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Jason P. Sheehan, Douglas Kondziolka, John Flickinger, and L. Dade Lunsford

Object. Nonfunctioning pituitary adenomas comprise approximately 30% of all pituitary tumors. The purpose of this retrospective study is to evaluate the efficacy and role of gamma knife radiosurgery (GKS) in the management of residual or recurrent nonfunctioning pituitary adenomas.

Methods. A review was conducted of the data obtained in 42 patients who underwent adjuvant GKS at the University of Pittsburgh between 1987 and 2001. Prior treatments included transsphenoidal resection, craniotomy and resection, or conventional radiotherapy. Endocrinological, ophthalmological, and radiological responses were evaluated. The duration of follow-up review varied from 6 to 102 months (mean 31.2 months). Fifteen patients were observed for more than 40 months. The mean radiation dose to the tumor margin was 16 Gy. Conformal radiosurgery planning was used to restrict the dose to the optic nerve and chiasm.

Tumor control after GKS was achieved in 100% of patients with microadenomas and 97% of patients with macroadenomas. Gamma knife radiosurgery was equally effective in controlling adenomas with cavernous sinus invasion and suprasellar extension. No patient developed a new endocrinological deficiency following GKS. One patient's tumor enlarged with an associated decline in visual function. Another patient experienced a deterioration of visual fields despite a decrease in tumor size.

Conclusions. Gamma knife radiosurgery can achieve tumor control in virtually all residual or recurrent nonfunctioning pituitary adenomas. Dose sparing facilitates tumor management even when the adenoma is close to the optic apparatus or invades the cavernous sinus.

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Mohamed Elsharkawy, Zhiyuan Xu, David Schlesinger, and Jason P. Sheehan

Object

Most intracranial schwannomas arise from cranial nerve (CN) VIII. Stereotactic radiosurgery is a mainstay of treatment for vestibular schwannomas. Intracranial schwannomas arising from other CNs are much less common. We evaluate the efficacy of Gamma Knife surgery on nonvestibular schwannomas including trigeminal, hypoglossal, abducent, facial, trochlear, oculomotor, glossopharyngeal, and jugular foramen tumors.

Methods

Thirty-six patients with nonvestibular schwannomas were treated at the University of Virginia Gamma Knife center from 1989 to 2008. The median patient age was 48 years (mean 45.6 years, range 10–72 years). Schwannomas arose from the following CNs: CN III (in 1 patient), CN IV (in 1), CN V (in 25), CN VI (in 2), CN VII (in 1), CN IX (in 1), and CN XII (in 3). In 2 patients, tumors arose from the jugular foramen. The median tumor volume was 2.9 cm3 (mean 3.3 cm3, range 0.07–8.8 cm3). The median margin dose was 13.5 Gy (range 9.3–20 Gy); the median maximum dose was 30 Gy (range 21.7–50.0 Gy).

Results

The mean and median follow-up times of 36 patients were 54 and 37 months, respectively (range 2–180 months). At the last radiological follow-up, the tumor size had decreased in 20 patients, remained stable in 9 patients, and increased in 7 patients. The 2-year actuarial progression-free survival was 91%. Higher maximum dose was statistically related to tumor control (p = 0.027).

Thirty-three patients had adequate clinical follow-up. Among them, 21 patients had improvement in their presenting symptoms, 8 patients were stable after treatment with no worsening of their presenting symptoms, 2 patients developed new symptoms, and 1 patient experienced symptom deterioration. Notably, 1 patient with neurofibromatosis Type 2 developed new symptoms that were unrelated to the tumor treated with Gamma Knife surgery.

Conclusions

Gamma Knife surgery is a reasonably effective treatment option for patients with nonvestibular schwannomas. Patients require careful follow-up for tumor progression and signs of neurological deterioration.

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John L. Gainer, Jason P. Sheehan, James M. Larner, and David R. Jones

OBJECTIVE

A new drug, trans sodium crocetinate (TSC), has been developed to enhance the delivery of oxygen to hypoxic tissues. Cancerous tumors, such as glioblastoma multiforme (GBM), are very hypoxic, and it has been suggested that radiation therapy (RT) is more beneficial if tumors are better oxygenated. A Phase I/II clinical trial was conducted to determine the effect of adding TSC to RT sessions.

METHODS

An open, single-arm clinical trial incorporating the standard of care (SOC) for GBM was conducted at 18 clinical sites. There were 6 weeks of RT consisting of 2 Gy/day for 5 days/week, beginning after an initial resection or stereotactic biopsy to confirm GBM. Temozolomide (TMZ), 75 mg/m2, was given before each RT session. The TSC, 0.25 mg/kg, was intravenously administered around 45 minutes before an RT session 3 days/week, usually on Monday, Wednesday, and Friday.

A Phase I run-in period included 2 cohorts. The first cohort contained 3 patients who were given a half dose of the intravenous TSC (that is, 0.25 mg/kg, 3 times per week for only the first 3 weeks of RT). After a Safety Monitoring Committee (SMC) had verified that no dose-limiting toxicity (DLT) had occurred, a second cohort of 6 patients was given the same dosage of TSC but for the full 6 weeks of RT. After the SMC verified that no DLTs had occurred, Phase II began, with the administration of the full 18 doses of TSC. Fifty additional patients were enrolled during Phase II.

Following the completion of RT, the patients rested for a month. After that, SOC TMZ chemotherapy (150–200 mg/m2) was administered for 5 days of the 1st week of 6 monthly cycles. No TSC was administered during this chemotherapy phase or later in the trial. Any other follow-up therapies were administered at the discretion of the individual investigators.

RESULTS

Kaplan-Meier analysis showed that 36% of the full-dose TSC patients were alive at 2 years, compared with historical survival values ranging from 27% to 30% for the SOC. Survival for the biopsy-only subset of patients was 40%, as compared with 42.9% for those patients having a complete resection before treatment. In addition, 2 of the 3 Phase I, Cohort 1 patients survived at 2 years. Contrast MRI data suggested that considerable pseudoprogression had occurred. Both Karnofsky Performance Status (KPS) scores and quality of life (QOL) questionnaires indicated that a good quality of life existed for most patients throughout the trial. No serious adverse events occurring in the trial were attributed to TSC.

CONCLUSIONS

This trial contained a single arm consisting of 59 patients. The results strongly suggested that adding TSC during RT is beneficial for the treatment of GBM. Trans sodium crocetinate offers a novel, easily implemented way to combat hypoxia in tumor tissue.

Clinical trial registration no.: NCT01465347 (clinicaltrials.gov)

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Mohana Rao Patibandla, Cheng-chia Lee, Athreya Tata, Gokul Chowdary Addagada, and Jason P. Sheehan

OBJECTIVE

Research over the past 2 decades has been characterizing the role of stereotactic radiosurgery (SRS) in the treatment of benign intracranial tumors, including meningiomas. However, few studies have examined the long-term outcomes of SRS treatment for posterior fossa meningiomas (PFMs). Furthermore, previous studies have typically used single diameter measurements when reporting outcomes, which can yield misleading results. The authors describe the use of SRS in the treatment of benign WHO grade I PFMs and correlate volumetric analysis with long-term outcomes.

METHODS

This study is a retrospective analysis of a prospectively maintained IRB-approved database. Inclusion criteria were a diagnosis of WHO grade I PFM with subsequent treatment via single-session SRS and a minimum of 3 follow-up MRI studies available. Volumetric analysis was performed on the radiosurgical scan and each subsequently available follow-up scan by using slice-by-slice area calculations of the meningioma and numerical integration with the trapezoid rule.

RESULTS

The final cohort consisted of 120 patients, 76.6% (92) of whom were female, with a median age of 61 years (12–88 years). Stereotactic radiosurgery was the primary treatment for 65% (78) of the patients, whereas 28.3% (34) had 1 resection before SRS treatment and 6.7% (8) had 2 or more resections before SRS. One patient had prior radiotherapy. Tumor characteristics included a median volume of 4.0 cm3 (0.4–40.9 cm3) at treatment with a median margin dose of 15 Gy (8–20 Gy). The median clinical and imaging follow-ups were 79.5 (15–224) and 72 (6–213) months, respectively. For patients treated with a margin dose ≥ 16 Gy, actuarial progression-free survival rates during the period 2–10 years post-SRS were 100%. In patients treated with a margin dose of 13–15 Gy, the actuarial progression-free survival rates at 2, 4, 6, 8, and 10 years were 97.5%, 97.5%, 93.4%, 93.4%, and 93.4%, respectively. Those who were treated with ≤ 12 Gy had actuarial progression-free survival rates of 95.8%, 82.9%, 73.2%, 56.9%, and 56.9% at 2, 4, 6, 8, and 10 years, respectively. The overall tumor control rate was 89.2% (107 patients). Post-SRS improvement in neurological symptoms occurred in 23.3% (28 patients), whereas symptoms were stable in 70.8% (85 patients) and worsened in 5.8% (7 patients). Volumetric analysis demonstrated that a change in tumor volume at 3 years after SRS reliably predicted a volumetric change and tumor control at 5 years (R2 = 0.756) with a p < 0.001 and at 10 years (R2 = 0.421) with a p = 0.001. The authors also noted that the 1- to 5-year tumor response is predictive of the 5- to 10-year tumor response (R2 = 0.636, p < 0.001).

CONCLUSIONS

Stereotactic radiosurgery, as an either upfront or adjuvant treatment, is a durable therapeutic option for WHO grade I PFMs, with high tumor control and a low incidence of post-SRS neurological deficits compared with those obtained using alternate treatment modalities. Lesion volumetric response at the short-term follow-up of 3 years is predictive of the long-term response at 5 and 10 years.

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Dale Ding, Zhiyuan Xu, Ian T. McNeill, Chun-Po Yen, and Jason P. Sheehan

Object

Parasagittal and parafalcine (PSPF) meningiomas represent the second most common location for intracranial meningiomas. Involvement of the superior sagittal sinus or deep draining veins may prevent gross-total resection of these tumors without significant morbidity. The authors review their results for treatment of PSPF meningiomas with radiosurgery.

Methods

The authors retrospectively reviewed the institutional review board–approved University of Virginia Gamma Knife database and identified 65 patients with 90 WHO Grade I parasagittal (59%) and parafalcine (41%) meningiomas who had a mean MRI follow-up of 56.6 months. The patients' mean age was 57 years, the median preradiosurgery Karnofsky Performance Status score was 80, and the median initial tumor and treatment volumes were 3 and 3.7 cm3, respectively. The median prescription dose was 15 Gy, isodose line was 40%, and the number of isocenters was 5. Kaplan-Meier analysis was used to determine progression-free survival (PFS). Univariate and multivariate Cox regression analyses were used to identify factors associated with PFS.

Results

The median overall PFS was 75.6 months. The actuarial tumor control rate was 85% at 3 years and 70% at 5 years. Parasagittal location, no prior resection, and younger age were found to be independent predictors of tumor PFS. For the 49 patients with clinical follow-up (mean 70.8 months), the median postradiosurgery Karnofsky Performance Status score was 90. Symptomatic postradiosurgery peritumoral edema was observed in 4 patients (8.2%); this group comprised 3 patients (6.1%) with temporary and 1 patient (2%) with permanent clinical sequelae. Two patients (4.1%) died of tumor progression.

Conclusions

Radiosurgery offers a minimally invasive treatment option for PSPF meningiomas, with a good tumor control rate and an acceptable complication rate comparable to most surgical series.

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Robert M. Starke, Chun-Po Yen, Dale Ding, and Jason P. Sheehan

Object

The authors performed a study to review outcomes following Gamma Knife radiosurgery for cerebral arteriovenous malformations (AVMs) and to create a practical scale to predict long-term outcome.

Methods

Outcomes were reviewed in 1012 patients who were followed up for more than 2 years. Favorable outcome was defined as AVM obliteration and no posttreatment hemorrhage or permanent, symptomatic, radiation-induced complication. Preradiosurgery patient and AVM characteristics predictive of outcome in multivariate analysis were weighted according to their odds ratios to create the Virginia Radiosurgery AVM Scale.

Results

The mean follow-up time was 8 years (range 2–20 years). Arteriovenous malformation obliteration occurred in 69% of patients. Postradiosurgery hemorrhage occurred in 88 patients, for a yearly incidence of 1.14%. Radiation-induced changes occurred in 387 patients (38.2%), symptoms in 100 (9.9%), and permanent deficits in 21 (2.1%). Favorable outcome was achieved in 649 patients (64.1%). The Virginia Radiosurgery AVM Scale was created such that patients were assigned 1 point each for having an AVM volume of 2–4 cm3, eloquent AVM location, or a history of hemorrhage, and 2 points for having an AVM volume greater than 4 cm3. Eighty percent of patients who had a score of 0–1 points had a favorable outcome, as did 70% who had a score of 2 points and 45% who had a score of 3–4 points. The Virginia Radiosurgery AVM Scale was still predictive of outcome after controlling for predictive Gamma Knife radiosurgery treatment parameters, including peripheral dose and number of isocenters, in a multivariate analysis. The Spetzler-Martin grading scale and the Radiosurgery-Based Grading Scale predicted favorable outcome, but the Virginia Radiosurgery AVM Scale provided the best assessment.

Conclusions

Gamma Knife radiosurgery can be used to achieve long-term AVM obliteration and neurological preservation in a predictable fashion based on patient and AVM characteristics.

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Or Cohen-Inbar, Athreya Tata, Shayan Moosa, Cheng-chia Lee, and Jason P. Sheehan

OBJECTIVE

Parasellar meningiomas tend to invade the suprasellar, cavernous sinus, and petroclival regions, encroaching on adjacent neurovascular structures. As such, they prove difficult to safely and completely resect. Stereotactic radiosurgery (SRS) has played a central role in the treatment of parasellar meningiomas. Evaluation of tumor control rates at this location using simplified single-dimension measurements may prove misleading. The authors report the influence of SRS treatment parameters and the timing and volumetric changes of benign WHO Grade I parasellar meningiomas after SRS on long-term outcome.

METHODS

Patients with WHO Grade I parasellar meningiomas treated with single-session SRS and a minimum of 6 months of follow-up were selected. A total of 189 patients (22.2% males, n = 42) form the cohort. The median patient age was 54 years (range 19–88 years). SRS was performed as a primary upfront treatment for 44.4% (n = 84) of patients. Most (41.8%, n = 79) patients had undergone 1 resection prior to SRS. The median tumor volume at the time of SRS was 5.6 cm3 (0.2–54.8 cm3). The median margin dose was 14 Gy (range 5–35 Gy). The volumes of the parasellar meningioma were determined on follow-up scans, computed by segmenting the meningioma on a slice-by-slice basis with numerical integration using the trapezoidal rule.

RESULTS

The median follow-up was 71 months (range 6–298 months). Tumor volume control was achieved in 91.5% (n = 173). Tumor progression was documented in 8.5% (n = 16), equally divided among infield recurrences (4.2%, n = 8) and out-of-field recurrences (4.2%, n = 8). Post-SRS, new or worsening CN deficits were observed in 54 instances, of which 19 involved trigeminal nerve dysfunction and were 18 related to optic nerve dysfunction. Of these, 90.7% (n = 49) were due to tumor progression and only 9.3% (n = 5) were attributable to SRS. Overall, this translates to a 2.64% (n = 5/189) incidence of direct SRS-related complications. These patients were treated with repeat SRS (6.3%, n = 12), repeat resection (2.1%, n = 4), or both (3.2%, n = 6). For patients treated with a margin dose ≥ 16 Gy, the 2-, 4-, 6-, 8-, 10-, 12-, and 15-year actuarial progression-free survival rates are 100%, 100%, 95.7%, 95.7%, 95.7%, 95.7%, and 95.7%, respectively. Patients treated with a margin dose < 16 Gy, had 2-, 4-, 6-, 8-, 10-, 12-, and 15-year actuarial progression-free survival rates of 99.4%, 97.7%, 95.1%, 88.1%, 82.1%, 79.4%, and 79.4%, respectively. This difference was deemed statistically significant (p = 0.043). Reviewing the volumetric patient-specific measurements, the early follow-up volumetric measurements (at the 3-year follow-up) reliably predicted long-term volume changes and tumor volume control (at the 10-year follow-up) (p = 0.029).

CONCLUSIONS

SRS is a durable and minimally invasive treatment modality for benign parasellar meningiomas. SRS offers high rates of growth control with a low incidence of neurological deficits compared with other treatment modalities for meningiomas in this region. Volumetric regression or stability during short-term follow-up of 3 years after SRS was shown to be predictive of long-term tumor control.

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Jason P. Sheehan, Ming-Hsi Sun, Douglas Kondziolka, John Flickinger, and L. Dade Lunsford

Object. Renal cell carcinoma is a leading cause of death from cancer and its incidence is increasing. In many patients with renal cell cancer, metastasis to the brain develops at some time during the course of the disease. Corticosteroid therapy, radiotherapy, and resection have been the mainstays of treatment. Nonetheless, the median survival in patients with renal cell carcinoma metastasis is approximately 3 to 6 months. In this study the authors examined the efficacy of gamma knife surgery in treating renal cell carcinoma metastases to the brain and evaluated factors affecting long-term survival.

Methods. The authors conducted a retrospective review of 69 patients undergoing stereotactic radiosurgery for a total of 146 renal cell cancer metastases. Clinical and radiographic data encompassing a 14-year treatment interval were collected. Multivariate analyses were used to determine significant prognostic factors influencing survival.

The overall median length of survival was 15 months (range 1–65 months) from the diagnosis of brain metastasis. After radiosurgery, the median survival was 13 months in patients without and 5 months in those with active extracranial disease. In a multivariate analysis, factors significantly affecting the rate of survival included the following: 1) younger patient age (p = 0.0076); 2) preoperative Karnofsky Performance Scale score (p = 0.0012); 3) time from initial cancer diagnosis to brain metastasis diagnosis (p = 0.0017); 4) treatment dose to the tumor margin (p = 0.0252); 5) maximal treatment dose (p = 0.0127); and 6) treatment isodose (p = 0.0354). Prior tumor resection, chemotherapy, immunotherapy, or whole-brain radiation therapy did not correlate with extended survival.

Postradiosurgical imaging of the brain demonstrated that 63% of the metastases had decreased, 33% remained stable, and 4% eventually increased in size. Two patients (2.9%) later underwent a craniotomy and resection for a tumor refractory to radiosurgery or a new symptomatic metastasis. Eighty-three percent of patients died of progression of extracranial disease.

Conclusions. Stereotactic radiosurgery for treatment of renal cell carcinoma metastases to the brain provides effective local tumor control in approximately 96% of patients and a median length of survival of 15 months. Early detection of brain metastases, aggressive treatment of systemic disease, and a therapeutic strategy including radiosurgery can offer patients an extended survival.

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Jason P. Sheehan, Zhiyuan Xu, David J. Salvetti, Paul J. Schmitt, and Mary Lee Vance

Object

Cushing's disease is a challenging neuroendocrine disorder. Although resection remains the primary treatment option for most patients, the disease persists if there is residual or recurrent tumor. Stereotactic radiosurgery has been used to treat patients with persistent Cushing's disease after a prior resection. The authors report on the long-term risks and benefits of radiosurgery for Cushing's disease.

Methods

A retrospective review of a prospectively collected database of radiosurgery patients was undertaken at the University of Virginia. All patients with Cushing's disease treated with Gamma Knife surgery (GKS) were identified. Those without at least 12 months of clinical and radiological follow-up were excluded from this analysis. Rates of endocrine remission, tumor control, and adverse events were assessed. Statistical methods were used to identify favorable and unfavorable prognostic factors.

Results

Ninety-six patients with the required follow-up data were identified. The mean tumor margin dose was 22 Gy. The median follow-up was 48 months (range 12–209.8 months). At the last follow-up, remission of Cushing's disease occurred in 70% of patients. The median time to remission among all patients was 16.6 months (range 1–165.7 months). The median time to remission in those who had temporarily stopped taking ketoconazole at the time of GKS was 12.6 months, whereas it was 21.8 months in those who continued to receive ketoconazole (p < 0.012). Tumor control was achieved in 98% of patients. New loss of pituitary function occurred in 36% of patients. New or worsening cranial neuropathies developed in 5 patients after GKS, with the most common involving cranial nerves II and III.

Conclusions

Gamma Knife surgery offers a high rate of tumor control and a reasonable rate of endocrine remission in patients with Cushing's disease. The cessation of cortisol-lowering medications around the time of GKS appears to result in a more rapid rate of remission. Delayed hypopituitarism and endocrine recurrence develop in a minority of patients and underscore the need for long-term multidisciplinary follow-up.

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Or Cohen-Inbar, Cheng-Chia Lee, Zhiyuan Xu, David Schlesinger, and Jason P. Sheehan

OBJECT

The authors review outcomes following Gamma Knife radiosurgery (GKRS) of cerebral arteriovenous malformations (AVMs) and their correlation to postradiosurgery adverse radiation effects (AREs).

METHODS

From a prospective institutional review board–approved database, the authors identified patients with a minimum of 2 years of follow-up and thin-slice T2-weighted MRI sequences for volumetric analysis. A total of 105 AVM patients were included. The authors analyzed the incidence and quantitative changes in AREs as a function of time after GKRS. Statistical analysis was performed to identify factors related to ARE development and changes in the ARE index.

RESULTS

The median clinical follow-up was 53.8 months (range 24–212.4 months), and the median MRI follow-up was 36.8 months (range 24–212.4 months). 47.6% of patients had an AVM with a Spetzler-Martin grade ≥ III. The median administered margin and maximum doses were 22 and 40 Gy, respectively. The overall obliteration rate was 70.5%. Of patients who showed complete obliteration, 74.4% developed AREs within 4–6 months after GKRS. Late-onset AREs (i.e., > 12 months) correlated to a failure to obliterate the nidus. 58.1% of patients who developed appreciable AREs (defined as ARE index > 8) proceeded to have a complete nidus obliteration. Appreciable AREs were found to be influenced by AVM nidus volume > 3 ml, lobar location, number of draining veins and feeding arteries, prior embolization, and higher margin dose. On the other hand, a minimum ARE index > 8 predicted obliteration (p = 0.043).

CONCLUSIONS

ARE development after radiosurgery follows a temporal pattern peaking at 7–12 months after stereotactic radiosurgery. The ARE index serves as an important adjunct tool in patient follow-up and outcome prediction.