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External beam radiation therapy (XRT) with concomitant temozolomide and 6 cycles of adjuvant temozolomide (5/28-day schedule) improves survival in patients with newly diagnosed glioblastoma compared with XRT alone. Studies suggest that dose-dense temozolomide schedules and addition of cytostatic agents may further improve efficacy. This factorial design phase I/II protocol tested dose-dense temozolomide alone and combined with cytostatic agents. Patients with newly diagnosed glioblastoma received fractionated XRT to 60 Gy concomitant with temozolomide (75 mg/m²)/day for 42 days). In the phase I portion, patients with stable disease or radiologic response 1 month after chemoradiation were randomized to adjuvant temozolomide alone (150 mg/m²/day, 7/14-day schedule) or with doublet combinations of thalidomide (400 mg/day), isotretinoin (100 mg/m²/day), and/or celecoxib (400 mg twice daily), or all 3 agents. Toxicity was assessed after 4 weeks. Among 54 patients enrolled (median age, 52 years; median Karnofsky performance status, 90), adjuvant treatment was not administered to 12 (22%), primarily because of disease progression (n = 10). All combinations were well tolerated. Grade 3/4 lymphopenia developed in 63% of patients, but no related infections occurred. One patient treated with temozolomide plus isotretinoin plus thalidomide had dose-limiting grade 3 fatigue and rash, and 1 patient receiving all 4 agents had dose-limiting grade 4 neutropenia. Venous thrombosis occurred in 7 patients, 4 of whom received thalidomide. From study entry, median survival was 20 months and the 2-year survival rate was 40%. Multiple cytostatic agents can be safely combined with dose-dense temozolomide. The factorial-based phase II portion of this study is currently ongoing.

BackgroundCancer control by radiotherapy (RT) can be improved with concurrent chemotherapy. Outpatient strategies for sarcomas that combine chemotherapy and RT are possible since supportive care and RT techniques have improved.MethodsThe current status of non-anthracycline chemotherapy in combination with radiation for high-risk sarcoma is reviewed.ResultsIfosfamide with mesna and newer activated ifosfamide agents (ZIO-201 and glufosfamide) have high potential to improve sarcoma cancer control. In Ewing's sarcoma and osteosarcoma, high-dose ifosfamide with mesna (2.8 g/m2/day of each x 5 days; mesna day 6) can be safely given to outpatients using continuous infusion. Reducing ifosfamide nephrotoxicity and central nervous system side effects are discussed. Other outpatient radiosensitization regimens include gemcitabine (600–1000 mg/m2/dose IV over 1 hour weekly x 2–3 doses), temozolomide (75 mg/m2/daily x 3–6 weeks), or temozolomide (100 mg/m2/dose daily x 5) + irinotecan (10 mg/m2/dose daily x 5 x 2 weeks). In osteosarcoma with osteoblastic metastases on bone scan, samarium (1 mCi/kg; day 3 of RT) and gemcitabine (600 mg/m2IV over 1 hour day 9 of RT) is a radiosensitization strategy. Future drugs for radiosensitization include beta-D-glucose targeted activated ifosfamide (glufosfamide) and sapacitabine, an oral nucleoside with in vitro activity against solid tumors including sarcomas.ConclusionsThe potential to treat major causes of sarcoma treatment failure (local recurrence and distant metastases) with concurrent chemotherapy during radiation should be considered in high-grade sarcomas.

Purpose: Activation of mitogen-activated protein kinase (MAPK) and members of the Akt pathway have been shown to promote cell proliferation, survival, and resistance to radiation. This study was conducted to determine whether any of these markers are associated with survival time and response to radiation in glioblastoma. Experimental Design: The expression of phosphorylated (p-)Akt, mammalian target of rapamycin (p-mTOR), p-p70S6K, and p-MAPK were assessed by immunohistochemical staining in 268 cases of newly diagnosed glioblastoma. YKL-40, a prognostic marker previously examined in these tumors, was also included in the analysis. Expression data were tested for correlations with response to radiation therapy in 131 subtotally resected cases and overall survival (in all cases). Results were validated in an analysis of 60 patients enrolled in clinical trials at a second institution. Results: Elevated p-MAPK expression was most strongly associated with poor response to radiotherapy, a finding corroborated in the validation cohort. For survival, higher expressions of p-mTOR, p-p70S6K, and p-MAPK were associated with worse outcome (all P < 0.03). YKL-40 expression was associated with the expressions of p-MAPK, p-mTOR, and p-p70S6K (all P < 0.02), with a trend toward association with p-Akt expression (P = 0.095). When known clinical variables were added to a multivariate analysis, only age, Karnofsky performance score, and p-MAPK expression emerged as independent prognostic factors. Conclusions: p-MAPK and activated members of the Akt pathway are markers of outcome in glioblastoma. Elevated expression of p-MAPK is associated with increased radiation resistance and represents an independent prognostic factor in these tumors.

Malignant meningiomas constitute a rare subset of meningiomas and display a marked propensity for postsurgical recurrence. This retrospective study evaluates the various parameters which alter the recurrence rate. The records of all malignant meningioma patients treated from 1984 through 1992 were reviewed, and the time to recurrence or current patient status was determined, and the influence of various patient and disease parameters were analyzed. Thirty-eight patients were treated with 48 malignant meningioma resections performed (28 total and 20 subtotal), 25 at initial presentation and 23 for recurrent disease; 19 patients received postoperative radiotherapy. Subtypes included 32 anaplastic meningioma, 11 hemangiopericytoma, 2 meningiosarcoma, and 3 papillary meningioma. Followup ranged from 3 to 144 months, with five patients excluded from analysis. Actuarial disease free/progression free survival (DFS) at 5 years was 39% following total resection versus 0% after subtotal resection (p=0.001). For all totally excised lesions, the 5-yr DFS was improved from 28% for surgery alone to 57% with adjuvant radiotherapy (p=NS). Adjuvant irradiation following initial resection increased the 5-yr DFS rates from 15% to 80% (p=0.002). When administered for recurrent lesions, adjuvant radiotherapy improved the 2-yr DFS from 50% to 89% (p=0.015), but had no impact on 5-yr DFS. Multivariate analysis indicates extent of resection, adjuvant radiotherapy, and recurrence status are independent prognostic factors. Malignant meningiomas display a tendency for post surgical recurrence, with recurrence significantly increased for multicentric and recurrent disease. Complete surgical resection and the administration of adjuvant irradiation following initial resection are crucial to long-term control.

Summary Background Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. Methods After resection, patients were classified as having average-risk medulloblastoma (≤1·5 cm 2 residual tumour and no metastatic disease) or high-risk medulloblastoma (>1·5 cm 2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23·4 Gy for average-risk disease and 36·0–39·6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. Findings Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75–94) in patients in the average-risk group and 70% (54–84) in those in the high-risk group (p=0·04); 5-year event-free survival was 83% (73–93) and 70% (55–85), respectively (p=0·046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0·04): 84% (74–95) for classic histology, 77% (49–100) for desmoplastic tumours, and 57% (33–80) for large-cell anaplastic tumours. Interpretation Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

Purpose White matter lesions (WMLs) have been described as a delayed effect of cranial irradiation in children with brain tumors, or a transient subacute effect characterized by an intralesional or perilesional reaction. We report the occurrence of subacute WMLs detected by magnetic resonance imaging (MRI) in children treated for medulloblastoma or primitive neuroectodermal tumor (PNET) and document the associated clinical, radiologic, and neurocognitive findings. Patients and Methods Among 134 patients with medulloblastoma or supratentorial PNET treated prospectively with risk-adjusted craniospinal irradiation and conformal boost to the tumor bed, followed by four high-dose chemotherapy (HDC) cycles with stem-cell rescue, 22 developed WMLs on T1-weighted imaging with and without contrast and/or T2-weighted imaging on MRI. Patients had ≥ 12 months of follow-up. Neurocognitive assessments included intelligence quotient (IQ) tests and tests of academic achievement. Results Twenty-two patients developed WMLs at a median of 7.8 months after starting therapy (range, 1.9 to 13.0 months). Lesions were predominantly in the pons (n = 8) and cerebellum (n = 6). Sixteen patients (73%) had WML resolution at a median of 6.2 months (range, 1.68 to 23.5 months) after onset; two patients developed necrosis and atrophy. Three developed persistent neurologic deficits. Cumulative incidence of WMLs at 1 year was 15% ± 3%. Patients with WMLs had a significant decline in estimated IQ (−2.5 per year; P = .03) and math (−4.5 per year; P = .003) scores. Conclusion WMLs in medulloblastoma or PNET patients treated with conformal radiotherapy and HDC are typically transient and asymptomatic, and may mimic early tumor recurrence. A minority of patients with WMLs develop permanent neurologic deficits and imaging changes. Overall, the presence of WMLs is associated with greater neurocognitive decline.

The purpose of this study was to determine if intensity modulated radiation therapy (IMRT) offers a better treatment plan compared to conventional radiotherapy for patients with pectus excavatum desiring breast-conserving therapy and to assess the feasibility of simultaneous modulated accelerated radiation therapy (SMART) boost. A patient with pectus excavatum desired breast-conserving therapy for her early stage breast cancer. She underwent lumpectomy and axillary lymph node dissection followed by chemotherapy. She was then referred for radiotherapy. A breast board (Med-Tec) with aquaplast body cast was used to limit the movement of the patient, chest wall, and breasts before planning a computed tomography (CT) scan. IMRT including dose-volume histogram (DVH) was compared to that of the conventional plan using parallel opposed tangential beams with a 15-degree wedge pair. Forty-five gray was prescribed to the whole breast to each plan, while 50 Gy was prescribed to the tumor bed using IMRT with SMART boost in 25 fractions over 5 weeks. The coverage of the whole breast was adequate for both plans. IMRT allowed a more homogeneous dose distribution within the breast at the desired dose range. With IMRT there is less volume of ipsilateral lung receiving the radiation dose that is above the tolerance threshold of 15 Gy when compared to that of the conventional plan. However, there is more volume of surrounding normal tissues (the heart, spinal cord, and contralateral breast and lung) receiving low-dose irradiation when IMRT was employed. SMART boost was feasible, allowing a mean dose of 57 Gy to be delivered to the tumor bed simultaneously along with the rest of the breast in 5 weeks. IMRT is feasible in treating early breast cancer patients with pectus excavatum by decreasing the ipsilateral lung volume receiving high-dose radiation when compared to the conventional method. SMART boost shortens the overall treatment time that may have potential radiobiological benefit.

Forty patients with advanced carcinoma of the cervix were prospectively treated by an intermodality approach using chemotherapy combination concomitant with split-course hyperfractionated radiation therapy (RT). Cisplatin (CDDP) (60 mg/m2) was administered before radiotherapy initiation followed by 5-fluorouracil (5-FU) (750 mg/m2) for 5 days during the first week of irradiation. The same schedule was repeated in the last week of the RT, with 5-FU administration (1,000 mg/m2) for only 3 days. RT consisted of 5,020 cGy to the pelvis, followed by two intracavitary applications for a total of 5,000-5,500 mg/h radium equivalent when possible: 140 cGy/fraction was administered in the morning and evening, with a 6-h interval. The remainder of the external beam radiation was delivered at a standard daily fractionation of 180 cGy/fraction to a total dose of 5,020 cGy. This regimen of RT with concomitant chemotherapy had minimal toxicity and did not cause significant prolongation of the treatment program. However, a high rate of late complications was noted in patients who had extended-field RT due to paraaortic lymph node involvement. Thirty-two patients had complete response (CR) (80%). 24 (75%) of whom have no evidence disease (NED), with a median follow-up of 24 months. Our study suggests that this regimen of combined chemotherapy and RT in this group of patients with poor prognosis is effective and well tolerated, with acceptable acute toxicity and late morbidity.

Peacock is a 3-D conformal treatment planning and delivery system for conformal radiation therapy which delivers intensity-modulated fields. A group of 13 patients were treated between March and February, 1995. Patient age ranged from 10 to 74. Six of the patients had previously received radiation therapy. Target volume was from 2.5 to 70 cm3: all treatments were fractionated, using single table angle plan with 270 degrees of rotation. A removable invasive cranial screw fixation device was used in all cases. Treated isodose line averaged 85%; conformality index was better than 2, with 0-5% of critical structure volume exceeding dose limits. Setup time averaged 8 min per fraction: treatment time ranged from 10 to 80 min. There were two equipment failures in 200 fractions/1,000 gantry rotations. Patient position averaged about 1 mm within initial setup. Follow-up has revealed no complications from the radiation.

Purpose: Based on the 3D‐3D image registration and mapping the imaging space to the stereotactic frame coordinate space, an online software was developed to automatically update the target isocenter position prior to each non‐invasive SRS/SRT treatment. The prescription dose can then be delivered to the entire target volume according to the treatment plan. Method and Materials: The key concept of SRS/SRT technique is the use of stereotactic coordinates to define the target volume and all other structures within the stereotactic frame space. This software will automatically setup stereotactic coordinate system through localize the 9‐rod positions of the stereotactic frame in computed tomography(CT)images. The CTimaging spaces of both planning and pretreatment are then mapped to the stereotactic coordinate spaces using transformation matrices. The correct target isocenter are determined by fusing pretreatment CT with the planning CT based on the mutual information derived from 3D volume CTimages. The final visual verification of the treatment isocenter is coincided with planning isocenter through the registration of a pair of orthogonal digitally reconstructedradiographs (DRRs) generated from pretreatment and planning CTimages.Results: A sphere and a rectangle structures within a SRS head phantom were chosen as the targets to evaluate the accuracy of our software. Within the head phantom, the accuracy for repositioned isocenter can be achieved within 0.1 mm for displacements and 0.2 degree for rotations. Also three non‐invasive SRS/SRT patient data sets were used to evaluate the software, and the results were verified with Radionics XKnife RT4 system, the translational discrepancies between reconstructed and optimized isocenters are within 0.5 mm. Conclusion: Using this software for the non‐invasive SRS/SRT treatment, patient setup accuracy within 0.5 mm can be achieved without the discomfort from the pin fixed to the patient's skull.

Purpose: The objective of this study is to demonstrate that the use of image registration and a non‐invasive head frame for SRS can achieve the same accuracy as the current invasive head‐ring SRS technique. Method and Materials: First, a head phantom was used to evaluate the accuracy of this procedure for aiming the target. Then, two SRT patients fixed with the GTC frame were treated with the proposed technique for ten treatments. The five‐point GTC alignment device was used to aid the repositioning of the GTC frame with respect of the original setup. This alignment device minimized the misalignment of the GTC frame in AP, lateral, and axial translations and the angular deviations about each of these axes on roll, tilt, and spin. Prior to each treatment, a daily CT scan with a localization device was acquired. Daily CTimages were registered with planning CT and MRIimages. The 9 rods on the daily CTimages were then identified, such that all the target, critical structures, and external contours from the planning images were transferred to the daily stereotactic coordinates. A new plan was generated. Results: In the head phantom study, the daily isocenter setup was verified to be within 0.2 mm accuracy based upon the portal images verse the planned DRRs. Optimized the dose distributions for each daily CTimages of ten treatments, the mean deviations of the daily isocenter from the planned isocenter are 0.2±0.12, −0.4±0.24, and −0.1±0.07 mm in AP‐, LAT‐, and VERT‐direction, respectively. The comparison of dose‐volume histograms is clearly revealed the prescribed dose enclosed the PTV for every treatment. Conclusions: The image‐guided noninvasive frame SRS has the capability of delivering high level accuracy of dose to the lesion without the discomfort from the pins fixed to the patient's skull.

8553 Purpose: To estimate the EFS of average-risk (AR) and high-risk (HR) SPNET treated with risk-adapted CSI and conformal primary site boost followed by 4 cycles of high-dose chemotherapy support...

To assess the therapeutic effectiveness of methotrexate (MTX) when administered in a liposome carrier, mice bearing intracranial L1210 leukemia were tested with liposomal MTX, free MTX, or saline. Single i.p. injections of liposomal MTX at doses of 5 mg/kg and 2.5 mg/kg prolonged survival of mice bearing intracranial L1210 leukemia. The same doses of the free drug did not prolong survival of the tumor-bearing mice. This system may have clinical application not only for MTX, but also other polar anticancer agents in the treatment for central nervous system malignancy.