Chemotherapy For Low-grade Gliomas Research Articles

A disulfidptosis-associated long noncoding RNA signature to predict low-grade glioma classification, prognosis, tumor microenvironment, and therapy regimens: Observational study.

This study aimed to investigate the function of disulfidptosis-associated long noncoding RNAs (DAlncRNAs) in low-grade gliomas (LGG) through bioinformatics analysis and construct a signature to predict the classification, prognosis, tumor microenvironment, and selection of immunotherapy and chemotherapy in LGG. Genomic, clinical, and mutational information of 526 patients with LGG was retrieved from The Cancer Genome Atlas repository. A nonnegative matrix factorization algorithm was applied to classify patients with LGG. Univariate, LASSO regression, and multivariate Cox regression analyses were performed to determine prognostic DAlncRNAs. Following the median risk score, we defined the sample as a high-risk (HR) or low-risk group. Finally, survival, receiver operating characteristic curve, risk curve, principal component, independent prognosis, risk difference, functional enrichment, tumor microenvironment, immune cell infiltration, mutation, and drug sensitivity analyses were performed. Patients were classified into C1 and C2 subtypes associated with disulfidptosis. Eight prognostic DAlncRNAs (AC003035.2, AC010157.2, AC010273.3, AC011444.3, AC092667.1, AL450270.1, AL645608.2, and LINC01571) were identified, and a prognostic signature of LGG was developed. The DAlncRNA-based signature was found to be an independent prognostic factor in patients with LGG, thereby constructing a nomogram. In addition, in the HR group, immune function was more active and the tumor mutation burden was higher. The patients were mainly composed of subtype C2, and their prognosis was worse. Immunotherapy and chemotherapy were predicted in the HR and low-risk groups, respectively. Our study, based on DAlncRNAs, highlights 2 disulfidptosis-associated LGG subtypes with different prognostic and immune characteristics and creates a novel disulfidptosis-associated prognostic signature, which may inform the classification, prognosis, molecular pathogenesis, and therapeutic strategies for patients with LGG.

A Win for Targeted Therapy in Pediatric BRAF-Mutant Gliomas.

Two reports from the phase II TADPOLE trial show the benefit of molecularly targeted therapy in pediatric brain tumors with BRAF mutations. Dabrafenib combined with trametinib was superior to chemotherapy in low-grade gliomas and yielded favorable responses in a single-arm study of high-grade ones, results that highlight the importance of biomarker testing in pediatric glioma care.

S100A gene family: immune-related prognostic biomarkers and therapeutic targets for low-grade glioma.

Background: Despite the better prognosis given by surgical resection and chemotherapy in low-grade glioma (LGG), progressive transformation is still a huge concern. In this case, the S100A gene family, being capable of regulating inflammatory responses, can promote tumor development.Methods: The analysis was carried out via ONCOMINE, GEPIA, cBioPortal, String, GeneMANIA, WebGestalt, LinkedOmics, TIMER, CGGA, R 4.0.2 and immunohistochemistry.Results: S100A2, S100A6, S100A10, S100A11, and S100A16 were up-regulated and S100A1 and S100A13 were down-regulated in LGG compared to normal tissues. S100A3, S100A4, S100A8, and S100A9 expression was up-regulated during the progression of glioma grade. In addition, genetic variation of the S100A family was high in LGG, and the S100A family genes mostly function through IL-17 signaling pathway, S100 binding protein, and inflammatory responses. The TIMER database also revealed a relationship between gene expression and immune cell infiltration. High expression of S100A2, S100A3, S100A4, S100A6, S100A8, S100A9, S100A10, S100A11, S100A13, and S100A16 was significantly associated with poor prognosis in LGG patients. S100A family genes S100A2, S100A3, S100A6, S100A10, and S100A11 may be prognosis-related genes in LGG, and were significantly associated with IDH mutation and 1p19q codeletion. The immunohistochemical staining results also confirmed that S100A2, S100A3, S100A6, S100A10, and S100A11 expression was upregulated in LGG.Conclusion: The S100A family plays a vital role in LGG pathogenesis, presumably facilitating LGG progression via modulating inflammatory state and immune cell infiltration.

LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE SUPRA-SELLAR PILOCYTIC ASTROCYTOMA

In-operable low grade gliomas (LGG) in the pediatric population continue to present a treatment dilemma. Due to the low-grade nature of these tumors, and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic regimen for these inoperable tumors includes vincristine (VCR) and carboplatin (Carbo). With advancements in the molecular characterization of gliomas, the role of targeted therapy has come into question. We present a 2-year-old female with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation) involving the hypothalamic/optic chiasm region. She presented with ataxic gait, bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism, which progressed to altered consciousness, and right hemiparesis due to location/mass effect of the tumor. She was initially treated with chemotherapy (VCR/Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy, resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months, follow up MRI showed slight increase in the solid portion of the tumor, with no clinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue with Dabrafenib. Our experience and literature review suggests that LGG with BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.

Current Salvage Treatment Strategies for Younger Children (

Pediatric low-grade gliomas (LGGs) are the most common brain tumors in children. Treatment of pediatric LGG can often be challenging, particularly when not resectable and refractory or recurrent following standard chemotherapy regimens. There is no current accepted standard of care salvage regimen for progressive LGG after the failure of first-line chemotherapy. A web-based survey was distributed to pediatric cancer centers throughout North America to inquire regarding institutional preferences of salvage treatment strategies after initial chemotherapy for LGG in children less than 10 years of age, as well as molecular testing preferences. Highlights from the survey results were as follows: vincristine/carboplatin (VC) and vinblastine (VBL) were the top 2 preferred salvage regimens for non-BRAF-altered pediatric LGG. BRAF and MEK inhibitors were the most preferred salvage regimens for BRAF V600e-mutated and BRAF fusion-positive pediatric LGG, respectively. VC ranked second. As high as 47.8% of North American centers would use conformal radiation for younger children with non-neurofibromatosis type 1 LGG after failing 2 to 3 chemotherapy regimens. Overall, 87% (87%) of North American institutions obtain some type of routine molecular testing for non-neurofibromatosis type 1-associated pediatric LGG cases. Less than 60% of centers obtain routine H3 K27M molecular testing for pediatric LGG with a midline location.

Toxicity Profile of Procarbazine Lomustine and Vincristine Chemotherapy in Low-Grade Glioma - Retrospective Review.

BackgroundThe role of Procarbazine Lomustine and Vincristine (PCV) chemotherapy is already established in terms of improving survival in low-grade glioma (LGG). This improved survival has led to the increasing administration of PCV to LGG patients over the past years. However, like other chemotherapies, serious hematological and non-hematological toxicities may occur. The purpose of this study was to evaluate the toxicity profile of PCV and its clinical relevance in our practice. Materials and MethodsWe reviewed 63 patients of LGG retrospectively who received chemotherapy PCV between January 2015 and January 2018 at Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore.ResultsSignificant hematological toxicity as grade 3 anemia, thrombocytopenia, and neutropenia occurred in 19%, 27%, and 46% respectively with PCV. Other toxicities such as neurotoxicity, vomiting and derangement of liver enzymes occurred in 3.2%, 19%, and 19% respectively. Patients who were on concurrent anticonvulsants had no increase in PCV toxicity. Survival was not impacted by hematological toxicities up to grade 3.ConclusionPCV chemotherapy is associated with major hematological, hepatic, and clinical toxicities (vomiting, constipation, and neuropathy). Hematological toxicities influenced the course of treatment in terms of delays and interruptions.

Abstract 3201: Molecular subtype specific biomarkers improve prediction of temozolomide therapy in low grade glioma

Abstract Introduction: Based on IDH mutation and 1p/19q codeletion, low grade glioma (LGG) could be classified into three groups with different prognosis : IDHmut-codel, IDHmut-non-codel and IDHwt,. Temozolomide (TMZ) is commonly used to reduce LGG recurrence and mortality. However, increasing studies have demonstrated MGMT promoter methylation status could not predict the therapeutic effect of TMZ in the different molecular subtypes of LGG. Therefore, promising molecular markers of TMZ chemotherapy in each subgroup is in urgent need. Methods: LGG data sets containing information of mutations and copy number aberrations (CNVs), as well as clinical records and treatment history were retrieved form The Cancer Genome Atlas. TMZ treated patients with intact PFS/OS information were selected(n=256). Kaplan-Meier and Cox's proportional hazard model were used to estimating survival and selecting predictive molecular makersin these TMZ-treated LGG.The Chinese Glioma Genome Atlas (CGGA) was used as independent validation data. Results: These patients were classified into IDHmut-codel (n=69), IDHmut-non-codel (n=127) and IDHwt (n=60) subgroups. MGMT promoter is methylated (MGMTpo-m) in 99% patients with IDHmut-codel .And the status of MGMT promoter methylation was not correlated with either PFS or OS in both IDHmut-non-codel and IDHwt cohorts. Based on the cox regression analysis, PIK3CA, mutated in 20% IDHmut-codel patients, significantly correlated with PFS (p=0.03) and OS (p=0.02) in this cohort. TTN obviously correlated with PFS (p=0.01) and OS (p < 0.01) in IDHmut-non-codel cohort. C9orf53, homozygous deletion in 40% IDHwt patients, significantly correlated with PFS (p=0.03) and OS (p < 0.01) in IDHwt cohort. Multivariate cox regression confirmed these three genes were independent predictors in each cohort. Notably, the combination of PIK3CA with TTN mutations (marked as PIK3CA/TTN) exhibited striking correlation with PFS (p < 0.01) and OS (p < 0.01) in the IDHmut cohort (IDHmut-codel and IDHmut-non-codel cohorts), and multivariate cox regression confirmed it was also an independent predictor of PFS (p < 0.01) and OS (p < 0.01). The predictive effect of PIK3CA/TTN was validated in an independent dataset CGGA. OS was significantly higher in PIK3CA/TTN patients (p = 0.04) and multivariate cox regression confirmed its independent predictive effect (p=0.04). Conclusion: Although MGMT methylation status is considered as the predictive markers for TMZ chemotherapy in LGG. In this work, we proved it could not predict TMZ efficacy in each molecular subtypes of LGG . However, PIK3CA, TTN, PIK3CA/TTN and C9orf53 were identified as promising molecular markers of TMZ in different subtypes of LGG: PIK3CA for IDHmut-codel, TTN for IDHmut-noncodel, C9orf53 for IDHwt subtype, and PIK3CA/TTN mutation for all IDH mutant LGG. Citation Format: Feng Jia, Feilong Zhao, Xiaoyan Zhang, Jiao Feng, Tonghui Ma, Tao Lv, Xiaohua Zhang. Molecular subtype specific biomarkers improve prediction of temozolomide therapy in low grade glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3201.

Radiotherapy and Chemotherapy in Low-Grade Glioma (LGG)

Radiotherapy and Chemotherapy in Low-Grade Glioma (LGG)

Mathematical analysis of a generalised model of chemotherapy for low grade gliomas

We study mathematical properties of a model describing growth of primary brain tumours called low-grade gliomas (LGGs) and their response to chemotherapy. The motivation for considering this particular type of cancer is its large impact on society. LGGs affect mainly young adults and eventually result in death, despite the tumour growth rate being slow. The model studied consists of two non-autonomous ordinary differential equations and is a generalised version of the model proposed by Bogdanska et al. (Math. Biosci. 2017). We discuss the stability of stationary states, prove global stability of tumour-free steady state and, in some cases, justify the existence of periodic solutions. Assuming that chemotherapy effectiveness remains constant in time, we provide analytical estimates and calculate minimal doses of the drug that should eliminate the tumour for particular patients with LGGs.

A Randomized Clinical Trial of Radiation With or Without Chemotherapy for Low-grade Gliomas.

A Randomized Clinical Trial of Radiation With or Without Chemotherapy for Low-grade Gliomas.

Dynamics and optimal control of chemotherapy for low grade gliomas: Insights from a mathematical model

We discuss the optimization of chemotherapy treatment for low-grade gliomas using a mathematical model. We analyze the dynamics of the model and study the stability of solutions. The dynamical model is incorporated into an optimal control problem for which different objective functionals are considered. We establish the existence of optimal controls and give a detailed discussion of the necessary optimality conditions. Since the control variable appears linearly in the control problem, optimal controls are concatenations of bang-bang and singular arcs.We derive a formula of the singular control in terms of state and adjoint variables.Using discretization and optimization methods we compute optimal drug protocols in a number of scenarios.For small treatment periods, the optimal control is bang-bang, whereas for larger treatment periods we obtain both bang-bang and singular arcs. In particular, singular controls illustrate the metronomic chemotherapy.

Chemotherapy for low-grade glioma: when, for whom, which regimen?

The role of chemotherapy in low-grade glioma has been redefined with the long-term follow-up of the RTOG 9802, which investigated adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy in addition to radiotherapy, and the results of EORTC trial 22033 in a similar patient population that compared temozolomide to radiotherapy. RTOG 9802 trial showed an increase in overall survival after adjuvant chemotherapy. Median overall survival increased from 7.8 to 13.3 years, with a hazard ratio of death of 0.59 (log rank: P = 0.002), and despite a 77% cross-over rate to chemotherapy in patients progressing after radiotherapy. The EORTC trial 22033 did not reveal differences in progression-free survival between patients treated initially with radiotherapy or with temozolomide. With these results and similar results of trials in anaplastic glioma, radiotheraphy with PCV is now to be considered standard of care for low-grade glioma requiring postsurgical adjuvant treatment. The optimal parameter for selecting patients for adjuvant PCV has not yet been fully elucidated. It is still unclear if temozolomide can replace PCV, but temozolomide is better tolerated than nitrosoureas. The current evidence supports treating patients with grade II and III glioma based on their molecular characteristics.

ATCT-32A PHASE II STUDY OF TEMOZOLOMIDE IN THE TREATMENT OF ADULT PATIENTS WITH SUPRATENTORIAL LOW-GRADE GLIOMA

INTRODUCTION: Optimal adjuvant management of low-grade gliomas (LGGs) remains controversial. Radiotherapy has been shown to improve progression-free survival compared to observation, but carries the potential for substantial late toxicity. In an effort to delay or obviate the need for radiotherapy, there has been increasing interest in the use of adjuvant chemotherapy in LGGs. However, there is a dearth of prospective studies with long-term follow-up evaluating the efficacy of adjuvant chemotherapy without radiation in patients with newly diagnosed LGGs. METHODS: Patients over the age of 18 with histologically proven supratentorial LGG (WHO grade II) who underwent subtotal resection or biopsy were eligible for enrollment. All patients received monthly cycles of oral Temozolomide (TMZ) for 12 months or until disease progression. Patients were assessed for radiographic response and progression with MRIs every two months during and after treatment. The primary outcome was objective radiographic response rate; secondary outcomes included progression-free and overall survival. RESULTS: 120 patients were enrolled in the trial (57 oligodendrogliomas, 20 oligoastrocytomas, 43 astrocytomas), with a median follow-up of 6.9 years. Objective responses were seen in 7 patients (6%), and 86% demonstrated stable or improved disease during treatment with TMZ. Median progression-free survival was 4.2 years, and median overall survival was 9.7 years. Partitioning analysis demonstrated favorable results in patients with disease confined to one hemisphere undergoing subtotal resection. Treatment was well tolerated with minimal toxicity. CONCLUSIONS: In this high-risk cohort of newly diagnosed LGGs undergoing subtotal resection or biopsy, adjuvant TMZ alone achieved progression-free survival comparable to that seen in similar cohorts treated with adjuvant radiation. TMZ was very well tolerated, and could be considered as adjuvant therapy in appropriately selected patients. Work is ongoing to determine the demographic, pathologic and molecular characteristics of patients who are optimal candidates for adjuvant TMZ.

Evaluation of low-grade glioma structural changes after chemotherapy using DTI-based histogram analysis and functional diffusion maps.

To explore the role of diffusion tensor imaging (DTI)-based histogram analysis and functional diffusion maps (fDMs) in evaluating structural changes of low-grade gliomas (LGGs) receiving temozolomide (TMZ) chemotherapy. Twenty-one LGG patients underwent 3T-MR examinations before and after three and six cycles of dose-dense TMZ, including 3D-fluid-attenuated inversion recovery (FLAIR) sequences and DTI (b = 1000s/mm(2), 32 directions). Mean diffusivity (MD), fractional anisotropy (FA), and tensor-decomposition DTI maps (p and q) were obtained. Histogram and fDM analyses were performed on co-registered baseline and post-chemotherapy maps. DTI changes were compared with modifications of tumour area and volume [according to Response Assessment in Neuro-Oncology (RANO) criteria], and seizure response. After three cycles of TMZ, 20/21 patients were stable according to RANO criteria, but DTI changes were observed in all patients (Wilcoxon test, P ≤ 0.03). After six cycles, DTI changes were more pronounced (P ≤ 0.005). Seventy-five percent of patients had early seizure response with significant improvement of DTI values, maintaining stability on FLAIR. Early changes of the 25th percentiles of p and MD predicted final volume change (R(2) = 0.614 and 0.561, P < 0.0005, respectively). TMZ-related changes were located mainly at tumour borders on p and MD fDMs. DTI-based histogram and fDM analyses are useful techniques to evaluate the early effects of TMZ chemotherapy in LGG patients. • DTI helps to assess the efficacy of chemotherapy in low-grade gliomas. • Histogram analysis of DTI metrics quantifies structural changes in tumour tissue. • Functional diffusion maps (fDMs) spatially localize the changes of DTI metrics. • Changes in DTI histograms and fDMs precede changes in conventional MRI. • Early changes in DTI histograms and fDMs correlate with seizure response.

A phase II study of temozolomide in the treatment of adult patients with supratentorial low-grade glioma.

2022 Background: Optimal adjuvant management of low-grade gliomas (LGGs) remains controversial. Radiotherapy has been shown to improve progression-free survival compared to observation, but carries the potential for substantial late toxicity. In an effort to delay or obviate the need for radiation, there has been increasing interest in the use of adjuvant chemotherapy in LGGs. However, there is a dearth of prospective studies with long-term follow-up evaluating the efficacy of adjuvant chemotherapy without radiation in patients with newly diagnosed LGGs. Methods: Patients over the age of 18 with histologically proven supratentorial LGG (WHO grade II) who underwent subtotal resection or biopsy were eligible for enrollment. Daily temozolomide (TMZ) was administered at 200 mg/m2 for 5 days, and repeated every 28 days for up to 12 cycles or until disease progression. Patients were assessed for radiographic response and progression with MRIs every two months during and after treatment. The primary outcome was ...

AT-42 * FACTORS ASSOCIATED WITH MALIGNANT TRANSFORMATION OF LOW-GRADE GLIOMA

BACKGROUND: There is no standard therapeutic regimen for low-grade glioma (LGG). We have suggested extent of resection (EOR) was strongly associated with prognosis of LGG. About half of LGG eventually show malignant transformation (MT), MT is an important factor in determining prognosis of LGG. Therefore, it is important to definite factors associated with MT. In this study, we investigated correlation between MT and genetic profile and adjuvant therapy in LGG. METHOD: 151 patients (Male: Female = 80:71) with LGG treated in our institute from 2000 to 2010 were retrospectively analyzed. Median follow-up period was 41months, follow-up ratio was 96°, and the average age was 39.1 year-old (15-65). Diffuse astrocytoma (DA) accounted 47 patients (31°), oligodendroglioma (O) was 55 patients (37°), oligoastrocytoma (OA) was 44 patients (29°). The median Mib-1 index was 4.8°. IDH1 mutation and co-deletion of 1p19q locus were analyzed by immunohistochemistry and FISH method, respectively. RESULT: The average and median EOR of T2 high area was 85° and 95°, respectively. ACNU based chemotherapy was performed in 35 patients and radiotherapy in 48 patients. IDH1 mutation and 1p19q co-deletion were 75° and 57%, respectively. 48 patients out of 151 recurred and 29 patients were MT. Patients without IDH1 mutation (P = 0.025) or 1p19q deletion (P = 0.001) showed significant higher rate of MT. In analysis of all patients, EOR strongly correlated with MT (P = 0.0002). EOR correlated with MT in DA (P = 0.0003) but not in oligodendroglial subtypes (P = 0.7). In IDH1 mutant group, chemotherapy reduced MT (P = 0.004), however, in IDH1 wild-type group, both radiotherapy (P = 0.004) and chemotherapy (P = 0.006) brought higher incidence of MT. CONCLUSION: EOR significantly prevented MT in DA. It was suggested that IDH1 was a predictive factor for MT following radiotherapy and chemotherapy in LGG. Extensive resection is required for IDH1 wild type DA.

RTOG 9802: Good Wines Need Aging

TO THEEDITOR:The article by Shaw et al 1 on adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in lowgrade gliomas is a long-awaited report of an important trial. The authors conclude that with the addition of PCV, progression-free survival but not overall survival (OS) is improved, and that for 2-year survivors, the addition of PCV chemotherapy conferred a survival advantage. Although interesting, the question is whether

Chemotherapy in low-grade gliomas

This review summarizes the recent studies in adults' diffuse low-grade gliomas (LGGs) chemotherapy, including response assessment and potential predictive biomarkers of chemosensitivity. Recent studies have confirmed that chemotherapy is an interesting treatment option in LGGs. About 25-50% of LGGs achieve radiological responses with temozolomide or a procarbazine-CCNU-vincristine (PCV) regimen. Clinical and quality-of-life improvements are commonly observed with more than half of the patients with epilepsy, demonstrating a significant reduction of seizure frequency. Dynamic volumetric studies have provided a better description of LGGs evolution after chemotherapy. They have shown that an ongoing volume decrease can be observed many months after chemotherapy discontinuation, particularly after PCV, raising the question of how and for how long should LGGs be treated. New response criteria have been defined by the Response Assessment in Neuro-Oncology group. In addition to 1p/19q codeletion and MGMT promoter methylation, IDH1 mutation might also be a potential predictive biomarker of chemosensitivity. It has now been widely accepted that chemotherapy is an interesting treatment option in LGGs. However, several questions remain unanswered regarding its optimal use. Ongoing phase III studies will allow a better delineation of the role of chemotherapy in LGGs and will also help to better determine the potential predictive value of a 1p/19q codeletion, a MGMT promoter methylation and an IDH1 mutation.

A mathematical model of diffuse low-grade gliomas treated with PCV chemotherapy.

2065 Background: Several questions remain unanswered regarding the optimal use of first-line chemotherapy in low-grade gliomas (LGGs). Dynamic studies assessing the impact of first-line chemotherapy have shown that after the termination of chemotherapy, LGGs frequently continue to decrease in volume despite chemotherapy no longer being administered. Understanding this phenomenon is likely to be crucial to optimize chemotherapy for LGGs. The aim of the present study was to develop a mathematical model that could accurately describe the evolution of LGGs growth dynamics during and after first-line PCV chemotherapy. Methods: The model was formulated as systems of ordinary differential equations distinguishing between two cell populations: a proliferative treatment-sensitive cell population and a quiescent treatment-resistant cell population that spontaneously undergoes apoptosis. Model evaluation was performed in a series of 21 patients treated with first-line PCV chemotherapy. Results: Consistent with the biology of LGGs, the model estimated that LGGs consist largely of quiescent cells. Despite large inter-individual variability, the model correctly predicted individual tumor response profiles in the 21 patients. In analyzing evolution over time of proliferative and quiescent cell compartments, the model suggested that in some patients the six-week interval between PCV cycles might be suboptimal and that lengthening the time interval between cycles might improve the duration of response. Conclusions: We propose a mixed-effects model that accurately describes the evolution of LGGs during and after PCV chemotherapy. This model suggests that tailoring the time interval between PCV cycles according to the individual growth characteristics of LGGs may be a possible means by which to increase the efficacy of PCV chemotherapy.

Chemotherapy for low-grade gliomas: When? How? How long?

Low-grade gliomas have remained among the most controversial brain tumors, in many ways, for decades. Their spontaneous behavior, as well as their response to therapy, is difficult to predict, and their outcome is highly variable. Standards of care are difficult to define for these tumors: subpopulations of patients certainly benefit from surgery, and radiotherapy prolongs progression-free survival, as may alkylating-agent chemotherapy. For all therapeutic interventions, timing is also a controversial issue. In this issue of Neuro-Oncology, Peyre and colleagues (1) report on the retrospectively determined time course of radiological responses to procarbazine + CCNU + vincristine (PCV) polychemotherapy in a series of 21 patients with low-grade gliomas, predominantly oligodendroglial, who had not previously been treated with radiotherapy or other chemotherapy. Six cycles of PCV were intended to be given. Unexpectedly, the median tumor diameters of all patients decreased during PCV therapy; more surprisingly, they continued to decrease in 20 of the 21 cases for a median duration of 2.7 years after cessation of PCV therapy (1). According to their modified Macdonald criteria (2), the rates of partial and minor responses were 5% and 38% at the end of PCV therapy but 38% and 42% at the time of maximal mean tumor diameter decrease, which occurred a median of 3.4 years after PCV therapy onset. While it is well recognized that response assessment in patients with low-grade gliomas is challenging (3), the authors are to be commended for carefully assessing imaging changes over a fairly long follow-up. Nevertheless, it is almost astonishing that all of their 21 patients showed a reduction of mean tumor diameter after PCV therapy. No data for a control group of patients treated with radiotherapy were presented. This would have helped to weigh these data against the suggested benefit from PCV therapy that may not correspond to everybody's clinical experience with this regimen. Admittedly, of 21 patients, 15 had oligodendrogliomas, and 4 had oligoastrocytomas. That tumor sizes in general may continue to shrink after the completion of a cytotoxic or more likely genotoxic stimulus is clinically recognized in irradiated tumors; it is often assumed that vasoocclusive, antiangiogenic effects are involved. Alternatively, Peyre et al. (1) propose that an altered balance between spontaneous cell death and proliferation might account for the delayed responses. If this occurs with radiotherapy, why should it not occur after delivery of a genotoxic signal via chemotherapy? Maybe this has just never been evaluated. Yet a related group of authors from France previously analyzed a similar group of low-grade glioma patients who were treated with temozolomide (4). The dynamics of tumor growth were quite different: although 92% of tumors responded initially, responses were often short-lasting despite continued treatment, and many tumors resumed growth early after the cessation of temozolomide. Importantly, the authors acknowledge the differential safety and tolerability of temozolomide versus PCV and refrain from treatment recommendations in favor of PCV on the basis of this small but impressive set of data.