Multisession stereotactic radiosurgery for large benign brain tumors of >3cm- early clinical outcomes (2024)

Table 1

Characteristics of the patients (N = 35)

Table 2

Dosimetery of the patients (N=35)

Patient selection

Following criteria was used to select the patient having tumor size >3 cm in maximum dimension for multisession SRS. 1) Recurrent / residual tumors: documented radiologic progression of disease after previous treatments. 2) New symptoms or symptomatic deterioration, and surgery was not possible for any reasons mentioned in inclusion criteria. 3) Patients had minimal symptoms related to mass effect at the time of presentation.

Mode of Diagnosis

A histopathological diagnosis was available for 17(48.6%) patients who underwent surgical resection. For 18 (51.4%) patients who had no surgery, the diagnosis was based on a combination of radiographic appearances, tumor location, pattern of contrast enhancement etc.

Clinical Evaluation

Before multisession SRS, detailed clinical assessment was carried out, including history, physical examination in particular a neurological examination, blood tests (complete blood examinations, base line pituitary hormone profile, if required), perimetery in cases of optic apparatus involvement, audiometery in cases of cerebellopontine (CP) angles tumors causing hearing impairment, comprehensive radiologic investigations including thin-slice, plain and contrast-enhanced magnetic resonance imaging (MRI) with specific sequences as needed, and high-resolution computed tomographic (CT) scans with contrast.

Stereotactic Radiosurgery Technique

CT simulation was carried out after preparing an immobilization device for a particular patient. Either head fix or thermoplastic sheet was used for brain, head & neck immobilization. Thin-slice (2 mm) high resolution CT images were obtained in all patients for planning purpose after the intravenous administration of 1-1.5 mL/ kg body weight non-ionic contrast ultravist 370 (Bayer healthcare- 1ml= Iopromide 0.769gm, 370 mg I /mL), using a siemens emotion-6, 6 slicer CT scanner.

High-resolution, thin-slice contrast enhanced CT images give an excellent visualization of tumors in reference to bones (e.g. cranial base tumors and the adjacent critical anatomy). Then Dicom CT images were transferred through digital link to treatment planning systems PRECISE and ERGO++. MRI scans with and without contrast were taken for all patients having different specific sequences for various pathologies. These MR images were transferred to ERGO++ treatment planning system.

Then radiation oncologist delineates the target and adjacent critical structures after having fusion of CT/ MRI images with or with out the help of radiologist. GTV (Gross tumor volume) was drawn by taking gadollinum enhanced tumor volume on T1 weighted MRI. Non-isocentric dose optimization was carried out by the treatment planning software to generate an acceptable treatment plan after multiple planning iterations. Best fit isodose line to the peripheral margin of GTV was selected to label it as prescription isodose line (Figure 1 to Figure 5 represent the patient with treatment planning). Later the approved plan was transferred to MOSAIQ (record & verify system), from there to machine (desktop pro). Images and counters were transferred to XVI (x-ray volume imager) and DRRs (Digitally reconstructed radiographes) were transferred to I-view GT (Display software for electronic portal imaging device). When patient enters the treatment room, after fixation, CBCT (cone beam CT) takes the images and XVI reconstruct and displays the images in 3-D visualization. Then reference CT scan sent from the treatment planning software to XVI was matched with the images taken by the CBCT just before the treatment. This process of matching is called “registration” of the images, that can be carried out manually or automatically, either on soft tissue density or bone density or combination of both. If deviations were recorded then corrections (shifts) were made and finally treatment was executed. The length of treatment ranges between 15 min- 45 min depending upon the complexity of the plan. After completion of treatment, patients were discharged with oral glucocorticoides for about 2 weeks.

Dose Selection

Multiple factors were considered at the time of dose selection. The dose and fractionation decision was individualized for each patient and was usually based upon the following factors: type of tumor, tumor volume, location of tumor, proximity of the critical organs, and history of previous irradiation and duration since last irradiation. Prescription isodose was finalized after reviewing the plan and selecting the best fit isodose line to the peripheral margin of the contoured gross tumor volume (GTV). Usually we kept an interfraction time of approximately 24 hours.

Dose selection for multisession stereotactic radiosurgery of large brain tumors was calculated by biologically effective dose (BED) using conventionally fractionated radiotherapy as a point of reference, assuming an α/β ratio of 3. Following formula was used,

BED= nd {1+ d / α/β}

Where as

n= total number of fractions

d=dose per fraction α/β = 3

Tumor Control

Tumor control was defined as no increase in tumor size (stable), tumor size reduction by at least 20% (smaller), tumor size increase by at least 10%(larger).

The median follow-up time was 6.4 months (range: 1-22.5months). Nine (25.7%) of 35 patients demonstrated a decrease in tumor volume (smaller) of greater than 20% on imaging. Tumor remained stable in 26 (74.3%) of 35 tumors. There was no increase in size of the tumors in any patient. On the basis of the last available radiology reports, the rate of tumor control was 100%. The representative cases of tumor reduction shown in Figures 6 and 7.

Follow-up

Clinical evaluation for first follow-up was carried out at 3 months after radiosurgery, patients were asked to visit the clinic or to update us about the health and to get MRI of the brain with and without contrast, then every 6 months for first two year and annually thereafter. For those patients who did not live locally, clinical follow-up was carried out by telephone interview and some times, in conjunction with local physicians and patient was asked to send the CD of MRI / CT Dicom images to us to make a comparative report and to update our follow-up record. Perimetery, audiometery or pituitary harmone profiles and other test may be requested, if have been done at the time of radiosurgery.

Imaging (MRI/CT) response was evaluated with the help of the radiologist. Tumor volume was assessed by measuring the tumor in three dimensions in axial, coronal, and saggital images (i.e., anteroposterior, lateral, and vertical) corresponding to the region of tumor enhancement. These values were recorded and used in the following formula for an idealized ellipsoid: (volume = 4/3π[length/2 x width/2 x height/2]) to assess radiologic response over time and scored as smaller, larger or stable in size. These values were compared to the absolute measures of tumor volume determined by the treatment planning system after countering at the time of radiosurgery. T2-weighted MRI scans were carefully observed for any high signal perilesional edema. Following observations were summarized in the final report prepared by treating physician and radiologist: volume at the time of radiosurgery, volume in the follow-up images and their size comparison, extent of loss of central enhancement, extent of necrosis, comparison of extent of perilesional edema, any mid line shift and other radiologic features.

Clinical Outcome

Complete disappearance of pre-radiosurgical neurological symptom was observed in 8 patients (22.9%), partial disappearance of pre-radiosurgical neurological symptom was seen in 13 (37.1%) and pre-radiosurgical neurological symptoms were stable in 13(37.1%) patients. One (2.9%) patient had worsening of symptoms after 3.5 months of treatment, that was relieved by using glucocorticoids till 5 months after SRS (Table 3), but the imaging studies showed stable disease with out any findings of radiation adverse effects.

The visual problems, eye movements, and improvement in modified House Brackmann grading score of fascial nerve palsy was observed in most of the patients.

Acute & Late Radiation toxicity

All patients tolerated treatment very well. No acute adverse radiation effects were observed till 6 weeks. Radiation related late side effects at 6 months were also not found in any patient.

In this series, 6 (17.1%) patients died from unrelated causes. Two (5.7%) patients died of unknown causes. Tumor was controlled and no disease progression or treatment-related side effects were seen in any of these patients.

Clinical Improvement Radiation Tolerance

Tuniz et al [18], reported that 20.6 % of the patients were having any improvement in preradiosurgical neurological symptoms while 73.5 % patients were having no change. In their series two patients had facial spasm relieved in 4-6 weeks and two had persistent nausea and vomiting relieved in 6 months. Paravati et al [21], reported about the subgroup of 26 patients with benign lesions out of which 21 were symptomatic at the time of fSRS (fractionated sterotactic radiosurgery). They found complete recovery of preradiosurgical symptoms in 66.6 % of patients. While 33.3 % patients had partial recovery from their preradiosurgical symptoms. Kim et al [31], reported preservation of visual functions in 96 % of the patients after multisession gamma knife radiosurgery for benign perioptic lesions. In this series, they observed improvement in 31.81 % of visual acuity and / or visual field defects, 63.63 % had stable or no change in visual functions and about 4 % experienced deterioration of visual acuity and visual fields. In our study complete symptomatic response was found in 22.9% of patients and partial improvement in preradiosurgical symptoms was found in 37.1 % of the patients, while 37.1% patients were having no change. Only 2.9 % had transient worsening of symptoms. Overall symptomatic response was 97.1 % which is consistent with the studies mentioned above.

Paravati et al [21], documented only 2 patient having RTOG grade III reactions, no patient experienced grade IV reaction. 3 Patients experienced grade II and 8 patients experienced grade I side effects. Late effects were seen in 3 patients at a median of 9 months after SRS, their symptoms were resolved in median interval of 3.5 months. 3 other patients had fascial spasm at 3-6 months after SRS and resolved with in 2 months. These findings were observed in all the patients included in the study having benign as wel as malignant tumors.

Tuniz et al [18], reported 2 patients with fascial spasm at 4-6 months after radiosurgery, improved partially at 4-6 weeks with glucocorticoides. No new permanent neuropathy was observed. Two patients had subacute worsening in symptoms resolved at 6 months. Four patients had radiologic signs of radiation injury. These imaging changes observed at mean time of 6 months after radiosurgery. All above resolved at median time of 6 months after radiosurgery. In our study, we had only one patient with worsening of symptoms at 4 months after radiosurgery, have been taking glucocorticoides till 5 months then relieved and had no signs of radiation injury on imaging. We did not find any patient with fascial spasm. Late effects were not observed in any of the patient included in our series.

Tumor Control

Paravati et al [21], have shown >20% reduction in 34.6% of the patients and Tuniz et al [18], have reported >20% tumor size reduction in 41.66 % of the patients. Benign tumor overall control rate was 100% in both the series. Kim et al [31], reported tumor volume decrease in 77% of the patients and 18 % had stable size. Overall control rate was 95 %. Only 5 % were found to have progression in tumor growth. While in our study, >20% tumor size reduction has been seen in 25.7 % of the patients, remaining all patients were having stable tumor size. Overall tumor control rate was 100%, which is equivalent or better than the mentioned studies. Where as the incidence of >20 % tumor size reduction is slightly lower than other two studies [18, 21], we assume that it is because of short follow-up time in our study and long term follow-up may result in more shrinkage of tumor size. Median follow-up time in Paravati et al [21], study was 24.7 months (range: 0-58 months), Tuniz et al [18], study was 31 months (range: 12-77months) and Kim et al

[31], study was 29 months (range: 14-44 months). Where as in our study, median follow-up time was 6.4 months (range: 1-22.5 months).

Dose Selection & Fractionation

Iwata et al [20], used two types of fractionation schedules. 21 Gy (range:17-21 Gy) in 3 fraction and 25Gy (range:22-25Gy) in 5 fractions for large non functional pituitary adenomas with median tumor volume of 5.1 ml (range : 0.7-64.3 ml) and found both the regimens effective for tumor control and safe for optic apparatus and neuroendocrine functions. Tuniz et al [18], used 24 Gy (16-25 Gy) delivered in median of 3 fractions (range: 2-5 fractions) prescribed at median of 78 % isodose line (range: 67-83% isodose line) for the median tumor volume of 19.3cm³ (range; 15.8-69.3cm³). They also found these fractionation doses effective and safe. Paravati et al [21], used median marginal dose of 22 Gy (15-50 Gy) in median of 3 sessions (range: 1-5 sessions) for the median tumor volume of 9.63 cm³ (range: 0.64 – 103 cm³). Adler et al [11], used total marginal dose of 20.3 Gy (range: 15-30 Gy) at mean isodose line of 80% (rang:70-95%). 38.77% patients were treated in 5 fractions, 4.08% were treated in 4 fractins,34.69 % received 3 fractions, and 22.44 % patients were treated in 2 fraction. Kim et al [31], used cumulative median marginal dose of 20 Gy (range: 15-20 Gy), prescription isodose was 50%(range: 46-50%). 95.4 % patients were treated in 4 fraction with 12 hours interval in each session, only 4.5 % patients were treated in 3 fractions with 24 hours interval in each session. We used 25 Gy (range: 20-27.5 Gy) in median of 5 fractions (range: 3-5 fractions) prescribed at median of 75% isodose line (range: 65-100% isodose line) for the median tumor volume of 49.4 cm³ (range: 15-184cm³). Only three patients were treated in three fraction schedule which was carried out on alternate days. While remaining 32 patients were treated in 5 fractions with 24 hours interval in each fraction and the dose was varied in relation to volumes: larger the volumes, lower the total and per fraction doses.

Unrelated Deaths

Tuniz et al [18], reported two (5.88%) unrelated deaths in their study. Adler et al [11], reported 4.08 % unrelated death. While we experienced 8 (22.9%) deaths. Cause of death was known for 6 patients, and was not tumor related. Two patients died of chest infection (new event), two died of uncontrolled diabetes mellitus (known comorbid), one with chronic renal failure (known comorbid) and one with CSF leakage as surgical complication. It is important to take special care of comorbid conditions, monitoring of blood sugar and blood pressure particularly when patients are using glucocorticoides.

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