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Progress in the Treatment of Malignant Gliomas Juan del Regato, M.D. Lecture - 1996 Theodore L. Phillips, M.D.

Progress in the Treatment of Malignant Gliomas Juan del Regato, M.D. Lecture - 1996 Theodore L. Phillips, M.D. Focus. • Glioblastoma and Anaplastic Astrocytoma • Adjuvant Treatments After Surgery • UCSF Experience. Topics to Be Covered. Incidence Variables influencing outcome

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Progress in the Treatment of Malignant Gliomas Juan del Regato, M.D. Lecture - 1996 Theodore L. Phillips, M.D.

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  1. Progress in the Treatment of Malignant GliomasJuan del Regato, M.D.Lecture - 1996Theodore L. Phillips, M.D.

  2. Focus • • Glioblastoma and Anaplastic Astrocytoma • • Adjuvant Treatments After Surgery • • UCSF Experience

  3. Topics to Be Covered • Incidence • Variables influencing outcome • The usefulness of Radiotherapy • Chemoradiation • Radiation Sensitizers • Interstitial Brachytherapy • Hyperthermia • Radiosurgery • Heavy Particles • Boron Neutron Capture Therapy • Future Directions

  4. Malignant Gliomas • Incidence and Prognostic • Variables

  5. Malignant Glioma Incidence+ • Histology Incidence rate/100,000* Prevalence (US) • Anaplastic Astroctyoma 0.4 2,000 • Glioblastoma 2.5 10,000 • +CBTRUS 90-92 • * Age adjusted

  6. 5-Year SurvivalEffect of Age and Histology+ • <21 21-44 45-64 >65 Total • Astrocytoma 72% 50% 13% 3% 31% • Glioblastoma 21% 13% 2% <1% 3% • + SEER 81-91

  7. Age Specific Rates+ • 0-24 25-34 35-44 45-54 55-64 65-74 • Anaplastic • Astrocytoma 0.2 0.4 0.5 0.6 0.8 1.3 • Glioblastoma 0.1 0.5 1.0 3.9 7.9 11.4 • + CBTRUS 90-92

  8. Malignant GliomasRTOG 8302 Cox Proportional Hazards ModelPrognostic Factors+ • Covariate Coefficient • Age 0.5278 (p < .0001) • Histology 1.3976 (p < .0001) • KPS 0.3917 (p = .0014) • Interval Hours 0.3668 (p = .0011) • RX* 0.2068 (p = .1089) • Extent of Surgery 0.3703 (p = .0144) • *RX = 64.8 Gy + 72.0 Gy + 76.8 Gy vs. 81.6 Gy +Nelson et al, 1993

  9. Malignant Gliomas Conclusions: Prognostic Variables • The Major Prognostic Variables Are: • 1) Histology - Anaplastic Astrocytoma vs. Glioblastoma Multiforme • 2) Performance Status > 80 • 3) Age: Young is good. • 4) Extent of Surgery

  10. Malignant Gliomas • Is Radiotherapy Useful • in • MALIGNANT GLIOMAS?

  11. Surgery vs. Surgery + RadiotherapyGlioblastoma + • Alive • Procedure Cases 6 Mo 12 Mo • Biopsy Only 65 5% 0% • Partial Resection 93 14% 4% • Biopsy + Radiotherapy (RT) 31 50% 16% • Partial Resection + RT 148 68% 32% +Taveras et al, 1962

  12. + Glioma Study - BTSG 69-01Anaplastic Glioma (AA + GBM) • Entered: 303 Valid Study Group: 222 • Median Survival (weeks) • VSG ATG* P Value • Conventional Care 14 17 --- • BCNU 18.5 25 .12 • Radiotherapy 35 37.5 .001 • BCNU + Radiotherapy 34.5 40.5 .001 + Walker et al, 1978 * ATG=adequately treated group: 50 Gy, 2 courses chemo; min. survival 8 weeks

  13. Malignant GliomasDose Response Relationships+ • Normal Dose (cGy) • (Whole Brain) #Pts. Median Survival (wks) Wilcoxon Test • 0 194 18 * • ≤ 4500 61 13.5 .35 * • 5000 56 28 .001 .003 * • 5500 33 36 .001 .001 0.174 * • 6000 270 42 .001 .001 .004 0.11 +Walker, Strike and Sheline, 1979

  14. Malignant GliomasHigh Dose Radiation+ • Median Survival • Median Dose Grade III Grade IV • 5000 cGy 43 wks 30 wks • 6000 cGy 82 wks 42 wks • 7500 cGy 204 wks 56 wks +Salazar et al, 1979

  15. Malignant GliomasRTOG 8302 Hyperfractionation+ • Survival • Dose (Gy) AA AA GBM • Partial Brain 18 mo MST 18 mo • 60 (std) (7401) 70% 19% • 60 (std) (7918) 75% 24% • 64.8 bid 68% 19% • 72 bid85%50 mo28% • 76.8 bid 70% 30 mo 25% • 81.6 bid 59% 33 mo 20% +Nelson et al, 1993

  16. Malignant Gliomas Conclusions: Conventional Radiotherapy • 1) Radiotherapy gives longer survival than surgery alone or surgery plus chemotherapy. • 2) There is a dose response relationship up to between 50-70 Gy. • 3) Partial Brain is superior to Whole Brain. • 4) Hyperfractionation is not of proven value. Most Malignant gliomas probably repair SLD as well as normal brain.

  17. Malignant Gliomas • The Role of Chemoradiation

  18. Report of BTSG 72-01+Malignant Gliomas • Total Population • Arm Percent Survival • #Pts. MST 12 mo 24 mo • Semustine 111 31 26 17 • Radiotherapy 118 37 37 14 • Carmustine + RT 120 49 48 19 • Semustine + RT 118 43 41 19 *Walker et al, 1980

  19. Report of BTSG 72-01+Malignant Gliomas • Valid Study Group • Arm Percent Survival • #Pts. MST 12 mo 24 mo • Semustine 81 24 15 7.5 • Radiotherapy 94 36 35 9.7 • Carmustine + RT 92 51 50 15.2 • Semustine + RT 91 42 37 12.2 • RT vs. RT + Carmustine - Mantel-Haenzel = 0.072 *Walker et al, 1980

  20. RTOG - ECOG Study+Astrocytoma Grades III + IV • Survival • Arm 45% K<60 Med (mo) 18 mo% • #Rand #Eval • Radiotherapy (RT) (60Gy) 167 148 AA 15.4 0% • GBM 8.7 9% • RT + Boost 114 105 AA 32.3 62% • GBM 7.7 11% • RT + BCNU 185 165 AA 27.0 71% • GBM 8.0 20% • RT + Semustine + DTIC 160 136 AA 22.0 58% • GBM 9.0 18% +Chang et al, 1983

  21. Malignant GliomasRTOG - ECOG StudySurvival by Performance Status and Age+ • Age • < 40 40-60 >60 • Performance Median Survival (months) • 70-100 32 11.2 8.4 • 40-60 17 7.4 4.7 • 20-30 --- 3.1 4.2 +Chang et al, 1983

  22. Malignant GliomasRTOG - ECOG StudyRe-Evaluation* • Arm Median Survival (months) P • Age 40-60 All Patients • 60 Gy 8.7 9.3 mo • 70 Gy 8.2 8.2 mo • 60 Gy + BCNU 12.0 p < .01 9.7 mo N.S. • 60 Gy MeCCNU/DTIC 10.1 10.1 mo +Nelson et al, 1988

  23. Gliomas - ChemotherapyPhase III Comparison of BCNU to PCV after RT with Hydroxyurea* Median Time to Progression # Pts BCNU # Pts PCV P value Anaplastic Astrocytoma K 70-100 41 68 wks 39 122 wks 0.2 K 40-60 4 65 wks 5 11 wks -- Glioblastoma Multiforme K 70-100 36 31 wks 37 29 wks 0.1 K 40-60 14 19.4 wks 12 8.4 wks 0.004 *Levin et al. 1985

  24. Malignant GliomasPhase II Evaluation of BFHM+ • Schema: Carmustine, 5FU, Hydroxyurea, and 6-MP • Time to Progression • Anaplastic Astrocytoma 46 weeks • Glioblastoma Multiforme 23 weeks +Levin et al, 1986

  25. Malignant GliomasMedian Time to Tumor Progression (in weeks)+ Glioblastoma Multiforme Other malignant gliomas (non-glioblastoma) • Stratification BHR BR Significance BHR BR Significance • (wks) (wks) (wks) (wks) • All Patients 42 31 .04* 50 73 NS • < .05** • Karnofsky rating 60/100 41 31 .04* 50 72 NS • .026** • Karnofsky rating 60/100 49 31 .03* 56 73 NS • Plus subtotal or total < .026** • Resection +BHR = BCNU, hydroxyurea, and radiation; BR=BCNU and radiation. *Gehan modification of the Wilcoxon-rank sum analysis. **Cox analysis based on actual hydroxyurea dose. Levin et al, 1979 VSG 99 Pts.

  26. Malignant Gliomas Time to Tumor Progression (TTP) and Survival for Patients with Anaplastic Gliomas other than GBM+ • Percentile (weeks) • Treatment 50 25 p TTP RT + HU + BCNU 62.7 142.3 .025 RT + HU + PCV 125.6 317.3 Survival RT + HU + BCNU 82.1 214.0 .021 RT + HU + PCV 157.1 n.a. } } +Levin et al, 1990

  27. Malignant Gliomas Time to Tumor Progression and Survival for Patients with Glioblastoma Multiforme+ • Percentile (weeks) • Treatment 50 25 p TTP RT + HU + BCNU 34.4 42.7 .106 RT + HU + PCV 37.4 72.0 Survival RT + HU + BCNU 57.4 71.0 .510 RT + HU + PCV 50.4 93.7 } } +Levin et al, 1990

  28. Malignant Gliomas Time to Tumor Progression (TTP) and Survival for Patients with Anaplastic Gliomas other than GBM+ • Percentile (weeks) • Treatment 50 25 p TTP RT + HU + BCNU 62.7 142.3 .025 RT + HU + PCV 125.6 317.3 Survival RT + HU + BCNU 82.1 214.0 .021 RT + HU + PCV 157.1 n.a. } } +Levin et al, 1990

  29. Malignant Gliomas Time to Tumor Progression and Survival for Patients with Glioblastoma Multiforme+ • Percentile (weeks) • Treatment 50 25 p TTP RT + HU + BCNU 34.4 42.7 .106 RT + HU + PCV 37.4 72.0 Survival RT + HU + BCNU 57.4 71.0 .510 RT + HU + PCV 50.4 93.7 } } +Levin et al, 1990

  30. Malignant Gliomas Conclusions: Chemoradiation • 1) Various chemotherapies have yielded modest improvements in time to progression and survival. • 2) Most early studies are not properly adjusted for prognostic variables. • 3) It is impossible to properly compare studies and choose the optimum regimen.

  31. Malignant Gliomas My Views: Chemoradiation • 1) Hydroxyurea is beneficial during radiotherapy for Glioblastoma. • 2) BCNU or PCV after radiotherapy are useful in Glioblastoma. • 3) The gain in survival over radiotherapy alone is 2-3 months. • 4) Randomized trials with proper selection and stratification are needed.

  32. Malignant Gliomas • Radiation • Sensitizers

  33. Malignant GliomasPhase III MisonidazoleMRC+ • 436 Patients • Eligible: Grades III + IV Astrocytoma • Doses: 45 Gy in 20 Fractions 600 mg/m2 x 20 days • Results: No significant difference +Bleehen et al, 1983

  34. Malignant GliomasPhase III MisonidazoleMRC+ • Miso + RT RT • Number of Patients 188 195 • Number Dead 168 179 • Median Survival Time - wks 33 36 • 6 mo survival % 59% 63% • 12 mo survival % 25% 28% +Bleehen et al, 1983

  35. Malignant GliomasPhase III MisonidazoleRTOG+ • AAF or GBM • Schema - # Pts. • RT + BCNU 60 Gy Whole Brain • 80 mg/m2/d x 3d q 6-8 wks 146 • RT + BCNU + Miso 2.5 g/m2 q wk x 6 wk 147 • K > 40 Age < 71 +Nelson et al, 1986

  36. Malignant GliomasPhase III MisonidazoleRTOG+ • Results Median (Survival - Months • XRT + BCNU AAF 30.3 • GBM 10.7 • XRT + BCNU + MISO AAF 13.2 • GBM 10.3 + Nelson et al, 1986

  37. Results of Protocol 6G91Glioblastoma • Phase II Trial of Chemotherapy and Radiosensitizer • Post Op - Pre Radiation: 5FU, Lomustine • During Radiotherapy: Hydroxyurea + Misonidazole • After Radiotherapy: Procarbazine and Vincristine • alternating with • Carmustine and 5FU

  38. Results of Protocol 6G91 • Patients Entered: 90 • Evaluable: 64 • Age: Median = 56 • Sex: Male = 75, Female = 25 • Karnofsky: 70-100% • Surgery: 95% Total or Subtotal Resection

  39. Results of Protocol 6G91 • Complete plus partial response 23% • Stable 73% • Progressive 3% • Median Time to Progression 41 weeks

  40. Protocol 6G61 vs. 6G91 6G61 6G91 BCNU PCV Response n=64 n=40 n=36 Complete + Partial 23% 20% 36% Stable 73% 72% 58% Progression 3% 8% 6% Median Time to Progression 41 wks 32 wks 37 wks

  41. Malignant Gliomas Comparison of Results in Anaplastic Astrocytoma+ • Median TTP Median Survival • WCSG • BCNU 73 wks • BCNU/HU 56 wks • 6G61 • BCNU 63 wks 82 wks • PCV 126 wks 157 wks • NCOG BUdR* 190 wks 208 wks • Randomized Trial Null + K ≥ 70 * Limited fields

  42. Malignant Gliomas Comparison of Results in Glioblastoma Chemotherapy and Halogentated Pyrimidines Median TTP Median Survival WCSG BCNU 31 wks BCNU/HU 49 wks 6G61 BCNU 34 wks 57 wks PCV 37 wks 50 wks 6G91 37.6 wks 50 wks NCOG BUdR* 34.5 wks 55.7 wks

  43. Malignant Gliomas Conclusions: Radiation Sensitizers • 1) Nitroimidazoles have proven of no value with fractionated Radiotherapy. • 2) Halogenated Pyrimidines had promise - but the RTOG Phase III trial for Anaplastic Astrocytoma showed no benefit. • 3) Etanidazole has Potential with Radiosurgery

  44. Malignant Gliomas • Brachytherapy

  45. Glioblastoma Multiforme Survival From Implant Boost

  46. Malignant Gliomas Conclusions: Brachytherapy • 1) Brachytherapy is of benefit for recurrent Anaplastic Astrocytoma and Glioblastoma Multiforme patients. • 2) Boost Brachytherapy is of benefit for Initial Treatment of GBM and leads to cure in some patients, particularly those under age 40.

  47. Malignant Gliomas • Hyperthermia

  48. Results of Hyperthermia for GlioblastomaA Randomized TrialUCSF P.K. Sneed et al. TOTAL PATIENTSARMS Entered 118 Brachy BoostBrachy & Heat Eligible 111 Randomized 80 40 40 Treated as Randomized 33 31 (35)+ +Number having Brachytherapy

  49. Randomized TrialHyperthermia for Glioblastoma Thermal Dose Parameters • Median Steady State T90 42.1o C • Thermal Dose Median 12 CEM 43oT90

  50. Randomized TrialInterstitial Hyperthermia for Glioblastoma Median Survival Group Brachy Alone Brachy & Heat P values # Pts Median Surv. #Pts. Median Surv. As Randomized 40 76 weeks 40 89 weeks 0.055 As Treated (Brachy) 33 76 weeks 35(31)* 91 weeks 0.014 * Number heated

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