Temozolomide during radiotherapy of glioblastoma multiforme

Background

Temozolomide-(TMZ)-based chemoradiotherapy defines the current gold standard for the treatment of newly diagnosed glioblastoma. Data regarding the influence of TMZ dose density during chemoradiotherapy are currently not available. We retrospectively compared outcomes in patients receiving no TMZ, TMZ during radiotherapy on radiotherapy days only, and TMZ constantly 7 days a week.

Patients and methods

From 2002–2012, a total of 432 patients with newly diagnosed glioblastoma received radiotherapy in our department: 118 patients had radiotherapy alone, 210 had chemoradiotherapy with TMZ (75?mg/m²) daily (7/7), and 104 with TMZ only on radiotherapy days (5/7). Radiotherapy was applied to a total dose of 60?Gy.

Results

Median survival after radiotherapy alone was 9.1 months, compared to 12.6 months with 5/7-TMZ and to 15.7 months with 7/7-TMZ. The 1?year survival rates were 33, 52, and 64%, respectively. Kaplan–Meier analysis showed a significant improvement of TMZ-7/7 vs. 5/7 (p = 0.01 by the log-rank test), while 5/7-TMZ was still superior to no TMZ at all (p = 0.02). Multivariate Cox regression showed a significant influence of TMZ regimen (p = 0.009) on hazard rate (+58% between groups) even in the presence of confounding factors age, sex, resection status, and radiotherapy dose concept.

Conclusion

Our results confirm the findings of the EORTC/NCIC trial. It seems that also a reduced TMZ scheme can at first prolong the survival of glioblastoma patients, but not as much as the daily administration.

     

Assessment of renal function after conformal radiotherapy and intensity-modulated radiotherapy by functional 1 H-MRI and 23 Na-MRI

Purpose

Adjuvant radiochemotherapy (RCHT) improves survival of patients with locally advanced gastric cancer. Conventional three-dimensional conformal radiotherapy (3D-CRT) results in ablative doses to a significant amount of the left kidney, while image-guided intensity-modulated radiotherapy (IG-IMRT) provides excellent target coverage with improved kidney sparing. Few long-term results on IMRT for gastric cancer, however, have been published. Functional magnetic resonance imaging (fMRI) at 3.0?T including blood oxygenation-level dependent (BOLD) imaging, diffusion-weighted imaging (DWI) and, for the first time, ²³Na imaging was used to evaluate renal status after radiotherapy with 3D-CRT or IG-IMRT.

Patients and methods

Four disease-free patients (2 after 3D-CRT and 2 after IMRT; FU for all patients >?5?years) were included in this feasibility study. Morphological sequences, axial DWI images, 2D-gradient echo (GRE)-BOLD images, and ²³Na images were acquired. Mean values/standard deviations for (²³Na), the apparent diffusion coefficient (ADC), and R2* values were calculated for the upper/middle/lower parts of both kidneys. Corticomedullary ²³Na-concentration gradients were determined.

Results

Surprisingly, IG-IMRT patients showed no morphological alterations and no statistically significant differences of ADC and R2* values in all renal parts. Values for mean corticomedullary ²³Na-concentration matched those for healthy volunteers. Results were similar in 3D-CRT patients, except for the cranial part of the left kidney. This was atrophic and presented significantly reduced functional parameters (p?=?0.001??p?=?0.033). Reduced ADC values indicated reduced cell density and reduced extracellular space. Cortical and medullary R2* values of the left cranial kidney in the 3D-CRT group were higher, indicating more deoxygenated hemoglobin due to reduced blood flow/oxygenation. (²³Na) of the renal cranial parts in the 3D-CRT group was significantly reduced, while the expected corticomedullary ²³Na-concentration gradient was partially conserved.

Conclusions

Functional MRI can assess postradiotherapeutic renal changes. As expected, marked morphological/functional effects were observed in high-dose areas (3D-CRT), while, unexpectedly, no alteration in kidney function was observed in IG-IMRT patients, supporting the hypothesis that reducing total/fractional dose to the renal parenchyma by IMRT is clinically beneficial.     

Fast neutron beam radiotherapy of glioblastoma multiforme.

Twenty-one patients with glioblastoma multiforme were treated with fast neutron beam irradiation of the whole brain. Therapy was well tolerated up to calculated doses of 1.850 radn+y in 12-18 increments over 6 weeks. The survival rate 6 month after initiation of treatment was 62%, not significantly different from conventional photon therapy; average posttreatment survival appears to be shortened compared to photon therapy. No improvement or prolonged maintenance of existing neurologic function was observed. Autopsy findings in seven patients showed replacement of tumor by coagulative necrosis persisting at least 16 months posttreatment, paucity of tumor cells with infrequent mitosis, and suppression of macrophage response. These findings differ from those in conventionally irradiated patients. No treatment-related changes were documented by conventional gross and histologic studies of the irradiated brains distant from the tumors. Thus the deaths of patients in this study appear to be related to unexplained causes other than progressive growth of tumor.     

Clinical and technical characteristics of intraoperative radiotherapy

Background

A joint analysis of clinical data from centres within the European section of the International Society of Intraoperative Radiation Therapy (ISIORT-Europe) was undertaken in order to define the range of intraoperative radiotherapy (IORT) techniques and indications encompassed by its member institutions.

Materials and methods

In 2007, the ISIORT-Europe centres were invited to record demographic, clinical and technical data relating to their IORT procedures in a joint online database. Retrospective data entry was possible.

Results

The survey encompassed 21 centres and data from 3754 IORT procedures performed between 1992 and 2011. The average annual number of patients treated per institution was 42, with three centres treating more than 100 patients per year. The most frequent tumour was breast cancer with 2395 cases (63.8?%), followed by rectal cancer (598 cases, 15.9?%), sarcoma (221 cases, 5.9?%), prostate cancer (108 cases, 2.9?%) and pancreatic cancer (80 cases, 2.1?%). Clinical details and IORT technical data from these five tumour types are reported.

Conclusion

This is the first report on a large cohort of patients treated with IORT in Europe. It gives a picture of patient selection methods and treatment modalities, with emphasis on the main tumour types that are typically treated by this technique and may benefit from it.     

MR-guided laser-induced interstitial thermotherapy of recurrent glioblastoma multiforme: preliminary results in 16 patients

We investigated the survival after laser-induced interstitial thermotherapy in 16 patients suffering from recurrent glioblastoma multiforme. The concept underlying the intervention is the cytoreduction of the tumor tissue by local thermocoagulation. All patients received standard chemotherapy (temozolomide). The median overall survival time after the first relapse was 9.4 months, corresponding to a median overall survival time after laser irradiation of 6.9 months. During the study, however, the median survival after laser coagulation increased to 11.2 months. This survival time is substantially longer than those reported for the natural history (<5 months) or after chemotherapy (temozolomide: 5.4-7.1 months). We conclude that cytoreduction by laser irradiation might be a promising option for patients suffering from recurrent glioblastoma multiforme. In addition, the data indicate the presence of a substantial learning curve. Future work should optimize the therapeutic regimen and evaluate this treatment approach in controlled clinical trials.     

Radiotherapy of glioblastoma multiforme

Purpose

With regard to the poor prognosis of patients with glioblastoma multiforme, the aspect of life quality with a minimal treatment time becomes essential. The purpose of the present study is to evaluate whether the results of a radiotherapy schedule using increased single fractions applied over a shortened treatment time is feasible without compromising treatment efficiency or providing more side effects than a conventionally fractionationed treatment.

Patients and Methods

A total of 38 patients (f=21, m=17, mean age 58 years) with histologically proven glioblastoma multiforme were irradiated after (partial) resection (n=29) or stereotactic surgery (n=9) with single doses of 3.5 Gy (ICRU) 5 fractions a week up to a total dose of 42 Gy following individual treatment planning.

Results

Median survival was 45.7 weeks, survival rate after 6 months was 80.9% and decreased to 34.2% after 12 months. Radiotherapy was tolerated without any important acute toxicity or any late side effects during the follow-up period.

Conclusions

The increase of the dose per fraction using a fraction size of 3.5 Gy enhanced neither acute nor late toxicity. The survival rate compared well to those described in the literature. Thus the shortened treatment schedule seems as efficient as conventional radiotherapy. Moreover, it seems preferable with regard to quality of life.     

Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme

Background

The goal of this study was to evaluate accelerated radiotherapy with and without temozolomide (TMZ) for glioblastoma multiforme (GBM).

Methods

This retrospective analysis evaluated 86 patients with histologically proven GBM who were treated with accelerated radiotherapy of 1.8 Gy twice daily to a total dose of 54 Gy within 3 weeks. Median age was 62 years and median Karnofsky index was 90. A total of 41 patients received radiotherapy only from 2002?C2005 and 45 patients were treated with TMZ concomitantly and after radiotherapy from 2005?C2007.

Results

Median overall survival (OS) was 12.5 months and 2-year OS was 15.4%. Patient characteristics were well balanced between the two groups except for better performance status (p = 0.05) and higher frequency of retreatment for the first recurrence (p = 0.02) in the TMZ group. Age at diagnosis (HR 2.83) and treatment with TMZ (HR 0.60) were correlated with OS in the multivariate analysis: treatment with and without TMZ resulted in median OS of 16 months and 11.3 months, respectively. Hematological toxicity grade > II was observed in 2/45 patients and 5/37 patients during simultaneous radiochemotherapy and adjuvant TMZ.

Conclusion

TMZ added to accelerated radiotherapy for GBM resulted in prolonged overall survival with low rates of severe hematological toxicity.     

Comparison of intensity-modulated radiotherapy with three-dimensional conformal radiation therapy planning for glioblastoma multiforme

This study was designed to assess the feasibility and potential benefit of using intensity-modulated radiotherapy (IMRT) planning for patients newly diagnosed with glioblastoma multiforme (GBM). Five consecutive patients with confirmed histopathologically GBM were entered into the study. These patients were planned and treated with 3-dimensional conformal radiation therapy (3DCRT) using our standard plan of 3 noncoplanar wedged fields. They were then replanned with the IMRT method that included a simultaneous boost to the gross tumor volume (GTV). The dose distributions and dose-volume histograms (DHVs) for the planning treatment volume (PTV), GTV, and the relevant critical structures, as obtained with 3DCRT and IMRT, respectively, were compared. In both the 3DCRT and IMRT plans, 59.4 Gy was delivered to the GTV plus a margin of 2.5 cm, with doses to critical structures below the tolerance threshold. However, with the simultaneous boost in IMRT, a higher tumor dose of 70 Gy could be delivered to the GTV, while still maintaining the uninvolved brain at dose levels of the 3DCRT technique. In addition, our experience indicated that IMRT planning is less labor intensive and time consuming than 3DCRT planning. Our study shows that IMRT planning is feasible and efficient for radiotherapy of GBM. In particular, IMRT can deliver a simultaneous boost to the GTV while better sparing the normal brain and other critical structures.     

Clinical radiobiology of glioblastoma multiforme

Background and purpose

The aim of this study was to estimate a radiobiological set of parameters from the available clinical data on glioblastoma (GB).

Patients and methods

A number of clinical trial outcomes from patients affected by GB and treated with surgery and adjuvant radiochemotherapy were analyzed to estimate a set of radiobiological parameters for a tumor control probability (TCP) model. The analytical/graphical method employed to fit the clinical data allowed us to estimate the intrinsic tumor radiosensitivity (α), repair capability (b), and repopulation doubling time (T _d ) in a first phase, and subsequently the number of clonogens (N) and kick-off time for accelerated proliferation (T _k ). The results were used to formulate a hypothesis for a scheduleexpected to significantly improve local control. The 95?% confidence intervals (CI_95?%) of all parameters are also discussed.

Results

The pooled analysis employed to estimate the parameters summarizes the data of 559 patients, while the studies selected to verify the results summarize data of 104 patients. The best estimates and the CI_95?% are α?=?0.12 Gy^?1 (0.10–0.14), b?=?0.015 Gy^?2 (0.013–0.020), α/b?=?8 Gy (5.0–10.8), T _d ?=?15.4 days (13.2–19.5), N?=?1?·?10⁴ (1.2?·?10³–1?·?10⁵), and T _k ?=?37 days (29–46). The dose required to offset the repopulation occurring after 1 day (D _prolif ) and starting after T _k was estimated as 0.30 Gy/day (0.22–0.39).

Conclusion

The analysis confirms a high value for the α/b ratio. Moreover, a high intrinsic radiosensitivity together with a long kick-off time for accelerated repopulation and moderate repopulation kinetics were found. The results indicate a substantial independence of the duration of the overall treatment and an improvement in the treatment effectiveness by increasing the total dose without increasing the dose fraction.     

小脑蚓部多形性胶质母细胞瘤1例

患者 女,18岁,头部持续性胀痛1周,以双颞部为重,伴恶心,无肢体无力。查体：神智清,回答切题,双侧瞳孔直径约3 mm,对光反射灵敏,病理反射未引出。CT 扫描第脑四室内见不规则等低混杂密度肿块,与小脑蚓部呈窄基底相连(图1)。MRI：第四脑室区见大小约26 mm×30 mm×32 mm 不规则长 T1长 T2为主混杂信号肿块,信号不均,与小脑蚓部呈窄基底相连,增强扫描呈不均匀强化(图2~6)。     

Prognostic factors in recurrent glioblastoma multiforme and anaplastic astrocytoma treated with selective intra-arterial chemotherapy

BACKGROUND AND PURPOSE: Factors predictive of primary brain tumor outcome have been studied extensively, although the prognostic value of radiologic data, such as MR imaging and angiographic characteristics, has not been studied in depth. The purpose of this study was to determine whether radiologic data were prognostic factors among patients with recurrent glioblastoma multiforme and anaplastic astrocytoma treated with selective intra-arterial chemotherapy. METHODS: Forty-six patients were enrolled in a Phase II study of intra-arterial chemotherapy with carboplatin and Cereport (Alkermes Inc.; Cambridge, MA), a bradykinin analog that selectively increases permeability of the blood-tumor barrier. MR imaging volumes of enhancing tumor, resection cavity, and T2 signal abnormality were measured with T1-weighted and T2-weighted sequences. Volumes were analyzed individually and in various combinations. Tumor vascularity was graded on angiograms. Outcome was measured by time to tumor progression and survival. RESULTS: Of 46 patients included in this study, 41 underwent evaluation. Thirty were male and 11 were female; mean age was 48.5 years. Karnofsky scores ranged from 70 to 100. Thirty-two patients had glioblastoma multiforme, whereas nine had anaplastic astrocytoma. Twenty-eight patients had tumor progression and 13 had stable disease. Twenty-three patients died after an average of 205 days; 18 were surviving at an average of 324 days from the start of intra-arterial chemotherapy. In multivariate analysis, time from diagnosis to intra-arterial chemotherapy was predictive both of time to tumor progression and survival. Net tumor volume and vascularity also were significant for survival. Age, Karnofsky performance status, histologic findings, gender, MR imaging area, resection cavity volume, T2 signal abnormality volume, and various combined volumes were not significant. CONCLUSION: If confirmed by further studies, radiologic factors such as tumor volume and angiographic vascularity should be considered in design and stratification of future chemotherapy trials.     

Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma

Backgroud

Evaluated in this study were the feasibility and the efficacy of concurrent low dose fractionated radiotherapy (LD-FRT) and chemotherapy as palliative treatment for recurrent/progressive glioblastoma multiforme (GBM).

Patients and methods

Eligible patients had recurrent or progressive GBM, Karnofsky performance status ≥?70, prior surgery, and standard radiochemotherapy treatment. Recurrence/progression disease during temozolomide (TMZ) received cisplatin (CDDP; 30 mg/m² on days 1, 8, 15), fotemustine (FTM; 40 mg/m² on days 2, 9, 16), and concurrent LD-FRT (0.3 Gy twice daily); recurrence/progression after 4 months from the end of adjuvant TMZ were treated by TMZ (150/200 mg/m² on days 1–5) concomitant with LD-FRT (0.4 Gy twice daily). Primary endpoints were safety and toxicity.

Results

A total of 32 patients were enrolled. Hematologic toxicity G1–2 was observed in 18.7?% of patients and G3–4 in 9.4?%. One patient (3.1?%) had complete response, 3 (9.4?%) had partial response, 8 (25?%) had stable disease for at least 8 weeks, while 20 patients (62.5?%) experienced progressive disease. The clinical benefit was 37.5?%. Median progression-free survival (PFS) and overall survival (OS) were 5 and 8 months, respectively. Survival rate at 12 months was of 27.8?%.

Conclusion

LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted.     

Re-irradiation after gross total resection of recurrent glioblastoma

Background

Currently, patients with gross total resection (GTR) of recurrent glioblastoma (rGBM) undergo adjuvant chemotherapy or are followed up until progression. Re-irradiation, as one of the most effective treatments in macroscopic rGBM, is withheld in this situation, as uncertainties about the pattern of re-recurrence, the target volume, and also the efficacy of early re-irradiation after GTR exist.

Methods

Imaging and clinical data from 26 consecutive patients with GTR of rGBM were analyzed. The spatial pattern of recurrences was analyzed according to the RANO-HGG criteria (“response assessment in neuro-oncology criteria for high-grade gliomas”). Progression-free (PFS) and overall survival (OS) were analyzed by the Kaplan–Meier method. Furthermore, a systematic review was performed in PubMed.

Results

All but 4 patients underwent adjuvant chemotherapy after GTR. Progression was diagnosed in 20 of 26 patients and 70% of recurrent tumors occurred adjacent to the resection cavity. The median extension beyond the edge of the resection cavity was 20?mm. Median PFS was 6 months; OS was 12.8 months. We propose a target volume containing the resection cavity and every contrast enhancing lesion as the gross tumor volume (GTV), a spherical margin of 5–10?mm to generate the clinical target volume (CTV), and a margin of 1–3?mm to generate the planning target volume (PTV). Re-irradiation of this volume is deemed to be safe and likely to prolong PFS.

Conclusion

Re-irradiation is worth considering also after GTR, as the volumes that need to be treated are limited and re-irradiation has already proven to be a safe treatment option in general. The strategy of early re-irradiation is currently being tested within the GlioCave/NOA 17/Aro 2016/03 trial.

     

Posterior fossa glioblastoma multiforme: MR findings.

PURPOSETo characterize the MR findings of glioblastoma multiforme in the posterior fossa.METHODSMR studies of nine patients with surgically proved posterior fossa glioblastoma multiforme were retrospectively evaluated. MR characteristics studied included tumor location, signal intensity, enhancement pattern, and presence of intratumoral hemorrhage, as well as presence of secondary hydrocephalus or metastatic spread.RESULTSThe tumors were located in the median portion of the cerebellum or brain stem in eight cases. Six extended into the fourth ventricle. Hydrocephalus was seen in four cases. Six cases demonstrated decreased T1- and increased T2-weighted signal intensities. Three cases demonstrated mixed signal intensities suggesting intratumoral hemorrhage. All of the eight patients who received contrast showed moderate to marked heterogeneous ringlike enhancement suggesting intratumoral necrosis. Multicentric/multifocal lesions or extraaxial metastases were identified in three of the nine cases, and there was extracranial extension into the cervical region in one case.CONCLUSIONGlioblastoma multiforme is a rare tumor in the posterior fossa. Differentiating it from metastatic tumor or malignant astrocytoma was difficult. However, combination of heterogeneous and ringlike enhancement, midline location, poorly defined margin, tumoral hemorrhage, concomitant multicentric/multifocal lesions, and extraaxial or extracranial metastasis may be clues for the prospective diagnosis of glioblastoma multiforme.     

Supratentorial glioblastoma: Neuroradiological findings and survival after surgery and radiotherapy

Few studies have attempted to correlate neuroimaging with outcome in patients with glioblastoma. Our aim was to evaluate the relationship between neuroradiological findings and survival in these patients. We studied 18 consecutive patients with glioblastoma who had undergone surgery and radiotherapy. We assessed the following features, using preoperative CT and/or MRI: tumour size, extent of necrotic area within the mass, extent of perifocal oedema and contrast enhancement. The mean survival was 14.2 ± 5 months (range 6–22). The extent of radiological evidence of necrosis within the mass correlated significantly with survival time, whereas tumour size, perifocal oedema and contrast enhancement did not.     

Intraoperative cobalt-60 treatment of glioblastoma multiforme

An intraoperative remote afterloading endocurietherapy (ECT) technique with high-activity 60cobalt (60Co) for the treatment of glioblastoma multiforme (GM) is described. The technique can be used for initial management of the unresectable tumor or for retreatment of patients with recurrent tumor who have been treated previously with surgery and postoperative radiotherapy. We present the technique, tumor response, radiographic findings, and survival of 38 glioblastoma patients treated with intraoperative 60Co.     

Childhood glioblastoma multiforme of the spinal cord

Astrocytoma accounts for more than 50% of all central nervous system tumours diagnosed, with particular prevalence in the 15- to 34-year-old age bracket, rarely arising in younger children. In 1995, a 7-year-old boy presented in Emergency with a 3-day history of severe radicular back pain and associated muscle spasms, exacerbated by lying on his back. Both bone scan and plain X-rays were unremarkable; however, MRI showed a 3-cm space-occupying lesion at the level of T5-T6. The patient proceeded to biopsy and partial excision of the tumour through laminectomy, histology confirming an anaplastic astrocytoma (glioblastoma multiforme), St Anne Mayo grade 4. Treatment consisted of a radical course of radiotherapy alone, delivering a total dose of 44.8 Gy at 1.6 Gy per fraction. The treatment comprised of three phases using two oblique wedged fields on a 6 MV linear accelerator. The patient remains disease free 7 years post treatment, with the only effect noted being a slight kyphoscoliosis at the site of the laminectomy and radiation. This report highlights the efficacy of combined surgery and radiation therapy in the management of spinal cord glioblastoma multiforme in preventing tumour recurrence, with acceptable morbidity. Further evaluation of the treatment efficacy would be difficult because of the scarcity of such cases.