RADIOTHERAPY IS THE OPTIMAL ADJUVANT TREATMENT IN LOW-GRADE GLIOMA

Transcription

1 RADIOTHERAPY IS THE OPTIMAL ADJUVANT TREATMENT IN LOW-GRADE GLIOMA Dr. Fernando Puebla Díaz Radiation Oncology HUCSC GEINO 2014 Madrid, November 27th-28th

2 Contents Introduction Phase II-III clinical trials in low-grade gliomas: Radiotherapy Chemotherapy Radiotherapy versus chemotherapy Radiotherapy versus radiochemotherapy Ongoing clinical trials Guidelines on management of low-grade gliomas Conclusions

3 Contents Introduction Phase II-III clinical trials in low-grade gliomas: Radiotherapy Chemotherapy Radiotherapy versus chemotherapy Radiotherapy versus radiochemotherapy Ongoing clinical trials Guidelines on management of low-grade gliomas Conclusions

4 Introduction -Astrocytoma: mutation TP53 50%;mutation IDH1 75% -Oligodendroglioma: codeleted 1p/19q 80%;mutation IDH1 80% -Oligoastrocytoma

5 Introduction UCSF low-grade glioma Scoring System based on 4 factors ( OS): 1) Tumor location in the presumed eloquent cortex 2) PS<80 3) Age>50 years 4) Tumor diameter>4cm

6 Introduction RISK FEATURES NCCN 2014 LOW RISK -Oligodendroglioma-oligoastrocytoma -Age<40 years -PS>70 -Tumor<6cm -Minor or no neurological deficit -Total resection (RTOG) -1p/19q codeleted -IDH 1 or 2 mutated -Female sex -MGMT promoter methylation HIGH RISK (3 o >) *Astrocytoma *Age 40 years -PS<70 *Tumor 6cm *Tumor crossing midline *Preoperative neurological deficit -Biopsy or subtotal resection (RTOG) -One or no deletions on 1p and 19q -IDH 1 o 2 not mutated -Increased perfusion on imaging

7 Contents Introduction Phase II-III clinical trials in low-grade gliomas: Radiotherapy Chemotherapy Radiotherapy versus chemotherapy Radiotherapy versus radiochemotherapy Ongoing clinical trials Guidelines on management of low-grade gliomas Conclusions

8 Phase II-III clinical trials in low-grade gliomas- Radiotherapy

9 Phase II-III clinical trials in low-grade gliomas- Radiotherapy

10 Phase II-III clinical trials in low-grade gliomas- Radiotherapy CONCLUSIONS PHASE III RADIOTHERAPY Timing Early post-operative radiotherapy improves PFS and controls seizures, but not OS radiation is delayed until disease progression Dose Low doses of radiation(45-54 Gy) are as effective as high doses and better tolerated

11 Phase II-III clinical trials in low-grade gliomas - Chemotherapy

12 Phase II-III clinical trials in low-grade gliomas - Chemotherapy

13 Phase II-III clinical trials in low-grade gliomas - Radio vs Chemotherapy RT VERSUS QTP Temozolomide chemotherapy versus radiotherapy in molecularly characterized (1p loss) low -grade glioma: A randomized phase III intergroup study by the EORTC/NCICCTG/ TROG/MRC-CTU (EORTC ). Meeting: 2013 ASCO Annual Meeting Background: Outcome of low-grade glioma (LGG) is highly variable. We investigated whether primary chemotherapy in comparison to standard radiotherapy (RT) prolongs progression-free (PFS) and overall survival (OS), and whether prognostic molecular factors could be defined. Methods: Progressive, symptomatic or high-risk patients with a LGG requiring treatment other than surgery were randomized (after stratification for 1p-status) to either conformal RT (50.4 Gy/28 fractions) or dose-dense temozolomide [TMZ] (75 mg/m² daily x 21 days, q28 days, max. 12 cycles). Primary endpoint was PFS, secondary analyses included OS and impact of 1p status. Results: 477 patients were randomized ( , median FU 45.5 months). Analysis was performed after 246 progression events. Hematological toxicity grade 3 was observed in 9.4% of TMZ patients. PFS was not significantly different, median OS not reached. 1p deletion was a positive prognostic factor irrespective of treatment (p-value stratified by treatment (PFS: ;HR= % CI( )/OS: 0.002;HR= % CI ( )). Conclusions: First -line treatment with TMZ compared to RT did not improve PFS in high-risk LGG patients. Although interaction test was not significant, there was a trend for inferior PFS in patients treated by TMZ with 1p intact, while OS may be better when 1p-deleted patients receive TMZ upfront. Survival analysis requires further maturation of the data.

14 Phase II-III clinical trials in low-grade gliomas - RT vs RQTP

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20 Phase II-III clinical trials in low-grade gliomas - RT vs RQTP CONCLUSIONS (SURVIVAL) RTOG 9802 HIGH RISK For patients with less than GTR or who are over 40, RT+PCV prolongs both progression-free and overall survival compared with RT alone First prospective study ever to demonstrate a treatment-related increase in survival in grade 2 glioma Median survival is increased by 5.5 years Five-year and 10-year survival are increased by 9% and 20%, respectively

21 Phase II-III clinical trials in low-grade gliomas RTOG 9802 LOW RISK

22 Phase II-III clinical trials in low-grade gliomas RTOG 9802 LOW RISK - SUMMARY Phase II study.111patients.follow up:4.4y OS 2-yr 99% and 5-yr 93% PFS 2-yr 82% and 5-yr 48% Prognostic factors (worse PFS): Tumor>4 cm Astrocytoma or oligoastrocytoma Residual tumor>1 cm Residual tumor (postoperative MR): 59%<1 cm:26% recurrence 32% 1-2 cm:68% recurrence 9% >2 cm: 89% recurrence

23 Phase II-III clinical trials in low-grade gliomas - Ongoing clinical trials RTOG 0424 Phase II non-randomized of concurrent temozolamide and radiotherapy followed by 12 cycles of temozolomide for highrisk patients. Objectives: OS 3-yr PFS Correlation between OS and PFS with MGMT promoter methylation

24 Phase II-III clinical trials in low-grade gliomas - Ongoing clinical trials RTOG 1072

25 Phase II-III clinical trials in low-grade gliomas - Ongoing clinical trials RTOG 0925 Observation in low risk LGG Will evaluate NCF,QQL and seizure control One of the following: Maximal safe resection with minimal residual disease(<2cms) Age<40 years with any extent of resection Age<50 years with a preoperative tumor <4 cm with any extent of resection

26 Contents Introduction Phase II-III clinical trials in low-grade gliomas: Radiotherapy Chemotherapy Radiotherapy versus chemotherapy Radiotherapy versus radiochemotherapy Ongoing clinical trials Guidelines on management of low-grade gliomas Conclusions

27 Guidelines on management of low-grade gliomas

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29 Guidelines on management of low-grade gliomas

30 Guidelines on management of low-grade gliomas

31 Guidelines on management of low-grade gliomas

32 Contents Introduction Phase II-III clinical trials in low-grade gliomas: Radiotherapy Chemotherapy Radiotherapy versus chemotherapy Radiotherapy versus radiochemotherapy Ongoing clinical trials Guidelines on management of low-grade gliomas Conclusions

33 Conclusions (I) For patients with high risk grade 2 glioma (less than GTR or >40 years), RT+PCV prolongs PFS and OS compared with RT alone In patients with low risk grade 2 glioma (GTR and <40 years), postoperative radiation therapy could improve PFS in patients with unfavorable prognostic factors: Age years with GTR with preoperative tumor 4-6 cms Astrocytoma / oligoastrocytoma Tumor residual >1-2cm Bad-controlled neurological symptoms(seizures)

34 Conclusions (II) LGG in elderly patients: 8% of all LGG More aggressive than in younger ones: OS 3 and 5 yr<40% Neurotoxicity of radiotherapy increases with age and dose of Gy 1p intact (EORTC ) IMRT

35 Conclusions(III) Potential radiation associated toxicity IMRT: better sparing of normal tissue PFS tumor progression is more detrimental to cognitive function than radiotherapy?

36 Conclusions (IV) The current management of LGG is multifactorial involving the interplay of the treatment modalities. Requires further investigations into several prognostic factors including treatment responsiveness of molecular markers. Prospective studies of modern RT techniques (IMRT-IGRT) are warranted to integrate patient reported outcomes of quality of life and neurocognitive function as primary end points in clinical trials.

37 Thank you for your attention!