PCV Chemotherapy Research Articles

P14.13 Incidence of pseudoprogression in high-grade IDH-mutant gliomas

Abstract BACKGROUND Pseudoprogression (PsP) is a well-known concern in IDH-wildtype glioblastomas. The aim of the present study was to describe its incidence in high-grade IDH-mutant gliomas. MATERIAL AND METHODS We retrospectively analyzed the characteristics of a consecutive series of high-grade IDH-mutant gliomas treated with radiotherapy (RT) with or without chemotherapy between March 2009 and September 2017. PsP was defined as a new enhanced lesion that occurred after RT and subsequently disappeared or remained stable during follow-up for a least 6 months. RESULTS The study population consisted of 38 anaplastic IDH-mutant and 1p/19q codeleted oligodendrogliomas, 34 IDH-mutant anaplastic astrocytomas and 18 IDH-mutant glioblastomas. Treatment consisted of radiotherapy alone (n=8, 9%), radiotherapy and PCV chemotherapy (n=63, 70%) and temozolomide radiochemotherapy (n=19, 21%). After a median follow-up of 3.5 years (range 1–8 years), 24 patients (28%) presented a PsP that occurred after a median delay of 10 months after radiotherapy (2 to 32 months). PsP was more frequent in patients treated with RT+PCV than in those treated with RT+TMZ (34% vs 10%, p=0.05). During the first two years after RT completion, 19 patients (21%) presented a PsP and 15 patients (17%) a true progression. At last follow-up, 1 patient (4%) in the PsP group had died compared to 10 patients (16%) in the group of patients without PsP. CONCLUSION PsP is a frequent issue in IDH-mutant high-grade gliomas. Its timing of onset is delayed compared to the timing of PsP onset reported in IDH-wildtype glioblastomas. The association between the use of PCV chemotherapy and PsP requires validation in an independent series.

P14.36 Treatment patterns by O6-methylguanine DNA methyltransferase promoter (MGMT) status in newly-diagnosed glioblastoma multiforme (GBM): a multi-country chart review study

Abstract INTRODUCTION This study explored the relationship between MGMT testing and treatment patterns of patients with newly-diagnosed GBM from France, Germany, Italy, Spain, the UK (EU5), and Canada. MATERIALS AND METHODS Medical oncologists and neuro-oncologists across EU5 and Canada completed a point in time, cross-sectional survey for the next eight GBM patients seen between May and July 2016 (GBM Disease-specific ProgrammeTM). Statistically significant differences (p<0.05) between groups are presented. RESULTS A total of 241 physicians reported on 1,747 GBM patients. 1L patients had mean age 59.7 years (SD=12.3) and 36% were female. Of 1,113 (64%) patients who had an MGMT test performed with results recorded (tested), 58% (n=651) were methylated and 42% (n=462) were unmethylated. The remaining 634 patients (36%) were MGMT untested or awaiting MGMT results at time of survey (untested). Overall, 63% of patients received surgery prior to their 1L drug therapy, 78% received radiotherapy (RT; mean 4.3 sessions) in conjunction with 1L drug therapy, 90% received corticosteroids during RT, and 89% received temozolomide (TMZ). Patients who received corticosteroids during RT received similar drug treatments to those that did not, but were less likely to receive surgery prior to 1L treatment (65% vs 83%). MGMT-tested patients were more likely to receive surgery (66% vs 57%) and RT (81% vs 71%) than untested patients. Tested patients were also more likely to receive TMZ (92% vs 83%), and less likely to receive procarbazine+/lomustine+/vincristine (PCV; 3% vs 7%) or other chemotherapies (5% vs 11%). For 1L patients that experienced side effects, the most common effects included fatigue (74%), nausea (60%), and appetite loss (59%). Untested patients were more likely to stop their 1L drug treatment due to progression/recurrence of GBM (44% vs 36%). Patients who received surgery prior to 1L treatment were more likely to receive TMZ than those who did not (93% vs 82%). Among MGMT tested patients at 1L, methylated patients were more likely to receive RT (84% vs 78%) and TMZ (95% vs 89%) than unmethylated patients, and less likely to receive PCV (2% vs 5%) or other chemotherapy (4% vs 7%). Methylated patients with reported treatment-related side effects were less likely to experience dehydration (0% vs 10%), loss of strength/unusual weakness (5% vs 25%), memory problems (16% vs 35%), and nausea (51% vs 75%). CONCLUSIONS More than one-third of GBM patients in EU5 and Canada are not tested for MGMT-methylation. Untested patients are less likely to receive standard treatments than tested patients. Generally, TMZ is used in most patients regardless of MGMT testing and status. MGMT-methylated patients are more likely to receive standard treatments and experience fewer side effects than MGMT-unmethylated patients.

OS7.4 Calculating the net clinical benefit in brain tumor clinical trials by combining survival and health-related quality of life data using two methods: quality adjusted survival effect sizes (QASES) and joint modelling (JM)

Abstract BACKGROUND The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to inform glioma patients and facilitate shared decision making. We applied two methods (i.e. Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM)) that combine survival and health-related quality of life (HRQoL) data into one outcome, to gain insight in the net clinical benefit of a treatment strategy. In addition, we assessed if both methods result in similar interpretations. MATERIAL AND METHODS We calculated the net clinical benefit in one randomized controlled trial, EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone, as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. Next, the combined effect size can be determined by weighing the emphasis put on survival or HRQoL (e.g. survival more important). JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting. RESULTS 288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (difference of 10.8 months). In contrast, the percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. The QASES corresponded to a reduction in the median OS difference from 10.8 months to 6.8 months when adjusted for the HRQoL scales/items, when given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL. CONCLUSION Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.

(P14) Cost Effectiveness of Radiation and Chemotherapy for High-Risk Low Grade Glioma

The standard of care treatment for maximally resected, high risk (≥ 40 years old or sub-totally resected) low grade glioma (LGG) patients was established by RTOG 9802, which showed an overall survival (OS) of 13.3 years for patients treated with radiotherapy (RT) + PCV (procarbazine, lomustine [CCNU], vincristine) chemotherapy compared to 7.8 years for RT alone. In the era of value-based health care, cost-effectiveness analyses (CEA) have the potential to inform coverage decisions and patient care. To our knowledge, there has been no study assessing the value of RT+PCV as adjuvant therapy for high risk LGG. We sought to analyze the cost-effectiveness of this strategy. The base case comprised patients with high risk LGG after maximal safe resection with indications for adjuvant therapy. A decision tree with an integrated three-state Markov model was created to follow patients treated with RT and RT + PCV. Patients existed in one of 3 health states: stable, progressive, and dead. All patients were assumed to be free of progression at baseline. Survival and freedom from progression were modeled to reflect the results of RTOG 9802 using time-dependent transition probabilities. Health utility values and costs of care were derived from the literature and national registry databases. Starting at initial age of 40 years (median age on RTOG 9802), patients were followed monthly over a maximum time horizon of 60 years after diagnosis (effectively over their remaining lifetimes). Analysis was conducted from the healthcare perspective. Probabilistic sensitivity analysis of modeled parameter distributions was conducted with Monte Carlo simulation of 10,000 samples. Modeled outcomes demonstrated agreement with clinical data in OS, progression free survival (PFS), and expected benefit of addition of PCV to adjuvant RT. In our model, 5-year and 10-year OS rates for RT+PCV vs RT alone were 71.5% vs. 64.8%, and 62.1% vs. 39.2%, respectively; 5-year and 10-year PFS rates for RT+PCV vs RT alone were 61.7% vs. 45.2%, and 50.5% vs. 20.1%, respectively. Patients treated with RT alone accrued 5.17 quality-adjusted life-years (QALYs) (9.63 life-years) at a cost of $139,598. Patients treated with RT+PCV accrued 9.94 QALYs (21.45 life-years) at a cost of $188,234. The addition of PCV to RT yielded an incremental benefit of 4.77 QALYs at an incremental monetary cost of $48,637, leading to an incremental cost-effectiveness ratio of $10,188 per QALY gained. Probabilistic sensitivity analysis demonstrates that cost-effectiveness of RT+PCV was insensitive to variations in modeled distributions of input parameters, with 99.96% probability of cost-effectiveness at a willingness-to-pay threshold of $100,000 per QALY. Based on the impressive benefits in outcomes observed in RTOG 9802, the addition of PCV chemotherapy to RT provides high value for cost in the treatment of patients with high-risk low grade glioma.

Perspectives of Personalized Chemotherapy of Gliomas Based on Molecular Tumor Profiling.

Histopathological typing and grading are the cornerstones of the World Health Organization classification of the central nervous system tumors. It provides clinicians with information on the natural course of the disease and thus guides therapeutic choices. Nonetheless, patients with histologically identical tumors may have different outcomes and response to therapy. In recent years, extensive research has been done on three molecular markers in adult gliomas, namely MGMT promoter methylation, 1p/19q co-deletion, and IDH1/IDH2 mutations. These markers may have either a prognostic or a predictive value, differentiation of which is often difficult as both can coexist. At present, MGMT promoter methylation is considered as a predictive marker for response of glioblastoma to chemotherapy with temozolomide, particularly in elderly patients, 1p/19q co-deletion is a molecular signature of oligodendroglial tumors and predictive marker for response of anaplastic gliomas to PCV chemotherapy, and IDH1/IDH2 mutations have a strong favorable prognostic value across all glioma histopathological grades.

Controversy in the Postoperative Treatment of Low-grade Gliomas

The optimal treatment for low-grade gliomas remains controversial. Neurosurgery, radiotherapy, and chemotherapy are the main treatment options. Despite advances in oncology, there are still a lot of uncertainties, and the optimal sequences, combinations, and timings of these procedures have not yet been optimized. It is still unclear whether temozolomide can replace effective, but toxic PCV chemotherapy (procarbazine, lomustine, vincristine) and whether temozolomide can be used upfront alone instead of radiotherapy alone. Mature results from phase III trials (CODEL, EORTC 22033-26033) will provide answers to these questions. Correlative analyses of survival data and molecular marker findings (1p/19q codeletion, IDH1/2 mutation, and MGMT promoter methylation status) are essential. Due to slow progressive nature of the disease, all clinical trials with low-grade gliomas are complicated by the need for long-term follow-up to obtain valid mature data, which makes any new treatment procedures or developments in basic research developed during the course of closed clinical trials difficult to apply in daily clinical practice. An example is the recently published RTOG 9802 study evaluating the role of adjuvant PCV in combination with radiotherapy for the treatment of high-risk low-grade glioma patients where the recruitment of patients was initiated almost two decades ago. Health-related quality of life after treatment of patients with expected long-term survival is also very important and its maintenance is currently the focus of considerable interest. The main objective of the present review is to summarize the results of key clinical trials and highlight controversial issues that could have an impact on future daily practice. Another aim is to discuss these issues in the light of newly established molecular markers from the new 2016 WHO Classification of Tumors of the Central Nervous System.Key words: glioma - astrocytoma - radiotherapy - temozolomide - PCV - cognition This work was supported by MH CZ - RVO (MMCI, 00209805) and by project of the Ministry of Education, Youths and Sports of the Czech Republic CEITEC 2020 (LQ1601). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 21. 2. 2017Accepted: 20. 3. 2017.

The Role of Chemotherapy in the Treatment of Low-grade Gliomas

The standard postsurgical options for low-grade gliomas include watchful waiting or radiotherapy depending on the risk factors for recurrence. The use of chemotherapy for the treatment of this disease is generally controversial, although the recently published results of the first of two large randomized phase III clinical trials (RTOG 9802 a EORTC 22033-26033), focusing on the evaluation of chemotherapy for the upfront treatment of newly diagnosed low-grade gliomas, are reassuring in this respect. The long-term results of a RTOG 9802 comparing radiotherapy alone with radiotherapy and six cycles of adjuvant PCV chemotherapy (procarbazine, lomustine, vincristine) in patients with high-risk low-grade gliomas will probably have an impact on daily clinical practice. The increase in median overall survival from 7.8 years to 13.3 years, mainly for patients with oligodendrogliomas, is unprecedented, but the toxicity of PCV is too high and molecular marker analysis remains inadequate. It is still unclear whether less toxic temozolomide can replace PCV and whether temozolomide can be used upfront alone instead of with radiotherapy. This question is addressed by the ongoing EORTC 22033-26033 study. The preliminary results show no significant difference in progression-free survival between patients receiving radiotherapy and those receiving temozolomide alone. Treatment with temozolomide was not associated with an improvement in cognitive function compared with treatment with radiotherapy. Despite limited follow-up, the study clearly confirmed the importance of molecular characterization of low-grade gliomas, as currently defined in the new 2016 WHO Classification of Tumors of the Central Nervous System. The aim of the review is to summarize available information from listed key clinical trials of chemotherapy for low-grade gliomas and draw attention to unresolved issues concerning the use of chemotherapy for the treatment of this disease.Key words: glioma - astrocytoma - chemotherapy - PCV - temozolomide - RTOG 9802 This work was supported by MH CZ - RVO (MMCI, 00209805) and by project of the Ministry of Education, Youths and Sports of the Czech Republic CEITEC 2020 (LQ1601). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 21. 2. 2017Accepted: 20. 3. 2017.

Cost-Effectiveness of Radiation and Chemotherapy for High-Risk Low Grade Glioma

The standard of care treatment for maximally resected, high risk (≥ 40 years old or sub-totally resected) low grade glioma (LGG) patients was established by RTOG 9802, which showed an overall survival (OS) of 13.3 years for patients treated with radiotherapy (RT) + PCV (procarbazine, lomustine [CCNU], vincristine) chemotherapy compared to 7.8 years for RT alone. In the era of value-based health care, cost-effectiveness analyses (CEA) have the potential to inform coverage decisions and patient care. To our knowledge, there has been no study assessing the value of RT + PCV as adjuvant therapy for high risk LGG. We sought to analyze the cost-effectiveness of this strategy. The base case comprised patients with high risk LGG after maximal safe resection with indications for adjuvant therapy. A decision tree with an integrated three-state Markov model was created to follow patients treated with RT and RT + PCV. Patients existed in one of three health states: stable, progressive, and dead. All patients were assumed to be free of progression at baseline. Survival and freedom from progression were modeled to reflect the results of RTOG 9802 using time-dependent transition probabilities. Health utility values and costs of care were derived from the literature and national registry databases. Starting at initial age of 40 years (median age on RTOG 9802), patients were followed monthly over a maximum time horizon of 60 years after diagnosis (effectively over their remaining lifetimes). Analysis was conducted from the healthcare perspective. Probabilistic sensitivity analysis of modeled parameter distributions was conducted with Monte Carlo simulation of 10,000 samples. Modeled outcomes demonstrated agreement with clinical data in OS, progression free survival (PFS), and expected benefit of addition of PCV to adjuvant RT. In our model, 5-year and 10-year OS rates for RT + PCV vs RT alone were 71.5% vs. 64.8%, and 62.1% vs. 39.2%, respectively; 5-year and 10-year PFS rates for RT + PCV vs RT alone were 61.7% vs. 45.2%, and 50.5% vs. 20.1%, respectively. Patients treated with RT alone accrued 5.17 quality-adjusted life-years (QALYs) (9.63 life-years) at a cost of $139,598. Patients treated with RT+PCV accrued 9.94 QALYs (21.45 life-years) at a cost of $188,234. The addition of PCV to RT yielded an incremental benefit of 4.77 QALYs at an incremental monetary cost of $48,637, leading to an incremental cost-effectiveness ratio of $10,188 per QALY gained. Probabilistic sensitivity analysis demonstrates that cost-effectiveness of RT + PCV was insensitive to variations in modeled distributions of input parameters, with 99.96% probability of cost-effectiveness at a willingness-to-pay threshold of $100,000 per QALY. Based on the impressive benefits in outcomes observed in RTOG 9802, the addition of PCV chemotherapy to RT provides high value for cost in the treatment of patients with high-risk low grade glioma.

Highlighting Advances in the Treatment of Gliomas

Highlighting Advances in the Treatment of Gliomas

Benefit with adjuvant chemotherapy in anaplastic astrocytoma

The role of chemotherapy for newly diagnosed anaplastic gliomas, particularly when combined with radiotherapy, has long been unresolved. Over the past few decades, despite no conclusive data, study findings have suggested that the addition of nitrosourea-based chemotherapy to radiotherapy could be beneficial. The NOA-04 trial 1 Wick W Hartmann C Engel C et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009; 27: 5874-5880 Crossref PubMed Scopus (668) Google Scholar revealed that initial treatment with chemotherapy (either temozolomide or procarbazine, lomustine, and vincristine [PCV]) or radiotherapy alone yielded similar results. Survival of patients with anaplastic glioma has been recognised as being strongly dependent on the presence or absence of the favourable 1p/19q co-deletion. This discovery resulted in secondary analyses of US and European trials, revealing improved survival in patients with co-deleted tumours who received combined radiation and PCV chemotherapy. 2 Cairncross G Wang M Shaw E et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2012; 31: 337-343 Crossref PubMed Scopus (777) Google Scholar , 3 van den Bent MJ Brandes AA Taphoorn MJ et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2012; 31: 344-350 Crossref PubMed Scopus (836) Google Scholar Separately, clear benefits were found with adding temozolomide to radiotherapy to treat newly diagnosed glioblastoma, 4 Stupp R Mason WP van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. 2005; 352: 987-996 Google Scholar which led to investigations of whether radiation plus temozolomide would benefit patients with non-co-deleted anaplastic gliomas (ie, anaplastic astrocytomas). Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup studyAdjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed. Full-Text PDF

Procarbazine, lomustine and vincristine for recurrent high-grade glioma.

Recurrent high-grade glioma (HGG) carries an extremely poor prognosis. There is no current standard of care or guideline-based recommendations. Nitrosourea-based multidrug chemotherapy or PCV - procarbazine, lomustine (CCNU) and vincristine - is one of the treatment options at recurrence. There has been no meta-analysis which looks at the benefits and harms of PCV chemotherapy in adults with recurrent HGG. To assess the effectiveness and safety of procarbazine, lomustine, and vincristine (PCV) chemotherapy with other interventions in adults with recurrent high-grade glioma. To investigate whether predefined subgroups of people benefit more or less from chemotherapy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, 2017), MEDLINE (1946 to 22 May 2017), and Embase (1980 to 22 May 2017). We searched trial registries including the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch) and the National Institutes of Health (NIH; ClinicalTrials.gov). We searched the reference lists of all identified studies; the electronic table of contents of the Journal of Neuro-Oncology (1983 to 2016) and Neuro-Oncology (1999 to 2016); and conference abstracts from the Society for Neuro-Oncology (SNO) and the American Society of Clinical Oncology (ASCO 2004 to 2016). We also searched unpublished grey literature and other regional databases. There were no language restrictions. Randomised controlled trials (RCTs), quasi-randomised trials (QRCTs), or controlled clinical trials (CCTs) where PCV was used to treat adults with recurrent HGG. Comparison arm included no chemotherapy, other second line chemotherapy or best supportive care. Two review authors extracted the data and undertook a 'Risk of bias' assessment and critical appraisal of the studies. We identified two RCTs meeting our inclusion criteria. The two trials tested different comparisons.One RCT included 35 participants and compared PCV with 'eight drugs in one day' multidrug chemotherapy, which is a combination of drugs with different mechanisms of action. Median survival was 6 months for the PCV group and 6.5 months for the 'eight drugs in one day' group. Adverse event outcomes were not graded or quantified. Progression-free survival (PFS) and quality of life (QoL) were not described in the methods and were not an outcome of interest. The sample size in this study was small, which lead to insufficient statistical power to detect clinical differences. According to the GRADE approach we judged the quality of evidence to be low for survival outcome and very low for chemotherapy toxicityThe second multi-institutional RCT included 447 participants and compared PCV with Temozolomide (TMZ). Participants were randomised into three arms to receive PCV, and two different regimens of TMZ in a 2:1:1 ratio at first recurrence. The trial reported a median overall survival of 6.7 months and 7.2 months for the PCV and TMZ group respectively. It reported a PFS of 3.6 months for the PCV group and 4.7 months for the TMZ group. There was no observed difference of effect on overall survival (hazard ratio (HR) 0.91, 95% CI 0.74 to 1.11; P = 0.35) or PFS (HR 0.89, 95% CI 0.73 to 1.08; P = 0.23) in participants receiving PCV or TMZ chemotherapy. The proportion of people with at least one grade 3 or 4 adverse event was not clinically important at 9.2% versus 12.2% in PCV and TMZ arms respectively. Mean QoL scores calculated at baseline, 12 weeks and 24 weeks was 51.9 versus 59.8 favouring TMZ (P = 0.04) which is statistically but not clinically significant and was less than the pre-defined 10 point change for moderate improvement. We judged the GRADE quality of evidence to be moderate for overall survival, PFS, and chemotherapy toxicity and low for QoL. Evidence is based on a single large trial analysis as the other trial was small, with inadequate power to detect survival difference. Chemotherapy-naive patients with HGG at first recurrence when treated with PCV or TMZ have similar survival and time-to-progression outcomes. Adverse events are similar and QoL scores are statistically but not clinically significant between TMZ and PCV. Further RCTs should be conducted with adequate power following CONSORT guidelines with emphasis on QoL outcomes.

The analysis to the latest changes in NCCN Guidelines of Central Nervous System Cancers about low-grade gliomas and glioblastoma

Gliomas are the most common primary tumors of the central nervous system, around 70 % of the malignant brain tumors are gliomas. In the NCCN Guideline Ver.1 2015, the assessment before systemic treatment, treatment principles and prognosis factors of gliomas has significantly changed based on the researches up to date, we try to analyze the reason and the effect of these changes. The most important change is the reintroduction of PCV chemotherapy in systemic treatment, which narrows the gap of prognosis between WHO II and III gliomas. Other changes including the assessment before systemic treatment, usage of RT and the promotion of evidence level about the Tumor Treating Fields.

IDH1 mutation is prognostic for diffuse astrocytoma but not low-grade oligodendrogliomas in patients not treated with early radiotherapy.

Despite accumulating knowledge regarding molecular backgrounds, the optimal management strategy for low-grade gliomas remains controversial. One reason is the marked heterogeneity in the clinical course. To establish an accurate subclassification of low-grade gliomas, we retrospectively evaluated isocitrate dehydrogenase-1 (IDH1) mutation in clinical specimens of diffuse astrocytomas (DA) and oligodendroglial tumors separately. No patients were treated with early radiotherapy, and modified PCV chemotherapy was used for postoperative residual tumors or recurrence in oligodendroglial tumors. Immunohistochemical evaluation of IDH status, p53 status, O(6)-methylguanine methyltransferase expression, and the MIB-1 index were performed. The 1p and 19q status was analyzed with fluorescence in situ hybridization. Ninety-four patients were followed for a median period of 8.5years. For DAs, p53 was prognostic for progression- free survival (PFS) and IDH1 was significant for overall survival (OS) with multivariate analysis. In contrast, for oligodendroglial tumors, none of the parameters was significant for PFS or OS. Thus, the significance of IDH1 mutation is not clear in oligodendroglial tumors that are homogeneously indolent and chemosensitive. In contrast, DAs are heterogeneous tumors including some potentially malignant tumors that can be predicted by examining the IDH1 mutation status.

Efficacy of Procarbazine, Lomustine, and Vincristine Chemotherapy for Recurrent Primary Central Nervous System Lymphomas.

BackgroundOptimal treatment for recurrent primary central nervous system lymphomas (PCNSLs) has not been defined yet and there is no general consensus about the salvage chemotherapy after high-dose methotrexate (HD-MTX)-based chemotherapy. The purpose of the present study was to evaluate the efficacy and safety of procarbazine, lomustine, and vincristine (PCV) chemotherapy for recurrent PCNSLs.MethodsWe reviewed eight immunocompetent patients (five males/three females, mean age: 56 years) who received salvage PCV chemotherapy (procarbazine 60 mg/m2, days 8 through 21: CCNU 110 mg/m2, day 1: vincristine 2 mg, days 8 and 28) for recurrent PCNSL and two patients switched to PCV chemotherapy due to severe adverse effects of HD-MTX chemotherapy. Radiologic responses, survival, and adverse effects were analyzed.ResultsOf the eight recurrent PCNSLs, three patients (37.5%) showed radiologic complete response, one patient (12.5%) showed partial response, and four patients (50%) showed progressive disease after PCV chemotherapy. Median progression free survival (PFS) from the first administration of PCV to relapse or last follow-up was 7 months (range 5-32 months) and median overall survival was 8 months (range 2-41 months). The two patients who switched to PCV chemotherapy showed PFS of 9 and 5 months from the beginning of PCV to relapse. The common side effects were thrombocytopenia, neutropenia, and peripheral neuropathy. There were 4 grade III or IV myelo-suppression, but no fatal complications, including severe hemorrhage or infection, were observed.ConclusionSalvage PCV chemotherapy has a moderate anti-lymphoma activity for recurrent PCNSLs after the HD-MTX-based chemotherapy with tolerable toxicity.

AT-56 * TREATMENT OF LARGE LOW-GRADE OLIGODENDROGLIAL TUMORS WITH UPFRONT PROCARBAZINE, LOMUSTINE, AND VINCRISTINE CHEMOTHERAPY WITH LONG FOLLOW-UP: A RETROSPECTIVE COHORT STUDY WITH GROWTH KINETICS

PURPOSE: We treated patients with newly diagnosed and large low-grade oligodendroglial tumors with upfront procarbazine, lomustine (CCNU) and vincristine (PCV) in our institution in order to delay RT. We now report long term follow-up on a cohort of patients treated between 1998 and 2006. METHODS: Patients were treated with PCV in cycles of 6 weeks, for a maximum of 6 cycles. Central pathology review, genotyping on 1p/19q loss and immunohistochemistry on the IDH1 mutational status and MIB-1 labeling was performed. The response to treatment was defined according to the RANO criteria; in addition change over time of mean tumor diameters (growth kinetics) was calculated. RESULTS: Thirty-two patients were treated, 18 of which were diagnosed with 1p/19q co-deleted tumors. Median follow-up duration was 8 years. The median overall survival (OS) was 120 months and the median progression-free survival (PFS) was 46 months. Growth kinetics showed an ongoing decrease of the mean tumor diameter after completion of chemotherapy, during a median time of 35 months (range 5-136 months), but an increase of the mean tumor diameter did not herald progression as detected by RANO criteria. 1p/19q co-deletion was associated with a significant increase in OS (median OS 83 months versus not reached for codeleted tumors; p = 0.003)) and PFS (median PFS 35 months versus 67 months for codeleted tumors; p = 0.024). Patients with combined 1p/19q loss had a 10 year PFS of 34% and the radiotherapy in these patients was postponed for a median period of more than 6 years. CONCLUSION: This long-term follow-up study indicates that upfront PCV chemotherapy is associated with long PFS and OS and delays radiotherapy for a considerable period of time in patients with low-grade oligodendroglial tumors, in particular with combined 1p/19q loss.

AT-13 * R9802: PHASE III STUDY OF RADIATION THERAPY (RT) WITH OR WITHOUT PROCARBAZINE, CCNU, AND VINCRISTINE (PCV) IN LOW-GRADE QLIOMA: RESULTS BY HISTOLOGIC TYPE

BACKGROUND: Recent results of R9802 (Buckner et al; J Clin Oncol 32:5s, 2014 (suppl; abstr 2000)) demonstrated that PCV given with RT at the time of initial diagnosis prolongs both progression-free survival (PFS) and overall survival (OS) for all patients enrolled in the trial. Herein, we report the impact of treatment on PFS and OS based upon specific histologic type. METHODS: Eligibility criteria included age 40 with any extent of resection, and supratentorial grade ll oligodendroglioma (O), oligo-astrocytoma (OA), or astrocytoma (A). Patients were stratified by age, histology, Karnofsky Performance Status, and presence versus absence of contrast enhancement on the preoperative imaging study and randomized to RT alone (54 Gy in 30 fractions) or RT followed by 6 cycles of PCV chemotherapy. In an exploratory analysis, we used the log rank test to compare survival and progression free survival (PFS) distributions for each histologic type. RESULTS: 251 eligible patients were accrued from 1998 to 2002: 107 had O, 79 had OA, and 65 had A. In total, 67% have progressed and 55% have died. Median PFS (RT vs. RT + PCV) overall, O, OA, and A, respectively, are 4.0 vs 10.4 (p 40 years of age, PCV + RT prolongs both OS and PFS compared with RT alone. The observed benefit is most definitive for O and OA patients.

Practice changing mature results of RTOG study 9802: another positive PCV trial makes adjuvant chemotherapy part of standard of care in low-grade glioma.

The long-term follow-up of the RTOG 9802 trial that compared 54 Gy of radiotherapy (RT) with the same RT followed by adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy in high-risk low-grade glioma shows a major increase in survival after adjuvant PCV chemotherapy. Median overall survival increased from 7.8 years to 13.3 years, with a hazard ratio of death of 0.59 (log rank: P = .002). This increase in survival was observed despite the fact that 77% of patients who progressed after RT alone received salvage chemotherapy. With this outcome, RT + PCV is now to be considered standard of care for low-grade glioma requiring postsurgical adjuvant treatment. Unfortunately, studies on molecular correlates associated with response are still lacking. This is now the third trial showing benefit from the addition of PCV to RT in grade II or III diffuse glioma. The optimal parameter for selecting patients for adjuvant PCV has not yet been fully elucidated, but several candidate markers have so far emerged. It is still unclear whether temozolomide can replace PCV and whether initial management with chemotherapy only is a safe initial treatment. Potentially, that may adversely affect overall survival, but concerns for delayed RT-induced neurotoxicity may limit acceptance of early RT in patients with expected long term survival. The current evidence supports that in future trials, grades II and III tumors with similar molecular backgrounds should be combined, and trials should focus on molecular glial subtype regardless of grade.

Joint modeling of longitudinal health-related quality of life data and survival.

In cancer research, outcome measures may co-vary. Treatment and treatment related impairment of health-related quality of life (HRQoL) may affect survival. When these effects are analyzed separately, bias may arise. Therefore, we investigated the combined effect of treatment and longitudinally measured HRQoL on survival. Patients with anaplastic oligodendrogliomas (n = 288) who were randomized (EORTC 26951) to radiotherapy (RT) alone or RT plus procarbazine, lomustine, and vincristine (PCV) chemotherapy were analyzed. HRQoL [appetite loss (AP)] was assessed with the EORTC QLQ-C30. We compared survival results from different analysis strategies: Cox model with treatment only [model 1 (M1)] or with treatment and time-dependent AP score [model 2 (M2)] and the joint model combining longitudinal AP score and survival [model 3 (M3)]. The estimated hazard ratio (HR) for RT plus PCV was 0.76 (95 % CI 0.58-1.00) for M1, 0.72 (0.55-0.96) for M2, and 0.69 (0.52-0.92) for M3. This corresponds to a lower risk of death of 24 % in M1, 28 % in M2, and 31 % in M3, for patients treated with RT plus PCV chemotherapy. AP resulted in an increased risk of death, with estimated HR of 1.06 (1.01-1.12) for M2 and 1.13 (1.03-1.23) for M3: Every 10-point increase of AP resulted in a 13 % increased risk of death in M3 as compared to 6 % in M2. Part of the survival benefit of treatment with RT plus PCV chemotherapy can be masked by the negative effect that this treatment has on patients' HRQoL. In our study, up to 7 % of the theoretical treatment efficacy was lost when AP was not adjusted through joint modeling.

Contemporary treatment of glioma with PCV chemotherapy in Manitoba

Contemporary treatment of glioma with PCV chemotherapy in Manitoba

P17.49 * TREATMENT STRATEGY FOR WHO GRADE III GLIOMAS: THE LESSONS LEARNED FROM THE RETROSPECTIVE MULTICENTER ANALYSIS OF 243 PATIENTS

OBJECTIVE: This retrospective analysis was performed to determine the efficacy, safety, and tolerability of treatment protocols including radiation therapy, concurrent chemoradiotherapy (CCRT) followed by adjuvant chemotherapy with temozolomide (TMZ), or PCV chemotherapy based on the status of molecular diagnosis in the treatment of patients with WHO grade III gliomas. MATERIALS: Two hundred forty three adult patients with WHO grade III glioma and aged > 17 years were enrolled from two institutions between 2004 and 2012. The pathological diagnoses were anaplastic astrocytomas (AA) in 150 patients and anaplastic oligodendrogliomas (AO) including anaplastic oliogoastrocytomas in 93 patients. Co-deleted group on 1p19q LOH analysis was 60 of available 183 patients and un-methylated group of MGMT promoter was 64 of available 170 patients. The AA patients received four different treatment protocols in same strategy in two institutions: radiation therapy only, CCRT with temozolomide, radiation therapy followed by PCV or temozolomide adjuvant chemotherapy, and nothing after surgery. The AO patients received also four different treatment protocols in same strategy in two institutions: radiation therapy only, CCRT with temozolomide, radiation therapy combined with PCV (neo- or) adjuvant chemotherapy, and temozolomide chemotherapy only after surgery. RESULTS: Overall survival (OS) and progression free survival (PFS) were superior in AO (98m and 61m) than in AA (34m and 23m) and 1p19q co-deleted group had significantly longer OS (98m vs 42m) and PFS regardless treatment protocols. In AA patients RT only group and CCRT with temozolomide group had the better OS and PFS than other two groups. Methylation status of MGMT promoter in these patients did not affect survival differences. In AO patients RT only group, PCV based chemotherapy group (neoadjuvant or adjuvant PCV), or CCRT with temozolomide groups had no statistically significant differences in survival data. However 1p19q co-deleted group had a much better survival data (OS 98m vs 53; PFS not reached yet vs 38m). CONCLUSION: 1p19q co-deletion (molecular diagnosis) may be more important than morphologic diagnosis in grade III gliomas. The methylation status of MGMT promoter is not important such as in case of grade IV, glioblastoma. Adjuvant PCV might improve OS and PFS in AO regardless of the timing of PCV, either pre-RTx. or post-RTx. CCRTx. with TMZ may improve OS in non co-deleted group and this will be one of good candidate for standard one. A randomized controlled study with a long-term follow-up may be mandatory to evaluate and to make a best treatment protocol for these tumors.