David R. Macdonald

Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE To examine the rate and duration of response of anaplastic oligodendrogliomas to a dose-escalated combination chemotherapy regimen consisting of procarbazine, lomustine (CCNU), and vincristine (PCV) and to evaluate the side effects of this treatment. METHODS In this single-arm multicentered phase II study, patients with measurable, newly diagnosed or recurrent, contrast-enhancing anaplastic oligodendrogliomas were treated with up to six cycles of PCV. Central pathology and radiology review were mandatory, and rigorous response criteria based on imaging were used. RESULTS Thirty-three patients entered the trial; nine were excluded subsequently, seven due to ineligible pathology. Eighteen of 24 eligible patients (75%) responded, nine completely (38%), four had stable disease (SD), and two progressed during the first cycle of PCV. Responses were observed in nine of 10 patients (90%) with a preexisting low-grade oligodendroglioma and 10 of 15 (67%) with necrotic tumors, called glioblastoma multiforme by some. Previously irradiated patients were as likely to respond to PCV as those newly diagnosed (11 of 15 [73%] v seven of nine [78%]). The median time to progression will be at least 25.2 months for complete responders, and was 14.2 months for partial responders and 6.8 months for stable patients. Four ineligible patients also responded to PCV; all had gliomas with oligodendroglial differentiation. All responders, eligible or ineligible, were stable or improved neurologically, but nine of 22 (41%) experienced a decline in Eastern Cooperative Oncology Group (ECOG) performance status of one grade while on PCV. Adverse events on treatment included a death from Pneumocystis pneumonia, a severe reversible encephalopathy due to procarbazine, an intratumoral hemorrhage, and a subdural hematoma. All other acute toxicities were anticipated and manageable. CONCLUSION Anaplastic oligodendrogliomas are chemosensitive brain cancers. Patients with these tumors respond predictably, durably, and often completely to PCV, and many tolerate a dose-escalated formulation. Cooperative group and randomized trials will be necessary to explore fully the role of chemotherapy in the treatment of aggressive oligodendrogliomas.

Supratentorial low-grade glioma in adults: an analysis of prognostic factors and timing of radiation.

PURPOSE To review the outcomes of patients with low-grade glioma diagnosed by modern imaging and treated at a center where postponing radiotherapy was common practice. METHODS We reviewed the records of patients (age > or = 18 years) with pathologically confirmed supratentorial low-grade fibrillary astrocytoma, oligodendroglioma, and mixed glioma treated at a regional cancer center in Canada between 1979 and 1995. RESULTS Median survival for the entire group (N = 167; mean age 40.6 years) was 10.5 years with 5- and 10-year survival rates of 72% and 50%, respectively. Median progression-free survival was 4.9 years with 5- and 10-year progression-free rates of 50% and 12%, respectively. Overall and progression-free survivals were longer for patients with an oligodendroglioma or mixed glioma than with astrocytoma (median 13 v 7.5 years, P = .003; progression-free 5.6 v 4.4 years, p = .054). Age at diagnosis < or = 40 years, seizures at presentation, minimal residual tumor after surgery, Karnofsky performance status > or = 70, and oligodendroglioma or mixed glioma pathology were associated with significantly longer median survival on univariate and multivariate analyses. Radiotherapy deferred until tumor progression (v immediate radiotherapy) was associated with longer survival on univariate analysis, but an imbalance in other variables accounted for this advantage such that timing of radiotherapy was not an independent (favorable or adverse) prognostic factor on multivariate analysis. CONCLUSION Patients with low-grade glioma diagnosed by modern imaging can be expected to live a long time; timing of radiotherapy may be a less important determinant of survival than nontreatment variables and residual tumor bulk.

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 Trial of Continuous Dose-Intense Temozolomide in Recurrent Malignant Glioma: RESCUE Study

PURPOSE Concomitant temozolomide (TMZ)/radiotherapy followed by adjuvant TMZ has increased survival in patients with glioblastoma multiforme (GBM). However, few options are effective for patients who experience treatment failure. We conducted a multicenter, phase II study to assess the efficacy and safety of continuous dose-intense TMZ for recurrent GBM. PATIENTS AND METHODS Patients with malignant glioma at progression after standard TMZ 150 to 200 mg/m(2) x 5 days in a 28-day cycle for three or more cycles were stratified by tumor type (anaplastic glioma group A, GBM, group B). Ninety-one patients with GBM were prospectively divided into three groups (early [B1], extended [B2], and rechallenge [B3]) according to the timing of progression during adjuvant therapy. All patients received continuous dose-intense TMZ 50 mg/m(2)/d for up to 1 year or until progression occurred. Response was assessed by using RECIST (Response Evaluation Criteria in Solid Tumors). Results A total of 116 of 120 patients were evaluable for efficacy. For patients with GBM, 6-month progression-free survival (PFS) was 23.9% (B1, 27.3%; B2, 7.4%; B3, 35.7%). One-year survival from time of study entry was 27.3%, 14.8%, and 28.6% for the B1, B2 and B3 groups, respectively. For patients with anaplastic glioma, 6-month PFS was 35.7%; 1-year survival was 60.7%. The most common grades 3 and 4 nonhematologic toxicities were nausea/vomiting (6.7%) and fatigue (5.8%). Grades 3 and 4 hematologic toxicities were uncommon. CONCLUSION Rechallenge with continuous dose-intense TMZ 50 mg/m(2)/d is a valuable therapeutic option for patients with recurrent GBM. Patients who experience progression during the first six cycles of conventional adjuvant TMZ therapy or after a treatment-free interval get the most benefit from therapy.

End Point Assessment in Gliomas: Novel Treatments Limit Usefulness of Classical Macdonald's Criteria

Recent trials in glioma have revealed significant limitations in the end points used. This requires a critical and comprehensive review of how brain tumor trials are conducted, particularly of which end points are defined and how response and progression are defined.

Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas

INTRODUCTION Allelic loss of the short arm of chromosome 1 predicts radiographic response to chemotherapy and long overall survival times in patients with anaplastic oligodendrogliomas. Using a database of patients with oligodendrogliomas in whom chromosome 1p status was known, we explored whether allelic loss of 1p also predicted longer duration of tumor control when radiotherapy was part of the initial treatment of these patients. MATERIALS AND METHODS We measured progression-free survival following radiotherapy in a cohort of patients with World Health Organization (WHO) Grade II and WHO Grade III oligodendrogliomas. The effects on progression-free survival of patient age, Karnofsky performance score (KPS), tumor grade when irradiated and chromosome 1p status were examined by univariate and multivariate statistical analyses. For the subset of patients with newly diagnosed anaplastic oligodendrogliomas, relationships between use of chemotherapy, chromosome 1p status and progression-free survival were also examined. RESULTS Fifty-five patients (29 male, 26 female; ages 18-75 years; median, 44 years; KPS 50-90, median 80) were irradiated for either a WHO Grade II (n = 19) or Grade III (n = 36) oligodendroglioma. Twenty-eight patients had chemotherapy immediately prior to radiotherapy, and 27 had chemotherapy at progression following radiotherapy. The median radiation dose was 54 Gy in 30 fractions. Loss of heterozygosity (LOH) at chromosome 1p was evident in 36 tumors and absent in 19. Overall median progression-free survival after radiotherapy was 40.4 months. Median progression-free survival was 55.0 months for patients whose tumors harbored 1p loss vs. 6.2 months for those patients whose tumors retained both copies of chromosome 1p (p < 0.001). On both univariate and multivariate analyses, chromosome lp loss was the principal independent predictor of longer progression-free survival for patients with Grade II and III oligodendrogliomas. For Grade III oligodendrogliomas, chemotherapy as an adjunct to radiotherapy prolonged tumor control for those patients whose tumors harbored allelic loss of chromosome 1p (p = 0.004). CONCLUSION These data suggest allelic loss of chromosome 1p in patients with oligodendroglial neoplasms predicts longer progression-free survival among patients receiving radiotherapy +/- chemotherapy as part of their initial treatment. Chromosome 1p loss may be an important stratification variable in future therapeutic trials of oligodendroglioma.

Supratentorial malignant glioma: Patterns of recurrence and implications for external beam local treatment

Pre- and postoperative computerized tomography scans, simulator films, and computerized tomography scans documenting tumor recurrence were analyzed on 70 patients with supratentorial malignant glioma treated with whole brain plus boost radiation therapy to determine sites of recurrence in relation to the boost. The boost was planned using the postoperative computerized tomography scan. Tumor recurred in 53 patients--within the boost in 38 (72%), partly outside the boost in 12 (23%), outside the boost but within the brain in one (2%), in the boost and in the spinal cord in one (2%), and in the spinal cord only in one (2%). All recurrences confined to the brain were found within 4 cm of the enhancing tumor as defined by the preoperative computerized tomography scan. Recurrences outside the boost were more common with inadequate boost margins, small boost volumes, temporal lobe tumors, and homolateral wedge pair technique. Survival was not adversely affected by recurrence outside the boost. We recommend that patients with malignant glioma be treated by parallel opposed fields with a margin that is 4 cm beyond the edge of the preoperative enhancing tumor, as seen on computerized tomography scan.

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma

Objective: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. Methods: The European Organization for Research and Treatment of Cancer (EORTC) 26981–22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. Results: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24–0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53–0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49–0.93). Conclusions: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.

Pretreatment factors predict overall survival for patients with low-grade glioma : A recursive partitioning analysis

PURPOSE Three databases were pooled and analyzed to determine which groupings of prognostic factors best predicted overall survival for patients with low-grade gliomas treated with surgery and immediate or delayed radiotherapy. METHODS AND MATERIALS Databases of patients with low-grade gliomas compiled at the London Regional Cancer Centre (LRCC), the Norwegian Radium Hospital (NRH), and the University of California, San Francisco (UCSF) were merged. Inclusion criteria for the pooled analysis included: age > or =18 years and histologically confirmed low-grade (World Health Organization Grade II) supratentorial fibrillary astrocytoma, oligodendroglioma or mixed oligoastrocytoma. Factors analyzed for prognostic significance included: age at diagnosis, gender, seizures at presentation, presence of enhancement on computed tomography (CT) or magnetic resonance imaging (MRI), Karnofsky Performance Status (KPS) at diagnosis, histology, extent of surgical resection, timing of radiotherapy, and treating institution. Univariate and multivariate analysis of overall survival for these factors was performed. Recursive partitioning was performed to generate prognostic groups using these factors. RESULTS From the combined databases, 401 patients were eligible for analysis. Median survival for the entire group was 95 months/7.9 years. On univariate analysis age 18-40, presence of seizures at presentation, KPS > or =70, treating institution, and absence of contrast enhancement were associated with improved overall survival. On multivariate analysis, these factors remained independent predictors of improved overall survival. Recursive partitioning analysis yielded four prognostic groups with statistically different median survivals (MS): Group I (n = 41: KPS <70, age >40) MS 12 months; Group II (n = 34: KPS > or =70, age >40, enhancement present) MS 46 months; Group III (n = 138: KPS <70, age 18-40 or KPS > or =70 age >40, no enhancement) MS 87 months; Group IV (n = 188: KPS > or =70, age 18-40) MS 128 months. CONCLUSION Clusters of pretreatment prognostic factors described subgroups of low-grade glioma patients with divergent overall survivals. Consideration of these prognostic subgroups may be important when considering timing of interventions for these patients and in the stratification of patients for clinical trials.