Lunsford LD, Somaza S, Kondziolka D, Flickinger JC.

Department of Neurological Surgery, Radiology and Radiation Oncology, University of Pittsburgh Medical Center, Pennsylvania, USA.

We believe that every patient who has clinical symptoms and neurodiagnostic imaging signs suggesting a low-grade glial neoplasm should undergo early diagnosis and treatment. Observation is not warranted for a tumor that has a median survival of 5 years.

The value of cytoreductive surgery for many patients has yet to be proven. It is incumbent on neurosurgeons who advocate this approach to show that this more aggressive treatment strategy is preferable to minimally invasive techniques, such as stereotactic biopsy followed by radiation therapy. Clearly, some patients who have a glial tumor require early cytoreductive surgery: those with mass effect and significant neurologic deficits. Otherwise, they will not be able to tolerate fractionated radiation therapy. Because the long-term survival rate is very poor, observation is not warranted in patients with suspected glial neoplasm.

Early stereotactic biopsy immediately identifies those patients who, in fact, have more anaplastic tumors and a much worse prognosis. Such patients may benefit from early, aggressive treatments such as cytoreductive surgery, chemotherapy, and radiation.

Applying this philosophy, we have achieved a median survival of more than 10 years in patients with astrocytoma. Most patients maintain a high KPS rating, and most do not require delayed cytoreductive surgery. Although we believe that the outcomes of future patients with astrocytomas will improve, we must establish whether such improvement is related to better therapeutic options, earlier recognition enabled by advanced neuroimaging, or the availability of corticosteroids (28, 30).

We also believe that neurosurgeons and neuro-oncologists should stop arguing over whether cytoreductive surgery is warranted. For some patients it is, and for others it is not. This prolonged controversy indicates the basic impotence with which neurosurgeons approach glial tumors. Our energy and efforts should be devoted toward more concrete and positive goals in terms of glial tumor management.

These goals include prolonged and higher-quality survival, reduced surgical and postoperative morbidity, and the development of new surgical, chemotherapeutic, and molecular tools that will allow us to improve clinical outcomes. Needless and senseless arguing over cytoreductive surgery versus biopsy, radiation versus no radiation, or any of these procedures versus observation alone trivialize the issues that face us and our patients: astrocytomas of the brain are neither indolent nor benign. The vast majority of our patients with astrocytomas are dead within 5 years, and almost all within 10. Our papers, our meetings, our approach should encourage us to pursue new basic science and clinical strategies to fight glial neoplasms. Surgery alone cures no patient with a glioma. Radiation therapy cures relatively few, and chemotherapy cures none. New ideas and new approaches are needed to improve the plight of our patients.

Publication Types:
Review
Review, Tutorial

PMID: 8846611 [PubMed - indexed for MEDLINE]

Duma CM, Lunsford LD, Kondziolka D, Bissonette DJ, Somaza S, Flickinger JC.

Department of Neurosurgery, University of Pittsburgh Medical Center, PA.

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)

PMID: 8109313 [PubMed - indexed for MEDLINE]

Somaza S, Kondziolka D, Lunsford LD, Kirkwood JM, Flickinger JC.

Department of Neurological Surgery, University of Pittsburgh, Pittsburgh Cancer Institute, Pennsylvania.

To determine local tumor control rates and survival of patients with melanoma metastases to the brain, the authors reviewed the results of 23 consecutive patients with a total of 32 tumors (19 patients had a solitary tumor and four had multiple tumors) who underwent adjuvant stereotactic radiosurgery.

Tumor locations included the cerebral hemisphere (24 cases), brain stem (four cases), basal ganglia (two cases), and cerebellum (two cases). Fifteen patients had associated cranial symptomatology and eight had incidental metastases. All patients had tumors of 3 cm or less in diameter (mean tumor volume 2.5 cu cm), and all received fractionated whole-brain radiation therapy (30 Gy) in addition to radiosurgery (mean tumor margin dose 16 Gy). Nineteen patients were managed with both modalities at the time of diagnosis; four underwent radiosurgery 3 to 12 months after fractionated whole-brain radiotherapy. The mean patient follow-up period was 12 months (range 3 to 38 months).

After radiosurgery, eight patients improved, 13 remained stable, and two deteriorated. One patient subsequently required craniotomy because of intratumoral hemorrhage; this patient and three others are living 13 to 38 months after radiosurgery. Nineteen patients died, 18 from progression of their systemic disease and one from another hemorrhage into a new brain metastasis. The local tumor control rate was 97%. Only two patients subsequently developed new intracranial metastases. The median survival period after diagnosis was 9 months (range 3 to 38 months).

The authors believe that stereotactic radiosurgery coupled with fractionated whole-brain irradiation is an effective management strategy for cerebral metastases from a melanoma. Multi-institutional trials are warranted to confirm that stereotactic radiosurgery results equal or surpass the outcome achieved with craniotomy and tumor resection.

PMID: 8410244 [PubMed - indexed for MEDLINE]

Kondziolka D, Somaza S, Flickinger JC, Claassen D, Lunsford LD.

Department of Neurological Surgery, University of Pittsburgh, Pennsylvania.

Because pentobarbital has been shown to reduce cerebral toxicity to single-fraction whole brain irradiation in a rat model, we sought to evaluate its cerebral radioprotective effects for stereotactic radiosurgery.

We hypothesized that concurrent high-dose pentobarbital anaesthesia (50 mg kg-1) during irradiation could delay or prevent the onset of radiation necrosis within the radiosurgical volume. Six rats were placed in pentobarbital or control groups, irradiated, and then evaluated at different intervals (60, 100, 150, 365 days; total = 48 animals studied).

All rats had 100 Gy radiosurgery to the right frontal brain region (a threshold dose for focal necrosis at 90 days). The radioprotective effects of pentobarbital were compared to ketamine anaesthesia (control) and evaluated for observed focal necrosis, size of necrotic lesion, blood vessel alterations, and to changes in cell nuclei. There was no difference between groups in the numbers of rats with necrosis at 100 days (p = 0.72), at 150 days (p = 0.77), or at 365 days (p = 0.77); no necrosis was observed in either group at 60 days. There was no difference in the size of the necrotic lesion at 100 days (p = 1.0), at 150 days (p = 0.39), or at 365 days (p = 0.07).

There was no difference between groups in observed blood vessel changes or nuclear changes at any time interval (p > 0.6). There was no animal morbidity related to radiosurgery.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 7708137 [PubMed - indexed for MEDLINE]

Lunsford LD, Somaza S, Kondziolka D, Flickinger JC.

Department of Neurological Surgery, University of Pittsburgh, Pennsylvania.

The authors investigated the outcome of stereotactic biopsy and radiotherapy in 35 consecutive adult patients with nonanaplastic, nonpilocytic astrocytomas who were diagnosed between 1982 and 1992. The median patient age at presentation was 32 years. All received fractionated external-beam radiation therapy (median dose 56 Gy) as the initial management strategy.

Additional treatment in two patients included intracavitary irradiation with colloidal phosphorus-32. Six patients (17%) had documented tumor progression during the follow-up interval and died. Three others died of causes unrelated to their tumor. Median survival after stereotactic biopsy and irradiation was 118 months (9.8 years). Median survival from the time of onset of neurological symptoms was 148 months (12.3 years).

Only three patients required delayed cytoreductive surgery. The outcome of brain astrocytomas, although improved because of earlier diagnosis and therapy, does not substantiate this tumor as having benign behavior; early recognition with neuroimaging, immediate histological diagnosis via stereotactic biopsy, and initial fractionated radiation therapy may provide the potential for longer survival for patients with low-grade astrocytomas. The majority of such surviving patients have a satisfactory quality of life, which is manifested by prolonged normal functional and employment status.

The survival data reported in this prospective Phase I-II clinical trial suggest that stereotactic biopsy and radiation therapy are appropriate initial management strategies for astrocytomas.

Publication Types:
Clinical Trial
Clinical Trial, Phase I
Clinical Trial, Phase II

PMID: 7897510 [PubMed - indexed for MEDLINE]

Radiosurgery: its role in brain metastasis management.

Flickinger JC, Lunsford LD, Somaza S, Kondziolka D.

Department of Neurological Surgery, Radiation Oncology, University of Pittsburgh School of Medicine, Pennsylvania, USA.

Stereotactic radiosurgery is effective in controlling brain metastasis at presentation and those that recur after radiotherapy. It is the treatment of choice for most patients with small solitary brain metastasis by virtue of its low morbidity, high-effectiveness, and cost.

Publication Types:
Review
Review, Tutorial

PMID: 8823777 [PubMed - indexed for MEDLINE]

Neurosurgery. 1997 Jul;41(1):203-8. Related Articles, Links

Kondziolka D, Somaza S, Martinez AJ, Jacobsohn J, Maitz A, Lunsford LD, Flickinger JC.

Department of Neurological Surgery, University of Pittsburgh, Pennsylvania, USA.

OBJECTIVE: Future improvements in the results of stereotactic radiosurgery will be related to better patient selection, dose planning, radiosensitization of the target, and, possibly, protection of the brain surrounding the target. 21-Aminosteroids may provide protection against brain radiation injury by inhibition of lipid peroxidation and a selective action on vascular endothelium. We hypothesized that the 21-aminosteroid U-74389G would reduce radiosurgery-related brain injury without attenuating the target volume response. METHODS: One hundred and forty-five rats were divided into four experimental groups before undergoing radiosurgery: control (n = 47); low-dose U-74389G (5 mg/kg of body weight, n = 30); high-dose U-74389G (15 mg/kg, n = 20); and methylprednisolone (2 mg/kg, n = 48). The drug was administered 1 hour before radiosurgery (4-mm gamma knife collimator) of the normal rat frontal lobe (single-fraction maximum doses of 50, 100, or 150 Gy) was performed. All brains underwent histological examination at 90 or 150 days to evaluate the diameters of necrosis and the findings of radiation-induced vasculopathy, brain edema, and gliosis. RESULTS: None of the animals that received 50-Gy radiation developed histological changes, whereas all of the animals that received 150-Gy radiation developed radiation necrosis without drug-induced protection from vascular changes or edema. In animals receiving 100-Gy radiation, high-dose aminosteroid reduced radiation-induced vasculopathy at 90 days (P = 0.06) and at 150 days (P = 0.02) and prevented regional edema at 90 days (P = 0.01) and at 150 days (P = 0.03). Low-dose aminosteroid and corticosteroid provided no protection. CONCLUSION: The 21-aminosteroid U-74389G provided protection after a single intravenously administered dose of 15 mg/kg against radiation-induced vasculopathy and edema. High-dose 21-aminosteroids seem to have optimal properties for radiosurgery, surrounding brain protection without reducing the therapeutic effect desired within the target volume.

PMID: 9218308 [PubMed - indexed for MEDLINE]

Acta Neurochir (Wien). 1997;139(4):343-7; discussion 347-8. Related Articles, Links

Jho HD, Carrau RL, McLaughlin MR, Somaza SC.

Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Encouraged by an experience with endoscopic transsphenoidal pituitary surgery, an endoscopic transsphenoidal technique was applied in a patient with a large chordoma in the posterior fossa. The patient was a 40-year-old man with a two-year history of progressive ataxia, a memory disorder and emotional instability. A magnetic resonance (MR) scan of the brain revealed a midline posterior fossa mass measuring 4 cm in diameter located between the clivus and the brainstem. The basilar artery and its bifurcation were encased by the tumor and the brainstem was also distorted by the tumor. Obstructive hydrocephalus was treated previously with a ventriculoperitoneal shunt and fractionated external beam radiation treatment was given without histological diagnosis at another hospital. Subtotal resection of the tumor was achieved utilizing an endoscopic transphenoidal technique through the patient's nostril. The portion of the tumor located behind the basilar artery was not resected in order to protect the brainstem perforating arteries. The patient showed dramatic improvement of his symptoms postoperatively. Residual tumor located behind the basilar artery was treated by stereotactic gamma-knife surgery. This is the first reported case of a large posterior fossa chordoma being treated by an endoscopic transsphenoidal technique.

Publication Types:
· Case Reports

PMID: 9202775 [PubMed - indexed for MEDLINE]

Pediatr Neurosurg. 1996 Sep;25(3):109-15. Related Articles, Links

Somaza SC, Kondziolka D, Lunsford LD, Flickinger JC, Bissonette DJ, Albright AL.

Department of Neurosurgery, University of Pittsburgh Medical Center, Pa., USA.

To examine the role of stereotactic radiosurgery in the adjuvant management of children with growing and unresectable deep-seated pilocytic astrocytomas, we reviewed our experience in 9 patients. The tumors were located in the dorsolateral pons (n = 2), midbrain (n = 1, cerebellar peduncle (n = 2), thalamus (n = 1), temporal lobe (n = 1), hypothalamus (n = 1), and caudate nucleus (n = 1). The mean tumor diameter was 16 mm (range, 11-25 mm). Seven patients had prior partial tumor resection, and 2 had a stereotactic biopsy. Two patients had failed fractionated radiotherapy and 7 were considered at risk for adverse radiation effects because of their age. The mean dose to the tumor margin at radiosurgery was 15 Gy (range, 12-18). During mean follow-up of 19 months (range 13-41 months), there was a marked decrease in tumor size in 5 patients; 4 patients had no further growth. No early or delayed morbidity was associated with radiosurgery. Gamma knife radiosurgery proved a safe and effective therapeutic tool in the management of children with deep, small volume pilocytic astrocytomas. Because this tumor often appears well-delineated on contrast-enhanced neuroimaging, we believe that conformal radiosurgical targeting accurately irradiates tumor cells. For small tumor volumes it can be used in place of fractionated larger-field radiotherapy. The ability to treat the tumor yet spare surrounding brain may reduce the surgical morbidity associated with attempted radical resection and the potential cognitive and endocrine disabilities associated with fractionated radiation therapy.

PMID: 9144708 [PubMed - indexed for MEDLINE]

J Neurosurg. 1996 Jun;84(6):1033-8. Related Articles, Links

Kondziolka D, Somaza S, Comey C, Lunsford LD, Claassen D, Pandalai S, Maitz A, Flickinger JC.

Department of Neurological Surgery, University of Pittsburgh, Pennsylvania, USA.

To identify histological changes and effects on survival in rats harboring C6 gliomas, the authors compared radiosurgery to different fractionated radiation therapy regimens including doses of calculated biological equivalence. Rats were randomized to control (54 animals) or treatment groups after implantation of C6 glioma cells into the right frontal brain region. At 14 days, treated rats underwent stereotactic radiosurgery (35 Gy to tumor margin; 22 animals), whole-brain radiation therapy (WBRT) (20 Gy in five fractions; 18 animals), radiosurgery plus WBRT (13 animals), hemibrain radiation therapy (85 Gy in 10 fractions; 16 animals) or single-fraction hemibrain irradiation (35 Gy; 10 animals). When compared to the control group (median survival 22 days), prolonged survival was identified after radiosurgery (p < 0.0001), radiosurgery plus WBRT (p < 0.0001), WBRT alone (p = 0.0002), hemibrain radiation therapy to 85 Gy (p < 0.0001), and 35-Gy hemibrain single-fraction irradiation (p = 0.004). Compared to the control group (mean tumor diameter, 6.8 mm), the tumor size was reduced in all treatment groups except WBRT alone. Reduced tumor cell density was exhibited in rats that underwent radiosurgery (p = 0.006) and radiosurgery plus WBRT (p = 0.009) when compared with rats in the control group, a finding not observed after any fractionated regimen. Increased intratumoral edema was identified after radiosurgery (p = 0.03) and combined treatment (p = 0.05), but not after fractionated radiation therapy or 35-Gy single-fraction hemibrain irradiation. In this animal model, the addition of radiosurgery significantly increased tumor cytotoxicity, potentially at the expense of radiation effects to regional brain. We found no difference in survival benefit or tumor diameter in animals that underwent radiosurgery compared to the calculated biologically equivalent regimen of 10-fraction radiation therapy to 85 Gy. The histological responses after radiosurgery were generally greater than those achieved with biologically equivalent doses of fractionated radiation therapy.

PMID: 8847568 [PubMed - indexed for MEDLINE]