation visual field examinations during follow-up visits.
Compared with the benign perioptic tumors treated, a higher dose was favored for the 2 malignant tumors, although, because treatment in both of these patients was largely palliative in intent, the optic apparatus dose constraints were highly prioritized. As a compromise between local control and potential optic pathway toxicity, the optic nerve metastasis was treated to 24 Gy in 4 fractions, while the anaplastic meningioma was treated to 22 Gy in 4 fractions. At the time of the last follow-up, both patients reported stable vision after fractionated GKRS.
Hearing Preservation for Vestibular Schwannoma
Four patients with vestibular schwannoma were treated with fractionated GKRS with the intent of hearing preservation. These tumors were all treated to 20 Gy in 4 fractions. The mean dose received by the cochlea ranged from 8.1 to 13.2 Gy, while the maximum cochlear dose ranged from 16.0 to 23.0 Gy. At the time of the most recent follow-up (median, 16.2 months; range, 4.3-19.8 months), all 4 patients treated for vestibular schwannoma maintained serviceable hearing on the side of treatment.
Reirradiation
Three patients were treated with fractionated GKRS for tumors that had been previously irradiated. Treated tumors included 1 meningioma, 3 brain metastases, and 1 retropharyngeal metastasis. All metastases demonstrated a radiographic response to treatment with fractionated GKRS, with a median reduction in tumor volume of 87.1% (range, 79.8%-100%). The characteristics of these patients and their tumors are summarized in Table 2. All patients were alive at the time of the most recent follow-up.
TABLE 2.
Characteristics of Reirradiation Patients
| Patient | Tumora | Location | Previous Treatment | Fractionated GKRS |
|---|---|---|---|---|
| A | 1. Meningioma | 1. Pineal | 1. Single-fraction GKRS, 12 Gy | 1. 24 Gy/4 fractions |
| B | 2. Intracranial metastasis | 2. Thalamus, left | 2. Single-fraction GKRS, 22 Gy | 2. 32 Gy/4 fractions |
| 3. Intracranial metastasis | 3. Cerebellum, right | 3. Single-fraction GKRS, 22 Gy | 3. 32 Gy/4 fractions | |
| 4. Intracranial metastasis | 4. Cerebellum, left | 4. Single-fraction GKRS, 22 Gy | 4. 32 Gy/4 fractions | |
| C | 5. Extracranial metastasis | 5. Retropharyngeal | 5. External beam radiotherapy, 66 Gy/33 fractions | 5. 32 Gy/4 fractions |
aCharacteristics of tumors that were treated with fractionated Gamma Knife radiosurgery (GKRS) for a local failure that occurred after previous treatment with conventionally fractionated radiotherapy or single-fraction GKRS. All GKRS treatments were prescribed to the 50% isodose line.
Radiographic Response
The treatment outcomes for all patients are summarized in Table 3. Of the 34 patients treated with fractionated GKRS, 28 patients had follow-up imaging with MRI available (Figure 2). The median interval between treatment and follow-up MRI was 6.0 months (interquartile range [IQR], 5.8-6.6). Overall, 24 of 28 patients (86%) with follow-up MRI had an interval response to therapy. There was an increase in the volume of enhancement on MRI in both patients with vestibular schwannoma who had follow-up imaging, which is presumed to represent a transient increase in tumor size secondary to treatment rather than true tumor progression.6,7 One patient with meningioma had an interval increase in tumor size, while all others had stable findings or evidence of response. All pituitary adenomas showed an interval response to therapy. Figure 3 shows the response seen for each individual tumor.
TABLE 3.
| Median Follow-up, All Patients (Range) | 9.2 mo (2-20 mo) |
|---|---|
| Tumor volume, n = 28 (%) | |
| Increased | 3 (11) |
| Stable | 1 (3) |
| Decreased | 24 (86) |
| Benign perioptic tumors (n = 19) | |
| Median follow-up (range) | 7.6 mo (4.3-17.2 mo) |
| Vision (%) | |
| Improved | 4 (21) |
| Stable | 15 (79) |
| Worsened | 0 (0) |
| Vestibular schwannoma (n = 4) | |
| Median follow-up, range | 16.2 mo (4.3-19.8 mo) |
| Hearing (%) | |
| Improved | 0 (0) |
| Stable | 4 (100) |
| Worsened | 0 (0) |
| Post-GKRS CNS toxicity (RTOG) (%) | |
| Grade 1 | 2 (6) |
| Grade 2 | 1 (3) |
| Grade ≥3 | 0 |
aCNS, central nervous system; GKRS, Gamma Knife radiosurgery; RTOG, radiation therapy oncology group.
bTreatment outcomes for patients treated with fractionated GKRS.
FIGURE 2.
Magnetic resonance imaging (MRI) of a pituitary adenoma before treatment A and 6 months posttreatment B, and an MRI of a large meningioma before treatment C and 6 months posttreatment D. Both patients were treated to a total dose of 20 Gy/4 fractions. Color version available online only.
FIGURE 3.
Tumor response to fractionated gamma knife radiosurgery as assessed by relative change in volume between pretreatment and follow-up magnetic resonance imaging (MRI) (performed 6 months posttreatment for benign tumors and 1-2 months posttreatment for malignant tumors). Color version available online only.
CNS Toxicity
Fractionated GKRS was well tolerated overall. Three patients experienced Radiation Therapy Oncology Group grade ≤2 toxicity after treatment, with no other adverse effects reported. The most significant toxicity reported was the acute development of seizures requiring the use of corticosteroids and antiepileptic medications occurring in a patient treated for a large parafalcine meningioma (19.5 cc) with which there was preexisting edema. The seizures resolved after a corticosteroid taper, however, the patient remained on antiepileptic therapy at the time of most recent follow-up.
DISCUSSION
Several indications have recently emerged for treatment with fractionated GKRS, including benign tumors greater than 10 cc in volume, vestibular schwannomas with intent of hearing preservation, benign tumors that are abutting the optics, and reirradiation of metastases that have failed prior radiosurgery. Studies of the immobilization accuracy of the Extend system have shown average errors of <1 mm, demonstrating that its accuracy is sufficient for fractionated radiosurgical treatment.2 While the current usage of fractionated GKRS is limited to institutions that have the Gamma Knife Extend system, the next generation Gamma Knife unit the Leskell Icon (Elekta), will make fractionated GKRS more accessible. It will also simplify immobilization due to the elimination of the Extend bite block.
Previously Reported Experiences With Fractionated GKRS
To our knowledge, there have only been 2 institutional experiences with fractionated GKRS using Extend that have been reported in the literature.8,9 The characteristics of the tumors treated in these series are summarized in Table 4. Patients treated in the series reported by Nguyen et al9 were typically treated to a dose of 20 Gy in 3 to 5 fractions,8 while the patients in the series reported by Devriendt et al8 were typically treated to a dose of 25 Gy in 5 fractions. Both series consisted predominantly of patients treated for meningioma in areas adjacent to the optic pathways, and there were no reports of visual toxicity after treatment with fractionated GKRS in either study.
TABLE 4.
Previously Reported Experiences With Fractionated Gamma Knife Radiosurgery Using Reproducible Immobilizationa
| Nguyen | Devriendt | |
|---|---|---|
| et al7 | et al8 | |
| No. of patients | 15 | 12 |
| Median age (range), yr | 57 (18-73) | 54.5 (39-88) |
| Sex, n (%) | ||
| Male | 6 (40) | 2 (17) |
| Female | 9 (60) | 10 (83) |
| Diagnosis, n (%) | ||
| Meningioma | 12 (80) | 11 (92) |
| Pituitary adenoma | 1 (6.7) | – |
| Acromegaly | 1 (6.7) | – |
| Pilocytic astrocytoma | 1 (6.7) | – |
| Craniopharyngioma | – | 1 (8) |
| Prior therapy, n (%) | ||
| Surgical resection | 7 (46.7) | 9 (75) |
| Single-session SRS | 1 (6.7) | – |
| Fractionated radiotherapy | 1 (6.7) | – |
| Median treatment volume (range), mL | 7.3 (1.2-22.7) | 7.4 (0.4-33.1) |
| Median margin dose (range), Gy | 20 (15-25) | 25 (24-25) |
| Median isodose line (range), % | 50 (50-50) | 64 (50-70) |
| No. fractions, n (%) | ||
| 3 | 6 (40) | – |
| 4 | 5 (33) | 1 (8) |
| 5 | 4 (27) | 11 (92) |
aSRS, stereotactic radiosurgery.
Large Meningiomas
Large inoperable meningiomas that are at high risk for posttreatment edema can be treated with fractionated GKRS.10,11 The advantage of fractionated GKRS over conventionally fractionated radiotherapy is the decrease in integral dose, which can lead to decreased deficits in cognition.12 Risk factors for symptomatic edema for meningiomas treated with single-fraction radiosurgery include preexisting edema,13 parasagittal location,14 and larger tumor size.15 Hypofractionated radiotherapy has been suggested to have a lower rate of symptomatic edema than single-fraction radiosurgery.10,11 Kuhn et al13 demonstrated that patients with tumors larger than 7 cc had a 4.9-fold increase in symptomatic edema compared with those with smaller tumors.
Hearing Preservation for Vestibular Schwannoma
Single-fraction radiosurgery has been shown to exhibit hearing preservation rates as high as approximately 75% in some studies;16-18 however, recent meta-analysis results suggest that the overall rate of hearing preservation with SRS may be closer to 50%.19 Conventionally, fractionated radiotherapy likely has a higher rate of hearing preservation, but this is at the cost of a higher integral dose of radiation.3 Given that the temporal lobes—particularly the hippocampi—anatomically rest on the cerebellopontine angle, this increased integral dose would be of concern for late cognitive toxicity.20 Recent data have suggested that hypofractionation can improve hearing over single-fraction radiosurgery.21 Furthermore, the local control afforded by hypofractionated radiotherapy has been shown to be equivalent to that seen with single-fraction radiosurgery.21,22
Tumors Abutting the Optics
Perhaps the most novel indication for fractionated GKRS is in tumors that are abutting the optic structures (ie, retinas, optic nerves, and optic chiasm). Single-fraction radiosurgery is not typically used to treat patients with tumors abutting the optics because of the exquisite sensitivity of the optic pathways to radiation—because of this, it is often not possible to treat such tumors to a curative dose while keeping the optic structures constrained below their tolerance dose.23 These tumors have therefore traditionally been treated with conventionally fractionated radiotherapy. With the recent advent of fractionated GKRS, however, these tumors can now be treated with a hypofractionated approach using a fractionation pattern of 5 Gy × 4 fractions without exceeding the tolerance dose of the optic pathway.5,9 With a 4-fraction scheme, the tolerance of the optics is estimated to be between 4 and 5 Gy per fraction.5 The sharp penumbra of GKRS therefore allows for treatment of these tumors in spite of mild abutment of the tumor and optics.
Reirradiation of Brain Metastases That Have Previously Received Radiosurgery
The use of radiosurgery in the retreatment of brain metastasis for local failure after previous radiosurgery has been a controversial practice. There are few reports in the scientific literature; therefore, the dose-volume tolerances are unknown.24 There are clinical scenarios, however, wherein repeat radiosurgery may be helpful, including a local failure in a patient that (1) is not an operative candidate, (2) has a surgically inaccessible lesion, or (3) cannot tolerate surgery because of an urgent need to continue systemic chemotherapy. Although whole-brain radiotherapy is a very reasonable salvage option in many of these cases,21 it can also delay systemic chemotherapy by several weeks, and may treat significantly more volume of the brain than what is affected by recurrent cancer. Because fractionation is thought to decrease the likelihood of radiation necrosis, and repeat single-fraction radiosurgery has a higher rate of radiation necrosis,24 hypofractionated reirradiation represents an intriguing clinical option. The present report represents the first published case of the use of fractionated GKRS for reirradiation of a metastasis that has experienced local failure.
Limitations
This series represents a single institution's preliminary experience with the use of the Extend system for fractionated GKRS, and as such, it is limited by relatively short follow-up and by the absence of prospective assessment of patient outcomes. Although there is some evidence to support the use of a total dose of 20 Gy in 4 fractions as a safe and effective dose in the treatment of benign perioptic tumors,4,9,25 this evidence is nevertheless relatively limited, and further investigation is necessary to better determine the efficacy and toxicity profile associated with this dose/fractionation scheme.
CONCLUSION
The advent of fractionated GKRS has increased the number of indications for treatment with the Gamma Knife unit, including allowing for treatment of larger lesions, tumors close to the optics, and retreatment of lesions previously treated with radiosurgery.
Disclosures
This report was partially funded by the National Institutes of Health grant P30 CA012197-40 (M.C.). The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
COMMENT
The manuscript reports a series of patients who were treated using multisession radiosurgery using the Gamma Knife Extend system. Traditionally, Gamma Knife radiosurgery had been performed in a single session because of the requirement of a headframe. The Extend system takes advantage of fractionation (multiple sessions) to improve safety for tumors close to organs at risk or larger tumors, which is reviewed in this manuscript.
The data presented here demonstrates the feasibility and initial results of multisession radiosurgery using Gamma Knife. More long-term research is necessary to demonstrate improved control and/or safety with multisession radiosurgery. This data is emerging using the linear accelerator (LINAC)-based systems.
Elekta is making multisession radiosurgery more facile with the development of the ICON system, which uses a mask for immobilization and cone-beam computed tomography (CT) for alignment. This will make the Gamma Knife system setup for multisession radiosurgery as simple as it currently is for LINAC-based radiosurgery. Consequentially, it will be interesting to see how the future of radiosurgery will shift with the adoption of this technology.
Samuel Chao
Cleveland, Ohio
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