Neuro-Oncology

Progression-free survival: An important

end point in evaluating therapy for recurrent
high-grade gliomas
Kathleen R. Lamborn, W. K. Alfred Yung, Susan M. Chang, Patrick Y. Wen,

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Timothy F. Cloughesy, Lisa M. DeAngelis, H. Ian Robins, Frank S. Lieberman, Howard
A. Fine, Karen L. Fink, Larry Junck, Lauren Abrey, Mark R. Gilbert, Minesh Mehta,
John G. Kuhn, Kenneth D. Aldape, Janelle Hibberts, Pamela M. Peterson, Michael D.
Prados; North American Brain Tumor Consortium
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA (K.R.L., S.M.C.,
M.D.P.); Department of Neuro-Oncology (W.K.A.Y., M.R.G., K.D.A.) and Data Management Center (J.H.,
P.M.P.), The University of Texas M. D. Anderson Cancer Center, Houston, TX; Dana-Farber Cancer Institute,
Boston, MA (P.Y.W.); Department of Neurosurgery, University of California Los Angeles, Los Angeles, CA
(T.F.C.); Memorial Sloan-Kettering Cancer Center, New York, NY (L.M.D., L.A.); University of Wisconsin
Hospital, Madison, WI (H.I.R., M.M.); Division of Neuro-Oncology, University of Pittsburgh Medical Center
Cancer Pavilion, Pittsburgh, PA (F.S.L.); Neuro-Oncology Branch, National Cancer Institute, National Institutes
of Health, Bethesda, MD (H.A.F.); Department of Neurology, The University of Texas Southwestern Medical
Center, Dallas, TX (K.L.F.); Department of Neurology, University of Michigan Hospital, Ann Arbor, MI (L.J.);
Pharmacotherapy Education and Research Center, The University of Texas Health Science Center, San Antonio,
TX (J.G.K.); USA

The North American Brain Tumor Consortium (NABTC) in NABTC phase II protocols between February 1998
uses 6-month progression-free survival (6moPFS) as the and December 2002. Outcome was assessed statistically
efficacy end point of therapy trials for adult patients with using Kaplan-Meier curves and Cox proportional haz-
recurrent high-grade gliomas. In this study, we investi- ards models. Median survivals were 39 and 30 weeks
gated whether progression status at 6 months predicts for patients with grade III and grade IV tumors, respec-
survival from that time, implying the potential for pro- tively. Twenty-eight percent of patients with grade III and
longed survival if progression could be delayed. We also 16% of patients with grade IV tumors had progression-
evaluated earlier time points to determine whether the free survival of .26 weeks. Progression status at 9, 18,
time of progression assessment alters the strength of the and 26 weeks predicted survival from those times for
prediction. Data were from 596 patient enrollments (159 patients with grade III or grade IV tumors (p , 0.001
with grade III gliomas and 437 with grade IV tumors) and hazard ratios , 0.5 in all cases). Including KPS,
age, number of prior chemotherapies, and response in
a multivariate model did not substantively change the
Received October 27, 2006; accepted May 20, 2007. results. Progression status at 6 months is a strong pre-
Address correspondence to Kathleen R. Lamborn, Department of dictor of survival, and 6moPFS is a valid end point for
Neurological Surgery, University of California San Francisco, 400 trials of therapy for recurrent malignant glioma. Earlier
Parnassus Ave., UC Clinics 808, San Francisco, CA 94143-0372 assessments of progression status also predicted survival
([email protected]). and may be incorporated in the design of future clinical

162Neuro-Oncology
Copyright 2008 by the
■JSociety
ULY 2006for Neuro-Oncology
 Lamborn et al.: Clinical trial end points for glioma

trials. Neuro-Oncology 10, 162 – 170, 2008 (Posted to the latter case, the lack of symptoms over time may not
Neuro-Oncology [serial online], Doc. D06-00187, March directly relate to changes in tumor burden during can-
4, 2008. URL http://neuro-oncology.dukejournals.org; cer treatment. Toxicity is treatment specific and is rou-
DOI: 10.1215/15228517-2007-062) tinely measured, and clearly it may influence symptoms
as well as tumor burden and location. PFS is another end
Keywords: brain tumors, clinical trial end points, point option and may represent a clinically meaningful
glioma, progression-free survival outcome, as deferral of progression would likely have a
secondary benefit of deferral of progressive neurological

E
nd points for clinical trials may serve a number of decline or reduction in the need for corticosteroids to
purposes, including assessment of safety, biologi- manage symptoms.
cal activity, and clinical benefit. From a regula- Ideally, evaluation of efficacy should be based on a
tory standpoint, survival and symptom improvement are multidimensional end point, taking into account imag-
most likely to lead to drug approval. Currently, however, ing, symptoms, and progression intervals. However,

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a U.S. Food and Drug Administration (FDA) initiative until this methodology is worked out, for the reasons
is evaluating alternative end points, including objective described above, the NABTC has chosen PFS as the pri-
response rates, progression-free survival (PFS), event-free mary end point for its studies.
survival, and improvement in a patient’s quality of life.1 The problems of using time-to-event analyses are well
The North American Brain Tumor Consortium described in FDA guidance on end points for approval of
(NABTC) currently uses 6-month PFS (6moPFS) as the cancer drugs and biologics.3 When PFS is used as the pri-
primary end point in phase II trials for treatment of mary efficacy end point, a fixed time point (in this case 6
patients with recurrent malignant gliomas. The NABTC months) reduces time-dependent assessment bias, such as
treats patients in a multiinstitutional setting, with an that caused by visit or imaging frequency. The use of the
emphasis on early-phase studies generally for patients 6-month fixed time point has also allowed the use of his-
with recurrent tumors. Patients in these studies have torical data from a separate database of research studies
documented progression before treatment, based on in patients with high-grade glioma conducted at several
MRI. This provides a baseline that can be used to judge institutions to provide a historical control.4 Using these
the effectiveness of the therapy by examining time to historical data, the NABTC was able to define success
further progression. Objective response, should it occur, or failure of a therapy without the immediate need for
is also assessed, but the success of the therapy is defined concurrent or randomized controlled studies. Because of
by the lack of further progression. the aggressive nature of these tumors, 6moPFS was also
PFS may have several advantages over other effi- thought to be a clinically meaningful goal.
cacy end points, such as those based on radiographic Ultimately, the goal of treatment is to improve sur-
response or symptom assessment. Objective radio- vival. If time to progression is correlated with survival,
graphic response, usually determined by area or volume then this would support the hypothesis that lengthen-
changes in contrast enhancement on sequential MRI, ing the time to progression would also lengthen survival
is unfortunately an imprecise method of determining time. We evaluated patients with progressive tumors
tumor burden and change over time. MRI, the best tool treated in clinical trials conducted by the NABTC. The
available for assessing response, provides only an esti- primary goal of the study was to determine, for this
mate of the actual tumor burden; it often represents a patient group, whether progression status at 6 months
combination of tumor and treatment effects and can- predicted survival from that time. We also wished to
not directly measure infiltrating disease. The sensitivity determine whether information on progression from
and specificity of MR-based imaging may improve over earlier assessments could suggest possible changes for
time using newer techniques, but those techniques have the design of future clinical trials.
not yet been validated for defining treatment response.
Objective radiographic response is rare in brain-tumor
clinical trials, and other end points need to be consid- Materials and Methods
ered. For instance, patients treated with temozolomide,
All patients treated in NABTC phase II trials between
a cytotoxic chemotherapy agent tested extensively in
February 1998 and December 2002 were included in
recurrent glioblastoma multiforme, did not show signifi-
this study (Table 1). Some studies included both a phase I
cant changes in radiographic response compared with
and a phase II component. For the purpose of this analy­
a concurrent control group treated with procarbazine
sis, all patients treated with the recommended phase II
or compared with historical controls. 2 Yet, this drug
dose who met the eligibility entry criteria for phase II
has now become a standard of care in newly diagnosed
were included even if they were enrolled in the phase I
disease.
portion. Patients treated with other phase I doses were
End points based on symptom assessment as a mea-
excluded.
sure of efficacy are also problematic in this patient popu-
Standard entry criteria included confirmed high-grade
lation. Symptom assessment may be strongly influenced
glioma (grades III and IV) and KPS > 60. All proto-
by tumor location and size. Small tumors may cause seri-
cols required central pathology review. In the few cases
ous neurological deficits when located in critical areas of
where tissue was not available for central review, local
the brain, and conversely, patients with large tumors in
pathology designation was accepted. The diagnosis was
“silent” areas may not manifest any signs of disease. In

Neuro-Oncology • april 2 0 0 8     163

Lamborn et al.: Clinical trial end points for glioma

Table 1. North American Brain Tumor Consortium phase II trials

Number of Patients

Trial Treatment Grade III Glioma Grade IV Glioma

97-01 Temozolomide and BCNU 0 36

97-05 Thymidine and carboplatin 11 34
98-01 CPT-11 15 49
98-03 Temozolomide and 13-cis retinoic acid 47 40
99-01 R115777 22 70
99-04 Temozolomide and thalidomide 0 44
99-05 Fenretinide 18 24
99-07 CPT-11 and temozolomide 9 26

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99-08 Imatinib 9 33
00-01 ZD1839 15 35
01-01 CCI-779 11 30
01-03 OSI-774 2 16
Abbreviation: BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea.

based on the most recent surgery for which data were was the date the patient was declared off-study due to
available at the time of protocol registration. Protocols progression.
specified stratification by tumor grade. Thus, all analy- PFS and overall survival were measured from time
ses were performed separately for patients with grade of registration unless the protocol included a surgery as
III and grade IV tumors. Grade III tumors included all part of the study, in which case the date of first post-
histological subtypes, including pure and mixed tumors. operative treatment was used as the baseline date. For
Because the protocols did not distinguish among sub- patients who died, survival was time between registra-
types, the analyses reported in this study were also per- tion and date of death. Patients not known to have died
formed without regard to subtype. Patients could be were censored for survival as of the last date known
entered in more than one protocol and were included alive. In general, the studies mandated repeat scans
for each protocol in which they were enrolled. Analyses every 8 weeks. To allow for some variability in timing of
were repeated including these patients only once, either the scans, we analyzed PFS status at 9, 18, and 26 weeks.
for the first or for the last protocol in which they were If a patient was removed from a study for a reason other
enrolled. Because the results were substantially the same, than progression, the patient was censored for further
only one analysis is presented. evaluation of progression in that study as of the date of
For all studies, response and progression were defined starting other therapy, if that was known. Otherwise,
using the Macdonald criteria.5 Because the primary end the date the patient was removed from the study was
point for these studies was 6moPFS, evaluable disease used. If the patient was followed routinely for progres-
(unidimensionally measurable lesions with margins not sion after being removed from the study and had pro-
clearly defined) or measurable disease (bidimensionally gression without further therapy, that progression date
measurable lesions with clearly defined margins) was was used. In cases where follow-up for progression was
allowed, and patients having a recent resection for pro- not consistent off-study, patients were censored for pro-
gressive tumor were permitted to enroll if that resection gression at the time they went off-study.
indicated the presence of tumor. In the latter situation, PFS and survival were estimated by using the Kaplan-
there was no requirement that residual tumor be pres- Meier method. The primary purpose of this study was to
ent after resection. Objective responses were centrally assess the ability of progression status to predict survival,
reviewed. Confirmation by repeat imaging was not and this was done using landmark analysis. For each
required. Objective response for measurable disease time point evaluated, all patients alive with known pro-
required a decrease in tumor size of 50% or greater in the gression status at that time were included in the analysis.
setting of stable neurological findings and no increase in Survival was measured from that time. Survival curves
steroid dose. Response for evaluable disease was based comparing outcome based on progression status were
on a subjective 7-point scale requiring at least a 12, or created using Kaplan-Meier curves and tested using the
definitely better, response. Progression was determined log-rank test. The results were confirmed using analyses
by the local institutional investigator and was defined stratified by protocol and stratified by whether or not
as an increase in tumor size of 25% or greater for mea- temozolomide was included as one of the treating agents.
surable disease and clear worsening, or a – 2 response, The Cox proportional hazards model was also used to
for evaluable disease. Failure to return for evaluation allow for incorporation of the putative and known prog-
due to death or deteriorating condition was considered nostic markers of age, KPS, and number of prior che-
to represent progression. In this case, progression date motherapy regimens. A further analysis was conducted

164    Neuro-Oncology • april 2008

 Lamborn et al.: Clinical trial end points for glioma

Table 2. Patient characteristics

Number of Patients (%)

Characteristic Grade III Glioma Grade IV Glioma Total

KPS
   60 8 (5)   23 (5)  31 (5)
   70 22 (14)   84 (19) 106 (18)
   80 41 (26) 154 (35) 195 (33)
   90 62 (39) 126 (29) 188 (32)
100 26 (16)   50 (11) 76 (13)
Age (years)
Median 44 52 49

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Range 20 – 74 21 – 84 20 – 84
Sex (male/female) 103/56 279/158 382/214
Race (white/other) 144/15 412/25 556/40
Surgery within 30 days priora 12 (8)    75 (17) 87 (15)
No. prior chemotherapy treatments
0 21 (13) 117 (27) 138 (23)
1 84 (53) 219 (50) 303 (51)
2 47 (30)   89 (20) 136 (23)
3 7 (4)   12 (3)  19 (3)
Responseb 12 PR, 2 CR (9) 30 PR (7) 42 PR, 2 CR (7)
a
Includes 11 patients in protocols that included a preoperative drug administration, but for whom progression-free survival
is measured from first postoperative chemotherapy treatment.
b
PR, partial response; CR, complete response.

including response. For that analysis, responders com- with grade III tumors and 59 patients with grade IV
prised patients who had been declared a responder at tumors were censored for progression. However, only
or before the specified time point. The conclusions were 13 and 39 patients (grades III and IV, respectively) were
the same for the univariate and supplemental analyses; censored before the primary end point of 6 months.
therefore, only the univariate results are presented here. Of the agents included in these trials, temozolomide
All p values presented are two-tailed. is the most accepted treatment for gliomas, and it was
part of the treatment regimen for about one-third of
the patients studied. Because temozolomide is now the
Results standard of care for newly diagnosed disease and is not
likely to be included in future salvage studies, a separate
The study population comprised 596 patient enrollments
summary of patient outcomes that takes into account
(159 with grade III and 437 with grade IV tumors). Of
administration of temozolomide is included in Table 3.
the grade III tumors, 101 were anaplastic astrocytoma,
Table 4 presents survival as a function of progression
39 were anaplastic oligodendroglioma, and 19 were
status for three time points. For this table, patients were
anaplastic mixed glioma. Forty-seven patients (12 with
included in a specified analysis only if they were known
grade III and 35 with grade IV tumors on first enroll-
to be alive beyond that time point and it was known
ment) were enrolled in two protocols. Of the patients
whether they had progressed by that time. Survival
who were initially enrolled with a grade III tumor, two
was measured from that time. The number of patients
had a grade IV tumor at the time of their second enroll-
excluded because they had died before the specified time
ment. No patients were enrolled in more than two pro-
point is provided. Patients listed under “status unknown”
tocols. Table 2 describes the patient population.
are those for whom either progression or survival status
As would be expected, PFS and overall survival tended
for that time point was unknown. For example, of the
to be longer for patients with grade III tumors (p , 0.01
patients with grade IV tumors, 223 were excluded from
and p , 0.001, respectively, log-rank test stratified by
the 26-week analysis: 195 had died before 6 months, 27
protocol). Table 3 presents estimated PFS and survival by
were excluded because progression status was unknown,
grade for selected time points. Six-month PFS was 28%
and one patient had disease progression but unknown
for patients with grade III tumors and 16% for those
survival status at 6 months. Patients censored for sur-
with grade IV tumors. The 6-, 12-, and 18-month sur-
vival are those known to have been alive at the specified
vival rates were 66%, 44%, and 27%, respectively, for
time point but for whom date of death is unknown.
patients with grade III tumors and 55%, 25%, and 13%
Progression status at 9, 18, and 26 weeks following
for those with grade IV tumors. Twenty-nine patients

Neuro-Oncology • april 2 0 0 8     165

Lamborn et al.: Clinical trial end points for glioma

Table 3. Patient outcome

Grade III Glioma Grade IV Glioma

Outcome TMZ Other Total TMZ Other Total

a
Progression-free survival
No. patients (no. censored) 56 (10) 103 (19) 159 (29) 146 (24) 291 (35) 437 (59)
% PFS (95% CI)b
   9 weeks 76 (63 – 86) 40 (30 – 50) 53 (45 – 61) 65 (56 – 72) 34 (28 – 40) 44 (40 – 49)
   18 weeks 52 (38 – 65) 22 (14 – 31) 33 (25 – 40) 40 (31 – 48) 17 (13 – 22) 25 (20 – 29)
   26 weeks 47 (33 – 59) 17 (10 – 26) 28 (21 – 35) 28 (21 – 36) 9 (6 – 13) 16 (12 – 20)
Median PFS (95% CI), weeks 24 (16 – 29) 8 (7 – 9) 11 (9 – 13) 15 (11 – 17) 7 (7 – 8) 8 (8 – 9)
Survivala

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No. patients (no. censored) 56 (11) 103 (19) 159 (30) 146 (10) 291 (12) 437 (22)
% Surviving (95% CI)b
   26 weeks 82 (69 – 90) 57 (47 – 66) 66 (58 – 73) 69 (61 – 76) 48 (43 – 54) 55 (51 – 60)
   52 weeks 51 (37 – 63) 40 (30 – 49) 44 (36 – 51) 37 (29 – 45) 19 (14 – 23) 25 (21 – 29)
   78 weeks 27 (16 – 39) 25 (17 – 34) 27 (20 – 34) 21 (15 – 28) 8 (5 – 12) 13 (10 – 16)
Median survival (95% CI), weeks 52 (37 – 60) 36 (24 – 49) 39 (32 – 54) 40 (33 – 47) 26 (23 – 29) 30 (27 – 33)
Abbreviations: TMZ, temozolomide; PFS: progression-free survival; 95% CI, 95% confidence interval.
a
Estimated from Kaplan-Meier curves.
b
From time of protocol registration or first subsequent postoperative treatment.

protocol registration was a strong predictor of survival months, seven within 9 weeks of their initial response
for both tumor grades. The Cox proportional hazards designation. When we performed a landmark analysis
model was used to estimate the hazard ratio for survival for each grade and time point, in a proportional hazards
as a function of whether or not a patient had progressed model with both response and progression status at that
by the specified time point. These hazard ratio estimates time included in the model, response was not close to
were consistent across time for each grade. For patients statistical significance and did not substantively change
with grade IV tumors, the hazard ratio was between 0.46 the predictive strength of progression status.
and 0.36, indicating a reduction in hazard of greater
than 50% for those who had not yet had disease pro-
gression. The estimated hazard ratios for patients with Discussion
grade III tumors were lower, ranging from 0.30 to 0.33.
We present here the results from an analysis of 12
Figures 1 and 2 show Kaplan-Meier curves for survival
NABTC phase II clinical trials of patients with recurrent
from 6 months for patients with grade III and grade IV
high-grade glioma. Our goal was to determine whether
tumors, respectively, based on progression status at 6
progression was a predictor of subsequent survival time
months. The curves from 9 and 18 weeks showed very
and also to evaluate the potential usefulness of progres-
similar survival patterns and are not presented here.
sion status at earlier time points. In this study, we were
Historically, response has been considered an indi-
able to document that progression status at 26 weeks
cation of an agent’s activity, although association of
was a strong predictor of survival, with a similar pattern
response with survival has often been difficult to con-
for progression status at 9 and 18 weeks.
firm when appropriate statistical procedures have been
Clearly, there are limitations to the use of a single
used to adjust for time biases. In this study there were
time point assessment of progression. If the actual time
few responses. Fourteen patients with grade III tumors
to progression is known, use of that information can
responded (9% of those evaluable for response); median
increase statistical power. There is a risk of missing ear-
time to response was 13 weeks (range, 8 – 67). Thirty
lier, potentially relevant differences not observed at the
partial responses were observed for patients with grade
prespecified time point. Objective response, which in
IV tumors (7%); median time to response was 12 weeks
some cases may ultimately be proven to be an important
(range, 4 – 58). Three (21%) of the grade III responders
surrogate for survival, is not factored into the design.
did not have successful treatment based on 6moPFS.
Finally, interpretation can be complicated if data are
One was censored at 10 weeks, and two had disease
missing due to patients being removed from the study
progression before 6 months (8 and 12 weeks after
without progression prior to the fixed time point. These
their initial response designation). Twelve (40%) of the
patients may have begun new therapies without pro-
grade IV responders did not have successful treatment
gression, died without an assessment of progression, or
based on 6moPFS. Of these 12, three were censored.
become lost to follow-up. On the basis of the principle
The remaining nine had disease progression before 6
of intent-to-treat, the usual calculation includes in the

166    Neuro-Oncology • april 2008

 Table 4. Survival as a function of progression status

Survivala

Status at 9 Weeks Status at 18 Weeks Status at 26 Weeks

PFS . Status PFS . Status PFS . Status

Grade Progressedb 9 Weeks Died Unknownc Progressedd 18 Weeks Died Unknownc Progressede 26 Weeks Died Unknownc

Grade IV
No. patients 196 181 40 20 202 90 118 27 160 54 195 28
No. censored for survivalf 4 18 9 11  —  8 11
Median survival (weeks) 16 37  —   —  16 42  —   —  18 52  —   —
% Alive at 6 months 33 64  —   —  33 74  —   —  35 76  —   —
% Alive at 1 year 12 32  —   —  12 39  —   —  15 49  —   —
p Value (log-rank) ,0.001 ,0.001 ,0.001
Hazard ratio 0.46 (95% CI: 0.37 – 0.56) 0.41 (95% CI: 0.31 – 0.54) 0.36 (95% CI: 0.25 – 0.51)
Grade III
No. patients 60 80 11 8 68 48 36   7 58 38   54   9
No. censored for survivalf 2 26 7 20  —  8 17
Median survival (weeks) 18 52  —   —  19 70  —   —  26 72  —   —
% Alive at 6 months 40 76  —   —  43 85  —   —  50 87  —   —
% Alive at 1 year 17 49  —   —  22 58  —   —  21 65  —   —
p Value (log-rank) ,0.001 ,0.001 ,0.001
Hazard ratio 0.32 (95% CI: 0.22 – 0.47) 0.30 (95% CI: 0.19 – 0.47) 0.33 (95% CI: 0.20 – 0.56)
a
Survival measured from the specified time point (9, 18, or 26 weeks).
b
Progressed <9 weeks, overall survival .9 weeks.
c
Patients whose progression and/or survival status at the specified time was unknown. (In only two cases — one grade III and one grade IV — was there a known progression time, but the survival status was unknown. In these cases, survival
was censored at 24 and 23 weeks, respectively.)
d
Progressed <18 weeks, overall survival .18 weeks.
e
Progressed <26 weeks, overall survival .26 weeks.

Neuro-Oncology • april
f
Patients who were known to be alive at the specified time but whose date of death was unknown.

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Lamborn et al.: Clinical trial end points for glioma

Survival probability

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Survival post 6 months (weeks)
Fig. 1. Survival from 6 months after study registration for patients with grade III gliomas who were alive at that time, comparing survival for
patients who had disease progression (solid line) with survival for those who did not have progression (dashed line) by 6 months.

denominator all patients enrolled and in the numerator ify based on tumor grade. Patients whose last surgery
only those known to be alive and progression-free at the indicated a grade III tumor had a better outcome as
specified time point. This is a conservative strategy. In a group than did patients with a diagnosis of a grade
the case of this patient population, if a therapy is suc- IV tumor. The grade III patient group undoubtedly
cessful, few patients should have missing data for the included patients whose tumor had upgraded since the
reasons stated above; therefore, it is not likely to be a last histological diagnosis because of the infrequency of
major problem in interpretation. Specification of a fixed additional surgeries after the initial treatment. If a more
point in time also reduces the effect of differences in accurate diagnosis of current histology were available at
timing of intermediate scans on data interpretation. the time of protocol enrollment, the difference in out-
The fixed time point also ensures that the results for the come between the patient groups would be expected to
study will be known no later than 6 months after the last be still larger.
patient is enrolled. For 6moPFS to be an appropriate end point for these
The results of this study confirm the need to strat- clinical trials, it should not only be reproducible but
Survival probability

Survival post 6 months (weeks)

Fig. 2. Survival from 6 months after study registration for patients with grade IV gliomas who were alive at that time, comparing survival for
patients who had disease progression (solid line) with survival for those who did not have progression (dashed line) by 6 months.

168    Neuro-Oncology • april 2008

 Lamborn et al.: Clinical trial end points for glioma

also have clinical relevance. In this study, we were able The documentation that progression predicts survival
to document that progression status at 26 weeks was a leads us to believe that treatments that extend PFS are
strong predictor of survival from that time point. We likely to increase overall survival, but this remains to be
saw a similar pattern for progression status at 9 and 18 proven. The studies included here were single-arm phase
weeks. II trials, limiting what can be concluded with regard to
A number of questions remain. Although done as post 6moPFS as a surrogate for survival in comparing treat-
hoc analyses, survival was closely associated with pro- ments. However, the results are consistent with the
gression status at time points before 6 months. This raises recently reported experience of the North Central Can-
the question of whether the earlier time points could be cer Treatment Group.7 In that report, the authors noted
used either in addition to or in place of 6moPFS. If it were a limitation in the conclusions owing to the results of all
possible to substitute 9-week PFS for 6moPFS, results trials being negative. Our current analysis included sev-
from trials could be determined earlier. It would also be eral trials that used temozolomide, a treatment that has
more practical to consider multistage designs. Our cur- subsequently been determined to be effective based on

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rent criterion for a successful/unsuccessful trial is 35% a survival end point (albeit in the treatment of patients
versus 15% 6moPFS for patients with grade IV tumors, with newly diagnosed tumors). While a comparison of
our primary test population. From this study we have an the studies with and without temozolomide does not
overall estimate of approximately 45% PFS at 9 weeks take into account any possible differences in prognostic
for this patient group. A corresponding increase of 20% factors between studies, it is encouraging that patients
in 9-week PFS would be from 45% to 65%. Whereas 32 in studies including temozolomide showed a much
patients are sufficient to have 90% power (with a one- improved 6moPFS and survival compared with patients
tailed a 5 0.1) for the 6moPFS end point, 44 patients (an treated in studies not including temozolomide, indicat-
increase of 38%) would be required to have similar power ing that 6moPFS could be effective in distinguishing
for the earlier time point. (If we assume an exponential this agent from other generally less effective therapies
distribution, then a 15% vs. 35% difference at 6 months in phase II trials.
would correspond to 52% vs. 70% PFS at 9 weeks, and In addition to the use of 6moPFS as an end point for
the required sample size for 90% power would be still phase II trials, the question arises as to whether this end
larger — 53 patients.) Also, an improvement in 6moPFS point could be used as a substitute for survival either for
ensures some degree of durability of effect. full approval or for accelerated approval of a new treat-
While it does not seem appropriate to replace 6moPFS ment. For reasons stated above, we believe that the data
with PFS at 9 weeks as the primary end point, with the support a statement that increasing 6moPFS can reason-
information available on the expected PFS rate at 9 ably be expected to increase survival. As with survival,
weeks and knowledge that PFS status at 9 weeks predicts there is clearly heterogeneity in PFS that is not related to
survival, we can now consider using that information to treatment. The nature of these factors needs to be fur-
create early stopping rules should the PFS be less than ther explored, and we plan to utilize these data to per-
would be expected. This would allow early stopping for form such evaluations. However, because it cannot be
trials in which the therapy is clearly not meeting expec- expected that all factors affecting survival and/or PFS at
tations. Such an approach would not be applicable for time of recurrence can be identified, randomized clinical
all situations. For example, trials of a targeted therapy trials would be required to confirm treatment effect.
might require the full patient number to determine if the The use of PFS for accelerated approval has the
therapy was differentially effective depending on a spe- potential to substantially shorten the time to access a
cific tumor marker. On the other hand, if patient entry promising treatment. For example, to have 90% power
had required the presence of a tumor marker that was for a hazard ratio of 1.8 consistent with the treatment
expected to lead to high success with targeted therapy, effect criterion used in the NABTC phase II trials (an
an early stopping rule based on 9-week PFS estimates increase in 6moPFS for grade IV patients from 15% to
would be appropriate. The best way to incorporate this 35%), assuming accrual requires 1 year with additional
information needs to be evaluated further, as do possible follow-up of 6 months and that PFS follows an exponen-
uses for the intermediate (18-week) results. tial distribution, a randomized trial would require 134
Unfortunately, the objective response rate remains so patients and could be completed in 1.5 years if PFS were
low that we feel that we have not suffered from a lack of the end point. For the same power, same hazard ratio,
consideration of this end point to date. Newer clinical and same number of patients, using survival as an end
trial methodologies can potentially allow for multiple point would require 3.5 years (assuming 15% survival
end points, 6 for example, response and 6moPFS, and at 1.5 years, consistent with the historical data). Because
these need to be investigated. patient heterogeneity and additional treatment options
The study as conducted demonstrated that a patient’s might result in a hazard ratio closer to 1 for a survival
progression status at a specified point in time is a strong comparison than for a PFS comparison, the study based
predictor of survival from that time. This provides docu- on a survival comparison might need to be still longer in
mentation supporting the general impression of clinicians order to have enough events for adequate power.
that delay in progression is positive, not only because it The strength of the results observed reassures us
delays the complications that accompany progression that for phase II trials, 6moPFS is a useful end point for
(which have a real clinical effect on the patients) but also evaluating new therapies. Status at earlier time points
because it indicates the likelihood of longer survival. may also provide important information, particularly as

Neuro-Oncology • april 2 0 0 8     169

Lamborn et al.: Clinical trial end points for glioma

a guide to reduce patient sample size in the setting of Acknowledgment

studies with negative results. Further research is needed
to validate these observations. Until there are validated This study was presented in part at the American Asso-
instruments for the assessment of symptomatic end ciation for Cancer Research/FDA Public Workshop on
points, it is unlikely that time to symptom deterioration Clinical Trial End Points in Primary Brain Tumors, Jan-
will become a commonly used end point in neurooncol- uary 20, 2006. We thank Ilona Garner, Department of
ogy clinical trials. On the basis of the results, we are Neurological Surgery, University of California San Fran-
convinced that progression is an important determinate cisco, for editorial support. This study was supported
of survival and that PFS may more directly define the by the following grants: NABTC grants CA62399,
benefit of the treatment being tested than does survival. CA62422, CA62412, U01CA62407-08, CA62455-08,
Given the large database and numbers of trials used in U01CA62405, CA62426, U01CA62399 022030 (for
the analysis, we believe that this end point is relevant to NABTC98-03 only), U01CA62399, 5-U01CA62399-09,
the patients we serve and that our results support the and U01CA62421-08; and General Clinical Research

Downloaded from https://academic.oup.com/neuro-oncology/article/10/2/162/1076077 by guest on 20 February 2024

idea of evaluating new research methodologies using Center grants M01-RR00079, CA16672, M01-RR00633,
this end point coupled with other measures of clinical M01-RR00056, M01-RR0865, M01-RR00042, and
benefit. M01-RR03186.

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