UPDATES ON CHEMOTHERAPY FOR LOW GRADE GLIOMAS

Transcription

1 UPDATES ON CHEMOTHERAPY FOR LOW GRADE GLIOMAS Antonio M. Omuro Department of Neurology Memorial Sloan-Kettering Cancer Center II International Neuro-Oncology Congress Sao Paulo, 08/17/12

2 CHALLENGES IN INTERPRETING LITERATURE ON LGG Relatively rare tumors Paucity of prospective or randomized studies Histological and molecular heterogeneity Clinical heterogeneity (differences in symptoms, tumor size, location in the brain) Newly diagnosed vs recurrence (+/- transformation) Studies require long-term follow-up Response difficult to assess Need to evaluate quality of life and neurocognitive function

3 HISTOLOGY STILL MATTERS MSKCC database ( ) N=1173 (LGG: N= 189) Courtesy: M. Rosenblum

4 HISTOLOGY MATTERS BUT THINGS ARE NOT SO SIMPLE Bourne et al.

5 RADIOGRAPHIC CHARACTERISTICS MATTER

6 TIMING OF TREATMENTS RARELY MATTERS FOR OVERALL SURVIVAL But it does matter for progression-free survival OS PFS

7 TIMING OF TREATMENTS RARELY MATTER FOR OVERALL SURVIVAL But it does matter for RT-related neurotoxicity Arch Neurol, 2005

8 COGNITIVE FUNCTION IN LGG Correa et al

9 PCV: THE CASE FOR CHEMOTHERAPY RTOG 9802: RT vs RT + PCV for high risk LGG (>= 40yo, subtotal resection) Shaw, JCO

10 RTOG 9802: RT VS RT + PCV FOR HIGH RISK LGG P=0.005 P=0.13 Med PFS: 4.4y vs NR; Med OS: 7.5 vs NR; 5y OS: 63% vs 72% Grades 3 and 4 toxicities: 11% vs 66% (P< 0.001) Median follow-up: 5.9 years Shaw, JCO

11 TEMOZOLOMIDE FOR LGG No randomized studies available Several small studies, with different eligibility Shaw, 2012

12 DELAYED CHEMOTHERAPY RESPONSES An example of a delayed response to temozolomide (TMZ) in a 42-year-old woman suffering from a low-grade oligodendroglioma after 6 (B) and 17 cycles (C) Hoang-Xuan K et al. JCO

13 WHAT IF CHEMOTHERAPY FAILS Re-resection: Updates histology and molecular status Radiotherapy if not already given PCV if temozolomide fails and vice-versa If those did not work: low-dose daily temozolomide, carboplatin, etoposide Clinical trials

14 IS THERE A ROLE FOR BEVACIZUMAB IN RECURRENT LGG? If no enhancing disease: No role Bevacizumab for grade III tumors (Delios et al): Total CR/ PR SD/ PD ORR % medpfs (wks) 6m-PFS % (95% CI) medos wks 1y-OS % (95%CI) All* 45 7/12 15/ (12, 36) (30-60) AA 29 5/9 8/ AO/ AOA 16 2/3 7/ Two grade 4 cerebral hemorrhages (both pts on anticoagulation

15 \ TARGETED THERAPIES FOR LGG: TARGETING PDGFR INHIBITORS PDGF and PDGFR overexpressed in LGG Phase II study of imatinib + hydroxyurea in recurrent or progressive LGG (Reardon et al) Astrocytoma (n = 32) Oligo (n = 32) All patients (n = 64) Median PFS 43.5 weeks 43.3 weeks y PFS 43.8 % 34.4% 39.1% 3y PFS 9.4 % 15.6 % 12.5 % 3y OS 74.7 % 75.4 % 75.5 % Responses Most patients had failed TMZ and about 50% had failed RT; patients with >1 recurrence fared worse (p= )

16 ARE MOLECULAR MARKERS HELPFUL? Predictive value of 1p/19q, IDH-1/2 mutations, MGMT promoter methylation and G-CIMP remains controversial. But the prognostic value is clear. Houillier et al.

17 EORTC UPCOMING TRIALS: EORTC PHASE III TRIAL (N=466) Eligibility: Grade II glioma age > 40 tumor > 5 cm crossing midline/unresectable neurological symptoms Stratification: Age Resection Histology (Oligo vs. Astro vs. mixed) 1p loss (yes/no/unknown.) Contrast enhancement Center Courtesy: R. Stupp Primary Endpoints: PFS, QOL and neurological function, predictive value of 1p loss Secondary Endpoint: Overall survival; molecular diagnosis and genotyping

18 UPCOMING TRIALS: ECOG E3F05 Phase III Symptomatic* or Progressive* LGG Surgery (may be temporally remote) Stratification Age (<> 40), KPS (60-70 vs 80+) 1p/19q status Post-op tumor <> 6 cm Enhancement +/- Translational correlates: 1p/19q; MGMT QoL RT RT + daily TMZ 12 cycles adjuvant TMZ D1-5 q28d * High Risk, Defined as: Age > 40 Symptomatic Radiographic Prog Uncontrolled seizures Event Monitoring Primary endpoint: 5 yr PFS Secondary endpoint: OS, QoL Sample Size: 546 Courtesy: D. Schiff

19 UPCOMING TRIALS: Pilot study of peptidebased vaccines combined with poly-iclc in LGG Cohort 1: Pts stable after surgery (no postoperative RT or chemotherapy). Cohort 2: Pts stable after surgery and RT. Cohort 3: Pts with recurrent grade 2 gliomas (prior chemo allowed) No corticosteroid will be allowed within 4 weeks prior to the first vaccine. Baseline MRI and other screening procedures will be done within 4 weeks prior to the 1st vaccination Vaccines: Peptide-vaccines Q3W (Wk 0-21) and i.m. poly-iclc (on days 0 and 4 following each vaccination) PBMC for immune studies (Q3W: Wk 12-24); MRI (Wks 12 & 24) Additional vaccines and poly- ICLC (Q12W) if applicable (Weeks) Courtesy of Dr Hideho Okada

20 LGG: CONCLUSIONS Patients with LGG are highly heterogenous Treatment decisions must be individualized: - Tumor location - Resectability - Histology - Molecular features - Radiographic features - Symptoms - Age - Overall prognosis Even when available, trial results may not apply to an individual patient at a given time, thus a critical appraisal and application of basic principles are necessary.

21 LGG: PRINCIPLES OF TREATMENT Treatments are rarely curative but patients may survive long time Preservation of neurologic function /quality of life is crucial Timing of treatments have low impact on overall survival and efficacy, but they do impact PFS and neurotoxicity rate. Chemotherapy most commonly used for recurrence, but has been increasingly utilized upfront. However, outside a clinical trial, upfront chemotherapy should be reserved for pts that need treatment and are most likely to respond (high risk or symptomatic oligodendroglial tumors, 1p/19q deletion, IDH1 mutations, methylated MGMT), or in combination with radiotherapy (for pts with very poor prognosis). Re-resection always welcome if progression Participation in clinical trials must be encouraged in order to answer the questions before they become obsolete.