close

Вход

Забыли?

вход по аккаунту

?

865

код для вставкиСкачать
1535
Final Report of a Phase 1/11 Trial of Hyperfractionated
and Accelerated Hyperfractionated Radiation Therapy
with Carmustine for Adults with Supratentorial
Malignant Gliomas
Radiation Therapy Oncology Group Study 83-02
Maria Werner-Wasik, M.D.'
Charles B. Scott, M.S?
Diana F. Nelson, M.D?
Laurie E. Gaspar, M.D."
Kevin J. Murray, M.D?
Jennifer A. Fischbach, M . D ~
James S. Nelson, M.D.'
Alan S. Weinstein, M . D . ~
Walter J. Curran, Jr., M.D?
' Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Radiation Therapy Onlcology Group, Philadelphia, Pennsylvania.
Department of Radiation Oncology, University
of Rochester, R'ochester, New York.
' Department
Of Radiation Oncology, Wayne
State University Detroit, Michigan.
Department of Radiation Oncology, Medical
College of Wisconsin, Milwaukee, Wisconsin.
Department of Radiation Oncology, LDS Hospital, Salt Lake City, Utah.
Department of Pathology, Louisiana State University, New Orleans, Lousiana.
Hematology/Oncology Associates, Moorestown, New Jersey.
Presented at the American Radium Society Annual
Meeting, Paris, France, A.pril 28-May 2, 1995.
Address for reprints: Maria Werner-Wasik,
M.D., Department of Radiation Oncology, Bodine Center for Caiicer Treatment, Thomas Jefferson University Hospital, 111 South 11th Street,
Philadelphia, PA 19107.
Received June 1, 1995; revision received August 28, 1995; accepted August 28, 1995.
(01996 American Canct?r Society
BACKGROUND. Efforts to improve local control and survival by increasing the dose
of once-daily radiation therapy beyond 70 Gray (Gy) for patients with malignant
gliomas have as yet been unsuccessful. Hyperfractionated radiation therapy (HF)
should allow for delivery of a higher total dose without increasing normal tissue
late effects, whereas accelerated hyperfractionated radiation therapy (AHF) may
minimize tumor repopulation by shortening overall treatment time. The Radiation
Therapy Oncology Group (RTOG) conducted a randomized Phase 1/11 study of
escalating doses of HF and AHF with carmustine (bis-chloroethyl nitrosourea
[BCNU]) for adults with supratentorial glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA). Primary study endpoints were overall survival and acute and
chronic treatment-related toxicity.
METHODS. From 1983 to 1989, 786 patients with supratentorial gliomas (81% with
GBM and 19% with AA) were stratified by histology, age, and performance status
and randomized to receive partial brain irradiation, utilizing either HF (1.2 Gy
twice daily to doses of 64.8, 72, 76.8, or 81.6 Gy) or AHF (1.6 Gy twice daily to
doses of 48 or 54.4 Gy). All patients received carmustine. The distribution of prognostic factors was similar in all arms.
RESULTS. There were 747 eligible and analyzable patients among 786 enrolled
patients (95%).Two patients had a Grade 5 and 65 patients had a Grade 4 chemotherapy toxicity. Two patients in the 81.6 Gy arm experienced late Grade 4 radiation
toxicity and there was 1 late radiation-associated death in the 54.4 Gy arm. The
rate of Grade 3 or worse radiation toxicity at 5 years, calculated by the delivered
dose level, was 3% in the lowest total dose arms (48 and 54.4 Gy), 4% in the
intermediate dose arms (64.8 and 72 Gy), and 5% in the highest dose arms (76.8
and 81.6 Gy) (P = 0.54). Survival rates at 2 and 5 years were: 21% and 11%,
respectively, for all patients; 62% and 41%, respectively, for AA patients; and 10%
and 4%, respectively, for GBM patients. There were no significant differences between the treatment arms with regard to median survival time (MST),when analyzed by the originally assigned dose. The MST for all patients varied between 10.8
months and 12.7 months ( P = 0.59); between 9.6 months and 11 months lor
patients with GBM (P = 0.43); and between 30.4 months and 85.8 months for
patients with AA (P = 0.78). Analysis of the survival rates for all patients by dose
received rather than by dose assigned revealed a 14% 5-year survival rate for the
lower HF doses (64.8 and 72 Gy), 11% for the higher doses (76.8 and 81.6 Gy), and
10% for the AHF doses (48 and 54.4 Gy)(P = 0.1). The subgroup of AA patients
had a better MST (49.9 months) in the lower received HF doses than in the higher
HF doses (34.6 months)(P = 0.35). In contrast, GBM patients who received
1536
CANCER April 15,1996 / Volume 77 / Number 8
the higher HF doses had survival superior to the patients in the AHF arms (MST
of 11.6 months and 10.2 months, respectively; P = 0.04).
CONCLUSIONS. The use of HF with BCNU and dose escalation up to 81.6 Gy is both
feasible and tolerable, although late toxicity increases slightly with increasing dose.
The best MST with the least toxicity were observed for AA in the lower received HF
doses (72 and 64.8 Gy). Accordingly, 72 Gy in two 1.2 Gy fractions was used as the
investigational arm of a completed Phase 111 trial (RTOG 90-06). In contrast, for GBM
patients, longer survival times were noted in the higher received HF doses (76.8 and
81.6 Gy), suggesting the role for further dose escalation. The low toxicity rate with
AHF arms suggest that further dose escalation is possible and is currently occurring
in RTOG 94-11. Cancer 1996; 721535-93. 0 1996 American Cancer Society.
KEYWORDS: glioma, glioblastoma multiforme, anaplastic astrocytoma, radiation
therapy, hyperfractionated radiation therapy, accelerated hyperfractionated radiation therapy, bis-chlorethyl nitrosourea.
M
alignant gliomas constitute 3 3 4 5 % of primary brain
tumors in adults’ and carry a very poor prognosis.
Two main histologies are glioblastoma multiforme (GBM)
and anaplastic astrocytoma (AA),with 5% and 18%, respectively, of patients surviving 5 years.’ Treatment modalities demonstrated to improve the survival of patients
with malignant gliomas over surgery alone include external beam radiation therapy (RT),’,j and bis-chloroethyl
(carmustine) (BCNU) or methylchloroethyl-cyclohexylnitrosourea (semustine) (MeCCNU) chemotherapy combined with external beam radiation therapy.’“ More recently, interstitial brain i m p l a n t ~either
,~
temporary-’ or
permanent,8 and stereotactic radiosurgery9-” or stereotactic radiation therapy” have been used successfully in
selected patients with malignant gliomas. However, despite major advances in treatment techniques, local tumor recurrence in the brain remains the overwhelming
pattern of failure and is cause of death because no uniformly effective salvage therapy exists for those recurrent
tumors. This suggests that the delivery of a higher dose of
radiation to the tumor may potentially result in improved
local control and therefore influence survival, because
the length of survival of patients with GBM has been reported to correlate with dose in most series.l3,I4Walker
et al.l5 described increasing median survival time (MST)
from 18 weeks without RT to 28 weeks with 50 Gray (Gy),
36 weeks with 55 Gy, and 42 weeks with 60 Gy, in their
secondary analysis of 3 successive Brain Tumor Study
Group protocols. No additional improvement was seen
in the Radiation Therapy Oncology Group 7401/Eastern
Cooperative Oncology Group (RTOG 7401/ECOG) study4
for patients receiving a total dose to the tumor of 70 Gy
versus those treated with 60 Gy. Treatment-related brain
necrosis is a radiation dose-limiting factor, as seen in
external beam radiation therapy combined with interstitial brain implants, in which a total dose to the tumor
of 110-120 Gy was associated with a 40% incidence of
reoperation necessary to alleviate mass effect, which in
turn was related in 71% of patients to the presence of
brain necrosis, with or without viable tumor cells.16The
incidence of brain necrosis with external beam RT has
been described by Marks et al.” as 0% with doses below
57 Gy to 17.9% for doses between 64.8 Gy and 75.6 Gy
(with 1.8-2 Gy fraction sizes).
As demonstrated in a classic study by Sheline et al.,IR
the incidence of brain necrosis increases with an increasing radiation fraction size. This was further supported by
Withers,I9 who observed that there is greater sparing of
late effects for slowly proliferating tissues (such as brain
tissue) with smaller fraction size. Therefore, delivery of a
larger number of smaller fractions, or hyperfractionation
(HF), may potentially allow a higher total dose delivered
to the brain tumor and improved local control with the
same probability of late effects.
Several studies of multiple daily fractionated radiation therapy in gliomas reported conflicting result^.^"^'^
A dose of 61.41 Gy in 3 0.89 Gp daily fractions resulted
in significantly improved survival (MST of 45 weeks) in
patients with gliomas, when compared with a dose of 58
Gy given in 2 Gy, once-daily fractions (MST of 29 weeks).”
Shin et al. reported a survival benefit to 40 Gy in 3 daily
fractions to the whole brain, followed by a once-daily
boost to a total of 50 Gy over 50 Gy given in a once-daily
2 Gy fraction.*’Another study (Brain Tumor Study Group
[BTSG] 77-02) randomized patients to 1 of 4 arms: whole
brain hyperfractionated radiation, 1.1 Gy twice daily to a
dose of 66 Gy with BCNU, versus once-daily whole brain
RT (2 Gy to 60 Gy), with either BCNU or BCNU and misonidazole, or streptozocin.” There was no significant difference between the 4 treatment arms (MST of 10.4
months for the hyperfractionated arm vs. 9.5 months for
the once-daily RT with BCNU). Finally, Payne et al. found
no improvement in survival with 36-40 Gy in 3 1 Gy
fractions over 50 Gy in 2 Gy once-daily fraction^.'^
Radiation Therapy for Malignant GliomasMlerner-Wasik et al.
Another fractionation scheme, in the form of accelerated hyperfractionated RT (AHF), (i.e., delivery of more
than 1 standard size [ 1.6-2 Gy] fractions daily), may minimize tumor cell repopulation by shortening the overall
treatment 1 ime, therefore increasing the probability of
tumor control for a given dose 1 e ~ e l . l ~
In 198.3, the Radiation Therapy Oncology Group
(RTOG)initiated a Phase 1/11RT dose escalation trial with
BCNU for patients with supratentorial malignant gliomas
(RTOG 83-02). The objective of the study was to determine the survival rate and the disease free survival rate
for patients with malignant gliomas treated with HF or
AHF to the progressively escalating doses, as well as to
determine normal tissue toxicity. The preliminary results
of the trial were reported p r e v i o u ~ l y . ~This
~ ~ ‘is~ the final
report of that study.
MATERIALS AND METHODS
Patient Characteristics
From 1983 to 1989, 786 patients with histologically confirmed unifcical supratentorial malignant gliomas, who
were 18-70 years of age, and had a Karnofsky Performance Status (KPS) of at least 60 and an estimated survival of at least 8 weeks, were enrolled on the study. The
patients were required to have normal hematologic parameters as well as normal renal and hepatic function. A
normal chest X-ray or a diffusion capacity of at least 75%
was required Written consent was obtained from the patient or the responsible family member. The informed
consent form was in keeping with guidelines established
by a local Human Investigations Committee upon recommendations of the RTOG Institutional Review Board, in
accordance with assurances filed with and approved by
the Department of Health and Human Services. Therapy
had to start within 4 weeks from surgery. Patients with
prior chemotherapy, head and neck RT, acquired immune deficiency syndrome (AIDS), or malignant neoplasms (except for skin cancers not on the head and neck
or in situ carcinoma of the uterine cervix) were not eligible for the study.
Eligible patients were stratified by histology (GBM vs.
AA), age (18-44 years vs. 45-55 years vs. 56-70 years),
and performance status (KPS > 80 vs. KPS < 80) and
randomized to 1 of the 6 treatment arms (4 HF arms
or 2 AHF arms)(Table 1). The randomization scheme as
described by Zelen et al. to achieve institutional balance
of treatment assignments was used with the three patient-related stratification variables.LG
Pretreatment evaluation included a complete history
and physical examination with a detailed neurologic examination and KPS assignment, as well as a complete
blood count, blood chemistries, and a chest X-ray. Preoperative and postoperative brain computed tomography
(CT) scans were mandatory.
I537
Radiation Therapy
Eligible patients were randomized to receive partial brain
irradiation, utilizing either HF (1.2 Gy twice daily to doses
of 64.8, 72, 76.8, or 81.6 Gy) or AHF (1.6 Gy twice daily
to doses of 48 or 54.4 Gy). Within the HF arms, the initial
randomization was to 3 arms, 64.8 Gy, 72 Gy, and 76.8
Gy. Because no Grade 3 or higher acute or late toxicity
was found, the 81.6 Gy arm was opened in October, 1985,
and the 64.8 Gy arm was closed at the same time. Subsequently, the 76.8 Gy arm was closed in February, 1986,
and a 1:2 randomization favoring the 81.6 Gy arm (vs. the
72.0 Gy arm) was initiated, and is referred to as a “final
randomization.” Within the AHF arms, initial plans calYed
for dose escalation to 60.8 Gy. However, because 1 death
was seen during the first year of accrual with the 54.4
Gy dose and was thought attributable to the treatmentrelated toxic effects, the study accrual was closed after
completing accrual to the initial 2 treatment arms. Megavoltage machines with energies of 1.25-10 mv were used
with source to axis distance of at least 80 cm. The target
volumes were based on the preoperative CT scan. The
initial target volume included the contrast-enhancing lesion and surrounding edema with a 2-cm margin and
was carried to a dose of 57.6 Gy on the HF arms and 35.2
Gy on the AHF arms. The cone-down volume included
the contrast-enhancing lesion only plus a 2.5-cm margin
and was treated to the assigned total dose. The maxiniuin
dose to the optic chiasm was recommended to be 60 Gy,
to the retina, 50 Gy, and to the brainstem, 60 Gy. The
dose was specified on the central ray at midseparation of
beams for the parallel opposed beams and at the intersection of the central ray of the beams for an arrangement
of two or more intersecting beams. RT was delivered with
two daily fractions, separated by 4 to 8 hours, 5 days per
week. A minimum dose of 4 mg of dexamethasone was
recommended during the RT course.
Chemotherapy
All patients received BCNU, 80 mg/m’ intravenously, on
Days 1, 2, and 3 of the first week of RT and subsequently
on 3 consecutive days every 8 weeks for a period of 1
year, to a maximum dose of 1440 mglm‘. For patients
older than 60 years, the BCNU dose during the first cycle
was decreased to 75% of a calculated full dose and increased again to the full dose during next cycles, if no
Grade 2 or higher hematologic toxicity was observed.
BCNU doses were modified according to the criteria presented in a report from a prior RTOG trial.28
Histopathology
A central pathology review process was used in the study
with all slides reviewed by one pathologist (J. S. N.) according to the RTOG/ECOG criteria. For a diagnosis of
GBM, a marked hypercellularity, foci of coagulation ne-
1538
CANCER April 15,1996 / Volume 77 / Number 8
TABLE 1
Distributlon of Patient Characteristicsby Treatment
% Male
Age
% < 40
% 40-59
% 60t
Mean
Range
KPS
% 80-100
% 60-70
% < 50
Neurologic
%Work
% Home
% Hospital
Previous surgery
% Biopsy only
% Partial resection
% Total resection
% Shunt & partial
Other
Tumor size (Institution)
X<5cm
% 5-10 cm
?’& >I0 cm
% Unknown
Tumor size (central review)
%<5cm
% 5-10 cm
Histology (Institutional review)
96 Astrocytoma
% Glioblastoma
W Other
% Unknown
Histology (Central review)
% Astrocytoma
% Gfiobfastorna
% Other
64.8 Gy
(N = 78)
72 Gy
(N = 158)
76.8 Gy
IN = 86)
81.6 Gy
(N = 120)
48
(N = 168)
54.4 Gy
(N = 137)
Total
(N = 747)
67
62
5a
64
62
65
63
14
46
40
53.2
26-70
20
46
34
51.2
21-70
23f
43
34
51.7
22.69
20
47
33
51.1
21-69
16
46
38
53.2
19-70
ia
39
43
53.1
19-70
19
44
37
52.3
19-70
64
30
6
69
27
4
70
27
3
73
27
0
70
30
0
70
30
0
70
2a
2
50
40
10
51
42
7
41
51
a
56
40
4
55
42
4
51
44
5
51
43
6
15
6
ia
1
0
23
56
21
0
0
17
69
14
25
54
20
0
0
1
0
31
51
17
0
1
27
72
22
0
0
24
56
19
<l
<I
33
53
3
11
37
49
3
11
30
52
3
14
41
50
4
5
46
45
2
7
4a
4a
2
2
41
49
2
8
34
66
(N = 56)
42
5a
(N = 132)
32
68
48
52
47
53
41
59
(N = 69)
37
63
(N = 100)
(N = 144)
(N = 109)
(N = 610)
26
72
2
0
32
68
0
0
28
69
3
0
32
68
0
0
27
72
<1
<1
29
70
1
0
29
70
12
21
79
0
(N = 1481
19
a1
0
(N = 84)
18
81
1
(N = 112)
22
78
0
20
a0
0
(N = 127)
19
a1
<I
(N = 690)
aa
0
(N = 75)
crosis, and vascular mural cell proliferation had to be
present. Mixed glioblastoma and fibrosarcoma (gliosarcoma) were included in the GBM group. For a diagnosis
of AA, one or more of the following features had to be
present: (1) increased cellularity; (2) pleomorphic nuclei
or cell bodies; (3) mitotic figures; (4) increase in blood
vessels with mild endothelial proliferation; and ( 5 ) spongioblastic or other incompletely differentiated glial cell^.'^
Patient Follow-Up
Patients were observed weekly during RT and monthly
thereafter. CT scans of the brain were obtained 4 months
(N = 144)
1
<1
after initiation of therapy, then every 3 months, and at
the time of neurologic deterioration. Disease free survival
and overall survival were measured from the day of randomization until documented deterioration by neurologic exams and CT scans, or until death.
Treatment-related effects on normal tissue were evaluated using RTOGlECOG toxicity criteria (Table 2) and
defined as acute if occurring within 90 days of the start
of treatment, or late if occurring or persisting beyond 90
days. Major effects included Grades 3 and higher, with
Grade 5 scored as fatal effects. All suspected major toxic
effects were reviewed by one of the study chairpersons
Radiation Therapy for Malignant GliomasMTerner-Wasik et al.
TABLE 2
Toxicity and Late Effects Criteria
Organ/tissue
Grade 3
Grade 4
Moist desquamation
Marked atrophy
Ulceration, necrosis
Ulceration
Alteration affecting function
<50oio of time of function
Function 2 50% affected
Function 2 50% affected
Not controlled by medication
Comatose
Skin
Acute
Chronic
Neurologic
Mental status
Motor paresis
Cerebellar function
Seizures
Paralysis
Confined to bed
Status epilepticus
Note: Anv toxic effect causing death was eraded as 5
(D. E. N. or W. J. C.) and only ascribed to the treatment
received, if there was no evidence of recurrent or progressive tumor on the CT scan or pathologic review.
Statistical Methods
Differences in pretreatment characteristics between the
randomized treatment arms were evaluated with the
Pearson chi-square test for differences in proportions.
The estimated probability for a late toxicity was calculated using a cumulative incidence that adjusts for patients dying without toxi~ity.~’
Differences in late toxicities were compared using the test statistic proposed by
Gray.3’All time events, including survival, were calculated
from the date of randomization. Survival was estimated
using the product-limit m e t h ~ d . Differences
~’
in survival
distributions were compared using the log rank statistiC.29,33
Patients receiving less than 44.8 Gy were not included
in the dose received analysis. All P values presented are
two-sided.
RESULTS
Patient Characteristics and Protocol Violations
Distribution of patient characteristics by treatment arm
is presented in Table 1. Distribution of prognostic factors
was similar in all arms.
The mean patient age was 52.3 years and 63% of the
patients were males. Median follow-up was 11.7 months
(range, 0.01- 126 months). Distribution of prognostic factors was similar in all arms. On the average, 70% of patients had KPS of 80% or greater, 19% of patients underwent total resection, 56% underwent partial resection,
and 51% had tumors of larger than 5 cm in diameter on
central review (W. J. C.) (Table 1). There was a discrepancy
between the institutional and central histology assignment, which has been documented e l ~ e w h e r e Seventy
.~~
percent of patients were diagnosed as having a GBM in
their institutions, but 81%had GBM on the central review.
1539
Twenty-nine percent had AA on institutional review versus 19% on central review. The total number of patients
entered on trial was 786. No On-Study form was available
for 11 patients (l%),and 28 patients (3.5%) canceled or
were ineligible. Overall, 747 of 786 patients (95%) were
eligible and analyzable.
Major unacceptable protocol violations were found
in 5.3% of patients with regard to radiotherapy delivery.
A radiation therapy major unacceptable deviation was
scored when the total dose deviated by 13% or greater
from the randomized dose at the central axis, when there
was interruption of the hyperfractionated schedule by 8
or more days, or when either the initial or the cone-down
field did not include the entire tumor volume. Radiation
therapy dose was delivered as per protocol guidelines in
650 of 745 of patients (87%).The proportions of patients
whose delivered dose was within 5 2.4 Gy from the assigned dose (or ? 3.2 Gy for AHF arms only) were as
follows: 90% for the 64.8 Gy arm; 90% for the 72 Gy arm,
82% for the 76.8 Gy arm; 79% for the 81.6 Gy arm, 94%
for 48 Gy arm, and 93% for the 54.4 Gy arm. Four percent
of all patients received a dose of less than 44.8 Gy and
less than 0.01% of patients were given more than 84 Gy.
Major unacceptable protocol violations were found
in 3% of patients with regard to chemotherapy delivery. A
chemotherapy major unacceptable deviation was scored
when failure to modify the BCNU dose resulted in termination of therapy, when protocol therapy was not given,
or when it was interrupted for more than one cycle unrelated to toxicity or disease progression.
Treatment-Related Toxicity
Two patients died because of chemotherapy-related fatal
cytopenia andlor infection (one in the 76.8 Gy arm and
one in the 54.4 Gy arm) and 68 patients experienced a
Grade 4 chemotherapy toxicity. The most common acute
chemotherapy toxicities were nausea and vomiting (89%
of patients), leukopenia (78%),thrombocytopenia (72%),
and gastrointestinal symptoms (39%).
The most common acute radiation toxicities were
skin reactions (74% of patients), followed by somnolence
(13%),ototoxicity (lo%), and mental status change (8%).
Overall, 14 patients (0.02%)experienced Grade 3 or worse
acute toxicity.
There were no early radiation-associated deaths and
there was 1 late death in the 54.4 Gy arm. Two patients
experienced late Grade 4 (1 hearing loss and 1 increased
intracranial pressure) radiation toxicity, both in the 81.6
Gy arm, and 14 patients experienced Grade 3 toxicity (4
in the 76.8 Gy arm). Overall, 27% patients suffered chronic
skin changes, 13% memory change, 14% somnolence,
12% mental status change, and 6% each hearing loss and
increased intracranial pressure.
At 5 years, 3% patients in either AHF arm had Grade
1540
CANCER April 15,1996 / Volume 77 / Number 8
TABLE 3
RTOG 83-02 Survival by Assigned Treatment
AHF
Low Dose HF
RTOG 83-02:SURVIVAL FOR AA PATIENTS
BY DOSE LEVEL RECEIVED
High Dose HF
Arm
CY
48
54.4
64.8
72
76.8
81.6
Pvalue
All patients
GBM
11.9
10.2
35.0
10.8
10.4
40.6
11.4
9.6
85.8
12.7
11
50
12.0
10.9
30.4
11.7
10.2
35.4
0.598
0.43
R
AA
E m
T
0.78
;
RTOC 83-02 Radiation Therapy Oncology Group Study 83-02. AHF: accelerated hyperfractionated
radiation therapy; HF: hyperfractionated radiation therapy; Gy: Gray: G B M glioblastoma multiforme;
AA: anaplastic astrocytoma.
40
I
V
E
20
~
0
1
RTOG 83-02: SURVIVAL FOR ALL PATIENTS
BY ASSIGNED TREATMENT
2
~~~~~~
6
4
3
YEARS FROM ONSTUDY
FIGURE 2. Radiation Therapy Oncology Group Study 83-02 survival for
patients with anaplastic astrocytoma by dose level received.
TABLE 4
RTOG 83-02 Survival by Dose Level Received
Dose level
Patient group
0
All patients
?
0
1
2
3
4
5
YEARS FROM ONSTUDY
FIGURE 1. Radiation Therapy Oncology Group Study 83-02 survival for
all patients by assigned treatment.
3 or worse toxicity versus 3% in the 64.8 Gy arm, 4% in
the 72 Gy arm, 6% in the 76.8 Gy and 5% in the 81.6 Gy
arm. The actuarial rate of Grade 3 or worse radiation
toxicity at 5 years, calculated by the delivered dose, was
3% in the lowest total dose arms (48 and 54.4 Gy), 4% in
the intermediate dose arms (64.8 and 72 Gy), and 5% in
the highest dose arms (76.8 and 81.6 Gy) ( P = 0.54). Two
percent of patients whose delivered dose was lowest (in
48 and 54.4 Gy arms) had this type of toxicity at 5 years,
versus 5% patients whose delivered dose was highest
(76.8 and 81.6 Gy) (P = 0.14).
Survival
Eighty-nine percent (663 of 747) patients died over the
study period. Overall survival rates at 2 and 5 years were
21% and 11%,respectively, for all patients; 62% and 41%,
respectively, for AA patients; and 10% and 4%, respectiveiy, for GBM patients. MST was 11.8 months for all
patients, 40.3 months for AA patients, and 10.6 months
for GBM patients. MST by the assigned treatment arm
AA
GBM
AHF
(48 and 54.4)
Low dose HF
(64 and 72)
High dose HF
(76 and 81)
P value
11.7
40.3
10.2
12.6
49.93
11.02
12.4
34.6
11.6
0.10
0.35
0.04
RTOG: 83-02: Radiation Therapy Oncology Group Study 83-02; AHF: accelerated hypetftactionated
radiation therapy: HF. hyperfractionated radiation therapy; AA: anaplastic astrocytoma; GBM: glioblastoma multiforme.
for all patients was as follows: on the HF arms, 11.4
months for 64.8 Gy, 12.7 months for 72 Gy, 12 months
for 76.8 Gy, and 11.7 months for 81.6 Gy (P= 0.598). For
the A H F arms, MST were 11.9 months for 48 Gy and 10.8
months for 54.4 Gy (Table 3 and Fig 1). MST for GBM
and AA patients by the assigned treatment arm are also
depicted in Table 3.
There were no significant differences between the
treatment arms with regard to MST (Table 3) or 5-year survival rates, when analyzed by the originally assigned dose.
Analysis of survival performed by dose actually received on
any single treatment arm did not reveal any advantage of
one particular treatment arm over another. When analysis
of sunrival was performed by the received dose levels (rather
than single arms), defined as “lower HF dose” (64.8 Gy and
72 Gy) versus “higher HF dose” (76.8 Gy and 81.6 Gy) versus
“AHF dose” (48 Gy and 54.4 Gy), the following observations
became manifest. For all patients, MST was 11.7 months in
the AHF dose level, 12.6 months in the low dose HF level,
Radiation Therapy for Malignant GliomasMlerner-Wasik et al.
1541
TABLE 5
RTOG 83-OZSURVIVM FOR GEM PATIENTS
W DOSE LEML RECEIVED
RTOG 83-02 Survival by Radiation Therapy Fractionation (HF vs AHP)
.I b 6 4 4 (11
64 IL 72 GY
Patient group
AHF
HF
P value
AA
GBM
40.3
42.30
10.2
10.80
0.67
0.08
7 6 6 L 1 1 1 GI
.
0
1
2
3
4
. .
5
E A R S FROM ONSNDY
FIGURE 3. Radiation Therapy Oncology Group Study 83-02 survival
for patients with supratentorial glioblastorna rnultiforrne by dose level
received.
and 12.4 months in the high dose HF level (P = 0.10). AA
patients had better MST (49.9 months) in the lower HF dose
level than in the higher HF dose level (34.6 months) and in
the AHF dose level (40.3 months) ( P = 0.35) (Table 3 and
Fig. 2 ) . In contrast, GBM patients who received the higher
HF doses had superior survival (11.6 months), when compared with the lower HF dose level (11.0 months) and AHF
dose level (10.2 months) ( P = 0.04) (Table 4 and
Fig. 3).
Patients' survival was further analyzed by the type of
assigned fractionation regimen used (AHF vs. HF). Only
3% of GBM patients treated on AHF arms were alive at 5
years versus 5% of patients on the HF arms, with MST of
10.2 months and 10.8 months, respectively ( P = 0.08).
Corresponding values for AA patients were 40% 5-year
survival on the AHF arms versus 41% on the HF arms,
with MST of 40.3 months and 42.3 months, respectively
( P = 0.67) (Table 5).
DISCUSSION
RTOG 83-02 was a Phase 1/11 study that was designed for
the purpose of identifying a potential RT dose, delivered
with either a tWF or HF regimen, that might be associated
with improved survival of patients with malignant gliomas. At the same time, toxicity of each treatment arm
was prospectively assessed.
A trend (of increasing Grade 3 or higher late treatment-related toxicity with the increasing total dose level
was identified, although the difference between the toxicities of the lowest dose level (48 and 54.4 Gy) and the
highest dose level (76.8 and 81.6 Gy) was statistically not
significant (f' = 0.54). Overall, the incidence of severe
toxic effects attributable to the delivered treatment was
low (3-5%), which justifies the conclusion that further
dose escalation may be feasible in both the AHF and HF
groups. No difference in adverse effects was seen between
the AHF and HF subgroups, but this might have been
due to the lower equivalent doses used in the AHF arms.
The originally planned dose escalation above 54.4 Gy in
the AHF subgroup did not occur because of 1 death observed during the study, believed to be attributable to
the treatment, and subsequently confirmed as such. The
incidence of Grade 6 white matter changes, as reported
by Corn et al.,35observed in patients on the AHF a r m
was lowest (1.6%) when compared with the intermediaie
HF dose range (64.8 Gy and 72 Gy) (4.6%) or the high
HF dose range (76.8 Gy and 81.6 Gy) (19.2%), further
supporting a feasibility of dose escalation for AHF. Higher
AHF doses (64 Gy and 70.4 Gy) are currently employed in
a Phase I1 dose escalation trial for radiosurgery-ineligible
GBM patients (RTOG 94-11).
There are several difficulties in making a precise evaluation of treatment-related brain injury and distinguishing it from recurrent or progressive tumor. Standard radiographic techniques, such as CT scans or magnetic resonance imaging (MRI) scans are unable to differentiate
those two entities with absolute certainty. Even two
promising modalities, 18F-FDG (fluorine-18-2-deoxy-2!fluoro-D-glucose) scans and thallium-201 single photon
emission computed tomography, although valuable in
distinguishing necrosis from tumor, '' will require more
time before their role is fully assessed. Consequently, the
scoring of treatment toxicity is imperfect. In addition,
because the survival of patients with gliomas is relatively
short, the full extent of late sequelae may not become
manifest before their death. The analysis of white matter
changes on follow-up MRI and CT scans available for 177
patients treated on the RTOG 83-02 study confirmed the
significant correlation of the incidence of severe white
matter changes with the total dose of HF RT, although no
correlation between Grade 2 or worse clinically observed
toxicity and those changes was found.'5 Due to these constraints, survival has been used as a measure of both
treatment efficacy and treatment toxicity.
There was no dramatic survival advantage observed
in this study for any of the treatment arms, whether analyzed by the assigned or delivered dose, because the study
was not specifically designed to achieve significant overall
1542
CANCER April 15,1996 / Volume 77 / Number 8
differences i n survival, but rather to choose t h e best of a
number of treatment options.
In fact, two different “best” arms were identified for
different histologies of malignant gliomas. Patients with
GBM, who received t h e highest doses (76.8 Gy and 81.6
Gy) survived significantly longer ( P = 0.041, when compared with patients receiving 48 Gy and 54.4 Gy. Although
the absolute gain of 1.4 m o n t h in MST may n o t be clinically meaningful, it clearly points t o t h e need for using
t h e highest possible doses for t h e treatment of GBM. In
addition, it suggests t h e role for further dose escalation,
because an acceptable Grade 3 or higher toxicity incidence (5%) was seen even with those highest doses and
no fatal toxicity was recorded.
In contrast t o patients with GBM, patients with AA
had best survival rates in t h e 64 Gy and 72 Gy arms ( P =
0.35) and n o t in t h e 76.8 Gy and 81.6 Gy arms, presumably
because of excessive treatment toxicity. This observation
was first reported in t h e initial analysis of t h e ~ t u d y , ‘ ~
b u t was applicable for b o t h histologies (AA and GBM).
Quality-adjusted survival analysis of all glioma patients
treated on RTOG 83-0237showed t h e longest quality-adjusted survival for patients treated on t h e 72 Gy and 64.8
Gy arms, with younger patients and patients with a high
KPS benefiting m o s t from t h e assignment t o t h e 72 Gy
arm. Accordingly, a recently completed Phase I11 RTOG
trial (90-06) used a dose of 72 Gy in 1.2 Gy twice-daily
fractions plus BCNU as an investigational arm, which was
compared with 60 Gy delivered in 2 Gy fractions plus
BCNU a n d will therefore enable a direct comparison of
HF and once-daily RT. Larramore e t al. reviewed survival
of patients with AA treated on four RTOG studies, two of
which included n e u t r o n irradiation and one, misonidazole as radiation sensitizer, in addition t o photon external
beam RT and BCNU.38The authors observed a decreasing
survival as t h e “aggressiveness” of t h e treatment increased. The weakness of t h e study lies in comparing
completely different treatment modalities. Because AA
appear t o respond differently t o therapy t h a n GBM, these
two entities may need to be studied i n separate trials in
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
t h e future.
Although interstitial brachytherapy for gliomas6”6 or
stereotactic radiosurgery“ seem promising, with impressive
survivals reported i n subsets of patients wirh gliomas, a
majority of patients with glioma do n o t qualify for brachytherapy or radiosurgery because of the size of their tumor~l”3Y
For those patients, efforts t o optimize external
beam radiation therapy m u s t continue, including identifymg the most effective and tolerable HF or AHF regimens.
15.
REFERENCES
16.
1.
Mahley SM, Mettlin C, Natarajan N, Laws ER, Peace BB.
National survey of patterns of care for brain tumor patients.
J Neurosurg 1989;71:826-36.
13.
14.
Walker MD, Green SB, Byar DP, Alexander E, Batzdorf U,
Brooks WH, et al. Randomized comparisons of radiotherapy
and nitrosoureas for the treatment of malignant glioma after
surgery. N Engl J Med 1980;303:1323-9.
Kristiansen K, Hagen S, Kollevold T, Torvik A, Holme I, Stat
M, et al. Combined modality therapy for operated astrocytomas grade 111and IV.Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on
survival time. A prospective multicenter trial of the Scandinavian glioblastoma study group. Cancer 1981;47:649-52.
Chang CH, Horton J, Schoenfeld D, Salazer 0,Perez-Tamayo
R, Kramer S, et al. Comparison of postoperative radiotherapy
and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. Cancer 1983;52:997- 1007.
Gutin PH, Prados MD, Phillips TL, Wara WM, Larson DA,
Leibel SA, et al. External irradiation followed by an interstitial high activity iodine-125 implant “boost” in the initial
treatment of malignant gliomas: NCOG study 6G-82-2. Int J
Radiat Oncol Biol Phys 1991;21:601-6.
Green SB, Shapiro WR, Burger PC, Selker RG, Van Gilder JC,
Saris S, et al. A randomized trial of interstitial radiotherapy
(RT) boost for newly diagnosed malignant glioma: brain tumor cooperative group (BTCG) Trial 8701. Proc. Am. SOC.
Clin. Oncol. 1994;13:174.
Gutin PH, Leibel SA,Wara WM, Choucair A, Levin VA, Philips
TL, et al. Recurrent malignant gliomas: survival following
interstitial brachytherapy with high-activity iodine-125
sources. J Neurosurg 1987:67:864-73.
Gaspar L, Zamorano L, Garcia L, Shamsa F, Warmelink C,
Yakar D. Malignant gliomas: permanent iodine-125 implants. Int J Radiut Oncol Biol Phys 1994;30 (1 Suppl):295
(1095).
Loeffler JS, Alexander E, Shea WM, Wen PY, Fine HA, Kooy
HM, et al. Radiosurgery as part of the initial management
of patients with malignant glioma. J Clin Oncol 1992;
10:1379-85.
Masciopinto JE, Levin AB, Mehta MP, Rhode BS. Stereotactic
radiosurgery for glioblastoma: a final report of 31 patients.
J Neurosurg 1995;82:530-5.
Mehta MP, Masciopinto J, Rosental J, Levin A, Chappell R,
Bastin K, et al. Stereotactic radiosurgery for glioblastoma
multiforme: report of a prospective study evaluating prognostic factors and analyzing long-term survival advantage.
Int J Radiat Oncol Biol Phys 1994;30(3):541-9.
Brada M, Laing RW, Graham J, Warrington AP, Hines F.
Fractionated stereotactic radiotherapy in the treatment of
recurrent high grade glioma: dose escalation study. Acta
Neurochir (Wien) 1993;122:151-5.
Rutten EHJM, Kazem I, Slooff JL, Walder AHD. Postoperative
radiation therapy in the management of brain astrocytomata-retrospective study of 142 patients. IntJRadiat Oncol
Biol Phys 1981;7:191-5.
Salazar OM, Rubin P, Feldstein ML, Pizzutiello R. High dose
radiation therapy in the treatment of malignant gliomas:
final report. Int J Radiat Oncol Biol Phys 1979;5:1733-40.
Walker MD, Strike TA, Sheline GE. An analysis of dose-effect
relationship in the radiotherapy of malignant gliomas. Int J
Radiat Oncol Biol Phys 1979;5:1725-31.
Scharfen CO, Sneed PK, Wara WM, Larson DA, Phillips TL,
Prados MD, et al. High activity iodine-125 interstitial implant for gliomas. Int J Radiut Oncol Biol Phys 1992;24:58391.
Radiation Therapy for Malignant GliomasiWerner-Wasik et al.
17. Marks JE, Baglan RJ, Prassad SC, Blank WF. Cerebral radionecrosis: incidence and risk in relation to dose, time, fractionation and volume. Int / Radiat Oncol Biol Phys
1981;7~243-52.
18. Sheline G, Wara WM, Smith V. Therapeutic irradiation and
brain surgery. Int/ Radiat Oncol Biol Phys 1980;6:1215-28.
19. Withers HR. Biologic basis for altered fractionation schemes.
Cancer 1985;552086-95.
20. Fulton DS, Urtasun RC, Shin KH, Geggie PHS, Thomas H,
Muller PJ, et al. Misonidazole combined with hyperfractionation in the management of malignant glioma. Int J Radiat
Oncol Biol Phys 1984;10:1709-12.
21. Shin KH, Muller PH, Geggie PHS. Superfractionation radiation therapy in the treatment of malignant astrocytoma.
Cancer 1983;52:2040-3.
22. Deutsch M, Green SB, Strike TA, Burger PC, Robertson JT,
Selker RG, et al. Results of a randomized trial comparing
BCNU plus radiotherapy, streptozocin plus radiotherapy,
BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative
treatment of malignant glioma. Int J Rudiut Oncol Biol Phys
1989;16:1389-96.
23. Payne D, Simpson WJ, Keen C, Platts ME. Malignant astrocytoma: hyperfractionated and standard radiotherapy with
chemotherapy in a randomized prospective clinical trial.
Cancer 1982;50:2301-6.
24. Curran WJ, Scott CB, Nelson JS, Weinstein AS, Phillips TL,
Murray K, et al. A randomized trial of accelerated hyperfractionated radiation therapy and BCNU for malignant glioma.
Cancer 1992;70:2909- 17.
25. Nelson DF, Curran WJ, Scott C, Nelson JS, Weinstein AS,
Ahmad K, et al. Hyperfractionated radiation therapy and
bis-chlorethyl nitrosourea in the treatment of malignant glioma-possible advantage observed at 72.0 Gy in 1.2 Gy BID
fractions: report of the RTOG protocol 8302. Int / Radiat
Oncol Biol Phys 1993;25:193-207.
26. Zelen M. The randomization and stratification of patients
of clinical rials. Int J Radiat Oncol Biol Phys 1979;5:172531.
27. Nelson DF, Schoenfeld D, Weinstein AS, Nelson JS, Wasserman
Goodman
et aL A randomized
Of
misonidazole sensitized radiotherapy plus BCNU and radiotherapy plus BCNU for treatment of malignant glioma after
surgery: preliminary results of an RTOG study. I n t J Radiat
Oncol BiolPhys 1983;9:1143-51.
Tp
RLp
1543
28. Nelson JS, Schoenfeld D, Tsukada Y, Fulling K, Lamarche J,
Peress N. Necrosis as a prognostic factor criterion in malignant, supratentorial astrocytic gliomas. Cancer 1983;525504.
29. Pet0 R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard
SV, et al. Design and analysis of randomized trials required
prolonged observation of each patient: 11. analysis and examples. B r / Cancer 1977;35:1-39.
30. Caplan RJ, Pajak TF, Cox JD. Analysis of the probability and
risk of cause-specific failure. Int J Radiat Oncol Biol Phys
1994;29:1183-6.
31. Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988;16:114154.
32. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J A m Star Assoc 1958;53:457-81.
33. Mantel N. Evaluation of survival data and two new rank
order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163-70.
34. Scott CB, Nelson JS, Farnan NC, Curran WJ, Murray KJ,
Fischbach AJ, et al. Central pathology review in clinical trials
for patients with malignant glioma: a report of RTOG 83-02.
Cancer 1995;76:307-13.
35. Corn BW, Yousem DM, Scott CB, Rotman M, Asbell S, Nelson
DF, et al. White matter changes are correlated significantly
with radiation dose. Cancer 1994;74:2828-35.
36. Kosuda S, Fuji H, Aoki S, Suzuki K, Tanaka Y, Nakamura
0, et al. Prediction of survival in patients with suspected
recurrent cerebral tumors by quantitative thallium-201 single photon emission computed tomography. Inr / Radiat
Oncol Bid Phys 1994;30:1201-6.
37. Murray KJ, Nelson DF, Issacson S, Scott C, Fischbach JA,
Porter A, et al. Quality adjusted survival analysis of malignant glioma patients treated with twice-daily radiation and
carmustine: a report of RTOG 83-02. Int J Radiat Oncol Biol
Phys 1995;31:453-9.
38. Laramore GE, Martz KL, Nelson JS, Griffin TW, Chang CH,
Horton J. Radiation therapy oncology group (RTOG! suMval
data on anaplastic astrowomas of the brain: does a more
aggressive form of treatment adversely impact survival? Int
/ Radiat Oncol Biol Phys 1989;17:1351-6.
39. Curran WJ, Scott CB, Weinstein AS, Martin L, Nelson JS,
Phillips TL, et al. Survival comparison of radiosurgery-eligible and -ineligible malignant glioma patients treated with
hyperfractionated radiation therapy and carmustine: a report of RTOG 83-02. J Clin Oncol 1993;11:857-62.
Документ
Категория
Без категории
Просмотров
3
Размер файла
825 Кб
Теги
865
1/--страниц
Пожаловаться на содержимое документа