Clinical Cancer Research Vol. 6, 597-601, February 2000
© 2000 American Association for Cancer Research
Molecular Oncology, Markers, Clinical Correlates |
Significance of Neuron-specific Enolase Levels before and during Therapy for Small Cell Lung Cancer1
James A. Bonner2,
Jeff A. Sloan,
Kendrith M. Rowland, Jr.,
George G. Klee,
John W. Kugler,
James A. Mailliard,
Martin Wiesenfeld,
James E. Krook,
Andrew W. Maksymiuk,
Edward G. Shaw,
Randolph S. Marks and
Edith A. Perez
Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905 [J. A. B., J. A. S., G. G. K, E. G. S., R. S. M.]; Carle Cancer Center CCOP, Urbana, Illinois 61801 [K. M. R.]; Illinois Oncology Research Association CCOP, Peoria, Illinois 61602 [J. W. K.]; Nebraska Oncology Group, Creighton University, University of Nebraska Medical Center and Associates, Omaha, Nebraska 68131 [J. A. M.]; Cedar Rapids Oncology Project CCOP, Cedar Rapids, Iowa 52403 [M. W.]; Duluth CCOP, Duluth, Minnesota 55805 [J. E. K.]; Saskatoon Cancer Centre, Saskatoon, Saskatchewan, S7N 4H4 Canada [A. W. M.]; and Mayo Clinic Jacksonville, Jacksonville, Florida 32224 [E. A. P.]
 |
ABSTRACT
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The
level of serum neuron-specific enolase (NSE) has been implicated as a
prognostic factor for patients with small cell lung cancer (SCLC). A
prospective evaluation was undertaken to assess the prognostic
significance of pretreatment NSE and treatment-induced minimum NSE
values in patients with SCLC. Patients from two Phase III North Central
Cancer Treatment Group trials [one for patients with extensive stage
SCLC and one for patients with limited stage SCLC] were asked
to enter this laboratory correlational trial. Both trials included
treatment with four to six cycles of etoposide and cisplatin, and 121
patients (71 extensive stage SCLC and 50 limited stage SCLC) were
entered into the present study of NSE. Pretreatment NSE values and
treatment-induced minimum NSE values were independent predictors of
time to progression and survival in multivariate analysis. Hazard rate
modeling allowed the formulation of specific relationships of NSE to
time to progression and survival. Pretreatment NSE levels inversely
correlated with time to progression and survival in these patients with
SCLC. Pretreatment NSE accounted for 28% of the variance in survival.
Both pretreatment NSE and treatment-induced minimum NSE were
independent prognostic predictors of time to progression and survival.
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INTRODUCTION
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The enolase enzymes are involved in the glycolysis pathway at the
conversion of 2-phosphoglycerate to phosphoenolpyruvate (1
, 2)
. Glycolysis is the process of anaerobic degradation of
glucose to lactic acid, but it is also an important preparatory pathway
for aerobic glucose catabolism. There are slight structural variations
in the enolases that predominate in various organ systems, and these
variations appear to be related to the environmental conditions that
may be present in various organ systems. For instance,
NSE3
is the
predominant enolase found in neural tissue, and the structural
characteristics of this enolase allow for greater stability in high
chloride concentrations compared with the enolases of other organ
systems. This structural characteristic is thought to be important for
enolase function in neural tissue because depolarizations result in
transient high concentrations of chloride.
With the development of antiserum to the enolase enzymes, it became
apparent that patients with the diagnosis of SCLC frequently had
increased levels of NSE compared with control patients
(2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
. Subsequently, it was discovered that NSE levels
correlated with the patients’ extent of disease (2
, 7
, 9
, 13
, 16)
, and therefore, the question arose as to whether NSE might
be a tumor marker that would allow the clinician an improved capacity
to assess an individual patient’s prognosis and additionally whether
NSE could be used to assess the potential for an individual patient to
respond to various therapies.
Therefore, the North Central Cancer Treatment Group embarked on a
prospective study of NSE in patients with SCLC with the following
goals: (a) determine whether baseline NSE levels correlated
with prognosis or response to therapy (or both); and (b)
determine whether the response of NSE after therapy correlated with
tumor response or patient survival (or both). To investigate these two
goals, patients from two prospective studies, one for patients with
ESSCLC and one for patients with LSSCLC, were asked to participate in a
prospective assessment of NSE levels before and during treatment of
their SCLC.
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PATIENTS AND METHODS
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A prospective laboratory correlational study was undertaken to
determine the significance of pretreatment, and the treatment-induced
minimum NSE values for patients with SCLC (both extensive stage disease
and limited stage disease). Patients from two North Central
Cancer Treatment Group prospective randomized trials were allowed to
enter onto this laboratory correlational study. The eligibility for
patients in the first trial included only those with ESSCLC, and the
eligibility for patients in the second trial included only those with
LSSCLC.
These trials were selected because both trials included primary
treatment with combination chemotherapy consisting of etoposide and
cisplatin. The patients who were entered on the trial for ESSCLC
(August 1990-July 1993) were treated with 4 cycles of etoposide (100
mg/m2) and cisplatin (30
mg/m2) on days 1, 2, and 3 of each monthly cycle.
They also were randomized to treatment with daily megestrol for 2 years
(beginning days 3–5) or placebo. The details of treatment and the
results of this trial have been published (17)
. The use of
megestrol did not significantly affect time to progression or survival
compared with placebo (17)
. The patients who were entered
on the trial for LSSCLC (September 1990–November 1996) were treated
with six cycles of etoposide and cisplatin. The dose schedules of
etoposide and cisplatin were identical to the first trial for cycles
four to six (whereas the patients received thoracic radiation therapy
during cycles four and five); however, the etoposide dose was slightly
higher (than the trial for the patients with ESSCLC) for the first
three cycles: 130 mg/m2. This trial included a
randomization to once-daily thoracic radiation therapy (50.4 Gy in 28
fractions) or twice-daily thoracic radiation therapy (48 Gy:1.5 Gy
twice daily with a 2-week break after 24 Gy; Ref. 18
).
Of the 567 patients (243 on the ESSCLC trial and 324 on the LSSCLC
trial) who were entered into the two trials, 121 participated in the
laboratory correlational study involving sampling of NSE (71 with
ESSCLC and 50 with LSSCLC) before and during treatment (April
1991–November 1992). All patients signed an Institutional Review
Board-approved statement of informed consent. Of the 19 institutions
that participated in the ESSCLC and LSSCLC trials, 18 and 16
participated in this trial, respectively. Patients who were entered on
this trial were assessed for NSE at the pretreatment visit, each visit
during treatment, and each follow-up visit (every 4 months for 3 years,
followed by every 6 months) until the time of progression. The assay
for NSE was an immunochemiluminescence assay that used two monoclonal
antibodies and was developed in an agreement with Hybritech and Dr.
George Klee of the Mayo Foundation (19)
.
The significance of the pretreatment NSE and minimum NSE was assessed
by hazard rate modeling in an effort to determine whether a
mathematical relationship existed between these values and time to
progression and overall survival (from study entry; Refs.
20
and 21
). Additionally, Spearman correlation
coefficients were calculated for the above potential relationships
(22)
. A multivariate analysis by the method of Cox was
used to determine independent prognostic factors (23)
.
Mean values were expressed with associated 95% confidence intervals.
Survival curves were constructed by the method of Kaplan and Meier
(24)
, and comparisons of these curves were made by the
log-rank test (25)
.
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RESULTS
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Of the 121 patients who were entered into this laboratory
correlational study, the median age was 63 years (range, 30 to 74
years). The median follow-up time for the living patients was 3.2
years, with a median potential follow-up time of 15 months. Of the 121
patients, 105 died. The initial goal of this study was to determine the
significance of the pretreatment NSE level. It was determined that
there was a statistically significant difference in the pretreatment
NSE levels of patients who had ESSCLC compared with those who
had LSSCLC, with mean values of 254 ± 36.4 ng/ml and 47.1 ±
4.9 ng/ml, respectively (P < 0.0001). A group of 100
normal adult volunteers showed a mean value of 16.4 ± 0.4 ng/ml.
This mean value for the group of normal adults is somewhat higher than
those of other published series in which means have generally been
12 ng/ml; however, it is certainly consistent with slight
variability in various control populations (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
.
The above results suggested that the baseline NSE value was of
prognostic significance regarding the extent of disease
(i.e., extensive disease versus limited disease).
Of the 121 patients who were entered into the study, 53 had a best
response of complete response. Patients who achieved this complete
response during therapy or immediately after therapy had a pretreatment
median NSE value of 53 ng/ml compared with a median value of 133 ng/ml
for patients who achieved less than a complete response
(P = 0.01). A scatterplot of baseline NSE
versus time to progression was constructed to initially
assess the possibility of an inverse relationship (Fig. 1
, left). Initial visual
inspection of the scatterplot revealed a suggestion that the patients
with higher baseline NSE values were more likely to have shorter
periods from registration to time of progression.
Hazard modeling for progression rate based on NSE was performed, and
the following equation describing the relationship of NSE and time to
progression was determined: H.R.(t) =
(Baseline H.R. at time t) x
e0.0024 (NSE value), where
H.R. is the hazard rate.
An example of the usefulness of this modeling is as follows. A 30-unit
increase in baseline NSE would result in a 7.4% increase in the hazard
rate of disease progression at any particular time. Because an inverse
relationship between baseline NSE and time to progression was found, a
scatterplot of baseline NSE versus overall survival was
created to initially assess whether a visual relationship existed
between these variables (Fig. 1
, right). The scatterplot
suggested a possible relationship, and mathematical modeling of the
hazard rate of death with respect to NSE was performed. The following
equation describing the relationship of NSE to overall survival was
determined: H.R.(t) = (Baseline
H.R. at time t) x
e0.0017 (NSE value), where
H.R. is the hazard rate.
Although the equation describing the relationship between the hazard
rate of death and pretreatment NSE resulted in a slightly reduced
coefficient of NSE compared with the coefficient for the relationship
of NSE to time to progression, there remained a statistically
significant relationship between NSE and the hazard rate of death
(P < 0.05). This relationship between pretreatment NSE
and the hazard rate of death was more easily illustrated by calculating
a Spearman correlation coefficient of the relationship
(r = -0.53, P = 0.0001). The square of
this correlation coefficient was used to derive the fact that 28%
of the variance in survival was attributed to NSE, and this percentage
is a high level of variance attributable to a single biological factor.
Next, a multivariate analysis was performed to assess whether
pretreatment NSE was an independent prognostic factor. The following
potential prognostic factors were included in the analysis:
pretreatment NSE, treatment-induced minimum NSE during the treatment
course, age, sex, stage of disease (extensive or limited), and
performance status (0 versus 1, versus 2).
Pretreatment NSE and minimum NSE were independent prognostic indicators
for time to progression and survival (Table 1)
.
Because the treatment-induced minimum NSE level was an independent
treatment-associated measure of time to progression and overall
survival, further analyses of this end point were undertaken. The
median number of NSE samples/patient was 5, with a range of 2–13. The
median time between the baseline NSE and the final NSE sample was 161
days, with a range of 16–928 days. The median time to the minimum NSE
value was 91 days. The median minimum value was used to separate
patients into two prognostic groups. This cutoff value was 12 ng/ml for
the overall population of patients. Patients with limited or extensive
stage disease who achieved minimum NSE values of less than the cutoff
value had statistically significant improvements in time to progression
and overall survival (Figs. 2
and 3)
.
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Fig. 2. The time to progression was prolonged
for the patients whose treatment-induced NSE minimum
(Min) value was  12 ng/ml compared with patients who
had higher values. *, adjusting for extent of disease, performance
status, age, sex, and baseline NSE.
|
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Fig. 3. The overall survival was prolonged for
patients whose treatment-induced NSE minimum (Min) value
was 12 ng/ml compared with patients who had higher values. *,
adjusting for extent of disease, performance status, age, sex, and
baseline NSE.
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DISCUSSION
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This prospective study of patients with LSSCLC and
ESSCLC revealed that the pretreatment serum NSE level was inversely
correlated with survival, and in the present study, this one prognostic
variable (NSE) appeared to account for 28% of the variance in
survival. Also, the pretreatment NSE level was inversely correlated
with response to treatment and the time to progression. Unlike many
trials, this trial evaluated NSE levels prospectively during treatment,
and therefore an assessment of the patients’ treatment-induced minimum
NSE (during treatment) could be made. In the Cox regression model, both
the pretreatment NSE and the minimum NSE (as well as stage) were of
independent prognostic significance with respect to survival.
Other authors have examined the prognostic significance of serum NSE in
patients with SCLC (7
, 12
, 13
, 16
, 26)
. In a recent study
by Jorgensen et al. (13)
, 770 patients were
studied from nine institutions. They found that pretreatment NSE was
the most powerful predictor of survival, followed by performance status
and stage of disease. They developed a prognostic index evaluation
system that assigned each patient an overall score based on the sum of
scores given for performance status, stage, and NSE. This system proved
to be fairly useful in categorizing four distinct prognostic groups.
The strong dependence of this system on pretreatment NSE corroborates
the results of the present series. They did not evaluate the prognostic
significance of treatment-induced minimum NSE.
Others also have confirmed the prognostic significance of pretreatment
serum NSE values, but only a few reports of small numbers of patients
have examined serial serum NSE levels that have allowed for the
assessment of treatment-induced minimum NSE levels. Nou et
al. (16)
performed a longitudinal study of NSE levels
in patients with SCLC. They acquired pretreatment NSE levels and NSE
levels at the time of response in 62 patients. In the group of 39
patients with limited-stage disease, the mean survival was 26.4 months
if the NSE at response was <12 ng/ml, and this survival appeared to
compare favorably with the overall survival of the patients with
limited-stage disease (although statistical comparisons were not done).
The results of the series by Nou et al. (16)
support the concept that certain cutoff values may be of prognostic
significance as minimum values during treatment. As in the present
series, the value of 12 ng/ml appeared to be an important cutoff value
for the minimum NSE level. Additional support for this concept comes
from a study reported by Johnson et al. (26)
.
An inverse relationship existed for the treatment-induced minimum NSE
and time to progression (26)
, similar to the results in
the present study (Fig. 2)
.
The biological ramifications of the clinical associations between NSE
and the time to progression or overall survival of patients with SCLC
are beginning to be explored (27
, 28)
. Recently, Brodin
et al. (27)
described a change in
radiosensitivity over a 6-month period of a SCLC line (U1906) grown in
culture. During the 6 months of culture, the cell line became
radioresistant compared with its initial sensitivity. The
radioresistant change was associated with an increased capacity to
repair radiation-induced damage, as illustrated by an increased
shoulder on the radiation survival curve. Also, the radioresistant
change was associated with increased adherence, decreased cytokeratin
content, and increased glucagon and NSE production. After 6 months of
culture, the cells’ morphology was more neural in appearance
(i.e., pseudopodia developed). The results from Brodin
et al. (27)
raise the question of whether a
mechanistic link may exist between NSE production and response to
current treatments. The general concept regarding the degree of neural
differentiation and its relationship to therapeutic response is the
subject of ongoing in vitro (13)
and clinical
studies. Further work is necessary to completely decipher the role of
NSE in the response to therapy and determine whether the potential
exists for the manipulation of response through the manipulation of
NSE.
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ACKNOWLEDGMENTS
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We thank the following groups and persons for their
participation: Geisinger Clinic and Medical Center CCOP,
Danville, PA 17822 (Dr. Suresh Nair); Rapid City Regional
Oncology Group, Rapid City, SD 59709 (Dr. Larry P. Ebbert); Toledo
Community Hospital Oncology Program CCOP, Toledo, OH 43610; and Sioux
Community Cancer Consortium, Sioux Falls, SD 57105 (Dr. Loren K.
Tschetter).
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FOOTNOTES
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was conducted as a collaborative
trial of the North Central Cancer Treatment Group and Mayo Clinic and
was supported in part by USPHS Grants CA-15083, CA-25224, CA-37404,
CA-35195, CA-52352, CA-35101, CA-35269, CA-37417, CA-35448, CA-63849,
CA-35272, CA-35113, CA-35103, and CA-35415 from the National Cancer
Institute, Department of Health and Human Services. 
2 To whom requests for reprints should be
addressed, at Department of Radiation Oncology, University of Alabama,
619 South 19th Street, WTI105, Birmingham, AL 35233-6832.
3 The abbreviations used are: NSE, neuron-specific
enolase; ESSCLC, extensive stage small cell lung cancer; LSSCLC,
limited stage small cell lung cancer; SCLC, small cell lung cancer.
Received 5/ 7/99;
revised 10/27/99;
accepted 11/ 2/99.
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ABSTRACT
INTRODUCTION
