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

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

• lt21 21-44 45-64 gt65 Total
• Astrocytoma 72 50 13 3 31
• Glioblastoma 21 13 2 lt1 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 lt .0001)
• Histology 1.3976 (p lt .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 gt 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 ATGadequately 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 bid 85 50 mo 28
• 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

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Report of BTSG 72-01Malignant 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 72-01Malignant 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 StudyAstrocytoma Grades III IV

• Survival
• Arm 45 Klt60 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
• lt 40 40-60 gt60
• 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 lt .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
• lt .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 lt .026
• Resection

BHR BCNU, hydroxyurea, and radiation BRBCNU
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 gt 40 Age lt 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 n64 n40
n36 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 PATIENTS ARMS Entered 118 Brachy
Boost Brachy 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 43o T90

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
51
Malignant Gliomas
Conclusions Hyperthermia

• 1) Phase II trials suggest a benefit in survival
  with T-90 gt 41.5.
• 2) Randomized trial proves a survival benefit
  with interstitial Hyperthermia and Brachytherapy.

52
Malignant Gliomas

• Radiosurgery

53
UCSF Gamma KnifeBoost Therapy for
Glioblastoma1991-1995

• 10 females
• 20 males Median age 56.6 Median KPS 90
• 17 Pts. Alive Median Followup 42 weeks from
  diagnosis
• 30 weeks from ??Knife Rx
• Median Survival Time 78 weeks from diagnosis

54
Abstract

• We performed multivariate analysis on 189 glioma
  patients treated with the Gamma Knife at 8
  different institutions and found that
  significantly improved survival from the date of
  radiosurgery was associated with 5 variables
  lower pathologic grade, younger age, increased
  Karnofsky performance status, smaller tumor
  volume, and unifocal tumor.
• We We conclude that groups of patients with
  glioma treated with radiosurgery or brachytherapy
  have similar survival, provided their group
  hazard ratios, which are based on 5 significant
  variables, are similar. This conclusion might be
  tested in formal trials which account for the 5
  significant variables.
• Larson et al.

55
Materials and MethodsVariables Analyzed (N18)

• Clinical age, KPS, gender, complications,
  chronic steroid dependency, extent of surgery,
  radiotherapy, brachy candidate
• Tumor path grade, site, number of lesions
  treated, primary/recurrent
• Technical tumor volume, number of isocenters,
  minimum dose, maximum dose, isodose,
  inhomogeneity
• Other Gamma Knife facility

56
Results - Survival
Pathologic Grade (N189)
Age (N189)
KPS (N182)
I
1.00 0.75 0.50 0.25 0.00
II
45 years
gt80
III
gt45 years
IV
80
Plt0.001
Plt0.001
Plt0.001
Tumor Volume (N187)
Number of Tumors (N189)
Hazard Ratio (N180)
1.00 0.75 0.50 0.25 0.00
3
10 cc
Unifocal
3ltHR12
Multifocal
gt10 cc
gt12
Plt0.001
Plt0.001
P0.010
0
1
2
3
5
6
0
1
2
3
5
6
4
4
0
1
2
3
4
5
6
Years after radiosurgery
57
Results - SurvivalOther Data

• Author Tumor Path Treatment Hazard Survival st
  atus ratio 1-yr 2-yr
• Sneed primary II brachy 2.6 88 81
• Sneed recurrent II brachy 3.4 64 46
• Sneed primary III brachy 5.5 78 59
• Sneed recurrent III brachy 6.0 54 29
• Shrieve recurrent II-IV radiosurgery 9.8 45 19
• Loeffler primary IV radiosurgery 12.8 74 24
• Sneed primary IV brachy 13.5 73 30
• Sneed recurrent IV brachy 14.7 48 24
• Hall recurrent III-IV radiosurgery 16.7 30 -
• survival from date of radiosurgery

58
Conclusions

• Survival after radiosurgery depends on 5
  selection factors KPS, age, pathology, volume,
  number of tumors.
• A hazard ratio model demonstrates that variations
  in reported survival following radiosurgery may
  be attributed mainly to differences in median
  values of these 5 factors.
• The HR model can be used to separate patients
  into better, intermediate, or poor prognosis
  groups.
• Survival following brachytherapy is similar to
  survival following radiosurgery, provided the 5
  variables are accounted for. However, formal
  trials are required to confirm this conclusion.

59
Malignant Gliomas
Conclusions Radiosurgery

• 1) For small tumors, Gamma Knife radiosurgery
  appears equal to Brachytherapy for recurrent
  Gliomas.
• 2) In a limited number of patients, Gamma Knife
  radiosurgery seems equal to Brachytherapy for
  initial Boost.

60
Malignant Gliomas

• Heavy Particles

61
Malignant Gliomas
Neutron Radiotherapy

• 45-50 Gy Whole Brain Photon Neutron Boost
• Median Survival
• RTOG Study 1 AA GBM
• Photon boost 26.3 mo 8.5 mo
• Neutron boost 15.8 mo 9.6 mo
• RTOG Study 2
• Dose Searching 22.0 mo 9.9 mo
• 3.6-6.0 Gy Boost
• 9/12 autopsies showed no tumor or dead tumor

Laramore et al, 1988
62
Malignant Gliomas

• Phase I-II Trial of Heavy Particles

Pts Median Survival Anaplastic Astrocytoma
11 7.6 mo Glioblastoma Multiforme 17 13.9
mo Mixed Photon and Helium or Neon
Castro et al, 1985
63
Malignant Gliomas
Neon Ion Treatment of Glioblastoma

• 15 Patients Randomized to 20 or 25 Gy/16 fx
• Time to Failure 7 - 9 mo
• Survival 9 - 11 mo
• 3 patients died w/o tumor 1 neg. autopsy 19 mo
• 1 survived 22 mo., probable necrosis

Castro et al, 1995 (abs)
64
Malignant Gliomas
Conclusions Heavy Particles

• 1) Both Neutrons and Neon Ions can sterilize GBM.
• 2) Survival is similar to that with conventional
  radiotherapy for GBM but worse for AA.
• 3) There appears to be no therapeutic ratio -
  doses which sterilize tumor cause lethal brain
  damage.

65
Malignant Gliomas

• Boron Neutron
• Capture Therapy

66
BROOKHAVEN BNCT TRIAL
Malignant Gliomas

• PHASE 1 TRIAL PART 1
• 15 PATIENTS treated
• BPA Fructose (3-4x Tumor/Blood)
• Brain Conc. Blood
• 250 mg/m2 slow infusion
• Min tumor dose with boron 10.5 Gy
• Maximum dose anywhere 10.5 Gy (brain conc)
• Median Survival 10.5 mo.
• No complications

67
BNL BNCT TRIAL
Malignant Gliomas

• PART 2 of PHASE I TRIAL
• 350 mg/m2 fructose BPA, short infusion
• Larger Collimator
• Opposed Beams
• Min Tumor Dose gt 20 Gy
• Normal Brain allowed areas of 12.6 Gy
• Started in April 96.

68
BNCT IN GLIOBLASTOMA

• 1. 3 Phase I Clinical Trials Underway with
  Epithermal Beams Brookhaven, MIT and Petten.
• 2. First two use BPA, Petten BSH.
• 3. BNL 45 pts, MIT 15 pts, Petten 10 pts treated.
• 4. MST 12 to 12.9 months, compared to expected
  (RPA-RTOG) of 8.9-11.1 months.
• 5. Minimum tumor doses too low. Need better drugs
  and/or better beams.

69
Malignant Gliomas
Conclusions Boron Neutron Capture Therapy

• 1) BNCT has promise but is not proven by any
  randomized trial.
• 2) Better drugs and epithermal beams are
  available now.
• 3) Clinical trials at BNL, MIT and Petten show
  encouraging results.
• 4) Better Beams with higher depth dose are needed
  as are drugs with higher tumor to blood ratios.

70
Malignant Gliomas

• Conclusions

71
Malignant Gliomas
Conclusions

• 1) Only Modest Progress has been made in the
  treatment of Malignant Gliomas.
• 2) Earlier Diagnosis, Improved Histopathology,and
  Improved Surgical resection have helped.
• 3) Future improvement depends on genetic and
  molecular discoveries.
• 4) Specific Guidelines can be given for treatment
  today

72
Malignant Gliomas
Specific Guidelines
Anaplastic Astrocytoma Radiotherapy - 5940
cGy/33 fx, Limited volume Followed by PCV
chemotherapy or Enter Patient in Trial

spare opposite hemisphere, 3D planning
73
Malignant Gliomas
Specific Guidelines
Glioblastoma Multiforme Small Tumors (lt 3.5 cm
Post-Op) Radiotherapy - 5940 cGy/33 fx with HU to
Limited Volume Boost with Gamma Knife
15-22Gy Follow with BCNU or Enter patient in a
Trial
74
Malignant Gliomas
Specific Guidelines
Glioblastoma Multiforme Larger
Tumors Radiotherapy - 5940 cGy/33 fx with HU,
Limited Volume Follow with BCNU or PCV or Enter
in Available Clinical Trial

75
FUTURE DIRECTIONS

• MAJOR NEW INITIATIVES INCLUDE
• 1. UNDERSTANDING THE GENETIC ABNORMALITIES
  CONTROL OF G1/S, CONTROL OF APOPTOSIS
• 2. UNDERSTANDING DETERMINANTS OF SENSITIVITY TO
  CHEMO AND RADIATION THERAPY DELETION OF 1P ETC.
• 3. DEVELOPMENT OF TUMOR SPECIFIC ANTIGENS.
• 4. NEW DRUG DELIVERY SYSTEMS.
• 5. VIRAL GENE THERAPY TO MODIFY GENETIC
  ABNORMALITIES.