Radiotherapy For Low-grade Glioma Research Articles

Optimal Combinations of Chemotherapy and Radiotherapy in Low-Grade Gliomas: A Mathematical Approach.

Low-grade gliomas (LGGs) are brain tumors characterized by their slow growth and infiltrative nature. Treatment options for these tumors are surgery, radiation therapy and chemotherapy. The optimal use of radiation therapy and chemotherapy is still under study. In this paper, we construct a mathematical model of LGG response to combinations of chemotherapy, specifically to the alkylating agent temozolomide and radiation therapy. Patient-specific parameters were obtained from longitudinal imaging data of the response of real LGG patients. Computer simulations showed that concurrent cycles of radiation therapy and temozolomide could provide the best therapeutic efficacy in-silico for the patients included in the study. The patient cohort was extended computationally to a set of 3000 virtual patients. This virtual cohort was subject to an in-silico trial in which matching the doses of radiotherapy to those of temozolomide in the first five days of each cycle improved overall survival over concomitant radio-chemotherapy according to RTOG 0424. Thus, the proposed treatment schedule could be investigated in a clinical setting to improve combination treatments in LGGs with substantial survival benefits.

SP-0390: Radiotherapy for low grade glioma in adults in 2017. What’s crazy!

SP-0390: Radiotherapy for low grade glioma in adults in 2017. What’s crazy!

Facing pseudoprogression after radiotherapy in low grade gliomas

Pseudoprogression has been defined as a transient increase in the contrast enhancement within the treated tumour after radiotherapy, which eventually subsides without any change in the anti-cancer therapy (1,2). This constitutes most likely a subacute post-treatment effect of radiotherapy characterised by a local inflammatory reaction on tumour cells and/or vascular injury resulting in increased permeability (1,2). The concept of pseudoprogression was initially developed in adults with high-grade gliomas treated with radiotherapy +/− alkylating agents (3); and it has subsequently been extended to other brain tumours, including low-grade gliomas (LGG). Pseudoprogression has been reported to occur more frequently when temozolomide is combined with radiotherapy (4,5), although the magnitude of this effect yet remains to be established (3). Pseudoprogression can produce a clinical impact both at an individual and at a population level. Firstly, increased contrast enhancement in adults with LGG is highly suggestive of malignant transformation (6), so undiagnosed pseudoprogression may cause major distress for the patients and their families, and can even result in initiation of a new anti-cancer therapy inappropriately. Secondly, because failure to exclude patients with pseudoprogression at the time of enrolment in clinical trials may lead to falsely elevated response rates (1). And finally, because failure to identify pseudoprogression whilst on trial, limits the validity of progression-free survival as a primary endpoint (1). Hence, a better understanding and diagnosis of pseudoprogression is crucial to ensure adequate clinical management and to minimise hindrance to clinical trials.

Facing pseudoprogression after radiotherapy in low grade gliomas

Facing pseudoprogression after radiotherapy in low grade gliomas

Incidence of pseudo-progression in low-grade gliomas treated with radiotherapy.

2051 Background: Pseudo-progression (psPD) is a well-known phenomenon in high-grade gliomas (HGG) after treatment with radiotherapy/temozolomide. However the incidence of psPD in low-grade glioma (LGG) after radiotherapy (RT) is unknown. Therefore, we retrospectively investigated the occurrence of psPD in a cohort of low grade glioma patients treated with RT. Methods: All patients with histologically proven LGG treated with RT between 2000 and 2011 were reviewed. MRI scans were reviewed by two independent reviewers before and after RT in periods of 3-6 months until progression leading to the start of a new treatment as judged by the treating physician. Furthermore clinical data including dexamethasone dose and epileptic activity was taken into account. Pseudo-progression was scored when a new enhancing lesion occurred after RT, and this disappeared or remained stable for at least a year without therapy. Results: Seventy-one patients were treated with RT for LGG. Sixty-four patients were deemed eligible for evaluation (3 were lost to follow up and 4 patients were not evaluable, due to a missing scans). The median follow-up was 7 years (range 1- 22 years). The median progression free survival was 3.1 years. The median overall survival time was 5.3 years. Sixty-three patients were evaluable for psPD (1 patient was evaluated for response only, because of gadolinium allergy). psPD was seen in 13 patients (20.6%). In two of these patients epilepsy may have played a role. Pseudo-progression occurred after a median of 10 months in a period of 3 – 78 months. The median duration of psPD was 6 months with a range of 2 – 26 months. It always occurred within the RT fields. The area of the enhancement at the time of pseudo-progression was significantly smaller compared to the area of enhancement during ‘true’ progression (median size 54 mm2 (range 12 – 340 mm2) versus 270 mm2 (range 30 – 3420 mm2), respectively; p = 0.009). Conclusions: psPD occurs frequently in LGG patients treated with RT. This supports the policy to postpone a new line of treatment until further progression is evident, especially when patients have small contrast enhancing lesions in the RT field.

Volumetric modulated arc therapy for hippocampal-sparing radiotherapy in transformed low-grade glioma: A treatment planning case report

Timing of radiotherapy for low-grade gliomas is still controversial due to concerns of possible adverse late effects. Prevention of possible late cognitive sequelae by hippocampal avoidance has shown promise in phase II trials. A patient with progressive low-grade glioma with gradual dedifferentiation into anaplastic astrocytoma is presented along with description of radiotherapy planning process attempting to spare the hippocampus. To our knowledge, this is the first described case using volumetric modulated arc technique to spare hippocampus during transformed low-grade glioma radiotherapy. Using modern intensity-modulated radiotherapy systems it is possible to selectively spare hippocampus together with other standard organs at risk. For selected patients, an attempt to spare hippocampus can be considered as long as other dose characteristics are not significantly compromised compared to standard treatment plan created without any effort to avoid hippocampus.

The effect of the addition of chemotherapy to radiotherapy on cognitive function in patients with low-grade glioma: Secondary analysis of RTOG 98-02.

2047 Background: The addition of PCV chemotherapy to radiotherapy (RT) for patients with WHO grade II glioma improves progression free survival (PFS) and overall survival (OS), for patients surviving at least 2 years (Shaw, J Clin Oncol 26: 2008). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long term survival. Methods: 251patients with WHO grade II glioma and age > 40 with any extent of resection, or age < 40 with subtotal resection/biopsy were randomized to RT (54Gy) or RT + PCV. 111 patients with age < 40 and gross total resection were observed. CF was assessed by mini-mental status exam (MMSE)at baseline and years 1, 3, and 5 for patients without progression. Change in MMSE score from baseline of > 3 points was considered clinically significant. Results: Overall, very few patients experienced significant decline in MMSE score, with a median follow-up time of 9.7 years for alive patients. There were no significant differences in the proportion of patients experiencing MMSE decline between study arms at any time point. The table below summarizes MMSE change from baseline over time. Neither baseline MMSE score nor change in MMSE at year 1 significantly predicted for OS or PFS, but there was a trend towards worse OS for patients with MMSE loss of ≥ 2 points [HR 1.73, 95% CI (0.86, 3.47), p=0.12]. Conclusions: The MMSE is a relatively insensitive tool that has not been validated in patients receiving cranial RT, and subtle changes in CF may have been missed. However, the addition of PCV to RT for low grade glioma did not result in significantly higher rates of MMSE decline than RT alone or observation. There was a trend towards an MMSE decline of ≥ 2 points at year 1 predicting for worse OS. [Table: see text]

Dummy run and conformity indices in the ongoing EORTC low-grade glioma trial 22033-26033: First evaluation of quality of radiotherapy planning

Purpose Early assessment of radiotherapy (RT) quality in the ongoing EORTC trial comparing primary temozolomide versus RT in low-grade gliomas. Materials and methods RT plans provided for dummy cases were evaluated and compared against expert plans. We analysed: (1) tumour and organs-at-risk delineation, (2) geometric and dosimetric characteristics, (3) planning parameters, compliance with dose prescription and Dmax for OAR (4) indices: RTOG conformity index (CI), coverage factor (CF), tissue protection factor (PF); conformity number (CN = PF × CF); dose homogeneity in PTV (U). Results Forty-one RT plans were evaluated. Only two (5%) centres were requested to repeat CTV–PTV delineations. Three (7%) plans had a significant under-dosage and dose homogeneity in one deviated >10%. Dose distribution was good with mean values of 1.5, 1, 0.68, and 0.68 (ideal values = 1) for CI, CF, PF, and CN, respectively. CI and CN strongly correlated with PF and they correlated with PTV. Planning with more beams seems to increase PTV Dmin, improving CF. U correlated with PTV Dmax. Conclusion Preliminary results of the dummy run procedure indicate that most centres conformed to protocol requirements. To quantify plan quality we recommend systematic calculation of U and either CI or CN, both of which measure the amount of irradiated normal brain tissue.

When should radiotherapy for low-grade glioma be given—immediately after surgery or at the time of progression?

When should radiotherapy for low-grade glioma be given—immediately after surgery or at the time of progression?

Should radiotherapy for low-grade glioma be given immediately after surgery or at the time of progression?

Should radiotherapy for low-grade glioma be given immediately after surgery or at the time of progression?

Hypofractionated Stereotactic Radiotherapy for Low Grade Glioma at McGill University: Long-term Follow-up

Small, well-defined, unresectable low-grade gliomas are attractive targets for stereotactic irradiation. Fractionated stereotactic irradiation of these targets has the theoretical benefit of increased normal tissue sparing beyond that provided by the physical characteristics of stereotactic radiosurgery. From July 1987 to November 1992, 21 patients were treated for low-grade glioma at our institution using a hypofractionated regimen of stereotactic radiotherapy. All patients had well-circumscribed, < 40 mm tumors. No patient had had prior radiotherapy. All lesions were histologically proven WHO grade I or II glial tumors. Lesions involved sensitive brain structures and were deemed unresectable. A typical dose of 42 Gy was delivered in 6 fractions over a two-week period using rigid immobilization and a linac-based dynamic stereotactic radiosurgical technique. Patients had a median age of 23 years (9-74) and were predominantly female (60%). Median tumor diameter was 20 mm. With a median follow-up for living patients of 13.3 years, the actuarial 5, 10, and 15-year overall survival rates are 76%, 71%, and 63%, respectively. Treatment was acutely well tolerated although three patients experienced late post-therapy complications. Our results and those of 241 patients treated in nine other institutional series are reviewed. Despite some examples of favorable short-term outcomes, all reported series are highly selected and thus likely biased. The data regarding the use of SRS is limited and, in our opinion, insufficient to claim a clear therapeutic advantage to SRS in the initial management of low-grade glioma. Our own results with hypofractionated stereotactic radiotherapy are similar to those expected with standard therapy.

Role of radiotherapy in the treatment of gliomas

Malignant gliomas are challenging tumors that are often treated with a multimodality approach. This article focuses on the role of radiotherapy in the management of these tumors. The role of radiotherapy in low-grade gliomas remains controversial and this review focuses on the importance of prognostic factors, recent randomized trials involving radiotherapy, and toxicity from radiotherapy. In terms of high-grade gliomas, radiotherapy has a more established role and this review will address methods that have been evaluated in order to improve radiotherapy outcome. Improvements in radiotherapy delivery, tumor imaging and biologic modifiers may ultimately lead to improved outcome in the treatment of these difficult tumors.

Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial

Postoperative policies of "wait-and-see" and radiotherapy for low-grade glioma are poorly defined. A trial in the mid 1980s established the radiation dose. In 1986 the EORTC Radiotherapy and Brain Tumor Groups initiated a prospective trial to compare early radiotherapy with delayed radiotherapy. An interim analysis has been reported. We now present the long-term results. After surgery, patients from 24 centres across Europe were randomly assigned to either early radiotherapy of 54 Gy in fractions of 1.8 Gy or deferred radiotherapy until the time of progression (control group). Patients with low-grade astrocytoma, oligodendroglioma, mixed oligoastrocytoma, and incompletely resected pilocytic astrocytoma, with a WHO performance status 0-2 were eligible. Analysis was by intention to treat, and primary endpoints were overall and progression-free survival. 157 patients were assigned early radiotherapy, and 157 control. Median progression-free survival was 5.3 years in the early radiotherapy group and 3.4 years in the control group (hazard ratio 0.59, 95% CI 0.45-0.77; p<0.0001). However, overall survival was similar between groups: median survival in the radiotherapy group was 7.4 years compared with 7.2 years in the control group (hazard ratio 0.97, 95% CI 0.71-1.34; p=0.872). In the control group, 65% of patients received radiotherapy at progression. At 1 year, seizures were better controlled in the early radiotherapy group. Early radiotherapy after surgery lengthens the period without progression but does not affect overall survival. Because quality of life was not studied, it is not known whether time to progression reflects clinical deterioration. Radiotherapy could be deferred for patients with low-grade glioma who are in a good condition, provided they are carefully monitored.

Can chemotherapy replace radiotherapy in low-grade gliomas? Time for randomized studies

For the last three decades surgery and radiotherapy have been the mainstay of treatment for patients with low-grade gliomas, despite a lack of support from randomized controlled trials. Recent developments in our knowledge of low-grade tumor chemosensitivity and the approval of temozolomide for treatment of gliomas have led to increased interest in chemotherapy for treating low-grade gliomas. Despite challenges, including response assessment and appropriate patient selection, several phase II studies investigating chemotherapeutic treatment of low-grade gliomas have yielded promising results. Although most of these phase II studies are of limited sample size, they have shown that chemotherapy might induce clinically relevant responses and disease stabilization in patients with low-grade gliomas. As expected, low-grade oligodendroglioma is sensitive to chemotherapy, but responses were also seen in astrocytic tumors. Randomized, controlled studies should be conducted to determine the clinical significance of responses observed in phase II studies and to assess time to progression. Two randomized, controlled studies are currently investigating chemotherapy in the treatment of low-grade gliomas. Although it will take years before the data are available, these studies will help define the role of chemotherapy in the treatment of low-grade gliomas. Perhaps then we can answer the question, can chemotherapy replace radiotherapy in low-grade gliomas?

Advances in magnetic resonance imaging of brain tumours.

Magnetic resonance imaging (MRI) of brain tumours provides excellent anatomical detail of brain tumours and can also reveal the biology, cellular structure and vascular dynamics of a tumour, although the use of such features in routine clinical practice has yet to be realized. In this review the latest advances in MRI of brain tumours are discussed and their clinical applications highlighted. A large international study is underway to develop more powerful methods for automated classification of MR spectra based on the acquisition of large datasets of tumour spectra. Diffusion weighted imaging can help in the distinction between gliomas and abscesses, and perfusion weighted imaging can predict response to radiotherapy in low grade gliomas as well as distinguishing between different types of cerebral metastases. Intraoperative MRI has now been shown to be technically feasible, safe and effective in obtaining histological information as well as increasing the likelihood of complete resection for pituitary tumours and gliomas. Functional MRI and magnetic source imaging are alternative modalities that help the surgeon to avoid eloquent brain areas but may occasionally provide misleading information. Diffusion tensor imaging can demonstrate the effect of a tumour on white matter tracts and provides complementary information to that from other techniques that reveal areas of eloquent cortex. Advances in MRI techniques are providing better diagnostic and therapeutic information, but can only ever be a surrogate marker of physiological and pathological processes; until it can routinely be used to image the brain at a cellular level, MRI will always be secondary to pathology in the final diagnostic evaluation.

Radiotherapy in low-grade gliomas: pros

Although surgery is generally accepted as an important initial treatment in patients with low-grade gliomas, the role of postoperative radiotherapy (RT) is the subject of ongoing controversy. What is the most appropriate timing of RT? Is it best to deliver RT immediately after surgery or to watch and wait until disease progression? Numerous retrospective studies have shown that immediate postoperative RT provides a survival benefit. A recently published prospective study conducted by the European Organisation for Research and Treatment of Cancer has also shown that immediate postoperative RT significantly improved 5-year progression-free survival, but overall survival was not improved. Given the uncertainty about the overall survival benefit of immediate RT and the potential for radiation-induced toxicity, it is important to consider prognostic factors when selecting patients. Subgroups of patients with poor prognostic factors are more likely to benefit from immediate postoperative RT. Available data indicate that a carefully balanced therapeutic approach is needed to optimize treatment outcomes in patients with low-grade gliomas. Patients with more aggressive disease and a high risk of malignant transformation will likely benefit from immediate RT, whereas patients with low-risk disease, particularly oligodendrogliomas, can reasonably be observed. However, one cannot exclude the possibility that delaying RT may result in a worse long-term clinical outcome.

Radiotherapy in low-grade gliomas: cons

Although postoperative radiotherapy (RT) is widely used in patients with low-grade gliomas (LGGs), its clinical benefit remains unproven. Because LGGs include diseases with many different histologies, cytogenetic patterns, and natural histories, evaluating the effect of any treatment for LGGs is difficult. Analysis of prognostic subgroups has shown median survival rates ranging from 1 to 10 years. The clinical benefit of postoperative RT in LGGs in retrospective studies is confounded by the heterogeneity of LGGs and treatment-related variables. These studies report conflicting results, most likely because of differences in patient populations. The only prospective, randomized trial comparing postoperative RT with observation failed to show a survival benefit but showed a modest, although statistically significant, improvement in time to progression. Given that two thirds of patients in the observation group received RT at progression, the absence of a survival benefit suggests that RT is active in LGGs, but that delayed RT may provide the same survival advantage as postoperative RT. Moreover, high-dose or whole-brain RT can cause cognitive deficits. Our opinion is that postoperative RT should not be administered routinely to patients with LGGs. If RT is deemed necessary, such as in progressive or inoperable disease causing neurologic symptoms, a total dose of ≤50 Gy with a fractional dose of ≤1.8 to 2 Gy should be administered using modern, highly conformal techniques. Ideally, RT should be used only within the context of clinical research protocols.

1028 Poster Fractionated stereotactic radiotherapy in low grade gliomas: long-term results

1028 Poster Fractionated stereotactic radiotherapy in low grade gliomas: long-term results

Prognostic factors for survival in adult patients with cerebral low-grade glioma.

To identify prognostic factors for survival in adult patients with cerebral low-grade glioma (LGG), to derive a prognostic scoring system, and to validate results using an independent data set. European Organization for Research and Treatment of Cancer (EORTC) trial 22844 and EORTC trial 22845 are the largest phase III trials ever carried out in adult patients with LGG. The trials were designed to investigate the dosage and timing of postoperative radiotherapy in LGG. Cox analysis was performed on 322 patients from EORTC trial 22844 (construction set), and the results were validated on 288 patients from trial 22845 (validation set). Patients with pilocytic astrocytomas were excluded from this prognostic factor analysis. Multivariate analysis on the construction set showed that age > or = 40 years, astrocytoma histology subtype, largest diameter of the tumor > or = 6 cm, tumor crossing the midline, and presence of neurologic deficit before surgery were unfavorable prognostic factors for survival. The total number of unfavorable factors present can be used to determine the prognostic score. Presence of up to two of these factors identifies the low-risk group, whereas a higher score identifies high-risk patients. The validity of the multivariate model and of the scoring system was confirmed in the validation set. In adult patients with LGG, older age, astrocytoma histology, presence of neurologic deficits before surgery, largest tumor diameter, and tumor crossing the midline were important prognostic factors for survival. These factors can be used to identify low-risk and high-risk patients.

Results of postoperative radiotherapy in low-grade gliomas

Purpose To evaluate results, prognostic factors and patterns of failure of the postoperative radiotherapy (PRT) for Low-Grade Gliomas (LGG). Methods Between 1985 and 1995, 158 patients with LGG (WHO II) received PRT. There were 116 astrocytomas, 17 mixed oligoastrocytomas, 25 oligodendrogliomas. Median age was 39 years (range: 17–74). Conventional treatment techniques and doses were employed (median total dose- 58 Gy, median dose per fraction – 2 Gy). All known parameters with possible influences on prognosis were analysed in univariate analysis (UA). Then a multivariate analysis (MA) was performed for variables with significance level p Results The minimum follow-up period for alive patient was 52 months. The 5- and 10-year actuarial overall survival rate were 55- and 41% respectively. The actuarial progression free survival rate were 48% and 29% for 5 and 10 years respectively. MA revealed that good WHO performance status (p=0.00001), duration of symptoms before treatment >12 months (p=0.00003), seizures at presentation (p=0.0001), age Median time to recurrence was 49.5 months (range: 1–134). The precise localisation of recurrence was possible in 69 pts (73%). All but three pts recurred within the initial tumour margin. Two of them recurred at 1–3 cm of the initial tumour margin, one recurred at distance, in the controlateral hemisphere. The last one was the only case of recurrence outside the previously irradiated volume. Median SAR was 8 months (range: 0.5–43). Information about treatment of recurrence was available in 76 pts (81%) – (11 – surgery, 9 – surgery and chemotherapy, 2 – surgery and radiotherapy, 8 – surgery, radiotherapy and chemotherapy, 1 – radiotherapy, 19 – chemotherapy, 26 – supportive care). There was no correlation between any treatment method and patient related parameters in the Spearman's rank test. In univariate analysis only addition of chemotherapy to recurrence management (p=0.001) and duration of symptoms before initial surgery >12 months (p=0.004) were associated with increased SAR. Surgery at recurrence and patient related parameters (age, performance status, neurologic function, seizures) did not influence survival. Conclusions Long-term results of the treatment were unfavorable for a majority of patients with LGG. Good WHO performance status, duration of symptoms before treatment >12 months, seizures at presentation, age