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Brain mets (2).pptx

  1. 1. Brain metastasis Topic: Is WBRT obsolete in multiple brain mets? Moderator: Dr. Subhash Gupta Addl. Professor Dept. of Radiation oncology AIIMS – New Delhi.
  3. 3. Nature Reviews Clinical Oncology volume 17, pages 279–299 (2020)
  5. 5. THIS IS WHAT WE KNOW!!!! Median Survival Time: Untreated 1 month Dexamethasone alone 1-2 months WBRT - Mostly 3-6 months. ► Short Overall Treatment Time
  6. 6. • Larger lesions (>4 cm) • Rapid relief of Mass effect and edema • WBRT remains standard of care in multiple brain mets. • Overall response rate 40-60% • Good intracranial control-75%. • Neurologic improvement is 25- 40%. • HA-WBRT shown to minimise Cognitive side effects. TREATMENT OPTIONS SURGERY WBRT SRS/SRT • Treatment of small, deep lesions or eloquent areas. • Favourable toxic profile. • Doesn’t eliminate all brain mets.
  7. 7. WBRT role in Brain metastasis • Headache 40-70% • Discontinuation of Corticosteroids 51% • Improvement of Performance Status 57% • Cerebral Dysfunction 40-50% • Improvement in Paresis 30-40% 1. Wong J, et al., Int J Radiat Oncol Biol Phys. 2009 Nov 15;75(4):1125-31. (N=129) 2. Komosinska K, et al., Acta Oncol. 2010 Apr;49(3):382-8. (N=91; KPS <70) 3. Van Oorschot B, et al., Breast Care (Basel). 2011;6(1):14-19. (Review)
  9. 9. WBRT might still have a role for patients with the best prognoses according to GPA score >2.5
  10. 10. • 88% patients-UPFRONT BRAIN METS-already worse group!!!! • Nearly 70% of patients had a KPS <70%. • The duration between diagnosis and randomization could be ≤8 weeks, an excessively long period. • The median survival was 2 months, lower than that in most studies and less than the poorest graded prognostic assessment class!!! How was QOL assessed?? • study design-SELECTION BIAS!!!! “clinicians were encouraged to approach potential participants about the trial if there was uncertainty in the clinicians’ or patients’ minds about the potential benefit of WBRT”. • Sub analysis has shown that the benefit in >5mets rather than 1-4 mets Is This a Flawed One-Size-Fits-All Approach?
  11. 11. • The clinical decision to treat brain mets with SRS or WBRT, or both depends on multiple factors. - Performance status - Control of systemic disese - Primary cancer type - Disease burden within brain and - Interval to progression. PATIENT GROUPS ARE HETEROGENEOUS !!
  12. 12. STUDY RESULT NOTES RTOG 9508 (WBRT vs WBRT+SRS) n=333 • SRS addition improved LC • WBRT+SRS improved OS in single brain metastasis, RPA-1, Size >2 cms. • Early and late toxicities did not differ greatly between treatment groups.(RTOG) • No advantage in Survival, local failures, neurological deaths with SRS in 2-3 mets. -NEGATIVE TRAIL for multiple mets. JROSG 99-1 Aoyama et al. (SRS vs SRS+WBRT) n=58 • At 12 months, adjuvant WBRT resulted in an increased Local control (p<0.05) • Decreased risk for new brain metastases (p<0.05). • No OS difference • SRS had 27.5% Local recurrence • SRS had 64% distant recurrence • SRS had 12months intracranial recurrence of 74.6%. • ?? Improved Neurocognition assessment. ( MMSE) Chang et al.(MD Anderson) (SRS vs SRS+WBRT) • SRS alone had higher neurocognition intact at 4 months. • SRS alone had higher OS • SRS had 87% retreatments. • WBRT group had more systemic deaths possible cause for lower OS EORTC 22952-26001 Kocher et al. (SRS/Sx Vs SRS/Sx+WBRT) • No differences in functional independence or OS between the study arms. • Adjuvant WBRT reduced the 2-year relapse rate at initial sites and new sites. • They did not evaluate cognitive function Brown et al.(N0574) (N=213) • Lesser cognitve deterioration by 28% • Greater QoL with SRS alone • No significant difference in functional independence. • Lesser intracranial failure with WBRT addition by 18.4% • Retreatments more in SRS alone 32%
  13. 13. • Intracranial recurrence and need for salvage treatment greater when WBRT was omitted. STUDY INTRACRANIAL RECURRENCE RETREATMENT after SRS Brown PD et al. 24.7% 32% Chang et al 73% 87% Aoyama H et al 74.6% 22% Kocher M et al 48% 31%
  14. 14. WBRT has doubled the OS. Survival gain by 10months. In NSCLC subgroup WBRT +SRS SRS RTOG 9508 Secondary Analysis JROSG 99-1 Secondary Analysis WBRT has doubled the OS. Survival gain by 6.1 months in NSCLC subgroup Pirzkall et al. WBRT addition resulted in superior OS benefit by 7.1 months.
  15. 15. JAMA Oncol. 2015;1(4):457-464. doi:10.1001/jamaoncol.2015.1145 • Superior median OS with DS-GPA 2.5-4.0 group in WBRT+SRS vs SRS is 16.7 vs 10.6 months.(p=0.04) • Increased 1-year rate of distant brain relapse (HR 8.31; p=0.04), • Increased 1-year local tumor failure (P = .002). • This resulted in more frequent use of salvage therapy (P <.001) in the SRS-alone arm. • Improved OS was attributed to fewer brain recurrences after WBRT. • MMSE deterioration was significantly longer for the WBRT plus SRS arm (16.5 months vs. 7.6 months; P = .05) Phase III trial of 1-4 lesions, NSCLC subgroup. SRS vs SRS+WBRT.
  16. 16. Sx+WBRT Sx+WBRT Sx Sx Sx+WBRT Sx -WBRT has decreased intracranial recurrence by 52%. -Improved Local control by 36%.(p<0.01) -Decreased neurological death.(p=0.03) Postoperative radiotherapy in the treatment of brain metastasis Patchell RA, JAMA. 1998 • leptomeningeal disease adjacent to the surgical cavity after radiosurgical treatment was reported to be as high as 16·9% Sx vs Sx+WBRT Sx vs Sx+SRS
  17. 17. -Those with >1 brain metastases also had a significantly greater risk of distant brain failure with a HR of 1.59 (95% CI 1.14-2.2) -SRS alone had 21% local failures & 47% distant failures. -Neurocognitive outcomes better with selected population . Data for QoL, functional status, cognitive effects were insufficient to determine effects of WBRT. -SRS only treatment approach results in significantly high incidence of local and distant failure. -No difference was observed for adverse effects and neurologic death between the treatments. -SRS only results in better QOL in short term Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases: meta-analysis -The addition of WBRT to radiosurgery improved local and distant brain control. -No differences in OS. -Many of these trials lacked quality of life outcomes, neurocognitive outcome. -Trials are needed to evaluate the use of neurocognitive protective agents and hippocampal sparing with WBRT.
  18. 18. Did the Brain RECURRENCES impact Neurocognition? • MMSE were worse in patients with uncontrolled tumours than in patients with controlled tumor. -Regine et al (2 studies) -Taylor et al.. The side effects of recurrent tumours are worse than the side effects of Preventive tumors. Regine WF et al,IJROBP 2002; 52
  19. 19. The value of 4-month neurocognitive function as an endpoint in brain metastases trials • NC primary deterioration – 4ms • Recovery - 8ms • Secondary deterioration – 12ms (Upto Baseline ONLY!!!) • MMSE is not a standard cognitive battery. • Sec.deterioration relating to ?NSC. Shunsuke O et al, J Neurooncol (2014) So, LONG FOLLOW-UP DATA IS NECESSARY TO DRAW CONCLUSION
  20. 20. Flaws in assessing cognition • Most studies use a time-to-event analysis instead of reporting cognitive function serially over time. • There is no prefect cognitive test. (Janelsins MC, Int Rev Psychiatry. 2014) • Most studies with median survival upto 4 to 6 months. • Short follow up data, most Cognitive functions recover later.(Armstrong et al, Shunsuke O et al,) • Validity of cognitive batteries used across studies- INCONSISTENT (Susan GR McDuff et al.) • The effects of chemo-brain on these analyses should be considered. • Impact of Local failures & distant failures on QoL not well reported. • Discordance between objective cognitive test results and subjective complaints is frequently observed in many neurologic populations.
  21. 21. RTOG 0614 Memantine during WBRT considered standard of care Brown et al. Neuro-Oncol 2013
  22. 22. Primary end point : the Hopkins Verbal Learning Test–Revised Delayed Recall (HVLT-R DR) at 4 months HA-WBRT is a technique that involves conformal avoidance of sub- granular zones of the hippocampi. • HVLT delayed recall of 7% compared to 30% in WBRT. (P=0.0003). • Comparable to that observed with SRS alone at a similar point in time in the prospective Chang et al. • Quality of life, assessment showed improvement in emotional well-being over the course of 6 months. • D100% of the hippocampus, predicted for greater decline in HVLT- DR. Journal of Clinical Oncology 32, no. 34 (December 01, 2014) 3810-3816.
  23. 23. • Phase 3 trial, non-blinded, Study time:2015- 18, n=518, Med follow-up:7.9 mos. • No increase in hippocampal relapses. • Significant reduction in cognitive failure risk was noted (HR, 0.76; P = 0.03). • Less fatigue (P = .04), less difficulty with remembering things (P = .01), and less difficulty with speaking. February,2020. DOI https://doi. org/10.1200/JCO.19. 02767
  24. 24. HR= 0.74 RTOG 0614 NRG CC001 HR= 0.78 Contributes to debate over SRS vs. WBRT for brain metastases RTOG 0614: HR=0.78 with addition of memantine to WBRT NRG CC001: HR=0.74 with addition of HA to WBRT+memantine Combined HR with memantine+HA = 0.78 x 0.74 = 0.58 Comparable to phase III trials favoring SRS in lieu of WBRT The incidence of cognitive deterioration with SRS alone at 12 months = 60% Paul D. Brown et al., JAMA 2016
  25. 25. Studies undergoing recruitment • Several trials are underway comparing the use of HA-WBRT against SRS • NCT03550391, • NCT03075072, • NCT04277403(HA-WBRT vs SRS in Patients With Multiple Brain Metastases HipSter), • NCT01592968, • ENCEPHALON trial. • AIIMS-IRCH-Dr Subhash Gupta/ Dr Sai Kumar
  26. 26. Will this model work out in INDIA? • Indian GDP per capita in India is expected to reach 1,45,679 Rs. (2020-21). • Cancer with a monthly expenditure of ₹ 5,121 tops the list. • Govt contribution in a person’s health expenditure is 20% only. • Did the QALY gained with SRS alone weighs considering retreatment costs ?
  27. 27. Is WBRT an evolution or revolution?
  28. 28. What about patients? • Recurrences in clinical practice can be devastating both physiologically and Psychologically to patients. • High recurrence rates makes close surveillance with imaging -COSTING TO PATIENT BOTH IN COMPLIANCE AND FINANCIALLY. • Always kept in mind about ‘Shared decision making’. • SOMETIMES PATIENTS MAY NOT GET WHAT DOCTOR IS CONVEYING. • IN METASTATIC SETTING, PATIENTS ACCEPT SOME RISK OF TOXICITY IN AN EFFORT TO IMPROVE THE HEALTH. • No difference in functional independence with addition of WBRT. • An OS benefit seen in patients with NSCLC who have favourable prognosis with addiction of WBRT to SRS.
  30. 30. REBUTTAL
  31. 31. Are Reports of Whole Brain Radiation Therapy's Demise Exaggerated?
  32. 32. • JLGK0901 SRS for multiple brain mets - Non randomised study - The investigators included multiple pathologies, multiple RPA classes, other prognostic indicators – CONFOUND RESULT, DIFFICULT CONCLUSION. - No of lesions not necessarily decide OS. - Treating multiple lesions – greater integral doses to Brain - equals to single fraction WBRT doses to Brain – isn’t it a contraindication??
  33. 33. • Chang et al: Found greater neurocognitive failure at 4months with WBRT+SRS vs SRS alone. Limitations: -Trend toward worse baseline cognition on TMT-Part A in the WBRT+SRS group -The lack of follow-up beyond 4 months. - Large volume disease in WBRT group -Significant difference in survival time between the treatment groups –?Selection bias. - WBRT group had more systemic deaths possible cause for lower OS.
  34. 34. Sometimes guidelines are confusing?? SRS = Cost + follow-up Imaging cost + Hospital visits + Psychological stress+ Retreatment costs+ Fear of recurrence
  35. 35. • Global HRQoL worsened more after the second disease progression. • The most affected scale scores- Loss of appetite, physical functioning, • Patients who experienced shorter survival – Severely deteriorated QoL. • Patient’s preference weighing tumor control vs treatment-related toxic effects remains a highly individual decision. No improved QoL
  36. 36. • HA-WBRT may be cost-effective for controlling brain metastases compared with other treatments. • Survive a median of 3 months - HA-WBRT is cost-effective • At 6 months, radiosurgery with whole-brain radiotherapy salvage was cost-effective,. • At 12 months, HA-WBRT is cost-effective • At 24 months, HA-WBRT is much more cost-effective • The highest value treatment in patients with notably prolonged survival was SRS plus HA-WBRT. • Radiosurgery was cost-effective in patients with short (3-6 months) prognosis, whereas HA-WBRT and SRS were both cost-effective in patients with longer (12-24 months) prognosis.
  38. 38. Is the Case Closed in Favour of WBRT for Brain Metastasis? • I believe the answer is YES. • The issue is neither closed nor simple. • Each patient should receive appropriate unbiased information of the pros and cons of each approach.
  39. 39. “No protocol fits every patient and no protocol perfectly fits any patient.” -James Brent Thank You (Bohmer et al. 2002)