Malignant Gliomas in Older Adults With Poor Prognostic Signs
Malignant Gliomas in Older Adults With Poor Prognostic Signs
The outlook for the majority of adult patients with malignant
gliomas has not improved since the Brain Tumor Study Group (BTSG)
trials of the 1970s ascertained a benefit from 55 to 60 Gy of
fractionated external-beam radiotherapy and carmustine (BiCNU)
following surgery [1-5]. The median survival time of patients
who participate in formal clinical trials is approximately 1 year
[2-4,6-12]. This dismal figure is almost certainly an overestimate,
since powerful selection factors lead patients with better prognostic
factors to enter clinical trials [8,9,13,14]. Patient age, functional
status, and tumor grade are the most important prognostic factors
[1,7,15]. It is only in the subgroup of patients with more favorable
prognostic signs that selection of therapy has any impact on survival
In 1960 Bouchard and Pierce reported that life expectancy in patients
with glioblastoma multiforme was better in those who received
radiotherapy than in those treated with surgery alone . Unfortunately,
only 4% of patients in the combined-modality treatment group were
alive at 10 years.
The BTSG conducted several randomized prospective postoperative
clinical trials in patients with malignant gliomas [1,3,5]. In
the first of these studies, the four treatment arms included surgery
plus: supportive therapy alone, carmustine alone, 50 to 60 Gy
of whole-brain radiotherapy alone, and carmustine plus radiotherapy.
The vast majority of the patients (90%) were classified as having
glioblastoma multiforme, 9% had anaplastic astrocytoma, and 1%
had other anaplastic gliomas.
The approximate median survival times, in weeks, for the four
treatments were: supportive care, 14; carmustine, 19; radiotherapy,
36; and carmustine plus radiotherapy, 35. The difference in survival
times between radiotherapy and either carmustine alone or supportive
care was statistically significant. This study thus constituted
the first demonstration, in a randomized trial, that radiotherapy
significantly increased median survival time for patients with
In a subsequent BTSG trial (trial 7201), median survival time
for treatment that included methyl-CCNU but not radiotherapy was
24 weeks. Significantly better survival times were seen with conventional
radiotherapy alone (36 weeks), radiotherapy plus methyl-CCNU (42
weeks), or conventional radiotherapy plus carmustine (51 weeks).
In the third major BTSG study (trial 7501), radiotherapy plus
methylprednisolone achieved a median survival time of 40 weeks,
and radiotherapy plus methylprednisolone plus carmustine attained
a survival time of 41 weeks. Significantly better survival times
were reported with both radiotherapy plus procarbazine (47 weeks)
and radiotherapy plus carmustine (50 weeks) [1-3].
Over a decade after BTSG trial 7201, the Central Nervous System
Cancer Consortium (CNSCC) conducted a randomized trial of conventional
radiotherapy plus carmustine vs conventional radiotherapy plus
diaziquone (AZQ). The median survival time from randomization
of all patients was 351 days, corresponding to approximately 69
weeks after diagnosis. Since randomization in this study occurred
approximately 8 weeks after completion of radiotherapy, or 15
to 20 weeks after diagnosis, this median survival time is based
on a subpopulation of patients who survived and maintained a Karnofsky
performance status (KPS) of at least 50% for 4 to 5 months after
diagnosis. This explains why the overall median survival in this
study exceeds that reported in most other trials [6,11].
Adjuvant Chemotherapy--Among the most extensively examined
areas in the treatment of malignant gliomas is the use of adjuvant
chemotherapy. Phase II trials of the nitrosoureas documented a
10% to 40% response rate for recurrent tumors . Because of
this activity, carmustine and methyl-CCNU were utilized in adjuvant
chemotherapy trials. Based on the previously cited BTSG trials,
many would argue that the best standard therapy of patients with
malignant gliomas should include nitrosourea chemotherapy. However,
only one of the three BTSG randomized trials that evaluated adjuvant
chemotherapy and included a no-chemotherapy arm showed a statistically
significant benefit of chemotherapy.
There are almost a limitless variety of "new" chemotherapy
programs to be tested in malignant gliomas or "old"
programs to be recycled with slight changes. A host of single-
and multi-agent programs have been tried, including carmustine;
lomustine; methyl-CCNU; bleomycin (Blenoxane); procarbazine, lomustine,
plus vincristine (Oncovin); AZQ; and mitomycin (Mutamycin) plus
To approach the question of the role of adjuvant chemotherapy
in malignant gliomas, Fine et al performed a meta-analysis of
the combined results from 16 randomized trials involving more
than 3,000 patients . They found a survival benefit attendant
to the use of chemotherapy, and that benefit occurred earlier
in patients with anaplastic astrocytoma than in those with glioblastoma
The survival times for malignant glioma following surgery, conventional
radiotherapy, and chemotherapy seem to have plateaued over the
past 25 years. In the free market of ideas, various "new"
therapies are held out as innovative and potentially efficacious.
Some of these alleged new ideas are, in fact, previously investigated,
venerable concepts that have resurfaced [19,20]. Examples include
multiple daily fractions of external-beam radiotherapy ; interstitial
brachytherapy1 [21-25]; localized or whole-body hyperthermia [26,27];
dose escalation with conventional fractionated radiotherapy [28,29];
radiosensitization with metronidazole, bromodeoxyuridine (BUDR),
iododeoxyuridine (IUDR), and neutron/boron capture [30-34]; radiolabeled
monoclonal antibodies; high-dose chemotherapy with autologous
bone marrow rescue; and gene therapy with retroviral vectors.
Radiosurgery--Stereotactic radiosurgery is a popular area
of current clinical investigation. Radiosurgery utilizes multiple
beams to tightly concentrate radiation dose to the tumor with
relative sparing of normal tissue. The most commonly used radiation
sources for radiosurgery are high-energy x-rays produced by a
linear accelerator; cobalt-60 gamma rays, as provided by the commercially
available Gamma Knife (Elekta Instruments, Decatur, Georgia);
and particle beams, such as the Harvard cyclotron beam.
Either before or following fractionated external-beam radiotherapy,
a radiosurgery "boost" may be given to the bulk of the
tumor-provided that the tumor volume does not exceed the limits
of the technology, ie, equal to or less than 3 to 4 cm. Fewer
than 20% of malignant gliomas meet this criterion [9,13,35]. Multiple
noncoplanar beams can be used as a boost for such larger lesions.
To improve the tolerance of normal tissues for radiosurgery of
larger volumes, the therapy is more highly fractionated. Thus,
at some point, highly fractionated radiosurgery intellectually
merges with precision conventional external-beam radiotherapy.
Study after study shows that patient age, tumor grade (glioblastoma
multiforme vs anaplastic astrocytoma), and patient performance
status are the pretreatment variables most predictive of outcome
[10-12,15,36,37]. In many clinical trials, the benefit of a new
therapy becomes less apparent in patients over 45 to 55 years
of age who have poor performance status. This observation is underscored
by the fact that only a select subgroup of malignant glioma patients
are entered into clinical trials-individuals who are unlikely
to be representative of the broader population. If the data supporting
the benefit of full-dose radiotherapy plus carmustine, as evidenced
by clinical trials, are derived from a highly select population,
then conventional wisdom in support of such therapy may fairly
be called into question.
Selection Bias in External-Beam Radiotherapy Plus Chemotherapy
Clinical Trials--Researchers from the University of Western
Ontario investigated selection bias in clinical trials of anaplastic
glioma . They collaborated with our group at Duke in a prospective
randomized clinical trial comparing AZQ to carmustine following
surgery and radiotherapy for malignant gliomas [6,11]. Because
of the Ontario provincial cancer care network, it was possible
to assess the percentage of patients in a catchment area of approximately
1.1 million persons who ultimately entered the trial. It was also
possible to evaluate how the loss of patients from the study biased
the survival predictions.
Of 217 initial patients with a clinical and radiographic diagnosis
of malignant glioma, 20 were too old and disabled to undergo a
biopsy to establish a tissue diagnosis. Of the remaining 197 adults
who had a biopsy-proven supra-tentorial malignant glioma, the
investigators studied how many remained eligible for the study.
The eligibility criteria were a Karnofsky performance score 50%
or greater, the absence of other medical conditions precluding
chemotherapy, and signed informed consent. At diagnosis, 100%
of the 197 patients met these eligibility criteria. Three weeks
later, at the start of radiotherapy, 68% were still eligible.
Six weeks later, at the end of radiotherapy, 47% were eligible.
Eight weeks later, when offered randomization between the two
drugs, 40% of the patients remained eligible. Seventy percent
of these remaining patients agreed to be randomized (28% of the
initial 197 patients).
The major reason patients became ineligible for the study were
a decrease in KPS, followed by significant medical problems precluding
participation and irregularities in the administration of external-beam
radiation that violated the protocol. Study patients lived significantly
longer than nonstudy patients (60 vs 25 weeks, P = .0001).
One can imagine that the results might have been even more dramatic
if an age cut off, ie more than 70 years, had been included as
a criterion for eligibility. When one considers the fact that
patients with progressive tumor during radiotherapy are excluded
from randomized studies of post-radiotherapy chemotherapy, case
selection is seen to be even more profound.
Selection Bias in Brachytherapy Clinical Trials--In a corollary
study, the Western Ontario group collaborated with Gutin of the
University of California at San Francisco and Leibel of Memorial
Sloan-Kettering Cancer Center . They took records of 101 malignant
glioma patients treated with conventional fractionated external-beam
radiotherapy and adjuvant chemotherapy and asked two experienced
surgeons and a radiotherapist to designate each patient as either
eligible or ineligible for adjuvant brachytherapy. None of the
patients had received such therapy. Overall, 32% of the patients
were deemed eligible for brachytherapy. In a similar review conducted
by the Radiation Therapy Oncology Group (RTOG) of their experience,
25% of patients were eligible for adjuvant brachytherapy .
Eligible patients lived longer than ineligible ones (16.6 vs 9.3
months), were younger, and had larger initial surgical resections
and better function. These findings suggest that better outcome
following adjuvant brachytherapy for malignant glioma is strongly
influenced by patient selection.
Recently, Curran et al published a recursive partitioning analysis
of prognostic factors uncovered in three RTOG malignant glioma
trials involving 1,578 patients . Patients were grouped according
to a variety of prognostic factors.
Median survival time ranged from a high of 58.6 months for the
9% of patients less than 50 years of age who had anaplastic astrocytoma
and normal mental status to a low of 4.6 months for the 17% of
patients 50 years of age or older who had a KPS less than 70%
and normal mental status and who received 54.4 Gy or less of external-beam
radiation therapy. Since the RTOG trials were confined to patients
70 years of age or younger, it is likely that the study overrepresented
the patient cohort with better prognostic factors.
Thus, inclusion of patients with poor prognostic factors in a
study may obscure the potential benefit of aggressive therapy
in patients with the more favorable prognosis. Conversely, inclusion
of patients with good prognostic factors may falsely promote the
usefulness of aggressive therapy.
The effects of case selection are summarized in Figure 1. This
analysis of data from the published literature clearly shows that
patients ultimately treated in clinical trials at academic medical
centers constitute a small minority of malignant glioma patients.
We are subjecting a large number of patients to forms of therapy
that have the potential to benefit very few. As the incidence
of brain tumors among the elderly increases, this problem will
become more apparent .