Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases.

BACKGROUND: The spread of systemic cancer to the brain is a common complication for cancer patients. Conventional radiotherapy offers modest palliation, and surgery is helpful only for the patient with a single metastasis in an accessible location. Stereotactic radiosurgery, a technique that permits the precise delivery of a high dose of radiation to a small intracranial target while sparing the surrounding normal brain, has been used as an alternative treatment for brain metastases. PURPOSE: Our medical center's 7-year experience with radiosurgery for metastases was reviewed to establish the effectiveness of the treatment and to understand the prognoses in patients so treated. METHODS: Retrospective analysis of hospital records, from 248 consecutive patients (421 lesions) that were treated with radiosurgery between May 1986 and May 1993, was performed. Patients were only excluded for a Karnofsky performance score of less than 70, evidence of acute neurologic deterioration, or tumor diameter more than 4 cm. Median follow-up was 26.2 months. Seventy-six percent of patients had recurrent disease, 69% had evidence of systemic disease, 69% had a single metastasis. Treatment was performed using a 6-MeV linear accelerator. The median tumor volume was 3 cm3. The median treatment dose was 1500 cGy. Whole brain radiotherapy was given to all newly diagnosed patients. Patients were followed by neurological examination and neuroimaging at regular intervals. Local control of disease was defined as a lack of progression of solid-contrast enhancement on computed tomography scan or magnetic resonance imaging. RESULTS: Median overall survival from radiosurgery was 9.4 months. The absence of active systemic disease, younger than 60 years of age, two or fewer lesions, and female sex were significantly associated with increased survival (two-sided P < .05). Actuarial local control rates were approximately 85% at 1 year and 65% at 2 years. Factors associated with a significantly decreased local control rate were location below the tentorium, recurrent tumor, and larger tumor volume (two-sided P < .05). Radioresponsive and radioresistant tumor types had similar control rates. The median drop in Karnofsky performance score at 1 year was 10%. CONCLUSIONS: The results of this retrospective analysis show that radiosurgery is an effective, minimally invasive outpatient treatment option for small intracranial metastases. Results of this study also indicate that radiosurgery not only provides local control rates equivalent to those from surgical series but is also effective in treating patients with surgically inaccessible lesions, with multiple lesions, or with tumor types that are resistant to conventional treatment.

Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma.

Recent studies have shown a survival benefit for patients with recurrent glioblastomas treated with stereotactic brachytherapy. On the basis of these encouraging results, we began a prospective study in 1987 to evaluate the use of brachytherapy in patients with newly diagnosed glioblastoma. Patients were considered eligible for this study if they met the following criteria: Karnofsky performance status 70% or greater; tumor size not greater than 5 cm in any dimension; a radiographically well delineated, supratentorial lesion not involving the ependymal surfaces; and pathologically confirmed glioblastoma. We treated 35 such patients between 1987 and 1990 with stereotactic brachytherapy as part of their initial therapy. The treatment protocol involved surgery, partial brain external-beam radiotherapy (59.4 Gy in 33 fractions), and stereotactic brachytherapy with temporary high-activity iodine 125 sources giving an additional 50 Gy to the tumor bed. Chemotherapy was not used in the initial management of these 35 patients. To compare our results with those obtained in a matched control group, we identified 40 patients with glioblastoma treated with surgery and external radiotherapy, with or without chemotherapy, between 1977 and 1986 at our institution. These patients had clinical and radiographic characteristics that would have made them eligible for the brachytherapy protocol. Survival rates at 1 and 2 years after diagnosis were 87% and 57%, respectively, for patients receiving brachytherapy versus 40% and 12.5%, respectively, for the controls (P less than .001). We conclude that stereotactic brachytherapy improves the survival of patients with glioblastoma when it can be incorporated into the initial treatment approach. Unfortunately, only about one in four patients with glioblastoma are suitable candidates for brachytherapy at the time of initial presentation.

Emergency prebiopsy radiation for mediastinal masses: impact on subsequent pathologic diagnosis and outcome.

From 1968 to 1983, 19 patients were treated at the Joint Center for Radiation Therapy for symptomatic mediastinal masses before a biopsy was obtained. This study evaluates the impact of radiation on the ability to establish a pathologic diagnosis and the results of subsequent empirical therapy if no diagnosis was established. Eight of the 19 (42%) patients were not able to have a histologic diagnosis established at the time of biopsy. Seven of these eight patients went on to receive empiric therapy for what was thought to be the most likely diagnosis on clinical grounds. Four of the seven have not relapsed; three who have relapsed were found to have the diagnosis for which they were empirically treated. The untreated patient relapsed with seminoma. Thus, the use of emergency irradiation for mediastinal masses is sometimes associated with the loss of pathologic diagnosis. These patients likely have a radioresponsive disease (ie, lymphoma or seminoma) that may be treated successfully on the presumed clinical diagnosis even when the histologic diagnosis is lost secondary to prebiopsy irradiation.

Primary lymphoma of bone in children: analysis of treatment results with adriamycin, prednisone, Oncovin (APO), and local radiation therapy.

Primary lymphoma of bone is an unusual extranodal presentation of pediatric non-Hodgkin's lymphoma (NHL). Treatment with radiotherapy alone has resulted in a disease-free survival rate of approximately 50% in most adult series. Between January 1973 and April 1985, 11 children with biopsy-proven NHL of bone were seen and treated at our institutions. The minimal clinical staging included chest and bone radiographs, a radionuclide bone scan, complete blood cell counts and serum chemistries, and a bone marrow aspirate and biopsy. The age range was 9 to 17 years with a median age of 14 years. Histology included diffuse lymphoblastic lymphoma in four patients and diffuse histiocytic lymphoma in seven. Each patient was treated with the Adriamycin/prednisone/Oncovin (APO) protocol and ten patients received concomitant radiation to the whole bone when possible and a boost to the primary lesion(s). The median tumor dose was 5,000 rad (range, 3,600 to 5,600). The median follow-up was 8 years. There have been no relapses, but two patients have developed second bone tumors 5 and 7 1/2 years after beginning therapy. Each second tumor arose directly in the radiation field. The overall 8-year actuarial survival is 83%. We conclude that APO and local radiation results in excellent overall survival for children with primary NHL of bone. The occurrence of two second bone tumors, however, raises questions regarding dose and/or the role of radiation for this disease.

Radiosurgery as part of the initial management of patients with malignant gliomas.

PURPOSE: Between May 1988 and May 1991, 41 patients with malignant gliomas were enrolled onto a prospective study designed to evaluate the role of radiosurgery as a component of initial management. PATIENTS AND METHODS: Thirty-seven patients underwent radiosurgery according to the protocol and were assessable for survival and complications of treatment. Diagnoses included glioblastoma multiforme (GBM) in 23 (62%) cases and anaplastic astrocytoma in 14 (38%) cases. In 20 (54%) cases, surgical resection was attempted initially, whereas 17 (46%) patients underwent biopsy only. Patients in the study group received external-beam radiotherapy that consisted of 5,940 cGy given in 33 fractions to partial brain fields that encompassed the primary tumor with a 3 to 4 cm margin. Radiosurgery, used as a technique for boosting the dose to any residual contrast-enhancing mass lesion, was given 2 to 4 weeks after the completion of conventional radiotherapy. Minimum radiosurgical doses ranged from 1,000 to 2,000 cGy (median, 1,200 cGy), whereas maximum doses ranged from 1,250 to 2,500 cGy (median, 1,500 cGy). The median tumor volume at the time of radiosurgery was 4.8 cm3 (range, 1.2 to 72 cm3). Adjuvant chemotherapy was not given. RESULTS: After a median follow-up of 19 months, only nine of 37 (24%) patients have died. Six patients (all glioblastoma multiforme) died of recurrent tumor, whereas death was attributable to complications of treatment in two cases and intercurrent disease in one case. Four patients with recurrent tumor failed at the margins of the radiosurgical treatment volume, whereas two patients progressed locally. One patient is alive with local and marginal failure. Seven (19%) patients underwent reoperation at a median time of 5 months (range, 1 to 14 months) after radiosurgery. CONCLUSION: We conclude that radiosurgery is a useful adjunct to other modalities in the initial management of patients with small, radiographically well-defined malignant gliomas.

The treatment of recurrent brain metastases with stereotactic radiosurgery.

Between May 1986 and August 1989, we treated 18 patients with 21 recurrent or persistent brain metastases with stereotactic radiosurgery using a modified linear accelerator. 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. The most common histology of the metastatic lesion was carcinoma of the lung (seven patients), followed by carcinoma of the breast (four patients), and melanoma (four patients). 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.

Primary lymphomas of the central nervous system: patterns of failure and factors that influence survival.

Primary lymphomas of the CNS are rare tumors accounting for less than 2% of all extranodal non-Hodgkin's lymphomas. The treatment for this disease has been disappointing. Radiation therapy and surgery have produced consistently poor control of this disease, with a median survival of 15 months. We have reviewed ten cases of primary lymphoma of the CNS treated at the Joint Center for Radiation Therapy or Dana-Farber Cancer Institute (Boston) from 1968 to 1981. All patients had biopsy-proven CNS lymphomas without systemic disease at presentation. In our series, control of CNS lymphoma was seen only in patients receiving craniospinal radiation or CNS-penetrating chemotherapy.

Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.

PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.

A phase I trial of a new recombinant human beta-interferon (BG9015) for the treatment of patients with recurrent gliomas.

Primary brain tumors represent an important cause of cancer-related morbidity and mortality in the United States. Despite advances in neurosurgery and radiotherapy, the median survival of patients with malignant gliomas remains less than 1 year. A contributing factor to the poor prognoses of these patients is the diffuse, infiltrative nature of these tumors, which limits the effectiveness of focal therapies (i.e., surgery and radiation). Unfortunately, standard chemotherapy has been of limited benefit in the treatment of malignant gliomas, underlying the necessity for new drugs with novel mechanisms of action. On the basis of promising in vitro and clinical data demonstrating significant antiglioma activity of purified IFN-beta and a synthetic IFN-beta (Betaseron), we conducted a Phase I trial of a new, nonmutated, glycosylated recombinant human IFN-beta (BG9015) in patients with recurrent, high-grade astrocytomas. In this trial, we demonstrate that the maximally tolerated dose of BG9015 is 6 million units/m2 delivered by intramuscular injection three times per week. Dose-limiting neurotoxicity was seen in both patients treated at 8 million units/m2. Additionally, we demonstrate that high BG9015 serum levels are associated with a fall in natural killer cell number, radiographic response, and prolonged survival. We conclude that BG9015 has activity in patients with malignant gliomas, although the therapeutic index may be narrow. Future studies will be needed to confirm the observation that natural killer cell number and activity as well as BG9015 serum levels are important markers of antitumor activity.

Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas.

PURPOSE: Analysis of tumor-derived genetic lesions has provided insights into molecular pathogenesis of human gliomas. Because these changes represent only one of several mechanisms that alter gene expression during tumorigenesis, it is likely that further information will be obtained from a careful analysis of important regulatory proteins present in these tumors. EXPERIMENTAL DESIGN: We have quantified the levels of key cell cycle/signaling proteins in 94 prospectively collected, meticulously preserved, "snap frozen" glioma specimens and have compared these levels with histopathological data and patient outcome. RESULTS: The results of these experiments confirm that the levels of wild-type tumor suppressor proteins, such as p53, pRB, PTEN, p14(ARF), and p16(INK4), are lost or severely reduced in most gliomas, and that epidermal growth factor receptor, 2human telomerase reverse transcriptase, and cyclin-dependent kinase 4 are overexpressed frequently and with a few exceptions, almost exclusively, in glioblastomas. In addition, we report frequent underexpression of E2F-1 (in 55% of gliomas) and cyclin E overexpression (in 26% of gliomas), which have not yet been reported on the genomic level. Several of these markers significantly correlated with histopathological grade, and the levels of five proteins showed significant association with patient outcome. In particular, overexpression of epidermal growth factor receptor, human telomerase reverse transcriptase, cyclin-dependent kinase 4, and cyclin E was largely restricted to glioblastomas and was significantly associated with reduced patient survivals. CONCLUSIONS: We conclude that the quantitation of cell cycle/signaling proteins from meticulously preserved glioma specimens provides further insights into the molecular pathogenesis of human gliomas and yields valuable prognostic information.

Systemic metastasis in glioblastoma may represent the emergence of neoplastic subclones.

Glioblastomas only rarely metastasize to sites outside the central nervous system, for reasons that are poorly understood. We report the clinicopathological and molecular genetic findings in 6 patients with metastatic glioblastoma. Four patients were under the age of 32 and all but 1 patient died within 2 yr of diagnosis. The number of metastases ranged from 1 to 3. At the time of death, 3 patients had apparent tumor control at their primary site. We evaluated DNA from both primary and metastatic glioblastomas for genetic alterations commonly found in glioblastomas: TP53 mutations, CDKN2A/p16 deletions, EGFR amplification, and allelic loss of chromosomes 1p, 10q and 19q. Four of 6 cases had TP53 mutations and only single cases had EGFR amplification, CDKN2A/p16 deletions, or allelic loss of 1p, 10q and 19q; 2 cases had no detectable genetic alterations. In 2 cases, the primary and metastatic tumors had identical genotypes. Remarkably, however, 2 cases had different TP53 alterations in the primary and metastatic lesions, or among the metastatic tumors, which suggests that some metastatic deposits may represent emergence of subclones that were not necessarily dominant in the primary tumor. The present observations and a review of the recent literature demonstrate that metastatic glioblastomas tend to occur in younger adults who do not follow long clinical courses, and may be characterized by TP53 mutations and differential clonal selection.

Complications of therapy for venous thromboembolic disease in patients with brain tumors.

Venous thromboembolic disease is a frequent complication in patients with intracranial malignancies. Because these patients are often perceived to be at increased risk of intracranial hemorrhage with anticoagulation, inferior vena cava (IVC) filters are frequently used in their treatment. We reviewed the records of 49 patients with intracranial malignancies and venous thromboembolic disease to determine the effectiveness of, and the complications resulting from, treatment. Of the 42 patients receiving IVC filters, a strikingly high percentage (62%) developed complications. Twelve percent developed recurrent pulmonary embolism, while 57% developed either IVC or filter thrombosis, recurrent deep venous thrombosis, or post-phlebitic syndrome. These complications severely reduced the quality of life of the affected patients. Only 15 of our patients were treated with anticoagulation, and seven of these received it because of continued thromboembolic disease. None of these 15 patients had proven hemorrhagic complications. This study suggests that the complication rate of IVC filters in patients with brain tumors is higher than commonly perceived and may outweigh the risk of anticoagulation.

The potential role of proton beams in radiation oncology.

Historically, major gains in the local control of large, deep-seated tumors treated with radiation have occurred whenever dose distributions have become more localized to the tumor. Better dose localization permits the delivery of higher tumor doses while delivering less dose to dose-limiting normal tissues. High-energy protons, because they stop abruptly in tissue at the end of their range and deposit most of their energy there, provide dose distributions that are superior to x-rays when used in comparable beam configurations. The installation of a hospital-based proton therapy facility at the Massachusetts General Hospital in Boston, MA, and the existing facility at Loma Linda University Medical Center, Loma Linda, CA, provide a potential for achieving higher rates of local control in tumors throughout the body.

Stereotactic radiosurgery and radiotherapy: new developments and new directions.

Stereotactic irradiation is a precise method for the delivery of focused radiation beams to small intracranial targets. Treatment can be administered in single or multiple fractions (radiosurgery or stereotactic radiotherapy, respectively). The technology has evolved rapidly because of advances in both hardware and software design. Clinical indications are unfolding through the prospective trial mechanism.

Pneumocystis carinii pneumonia during steroid taper in patients with primary brain tumors.

Pneumocystis carinii causes life-threatening pneumonitis (PCP) in immunocompromised individuals. In the non-AIDS (acquired immunodeficiency syndrome) population, PCP is frequently associated with corticosteroid therapy, and the rodent model uses corticosteroid-induced immunosuppression to provoke PCP. Although patients with intracranial tumors are frequently treated with long courses of corticosteroids, there have been very few descriptions of PCP in this population. We report the diagnosis and treatment of PCP in four patients over a 12-month period with intracranial neoplasms who developed symptoms during corticosteroid taper. Effective prophylaxis against PCP exists and should be considered for patients with intracranial neoplasms receiving long-term steroids.

The development of Graves' disease following radiation therapy in Hodgkin's disease.

Radiation-related thyroid dysfunction is a common occurrence in patients with Hodgkin's disease treated with mantle field radiation. Although chemical and clinical hypothyroidism are most commonly seen, Graves' disease has also been described. We have examined the records of 437 surgically staged patients who received mantle field irradiation between April 1969 and December 1980 to ascertain the frequency of manifestations of Graves' disease. Within this group, seven patients developed hyperthyroidism accompanied by ophthalmic findings typical of those seen in Graves' disease. The actuarial risk of developing Graves' disease at 10 years following mantle irradiation for Hodgkin's disease was 3.3% in female patients and 1% in male patients in this study. The observed/expected ratios were 5.9 and 5.1 for female and male patients, respectively. This observed risk significantly exceeded that seen in the general population.

Extremity preservation by combined modality therapy in sarcomas of the hand and foot: an analysis of local control, disease free survival and functional result.

A primary tumor arising in the hand or foot represents an uncommon presentation for patients with Ewing's sarcoma (ES) or soft tissue sarcoma (STS). While there exists considerable literature on the treatment of extremity sarcomas, very little deals specifically with lesions of the hand or foot. It remains controversial whether these lesions can be successfully treated with combined modality therapy which preserves the extremity and maintains function. From 1972 to 1979, 10 patients with sarcomas arising in the hand or foot were treated with combined modality therapy at the National Cancer Institute. Seven patients with ES of bone received local irradiation to 5000 rad and combination chemotherapy following an incisional biopsy. Three patients with STS received a gross tumor excision and local irradiation to 6000 rad. One STS patient also received combination chemotherapy. Local control was achieved in nine patients (90%) with a follow-up of 30-119 months (median 56 months). These patients have complete or almost complete function of the treated extremity. Nine patients are alive with five patients remaining disease-free following the initial combined modality treatment. Two patients with Ewing's sarcoma relapsed (1 patient with both local and distant failure) at 26 and 58 months and were again rendered disease-free with surgery, total body irradiation and further chemotherapy. One patient relapsed for a second time, being disease-free from the first relapse for 30 months. We conclude that for selected patients with sarcomas arising in the hand or foot, combined modality therapy which leaves the extremity intact results in excellent local tumor control and preserves function. Careful treatment planning is an essential aspect of successful radiation therapy of a hand or foot primary. Our treatment recommendations are outlined. This approach is a viable alternative to amputation in these patients.

A 10-year experience of pediatric brachytherapy.

PURPOSE: The purpose of this project was to review the brachytherapy experience in the pediatric population at the Joint Center for Radiation Therapy (JCRT) with respect to efficacy and morbidity. METHODS AND MATERIALS: Treatment outcome was reviewed for 18 children between the ages of 6 months and 23 years who received 19 implants between 1982 and 1992 at JCRT. Fourteen children received permanent Iodine-125 seed implants placed in the operative tumor bed at the time of resection. Two children received sterotactically placed afterloaded high-activity I-125 seed brain implants, and one child received a high-activity I-125 brain implant followed by a permanent I-125 seed brain implants 3 years later. One girl received a temporary Iridium-192 volume implant for a vulvar rhabdomyosarcoma. Among the 15 permanent I-125 implants, the cases included five primary brain tumors, one metastatic brain tumor, six sarcomas, and one each of the following: suprarenal neuroblastoma, hepatoblastoma, and adenocarcinoma of the pancreas. All patients underwent surgery and most patients (15 out of 18) received external beam radiotherapy to a field that included the implant. RESULTS: The median follow-up from the time of diagnosis for patients who remain alive is 55 months (range 24 to 119 months), and the median follow-up from the time of implant is 46 months (15 to 60 months). Disease was controlled in the area of the implant in 13 of 17 evaluable cases. Two patients experienced treatment-related morbidity; one patient developed severe desquamation related to an "adriamycin recall reaction," and one patient died of postoperative complications. CONCLUSION: Despite the heterogeneous mix of cases, the use of brachytherapy in this pediatric population resulted in several cases of long-term disease control, and the overall morbidity was very low. Therefore, in properly selected pediatric cases, brachytherapy appears to be an efficacious adjunct to multimodality cancer management.

A phase I study of etanidazole and radiotherapy in malignant glioma.

PURPOSE: To determine the maximum tolerable total dose (MTD) of etanidazole (ETA) when administered with external beam radiotherapy (XRT) and as a continuous infusion during stereotactic brachytherapy for patients with malignant glioma (anaplastic astrocytoma or glioblastoma multiforme or mixed cell tumors). METHODS AND MATERIALS: Seventy previously untreated patients were entered in a Phase I study. Prior to initiation of treatment, patients were stratified according to whether or not they were candidates for interstitial implantation. The implant patients (IMP, n = 17 pt) received accelerated fractionation XRT 20 Gy BID (6 h apart) to 40 Gy in 2 weeks with ETA 2 gm/m2 x 6 doses, a 2 week break and then interstitial implant to 50 Gy (4-7 days) with a continuous infusion of ETA over 90-96 h. The two sequentially conducted nonimplant arms started with accelerated fractionation XRT 2 Gy BID (6 h apart) to 40 Gy in 2 weeks with ETA 2 gm/m2 x 4-5 doses/week. NonIMP 1 arm (n = 38) received a 2-week break before standard fractionated boost XRT of 20 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. NonIMP 2 arm (n = 14) did not have the 2-week break. All patients had plasma pharmacokinetic monitoring of ETA. RESULTS: The dose-limiting toxicity (DLT) in the IMP group was the cramping/arthralgia syndrome (4) and the cumulative MTD was 26 gm/m2. For both nonIMP 1 and 2 the DLTs were peripheral neuropathy and the cramping-arthralgia syndrome. The MTD for nonIMP 1 was 34 gm/m2 and nonIMP 2, 30 gm/m2. CONCLUSION: The clinical efficacy and radiation-related toxicity of these regimens are being evaluated. The doses of ETA that can be used with accelerated fractionation and with external beam irradiation plus brachytherapy have been established.

Variables associated with the development of complications from radiosurgery of intracranial tumors.

Between 5/21/86 and 11/1/89, we treated 64 recurrent or inoperable intracranial tumors in 60 patients (40 primary, 24 metastatic) with stereotactic radiosurgery using a modified 6 MeV linear accelerator at the Joint Center for Radiation Therapy. Patients were followed until death or 1/1/90. The median follow-up was 8 months (2-43 months). Fourteen patients experienced complications from 12 hours to 7 months (median 3 months, but only two patients more than 4 months) following radiosurgery. To determine variables related to complication, we calculated integral dose-volume histograms for 61/64 lesions and the surrounding CT-defined normal tissue. We excluded 16 lesions in 15 patients for follow-up less than 4 months (12 patients) or insufficient treatment information (3 patients). The variables for which higher values were associated with significantly more toxicity in a univariate score test were: a) tumor dose inhomogeneity (p less than 0.00001), b) maximum tumor dose (p = 0.00002), c) number of isocenters (p = 0.00002), d) maximum normal tissue dose (p = 0.00005) and e) tumor volume (p = 0.0001). These variables were all highly correlated with tumor dose inhomogeneity (coefficients of rank correlation 0.75-0.81). Tumor dose inhomogeneity had a much higher loglikelihood in a logistic model than any other single variable and a higher loglikelihood than any other two variables combined. None of the 21 patients with metastatic lesions experienced a complication. When we excluded the metastatic lesions, the above five variables remained significant in univariate tests. The mean tumor dose, number of treatment arcs, total degrees of arc, tumor location, previous radiotherapy, tumor geometry, pretreatment performance status, collimator size, and age were not significantly associated with toxicity. We conclude that radiosurgery of intracranial tumors is associated with a low risk of complications for lesions less than 10cc treated with a single isocenter to maximum tumor doses less than 25 Gy with tumor dose inhomogeneity less than 10 Gy, but that treatment of larger lesions will require new treatment strategies which reduce the tumor dose inhomogeneity associated with multiple isocenter treatments.