Christopher M. Duma

Tolerance of cranial nerves of the cavernous sinus to radiosurgery

PURPOSE Stereotactic radiosurgery is becoming a more accepted treatment option for benign, deep seated intracranial lesions. However, little is known about the effects of large single fractions of radiation on cranial nerves. This study was undertaken to assess the effect of radiosurgery on the cranial nerves of the cavernous sinus. METHODS AND MATERIALS We examined the tolerance of cranial nerves (II-VI) following radiosurgery for 62 patients (42/62 with meningiomas) treated for lesions within or near the cavernous sinus. Twenty-nine patients were treated with a modified 6 MV linear accelerator (Joint Center for Radiation Therapy) and 33 were treated with the Gamma Knife (University of Pittsburgh). Three-dimensional treatment plans were retrospectively reviewed and maximum doses were calculated for the cavernous sinus and the optic nerve and chiasm. RESULTS Median follow-up was 19 months (range 3-49). New cranial neuropathies developed in 12 patients from 3-41 months following radiosurgery. Four of these complications involved injury to the optic system and 8 (3/8 transient) were the result of injury to the sensory or motor nerves of the cavernous sinus. There was no clear relationship between the maximum dose to the cavernous sinus and the development of complications for cranial nerves III-VI over the dose range used (1000-4000 cGy). For the optic apparatus, there was a significantly increased incidence of complications with dose. Four of 17 patients (24%) receiving greater than 800 cGy to any part of the optic apparatus developed visual complications compared with 0/35 who received less than 800 cGy (p = 0.009). CONCLUSION Radiosurgery using tumor-controlling doses of up to 4000 cGy appears to be a relatively safe technique in treating lesions within or near the sensory and motor nerves (III-VI) of the cavernous sinus. The dose to the optic apparatus should be limited to under 800 cGy.

Stereotactic radiosurgery of cavernous sinus meningiomas as an addition or alternative to microsurgery.

To evaluate the response of cavernous sinus meningiomas to stereotactic radiosurgery, we reviewed our 54-month experience with 34 patients. All patients underwent radiosurgery with a 201-source cobalt-60 gamma unit. Twenty-eight patients (82%) had previous histological confirmation of a meningioma (1 to 5 cranial base craniotomies per patient); 6 (18%) were treated on the basis of neuroimaging criteria alone. The single-fraction radiation tumor margin dose (10 to 20 Gy) was designed to conform to the irregular tumor volumes in all patients. The maximum radiation dose to the optic nerve or tract was reduced to 9 Gy in 31 patients. No patient had tumor growth (100% tumor control) during the follow-up interval (median, 26 mo). Tumor regression was observed in 56% of patients imaged at an average of 18 months. Eight patients (24%) improved clinically at follow-up examinations. Four patients developed new or worsened cranial nerve deficits during the follow-up interval; two had subsequent full improvement. No patient developed an endocrinopathy or new extraocular muscle paresis. Stereotactic radiosurgery, using multiple isocenter dosimetry facilitated by the gamma unit, is an accurate, safe, and effective technique to prevent the growth of tumors involving the cavernous sinus. Despite the proximity of such tumors to adjacent cranial nerves, complications were rare. The maximum length of hospital stay was 36 hours, and all patients returned to their preoperative employment status within 3 to 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Gamma knife radiosurgery for acoustic tumors: multivariate analysis of four year results

In order to evaluate the results of radiosurgery for acoustic tumors and to identify optimum treatment parameters, an analysis of tumor control, as well as incidences of hearing loss, facial and trigeminal neuropathies was undertaken. Between August 1987 and August 1991, 134 patients with 136 acoustic tumors received stereotactic gamma knife radiosurgery at the University of Pittsburgh. Median follow-up was 24 months (range: 6-56 months). Tumor volumes ranged from 0.10 to 17.00 cm3 (median = 2.75 cm3). From one to ten isocenters were utilized per tumor treated (median = 3). Minimum tumor doses varied from 12 to 20 Gy (median = 17 Gy). The 4-year actuarial tumor control rate was 89.2 +/- 6.0%. Some degree of hearing (by pure tone audiometry) was preserved in 71.0 +/- 4.4% of patients. The actuarial rates for preservation of either pretreatment hearing level or useful hearing were 34.4 +/- 6.6% and 35.1 +/- 97% respectively. Respectively, the actuarial incidences of postradiosurgery facial and trigeminal neuropathies were 29.0 +/- 4.4% and 32.9 +/- 4.5%, respectively. No significant factors affecting tumor control were identified. Multivariate analysis identified a significantly increased risk of hearing loss in patients with neurofibromatosis (p = 0.0003) as well as decreased risks of facial and trigeminal neuropathies with both decreasing tumor diameter (p = 0.001) and increasing number of isocenters treated (p = 0.003). Radiosurgery is a safe and effective treatment for acoustic neuromas with acceptable morbidity that may be lowered by the use of multiple isocenter treatment techniques and by earlier treatment of small tumors.

Intralesional Lymphokine-activated Killer Cells as Adjuvant Therapy for Primary Glioblastoma

Despite recent advances, median survival for patients with resectable glioblastoma multiforme (GBM) is only 12 to 15 months. We previously observed minimal toxicity and a 9.0-month median survival after treatment with intralesional autologous lymphokine-activated killer (LAK) cells in 40 patients with recurrent GBM. In this study, GBM patients were treated with adjuvant intralesional LAK cells. Eligible patients had completed primary therapy for GBM without disease progression. LAK cells were produced by incubating autologous peripheral blood mononuclear cells with interleukin-2 for 3 to 7 days and then placed into the surgically exposed tumor cavity by a neurosurgeon. The 19 men and 14 women had a median age of 57 years. Prior therapy included surgical resection (97%), partial brain irradiation (97%), γ knife radiosurgery (97%), and temozolomide chemotherapy (70%). Median time from diagnosis to LAK cell therapy was 5.3 months (range: 3.0 to 11.1 mo). LAK cell treatment was well tolerated; average length of hospitalization was 3 days. At the time of this analysis, 27 patients have died; the median survival from the date of original diagnosis is 20.5 months with a 1-year survival rate of 75%. In subset analyses, superior survival was observed for patients who received higher numbers of CD3+/CD16+/CD56+ (T-LAK) cells in the cell products, which was associated with not taking corticosteroids in the month before leukopheresis. Intralesional LAK cell therapy is safe and the survival sufficiently encouraging to warrant further evaluation in a randomized phase 2 trial of intralesional therapies with LAK or carmustine-impregnated wafers.

Radiosurgery for Vascular Malformations of the Brain Stem

The challenges associated with microsurgery of vascular malformations located in the midbrain, pons and medulla have promoted the development of alternative therapeutic techniques. To assess the efficacy and safety of radiosurgery in the management of brain stem vascular malformations we reviewed our 5-year experience in 50 patients evaluated between 4 and 51 months (mean, 25 months) after radiosurgery. Twenty-eight patients (56%) underwent gamma unit radiosurgery for symptomatic arteriovenous malformations (AVMs), and 22 patients (44%) for angiographically occult vascular malformations (AOVMs). Patients varied in age from 7 to 76 years (mean, 39 years). Forty-one patients (82%) had from 1 to 5 hemorrhages prior to gamma knife radiosurgery. Ten (20%) had one or two prior unsuccessful operations, and 37 (74%) presented with a neurological deficit. Of the patients with AVMs, 6 were considered Spetzler Grade III, and 22 (79%) Grade VI (inoperable: major component within the brain stem parenchyma). Forty-four malformations (88%) were adjacent to or within the midbrain and pons; the remainder involved the medulla. Average malformation diameters varied from 6 to 30.4 m (mean, 20.6; mean volume 4614 mm3). The minimal radiation dose to the margin of the malformations ranged from 12 to 25.6 Gy (mean, 18.9 Gy). Of the 28 patients with AVMs, 8 had follow-up angiograms at a minimum of 2-years after radiosurgery (or sooner if their MRIs suggested obliteration). Of these patients, 7 (88%) showed complete obliteration of their malformations. No patients with AOVMs rehemorrhaged if more than 15 months elapsed after radiosurgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereotactic radiosurgery for intracranial hemangioblastomas: a retrospective international outcome study

OBJECT The purpose of this study was to evaluate the role of stereotactic radiosurgery (SRS) in the management of intracranial hemangioblastomas. METHODS Six participating centers of the North American Gamma Knife Consortium and 13 Japanese Gamma Knife centers identified 186 patients with 517 hemangioblastomas who underwent SRS. Eighty patients had 335 hemangioblastomas associated with von Hippel-Lindau disease (VHL) and 106 patients had 182 sporadic hemangioblastomas. The median target volume was 0.2 cm(3) (median diameter 7 mm) in patients with VHL and 0.7 cm(3) (median diameter 11 mm) in those with sporadic hemangioblastoma. The median margin dose was 18 Gy in VHL patients and 15 Gy in those with sporadic hemangioblastomas. RESULTS At a median of 5 years (range 0.5-18 years) after treatment, 20 patients had died of intracranial disease progression and 9 patients had died of other causes. The overall survival after SRS was 94% at 3 years, 90% at 5 years, and 74% at 10 years. Factors associated with longer survival included younger age, absence of neurological symptoms, fewer tumors, and higher Karnofsky Performance Status. Thirty-three (41%) of the 80 patients with VHL developed new tumors and 17 (16%) of the106 patients with sporadic hemangioblastoma had recurrences of residual tumor from the original tumor. The 5-year rate of developing a new tumor was 43% for VHL patients, and the 5-year rate of developing a recurrence of residual tumor from the original tumor was 24% for sporadic hemangioblastoma patients. Factors associated with a reduced risk of developing a new tumor or recurrences of residual tumor from the original tumor included younger age, fewer tumors, and sporadic rather than VHL-associated hemangioblastomas. The local tumor control rate for treated tumors was 92% at 3 years, 89% at 5 years, and 79% at 10 years. Factors associated with an improved local tumor control rate included VHL-associated hemangioblastoma, solid tumor, smaller tumor volume, and higher margin dose. Thirteen patients (7%) developed adverse radiation effects (ARE) after SRS, and one of these patients died due to ARE. CONCLUSIONS When either sporadic or VHL-associated tumors were observed to grow on serial imaging studies, SRS provided tumor control in 79%-92% of tumors.

Skull base chondrosarcoma radiosurgery: report of the North American Gamma Knife Consortium

OBJECT Stereotactic radiosurgery (SRS) is a potentially important option for patients with skull base chondrosarcomas. The object of this study was to analyze the outcomes of SRS for chondrosarcoma patients who underwent this treatment as a part of multimodality management. METHODS Seven participating centers of the North American Gamma Knife Consortium (NAGKC) identified 46 patients who underwent SRS for skull base chondrosarcomas. Thirty-six patients had previously undergone tumor resections and 5 had been treated with fractionated radiation therapy (RT). The median tumor volume was 8.0 cm3 (range 0.9-28.2 cm3), and the median margin dose was 15 Gy (range 10.5-20 Gy). Kaplan-Meier analysis was used to calculate progression-free and overall survival rates. RESULTS At a median follow-up of 75 months after SRS, 8 patients were dead. The actuarial overall survival after SRS was 89% at 3 years, 86% at 5 years, and 76% at 10 years. Local tumor progression occurred in 10 patients. The rate of progression-free survival (PFS) after SRS was 88% at 3 years, 85% at 5 years, and 70% at 10 years. Prior RT was significantly associated with shorter PFS. Eight patients required salvage resection, and 3 patients (7%) developed adverse radiation effects. Cranial nerve deficits improved in 22 (56%) of the 39 patients who deficits before SRS. Clinical improvement after SRS was noted in patients with abducens nerve paralysis (61%), oculomotor nerve paralysis (50%), lower cranial nerve dysfunction (50%), optic neuropathy (43%), facial neuropathy (38%), trochlear nerve paralysis (33%), trigeminal neuropathy (12%), and hearing loss (10%). CONCLUSIONS Stereotactic radiosurgery for skull base chondrosarcomas is an important adjuvant option for the treatment of these rare tumors, as part of a team approach that includes initial surgical removal of symptomatic larger tumors.

Upfront boost Gamma Knife “leading-edge” radiosurgery to FLAIR MRI–defined tumor migration pathways in 174 patients with glioblastoma multiforme: a 15-year assessment of a novel therapy

OBJECTIVE Glioblastoma multiforme (GBM) is composed of cells that migrate through the brain along predictable white matter pathways. Targeting white matter pathways adjacent to, and leading away from, the original contrast-enhancing tumor site (termed leading-edge radiosurgery [LERS]) with single-fraction stereotactic radiosurgery as a boost to standard therapy could limit the spread of glioma cells and improve clinical outcomes. METHODS Between December 2000 and May 2016, after an initial diagnosis of GBM and prior to or during standard radiation therapy and carmustine or temozolomide chemotherapy, 174 patients treated with radiosurgery to the leading edge (LE) of tumor cell migration were reviewed. The LE was defined as a region outside the contrast-enhancing tumor nidus, defined by FLAIR MRI. The median age of patients was 59 years (range 22-87 years). Patients underwent LERS a median of 18 days from original diagnosis. The median target volume of 48.5 cm3 (range 2.5-220.0 cm3) of LE tissue was targeted using a median dose of 8 Gy (range 6-14 Gy) at the 50% isodose line. RESULTS The median overall survival was 23 months (mean 43 months) from diagnosis. The 2-, 3-, 5-, 7-, and 10-year actual overall survival rates after LERS were 39%, 26%, 16%, 10%, and 4%, respectively. Nine percent of patients developed treatment-related imaging-documented changes due to LERS. Nineteen percent of patients were hospitalized for management of edema, 22% for resection of a tumor cyst or new tumor bulk, and 2% for shunting to treat hydrocephalus throughout the course of their disease. Of the patients still alive, Karnofsky Performance Scale scores remained stable in 90% of patients and decreased by 1-3 grades in 10% due to symptomatic treatment-related imaging changes. CONCLUSIONS LERS is a safe and effective upfront adjunctive therapy for patients with newly diagnosed GBM. Limitations of this study include a single-center experience and single-institution determination of the LE tumor target. Use of a leading-edge calculation algorithm will be described to achieve a consistent approach to defining the LE target for general use. A multicenter trial will further elucidate its value in the treatment of GBM.

Spinal epidural metastasis in an endometrial carcinoma patient

► The incidence of CNS metastases from endometrial cancer is quite uncommon. ► We report on an endometrial cancer patient who developed a metastatic epidural mass. ► Oncology physicians should remain vigilant in order to effectuate prompt treatment and potentially benefit the patients outcome.

Correction: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma [J Transl Med., 16, (2018) (142)] DOI: 10.1186/s12967-018-1507-6

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.