Stereotactic Volume Modulated Arc Radiotherapy in Canine Meningiomas: Imaging-Based and Clinical Neurological Posttreatment Evaluation
ABSTRACT
A prospective study to assess high-dose hypofractionated volume modulated arc radiotherapy feasibility and efficacy in canine meningiomas was conducted. Thirty-nine patients with encephalic and spinal meningiomas assumed from MRI findings were recruited and received high-dose hypofractionated volumetric modulated arc radiotherapy by a linear accelerator equipped with an external beam modulator micro-multileaf collimator and an XVI cone beam computed tomography system. The prescribed mean dose was 33 Gy in five fractions. The treatment feasibility was tested through planned and delivered dose agreement checks. Regular clinical examinations were performed during and after irradiation time, with regard to mentation, deambulation, cranial nerve dysfunction, and seizures. Serial MRI exams were done 60 days after irradiation and after 4, 6, 12, 18, and 24 mo. Volumetric disease reduction criteria implemented with clinical neurological systematic evaluation were adopted to assess the course and to categorize patients’ responses. Complete and partial responses were observed on the whole in 65.5% of alive patients 24 mo after irradiation. Two-yr overall and disease-specific survival rates were 74.3% and 97.4%, respectively, and the putative radiotoxic effects were found to be few and slight.
Introduction
Meningiomas represent about 50% of encephalic tumors in dogs.1 Surgery is presently considered the treatment of choice for these tumors, although radiotherapy and chemotherapy are used for tumors considered unresectable due to their localization or to comorbidity-related risks.1,2 Radiation therapy (RT) has also been considered as a definitive therapy or as an adjuvant setting after surgery. Because the works in literature are essentially retrospective, there are no reliable data about the history of the meningiomas once they have been irradiated to allow the definition of important parameters, such as specific disease survival, progression-free survival, response, and posttreatment imaging-based volumetric evaluation.1,3,4 The aim of this work was to evaluate the effectiveness of primary curative frameless radiotherapy in canine meningiomas using a high dose level with volume modulated arc radiotherapy (VMAT) technique and to assess a combined response evaluation system (CRES) composed of imaging-based posttreatment evaluation implemented with clinical and neurological serial examinations.
Materials and Methods
A prospective, single-institution clinical research study was conducted from January 2010 to January 2012 on client-owned dogs suffering from meningiomas treated with high-dose hypofractionated volume modulated arc radiotherapy (HDH-VMAT). The diagnosis of meningioma was posed on the basis of brain and spine MRI examination, as reported in literature.5–8 According to most recent studies, the MRI criteria for presumptive diagnosis of meningioma were the occurrence of a single, solid, broad, dural-based, extra-axial mass with distinct margins and the presence of intense and uniform enhancement with a dural tail sign.5–8
The MRI examinations were conducted using a 1.5 T superconductive whole-body MRIa scanner with gradients of 70 millitesla/meter. A quadrature knee and a quadrature spine coil were used. A standardized patient positioning technique was developed: dogs under sedation were positioned in sternal recumbency for brain lesions and dorsal recumbency for spinal lesions, with head first. The MRI protocol provided the following scan sequences: a pulse sequence turbo spin echo T2-weighted with repetition time (TR) 3,500 msec, echo time (TE) 130 msec, 2 acquisitions (NEX), 512 × 512 matrix; a fluid attenuated inversion recovery with TR 3,000 msec, TE 150 msec, inversion time 50 msec, 2 NEX, 512 × 512 matrix; a spin echo T1-weighted with TR 450 msec TE 5 msec, 2 NEX, 512 ×512 matrix; a fast field echo T1- weighted with TR 450 msec, TE 5 msec, 2 NEX, 512 × 512 matrix, either under basal conditions or after contrast medium IV injection. Sequences were oriented in the sagittal, dorsal, and axial plan and slice thickness was set at 2 mm without intersection gap. For postcontrast images, gadodiamideb 0.5 mmol/mL was administered at the dose of 0.2 mL/kg in the cephalic vein; the injection was performed with a high-pressure injection systemc with standardized infusion rate of 3 mL/s and time of acquisition at 5 min postinjection.
The computed tomography (CT) simulations were performed within 1 wk after the MRI examination using a multidetector CT scannerd. For all the dogs, a wooden cradle containing a vacuum mattress with a plastic bite block to fit the upper dentition was provided. The provisional isocenter was marked with three radiopaque fiducials on the wooden cradle. The parameters used for the CT simulation were as follows: 200 mAs, 120 Kv, pitch 0.6, rotation 1 s, slice thickness 1.5 mm. For postcontrast images, iomeprole 350 mg/mL was administered at the dose of 2 mL/kg in the cephalic vein; the injection was performed with a high-pressure injection systemc with standardized infusion rate of 3 mL/s and time of acquisition 5 s postinjection.
The dogs received a radiotherapy treatment by an linear acceleratorf equipped with an external beam micro-multileaf collimator and an XVI cone beam computed tomography system (CBCT). HDH-VMAT treatments were planned using a Monte Carlo statistical algorithm and the software for treatment planning systemg. MRI and CT images fusion was routinely performed during the planning.
The gross tumor volume (GTV) was defined as the contrast-enhanced lesion on fused CT and MRI images; the clinical target volume encompassed the GTV with supplementary contouring of the dural tail if present. The planning target volume (PTV) was realized by expanding the clinical target volume by 1 mm in all directions. The considered organs at risk (OARs) were eyes, optic pathway, basal ganglia, cerebrum, hypothalamus and hypophysis, brain stem, cerebellum, spinal cord, inner ear, trachea, esophagus, and lungs. PTV and OARs were contoured on an interactive pen display graphic tableth. The high-dose hypofractionated protocol consisted of 33 Gy in five fractions delivered in 5 continuous days. The OARs dose constraints were derived from the human ones described by the American Association of Physicists in Medicine Task Group 101.9 For all patients, a specific plan setup was elaborated with a single 360° arc optimized over continuous dose rate variation, leaf position, and gantry rotational speed for obtaining target coverage and optimized for OARs sparing. The evaluation of the plan effectiveness was performed by means of standard dose volume histograms and the conformity index (CI) value defined as CI = VPrescription/VolumeTarget.10 The CI describes which way the observed isodose level conforms to the target volume shape.10
In detail, the PTV coverage was considered acceptable for the 95% isodose volume coverage (V95%) and the high 107% isodose volume coverage (V107%) levels PTV volume receiving less than 95% and more than 107% dose prescription of 5% and 7% respectively. For the CI, the 95% isodose level was considered as VPrescription and the acceptability value was CI 95% ≤ 1.3.
The treatment feasibility was evaluated by checking the planned and delivered agreed dose by a “patient-based” quality assurance procedure “in air” using an amorfous silicon electronic portal imager devicei and a dosimetry check (DC) system softwarej. In order to state the small tumor’s volume, a further absolute dose comparison was performed with the Delta4 systemk. In both cases, the agreement was parameterized by the gamma (γ) function, with a dose agreement of 3% and distance to agreement of 3 mm and an acceptance criteria of γ < 1 in more than the 93% of comparison points.11
The mean delivery time, defined as approximate time needed in the linear accelerator "beam-on" phase, was also investigated. Correct patient setup was evaluated for each treatment session using the XVI CBCT and a 2-mm tolerance displacement level was considered acceptable. The repositioning criterion of 5 mm maximum displacement was adopted. In order to check the differences between the planned dose and the delivery dose during different fractions, an “on transit” control was performed using the DC system “in vivo.”
All irradiated dogs received 0.1 mg/kg of periprocedural dexametazonel and anti-inflammatory doses of oral methylprednisolone sodium succinatem tapered over 3 wk. Phenobarbitaln or topiramateo or levetiracetamp were administered to dogs with seizures as presenting complaints.
Regular neurological clinical examinations were performed on a daily basis during irradiation time, then weekly (for the first mo), and finally, monthly examinations were performed with regard to mentation, deambulation, cranial nerve dysfunction, and seizures.12 The need for ancillary medications, particularly corticosteroids and anticonvulsant drugs, was regularly filed. For the imaging response assessment protocol, serial MRI examinations were done 60 days after irradiation and then after 4, 6, 12, 18, and 24 mo (Figures 1, 2). All the MRI scans were performed with the same scanner used for the diagnosisa and with the same scanning parameters. The volumetric tumor reduction was analyzed on transverse postcontrast T1-weighted images using a semiautomated segmentation method. Other parameters evaluated by interobserver agreement were the change of signal intensity of the tumor and of surrounding brain or spinal cord on turbo spin echo T2-weighted pulse sequence (TR 3,500 msec, TE 130 msec, 2 NEX, 512 × 512 matrix), the contrast uptake of the tumor on fast field echo T1-weighted pulse sequence (TR 450 msec, TE 5 msec, 2 NEX, 512 × 512 matrix), and the presence of mass effect (Table 1).
Citation: Journal of the American Animal Hospital Association 54, 2; 10.5326/JAAHA-MS-6488
Citation: Journal of the American Animal Hospital Association 54, 2; 10.5326/JAAHA-MS-6488
Specific response evaluation criteria were established to assess the course after irradiation. Volumetric MRI evaluation was accounted according to Veterinary Cooperative Oncology Group Response Evaluation Criteria In Solid Tumors criteria and implemented with clinical follow-up examinations (CRES).13,14 In Table 2, the categorical attribution criteria are defined: patients were ascribed to the Complete Response (CR) group, Partial Response (PR) group, Stable Disease (SD) group, or Progressive Disease group depending on tumor volume variation and clinical status. Radiation toxicities were clinically evaluated and graded according to Veterinary Radiation Therapy Oncology Group criteria.15,16 One-yr and two-yr overall and disease-specific survival rates were built according to the Kaplan-Meier method.
Results
Thirty-nine dogs were enrolled (6 neutered males, 14 intact males, and 19 spayed females), with a median age of 9.8 yr (mean 9.6, range 7–14 yr). This cohort included 13 mixed-breed dogs, 7 boxers, 5 German shepherds, 4 golden retrievers, 2 Dalmatians, and 1 each of 8 other breeds. All dogs had a single lesion. Neurolocalization included 19 encephalic supratentorial (14 frontal, 3 parietal, 2 occipital), 14 encephalic infratentorial (12 brain stem, 2 cerebellum), and 6 spinal (4 cervical, 2 thoracic). Presenting complaints included seizures (21/39), cranial nerve deficits (10/39), altered mentation (7/39), and paresis (8/39). The mean GTV volume at the first CT simulation time measured was 3.0 ± 1.2 cm3 (range 1–8 cm3) and the mean PTV was 4.0 ± 1.8 cm3 (range 1.5–9.9 cm3). A treatment with one 360° arc was devised for all the patients. Plan details were 1,700 ± 200 MU, 137 ± 5 control points, 2.3 ± 0.4 modulation degrees, and 2 mm of margin to target and to OARs. The dose constraints were derived by the American Association of Physicists in Medicine Task Group 101. Mean delivery time was 180 s.
All the plans fulfilled the PTV, the OARs, and the CI constraints and no plan was rejected.
The obtained mean doses were 33.5 ± 0.2 Gy for the GTV and 33.3 ± 0.3 Gy for the PTV. The V95% was 99.6 ± 0.2% for the GTV and 96.2 ± 0.5% for the PTV. Finally, the V107% was 9.0 ± 1.5% for the GTV and 7 ± 2% for the PTV. An example of dose distribution is shown in Figure 3. Similar results were obtained for all the patients.
Citation: Journal of the American Animal Hospital Association 54, 2; 10.5326/JAAHA-MS-6488
The mean DC agreement between the planned and delivered doses showed a mean value over all the patients’ data of 95 ± 2% points with γ < 1 showing treatment feasibility. The quality assurance check by the Delta4 system resulted in a similar 97 ± 2% value, confirming a good agreement between the results of the two methods and between the delivered plan and the calculated one.
During serial clinical examinations, reduction of frequency and/or intensity of seizures (18/21), reduction of detectable cranial nerve deficits (6/10), normalization of mentation as subjectively stated (7/7), and amelioration of the deambulation (8/8) were observed.
One dog, suffering from an invasive frontal meningioma, experienced a recurrence of presenting complaints 136 days after the end of the irradiation. MRI examination showed a progressive disease with increased volume and mass effect. No other dogs died from the meningioma during the follow-up. Survivals assessed by the Kaplan-Meier method are reported in Figure 4. The median survival time was not reached. Overall 1-yr and 2-yr survivals were 84.6% and 74.3%, respectively. A 24-mo disease-specific survival rate of 97.4% was estimated.
Citation: Journal of the American Animal Hospital Association 54, 2; 10.5326/JAAHA-MS-6488
Repeated MRI examinations showed variations of irradiated lesions (Figures 1, 2).
MRI data from subsequent examinations are listed in Table 1: volumetric criteria were considered together with T2-weighted and T1-weighted signal intensity, contrast enhancement, surrounding T2-hyperintensity, and mass effect.
The categorical assignment to the CR, PR, SD, and Progressive Disease groups, resulting from the CRES posttreatment evaluation during the 24-mo follow-up, are reported in Table 3. None of the 21 patients affected by seizures at presentation and receiving phenobarbitalh or topiramatei or levetiracetaml as anticonvulsants interrupted the therapy. Oral administration of methylprednisolone sodium succinateg was prescribed to all patients. Corticosteroid dose was increased only for the patient who died of meningioma recurrence, whereas five patients received stable steroid dose during the follow-up and the remaining patients received gradually reduced doses.
According to Veterinary Radiation Therapy Oncology Group toxicity criteria, adverse events potentially related to HDH-VMAT were limited to grade I in one dog (transient altered mentation, successfully treated with corticosteroids).
Discussion
The technical difficulties of conformal radiation therapy of canine meningiomas, with particular regard to the shape irregularity, small size, and proximity to critical neural structures as well as to markedly inhomogeneous structures, have been dealt with through the use of VMAT.3,17,18 To the authors’ knowledge, no prospective studies on VMAT RT of canine meningiomas have already been published, and retrospective RT papers show a lack of homogeneity in the treatment regimens.
The present research shows an overall 2-yr survival of 74.3%, with an estimated disease-specific survival rate of 97.4%, with putative radiotoxic effects being rare, so that effectiveness of the technique is demonstrated. In particular, high-dose hypofractionation improves local tumor control probability, whereas VMAT permits more OARs sparing.
The agreement between the prescribed and the delivered dose was considered to be the primary step in irradiating the canine meningiomas, due to the target dimensions and the VMAT sharp dose gradients. The radiation dose of 33 Gy was derived from the literature data on meningioma sensitivity (α/β value of 3.76 Gy with 95% confidence interval: 2.8–4.6 Gy), and in order to compare our regimen with published data, the concept of the biologically effective dose (BED) was used.19,20 An α/β of 3 Gy was applied for late responding tissues and late radiotoxic effects, whereas a value of 10 Gy was applied for acute responding tissues and acute radiotoxic effects.21 The BED of a typical three-dimensional conformal RT protocol for human meningioma (27 fractions of 2 Gy for a total dose of 54 Gy given in 6 wk) was a Gy3 value of 90 Gy.22 The BED of our regimen (33 Gy given in 5 days) was 105.6 Gy (17% higher).
The use of a dedicated cradle with a vacuum mattress, a bite block, and the XVI CBCT check performed before each session allowed for the realization of a frameless high-precision radiotherapy in more than one fraction without any invasive device and with results comparable to surgery and better than the reported results of conformal RT.23–25
The Monte Carlo statistic calculation algorithm allowed a better dose calculation at different tissue interfaces, where higher punctual doses could be generated. Moreover, doses to the OARs were lower than the constraints, showing the possibility of further dose escalation to the PTV.9
The tumor local control probability obtained in this study proved to be better than conformal RT reported results and, more significantly, is even better than the one obtained with gold standard surgery with resectable patients.24,25 In fact, a recent RT study reports a 1-yr and 2-yr disease-specific survival of 60% and 21%, respectively, with a median of 493 days.3 The median survival time of dogs suffering from meningiomas treated with RT alone ranges from 5 to 12 mo, as shown by many published studies.16,26–28 Standard surgery papers reported a median survival time of 7 mo for dogs treated with surgery alone (range 0.5–22 mo).8,23 It is important to note that recent surgical works focusing on improved tumor removal by ultrasonic aspiration and neuroendoscopy reported median survival times of 40–70 mo, which appears to be better than the results of our study.29,30 For a correct comparison, longer follow-up and better patient statistics are needed, but further stratification is probably necessary of both surgery and our work outcomes to better evaluate small differences.
To the best of authors’ knowledge, no standardized neuro-oncology volumetric response evaluation criteria have been formulated in veterinary trials. In this study, volumetric assessment of the tumor was mandatory for the RT planning at the time of diagnosis, so an imaging-based volumetric posttreatment evaluation was considered particularly suitable for response evaluation.
Meningiomas are strong enhancing masses, iso/hypointense in T2-weighted sequences if compared with the normal gray matter, easily distinguished from the surrounding hyperintense edema that may be present. They often exhibit marked mass effect, and they are usually well demarcated in comparison with the surrounding brain, with infrequent cystic component in canine patients. The contrast enhancement pattern is homogeneous with clear margins. The MRI characteristics of canine meningiomas make it easy to perform a volumetric standardized measurement on contrast-enhanced T1-weighted pulse sequences. As a matter of fact, the implementation of the response assessment in neuro-oncology with clinical neurological serial examinations provides additional information that fulfills a categorical therapeutic response evaluation.
Using the CRES response assessment, made of volumetric measurements and clinical data assessment, 87.2% of patients showed SD 2 mo after irradiation, 7.7% showed PR, and 5.1% showed CR. PR was observed in 48.3% of patients 24 mo after irradiation and CR in 17.2%. Among living animals, none of the patients at the 24-mo follow up showed progressive disease (Table 3).
Even though a considerable number of patients showed SD 2 mo postirradiation (34/39) with no volumetric reduction on MRI (Table 3), we observed variations in T2-weighted signal intensity and contrast enhancement. In particular, on MRI examinations 2–4–6 mo posttreatment, the majority of encephalic meningiomas with supratentorial localization showed a reduction of T2-signal intensity, whereas infratentorial meningiomas showed increased T2-weighted signal. At the same time, supratentorial and infratentorial meningiomas showed a decreased contrast enhancement independently from volume variations. Considering the whole cohort 2 mo postirradiation, contrast uptake was found reduced in 41% of patients and mass effect was decreased in 90%. Because no animal has been subjected to histological examination of the irradiated lesions, only hypotheses can be advanced to explain these findings. An increase of free water, a reduction of cell density, and tumor vascularization could play a role in signal intensity and contrast enhancement variations.
Clinical neurological evaluation of postirradiated patients deserves some observations. Except for patients who showed CR, corticosteroids administration was maintained with stable or decreased dose for all the study duration. This might have played a role in reducing clinical signs with particular reference to the patients categorized as SD that did not display volume reduction. Nevertheless, authors believe that in the long-term clinical improvement, the main role is exerted by the radiation effects. Because clinical signs resulting from meningioma are essentially compressive, often complicated by inflammation and edema in the brain or spinal cord, improvement in these patients could be due to the reduction of peritumoral edema and mass effect. This finding suggests that radiation treatment not only provides for a reduction of the compression exerted by the neoplastic lesion, but also contributes on its own to reducing inflammation caused by neoplastic tissue.
The limitations of this prospective study are the lack of histopathological confirmation and immunohistochemical or molecular tests to determine the histological degree of meningiomas. However, presumptive diagnosis by imaging is validated by several veterinary medicine papers that have assessed 89–100% MRI sensitivity in differentiating neoplastic from nonneoplastic intracranial lesions and 70–96% specificity in identifying tumor type.6–8,26,27,31 Similar results are reported in the literature on human treatment.32
Conclusion
In conclusion, HDH-VMAT is a valid therapeutic option for encephalic and spinal canine meningiomas. Two-yr overall and disease-specific survivals are much longer than published data on conventional RT and are similar to standard surgery but with fewer and slighter adverse effects. It should be taken into consideration that the volumetric MRI evaluation together with the proposed CRES for the assessment of the posttreatment course and a composite response system should be formulated and validated for veterinary patients.
Dog, male, 8 yr, boxer. At the top T2-weighted image, at the bottom T1-weighted images, on the left at the diagnosis time, on the right 8 mo after radiation therapy. Please note the reduction of the mass volume and contrast enhancement, the disappearance of the brainstem edema, and the increased T2-weighted hyperintensity of the tumor.
Dog, female, 12 yr, small mixed breed. On the left axial T2-weighted images, on the right T1-weighted postcontrast sequence of the brain at the diagnosis time (A), 8 mo after radiation therapy (B) and 18 mo after radiation therapy (C). Although the tumor volume is constant, the reduction of contrast enhancement and decreased mass effect are evident.
Isodose distribution and dose volume histogram computed by the treatment planning system software of the same dog as in Figure 1 .
Kaplan-Meier survival analysis: the red line represents the disease-specific survival rate and the blue line the overall survivals during the 24 mo follow-up.
Contributor Notes
