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Extent of resection in the treatment of gliomas

Extent of resection in the treatment of gliomas. Fred G. Barker II, M.D. Neurosurgical Grand Rounds Massachusetts General Hospital February 28, 2008. EOR questions. GTR vs biopsy? Debulking vs biopsy? GTR vs. near-GTR? GTR vs. GTR plus margin of “normal” tissue (lobectomy)?.

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Extent of resection in the treatment of gliomas

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  1. Extent of resection in the treatment of gliomas Fred G. Barker II, M.D. Neurosurgical Grand Rounds Massachusetts General Hospital February 28, 2008

  2. EOR questions • GTR vs biopsy? • Debulking vs biopsy? • GTR vs. near-GTR? • GTR vs. GTR plus margin of “normal” tissue (lobectomy)?

  3. Resection of malignant glioma • Cochrane Review, Metcalfe & Grant, 2001 • “The electronic database search yielded 2100 citations. Of these, 2 articles were identified for possible inclusion, however both were excluded. The hand search and personal communication were similarly unproductive. No studies were included in the review and no data were synthesized.”

  4. Goals of surgery for malignant gliomas • 1. Providing diagnosis • 2. Relieving symptomatic mass effect • 3. “Setting up” postoperative externally delivered therapies • 4. Prolonging survival through cytoreduction • 5. Applying locally-delivered therapies

  5. 1. Providing a diagnosis Main differentials: stroke – DWI, vascular distribution; “infection” (i.e. encephalitis) – susceptibility, location; demyelinating disease – incomplete ring sign T1 with gad FLAIR T1 with gad post 6 wk

  6. Providing a diagnosis • Nonenhancing tumors are not always low-grade Chance of anaplasia increases in older patients (50% by mid-40’s) Barker et al. (UCSF), Cancer 1997

  7. Providing a diagnosis • Gliomas are notoriously heterogeneous • More extensive resections more frequently provide higher grade diagnosis • Glantz et al., Neurology, 1991 • higher grade diagnosis more likely as extent of resection increased

  8. Providing a diagnosis • Stereotactic bx: grade 2; resection grade 3

  9. Providing a diagnosis • Perry et al., Cancer 1999 • identification of oligo component in grade 3 tumors was more likely as extent of resection increased (p = 0.01) • % containing oligo components: • Bx 3% • STR 29% • GTR 43%

  10. Providing a diagnosis • Aghi et al., unpublished MGH data (grade 2) • % containing oligo components: • Bx 46% (more specimens -> more oligo) • GTR 89% p < 0.001 • Carter et al., unpublished SEER data (grade 2) • % containing oligo components: • Bx 32% • Resection 62% p < 0.001

  11. Probability of oligo-containing histology has increased significantly with time 100% p < 0.001 80% 60% Probability Astro 40% Oligo 20% Oligoastro 0% 1985 1990 1995 2000 Year of diagnosis SEER data; Carter BS et al unpublished

  12. Probability of oligo-containing histologyvs. literature on chemo for oligos 40% 20 SEER % oligos 30% Number of articles on chemo for oligos Probability of oligo diagnosis 20% 10 PubMed # articles on chemo for oligos 10% 0 0% 1985 1990 1995 2000 Year of diagnosis SEER, PubMed data; Carter BS et al unpublished

  13. Providing a diagnosis • Jackson et al., Neuro-Oncol 2001 • 81 pts referred to MD Anderson after stereo bx elsewhere who were accepted for resection • >95% resection in 57% of patients • 38% had different pathology even after central review of outside slides; 26% would affect treatment • Mortality/major morbidity in 17%

  14. Providing a diagnosis • MR spectroscopy can assist in choosing a biopsy target

  15. 2. Relieve mass effect • Obvious and frequent success in most neurosurgeons’ experience in relieving neurological symptoms from mass effect • Possible effect in increasing KPS in malignant glioma • Low grade glioma: relieving medically intractable seizures

  16. Relieve mass effect • Ciric et al., Neurosurgery 1987 • neurologic condition at discharge • EOR Improve Same Worse • Partial 0% 60% 40% • Near GT 30% 70% 0% • GT 41% 55% 4%

  17. Relieve mass effect • Sawaya et al., Neurosurgery 1998 • 30% of all patients had improved KPS after resection • 8% had decreased KPS • % “major neurologic complications”: • Partial 12% • Subtotal 15% • Total 7%

  18. Relieve mass effect • Fadul et al., Neurology 1988 • Neurologic deterioration • (1 week postop) • Bx 29% • Partial 39% • Subtotal 30% • Total 20% • most hemorrhages and herniations occurred after bx or partial resection

  19. 3. “Setting up” postoperative therapies • Is response to postoperative adjuvant radiation in newly-diagnosed glioblastoma improved by prior resection? Neurosurgery 49:1288, 2001

  20. Response to radiation after surgery • 301 GM pts treated using two prospective UCSF clinical protocols • age, KPS, extent of resection, radiation response recorded prospectively • radiation response assessed by imaging criteria (postop image compared with post-XRT image)

  21. Results • More extensive surgical resection predicted better imaging-assessed response to postoperative adjuvant radiation in both univariate and multivariate analyses (adjusted for age, KPS)

  22. “Setting up” postoperative therapies • Resection and TMZ – EORTC 26981 (Stupp) • 2-year survival median survival • +TMZ -TMZ +TMZ -TMZ • GTR 37% 14% 18m 14m • STR 23% 9% 14m 12m • Bx 10% 5% 9m 8m van den Bent et al., Eur J Cancer 2005 [abstr]

  23. Subset Analysis – Overall Survival

  24. “Setting up” postoperative therapies • Keles et al. J Neurosurg 2004 • 119 pts with recurrent GM • Reoperation -> TMZ • Volume of disease at start of chemotherapy was a significant predictor of time to progression and survival (progression risk doubled for 10-15cc residual mass c/w GTR, quadrupled for >15 cc)

  25. 4. Prolong survival • Cushing believed that resection extended survival in malignant gliomas but recognized shorter and shorter intervals between operation as the disease progressed – “ideally all should be operative mortalities” • McKenzie first to replace bone flap after resection to limit prognosis, but generally benefit of resection was not questioned

  26. Review Article

  27. 4. Prolong survival Nazzaro and Neuwelt, 1990 Reviewed neurosurgical literature 1940 - 1990 (184 refs) “This analysis shows that there is little justification for dogmatic statements concerning the relationship between increasing patient survival times and aggressive surgical management …”

  28. Nazzaro and Neuwelt, 1990 • Failure to adjust for other prognostic factors such as age • Failure to adjust for difference in postop treatments* • Failure to use “any form of statistical analysis” • All studies had retrospective design • Failure to adjust for resectability • *logical fallacy – resection does influence chance of tolerating XRT as well as chance of reoperation

  29. Prolong survival • Considering the more than 30 years of experience and apparent failure, does it not seem that the ostensible myth of the benefit of cytoreduction for the “isolated sake of cytoreduction” needs to placed on the intellectual scrap heap? • -- Michael L.J. Apuzzo

  30. Prolong survival • Many multivariate analyses of survival after resection of GM (nonrandomized) now provide evidence that extent of resection is an independent prognostic factor for survival (independent of age and KPS)

  31. Prolong survival • Laws et al., JNS 2003 (GO project) • 788 patients (1997-2001) • Resection was favorable prognostic factor (compared to biopsy) after correction for age, KPS, and after omission of patients with multifocal disease

  32. Survival in GMstratified byextent of resection(nonrandomized) 1.0 0.8 p < 0.001 0.6 Proportion surviving GTR 0.4 STR 0.2 Bx 0.0 0.0 0.5 1.0 1.5 2.0 Years after diagnosis Barker et al. (UCSF), JNS 1996

  33. Survival in GM stratified by extent of resection(nonrandomized) Extent of MST 1-yr 2-yr 5-yr resection (months) Gross total 17 72% 31% 12% Subtotal 11 47% 15% 2% Biopsy 7 23% 2% 0% Barker et al. (UCSF), JNS 1996

  34. Survival after biopsy or resection of supratentorial lobar glioblastoma: a population-based study Manish K. Aghi, M.D., Ph.D., William T. Curry Jr., M.D., Bob S. Carter, M.D., Ph.D. and Fred G. Barker II, M.D. Neurosurgical Service Massachusetts General Hospital Harvard Medical School

  35. 11,134 glioblastoma patients diagnosed 1988 to 2001 11,108 intracranial tumors 7,423 supratentorial lobar tumors 6021tumors did not cross the midline or tentorial notch, had not spread outside brain, through CSF or to spine, had no contraindications to surgery, and had a surgical procedure specified (size known for 3520 tumors) Results

  36. Results • Factors predicting biopsy over resection: • Older age (odds ratio 1.38 per decade) • Smaller tumor size (odds ratio 0.84 per cm) • Tumor location (parietal – highest chance of biopsy, temporal lowest) • Histology (glioblastoma – highest chance of biopsy, giant cell glioblastoma lowest) • Unmarried status • SEER registry

  37. Probability of biopsy rather than resection:Relation to age and tumor size Prob (biopsy) Tumor size (mm) Age

  38. Results: survival 1.0 RESECTION BIOPSY 0.8 0.6 Survival 0.4 0.2 All pts had postop XRT 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Years after diagnosis Median survival – 12 months for resection 7 months for biopsy

  39. Results • Biopsy rates vary by SEER registry: 13% 12% 22% 13% 15% 4% 22% 15% 23% 27% 15%

  40. Probability of XRT vs. tumor sizefor biopsied & resected patients 90% 85% 80% Resection Probability of postop XRT 75% 70% Biopsy 65% 60% 0 20 40 60 80 Tumor size (mm)

  41. Survival Rates and Patterns Cancer 2006;106:1358

  42. Prolong survival - subgroups • Do all glioblastoma patients benefit equally from extensive resection? • Potentially important subgroups: • patients with mass effect • younger patients

  43. Mass effect and GM resection • Kreth et al., Cancer 1999 • Stereo bx+XRT c/w resection+XRT • 225 patients, supratentorial GM • Tumor resection effective only in group with midline shift (P < 0.01)

  44. Graph

  45. Age and GM resection 1.0 GTR Survival in GM stratified by extent of resection 0.8 0.6 Proportion surviving STR Age 16 to 39 N = 47 p = 0.01 0.4 Bx 0.2 0.0 0.0 0.5 1.0 1.5 2.0 Years after diagnosis

  46. Survival in GMstratified byextent of resection 1.0 0.8 Age 40 to 49 N = 58 p = 0.01 0.6 GTR Proportion surviving 0.4 STR 0.2 Bx 0.0 0.0 0.5 1.0 1.5 2.0 Years after diagnosis

  47. Survival in GMstratified byextent of resection 1.0 0.8 Age 50 to 64 N = 114 p = 0.12 0.6 Proportion surviving 0.4 GTR 0.2 STR Bx 0.0 0.0 0.5 1.0 1.5 2.0 Years after diagnosis

  48. Survival in GMstratified byextent of resection 1.0 0.8 Age 65 to 79 N = 80 p = 0.04 0.6 Proportion surviving 0.4 GTR STR 0.2 Bx 0.0 0.0 0.5 1.0 1.5 2.0 Years after diagnosis

  49. Survival after GM resection: subgroups Source: Aghi et al, unpub (SEER)

  50. Grade II astro / oligo / oligoastroSurgery Total N = 599

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