Faculty Bibliography

OBJECT: To determine if the combination of radiosurgery and tumor cell vaccine would enhance the therapy of metastatic lesions of the central nervous system (CNS), the authors examined the antitumoral effects of radiosurgery and cytokine-transduced tumor cell vaccine. METHODS: Fifty-five rats underwent intracranial implantation of 5 x 10(3) MADB 106 cells. On Day 3 after tumor implantation, 34 rats were inoculated in the flank with nonirradiated MADB 106 cells that had been retrovirally transduced to express granulocyte-macrophage colony-stimulating factor or interleukin-4. Twenty-seven rats (17 animals that had received the vaccine and 10 that had not) underwent radiosurgery performed using a gamma knife at maximum doses of 32 Gy on Day 5. No animals in the untreated group or in the vaccine-alone groups survived longer than 21 days. Animals treated by ra diosurgery alone displayed prolonged survival in comparison with untreated animals (p < 0.0001), but only one of 10 animals survived longer than 55 days. In contrast, 14 of 17 animals that received the combination therapy of radiosurgery and vaccination survived longer than 55 days (p = 0.0003 compared with animals that underwent radiosurgery alone). On Day 55, the long-term survivors were challenged by parental MADB 106 cells, which were implanted in the contralateral hemisphere. All animals from the combination therapy groups survived longer than 50 days after this challenge, but the single survivor from the radiosurgery-alone group died of tumor growth in 27 days. CONCLUSIONS: The combination of radiosurgery and cytokine gene-transduced tumor cell vaccine markedly prolonged animal survival and protected animals from a subsequent challenge by parental tumor cells placed in the CNS. The data provided by this study indicate that this combination therapy represents a strategy that may have clinical applicability for single and/or multiple metastatic brain tumors.

Multiple brain metastases (BrM) are a common challenge to patients with cancer. Tumour resection is used mainly for patients with large tumours that cause acute neurological syndromes. The prognosis, even after treatment with whole brain radiation therapy (WBRT), is poor with average expected survivals less than six months. For this reason, numerous centres have evaluated the role of stereotactic radiosurgery (SRS) in patients with solitary or multiple tumours. We conducted a randomised trial that compared radiosurgery plus WBRT to WBRT alone. The rate of local failure at one year was 100% after WBRT alone but only 8% in patients who had boost radiosurgery. The median time to local failure was six months after WBRT alone in comparison to 36 months after WBRT plus radiosurgery (p=0.0005). The median time to any brain failure was improved in the radiosurgery group (p=0.002). Survival was related to extent of extracranial disease (p=0.02). Combined WBRT and radiosurgery for patients with two to four BrM significantly improves control of brain disease. WBRT alone, for years the standard treatment, does not appear to provide lasting and effective care for most patients. Controversies remain in patient selection, number of BrM suitable for treatment, concomitant management of extracranial disease, and timing of therapy.

The goal of stereotactic radiosurgery by definition is "the delivery of a single, high dose of radiation allowing the precise and complete destruction of chosen target structures containing healthy and/or pathological cells, without significant concomitant or late radiation damage to adjacent tissues". This effect is obtained by the precise focusing of multiple low energy radiation beams crossing at the target. Three different techniques can be used for radiosurgery: linear accelerator (LINAC) based radiosurgery, Bragg-peak (proton) therapy and Gamma Knife radiosurgery. Leksell Gamma Knife (LGK) is a dedicated neurosurgical device for brain surgery to destroy predetermined intracranial targets through the intact skull. It operates via the radiobiological effect of stereotactically directed, highly focused ionizing gamma-beams of 201 cobalt-60 sources. The LGK offers the best precision of target during irradiation. The mechanical accuracy is about 0.3 mm, which makes it particularly suitable for highly sophisticated neurosurgical interventions. Radiosurgery was originally developed to treat functional neurological disorders, but soon after its introduction cerebral arteriovenous malformations, and brain tumors became the main targets for the technique. Since the first LGK installation at the Sophiahemmet Hospital, Stockholm, Sweden in 1967, over 150,000 patients have already been treated in more than 150 units worldwide. The accumulated clinical experience with the LGK has established this method as the "golden standard" of radiosurgery. In December 1999, a new development, the LGK Model-C was installed at the Centre Gamma Knife, Universite Libre de Bruxelles, Hopital Academique Erasme, Brussels, Belgium. This was followed by completion of two similar units in Krefeld, Germany, and at the Presbyterian University Hospital, Pittsburgh, Pennsylvania, U.S.A. The major innovation in the design of the LGK Model-C is the robotic Automatic Positioning System, which allows computer-controlled automatic and sequential positioning of multiple shots during treatment. Thus all steps of the procedure are performed through an unbroken digital chain, from stereotactic image acquisition to the control of the irradiation sequence. This represents a significant achievement which increases the accuracy and practicality of the treatment. The technical details of the method are described, and the main treatment indications are reviewed.