Brain Metastases: Surgery & Radiation written and compiled by doctordee

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Neurosurgery

Brain metastases from sarcoma are uncommon, usually occurring with or after lung metastasis. Because brain metastases from sarcoma are refractory to alternative treatment, surgical excision is indicated when feasible. Surgery is effective in treating selected patients with sarcoma metastatic to the brain. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis; the presence of concurrent lung metastases is not a contraindication to surgery. Long-term survival is possible in some patients. [1,2, 3, 4] For the latest updates, do the searches: Search Pubmed for Surgery and LMS Brain Metastases Search Pubmed for Surgery and Sarcoma Brain Metastases Annotated References for Neurosurgery 1. Surg Neurol 1998 Apr;49(4):441-4 Sarcoma metastatic to the brain: a series of 15 cases. Salvati M, Cervoni L, Caruso R, Gagliardi FM, Delfini R. Department of Neurosurgery, Neurological Mediterranean Neuromed Institute, IRCCS, Pozzilli (IS), Italy. "...We report on 15 patients surgically treated for intraparenchymal brain metastases from sarcoma, including six osteosarcomas, five leiomyosarcomas, two malignant fibrous histiocytomas, and two alveolar soft-part sarcomas (ASPS)." "...Median survival after craniotomy was 9.3 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 12.8 versus 5.3 months for those with a Karnofsky performance score < 70 (p=0.03). Patients with evidence of only lung metastases at the time of surgery (nine cases) survived 8.6 months, which was similar to the 10.4-month survival for patients with disease limited to the brain (p=0.1). The two patients with alveolar soft-part sarcomas are alive at 15 and 20 months after surgery." "...We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain and that patients with metastasis from ASPS may have a relatively good prognosis if they are surgically treated. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis; the presence of concurrent lung metastases is not a contraindication to surgery." Cancer Radiation Links PMID: 9537665 2. Ann Surg Oncol 1995 Sep;2(5):392-9 Resection of brain metastases from sarcoma. Wronski M, Arbit E, Burt M, Perino G, Galicich JH, Brennan MF. Neurosurgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. "... Brain metastases from sarcoma are rare, and data concerning the treatment and results of therapy are sparse. ... We retrospectively reviewed 25 patients with brain metastases from sarcoma of skeletal or soft-tissue origin, surgically treated in a single institution during 20 years." "... In 18 patients the brain lesion was located supratentorially, and in 7 patients infratentorially. Median age at brain metastasis diagnosis was 25 years. Median time from primary diagnosis to diagnosis of brain metastasis was 26.7 months. Lung metastases were present in 19 patients and in 8 patients they were synchronous with the brain lesion. Pulmonary metastases were resected in 12 patients (48% of total, and 63% of those with pulmonary lesions). The overall median survival from diagnosis of the primary sarcoma was 38 months and from craniotomy was 7 months. The presence or absence of lung lesions did not alter the median survival as calculated from diagnosis of brain metastasis. Overall percent survival was 40% at 1 year and 16% at 2 years." "...Because brain metastases from sarcoma are refractory to alternative treatment, surgical excision is indicated when feasible. Brain metastases from sarcoma are uncommon, usually occurring with or after lung metastasis. Long-term survival is possible in some patients." Fetch PMID: 7496833 3. Gynecol Oncol 1994 Aug;54(2):237-41 Leiomyosarcoma of the uterus metastatic to brain: a case report and a review of the literature. Wronski M, de Palma P, Arbit E. Neurosurgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021. Central nervous system metastases are an unusual sequela of uterine sarcomas. A single brain metastasis from a leiomyosarcoma occurred in a 60-year-old woman, 6.5 years after hysterectomy and more than 2 years following the diagnosis of bilateral lung metastases, treated by combination chemotherapy. After resection of the cerebral metastasis, she was treated with brain radiation therapy and survived 2.5 years. Only seven other cases of uterus leiomyosarcoma metastatic to the brain have been published. Review of reported cases Fetch PMID: 8063254 4. Neurosurgery 1994 Aug;35(2):185-90; discussion 190-1 Sarcoma metastatic to the brain: results of surgical treatment. Bindal RK, Sawaya RE, Leavens ME, Taylor SH, Guinee VF. Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston. We report on 21 patients surgically treated for intraparenchymal brain metastasis from sarcoma, including six osteosarcomas, four leiomyosarcomas, three malignant fibrous histiocytomas, two alveolar soft-part sarcomas, two Ewing's bone sarcomas, one extraskeletal osteosarcoma, one extraskeletal Ewing's sarcoma, and two unclassified sarcomas. Median survival after craniotomy was 11.8 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 15.7 versus 6.6 months for those with a Karnofsky performance score < or = 70. Patients undergoing complete resection survived 14.0 versus 6.2 months for patients undergoing incomplete resection. Patients with evidence of lung metastases at the time of surgery survived 11.8 months, which was similar to the 10.5-month survival for patients with disease limited to the brain. The two patients with alveolar soft-part sarcoma are alive at 16 and 25 months after surgery. We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain and that patients with metastasis from alveolar soft-part sarcoma may have a relatively good prognosis if they are surgically treated. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis, whereas the presence of concurrent lung metastases is not a contraindication to surgery. Fetch PMID: 7969824 5. Cancer 1985 Mar 15;55(6):1382-8 Surgical treatment of brain metastases. Clinical and computerized tomography evaluation of the results of treatment. Sundaresan N, Galicich JH. The results of treatment of brain metastases in a series of 125 patients who underwent surgery with or without postoperative radiation from 1978 through 1982 were analyzed. The major sites of primary tumor included the lung (40%), melanoma-skin (11%), kidney (11%), colon (8%), soft tissue sarcoma (8%), breast (6%), and a variety of others (15%). At the time of craniotomy, disease was considered limited to the central nervous system in 63 patients (50%). After surgery, 83 patients (66%) were neurologically improved, and 26 (21%) had their deficits stabilized. The overall median survival was 12 months, and 25% lived 2 years. Eight patients (12%) are alive 5 years or more following surgery. Survival varied with site of primary tumor, location of brain metastasis, extent of systemic disease, and neurologic deficit at time of craniotomy. Over a follow-up period ranging from 18 months to 6 years, 42 patients (34%) developed either local recurrences or other sites of brain metastases. These data suggest that although craniotomy followed by radiation is highly effective in the initial treatment of selected patients with brain metastases, alternate therapies require investigation in view of the high central nervous system relapse rate in long-term survivors. Fetch PMID: 3971308

Radiation

Brain metastases are often irradiated with focused beams, as in the gamma knife or cyber knife or radiosurgery, and sometimes the whole brain is irradiated with a diffuse beam to prophylactically prevent further metastases from growing. For the latest updates Search Pubmed for Fetch Search Pubmed for Radiation and Sarcoma Brain Metastases Radiation and Brain Metastases Cerebral Radiation Necrosis One of the toxic and late effects of brain irradiation is Cerebral Radiation Necrosis. With radiation necrosis of the brain, MRI scans show the progressive deterioration of white matter. Late delayed effects, occurring several months to many years later, are classified into diffuse white-matter injury, radiation-induced arteriopathy & stroke, with associated death of brain tissue. These reactions are due to death of brain tissue caused by radiation-damaged blood vessels. Cerebral Radiation Necrosis generally occurs a few months to years after radiation therapy. Symptoms include decreased intellect, memory impairment, confusion, personality changes and alteration of the normal function of the area irradiated. Memory impairment, fine motor coordination, and other difficulties in thinking and functioning are not unusual after irradiation. These symptoms were related to the total dose of the radiation delivered. Cerebral Radiation Necrosis -- Annotated References J Radiol 2002 Nov;83(11):1749-57 [CT and MRI aspects of 28 patients with cerebral radiation necrosis irradiated for ORL tumors: correlation with the radiation technique] [Article in French] ...To describe and correlate with radiation therapy the occurrence of cerebral radiation necrosis in patients irradiated for nasopharyngeal or ethmoidal tumor. ... From 1986 to 1998, 1 201 patients... were treated by radiotherapy. Twenty-eight developed cerebral necrosis. ... The incidence of cerebral radionecrosis was 2.33%. The time interval between treatment and necrosis ranged from 2 months to 9 years. ... . Lesions were localized ... The doses related to the areas of necrosis ranged from 13 to 135Gy. In 2 cases necrosis was situated at the boundaries of the radiation field. Imaging follow-up showed complete (n=3) or incomplete remission (n=1), lesion progression (n=11), cerebral atrophy (n=5) and stability (n=7). ...New technologies may reduce the incidence of this complication. Fetch PMID: 12469012 Ann Dermatol Venereol 2002 Jan;129(1 Pt 1):41-5 [Delayed cerebral radionecrosis following radiation therapy of cutaneous squamous cell carcinomas of the head][Article in French] ... Little is known of cerebral radionecrosis following radiotherapy. This may be related to their rare occurrence and/or to the difficulties in establishing diagnosis. The delay of occurrence after radiotherapy can vary between a few months and several years, and the lesions are directly correlated with the doses and the fractioning of the X-rays. Intracerebral localization of the tumour is the main differential diagnosis. Localized and cystic forms of cerebral radionecrosis can be treated by surgery. Treatment otherwise relies on systemic steroids. Fetch PMID: 11937928 Eur J Radiol 2001 Sep;39(3):133-8 Late temporal lobe necrosis in patients with nasopharyngeal carcinoma: evaluation with combined multi-section diffusion weighted and perfusion weighted MR imaging. Late temporal lobe necrosis is a well-known and serious complication in patients with nasopharyngeal carcinoma (NPC) following radiotherapy. Owing to the close proximity to the skull base, the medial temporal lobes are inevitably included in the target volume of irradiation. ...Since late temporal lobe necrosis is probably caused by damage of the endothelium of vessels and ischemia, perfusion and diffusion mismatch might imply injured tissue but potentially salvageable brain tissue. ... Fetch PMID: 11566238 J Neurooncol 2001 Jan;51(2):143-50 Acute hemorrhage in late radiation necrosis of the temporal lobe: report of five cases and review of the literature. Hemorrhage in late cerebral radiation necrosis is a rare complication after radiotherapy ... In a review of the literature, the authors identified a total of 27 such cases. The interval period between the onset of hemorrhage and cranial irradiation is long (mean = 7.8 years). The most prominent histological feature was the proliferation of large, dilated and thin-walled new blood vessels in a background of gliosis and fibrinoid necrosis of vessels. Rupture of these thin-walled new blood vessels is the proposed mechanism of hemorrhage in this condition. Fetch PMID: 11386411 Int J Radiat Oncol Biol Phys 2000 Jan 1;46(1):51-5 Neurocognitive effects of therapeutic irradiation for base of skull tumors. ... Nineteen patients who received paranasal sinus irradiation at least 20 months and up to 20 years before assessment were given a battery of neuropsychologic tests of cognitive function,,, . The median radiation dose was 60 Gy (range 50-68 Gy) in fractions of 1.8 to 2 Gy. ... Memory impairment was found in 80% of the patients, and one-third manifested difficulty with visual-motor speed, frontal lobe executive functions, and fine motor coordination. Two of the patients had frank brain necrosis with resultant dementia and blindness, and three had evidence of brain atrophy. Three of the fourteen patients without documented cerebral atrophy or necrosis were disabled from their normal activities. Three patients also developed pituitary dysfunction. Neurocognitive symptoms were related to the total dose of radiation delivered but not to the volume of brain irradiated, side of radiation boost, or chemotherapy treatment. The pattern of test findings was consistent with radiation injury to subcortical white matter. ... Radiation therapy for paranasal sinus cancer may cause delayed neurocognitive side effects. Currently, however, the development of severe adverse effects appears to be decreasing because of improvements in the techniques used to deliver radiation. Lowering the total dose and improving dose distributions should further decrease the incidence of delayed brain injury due to radiation. Fetch PMID: 10656372

Whole Brain Irradiation

Whole brain irradiation is meant to decrease growth of more metastases, prophylactically. It can increase survival time. However, there are symptoms from its use. "Early toxicity consisted of headache, nausea, fatigue, concentration problems and alopecia. These symptoms and signs were mild and usually reversible within a few months. Late toxicity was studied in patients whose survival exceeded two years." Seven of the prophylactically irradiated survived for more than two years, while no control patients survived for more than two years. "Memory problems were seen in six of the seven patients. These problems were non-disabling and, once established, remained stable for months to years. The most prominent radiologic abnormalities were cortical atrophy and leukoencephalopathy, found in four of the five patients who underwent radiologic follow-up examination. "J Neurooncol 1997 Nov;35(2):153-60 "In patients with brain metastasis from lung cancer, we have been able to control local recurrence in approximately 80% of cases. But many of them tend to show brain atrophy with mental deterioration developing a few months after whole brain radiation. To prevent brain atrophy, we have attempted treating patients, whose metastasis was diagnosed as single, by intra-operative radiotherapy (IOR) alone following surgical resection ,,," Acta Neurochir (Wien) 1994;131(1-2):91-6 Whole Brain Irradiation -- Annotated Citations Radiology 1999 Sep;212(3):755-9 Phases IB and II multidose trial of gadolinium texaphyrin, a radiation sensitizer detectable at MR imaging: preliminary results in brain metastases. Viala J, Vanel D, Meingan P, Lartigau E, Carde P, Renschler M. Department of Radiology, Institut Gustave-Roussy, Villejuif, France. ,,,, , and to determine an appropriate intravenous dose of gadolinium texaphyrin [a tumor-selective radiation sensitizer that is detectable at MR imaging ],,, and the response to treatment. Ten daily intravenous injections of gadolinium texaphyrin, each followed by whole-brain radiation therapy (total of 10 fractions, 30 Gy), were administered to patients with brain metastases in a multicenter study. ,,, MR imaging revealed selective drug uptake in metastases, without enhancement of normal brain tissue. In 10 patients, tumor uptake was higher after the 10th injection than after the first injection, which indicated accumulation of gadolinium texaphyrin in metastases. One lesion was visible only after the 10th injection ,,,. Response to treatment was defined as a reduction in the size of the metastases ,,,; seven patients achieved partial remission with tumor regression exceeding 50% of the initial size, and four achieved a minor response with less than 50% tumor regression. These preliminary results indicate that gadolinium texaphyrin is tumor selective and that brain metastases can be depicted at MR imaging long after the administration of gadolinium texaphyrin. phase i Clinical trial, phase ii Multicenter study Fetch PMID: 10478243 Radiother Oncol 1998 Jan;46(1):29-32 Brain-only metastases of small cell lung cancer; efficacy of whole brain radiotherapy. An EORTC phase II study. Postmus PE, Haaxma-Reiche H, Gregor A, Groen HJ, Lewinski T, Scolard T, Kirkpatrick A, Curran D, Sahmoud T, Giaccone G. Free University Hospital Amsterdam, The Netherlands. ...To evaluate the efficacy of WBRT as a single treatment modality in patients with brain metastases of small cell lung cancer. ,,,. Twenty ,,, patients were evaluable for response. In six patients a complete response was seen and in five patients a partial response was seen giving a response rate of 50% ,,,. Response duration was 5.4 months (range 63-260 days) and median survival was 4.7 months (range 14-743 days). In the majority of patients the first site of progression after WBRT was in the central nervous system. Twelve of the patients had stabilization or improvement of the neurological function. ...WBRT for brain metastases of small cell lung cancer gives a 50% response rate with stabilization or improvement of neurological function. Response duration and survival are short. Clinical trial, phase ii Multicenter study Fetch PMID: 9488124 Radiother Oncol 1997 Oct;45(1):17-22 Accelerated radiotherapy for brain metastases. Nieder C, Nestle U, Niewald M, Schnabel K. Department of Radiotherapy, University Hospital, Homburg/Saar, Germany. ...Two novel fractionation schedules for whole-brain irradiation were applied to patients with brain metastases. ...We applied 2 x 2.5 Gy/day to a total dose of 30 Gy (schedule 1) or 2 x 1.8 Gy/day to a total dose of 50.4 Gy (schedule 2) ,,,The 30 Gy schedule was also used in adjuvant treatment for resected brain metastases. We compared the results of 15 patients who underwent the 50.4 Gy schedule and 47 patients who were treated up to 30 Gy with those of a historical patient group, treated with one daily fraction of 3 Gy up to 30 Gy (n = 283). ... no therapeutic gain was seen for the 50.4 Gy group. Patients treated with the accelerated 30 Gy schedule had a significantly worse progression-free survival and a higher rate of late radiation toxicity than the historical group. In contrast, no severe acute toxicity was observed. ...Considering progression-free survival and late toxicity, the accelerated 30 Gy schedule cannot be recommended ,,,. Radiotherapy with a higher total dose (50.4 Gy) showed no advantage. Controlled clinical trial Fetch PMID: 9364627 J Neurooncol 1997 Nov;35(2):153-60 Efficacy and safety of prophylactic cranial irradiation in patients with small cell lung cancer. van de Pol M, ten Velde GP, Wilmink JT, Volovics A, Twijnstra A. Department of Neurology, University Hospital Maastricht, The Netherlands. ...Prophylactic cranial irradiation (PCI) as part of the treatment regimen for patients with limited stage small cell lung cancer (SCLC) remains controversial. ...thirty-nine patients with limited stage SCLC who had shown complete remission after chemotherapy were enrolled prospectively into the non-randomized study. Eighteen of them received PCI (PCI+), while 21 did not (PCI-). ... The frequencies of brain metastases were not significantly different between the groups (Fisher's exact test, p = 0.207), but brain metastases in PCI+ patients tended to occur later (log rank, p = 0.008). Overall survival was significantly longer in PCI+ patients (log rank, p < 0.001). Early toxicity consisted of headache, nausea, fatigue, concentration problems and alopecia. These symptoms and signs were mild and usually reversible within a few months. Late toxicity was studied in patients whose survival exceeded two years. Seven PCI+ patients survived for more than two years, while no PCI- patients survived for more than two years. Memory problems were seen in six of the seven patients. These problems were non-disabling and, once established, remained stable for months to years. The most prominent radiologic abnormalities were cortical atrophy and leukoencephalopathy, found in four of the five patients who underwent radiologic follow-up examination. ...This non-randomized study suggests that PCI may be effective by decreasing the frequency of brain metastases and by increasing the brain metastasis-free survival and overall survival, with a minor risk of clinical and radiologic neurotoxicity. Clinical trial Fetch PMID: 9266453 Am J Clin Oncol 1997 Apr;20(2):158-60 The role of hyperfractionated re-irradiation in metastatic brain disease: a single institutional trial. Abdel-Wahab MM, Wolfson AH, Raub W, Landy H, Feun L, Sridhar K, Brandon AH, Mahmood S, Markoe AM. Department of Radiation Oncology, University of Miami School of Medicine, Florida 33136, U.S.A. Progression of brain metastases after brain irradiation has prompted several studies on retreatment of the brain. Increased durations of survival and improved quality of life have been reported. Fifteen patients with previously treated brain metastases were entered into this pilot study between May 1990 and January 1994. All patients had neurologic and/or radiologic evidence of progression of brain metastases. ,,, The median interval between the first treatment and retreatment was 10 months. All patients received whole-brain irradiation with or without a boost for their initial treatment course. Doses ranged from 3,000 to 5,500 cGy for initial treatments (median, 3,000). Retreatment consisted of limited fields ... Patients were retreated with a median dose of 3,000 cGy (range, 600-3,000 cGy). A median cumulative dose of 6,000 cGy was achieved. ,,, Retreatment was tolerated without serious complications. Of the 15 patients treated, nine (60%) experienced improvement, and five (27%) had stabilization of neurologic function and/or radiographic parameters. Median survival was 3.2 months; two of the reirradiated patients survived >or = 9 months. reirradiation is a viable option in patients with recurrent metastatic lesions of the brain, and the use of a limited retreatment volume makes this a well-tolerated, low-morbidity treatment that leads to clinical benefits and, in some instances, enhanced survival. The influence of hyperfractionation on the outcome needs to be investigated further in large series. Clinical trial Fetch PMID: 9124191 Acta Neurochir (Wien) 1994;131(1-2):91-6 New treatment protocol by intra-operative radiation therapy for metastatic brain tumours. Nakamura O, Matsutani M, Shitara N, Okamoto K, Kaneko M, Nakamura H, Asai A, Ueki K, Shimizu T, Tanaka Y, et al. Department of Neurosurgery, Tokyo Metropolitan Komagome Hospital, Japan. In patients with brain metastasis from lung cancer, we have been able to control local recurrence in approximately 80% of cases. But many of them tend to show brain atrophy with mental deterioration developing a few months after whole brain radiation. To prevent brain atrophy, we have attempted treating patients, whose metastasis was diagnosed as single, by intra-operative radiotherapy (IOR) alone following surgical resection ,,, Fetch PMID: 7709790

Gamma Knife and Stereotactic Radiation

These are attempts to focus the beam so that the Xrays or Gamma rays are kept tightly to the contours of the tumor, and do less scattering through normal tissue. It is impossible with this modality to completely spare normal tissue from any exposure to radiation, but it does help preserve tissue. Search Pubmed for Stereotactic Radiation and Brain Metastases Search Pubmed for Gamma Radiation and Brain Metastases Gamma Knife / Stereotactic Radiation -- Annotated Citations Stereotact Funct Neurosurg 2000;74(1):37-51 Gamma knife radiosurgery for the treatment of brain metastases. Sansur CA, Chin LS, Ames JW, Banegura AT, Aggarwal S, Ballesteros M, Amin P, Simard JM, Eisenberg H. Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201-1595, USA. One hundred and ninety-three patients with brain metastases from various primary sites received Gamma Knife radiosurgery (GKR) from July 1992 to August ,,, Survival follow-up was available on 173 patients. Whole-brain radiation therapy was also administered to 148 of these patients. The median survival was 13.1 months from initial detection of brain metastases, and 7.5 months from GKR. Univariate and multivariate analyses were performed to determine prognostic factors that influenced survival following GKR. Enhanced survival is observed in patients with radiosensitive tumor types, supratentorial tumor, history of brain tumor resection, controlled primary site, and absent extracranial metastases. Local lesion control was obtained in 82% of the patients according to their last follow-up MRI scan. GKR is an effective means of treating patients with brain metastases. Copyright 2000 S. Karger AG, Basel [permission to use abstract obtained] Fetch PMID: 11124663 J Clin Oncol 1990 Apr;8(4):576-82 Comment in: J Clin Oncol. 1990 Apr;8(4):571-3 The treatment of recurrent brain metastases with stereotactic radiosurgery. Loeffler JS, Kooy HM, Wen PY, Fine HA, Cheng CW, Mannarino EG, Tsai JS, Alexander E 3rd. Neurosurgical Service, Brigham and Women's Hospital, Boston, MA. ,,, To be eligible for radiosurgery, patients had to have a performance status of greater than or equal to 70% and have no evidence of (or stable) systemic disease. All but one patient had received prior radiotherapy, and were treated with stereotactic radiosurgery at the time of recurrence. Polar lesions were treated only if the patient had undergone and failed previous complete surgical resection (10 patients). Single doses of radiation (900 to 2,500 cGy) were delivered to limited volumes (less than 27 cm3) using a modified 6MV linear accelerator. ,,, With median follow-up of 9 months (range, 1 to 39), all tumors have been controlled in the radiosurgery field. Two patients failed in the immediate margin of the treated volume and were subsequently treated with surgery and implantation of 125I to control the disease. Radiographic response was dramatic and rapid in the patients with adenocarcinoma, while slight reduction and stabilization occurred in those patients with melanoma, renal cell carcinoma, and sarcoma. The majority of patients improved neurologically following treatment, and were able to be withdrawn from corticosteroid therapy. Complications were limited and transient in nature and no cases of symptomatic radiation necrosis occurred in any patient despite previous exposure to radiotherapy. Stereotactic radiosurgery is an effective and relatively safe treatment for recurrent solitary metastases and is an appealing technique for the initial management of deep-seated lesions as a boost to whole brain radiotherapy. Fetch PMID: 2179476 Neurochirurgie 1999 Dec;45(5):393-7 [Radiosurgery for brain metastases]. [Article in French] Nataf F. Service de Neurochirurgie, CH Sainte-Anne, 1, rue Cabanis, 75674 Paris Cedex 14, France. This article presents the state of art in radiosurgery as a new therapeutic strategy of brain metastases. Radiosurgery of brain metastases is ten years old and we propose to make an update of the literature. X-rays and gamma-rays are commonly used for radiosurgery and does not make a difference for dosimetry and precision. Selected patients for this treatment have usually good Karnofsky status and the mean size of their metastases is about 20 mm. Mean number of metastases treated in the same procedure is 2. Most frequent primary sites are lung and breast, but also kidney and skin (malignant melanoma) which are supposed to be radioresistant and so often untreatable by other techniques. Usual dose administrated ranges between 15 and 25 Grays in center of target with a 80% isodose in peripheral. Results are quite good for local control (80% to 100%) but survival does not seem to be improved (11 months). Radiation complication rate is 4% and sometimes hemorrhagic complications occur (1 to 2%). For local control, quality of life and cost/benefit ratio, there are strong arguments in favor of radiosurgery, especially for radioresistant metastases in spite of the lack of improvement of survival duration. Moreover published studies do not allow any comparison with efficacy of surgery and radiosurgery, whole brain radiosurgery and radiosurgery of the present metastases. Evaluations are still going on in several centers. Their results will allow more precise indications of this technique. Fetch PMID: 10717588 Int J Radiat Oncol Biol Phys. 1991 Jun;20(6):1287-95. Radiosurgery for solitary brain metastases using the cobalt-60 gamma unit: methods and results in 24 patients. Coffey RJ, Flickinger JC, Bissonette DJ, Lunsford LD. Department of Neurosurgery, Mayo Clinic, Rochester, MN 55905. To define the role of stereotactic radiosurgery in the treatment of metastatic brain tumors we treated 24 consecutive patients ... with the 201-source 60Co gamma unit ... All tumors were less than or equal to 3.0 cm in greatest diameter [none were sarcomas]. Twenty patients received a planned combination of 30-40 Gy whole brain fractionated irradiation and a radiosurgical "boost" of 16-20 Gy to the tumor margins; ...During this 23-month period (median follow-up of 7 months) no patient died from progression of a radiosurgically-treated brain metastasis. ... To date, median survival after radiosurgery has been 10 months; 1-year survival was 33.3%. Stereotactic radiosurgery eliminated the surgical and anesthetic risks associated with craniotomy and resection of solitary brain metastases. Radiosurgery also effectively controlled the growth of tumors considered "resistant" to conventional irradiation. Fetch PMID: 1646195

Intraoperative Radiation

Search Pubmed for Intraoperative Radiation and Brain Metastases Acta Neurochir (Wien) 1994;131(1-2):91-6 New treatment protocol by intra-operative radiation therapy for metastatic brain tumours. Nakamura O, Matsutani M, Shitara N, Okamoto K, Kaneko M, Nakamura H, Asai A, Ueki K, Shimizu T, Tanaka Y, et al. Department of Neurosurgery, Tokyo Metropolitan Komagome Hospital, Japan. In patients with brain metastasis from lung cancer, we have been able to control local recurrence in approximately 80% of cases. But many of them tend to show brain atrophy with mental deterioration developing a few months after whole brain radiation. To prevent brain atrophy, we have attempted treating patients, whose metastasis was diagnosed as single, by intra-operative radiotherapy (IOR) alone following surgical resection. Among 43 patients, 19 patients who had no metastases other than the brain metastases, were chosen as subjects for active treatment (surgical resection+IOR). Their 1-year survival rate was 75%. Fourteen out of 27 patients with brain metastases from lung cancer received active treatment and their 1-year survival rate was 74%. This result was not inferior to our result of 71 patients who received surgical resection and whole brain irradiation. When no preventive whole brain irradiation was performed, patients were observed every 8 weeks by CT scan in order to ascertain tumour recurrence limited to the treated site or appearance of any new metastatic lesion remote from the treated site. Among all 43 patients, local recurrence was recognized in 7 cases and remote recurrence was observed in 7 cases. Within 6 months, local and remote recurrence was found in 3 cases each. These results were almost the same as those for the usual therapy (surgery plus whole brain irradiation). If such a new lesion is detected, additional radiation can be performed with the possibility of achieving complete remission. Fetch PMID: 7709790

Radioisotope

Radioisotope treatment of brain cancer is done by brachytherapy, by placing the radioisotope [the source of the radiation] directly in or around the tumor or tumor cavity. It is often done by packaging the radioisotope so that it can be easily physically placed in the cavity where the tumor has ben surgically removed. In the case if Iodine-131, the radioisotope is inside plastic tubing, which allows removal of the pellets. The GlialSite system uses a catheter that has a ballon on it, and the balloon is filled with the radioisotope in solution. At the end of treatment, the liquid from the balloon is removed, deflating the balloon, and the catheter removed. Sometimes radioisotopes are permanently implanted in the surgical cavity. Search Pubmed for Radioisotope Treatment of Brain Metastases Further Information: 1. News Release 16 MAY 2001 Wake Forest University Baptist Medical Center. WINSTON-SALEM, N.C. - Physicians at Wake Forest University Baptist Medical Center are the first in the world to treat a brain tumor patient with the newly FDA-approved GliaSite" Radiation Therapy System (RTS). The GliaSite RTS delivers site-specific, internal radiation to malignant brain tumors, treating the target area while minimizing exposure to healthy tissue. Stephen B. Tatter, M.D., Ph.D., assistant professor of neurosurgery at Wake Forest University School of Medicine, said "GliaSite represents an important new treatment option for malignant brain tumors. Until now, treatment for patients with recurrent brain tumors has been extremely limited. Radiation combined with surgery is the single most effective treatment, and the GliaSite RTS will enable these patients to receive additional radiation, while minimizing the risks associated with external beam radiation." The device is a balloon catheter that is inserted into the cavity created by surgical removal of the malignant brain tumor and filled with liquid radiation. Over a course of three to seven days, GliaSite delivers radiation directly to the tissue surrounding the cavity, where tumors are most likely to recur. ,,, Traditionally, patients are first treated with external beam radiation therapy, in which the radiation travels from outside the body to the tumor site, passing through healthy brain tissue. While this treatment is proven to delay tumor regrowth, a second course of external beam radiation is rarely an option due to the high risk of damage to healthy tissue. "It's a significant advancement to be able to offer an improved therapy that delivers radiation directly to the site of the cancer, while maintaining the quality of life for patients by completing the treatment in just one week," said Tatter. In addition, study results suggest that the survival rate of these patients is favorable in comparison to the next best secondary treatment, which is surgery plus chemotherapy wafers. Safety and performance of the device were demonstrated in a National Cancer Institute (NCI)-sponsored, multi-centered study. Tatter was the principal investigator for the national study, which involved patients with recurrent brain tumors. All of the patients had undergone previous surgery and radiation therapy, and more than half had received chemotherapy. The median survival rate of the patients is currently 14 months, with patients still being followed, a substantial improvement over the results historically seen with other treatments. Additionally, GliaSite has the potential to be used in combination with external beam radiation when treating newly diagnosed tumors, and there is substantial interest in using the device in combination with surgical removal of metastatic brain tumors. The GliaSite RTS was developed by Proxima Therapeutics Inc., a Georgia-based developer and marketer of site-specific cancer treatments. 2. Int J Oncol. 2002 Oct;21(4):817-23. Results of interstitial brachytherapy for malignant brain tumors. Mayr MT, Crocker IR, Butker EK, Williams H, Cotsonis GA, Olson JJ. Department of Neurosurgery, Naval Medical Center Portsmouth, Portsmouth, VA 23708, USA. We evaluated the efficacy of brachytherapy in patients with malignant brain tumors and assessed the factors associated with longer disease control after treatment. From June 1989 to October 1995, 73 patients were treated with stereotactic brachytherapy with temporary placement of iodine-125 implants. ... Eleven patients (16%) developed radiation necrosis. Nine patients (13%) developed other complications. Age and histologic diagnosis were significant predictors of survival from diagnosis. Age and KPS were independent predictors of time to failure after implant. Certain characteristics, specifically younger age (<55), and a higher KPS (Complications, some of which are life-threatening, can and do occur. Fetch PMID: 12239621 3: Neurol Neurochir Pol. 2001;35 Suppl 5:5-11. [Stereotactic biopsy and brachytherapy in the diagnostics and treatment of brain tumors--preliminary report] [Article in Polish] Radek A, Grochal M, Gasinski P, Zielinski K, Kopczynski J, Sobotkowski J, Grzelak M, Lyczak P, Blaszczyk B. Kliniki Neurochirurgii Szpitala Klinicznego Wojskowcj Akademii Medycznej, Lodzi. Promising results have been obtained using brachytherapy in the treatment of brain tumors. Between November 99 and August 2000, 28 patients with brain tumors ... underwent implantation of temporary iridium 192 sources with stereotactic technique. This group received external beam radiation therapy (45 Gy) following implantation. Patients were followed-up with CT scans every 3 months. Serious complications occurred in two patients (postradiation brain oedema)... Fetch PMID: 11935681 4. Int J Radiat Oncol Biol Phys. 2000 Oct 1;48(3):831-6. Extraneural metastatic glioblastoma after interstitial brachytherapy. Houston SC, Crocker IR, Brat DJ, Olson JJ. Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA. This is a report of 3 cases of extraneural metastasis of glioblastoma after interstitial radiation and assessment of pertinent literature addressing concern over an increased risk of these events with this therapy. ... In a series of 82 patients treated with (125)I brachytherapy for primary malignant brain tumors over a 7-year interval, 3 cases of extraneural glioblastoma were identified. The multicatheter technique for delivery of (125)I sources was utilized in all. Extraneural metastases were documented by imaging studies or biopsy. Over the same period, 310 patients with primary malignant brain tumors were treated without brachytherapy. ...Biopsy-proven scalp and skull metastases occurred in 2 patients, at 3 and 8 months following brachytherapy. Each developed radiographic evidence of systemic metastases at 7 and 14 months postbrachytherapy, respectively. The third patient developed biopsy-proven cervical node involvement 4 months after brachytherapy. No patients with malignant gliomas undergoing craniotomy or stereotactic biopsy, but not brachytherapy, during the same time period developed extraneural metastases. Incidence in previously reported series commenting on this otherwise rare process range from 0% to 4.3%. The incidence of extraneural metastases in this series is 3.7% (3/82) and is comparable to those reports. CONCLUSIONS: Percutaneous catheter-delivered brachytherapy may be associated with an increased incidence of extraneural metastatic glioma. [what this means, actually, is that tumor might track along the catheter or incision lines used for the brachytherapy, AND that there might be tumor made metastatic by the procedure. Be Warned. ed.] Fetch PMID: 11020581 5. J Neurooncol. 1997 Jul;33(3):213-21. Permanent low-activity iodine-125 implants for cerebral metastases. Schulder M, Black PM, Shrieve DC, Alexander E 3rd, Loeffler JS. Brain Tumor Center, Brigham and Women's Hospital, Dana Farber Cancer Institute, Boston, MA, USA. schulder@umdnj.edu Beginning in 1987, selected patients with metastatic brain tumors were treated with permanent implants of low-activity radioactive iodine-125(125I) seeds. These patients underwent craniotomy, gross total resection of the metastatic lesion, and placement of the seeds. In general, criteria for treatment included the presence of a recurrent tumor with a volume too large to permit radiosurgery, and a Karnofsky Performance Score of 70 or higher. Thirteen patients underwent 14 implant procedures; all received external whole-brain radiotherapy. Implant dose ranged from 43 Gy to 132 Gy, with a mean of 83 Gy. Survival after implantation ranged from 2 weeks to almost 9 years, with a median of 9 months. Clinical and radiographic local control was obtained in 9 patients. Two patients died of acute, postoperative complications within a month of implantation, so no information regarding tumor control is available for them. Late complications included a bone flap infection in one patient and a CSF leak in another; both were treated without further sequelae. These results demonstrate that permanent 125I implants can results in good survival and quality of life, and occasionally can yield long-term survival. Potentially, it is a cost-effective treatment in that a separate procedure for stereotactic implantation or radiosurgery is not needed, as is the case with the use of temporary high-activity seeds. The permanent implantation itself adds less than 10 minutes to the craniotomy, and the risk of symptomatic radiation necrosis is low. We recommend consideration of this procedure in patients harboring large, recurrent metastatic tumors that require further surgery. Fetch PMID: 9195493 6. Am J Clin Oncol. 1996 Aug;19(4):351-5. Late onset of isolated central nervous system metastasis of liposarcoma--a case report. Arepally G, Kenyon LC, Lavi E. Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia 19104, USA. Metastatic soft-tissue sarcoma of the central nervous system (CNS) is exceedingly rare. We report a case of a 56-year-old male treated for a right lower extremity liposarcoma at the age of 30 years, whose first recurrence was an intracerebral metastasis occurring 26 years after resection of the primary tumor. Initial treatment of the metastasis with surgical resection and adjuvant radiotherapy was followed rapidly by CNS recurrence in 3 months. Further debulking and interstitial brachytherapy were unsuccessful in controlling disease progression. Clinical presentation and treatment of brain metastases in soft-tissue sarcoma are discussed. Fetch PMID: 8677903 7. Neurosurg Clin N Am. 1996 Jul;7(3):485-95. Interstitial brachytherapy for intracranial metastases. McDermott MW, Cosgrove GR, Larson DA, Sneed PK, Gutin PH. Department of Neurosurgery, University of California at San Francisco, USA. In large medical centers, the availability of radiosurgery has relegated brachytherapy to a lesser role in the treatment of newly diagnosed solitary brain metastases. However, the treatment planning in radiosurgery is complex, and in some case the hardware is prohibitively expensive; low or high dose rate brachytherapy requires only a stereotactic frame, commercially available software, and encapsulated radionuclides or newer tiny linear accelerators. Interstitial brachytherapy also remains an option for the treatment of recurrent solitary metastases when other forms of treatment have failed. This article reviews the radiobiology of low and high dose rate interstitial brachytherapy, the University of California San Francisco (UCSF) results using iodine-125 implants, and early experience with the photon radiosurgery system (PRS) at Massachusetts General Hospital for the treatment of brain metastases. Fetch PMID: 8823776 8. Can J Neurol Sci. 1995 Feb;22(1):13-6. Brachytherapy for recurrent single brain metastasis. Bernstein M, Cabantog A, Laperriere N, Leung P, Thomason C. Division of Neurosurgery, Toronto Hospital, Ontario, Canada. Of 112 stereotactic high-activity iodine-125 implants for malignant brain tumors done as of July 1, 1994, ten have been done for recurrent single brain metastasis and constitute the study group described herein. All patients had initially undergone craniotomy for tumor resection followed by fractionated external beam whole brain radiation and recurred at the same site in the brain. The interval between initial cancer therapy and occurrence of the brain metastasis was 13-156 weeks (median: 63 weeks). The interval between initial treatment of the brain metastasis and its recurrence treated with brachytherapy was 13-69 weeks (median: 35 weeks). Minimum brachytherapy dose administered was 70 Gy at a median dose rate of 67 cGy/hour. Eight patients have died. Two died suddenly at 2 and 13 weeks post-implant of presumed pulmonary embolus. Five died of recurrence of the brain metastasis at 20, 39, 52, 103, and 143 weeks post-implant, and one died of systemic metastases at 40 weeks post-implant. Two patients remain alive 183 and 324 weeks post-implant. High-activity iodine-125 brachytherapy appears to be of benefit for selected patients with recurrent single brain metastasis but larger, and preferably randomized studies are needed. Fetch PMID: 7750066 9. Acta Neurochir Suppl (Wien). 1995;63:29-34. Interstitial irradiation of brain metastases. Alesch F, Hawliczek R, Koos WT. Neurochirurgische Universitatsklinik, Wien, Austria. Randomized studies have shown that survival in patients with single brain metastases is significantly higher after the combined treatment of surgical removal and whole-brain irradiation than after whole-brain radiation therapy alone. In patients with deep-seated lesions or those located in critical sites of the brain, as well as in cases in which the patient's general condition makes general anaesthesia difficult or impossible microsurgical resection usually cannot be performed or only with an increased surgical risk. Stereotactic radiosurgery, which can be done by means of convergent beam irradiation or by the implantation of highly loaded 125I seeds, provides an alternative to open procedures. In the following we report on our results using a stereotactic radiosurgical technique. A series of 20 treatments is presented, in which biopsy was performed and 125I seeds were implanted, both under stereotactic conditions in the same session. The 125I seeds were sealed in a teflon catheter, were left indwelling temporarily, and then removed after application of the prescribed radiation dose (6,000cGy at the tumour margin). There was only one recurrence in our series, complications occurred in only one patient by temporary aggravation of a pre-existing hemiparesis. Our results indicate that interstitial irradiation of brain metastases is a valuable, less stressful alternative to both open microsurgery as well as to stereotactic radiosurgical convergent beam irradiation. Fetch PMID: 7502724 10. Br J Neurosurg. 1995;9(5):593-603. Comment in: Br J Neurosurg. 1996 Apr;10(2):229. Interstitial iodine-125 radiosurgery for cerebral metastases. Ostertag CB, Kreth FW. Abteilung Stereotaktische Neurochirurgie, Neurochirurgische Universitatsklinik Freiburg, Germany. The current study evaluates the efficacy of interstitial 125-iodine radiosurgery (brachytherapy) in 93 patients with circumscribed, spherical, mostly solitary metastases. In all patients the histological diagnosis was established by stereotactic biopsy. The treatment results of three therapeutic regimens have been examined retrospectively: Group A (38 patients) had interstitial radiosurgery with a reference tumour dose of 60 Gy in combination with percutaneous radiotherapy (40 Gy). Group B (34 patients) was treated by interstitial radiosurgery alone (reference dose 60 Gy). Group C (21 patients with recurrent metastases after previous radiotherapy/surgery) was treated by interstitial radiosurgery alone (reference dose 60 Gy). Median survival after interstitial radiosurgery was 17 months in group A, 15 months in group B, 6 months in group C. Favourable prognostic factors were a Karnofsky performance rating > or = 70, solitary metastasis, absence of disseminated disease, and a time interval > 1 year between diagnosis of the primary tumour and diagnosis of the cerebral metastases. Interstitial radiosurgery plus percutaneous radiotherapy did not prove to be superior to interstitial radiosurgery alone. No patient died of a locally irradiated metastasis. We conclude that interstitial radiosurgery achieves control of the growth of solitary spherical cerebral metastases in any location without radiation toxicity. [This may not be true of sarcomas. Ed.] Fetch PMID: 8561931

Proton Beam Therapy

Proton radiation is a form of external-beam radiation treatment. Radiation oncologists (physicians who specialize in radiation treatments) can treat in two major ways: by implanting radioactive materials in the body [brachytherapy] or by using machines to generate beams that penetrate the body from outside [external beam]. Proton radiation is delivered by the second method. Other forms of external-beam radiation therapy include x-ray therapy and Cobalt-60 gamma-ray therapy. External beam radiation does not remain in the body. Your body does not become radioactive, and there is no risk of radiation exposure to others. Proton beam therapy is an external beam radiation treatment that delivers high dose radiation to a very localized site. Protons, being particles instead of x-rays, slow down faster than photons. They deposit more energy as they slow down, culminating in a peak (called a Bragg peak). This allows the majority of radiation to be delivered to the target site with less scattering of radiation around and beyond to the adjacent normal tissues. Proton beams can be conformed [shaped in three dimensions] to fit the target area. The beam can be carefully shaped to the dimensions of the tumor, and so deliver most of the radiation to the targeted tumor mass, not to the surrounding normal tissue. This tissue-sparing is unique to proton beam therapy. Proton beam radiotherapy contrasts with conventional Xray or Gamma ray radiation therapy [often called PHOTON beam] due to the unique properties of minimal scatter as the proton beams pass through the tissue, and deposit the ionizing energy at a precise depth (the Bragg peak). Thus radiation exposure to surrounding normal tissues is minimized, permitting higher radiation doses to the target area and improved local control, with less damage and side effects. Protons, which are positively charged subatomic particles, deposit energy differently than x-ray beams do. Compared to an x-ray beam, a proton beam that is delivered with sufficient energy (or "modulated") has a low "entrance dose" (the dose in front of the tumor), a high-dose "Bragg peak" region, which is designed to cover the entire tumor, and no "exit dose" beyond the tumor. In contrast, X-ray beams may deposit most of their dose in tissues in front of the tumor, and continue to sleet through the body after passing through the target area. As of November 1, 2002, more than 32,000 patients around the world had been treated with proton beam radiotherapy. The effectiveness of proton beams for treating cancer show in almost every tumor site examined. The higher tumor doses and lower normal-tissue exposure have improved local control and reduced acute and late complications as compared with x-ray therapy. [from Loma Linda website information] As of November 2003 there are two major hospital-based facilities that treat patients with proton beams on a regular basis: Loma Linda University Medical Center (LLUMC), in southern California and the Northeast Proton Treatment Center, which opened in November 2001 at Massachusetts General Hospital in Boston. Another U.S. facility, the Midwest Proton Radiotherapy Institute will open at Indiana University, soon. About Loma Linda Current Opinion in Orthopaedics 2002; 13(6):434-439 Proton beam therapy in the management of bone and soft tissue sarcomas Thomas F. DeLaney, MD For cancer treatment, protons, the nuclei of hydrogen atoms, can be accelerated to high energies, extracted, and transported to treatment rooms where the proton beam undergoes a series of modifications (spreading, modulation, and shaping) that conform the dose in a particular patient to the tumor target. Because of their charge and mass, there is no dose delivered beyond the desired target. Proton beam therapy thus provides a means to reduce both the volume of irradiated normal tissues and the radiation dose they receive. This may permit higher doses to the tumor and achieve a higher tumor control probability without increasing the frequency or severity of treatment-related morbidity. Additionally, the more conformal treatment volumes of proton therapy should result in a reduced frequency and severity of comorbidity between radiation and chemotherapy, thus allowing for improved tolerance of the patient to therapy, better treatment compliance, and increased treatment intensity. For more information Search Pubmed Proton Beam and Sarcoma Search Pubmed Proton Beam and Brain Metastases Go To Proton Page About proton beam

Fast Neutrons

There will be two applications of Neutron bombardment discussed here. One is Fast Neutrons, the other is Boron Neutron Capture Therapy. Fast Neutrons Treatment with Fast Neutrons is done at the Midwest Institute for Neutron Therapy at Fermilab. High energy neutron therapy [also called fast neutron therapy] is appropriate for patients with localized brain metastasis from primary sarcoma. For more information Go To Neutrons Page Boron Neutron Capture Therapy [BNCT] for Brain Tumors Treatment of some primary brain cancers by surgery, chemotherapy, and conventional radiation has had only limited success. These tumors recur, usually close to the original margins. Effective therapy must cover a larger volume that has been defined. The problem is how to achieve eradication of all tumor cells without damaging or destroying normal brain cells. Boron neutron capture therapy [BNCT] is based on a nuclear reaction that occurs when the stable isotope boron-10 is irradiated with neutrons to produce boron-11. Boron-11 is not stable, and it undergoes immediate nuclear fission to produce high energy alpha particles and lithium-7 nuclei. These heavy charged particles have path lengths of approximately the diameter of a cell, so deposit most of their energy, and do most of their damage, within the cells that contain boron. If enough low energy neutrons reach the boron-10, and the boron-10 is selectively delivered to the tumor in higher amounts than to the normal tissues, then the tumor cells can be destroyed selectively because of the Boron capture reaction. Results of clinical trials in the 1950's and '60's required more tumor selective boron-containing drugs, and higher energy neutron beams with greater tissue penetrating properties. The development of reactor based epithermal beams is available in the US, Japan, Argentina, and several European countries. Molecular targeting of tumor cell's overexpressed receptors [like EGFR and PDGF] is being actively researched. BNCT is an experimental technique. Journal of Neuro-Oncology 62: 1-5, 2003. A critical assessment of boron neutron capture therapy: an overview Rolf F. Barth Dept of Pathology, Ohio State University, Columbus OH USA Full Text Article For More Information Search Pubmed for Boron Neutron Capture and Brain Metastases Annotated Medical Journal Citations" Neurooncol. 2003 Mar-Apr;62(1-2):101-9. Assessment of the results from the phase I/II boron neutron capture therapy trials at the Brookhaven National Laboratory from a clinician's point of view. Diaz AZ. Roswell Park Cancer Institute, Buffalo, NY 14263, USA. aidnag.diaz@roswellpark.org Boron neutron capture therapy (BNCT) represents a promising modality for a relatively selective radiation dose delivery to the tumor tissue. The key to effective BNCT of tumors such as glioblastoma multiforme (GBM) is the homogeneous preferential accumulation of 10B in the tumor, including the infiltrating GBM cells, as compared to that in the vital structures of the normal brain. ... it is the ratio of the 10B concentration in tumor cells to that in the normal brain cells and the blood that will largely determine the therapeutic gain of BNCT. Clinical Trial, Phase II Fetch PMID: 12749706 2: J Neurooncol. 2003 Mar-Apr;62(1-2):111-21. A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease. Busse PM, Harling OK, Palmer MR, Kiger WS 3rd, Kaplan J, Kaplan I, Chuang CF, Goorley JT, Riley KJ, Newton TH, Santa Cruz GA, Lu XQ, Zamenhof RG. Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. pbusse@caregroup.harvard.edu A phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. ...Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT. Clinical Trial, Phase I Fetch PMID: 12749707 compiled by doctordee November 2003

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