Efficacy of Dose-Escalated Hypofractionated Radiosurgery for Arteriovenous Malformations.

There is considerable controversy about the management of arteriovenous malformations (AVMs) that are high risk for surgical resection. Stereotactic radiosurgery (SRS) has a reported success rate of less than 50% with unacceptably high rates of radiation necrosis with larger AVM volumes. Neither volume staging nor hypo-fractionated SRS have conclusively been demonstrated to improve results. We hypothesized that the failure of previous hypo-fractionation SRS trials was due to an insufficient biologically effective dose (BED) of radiation. We initiated a pilot study of treating AVM patients with a total dose divided into three or five fractions designed to deliver the equivalent BED of 20 Gy in a single fraction (α/ß =3). We performed a retrospective analysis of 37 AVM patients who had a minimum of two years of follow-up or underwent obliteration. Patients were treated with 30 Gy/3 fractions, 33 Gy/3 fractions, or 40 Gy/5 fractions using a CyberKnife device (Accuracy Incorporated, Madison, Wisconsin, United States). The primary endpoint was complete AVM obliteration, determined by MRA imaging. Most obliterations were confirmed with diagnostic cerebral angiography. Secondary endpoints were post-radiosurgery hemorrhage and radiation-related necrosis. Kaplan-Meier analysis was used to determine obliteration rates. From 2013 to 2021, 37 patients fitting inclusion criteria were identified (62% male, average age at treatment = 48.88 years). Fifteen (41%) patients had prior treatment (surgery, radiosurgery, embolization) for their AVM, 32 (86%) had AVMs in eloquent locations, 17 (46%) had high-risk features, and 14 (38%) experienced AVM rupture prior to treatment. The average modified radiosurgery-based AVM score (mRBAS) was 1.81 (standard deviation (SD)= 0.52), and the mean AVM volume was 6.77 ccs (SD = 6.09). Complete AVM obliteration was achieved in 100% of patients after an average of 26.13 (SD = 14.62) months. The Kaplan-Meier analysis showed AVM obliteration rates at one, two, and three years to be 16.2%, 46.9%, and 81.1%, respectively. Post-operative AVM rupture or hemorrhage occurred in one (2.7%) patient, after nine months. Radiation necrosis occurred in four (11%) patients after an average period of 17.3 (SD =14.7) months. The SRS dose used in this study is the highest BED of any AVM hypofractionation trial in the published literature. This study suggests that dose-escalated hypofractionated radiosurgery can be a successful strategy for AVMs with acceptable long-term complication rates. Further investigation of this treatment regimen should be performed to assess its efficacy.

A Pilot Study of Hypofractionated Radiosurgery for Trigeminal Neuralgia.

The primary late toxicity of radiosurgery treatment for trigeminal neuralgia (TN) is facial numbness due to trigeminal nerve dysfunction. Although most patients prefer loss of facial sensation to TN, severe loss of facial sensation can be debilitating. In order to try to obtain high pain control rates while minimizing the risk of late facial numbness, we elected to treat patients on the distal trigeminal nerve with a three-fraction regimen over consecutive days instead of one fraction. Our goal was to relieve the pain while also allowing the trigeminal nerve time to repair radiation damage between treatments in an attempt to minimize the risk of permanent facial numbness. Patients in a pilot study, approved by an Institutional Review Board (IRB), received a treatment regimen of 99 Gy, administered in three consecutive daily fractions of 33 Gy each, with the dosage targeted to the 80% line. This dose was selected to approximate a biologically equivalent dose of 80 Gy maximal dose to the trigeminal nerve. Forty-eight patients were treated with CyberKnife Radiosurgery (CKRS; 99 Gy/3 fractions) for TN from 2016 to 2022, with at least one year of follow-up. The Barrow Neurological Institute (BNI) scale was used to assess facial pain, and Kaplan-Meier analysis was used to assess adequate pain relief. Thirty-eight (84%) patients experienced adequate pain relief, defined as a BNI score of I-IIIb, after a median of 1.5 months following CKRS. Treatment failure (BNI=IV-V) occurred in 12 (25%) patients after a median of 6 months following initial pain relief. The actuarial probability of pain relief at 6, 12, and 24 months post-CKRS were 87.4%, 83.7%, and 83.7%, respectively. Facial numbness was experienced in 24 (50%) cases after a median of 10 months following CKRS. Typical facial pain (p=0.034) and vascular compression (p=0.039) were the only predictors of better treatment outcomes using univariate Cox survival analysis, and vascular compression (p= 0.037) was the only predictor in multivariate Cox survival analysis. Hypofractionated treatment to the distal trigeminal nerve segment does not appear to offer an advantage in treating TN, due to similar rates of pain relief but with an unacceptably high rate of late facial numbness.

Salvage Radiosurgery for Recurrent Cardiac Sarcoma: A Case Report.

Primary cardiac sarcoma is a rare malignant tumor that arises from the cardiac myocardium. Surgical resection is the standard of care, and median survival ranges from 6 to 12 months. The role of salvage chemotherapy and radiation is not well defined. A 53-year-old female presented with acute congestive heart failure and underwent complete surgical resection of an undifferentiated pleomorphic sarcoma of the left atrium, followed by six cycles of adjuvant doxorubicin/hydroxydaunorubicin and ifosfamide. An MRI scan demonstrated an asymptomatic, 24 mm, recurrent atrial mass. The patient was treated with frameless robotic radiation therapy over three weeks. The tumor was treated with a dose of 72 Gy in 15 fractions to the 84% isodose line. A repeat cardiac MRI at four weeks showed in-field local progression with greater protrusion into the left atrium and invasion of the left ventricle. The patient therefore elected to proceed with salvage single-fraction frameless robotic radiosurgery. 25 Gy in one fraction was prescribed to the 76% isodose line. She tolerated treatment well without any acute toxicity and was subsequently treated with a variety of chemotherapy regimens, including tyrosine kinase inhibitors (TKIs) and immunotherapy. Unfortunately, the patient relapsed with metastases in the spine and pelvis. She underwent palliative radiation therapy at multiple bony sites with a partial response. She resumed chemotherapy treatment with TKIs but passed away due to septic shock without evidence of local failure. Fractionated SBRT was ineffective at controlling our patient's cardiac sarcoma. Our patient demonstrated local control of disease at 12 months after salvage of 25 Gy in one fraction of radiosurgery without any evidence of cardiac toxicity. High-dose single-fraction radiosurgery is a reasonable palliative option for long-term local control of unresectable cardiac sarcomas.

Concurrent Radiation and Targeted Therapy for Papillary Craniopharyngioma: A Case Report.

Craniopharyngiomas are rare epithelial malformations in the sellar or suprasellar regions of the craniopharyngeal ducts. Complete surgical resection is difficult due to the location of the base of the skull and the risk of injury to vital neurological structures. Fractionated radiation is effective in controlling residual tumors, but craniopharyngiomas can progress during treatment. The papillary subtype is driven by BRAF V600E mutations. Treatment with BRAF and MEK inhibitors alone has a response rate of 90% but a median progression-free survival of only 12 months. A 57-year-old female presented in May 2017 with complaints of headaches and blurriness in her right eye. Brain MRI demonstrated a 2 cm suprasellar mass engulfing the right optic nerve and optic chiasm. The patient underwent a transsphenoidal hypophysectomy with pathology consistent with a benign pituitary adenoma. Follow-up imaging in August, however, showed recurrence, and a re-resection was performed which surprisingly demonstrated papillary craniopharyngioma. Due to subtotal resection, the patient elected to proceed with intensity-modulated radiation therapy (IMRT) to the tumor bed in April of 2018 with an intended dose of 5400 cGy. After treatment with 2160 cGy in 12 fractions, the patient experienced visual deterioration and progression of the cystic tumor. The patient underwent another debulking procedure but due to rapid recurrence, an endoscopic transsphenoidal fenestration was performed. On postoperative imaging, a cystic mass was still engulfing the right optic nerve and chiasm. Due to the extended break and limited radiation tolerance of the optic chiasm, we elected to re-treat the tumor with an additional 3780 cGy IMRT in conjunction with one cycle of Taflinar and Mekinist, which was completed in August 2018. The cumulative dose to the optic chiasm was 5940 cGy.The patient had an excellent clinical response to treatment with the improvement of vision in her right eye. A brain MRI on 3/29/2019 demonstrated no residual craniopharyngioma. Four-year follow-on CT scan showed no evidence of tumor recurrence. The patient had preservation of vision and did not suffer any late neurological toxicity or new endocrine deficiency. Surgical resection and radiation were ineffective at treating our patient's craniopharyngioma due to rapid cystic progression. This is the first case report in the literature detailing concurrent radiation therapy with BRAF and MEK inhibitors for papillary craniopharyngioma. Despite a suboptimal dose of radiation, our patient had no tumor recurrence and no late toxicity four years after treatment. This represents a potentially novel treatment strategy in this challenging entity.

Feasibility evaluation of novel AI-based deep-learning contouring algorithm for radiotherapy.

PURPOSE: To evaluate the clinical feasibility of the Siemens Healthineers AI-Rad Companion Organs RT VA30A (Organs-RT) auto-contouring algorithm for organs at risk (OARs) of the pelvis, thorax, and head and neck (H&N). METHODS: Computed tomography (CT) datasets from 30 patients (10 pelvis, 10 thorax, and 10 H&N) were collected. Four sets of OARs were generated on each scan, one set by Organs-RT and the others by three experienced users independently. A physician (expert) then evaluated each contour by assigning a score from the following scale: 1-Must Redo, 2-Major Edits, 3-Minor Edits, 4-Clinically usable. Using the highest-scored OAR from the human users as a reference, the contours generated by Organs-RT were evaluated via Dice Similarity Coefficient (DSC), Hausdorff Distance (HDD), Mean Distance to Agreement (mDTA), Volume comparison, and visual inspection. Additionally, each human user recorded the time to delineate each structure set and time-saving efficiency was measured. RESULTS: The average DSC obtained for the pelvic OARs ranged between (0.81 ± 0.06)Rectum and (0.94 ± 0.03)Bladder . (0.75 ± 0.09)Esophagus to ( 0.96 ± 0.02 ) Rt . Lung ${( {0.96 \pm 0.02} )}_{{\mathrm{Rt}}.{\mathrm{\ Lung}}}$ for the thoracic OARs and (0.66 ± 0.07)Lips to (0.83 ± 0.04)Brainstem for the H&N. The average HDD in cm for the pelvis cohort ranged between (0.95 ± 0.35)Bladder to (3.62 ± 2.50)Rectum , (0.42 ± 0.06)SpinalCord to (2.09 ± 2.00)Esophagus for the thoracic set and ( 0.53 ± 0.22 ) Cerv _ SpinalCord ${( {0.53 \pm 0.22} )}_{{\mathrm{Cerv}}\_{\mathrm{SpinalCord}}}$ to (1.50 ± 0.50)Mandible for the H&N region. The time-saving efficiency was 67% for H&N, 83% for pelvis, and 84% for thorax. 72.5%, 82%, and 50% of the pelvis, thorax, and H&N OARs were scored as clinically usable by the expert, respectively. CONCLUSIONS: The highest agreement registered between OARs generated by Organs-RT and their respective references was for the bladder, heart, lungs, and femoral heads, with an overall DSC≥0.92. The poorest agreement was for the rectum, esophagus, and lips, with an overall DSC⩽0.81. Nonetheless, Organs-RT serves as a reliable auto-contouring tool by minimizing overall contouring time and increasing time-saving efficiency in radiotherapy treatment planning.

Adult patients with supratentorial pilocytic astrocytoma: long-term follow-up of prospective multicenter clinical trial NCCTG-867251 (Alliance).

BACKGROUND: Pilocytic astrocytoma is a rare tumor in adults. This report is of a prospective clinical trial with long-term follow-up. METHODS: Between 1986 and 1994, 20 eligible adults with supratentorial pilocytic astrocytomas were enrolled in a prospective intergroup trial of radiotherapy (RT) after biopsy (3 patients) or observation after gross (11 patients) or subtotal (6 patients) resection. RESULTS: At the time of analysis (median follow-up, 20.8 years), 2 patients (10%) have died and 18 patients (90%) are alive. Neurologic and cognitive function were stable or improved over time for the majority of patients. No toxic effects of treatment or malignant transformations have been recorded at last follow-up. For the entire cohort the 20-year time to progression and overall survival rates are 95% and 90% respectively. The cause of death (2.2 and 16.1 years after enrollment) in both patients was unrelated to tumor although both were biopsy-only patients. One subtotally resected tumor progressed 1 month after enrollment requiring P32 injection into an enlarging cyst. Because of further progression this patient required RT 18 months later. This patient is alive without evidence of progression 18 years after RT. CONCLUSION: The long-term follow-up results of this prospective trial confirm that adults with pilocytic astrocytomas have a favorable prognosis with regard to survival and neurologic function. Close observation is recommended for adults with pilocytic astrocytomas, reserving RT for salvage, as the majority remain stable after gross or subtotal resection and no adjuvant therapy.

A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320.

BACKGROUND: A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the blood-brain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS. METHODS AND MATERIALS: NSCLC patients with 1 to 3 brain metastases were randomized to receive WBRT (2.5 Gy × 15 to 37.5 Gy) and SRS alone, versus WBRT + SRS + TMZ (75 mg/m(2)/day × 21 days) or ETN (150 mg/day). ETN (150 mg/day) or TMZ (150-200 mg/m(2)/day × 5 days/month) could be continued for as long as 6 months after WBRT + SRS. The primary endpoint was OS. RESULTS: After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively), although the differences were not statistically significant. Time to central nervous system progression and performance status at 6 months were better in the WBRT + SRS arm. Grade 3 to 5 toxicity was 11%, 41%, and 49% in arms 1, 2, and 3, respectively (P<.001). CONCLUSION: The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms.