PURPOSE: Patients with refractory solid tumors were treated with the combination of fractionated radiation therapy and multiple-dose intravenous tirapazamine to determine the toxicities and maximum tolerated dose of tirapazamine when given concurrently with radiation therapy. METHODS: Patients received radiation therapy in accordance with standard treatment practice in relation to fraction size and number of fractions for their particular cancer. In all cases, the course of radiation therapy exceeded the time of tirapazamine administration. Initially, tirapazamine was administered 5 days per week for 2 weeks for a total of 10 doses. After the first 8 patients, the schedule was changed to 3 times per week (Monday, Wednesday, Friday) for 4 weeks for a total of 12 doses. Between 3 and 6 patients were treated at each dose level. RESULTS: A total of 43 patients were treated in the study between 1991 and 1995. All patients were 18 years old or older, had a Karnofsky performance status of > or = 60% and had adequate hematologic, hepatic, and renal function. Dose escalation began at 9 mg/m(2)/dose and was increased using a modified Fibonacci schema. The maximum tolerated dose was not reached and dose escalation was stopped at 260 mg/m(2) because of other data that became available suggesting 330 mg/m(2) was associated with dose-limiting toxicity (1, 2). CONCLUSION: Tirapazamine in doses of up to 260 mg/m(2) times 12 doses can be given safely with fractionated radiation therapy. This dose appears to result in adequate plasma exposure (2) for radiation sensitization, and this schedule is being tested in a Phase II trial by the Radiation Therapy Oncology Group to determine if tirapazamine is a radiation enhancer in the clinic.

Adult↗

PubMed1999

Role of radiosurgery in the management of central nervous system metastases.

Radiosurgery is being used more routinely to treat patients with inoperable, recurrent, or multiple brain metastases from systemic cancer. Results in > 2000 treated patients have been published during the past 8 years. These results indicate that permanent local control can be obtained in > 80% of treated lesions with complications in < 10% of patients. Success is independent of the histology, ie, melanoma vs adenocarcinoma, of the treated lesion or number of lesions treated. The long-term results of radiosurgery compare favorably with those seen following surgical resection. The cost-effectiveness of radiosurgery compared to surgical resection favors an expanded role for this technology in the treatment of selected patients with brain metastases.

Brain Neoplasms↗

PubMed1999

Stereotactic Irradiation: potential new treatment method for brain metastases resulting from ovarian cancer.

Stereotactic irradiation (radiosurgery) is a method of precisely focusing well-defined beams of radiation at small intracranial targets. The technique has been applied to the treatment of brain lesions that are benign (e.g., arteriovenous malformations, meningiomas, pituitary adenomas) and malignant (e.g., gliomas, metastases). This paper introduces preliminary data suggesting the possible value of radiosurgery in the management of ovarian cancer metastatic to the brain. Among 32 women with ovarian cancer metastatic to the brain treated with whole brain irradiation, nine (29%) experienced a complete radiographic response, compared with two of the five patients (40%) treated with radiosurgery. The 2-year survival rate was 60% among those treated with radiosurgery and 15% among those who received whole brain irradiation without radiosurgical boost. Stereotactic irradiation may be of clinical benefit to select patients with brain metastases resulting from ovarian cancer. A prospective randomized trial has been implemented by the Radiation Therapy Oncology Group (RTOG 95-08) to determine whether such observations are reproducible on a national scale.

Adult↗

PubMed1999

Novel radiation technologies for malignant gliomas.

Despite the advent of new technologies available for the imaging of brain tumors and the evolution of methods to deliver more focused radiation therapy, most malignant gliomas recur locally. Therapies aimed at increasing local control of gliomas will set the stage for improved survival in a disease with a dismal overall prognosis. This review focuses on several radiotherapeutic approaches to dose escalation that may help improve local control.

Brachytherapy↗

PubMed1999

Allergic skin reactions to anticonvulsant medications in patients receiving cranial radiation therapy.

PURPOSE: Erythema multiforme and Stevens-Johnson syndrome have been associated with anticonvulsant medications (AEDs) in patients with brain tumors receiving cranial irradiation. AEDs are also known to cause mild drug rashes. The incidence of these complications has not been well studied among patients with brain tumors. We reviewed the records of patients with brain tumors treated with cranial radiation and AEDs to assess the frequency of both severe and mild skin reactions. METHODS: Retrospective review of 289 radiotherapy records of consecutively treated patients from 1988 to 1993. RESULTS: Only one of 289 patients developed erythema multiforme. Milder rashes, however, occurred in 18% of exposures to AEDs including 22% of exposures to phenytoin, compared with the expected rate of 5-10%. Most of the mild drug rashes occurred before the initiation of radiotherapy, suggesting that radiation was not the cause of these reactions. CONCLUSIONS: Severe skin rashes are rare among patients with brain tumors receiving radiation therapy and AEDs. There is, however, an increased frequency of mild drug rashes among patients with brain tumors that does not appear related to radiation.

Adolescent↗

PubMed1999

Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome.

OBJECT: To assess the value of stereotactic radiosurgery (SRS) as adjunct therapy in patients suffering from glioblastoma multiforme (GBM), the authors analyzed their experience with 78 patients. METHODS: Between June 1988 and January 1995, 78 patients underwent SRS as part of their initial treatment for GBM. All patients had undergone initial surgery or biopsy confirming the diagnosis of GBM and received conventional external beam radiotherapy. Stereotactic radiosurgery was performed using a dedicated 6-MV stereotactic linear accelerator. Thirteen patients were alive at the time of analysis with a median follow-up period of 40.8 months. The median length of actuarial survival for all patients was 19.9 months. Twelve- and 24-month survival rates were 88.5% and 35.9%, respectively. Patient age and Radiation Therapy Oncology Group (RTOG) class were significant prognostic indicators according to univariate analysis (p < 0.05). Twenty-three patients aged younger than 40 years had a median survival time of 48.6 months compared with 55 older patients who had 18.2 months (p < 0.001). Patients in this series fell into RTOG Classes III (27 patients), IV (29 patients), or V (22 patients). Class III patients had a median survival time of 29.5 months following diagnosis; this was significantly longer than median survival times for Classes IV and V, which were 19.2 and 18.2 months, respectively (p = 0.001). Only patient age (< 40 years) was a significant prognostic factor according to multivariate analysis. Acute complications were unusual and limited to exacerbation of existing symptoms. There were no new neuropathies secondary to SRS. Thirty-nine patients (50%) underwent reoperation for symptomatic necrosis or recurrent tumor. The rate of reoperation at 24 months following SRS was 54.8%. CONCLUSIONS: The addition of a radiosurgery boost appears to confer a survival advantage to selected patients.

Actuarial Analysis↗

PubMed1999

Stereotactic proton radiosurgery.

The technique of stereotactic proton radiosurgery is discussed in depth in this article. The physics of the proton beam in radiosurgery is explained, and the different factors of beam delivery are examined. These key factors (correspondence to shape, accuracy of delineation of volume, correspondence to volume, and accuracy of delivery vary) with each of the radiosurgical techniques, from Gamma Knife surgery to linear accelerator therapy. Clinical series in the use of proton radiosurgery are also presented, with an emphasis on efficacy and uses.

Biophysical Phenomena↗

PubMed1999

The role of radiosurgery for glial neoplasms.

Malignant gliomas are one of the most serious challenges in clinical neurosurgery. Despite advances in surgical and radiation techniques, chemotherapy, and other systemic antineoplastic regimens, such as gene therapy and immunotherapy, patients who suffer from malignant gliomas often succumb to their disease. Although some success has been made with forms of enhanced surgical guidance and localized radiotherapy, current techniques are unable to eradicate the infiltrative glioma cells.

Brain Neoplasms↗

PubMed1999

Management of brain metastases.

Brain metastases are the most common type of brain tumor in adults and are an increasingly important cause of morbidity and mortality in cancer patients. In recent years, important advances have been made in the diagnosis and management of brain metastases. These advances include the widespread use of magnetic resonance imaging (MRI), enabling small metastases to be detected; the introduction of stereotactic radiosurgery; and the performance of studies that have clarified the role of surgery and postoperative radiation therapy for single brain metastases. As a result, most patients receive effective palliation, and the majority do not die from their brain metastases. However, further studies are needed to define the optimal role of conventional treatments and to develop more effective novel therapies.

Brain Neoplasms↗

PubMed1999

The case for radiosurgery.

Brain metastases represent a significant health-care problem, with almost 200,000 patient in the Unite States annually suffering from symptomatic parenchymal lesions. Lung, breast, melanoma, renal, and gastrointestinal cancers contribute the majority of lesions that come to clinical attention. Although median survival once brain metastases are diagnosed is less than a year, timely therapy can restore neurological function and can often prevent further neurological complications of cancer for the duration of a patient's survival. Important prognostic features associated with improved survival include the absence of extracranial disease progression, young age, a high pretreatment neurological status, one to three versus more than three lesions, and a long interval from primary disease diagnosis to the development of brain metastases. The need to aggressively treat brain metastases effectively is becoming increasingly important, however, as advances in the treatment of systemic disease result in an increasing number of patients developing brain metastases in the setting of limited systemic disease. For many such patients, surgery provides the best therapy, but results are still not encouraging because even patients with the best prognostic indicators often die within 18 to 24 months. Until Superior treatment modalities are developed, the judicious use of available techniques for treatment of patients with limited systemic disease provides the best opportunities for palliation and extended survival. Perhaps the most significant development in the treatment of patients with brain metastases during the last decade is the increasing use of radiosurgery. For patients with a single lesion, local control and survival rates of radiosurgery compare well with those produced with surgical resection. Radiosurgery remains an important treatment modality and, when used promptly, can reverse neurological deficits, often for the remainder of a patients life. There is compelling evidence to suggest that aggressive local therapy (surgery or radiosurgery) for patients with a single brain metastasis produces superior survival and quality of life compared with treatment with whole brain radiotherapy alone. However, surgery should be restricted to the minority of patients for whom brain metastases represents the life-threatening site of their disease. For an asymptomatic or mildly symptomatic patient with a lesion smaller than 3 cm in diameter, radiosurgery is an excellent alternative to surgery. Although radiosurgery is a noninvasive procedure, the same selection criteria should be considered as for those patients undergoing surgical resection.

Brain Neoplasms↗

PubMed1998

Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas.

PURPOSE: To retrospectively evaluate the initial clinical results of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) for pituitary adenomas with regard to tumor and hormonal control and adverse effects of the treatment. SUBJECTS AND METHODS: Forty-eight patients with pituitary adenoma who underwent SRS or SRT between September 1989 and September 1995 were analyzed. Of these, 18 received SRS and 30 received SRT. The median tumor volumes were 1.9 cm3 for SRS and 5.7 cm3 for SRT. Eleven of the SRS and 18 of the SRT patients were hormonally active at the time of the initial diagnosis. Four of the SRS and none of the SRT patients had a history of prior radiation therapy. Both SRS and SRT were performed using a dedicated stereotactic 6-MV linear accelerator (LINAC). The dose and normalization used for the SRS varied from 1000 cGy at 85% of the isodose line to 1500 cGy at 65% of the isodose line. For SRT patients, a total dose of 4500 cGy at 90% or 95% of the isodose line was delivered in 25 fractions of 180 cGy daily doses. RESULTS: Disease control-The three year tumor control rate was 91.1% (100% for SRS and 85.3% for SRT). Normalization of the hormonal abnormality was achieved in 47% of the 48 patients (33% for SRS and 54% for SRT). The average time required for normalization was 8.5 months for SRS and 18 months for SRT. Adverse effects-The 3-year rate of freedom from central nervous system adverse effects was 89.7% (72.2% for SRS and 100% for SRT). Three patients who received SRS for a tumor in the cavernous sinus developed a ring enhancement in the temporal lobe as shown by follow-up magnetic resonance imaging. Two of these cases were irreversible and were considered to be radiation necrosis. None of the 48 patients developed new neurocognitive or visual disorders attributable to the irradiation. The incidence of endocrinological adverse effects were similar in the two groups, resulting in 3-year rates of freedom from newly initiated hormonal replacement of 78.4% (77.1% for SRS and 79.9% for SRT). CONCLUSION: Considering the relatively high incidence of morbidity observed in the SRS group, we recommend SRT as the primary method of radiation therapy for pituitary tumors. When treating a lesion in the cavernous sinus with SRS, special attention should be paid to dose distribution in the adjacent brain parenchyma. Longer follow-up is necessary before drawing any conclusions about the advantages of these techniques over conventional external beam radiation therapy.

Adenoma↗

PubMed1998

Survival results from a phase I study of etanidazole (SR2508) and radiotherapy in patients with malignant glioma.

PURPOSE: To report the survival results from a previous Phase I study of etanidazole (ETA) and radiotherapy in patients with glioblastoma multiforme (GBM n = 50) or anaplastic astrocytoma (AA n = 19) and examine survival according to age, Karnofsky performance status (KPS), and implant status. PATIENTS AND METHODS: In a previous Phase I study, 70 previously untreated patients (median age 49) with malignant gliomas were accrued. One patient was excluded from analysis because pathology was unverifiable. All had KPS > or = 70. Prior to initiation of treatment, patients were stratified according to whether they were candidates for interstitial implantation. The implant patients (IMP n = 14) received accelerated fractionation radiotherapy (XRT) 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m2 x 6 doses, a 2 week break, and then interstitial implant for an additional 50 Gy (4-7 days) with a continuous infusion of ETA over 90-96 hours. There were 55 patients treated on two sequentially conducted non-implant arms. These patients started with accelerated fractionation XRT 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m2 x 4-5 doses/week. Non-IMP1 arm (n = 41) received a 2-week break before standard fractionated boost XRT of 2 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. Non-IMP2 arm (n = 14) did not have the 2-week break. All patients had plasma pharmacokinetic monitoring of ETA. Subsequent follow-up study provided information regarding long-term survival status of this group of patients. The Phase I toxicity evaluation was conducted according to the RTOG toxicity scale and was found well tolerated in both groups. Overall actuarial survival was plotted for all patients, by histologic group, and by implant status. Subset analyses of GBM patients by age (< or = 49 or > 49 years), KPS (< or = 80 or > 80) and implant versus non-implant were also performed. RESULTS: Median survival of GBM patients was 1.1 years and that of anaplastic astrocytoma patients was 3.1 years (p = 0.0001). In GBM patients, KPS > 80, implanted patients, and age < or = 49 were factors found not to be associated with a statistically improved survival. CONCLUSION: The results of survival in this Phase I etanidazole study of patients with anaplastic astrocytoma are comparable to the results from other studies using bromodeoxyuridine, iododeoxyuridine, or procarbazine, lomustine (CCNU), and vincristine. The use of etanidazole with accelerated radiotherapy does not appear to improve survival in patients with glioblastoma multiforme compared to those treated with conventional therapies.

Adult↗

PubMed1998

Linac radiosurgery at the Joint Center for Radiation Therapy.

The Joint Center for Radiation Therapy (JCRT) has treated intra-cranial lesions with high-dose single fraction stereotactic radiosurgery (SRS) since 1986 and with multi-fraction stereotactic radiotherapy (SRT) since 1992. This paper describes the JCRT techniques for treatment planning and delivery for SRS, and to a limited extent for SRT. LINAC quality assurance, treatment delivery, and patient management for stereotactic radiosurgery and stereotactic radiotherapy technique are closely related at the JCRT, although differences exist. An historical retrospective of our experience with stereotactic techniques including imaging modalities, treatment planning techniques, optimization methods, and treatment delivery is presented. Three treatment planning approaches, single isocenter, multiple isocenter, and micro-jaw field shaping are used to demonstrate the capabilities and technical dosimetric features of each approach. The major planning differences and clinical of each technique are described. From our experience, lesions less than 3.0 cm in maximum extent are well treated with circular fields using either a single or multiple isocenter configuration. Lesions greater than 3.0 cm in maximum extent usually benefit from field shaping using the micro-jaws. For these large lesions, the shaped field approach typically improves the dose homogeneity as well as reduces the amount of healthy brain irradiated. Our physicians choose between the three techniques to meet the desired clinical outcome the patient's situation requires.

Boston↗