M. J. B. Taphoorn

Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Newly Diagnosed Anaplastic Oligodendroglioma: Long-Term Follow-Up of EORTC Brain Tumor Group Study 26951

PURPOSE Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT). PATIENTS AND METHODS Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis. RESULTS A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance. CONCLUSION The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.

IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group

Purpose: Recent studies have shown the prognostic significance of IDH1 mutations in glioma. It is yet unclear if IDH1 mutations are predictive for outcome to chemotherapy. We determined the effect of IDH1 mutations on progression-free survival and overall survival (OS), and its correlation with other clinical and molecular features in the prospective randomized European Organization for Research and Treatment of Cancer study 26951 on adjuvant procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine (PCV) in anaplastic oligodendroglioma. Experimental Design: IDH1 and IDH2 alterations of the mutational hotspot codons R132 and R172 were assessed by the bidirectional cycle sequencing of PCR-amplified fragments. MGMT promoter methylation was assessed using methylation-specific multiplex ligation–dependant probe amplification based on methylation-sensitive restriction analysis. Loss of chromosomes 1p, 19q, 10, and 10q and the gain of 7 and the EGFR gene were assessed with fluorescence in situ hybridization. Results: From 159 patients, sufficient material was available for IDH1 analysis. In 151 and 118 of these patients, respectively, the 1p/19q status and the MGMT promoter methylation status were known. In 73 cases (46%), an IDH1 mutation was found and only one IDH2 mutation was identified. The presence of IDH1 mutations correlated with 1p/19q codeletion and MGMT promoter methylation, and inversely correlated with loss of chromosome 10, EGFR amplification, polysomy of chromosome 7, and the presence of necrosis. IDH1 mutations were found to be prognostic in the radiotherapy- and the radiotherapy/PCV-treated patients, for both progression-free survival and OS. With Cox proportional hazard modeling for OS with stepwise selection, IDH1 mutations and 1p/19q codeletion but not MGMT promoter methylation were independent prognostic factors. Conclusion: In this homogeneously treated group of anaplastic oligodendroglioma patients, the presence of IDH1 mutations was found to carry a very strong prognostic significance for OS but without evidence of a predictive significance for outcome to PCV chemotherapy. IDH1 mutations were strongly associated with 1p/19q codeletion and MGMT promoter methylation. Clin Cancer Res; 16(5); 1597–604

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Phase II Study of First-Line Chemotherapy With Temozolomide in Recurrent Oligodendroglial Tumors: The European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971

PURPOSE Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. PATIENTS AND METHODS In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed. RESULTS Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.

Response rate and prognostic factors of recurrent oligodendroglioma treated with procarbazine, CCNU, and vincristine chemotherapy

Objectives: To determine the response rate and factors correlated with response of oligodendroglial tumors to procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy. Design: Retrospective, observational multicenter study. Methods: Patients treated with PCV or intensified PCV chemotherapy for a recurrent oligodendroglial tumor after surgery and radiation therapy with measurable disease were retrospectively evaluated for response. A 50% reduction in cross-sectional enhancing tumor area was considered a partial response. Stabilized or responding patients received six cycles of PCV unless unacceptable toxicity occurred. Results: Fifty-two patients were included; median time to progression (MTP) for the entire group was 10 months. In 17% of patients a complete response (MTP, 25 months) was obtained, and in 46% a partial response (MTP, 12 months) was obtained. Median overall survival was 20 months. Although treatment was discontinued for toxicity in seven patients, it was generally well tolerated. The intensified PCV regimen was more toxic. Patients initially presenting with seizures and patients with tumor necrosis in histologic specimens had a better response rate in contrast to patients who had their first relapse within 1 year of first treatment (surgery and radiation therapy). Conclusions: Oligodendroglial tumors are chemosensitive, but most patients will have relapsed after 12 to 16 months. New studies must aim at improving initial treatment and second-line chemotherapy.

An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients

AIMS The psychometric properties of the EORTC QLQ-BN20, a brain cancer-specific HRQOL questionnaire, have been previously determined in an English-speaking sample of patients. This study examined the validity and reliability of the questionnaire in a multi-national, multi-lingual study. METHODS QLQ-BN20 data were selected from two completed phase III EORTC/NCIC clinical trials in brain cancer (N=891), including 12 languages. Experimental treatments were surgery followed by radiotherapy (RT) and adjuvant PCV chemotherapy or surgery followed by concomitant RT plus temozolomide (TMZ) chemotherapy and adjuvant TMZ chemotherapy. Standard treatment consisted of surgery and postoperative RT alone. The psychometrics of the QLQ-BN20 were examined by means of multi-trait scaling analyses, reliability estimation, known groups validity testing, and responsiveness analysis. RESULTS All QLQ-BN20 items correlated more strongly with their own scale (r>0.70) than with other QLQ-BN20 scales. Internal consistency reliability coefficients were high (all alpha0.70). Known-groups comparisons yielded positive results, with the QLQ-BN20 distinguishing between patients with differing levels of performance status and mental functioning. Responsiveness of the questionnaire to changes over time was acceptable. CONCLUSION The QLQ-BN20 demonstrates adequate psychometric properties and can be recommended for use in conjunction with the QLQ-C30 in assessing the HRQOL of brain cancer patients in international studies.

Cognitive status and quality of life in patients with suspected versus proven low-grade gliomas

Background: The preferred management of patients with suspected low-grade gliomas (S-LGG) remains controversial. The benefits of resection or radiotherapy early in the course of the disease have not been proven in terms of survival. Little is known about the effects of early therapy on quality of life (QOL) and cognitive status. The authors compared functional status, QOL, and cognitive status of patients suspected of having a LGG, in whom treatment was deferred, and patients with proven LGG (P-LGG), who underwent early surgery. Methods: The authors recruited 24 patients suspected of having an LGG. These patients were matched with 24 patients with a histologically proven LGG and healthy control subjects for educational level, handedness, age, and gender. The two patient groups were also matched for tumor laterality, use of anticonvulsants, and interval between diagnosis and testing. Functional status was determined in both patient groups. QOL and cognitive status were compared between the three groups. Results: Matching criteria and functional status did not differ significantly between groups. Both patient groups scored worse on QOL scales than healthy control subjects. Unoperated patients with S-LGG scored better on most items than patients with P-LGG. Cognitive status was worse in both groups than in healthy control subjects, but, again, patients with S-LGG performed better than patients with P-LGG. Conclusion: These data suggest that a wait-and-see policy in patients with S-LGG has no negative effect on cognitive performance and QOL.

Normative data for the EORTC QLQ-C30 and EORTC-sexuality items in the general Dutch population

AIM The aim of the present study was to generate Dutch reference data for the EORTC QLQ-C30 and for five sexuality items from the EORTC QL-item bank. Furthermore, to evaluate the relative impact of self-reported health problems on these outcomes and compare the Dutch normative EORTC QLQ-C30 overall QoL with available Scandinavian and German normative data. METHODS QLQ-C30 and sexual item normative data were obtained from the Health and Health Complaints project from CentERdata. The CentERpanel is an online household panel consisting of more than 2000 Dutch households, representative of the Dutch-speaking population in the Netherlands. RESULTS The questionnaire was completed by 1731 (78%) CentERpanel members. For both men and women, functional health (except emotional functioning) decreased with age, and the symptoms pain and fatigue increased with age. Men scored statistically but never clinically significantly better on most functional scales than women. Men reported higher levels of sexual interest and activity than women. All subgroups of participants with health problems reported lower physical and role functioning and overall quality of life (QoL). Those with depression (n=79) reported functioning scores 20-30 points lower than participants without any condition. Dutch men and women reported high levels of overall QoL as compared to previously published Scandinavian and German normative data. CONCLUSION Age, gender and other health problems are important when comparing QoL and sexuality among different cancer cohorts. Normative data on QoL and sexuality are needed to interpret QoL issues among the growing group of (long-term) cancer survivors.

PCV chemotherapy for recurrent glioblastoma multiforme

The authors evaluated response, time to progression (TTP), survival, prognostic factors, and toxicity in 63 patients with a recurrent glioblastoma multiforme treated with procarbazine, lomustine, and vincristine (PCV) chemotherapy. Complete and partial response was observed in two (3%) and five patients (8%). In 16 patients (25%), stable disease was observed. Median TTP and survival were 13 and 33 weeks. Age < 40 years and Karnofsky Performance Status ≥ 90 were associated with longer TTP and survival. PCV treatment was generally well tolerated.

Patient Self-Reports of Symptoms and Clinician Ratings as Predictors of Overall Cancer Survival

BACKGROUND The National Cancer Institutes Common Terminology Criteria for Adverse Events (NCI-CTCAE) reporting system is widely used by clinicians to measure patient symptoms in clinical trials. The European Organization for Research and Treatment of Cancers Quality of Life core questionnaire (EORTC QLQ-C30) enables cancer patients to rate their symptoms related to their quality of life. We examined the extent to which patient and clinician symptom scoring and their agreement could contribute to the estimation of overall survival among cancer patients. METHODS We analyzed baseline data regarding six cancer symptoms (pain, fatigue, vomiting, nausea, diarrhea, and constipation) from a total of 2279 cancer patients from 14 closed EORTC randomized controlled trials. In each trial that was selected for retrospective pooled analysis, both clinician and patient symptom scoring were reported simultaneously at study entry. We assessed the extent of agreement between clinician vs patient symptom scoring using the Spearman and kappa correlation statistics. After adjusting for age, sex, performance status, cancer severity, and cancer site, we used Harrell concordance index (C-index) to compare the potential for clinician-reported and/or patient-reported symptom scores to improve the accuracy of Cox models to predict overall survival. All P values are from two-sided tests. RESULTS Patient-reported scores for some symptoms, particularly fatigue, did differ from clinician-reported scores. For each of the six symptoms that we assessed at baseline, both clinician and patient scorings contributed independently and positively to the predictive accuracy of survival prognostication. Cox models of overall survival that considered both patient and clinician scores gained more predictive accuracy than models that considered clinician scores alone for each of four symptoms: fatigue (C-index = .67 with both patient and clinician data vs C-index = .63 with clinician data only; P <.001), vomiting (C-index = .64 vs .62; P = .01), nausea (C-index = .65 vs .62; P < .001), and constipation (C-index = .62 vs .61; P = .01). CONCLUSION Patients provide a subjective measure of symptom severity that complements clinician scoring in predicting overall survival.