Radiotherapy For High-grade Glioma Research Articles

18F Fluoroethyltyrosine-Positron Emission Tomography-guided Radiotherapy for High-grade Glioma

18F Fluoroethyltyrosine-Positron Emission Tomography-guided Radiotherapy for High-grade Glioma

EORTC 22972–26991/MRC BR10 trial: Fractionated stereotactic boost following conventional radiotherapy of high grade gliomas: Clinical and quality-assurance results of the stereotactic boost arm

Background and purpose The EORTC trial No. 22972 investigated the role of an additional fractionated stereotactic boost (fSRT) to conventional radiotherapy for patients with high grade gliomas. A quality-assurance (QA) programme was run in conjunction with the study and was the first within the EORTC addressing the quality of a supposedly highly accurate treatment technique such as stereotactic radiotherapy. A second aim was to investigate a possible relation between the clinical results of the stereotactic boost arm and the results of the QA. Materials and methods The trial was closed in 2001 due to low accrual. In total, 25 patients were randomized: 14 into the experimental arm and 11 into the control arm. Six centres randomized patients, 8 centres had completed the dummy run (DR) for the stereotactic boost part. All participating centres (9) were asked to complete a quality-assurance questionnaire. The DR consisted of treatment planning according to the guidelines of the protocol on 3 different tumour volumes drawn on CT images of a humanized phantom. The SRT technique to be used was evaluated by the questionnaire. Clinical data from patients recruited to the boost arm from 6 participating centres were analysed. Results There was a full compliance to the protocol requirements for 5 centres. Major and minor deviations in conformality were observed for 2 and 3 centres, respectively. Of the 8 centres which completed the DR, one centre did not comply with the requirements of stereotactic radiotherapy concerning accuracy, dosimetry and planning. Median follow-up and median overall survival were 39.2 and 21.4 months, respectively. Acute and late toxicities of the stereotactic boost were low. One radiation necrosis was seen for a patient who has not received the SRT boost. Three reported serious adverse events were all seizures and probably therapy-related. Conclusions Overall compliance was good but not ideal from the point of view of this highly precise radiation technique. Survival in the subgroup of patients with small volume disease was encouraging, but the study does not provide sufficient information about the potential value of fSRT boost in patients with malignant glioma.Toxicity due to an additional stereotactic boost of 20 Gy in 4 fractions was low and may be considered as a safe treatment option for patients with small tumours.

Noscapine Enhances Tumor Radioresponse in the GL261 Glioma Model: Implications for Glioma Therapy

There is a pressing need for adjunctive therapies to enhance the effectiveness of radiotherapy in high grade glioma. Recently we showed that a novel microtubule binding agent, noscapine, demonstrated antiangiogenic activity in vitro (Newcomb et al., Int J Oncol 2006;28:1121–30). When compared to taxane noscapine has a low toxicity profile and similar antiangiogenic properties, and has demonstrated antitumor activity in several animal models of cancer, We tested whether noscapine enhances the effects of ionizing radiation in the GL261 syngeneic murine glioma tumor model.

A phase I trial using the proteasome inhibitor bortezomib and concurrent temazolomide and radiotherapy for high grade gliomas

2061 Background: Improving the response of patients with high-grade astrocytomas continues to remain a challenge despite advances in chemoradiation. Preclinical studies have demonstrated the importance of the NF-kappaB pathway treatment resistance and enhancement of radiosensitivity by proteasome inhibition. This open-label, phase I study evaluated the safety of 3 dose levels (0.7, 1.0, 1.3 mg/m2/dose) of intravenously administered bortezomib, a reversible proteasome inhibitor with unique properties in combination with chemoradiation. Methods: Eligible patients had a diagnosis of high-grade glioma. Other requirements included performance status 0–1 and adequate hematologic reserve. Previous radiotherapy and/or chemotherapy was allowed. Patients received fraction sizes of XRT that ranged from 1.8–3.5 Gy/day for total doses between 35–66 Gy. During radiotherapy, temozolomide was administered continuously at a daily dose of 75 mg/m2. The starting dose level of bortezomib was 0.7 mg/m2/ days 1, 4, 8, 11 of 21-day cycle for up to 2 cycles. This was followed by 1.0 mg/m2 and 1.3 mg/m2 dose levels. The primary endpoint of the study was dose-limiting toxicity (DLT), defined as any Grade 4–5 toxicity or Grade 3 toxicity(ies) requiring hospitalization and/or XRT interruption. Response was also assessed (1-month post-XRT brain MRI). Results: A total of 27 patients were enrolled. There were no DLTs observed in any dose groups. Grade 1 and 2 toxicities consisted of stomatitis, erythema, and alopecia. Of 24 patients evaluable for response, 1 patient had no evidence of disease, 3 patients had a PR; 9 patients had stable disease and 11 patients had progressive disease. Conclusions: Bortezomib can be combined at full dose with concurrent temozolomide and radiation therapy with minimal adverse effects. Correlative translational endpoints are still pending. The results observed justify further evaluation in a phase II setting. [Table: see text]

Intensity-modulated radiotherapy in high-grade gliomas: Clinical and dosimetric results

To report preliminary clinical and dosimetric data from intensity-modulated radiotherapy (IMRT) for malignant gliomas. Fifty-eight consecutive high-grade gliomas were treated between January 2001 and December 2003 with dynamic multileaf collimator IMRT, planned with the inverse approach. A dose of 59.4-60 Gy at 1.8-2.0 Gy per fraction was delivered. A total of three to five noncoplanar beams were used to cover at least 95% of the target volume with the prescription isodose line. Glioblastoma accounted for 70% of the cases, and anaplastic oligodendroglioma histology (pure or mixed) was seen in 15% of the cases. Surgery consisted of biopsy only in 26% of the patients, and 80% received adjuvant chemotherapy. With a median follow-up of 24 months, 85% of the patients have relapsed. The median progression-free survival time for anaplastic astrocytoma and glioblastoma histology was 5.6 and 2.5 months, respectively. The overall survival time for anaplastic glioma and glioblastoma was 36 and 9 months, respectively. Ninety-six percent of the recurrences were local. No Grade IV/V late neurologic toxicities were noted. A comparative dosimetric analysis revealed that regardless of tumor location, IMRT did not significantly improve target coverage compared with three-dimensional planning. However, IMRT resulted in a decreased maximum dose to the spinal cord, optic nerves, and eye by 16%, 7%, and 15%, respectively, owing to its improved dose conformality. The mean brainstem dose also decreased by 7%. Intensity-modulated radiotherapy delivered with a limited number of beams did not result in an increased dose to the normal brain. It is unlikely that IMRT will improve local control in high-grade gliomas without further dose escalation compared with conventional radiotherapy. However, it might result in decreased late toxicities associated with radiotherapy.

Neoadjuvant cisplatin and etoposide, with or without tamoxifen, prior to radiotherapy in high-grade gliomas: a single-center experience

Neoadjuvant chemotherapy (CT), prior to radical radiotherapy (RT), in the treatment of high-grade gliomas may offer several advantages over standard adjuvant CT. The addition of tamoxifen, which can circumvent P-glycoprotein (P-gp)-mediated chemo-resistance, also merits attention. We have evaluated the neoadjuvant regimen of cisplatin and etoposide after surgery of grade III-IV gliomas and prior to radical RT, with regard to response rates (RRs), overall survival (OS) and time to progression (TTP). The synergistic activity between etoposide and tamoxifen was also studied. Forty-four patients were included. CT regime: cisplatin 100 mg/m2 on day +1 and etoposide 100 mg/m2 on days +1 to +3 every 3 weeks for 3 cycles. The initial 24 were also treated with high-dose tamoxifen, 275 mg/m2 on days -3 to +3. An immunohistochemical analysis of P-gp, p53, vascular endothelial growth factor, Ki67 and bcl-2 was also performed. Median follow-up was 11.57 months. In the 16 patients with measurable disease after surgery, a RR of 12.5% was seen, with 37.5% of disease stabilizations and 31.25% of progressions. The median OS and TTP were 11.3 and 5.7 months. Excluding the three deaths possibly related to tamoxifen, grade 3-4 was low, mainly emesis. Favorable prognostic factors were age less than 60 years, extent of surgery, absence of measurable disease, and the absence of radiological necrosis and ring enhancement. Only high p53 expression was associated with better OS. We conclude that neoadjuvant cisplatin and etoposide is a feasible regime, although any real advantage over standard adjuvant CT is dubious. Short-course high-dose tamoxifen should not be used alongside primary CT.

T2 weighted MRI in assessment of volume changes during radiotherapy of high grade gliomas

To determine whether any changes in gross tumor volume occur between pre treatment MRI and week 5 MRI in high grade gliomas treated by conformal radiotherapy. Between July 2003-July 2005, 17 patients with WHO grades 3 and 4 malignant gliomas treated with conformal radiotherapy to a total dose of 60 Gy were included in this retrospective study. All patients had undergone T2 weighted MRI a day before treatment and then again at end of week 5 of treatment for definition of initial and boost fields respectively. Gross tumor volumes were delineated on the two MRI's of each patient and the differences were noted. Two patients with multifocal disease were excluded from the final analysis. Of the 15 patients with unifocal disease, 12/15 cases (80%) showed a reduction in tumor volumes (median 54.85 cc). Of these, 4/15 (26.6%) cases (two each of grade 3 and grade 4 gliomas) had an objective reduction in GTV (> or = 50%) and 3/15 (20%) cases (two of grade 4 and one of grade 3 gliomas) demonstrated an increase in tumor volume (median 14 cc). This study has shown that a change in gross tumor volume occurred in almost all patients on week 5 MRI. The likelihood of treatment success would appear to be decreased if the tumour is not within the treatment field and hence it may be worthwhile to do a mid treatment MRI for definition of boost volumes especially in dose escalation trials employing highly conformal radiotherapy fields.

Intensity modulated radiotherapy in high grade gliomas: Clinical and dosimetric results

Intensity modulated radiotherapy in high grade gliomas: Clinical and dosimetric results

Intensity modulated radiotherapy in high grade gliomas: Clinical and dosimetric results

1532 Background: Intensity Modulated Radiotherapy (IMRT) is an emerging treatment for brain tumors, but there is very little clinical or dosimetric data on doses and outcomes from IMRT treatment for malignant gliomas. This study reports the preliminary data with IMRT in these tumors. Methods: Sixty six consecutive high grade gliomas were treated between January 2001 and December 2003 with dynamic multileaf collimator IMRT with inverse planning. A dose of 59.4–60Gy using 1.8–2.0 Gy per fraction was delivered. 3–5 non-coplanar beams were used for the IMRT plan to cover at least 95% of the target volume with the prescription isodose line. Glioblastoma accounted for 62% of the cases and oligodendroglioma histology (pure or mixed) was seen in 16.7% of the cases. Surgery was restricted to biopsy only in 26% of the patients. 80% of the patients received adjuvant chemotherapy. Results: With a median follow-up of 18 months, 85% of the patients have relapsed. The median disease free survival for anaplastic glioma and glioblastoma were 5.6 and 2.5 months. The median overall survival for the anaplastic glioma and glioblastoma histologies were 16.5 and 10.6 months respectively. 96% of the recurrences were local. No grade IV delayed neurological toxicities were noted. A comparative dosimetric analysis revealed that regardless of tumor location, IMRT did not improve target coverage compared to conventional 3-dimensional treatment planning. However, the use of IMRT resulted in a decreased dose to spinal cord, optic chiasm and brain stem by 19%, 4.5% and 8% respectively due to its improved dose conformality. Use of IMRT did not result in an increase of the dose received by the normal brain. Conclusions: Use of IMRT did not increase either the disease free survival or the overall survival in patients with malignant gliomas when compared to historical controls. It is unlikely that IMRT will improve the local control in high grade gliomas without further dose escalation. However, it may result in decreased late toxicities associated with radiation therapy. No significant financial relationships to disclose.

Radiotherapy for high-grade gliomas. Does altered fractionation improve the outcome?

The publication of Radiation Therapy Oncology Group (RTOG) Study 83-02 in 1996 stimulated further investigations of altered fractionation, i. e., application of more than one fraction per day, in high-grade gliomas. This review summarizes the results of trials published between January 1997 and June 2002. To identify suitable trials, a Medline search was performed by use of the following key words: brain tumors/astrocytoma/glioma/high-grade glioma/malignant glioma/glioblastoma multiforme and accelerated radiotherapy/hyperfractionated radiotherapy/altered fractionation. In addition, the search was extended to reference lists of articles and textbooks. Whenever possible, data were extracted from the original papers on an intention-to-treat basis, i. e., patients with protocol violations were not excluded for the purpose of this analysis. Studies in brain stem gliomas, pediatric patients and studies which achieved acceleration by radiosurgery, stereotactic radiotherapy, or brachytherapy rather than conventional external-beam treatment were not included. An exploratory analysis of 2-year survival was also performed. For this purpose, the 2-year survival rate was extracted from each individual study. The total number of 2-year survivors was then calculated for each treatment strategy and compared by use of the chi(2)-test. The authors identified 1,414 patients from 21 studies; two of these were randomized phase III studies. In seven studies (658 patients), chemotherapy or radiosensitizers were not administered in addition to radiotherapy. The others provide a very heterogeneous set of data, because a large variety of drugs and administration schedules was used. Seven studies included patients with glioblastoma multiforme only, two were limited to patients with anaplastic gliomas. Dose per fraction was 1.2-1.8 Gy in 17 studies and 1.9-2.65 Gy in four. Overall treatment time was 12-31 days, except for one study. Three out of five studies where three fractions per day were administered, included a 2-week break (split-course studies). None of the studies reported a significant improvement in survival by altered fractionation in comparison to either institutional historical controls or their respective randomized control arm. Doses of 60-70 Gy do not appear to improve survival compared to 50-60 Gy. The current data provide no arguments for use of three instead of two fractions per day. Median survival was 10 months after radiotherapy alone (658 patients) and 11 months after combined treatment (756 patients). Regarding 2-year survival rates, radiotherapy alone resulted in 13%, combined chemoradiation or use of sensitizers in 23% (p < 0.0001). However, prognostic factors such as tumor histology were not equally distributed and favor the combined-treatment group. Evaluation of six studies of conventional radiotherapy alone resulted in data from 571 patients. Their median survival was 10.8 months. Cumulative 2-year survival amounted to 15%. The studies of conventional radiotherapy plus chemotherapy or sensitizers included 1,115 patients with a median survival of 11 months (2-year survival rate 18.5%). Altered fractionation shortens the overall treatment time for adult patients with supratentorial high-grade gliomas. However, there is no significant survival improvement.

Early effects of irradiation on [(123)I]-IMT and [(18)F]-FDG uptake in rat C6 glioma cells.

Single-photon emission computed tomography (SPECT) using 3-[(123)I]-iodo-L-alpha-methyltyrosine ([(123)I]-IMT) and positron emission tomography (PET) using 2-[(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]-FDG) are valuable tools for the distinction between viable tumor and radionecrosis in patients receiving radiotherapy for high-grade gliomas. However, to date, little is known about the early effects of radiation on [(123)I]-IMT and [(18)F]-FDG uptake in gliomas. To determine the early effects of irradiation on [(123)I]-IMT and [(18)F]-FDG uptake in gliomas, in vitro studies were performed using rat C6 glioma cells. The glioma cells were irradiated with 20 Gy which is a common dose applied to patients receiving intraoperative radiotherapy. Subsequently, the early kinetics of [(123)I]-IMT and [(18)F]-FDG uptake in glioma cells were monitored for 3 days. Micromorphometric examinations of the irradiated glioma cells revealed that about 25% of the viable cells transformed into giant cells. [(123)I]-IMT uptake per 10(5) viable glioma cells was unchanged on the 1st day post irradiation, but showed a significant increase on the 2nd and 3rd day following radiotherapy (p < 0.01). In addition, there was a moderate increase in [(18)F]- FDG accumulation per 10(5) viable glioma cells during the first 3 days after irradiation (p < 0.05). The maximum increase in early [(123)I]-IMT uptake 1 h after application surpassed that of [(18)F]-FDG (p < 0.01). Rat C6 glioma cells show an early increase in [(123)I]-IMT and [(18)F]-FDG uptake following irradiation which may be partly due to giant cell formation. These data suggest that [(123)I]-IMT SPECT and [(18)F]-FDG PET may be promising procedures for the early prediction of the therapeutic response of gliomas to radiotherapy.

32 Radiotherapy for high-grade glioma: Is altered fractionation beneficial?

32 Radiotherapy for high-grade glioma: Is altered fractionation beneficial?

Modifying radical radiotherapy in high grade gliomas; shortening the treatment time through acceleration

Purpose: To evaluate the efficacy and toxicity of accelerated radiotherapy in patients with primary high grade glioma, where acceleration is used as a means of delivering a shortened course of radical radiotherapy. Patients and methods: Two-hundred and eleven patients with primary high grade glioma were treated at the Royal Marsden NHS Trust between 1987 and 1997 with accelerated radiotherapy (55 Gy in 34 fractions twice daily), to planning target volume (PTV) defined as enhancing tumour and a 3 cm margin. All had histologically confirmed high grade glioma (53 anaplastic astrocytoma, 137 glioblastoma multiforme, 4 gliosarcoma, 5 gemistocytic astrocytoma, 12 high grade astrocytoma not otherwise specified). The mean Karnofsky performance status (KPS) was 90 and median age was 54 years (range 19–77). Results: Of 211 patients entered, 201 were able to complete radiotherapy; 39 patients (19%) had deterioration in KPS during radiotherapy and this was transient in 11. Median survival of 211 patients was 10 months with 1 year, 2 year, and 3 year survival probabilities of 38%, 14%, and 8% respectively. Age and extent of excision were independent prognostic factors for survival. Previous comparison to matched cohort receiving 60 Gy in 30 daily fractions did not demonstrate significant survival difference. Conclusion: Accelerated radiotherapy is a feasible treatment approach for patients with high grade glioma. The survival and functional outcome are comparable to conventional radiotherapy and the treatment is without serious acute toxicity. While acceleration of conventional dose irradiation could be tested in randomised studies, it is unlikely this approach would result in a clinically meaningful survival benefit. Accelerated radiotherapy therefore remains one of the ways of delivering radical irradiation in patients with high grade glioma. However, it adds complexity to what is a palliative treatment regimen and the rationale and advisability should be re-examined, particularly in terms of impact on quality of life, true patient preference, and health economic considerations.

2058 Accelerated fractionation radiotherapy for high-grade gliomas

2058 Accelerated fractionation radiotherapy for high-grade gliomas

Carboplatin and VM26 during radiotherapy in high grade gliomas

Carboplatin and VM26 during radiotherapy in high grade gliomas

Radiotherapy for high grade gliomas

This presentation will review recent data on the treatment of high grade gliomas. It deals primarily with results of radiotherapy even though several of the clinical trials to be considered also included chemotherapy. Present emphasis will be on, but not limited to, the larger prospective randomized trials conducted by various cooperative clinical groups in the United States, the United Kingdom and on the continent.

Radiotherapy in high grade gliomas

Radiotherapy in high grade gliomas

Back to the future--radiotherapy in high grade gliomas.

Revue sur l'utilisation de la radiotherapie dans le traitement de gliome. Interet des radiosensibilisants