Among the study population, 4 patients were male and 3 were female. The cohort mean age at the time of ICSRT was 40.8 years (range, 32.3–52.5 y). The mean fractionated radiation dose to the posterior fossa was 44.2 Gy (range, 43.2–45.0 Gy). One patient received a stereotactic radiosurgery treatment of 22 Gy to a single dominant cerebellar lesion 12.4 months prior to treatment with ICSRT, whereas no other study patients received any additional radiation therapy prior to or after undergoing ICSRT. The mean fractionated dose to the spine was 44.1 Gy (range, 37.5–51.6 Gy). The initial target volumes for both the posterior fossa and the spine were treated without field modifications or tumor volume reductions, and therefore most patients had radiation administered to 43.2 Gy in 24 fractions over 4.8 weeks.
Number of Lesions and Tumor Volumes
Among all patients, there were a total of 84 hemangioblastomas prior to ICSRT (Table ). Lesions were solid (n = 72) or cystic (n = 12). Patients had an average of 4.1 tumors in the cerebellum (range, 1–10) and 7.9 tumors in the spine and brainstem (range, 4–16). The mean pre-ICSRT patient tumor volume was 3.59 cm3 (range, 0.02–22.15 cm3) for cerebellar tumors and 1.90 cm3 (range, 0.13–4.16 cm3) for spine and brainstem tumors, for a mean total tumor volume of 5.48 cm3 (range, 0.19–26.31 cm3) among all study patients.
Number and volume of hemangioblastomas before and after ICSRT
When assessing the treatment response for the cohort within the first year following ICSRT, overall tumor volume stability of spine and brainstem lesions were noted. Surveillance imaging performed at a mean of 6.4 months following ICSRT showed that the mean tumor volume had increased 1.7% to 1.93 cm3 (range 0.09–4.31 cm3). This mean tumor volume decreased to 1.3% below the pre-ICSRT mean tumor volume at 12 months. Surveillance imaging was performed at a mean of 12.6 months following radiotherapy (1.87 cm3, range 0.09–4.39 cm3). The mean tumor volume for cerebellar tumors had increased 25.1% at 6 months surveillance (4.49 cm3, range 0.02–28.48 cm3) and 28.5% above the pre-ICSRT baseline at 12 months surveillance (4.61 cm3, range 0.01–29.11 cm3). This increase in tumor volume, however, was attributable largely to a single patient with very rapid cerebellar tumor volume growth just prior to beginning radiotherapy who experienced continued rapid growth in the first year following ICSRT.
At a mean follow-up of 73.8 months (range 40.3–155.6 months) after the completion of ICSRT, 91 total hemangioblastomas were identified among the study population, for an 8.3% increase in the number of lesions. The mean number of tumors following ICSRT remained constant in the cerebellum (4.1, range 0–9) and increased in the spine and brainstem to 8.9 (range 3–16). The mean post-ICSRT tumor volume increased 36.6% to 4.90 cm3 (range 0.00–30.53 cm3) for all cerebellar lesions but remained largely stable for spine and brainstem lesions (1.97 cm3, range 0.11–4.58 cm3, +3.8%). The mean total tumor volume for the cohort increased 25.3% to 6.87 cm3 (range 0.11–35.11 cm3).
Complete radiographic resolution was achieved in 17.9% of hemangioblastomas identified on MR imaging immediately prior to ICSRT (Fig. ). Among previously identified lesions, 9 spine and brainstem tumors and 6 cerebellar tumors resolved, with 7 (46.7%) of these lesions resolving within the first 6 months following ICSRT and the majority (66.7%) resolving within 13 months of radiation. Only 2 tumors (13.3%) resolved more than 2.5 years after ICSRT. On surveillance imaging, 22 new lesions were identified among the cohort, with 16 new spine and brainstem lesions and 6 new cerebellar tumors.
Fig. 2. New and resolved hemangioblastomas following ICSRT. The number of lesions that have resolved are shown by bars to the left of the middle and the number of lesions that are new are to the right of the middle. Although some patients had more new than resolved (more ...)
In total, 23.9% (20/84) of hemangioblastomas identified on neuroimaging immediately prior to ICSRT were shown to have regressed following radiotherapy and remained at <50% of their original tumor volume on the most recent surveillance neuroimaging. Lesions present at initial presentation that completely resolved or remained at <50% of their original tumor volume were somewhat more likely to be solid than cystic (26.4% vs. 8.3%, P = .18), although this difference was not statistically significant. All but one lesion that showed regression were initially noted to be less than 1 cm in maximum diameter, which may be a potential threshold for treatment. Conversely, 25.0% (21/84) of lesions progressed or had an increase in volume by >50% following the completion of ICSRT. Lesions that progressed were significantly more likely to be cystic (50.0% vs. 20.8%, P = .03). The remaining 51.2% (43/84) exhibited prolonged size and volume stability following ICSRT.
Prior to ICSRT, study patients required a total of 33 separate surgical procedures to remove 47 CNS hemangioblastomas (Fig. ). In the 73.8 months prior to ICSRT, 17 surgical procedures to remove 28 lesions were performed, and during the mean follow-up of 73.8 months after radiation, only 4 surgical procedures among the cohort were performed to resect 8 symptomatic or progressive lesions.
Fig. 3. Surgical interventions before and after ICSRT. The number of surgeries is depicted by a set of 3 bars for each patient: the first being the total number of surgeries the patient had before ICSRT, the second the number of surgeries in the mean of 89.2 (more ...)
Neurologic Signs and Symptoms
Three patients were maintained on steroid therapy prior to beginning ICSRT and all patients reported neurologic symptoms and had positive neurologic signs on physical examination prior to receiving radiotherapy. On examination, motor findings included upper extremity motor weakness (N = 3), lower extremity motor weakness (N = 3), and difficulty with ambulation (N = 4). Sensory signs and symptoms included upper extremity paresthesias or decreased sensation (N = 4), lower extremity paresthesias, decreased proprioception or decreased sensation to touch (N = 5), sustained upper extremity tremors, decreased fine motor coordination, or decreased control of range of motion (N = 3), and sustained lower extremity clonus, tremors, spasms, or decreased control of range of motion (N = 4). Patients reported pain in their necks (N = 1) and backs with or without lower extremity radiation (N = 4). Visual and hearing examinations revealed decreased visual acuity (N = 2), nystagmus or strabismus (N = 2), and hearing loss (N = 2). Patients also experienced dizziness or lightheadedness (N = 1) and nausea and emesis (N = 1).
Following ICSRT, 2 patients were successfully weaned off of steroids within 2 week and 3 months, respectively, of radiotherapy completion. Steroid administration was not started during ICSRT for any patient. One patient reported a significant improvement in lower back pain and lower extremity paresthesias following ICSRT. He was also found to have resolution of previously identified proximal lower extremity motor weakness. Signs and symptoms directly attributable to CNS hemangioblastomas exhibited prolonged stabilization in 4 patients, with 1 of these patients also having decreased back pain and decreased analgesic dependence. One patient, however, has become largely wheelchair dependent and has had increased back pain and difficulty with balance since receiving radiation therapy. His post-ICSRT course has been complicated by the diagnosis of bilateral renal cell carcinomas requiring multiple surgical procedures. One patient reported a mild increase in intermittent lower back pain with radiation into the right lower extremity that became clinically significant nearly 10 years after completing ICSRT.
Three patients in this cohort, who suffered from VHL-associated pancreatic and renal neoplasms, died from progressive VHL disease that was not directly attributable to CNS hemangioblastomas. Patients died at a mean of 3.0 years following ICSRT (range, 0.3–5.4 years). For the entire cohort, the estimated OS was 85.7% at 2 years, 71.4% at 5 years, and 57.1% at 7 years.
ICSRT was well tolerated among the study population. Three patients developed grade ≥2 acute toxicity following the criteria of the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC), and no patient developed acute hematologic toxicity. Acute toxicities included skin erythema (grade 1 in 2 patients, grade 2 in 1), esophagitis (grade 1 in 2, grade 3 in 1), and gastrointestinal (grade 1 abdominal discomfort in one, grade 2 nausea/emesis in two). Furthermore, no patient developed subacute radiation-induced toxicity or grade ≥1 RTOG/EORTC late toxicity of the spinal cord or brain.