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Management Of Recurrent GBM
And Role Of Bevacizumab
Dr Ajeet Kumar Gandhi
MD (AIIMS), DNB, UICCF (MSKCC,USA)
Assistant professor, Radiation oncology
Dr RMLIMS, Lucknow
Focal RT daily—30 x 200 cGy;
total dose: 60 Gy
TMZ 75 mg/m2 PO QD for 6 weeks,
then 150-200 mg/m2 PO QD on Days 1-5 every 28 days for 6 cycles
Concomitant
TMZ + RT*
Adjuvant TMZ
Wks6 10 14 18 22 26 30
RT Alone
R 0
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.
Phase III Study: New GBM: Radiation ± Temozolomide
Stupp R, et al. N Engl J Med. 2005;352:987-996.
Phase III Study: New GBM. Radiation ± Temozolomide
Stupp R, et al. N Engl J Med. 2005;352:987-996. Stupp et al. Lancet Oncol, 10:559-66, 2009
100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 36 42
ProbabilityofOS(%)
Months
Median Survival
RT + temozolomide: 14.6 months
RT alone: 12.1 months
Recurrent Glioblastoma
• Recurrence in GBM is a rule rather than exception
• Diagnosis of recurrence:
• Pseudo-Progression (5-30%): Transient increase of contrast enhancing
tumour within 3 months of completion of CTRT
• Pseudo-responses: Divergent effects on T1 contrast vs. FLAIR images
[Anti-angiogenic therapies]
• Updated RANO criteria: Restrictive parameters within 3 months,
corticosteroids use, T2 FLAIR changes
• Advanced imaging: Perfusion imaging, Dynamic susceptibility contrast,
Apparent diffusion coefficient and MR spectroscopy, 18F-FET-PET
• Pseudo-progression
• Psuedo-response
Further Treatment for Progression
• Surgery
• Radiation
• 2nd line chemotherapy/targeted therapy/ Immunotherapy
Surgery for recurrent/progressive GBM
• Retrospective series: Benefit (Guyotat 2000, McNamara 2014, Wornle 2015); No
Benefit (Franceschi 2015)
• Scales based on retrospective series:
• Park 2010 (JCO): tumor involvement in non-eloquent areas, small tumour
volume (<50 cm3)and good performance status (KPS > 80%)
• Park 2013 (Neuro-Oncology): KPS and ependymal involvement
• Prospective Series:
• Prospective registry study of 764 patients (Nava et al Neuro Oncol 2014): No
benefit
• Meta-Analysis of 8 prospective phase I/II trials (Gorlia et al 2012): No Benefit)
• Complete resection may be associated with better survival (Suchorska 2015
DIRECTOR Trial; Yong 2014)
Surgery for recurrent/progressive GBM
• Select group of patients may benefit from surgery:
• Confirmed progression and PFI (longer is better)
• Good performance status (KPS ≥ 80), tumour in non-eloquent area,
non-ependymal involvement, small tumour volume, GTR possible
• ? MGMT methylation status
• Other benefits of surgery:
• Diagnosis of recurrent disease (vs. radiation necrosis)
• Confirmation of initial histology
• Determination of molecular markers for biomarker-based decision
making
Surgery for recurrent/progressive GBM
Re-irradiation for recurrent GBM
• Role less defined: Lack of prospective RCT
• Stereotactic Radiosurgery: 30-36 Gray in 2-3.5 Gray per fraction
• Young age, good KPS, small volume disease (Ryu et al 2014; Combs et
al 2007)
• Interval less than 6 months (Fogh et al 2010) or >6-12 months (Combs
et al 2013)
• Stereotactic Radiosurgery with BEV:
• Ionizing radiation up regulates VEGF, stimulating angiogenesis
• BEV could counteract angiogenesis
• BEV could also mitigate radiation induced inflammation, edema and
necrosis
Management of recurrent Glioblastoma and role of Bevacizumab
Brachytherapy for recurrent GBM
• Resection plus placement of I-125 seeds (Patel et al 2000; Larson et al):
Median survival 52 weeks
• Resection->I-125 seeds-> Resurgery (Mayr et al 2002; Boisserie et al 1996):
Median survival 35-56 weeks
• Resection plus Gliasite brachytherapy (Chan et al 2005): Median survival 36
months
• HDR interstitial brachytherapy sole (Tselis et al; 2007): Median survival 37
months
Brachytherapy for recurrent GBM
Management of recurrent Glioblastoma and role of Bevacizumab
Chemotherapy for recurrent GBM
• Sparse number of trials
• Older trials before 2005, TMZ-naïve patients
• Different endpoints and response criteria impede comparability
• Varied treatment options without
• Treatment options:
• Nitrosoureas
• TMZ
• Bevacizumab/ Combination BEV
• Immunotherapy/experimental therapy/clinical trial
Nitrosourea monotherapy / combination
• Carmustine [BCNU], Lomustine [CCNU] cross blood brain barrier: Use
limited because of prolonged haematological toxicity and ILD
• CCNU has good single agent activity (100-130 mg/m2 q 6 weekly): MGMT
methylated patients (Taal et al 2014)
• CCNU combination with TMZ: Severe and frequent haematological toxicity
• Combination of CCNU with BEV:
• BELOB phase II trial (Taal et al 2014): Prolonged median PFS and OS and
PFS-6
• Weathers et al 2015: Benefit for first relapse, improved median OS
• EORTC 26101 trial: Improved PFS but not OS
The combination of bevacizumab and lomustine met pre-specified criteria & should be evaluated further
The study do not support a role for single-agent bevacizumab in the treatment of recurrent glioblastoma
N Engl J Med 2017;377:1954-63.
EORTC - 26101
2:1 ratio
Primary end point - overall survival
Bev + Lom vs Lom alone:
Similar OS but significant improvement with PFS
N Engl J Med 2017;377:1954-63.
Adverse events & further course of treatment
Conclusions of EORTC - 26101
• Adding bevacizumab to lomustine did not confer a survival advantage over
lomustine alone but prolonged progression-free survival.
• There were no unexpected findings from assessments of toxic effects.
• Addition of bevacizumab in the current trial did not result in reduced use of
glucocorticoids
• MGMT status was not predictive of benefit from the combined therapy.
• This trial led to the full approval of Bevacizumab in recurrent GBM by USFDA in Dec
2017.
Temozolomide in recurrent GBM
• TMZ superior to procarbazine (Yung et al 2000)
• TMZ-5 not inferior to PCV (Brada M et al 2010; JCO)
• Several schedules evaluated in recurrent GBM:
• TMZ 150–200 mg/m2for5 out of 28 days
• Low dose daily TMZ (40–50 mg/m2/d)
• 1-week-on/1-week-off(150 mg/m2for 7 days every 14 days)
• 3-week-on/1-week-off (75–100 mg/m2for 21 days every 28 days)
• MGMT promoter methylation prognostic (PFS 39.7% vs. 6.9%): DIRECTOR
trial
• Several combinations: BEV, Cisplatin, Irinotecan, Liposomal Doxorubicin
Bevacizumab monotherapy and combination
BRAIN Study: Survival Data Comparing Bevacizumab versus
Bevacizumab plus Irinotecan in Recurrent GBM
Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.
Single-agent Bevacizumab demonstrated an objective response for a clinically meaningful duration
J Clin Oncol 27:4733-4740. © 2009
Phase II study involving 167 patients with recurrent glioblastoma (rGBM) previously treated with temozolomide (TMZ) and
radiotherapy (RT). Patients were randomized to receive either Bevacizumab alone 10mg/kg/ 2wkly (n=85) or Bevacizumab
plus irinotecan† (n=82) for up to 104 weeks
BRAIN Study: Survival Data Comparing Bevacizumab versus
Bevacizumab plus Irinotecan in Recurrent GBM
Bevacizumab
(n = 85)
Bevacizumab +
Irinotecan
(n = 82)
ORR 28.2% 37.8%
6month PFS 42.6% 50.3%
12-months survival 38% 38%
18-months survival 24% 18%
24-months survival 16% 17%
30-months survival 11% 16%
Cloughesy T et al. Proc ASCO 2010;Abstract 2008. Henry S. Friedman etal. J Clin Oncol 27:4733-4740. © 2009
Phase II study involving 167 patients with recurrent glioblastoma (rGBM) previously treated with temozolomide (TMZ) and
radiotherapy (RT). Patients were randomized to receive either Bevacizumab alone 10mg/kg/ 2wkly (n=85) or Bevacizumab
plus irinotecan† (n=82) for up to 104 weeks
Bevacizumab monotherapy and combination
• TMZ plus BEV: Less promising than combination with CCNU
(Sepulveda et al 2015)
• Other combinations: Irinotecan, Carboplatin, Etoposide, Erlotinib,
Sorafenib, Vorinostat etc: No efficacy signal beyond single agent
BEV
• Maintenance BEV (CABARET phase II trial, Hovey et al 2015): No
benefit
Management of recurrent Glioblastoma and role of Bevacizumab
Management of recurrent Glioblastoma and role of Bevacizumab
Immunotherapy
• Clinical trials of immunotherapy predominantly focusing on DC
vaccines and antibodies targeting immunosuppressive checkpoints
have achieved promising immune activity and clinical responses.
• However, durable and sustained responses remains to be seen.
Boyuan Huang, Hongbo Zhang, Lijuan Gu, et al., “Advances in Immunotherapy for Glioblastoma Multiforme,” Journal of Immunology Research, vol. 2017, Article ID 3597613, 11 pages, 2017.
doi:10.1155/2017/3597613
Treatment Algorithm: Recurrent GBM
Conclusion
• The RANO criteria : Most accepted approach for diagnosis of
progression and response in recurrent GBM
• Evidence for repeat surgery or re-irradiation is limited but
beneficial in selected patients
• Nitrosoureas still represent the most widely accepted standard
option for systemic chemotherapy at recurrence.
• MGMT promoter methylation may emerge as a predictive
biomarker for benefit of TMZ re-challenge in recurrent GBM
Conclusion
•The best schedule of TMZ at recurrence has not been
defined, and may be scheduling matters less than previously
thought.
•There is clinical activity of Bevacizumab monotherapy at
recurrence, but an effect on overall survival is uncertain.
•Prospective data from phase II trials pointed towards
efficacy of a combination regimen with Nitrosoureas which
was not confirmed in phase III.
•Immunotherapeutic concepts are currently under evaluation
Thank You

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Management of recurrent Glioblastoma and role of Bevacizumab

  • 1. Management Of Recurrent GBM And Role Of Bevacizumab Dr Ajeet Kumar Gandhi MD (AIIMS), DNB, UICCF (MSKCC,USA) Assistant professor, Radiation oncology Dr RMLIMS, Lucknow
  • 2. Focal RT daily—30 x 200 cGy; total dose: 60 Gy TMZ 75 mg/m2 PO QD for 6 weeks, then 150-200 mg/m2 PO QD on Days 1-5 every 28 days for 6 cycles Concomitant TMZ + RT* Adjuvant TMZ Wks6 10 14 18 22 26 30 RT Alone R 0 *PCP prophylaxis was required for patients receiving TMZ during the concomitant phase. Phase III Study: New GBM: Radiation ± Temozolomide Stupp R, et al. N Engl J Med. 2005;352:987-996.
  • 3. Phase III Study: New GBM. Radiation ± Temozolomide Stupp R, et al. N Engl J Med. 2005;352:987-996. Stupp et al. Lancet Oncol, 10:559-66, 2009 100 90 80 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 ProbabilityofOS(%) Months Median Survival RT + temozolomide: 14.6 months RT alone: 12.1 months
  • 4. Recurrent Glioblastoma • Recurrence in GBM is a rule rather than exception • Diagnosis of recurrence: • Pseudo-Progression (5-30%): Transient increase of contrast enhancing tumour within 3 months of completion of CTRT • Pseudo-responses: Divergent effects on T1 contrast vs. FLAIR images [Anti-angiogenic therapies] • Updated RANO criteria: Restrictive parameters within 3 months, corticosteroids use, T2 FLAIR changes • Advanced imaging: Perfusion imaging, Dynamic susceptibility contrast, Apparent diffusion coefficient and MR spectroscopy, 18F-FET-PET
  • 6. Further Treatment for Progression • Surgery • Radiation • 2nd line chemotherapy/targeted therapy/ Immunotherapy
  • 7. Surgery for recurrent/progressive GBM • Retrospective series: Benefit (Guyotat 2000, McNamara 2014, Wornle 2015); No Benefit (Franceschi 2015) • Scales based on retrospective series: • Park 2010 (JCO): tumor involvement in non-eloquent areas, small tumour volume (<50 cm3)and good performance status (KPS > 80%) • Park 2013 (Neuro-Oncology): KPS and ependymal involvement • Prospective Series: • Prospective registry study of 764 patients (Nava et al Neuro Oncol 2014): No benefit • Meta-Analysis of 8 prospective phase I/II trials (Gorlia et al 2012): No Benefit) • Complete resection may be associated with better survival (Suchorska 2015 DIRECTOR Trial; Yong 2014)
  • 8. Surgery for recurrent/progressive GBM • Select group of patients may benefit from surgery: • Confirmed progression and PFI (longer is better) • Good performance status (KPS ≥ 80), tumour in non-eloquent area, non-ependymal involvement, small tumour volume, GTR possible • ? MGMT methylation status • Other benefits of surgery: • Diagnosis of recurrent disease (vs. radiation necrosis) • Confirmation of initial histology • Determination of molecular markers for biomarker-based decision making
  • 10. Re-irradiation for recurrent GBM • Role less defined: Lack of prospective RCT • Stereotactic Radiosurgery: 30-36 Gray in 2-3.5 Gray per fraction • Young age, good KPS, small volume disease (Ryu et al 2014; Combs et al 2007) • Interval less than 6 months (Fogh et al 2010) or >6-12 months (Combs et al 2013) • Stereotactic Radiosurgery with BEV: • Ionizing radiation up regulates VEGF, stimulating angiogenesis • BEV could counteract angiogenesis • BEV could also mitigate radiation induced inflammation, edema and necrosis
  • 12. Brachytherapy for recurrent GBM • Resection plus placement of I-125 seeds (Patel et al 2000; Larson et al): Median survival 52 weeks • Resection->I-125 seeds-> Resurgery (Mayr et al 2002; Boisserie et al 1996): Median survival 35-56 weeks • Resection plus Gliasite brachytherapy (Chan et al 2005): Median survival 36 months • HDR interstitial brachytherapy sole (Tselis et al; 2007): Median survival 37 months
  • 15. Chemotherapy for recurrent GBM • Sparse number of trials • Older trials before 2005, TMZ-naïve patients • Different endpoints and response criteria impede comparability • Varied treatment options without • Treatment options: • Nitrosoureas • TMZ • Bevacizumab/ Combination BEV • Immunotherapy/experimental therapy/clinical trial
  • 16. Nitrosourea monotherapy / combination • Carmustine [BCNU], Lomustine [CCNU] cross blood brain barrier: Use limited because of prolonged haematological toxicity and ILD • CCNU has good single agent activity (100-130 mg/m2 q 6 weekly): MGMT methylated patients (Taal et al 2014) • CCNU combination with TMZ: Severe and frequent haematological toxicity • Combination of CCNU with BEV: • BELOB phase II trial (Taal et al 2014): Prolonged median PFS and OS and PFS-6 • Weathers et al 2015: Benefit for first relapse, improved median OS • EORTC 26101 trial: Improved PFS but not OS
  • 17. The combination of bevacizumab and lomustine met pre-specified criteria & should be evaluated further The study do not support a role for single-agent bevacizumab in the treatment of recurrent glioblastoma
  • 18. N Engl J Med 2017;377:1954-63. EORTC - 26101 2:1 ratio Primary end point - overall survival
  • 19. Bev + Lom vs Lom alone: Similar OS but significant improvement with PFS N Engl J Med 2017;377:1954-63.
  • 20. Adverse events & further course of treatment
  • 21. Conclusions of EORTC - 26101 • Adding bevacizumab to lomustine did not confer a survival advantage over lomustine alone but prolonged progression-free survival. • There were no unexpected findings from assessments of toxic effects. • Addition of bevacizumab in the current trial did not result in reduced use of glucocorticoids • MGMT status was not predictive of benefit from the combined therapy. • This trial led to the full approval of Bevacizumab in recurrent GBM by USFDA in Dec 2017.
  • 22. Temozolomide in recurrent GBM • TMZ superior to procarbazine (Yung et al 2000) • TMZ-5 not inferior to PCV (Brada M et al 2010; JCO) • Several schedules evaluated in recurrent GBM: • TMZ 150–200 mg/m2for5 out of 28 days • Low dose daily TMZ (40–50 mg/m2/d) • 1-week-on/1-week-off(150 mg/m2for 7 days every 14 days) • 3-week-on/1-week-off (75–100 mg/m2for 21 days every 28 days) • MGMT promoter methylation prognostic (PFS 39.7% vs. 6.9%): DIRECTOR trial • Several combinations: BEV, Cisplatin, Irinotecan, Liposomal Doxorubicin
  • 24. BRAIN Study: Survival Data Comparing Bevacizumab versus Bevacizumab plus Irinotecan in Recurrent GBM Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma. Single-agent Bevacizumab demonstrated an objective response for a clinically meaningful duration J Clin Oncol 27:4733-4740. © 2009 Phase II study involving 167 patients with recurrent glioblastoma (rGBM) previously treated with temozolomide (TMZ) and radiotherapy (RT). Patients were randomized to receive either Bevacizumab alone 10mg/kg/ 2wkly (n=85) or Bevacizumab plus irinotecan† (n=82) for up to 104 weeks
  • 25. BRAIN Study: Survival Data Comparing Bevacizumab versus Bevacizumab plus Irinotecan in Recurrent GBM Bevacizumab (n = 85) Bevacizumab + Irinotecan (n = 82) ORR 28.2% 37.8% 6month PFS 42.6% 50.3% 12-months survival 38% 38% 18-months survival 24% 18% 24-months survival 16% 17% 30-months survival 11% 16% Cloughesy T et al. Proc ASCO 2010;Abstract 2008. Henry S. Friedman etal. J Clin Oncol 27:4733-4740. © 2009 Phase II study involving 167 patients with recurrent glioblastoma (rGBM) previously treated with temozolomide (TMZ) and radiotherapy (RT). Patients were randomized to receive either Bevacizumab alone 10mg/kg/ 2wkly (n=85) or Bevacizumab plus irinotecan† (n=82) for up to 104 weeks
  • 26. Bevacizumab monotherapy and combination • TMZ plus BEV: Less promising than combination with CCNU (Sepulveda et al 2015) • Other combinations: Irinotecan, Carboplatin, Etoposide, Erlotinib, Sorafenib, Vorinostat etc: No efficacy signal beyond single agent BEV • Maintenance BEV (CABARET phase II trial, Hovey et al 2015): No benefit
  • 29. Immunotherapy • Clinical trials of immunotherapy predominantly focusing on DC vaccines and antibodies targeting immunosuppressive checkpoints have achieved promising immune activity and clinical responses. • However, durable and sustained responses remains to be seen. Boyuan Huang, Hongbo Zhang, Lijuan Gu, et al., “Advances in Immunotherapy for Glioblastoma Multiforme,” Journal of Immunology Research, vol. 2017, Article ID 3597613, 11 pages, 2017. doi:10.1155/2017/3597613
  • 31. Conclusion • The RANO criteria : Most accepted approach for diagnosis of progression and response in recurrent GBM • Evidence for repeat surgery or re-irradiation is limited but beneficial in selected patients • Nitrosoureas still represent the most widely accepted standard option for systemic chemotherapy at recurrence. • MGMT promoter methylation may emerge as a predictive biomarker for benefit of TMZ re-challenge in recurrent GBM
  • 32. Conclusion •The best schedule of TMZ at recurrence has not been defined, and may be scheduling matters less than previously thought. •There is clinical activity of Bevacizumab monotherapy at recurrence, but an effect on overall survival is uncertain. •Prospective data from phase II trials pointed towards efficacy of a combination regimen with Nitrosoureas which was not confirmed in phase III. •Immunotherapeutic concepts are currently under evaluation