성균관대학교삼성창원병원신경외과학교실신경종양학 김영준
INTRODUCTIONS Low grade gliomas (LGG) - heterogeneous group of tumors with astrocytic, oligodendroglial, ependymal, or mixed cellular histology - In adults diffuse, infiltrating variety of tumors classified as WHO grade II lesions slow and continuous growth preceding anaplastic transformation 1) low grade astrocytomas : fibrillary, protoplasmic, and gemistocytic variants 2) oligodendrogliomas 3) mixed oligoastrocytomas - longstanding standard treatment includes 1) surgical resection of tumors when feasible, 2) followed by radiotherapy in incomplete resection, and 3) followed by chemotherapy at recurrence. but, historically considered to be poorly response to chemotherapy
Management of LGG patients has been a matter of debate 1. poorly studied natural course of LGG for a long time - the vast majority of investigators considered LGG as a stable and benign brain tumor and wait and see approach was advocated for many years - LGG usually affects young adults enjoying a normal life without or with only mild deficit on a standard neurologic examination - even AED can control the seizure in 80-90% of LGG patients 2. traditional thought that this infiltrative tumor cannot be removed without generating neurological and functional sequences - in particular when LGG is located in or close to eloquent area 3. deep argument that surgical removal had no impact on the natural history of LGG in the classic literatures - only biopsy for histopathological diagnosis - single follow-up or radiotherapy according to the morphological criteria - recently, prolonged OS from 61.1 to 90.5 month with GTR in meta-analysis
Recent conceptual advances of LGGs management : due to technical and knowledge advances in genetics, cognitive neurosciences, imaging, and treatment revolutionized of LGGs 1. Advanced knowledge of LGG biology 1) these aggressive tumors not are stable but grow continuously 2) these tumors migrate along the white matter pathways 3) inevitably progress to a higher grade of malignancy leading to neurologic disability and ultimately to death 2. Mechanism of neuroplasticity : cerebral processing of interaction between the disease and the host - development in brain-mapping techniques makes the benefit-risk ratio of surgery increase 3. Integration of onco-functional balances of surgical resection in an individualized multimodal therapeutic strategies : improving QOL
New insights into the natural course of LGGs 1. LGG is not stable disease at all - objective calculation of growth rate : linear increase of about 4mm/year (based on at least 2 MRIs spaced 3 months apart before any treatment) - the concept of PFS is meaningless in LGG before any treatment or incomplete surgical resection - inverse correlation between growth rate and survival in LGG 2. Migration of tumor cells along the white matter tracts - LGG is not a tumor mass but is an infiltrating chronic disease progressively invading CNS, especially the subcortical connectivity 3. LGG inescapably become malignant leading to death - OS of LGG patients by EORTC data (J Clin Oncol 2002;20:2076-2084) patients with favorable prognostic score : 7.7 years poor prognostic score : 3.2 years - LGG is not a benign tumor, but cancerous disease
Spontaneous worse prognostic factors of LGGs Pignatti F et al. J Clin Oncol 2002; 20: 2076-2084 Soffieti R et al. Eur J Neurol 2010; 17: 1124-1133 Clinical Age > 40 years Presence of neurological deficit Absence of seizure at onset KPS < 70 MMSE score < 25/30 Radiological Large tumors (>5~6cm) Tumors crossing midline Rapid growth rate Presence of contrast enhancement High CBV and high uptake of 11 C-MET Lipid & lactate on MRS STR >> GTR Molecular Absence of 1p19q codeletion Absence of IDH1 mutation Histological better outcome in oligodendroglioma than astrocytoma MIB index 8%
- Association between LGG tumor burden and patients outcome (JCO 2008;26:1338)
Individualized multi-stage therapeutic strategies in LGGs 1. Role of only one specific treatment without global view in the traditional literatures and studies 2. Switching goal to more holistic view - based on the anticipation of personalized and long-term multi-stage therapeutic approach - different points from traditional attitude 1) proposing earlier and maximal surgical resection 2) repeating treatment : 2 to 4 surgical resection spaced by several years 3) reversing the traditional order of therapies : neoadjuvant chemotherapy followed by surgery after tumor shrinkage (initially TMZ and followed by PCV) : no early radiotherapy 4) ultimate goal of increasing both OS and QOL
UPFRONT CHEMOTHERAPY The rationale for upfront chemotherapy of LGGs to radiotherapy : to avoid radiotherapy and thus to avoid potential radiation-induced cognitive effects, especially in large unresectable LGGs 1. a recent study clearly showed that LGGs patients who receive radiotherapy have a progressive cognitive decline (Lancet Neurol 2009; 8:810 818) : LGG patients who received radiotherapy showed a progressive decline in attentional functioning, even those who received fraction doses that are regarded as safe ( 2 Gy) 2. upfront chemotherapy as an effective treatment in LGGs through several phase II studies 1) a 50 75% response rate (including minor response) 2) a 24 48 months median duration of response
The response of upfront chemotherapy for LGGs : more frequent of minor response than partial response (Peyre et al. Neuro Oncol 2010; 12:1078 1082 / Richard et al. Ann Neurol 2007; 61:484 490) 1. slow, progressive and delayed response : median time to maximum response of approximately 12 months 2. response rate and duration of response 1) higher in patients with 1p/19q codeletion 2) also commonly observed in non-1p/19q codeleted LGG 3. commonly observed clinical improvement : even when there is no clear radiological response, more than half of the patients with epilepsy demonstrating a significant reduction of seizure frequency
- Slow and progressive response to TMZ of a patient with a low-grade oligodendroglioma of 1p19q codeletion (A)MRI before TMZ (B)after 12 cycles of TMZ (C)after 24 cycles of TMZ
- Minimal response of TMZ for LGGs (Brada M, et al. Ann Oncol 2003; 14: 17151721) Oligodendrogliomas Astrocytoma baseline and post-tmz cycle 12 baseline and post-tmz cycle 12
- Delayed response to TMZ in WHO grade II oligodendroglioma (FLAIR image) : TMZ as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions (Hoang-Xuan K, et al. J Clin Oncol 2004; 22: 3133-3138) (A) Before TMZ (B) after six cycles of TMZ (C) partial response after 17 cycles
ADJUVANT CHEMOTHERAPY The objective of adjuvant chemotherapy after radiotherapy : to increase survival in LGGs with poor prognostic factors 1. Phase III randomized trial of radiotherapy plus PCV chemotherapy for supratentorial adult LGG : RTOG 9802 (Shaw EG et al. JCO 2012; 30: 3065-3070) P=0.020 P<0.001
2. Phase 2 study of TMZ-based concurrent chemoradiation therapy for high-risk LGG patients : RTOG 0424 (Fisher BJ et al, Int J Radiat Oncol Biol Phys 2015; 91: 497-504) - High risk group 3 following factors 1)age 40 years 2)astrocytoma histology 3)bi-hemispherical tumor 4)preoperative tumor diameter 6 cm 5)preoperative neurological function status of >1-3-year OS : 73.1% 3-year PFS : 59.2% - longer OS compared to historical control
SALVAGE CHEMOTHERAPY Second-line chemotherapy with TMZ in recurrent oligodendroglioma after PCV chemotherapy: EORTC 26972 (den Bent MJ et al. Ann Oncol 2003; 14: 599-602) - In a prospective non-randomized multicenter phase II trial patients were treated with TMZ 150 mg/m 2 on days 1 5 in cycles of 28 days for 12 cycles - 12 of 24 patients (50%) evaluable for response to first-line PCV chemotherapy had responded to TMZ 1) median TTP for responding patients : 8.0 months 2) 6-month PFS : 29% 12-month PFS : 11% - TMZ may be regarded as the preferred second-line treatment in OD after failure of PCV chemotherapy
Phase II study of first-line chemotherapy with TMZ in recurrent oligodendroglial tumors after surgery and radiotherapy : the EORTC Study 26971 (van den Bent MJ et al. J Clin Oncol 2003; 21: 2525-2528) - In a prospective, nonrandomized, multicenter, phase II trial : patients who had a recurrence after prior surgery and radiotherapy : 200 mg/m 2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles - TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent oligodendroglioma 1) a complete (n = 10) or partial response to TMZ in 20 (52.6%) of 38 patients 2) median TTP of 10.4 months for all patients 13.2 months for responding patients 3) 12-months PFS from the start of treatment : 40% of patients
CHEMOTHERAPY REGIMEN The most common chemotherapy regimen of TMZ and PCV : no direct comparison study evaluating the efficacy of PCV and TMZ in LGGs - TMZ versus PCV in recurrent high grade gliomas in phase III trials (Brada M, et al. J Clin Oncol 2010; 28: 4601-4608) P=0.350 P=0.229
- upfront TMZ versus PCV followed by radiotherapy in anaplastic gliomas in phase III trials (Wick W et al. J Clin Oncol 2009; 27: 5874 5880)
- upfront PCV chemotherapy might be more effective in terms of PFS (but not of OS) than upfront TMZ in 1p/19q codeleted AO (Lassman AB et al. Neuro-Oncol 2011; 13: 649-659) : International retrospective study of over 1000 adults with AO
Temozolomide in LGGs : currently the preferred drug to treat LGGs either upfront or at recurrence because usually better tolerated than PCV chemotherapy also easier to administrate 1. upfront TMZ does not alter the QOL of LGG patients but improves : no change in scores of Box plots at each TMZ chemotherapy cycle compared to baseline for five realms of QOL and Functional Assessment of Cancer Therapy General (FACT-G). (Liu R et al. Neuro-Oncol 2009; 11: 59 68)
2. upfront chemotherapy with a protracted TMZ schedule in LGG : 75mg/m 2 /day in 11-week cycles of 7 weeks on/4 weeks off or 75mg/m 2 /day in 4-week cycles 3 weeks on/1 week off 1) rationale for the protracted dose-dense TMZ regimens : it can theoretically overcome MGMT resistance 2) apparently similar to those obtained with the classical TMZ regimen (Pouratian N, et al. J Neurooncol 2007; 82: 281 288) (Tosoni A, et al. J Neurooncol 2008; 89: 179 185) (Kesari S, et al. Clin Cancer Res 2009; 15: 330 337) 3) reversely, even the 3 weeks on/1 week off regimen appeared to be less effective than the classical regimen in a phase III trial in recurrent HGGs (Brada M, et al. J Clin Oncol 2010; 28: 4601-4608)
DURATION OF CHEMOTHERAPY TMZ treatment in LGG - a prolonged duration of treatment might be important to achieve a prolonged response Kaloshi G, et al. Neurology 2007; 68: 1831 1836 Hoang-Xuan K, et al. J Clin Oncol 2004; 22: 3133 3138 : to treat LGGs with TMZ rather than PCV chemotherapy (its cumulative toxicity) - discontinued TMZ in the absence of progression in a dynamic volumetric study (after a median period of 18 cycles) : occurrence of their regrowth within 1 year in 60% of LGGs Ricard D, et al. Ann Neurol 2007; 61: 484 490 - in continuously responding patients, many neurooncologists give TMZ for up to 24 or more cycles Viaccoz A et al. Curr Opin Oncol 2012; 24: 694-701
PCV chemotherapy for LGGs - commonly a prolonged (>2 years) and ongoing response after chemotherapy termination in dynamic volumetric study, despite the shorter duration of PCV chemotherapy than the duration of TMZ chemotherapy Peyre M, et al. Neuro Oncol 2010; 12: 1078 1082
- Evolution of the mean tumor diameter (MTD) before, during, and after PCV chemotherapy Peyre M, et al. Neuro Oncol 2010; 12: 1078 1082 decrease in the MTD (green curves) during PCV chemotherapy persistent decrease in the MTD (red curves) after PCV chemotherapy discontinuation
RADIOLOGICAL RESPONSE Limited role of McDonald criteria on estimating the chemotherapeutic response of LGGs without enhancement Complete response Partial response Stable disease Progressive disease McDonald criteria - Disappearance of all enhancing measurable and non-measurable disease (sustained for 4 weeks) - No new lesions / No corticosteroids - Clinically stable or Improved - 50% decrease of all measurable enhancing lesions (sustained for 4 weeks) - No new lesions - Clinically stable or Improved - Clinically stable - Does not qualify for CR, PR, or progression - 25% increase in enhancing lesions - Any new lesion Modified McDonald criteria - Disappearance of all index lesions (sustained for 4 weeks) / No new lesions - No worsening of all non-index lesions (sustained for 4 weeks), with no evidence of PD - Improved or stable neurological symptoms - 50% decrease (sum of lesion diameters) of all index lesions (sustained for 4 weeks) - No progression of non-index lesions nor new lesion - Improved or stable neurological symptoms - Improved or stable neurologic symptoms - Does not qualify for CR, PR, or progression - 25% increase in enhancing lesions - Unequivocal progression of existing non-index lesions Olivier L, et al. Curr Neurol Neurosci Rep 2013; 13: 347
Response assessment in neurooncology (the RANO group) Van den Bent M, et al. Lancet Oncol 2011; 12: 583 593 Complete response Partial response Stable disease Progressive disease Imaging feature - disappearance of all enhancing disease (measurable and nonmeasurable) - sustained for at least 4 weeks - stable or improved non enhancing FLAIR/T2 lesions - no new lesions - 50% or more decrease of all measurable enhancing lesions - sustained for at least 4 weeks - no progression of nonmeasurable disease - stable or improved non enhancing FLAIR/T2 lesions - no new lesions - does not qualify for complete response, partial response or progression - stable non-enhancing FLAIR/T2 lesions - 25% of more increase in enhancing lesions despite stable or increasing steroid dose - increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes - any new lesions Clinical feature - no corticosteroids (physiological replacement doses allowed) - clinically stable or improved - stable or reduced corticosteroids (compared to baseline) - clinically stable or improved - stable or reduced corticosteroids (compared to baseline) - clinically stable - clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease)
Limitation of RANO criteria on assessment of chemotherapeutic response at LGGs 1. LGGs are never stable after chemotherapy nor before chemotherapy 2. mean tumor diameter (MTD) in LGGs decreases to minimum before recurrence : LGGs typically present a progressive and ongoing decrease in MTD that can last many months after chemotherapy disruption 3. mean tumor diameter (MTD) in LGGs treated with upfront chemotherapy increase in almost all LGG patients : the rate of partial response of 5% at the end of PCV chemotherapy, but maximal response of 35% at 3.4 years after PCV discontinuation 4. similar response to first-line radiotherapy 5. to precisely assess the impact of chemotherapy, both the duration and the magnitude of the MTD decrease should be measured
PREDICT THE RESPONSE Candidate for favorable factors of response : this needs to be confirmed in prospective clinical trials 1. 1p/19q codeletion 2. possibly methylation of the MGMT promoter 3. the IDH1 mutation upfront chemotherapy with 1p19q codeletion in LGGs 1. TMZ with 1p19q codeletion (Kaloshi G, et al. Neurology 2007; 68: 1831-1836) : total of 149 consecutive patients in the retrospective, single center observational study 1) higher response rate to chemotherapy : 72% vs 46% (p=0.02) 2) longer duration of objective response : >40 months vs 20 months (p=0.017) 3) longer PFS (p=0.00041) and OS (p=0.04)
- Conclusion : 1) LGGs respond to TMZ 2) loss of chromosome 1p/19q predicts both a durable chemosensitivity and a favorable outcome Progression-free survival Overall survival according to the 1p/19q loss of heterozygosity status
2. TMZ with 1p19q codeletion (Levin N, et al. Cancer 2006; 106:1759 1765) : total of LGGs patients in the retrospective, single center observational study 1) objective responses in 17 patients (61%) 2) the median TTP of 31 months 3) PFS rate of 70% at 24 months 4) Loss of chromosome 1p were associated with objective response (p=0.003) 3. PCV with 1p19q codeletion (Stege EM, et al. Cancer 2005; 103:802 809) : total of 16 newly diagnosed ODs and OA patients in the retrospective, single center observational study 1) objective response in 13 patients (81.3%) 2) progression in only 1 patient (6.3%) 3) newly diagnosed patients with OD tumors, with or without loss of 1p/19q, well responded to PCV chemotherapy
MGMT gene promoter methylation in LGGs 1. TMZ chemotherapy with methylated MGMT gene promoter in LGGs (Levin N, et al. Cancer 2006; 106:1759 1765) : MGMT protein expression was analyzed by immunohistochemistry staining 1) The highest MGMT protein expression level in LGGs from patients with intact 1p (positive nuclear staining of > 50%) - maximal radiographic response of SD 2) tumors with 1p LOH and lower MGMT protein expression - also demonstrated an objective radiographic response - significant association between loss of chromosome 1p and MGMT protein expression
2. MGMT methylation: a marker of response to TMZ in LGGs (Everhard S et al. Ann Neurol 2006; 60: 740-743) : evaluation of methylation status of MGMT gene promoter in 68 LGGs patients treated by neoadjuvant TMZ - methylated MGMT gene promoter in 63 of 68 (92.6%) patients characteristics responsive nonresponsive p-value PFS (mo) p-value MGMT gene promoter <0.001 unmethylated 3 2 0.012 6 methylated 58 5 29.5 1p19q 0.041 intact 34 5 0.028 23 lost 22 0 35 Histology of LGGs 0.527 oligodendroglioma 38 4 0.773 28 oligoastrocytoma 16 2 20 astrocytoma 7 1 34
IDH1 mutation in LGGs (Houillier C, et al. Neurology 2010; 75:1560 1566) : case study of 271 LGGs to evaluate the correlation with of upfront TMZ and OS 1. IDH mutations in 132/189 patients (70%) 2. association of IDH mutation with outcome 1) prolonged overall survival in univariate (p=0.002) and multivariate analysis (p=0.003) 2) a higher rate of response to TMZ (p=0.01) 1p19q codeletion + IDH mutation None of these alteration Only IDH mutation PFS according to IDH status in the untreated group
Summaries of clinical relevant molecular markers in LGGs Biological significance Method of assessment Clinical relevance 1p19q codeletion - Biological role unclear : codeletion of chromosomal arms 1p and 19q linked to oligodendroglial morphology : candidate genes CIC and FUBP1 are under evaluation PCR, FISH Controversial, probably prognostically favorable MGMT gene promoter methylation DNA repair Methylation-specific PCR Controversial IDH1/2 mutation Link to DNA and histone methylation, energy metabolism, and pro-angiogenic pathways Immunohistochemistry (IDH1R132H) or sequencing Prognostically favorable Weller M et al, Neuro-Oncol 2012; 14: 100-108
SUMMARIES Chemotherapy is an interesting treatment option, especially as an upfront treatment in large unresectable LGGs with a 1p/19q codeletion Dynamic volumetric studies have recently provided a better description of the evolution of LGGs after chemotherapy, and new response criteria have been defined by the RANO group Ongoing phase III studies that compare the efficacy of TMZ alone or in association with radiotherapy to radiotherapy alone will allow a better delineation of the role of chemotherapy in LGGs (EORTC 22033 26033/CE5). These studies will also help to determine the potential predictive value of a 1p/19q codeletion, a MGMT promoter methylation and an IDH1 mutation