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Prognostic Factors in Advanced Nonseminomatous
Testicular Cancer
A Multivariate Logistic Regression Analysis
JEAN P. DROZ, MD," ANDREW KRAMAR, MSc,t MARWANE GHOSN, MD,* GILLES PIOT, MD,* ANNIE REY, AS,?
CHRISTINE THEODORE, MD,* PIERRE WIBAULT, MD,* BERNARD H. COURT, MD,§ JEAN L. PERRIN, MD,§
JEAN P. TRAVAGLI, M D , ~DOMINIQUE BELLET, MD,/I J. M. CAILLAUD, MD,II
JOSE L. PICO, MD,' AND MARCEL HAYAT, MD*
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In order to define prognostic factors for advanced stage of nonseminomatous germ cell tumors (NSGCr)
of the testis, the authors reviewed 84 patients treated from 1978 through 1985. The survival rate was
51% at 3 years. Patients with elevated seric levels of human chorionic gonadotropin (HCG) and/or
alpha-fetoprotein (AFP), or the presence of an abdominal mass had significantly worse survival. Only
HCG and AFP levels retained their significance when multivariate Cox analysis was performed. The
probability that a patient achieves a complete remission (CR) was assessed by a function of certain
patient characteristics using a multivariate logistic regression analysis. The significant variables were a
function of HCG and AFP values. Since both variables are related to the CR rate and survival the
authors define the obtention of a CR as a unique outcome of interest. The probability of a CR greater
than 70%adequately separates the patients into two prognostic subgroups. This model currently is being
used to enrole NSGCT patients in a prospective modulated clinical trial according to these prognostic
factors.
Cancer 62564-568,1988.
T
Of advanced Stage
of nonseminomatous germ cell tumors (NSGCT)
of the testis has been greatly improved by modern
chemotherapy regimens including cisplatin.1-4 Nevertheless the complete remission rate is still low in some
subgroups of patients.*p3
Some prognostic factors have been described by different authors: size and number of lung metastasis,596
palpable abdominal mass,' visceral meta~tasis,~
performance status,'
choriocarcinoma component,"
presence of human chorionic gonadotropin (HCG),'."
HCG level,73 O3 2* alpha-fetoprotein (Am) level, 2,
lactate dehydrogenase (LDH) level,7 rate of markers'
decrease during ~hemotherapy,'~
prior treatment7," and
time between diagnosis and treatment.I2 These factors
often are correlated and their combined statistical imHE RESULT OF THE TREATMENT
portance needs to be investigated with multivariate analyses.
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Patients and Methods
Eighty-four patients with advanced stage of NSGCT
of the testis, treated between January 1978 and February
1985, at Institut Gustave-Roussy (IGR) were reviewed.
The histologic material of all the patients was reviewed
by the same pathologist and classified according to the
World Health Organisation (WHO) classification.'' The
advanced stage was defined as the presence of a palpable
abdominal mass (greater than 10 cm at computerized
tomography [CT] scan or ultrasonography), and/or the
presence of distant metastases. The biological markers,
AFP, HCG, P-HCG, were determined in all patients
before therapy by a radioimmunoassay. Alpha-fetoprotein was expressed in ng/l (normal, <30 ng/l) and HCG
in mIU/ml(6.6 mIU/ml = 1 ng/l; normal, <10 mIU/
ml). Lactate dehydrogenase was performed in a very
small proportion of patients.
Patients were treated by three successive protocols
(Table 1). Between January and December 1978, 18
patients were treated by IGR protocol T78. The IGR
protocol T79 then was administered to 41 patients be-
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3"
'
From the Departments of *Medicine, tstatistics, $Radiotherapy,
§Urology, (1 Biology, and llPathology,Institut Gustave-Roussy,France.
Address for reprints: Jean-Pierre Droz, MD, Department of Medicine, Institut Gustave-Roussy, Rue Camille Desmoulins, 94800-Villejuif-France.
The authors thank Dr. Goupil, Dr. Kerbrat, and Dr. Fargeot for
providing data from the Urologic Intergroup from the French Federation of Cancer Centers, and Mrs. M. Belleteste for secretarial help.
Accepted for publication January 9, 1988.
564
No. 3
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PROGNOSTIC
FACTORS
IN TESTIS
CANCER
tween January 1979 and December 1981.16The last 25
patients were treated by IGR protocol T82 between
January 1982 and February 1985. All patients were previously untreated before entering these three successive
protocols.
Droz et al.
565
TABLE1. Chemotherapy Regimens
T78
T79
VAB-3 regimen (12 patients) PVB (6 patients)
Doxorubicin
25 mg/m2
dl
Vinblastine
7 mg/m2
d2
d 2, 3, 4, 5 in CI
Bleomycin
7 mg/m2/d
Dactinomycin
0.3 mg/m2/d
d 3,4
Cyclophosphamide
200 mg/m2/d
d 3,4
90 mg/m2
d4
Cisplatin
Vinblastine
I mg/m2
dl
I0 mg/m2/d
d 1, 2, 3, 4 in CI
Bleomycin
Dactinomycin
0.3 mg/m2/d
d 2, 3
Cyclosphamide
200 mg/m2
d2,3
Cisplatin
100 mg/m2
d2
Analysis and Statistical Methods
The initial characteristics of the patients, the histologic type of the tumor, the treatment regimens, and the
follow-up data were registered on a specific form. Data
were analyzed using a general database management
sy~tem.’~
Complete remission (CR) was defined as the disappearance of any clinical or radiologic evidence of metastasis and normalisation of HCG and AFT markers. In
case of clinical and/or radiologic partial response and
normalization of HCG and AFP markers, patients were
submitted to a surgical excision of residual disease. If the
histologic pattern of the removed lesions was necrosis,
fibrosis, or mature teratoma, the patient was classified as
a complete response. All records were reviewed by one
investigator. The criteria of CR were the same throughout the period of the study.
The obtainment of a CR was defined as a unique goal
for identifying prognostic factors. The importance of
each known prognostic factor measured at diagnosis on
the achievement of a complete remission was analysed
using a x2 test. A logistic regression analysis” then was
performed in order to identify prognostic factors for a
predictive CR rate. Patients were then classified according to whether or not their probability of a CR was
greater than 70%.
The origin of survival was the date of the primary
chemotherapy and the endpoint was the date of last
follow-up or death of the patient. Survival curves were
estimated by the Kaplan-Meier method. l9 The log-rank
test” was used to select variables to be included in the
Cox regression analysis.’l All variables which were significant at the 5% level in the univariate analysis were
included in the multivariate analysis. Model selection
for identifying the variables that have an important effect on survival was based on a forward stepwise procedure. The variables were entered on the basis of significance calculated from a large sample partial likelihood
ratio test.
.
T82
VAB-3: vinblastine, bleomycin, actinomycin, doxorubicin, cisplatin, cyclophosphamide; PVB: cisplatin, vinblastine, bleomycin; CI:
continuous infusion.
no significant difference as to survival between the three
groups. Three patients had some biological variables not
available for study.
Complete Remission
The probability (P) of a patient with advanced-stage
NSGCT achieving a CR was assessed by a function of
certain patient characteristics using a multivariate logistic regression analysis. The characteristics included were
those found significant in an univariate analysis (Table
2). The significant variables were HCG and AFP values
and the presence of an abdominal mass, as well as the
presence of visceral metastasis. The probability (Pi)for a
patient i to be in CR is as follows:
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TABLE2. Complete Remission Rate According
to Patient Characteristics
Prognostic variables
Histopathologic characteristics
Choriocarcinoma component
No choriocarcinoma component
Markers
HCG (mIU/ml)
<10
10-6000
>6000
AFP (ng/ml)
130
30- 1000
> 1000
Lung metastasis
No
5 2 cm and <5/lung
2 2 cm and/or >5/lung
Abdominal mass
No
Yes
Visceral metastasis
No
Yes
No.
CR
Percent
Pvalue
46
38
28
23
60
60
NS
22
38
21
17
26
7
77
68
33
<0.01
42
22
17
28
17
~0.01
5
66
77
29
31
21
32
19
16
16
61
76
50
47
37
33
18
70
48
o.04
76
8
49
64
25
o.03
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Results
The clinical findings and the histologic features were
not different between the three treatment protocols. The
overall CR rate was 61%,and it was not significantly
different between the three groups (IGR T78 = 12/18;
IGR T79 = 26/41; IGR T82 = 13/25). The overall survival rate at 3 years was 5 1%. A log-rank analysis showed
2
NS
CR: complete remission; HCG: human chorionic gonadotropin;
AFP: alpha-fetoprotein;N S not significant.
566
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CANCERAugust 1 1988
..................................................
1o
7'"'
Vol. 62
the two groups (CR versus non-CR) and the correct predictions were similar.
Complete Remission Analysis of an Independant
Data Set
0
0.2
0.4
0.6
0.8
PROBABILITY
The validity of our model was then tested against a
sample of 29 patients treated by the Intercenter Urologic
Group of the French Federation of Cancer Centers. The
patients were previously untreated but received different
classical regimens of cisplatin-containing chemotherapy. The observed responses were compared against responses predicted by our linear function and correctly
predicted 72% overall. The correct prediction of not responding eventually was 69% (1 1/16) and the correct
prediction of responding eventually was 77% ( 1O/ 13).
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FIG.1. Probability of CR in observed non-CR group.
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Survival
Pi = exp(hi)/(1 + exp(hi))
where hi is a linear function of several variables for patient i. The coefficients were estimated by maximizing
the likelihood function and the significance of variables
were tested using the likelihood ratio test. The following
variables were retained by the model after a forward
stepwise procedure: initial HCG and initial AFP values.
The estimated linear function was as follows:
hi
=
1.90 - 0.033 VAFPi
- 0.02 1
lHCGi + 0.033 HCGi/ 1.000
The correct overall prediction was 75% (61/81); the
correct prediction of not responding eventually was 77%
(24/3 1) (Fig. 1);and the correct prediction ofresponding
eventually was 74% (Fig. 2). The cutoff point at 70%was
chosen because it achieved the best separation between
................................
....
20
>
a
hit) = hdt)
X
exp(0.634 H 1 + 1.495 H2
+ 0.187 A 1 + 1.045 A2)
where HI = 1 if 10 IHCG < 6000,O otherwise; H2 = 1
if HCG > 6000, 0 otherwise; A1 = 1 if 30 s AFP
< 1000, 0 otherwise; and A2 = 1 if AFP 2 1000, 0
otherwise.
Table 4 shows the relative risk of death for different
combinations of HCG and AFP for this model. For example, the relative risk for a patient with HCG = 2000
and AFP = 300 is 2.42 times greater than the risk for the
reference category which is defined as HCG < 10 and
AFP < 30.
20
Discussion
z
3
At the time of analysis, 39 of the 84 patients had died.
The median follow-up was 3 years. The survival rate at 3
years was 5 1%. Eight variables were tested in a univariable analysis using the log-rank test (Table 3). Forward
stepwise procedure using the Cox proportional hazards
model revealed the prognostic significance of serum
HCG and serum AFP levels. Interactions between HCG
and AFP were tested for using a likelihood test and were
not found to be significant. The hazard function of the
Cox survival model is given by the following:
In
a
10
5 -I
..................................
0
0
0.2
0.4
0.8
0.6
PROBIBILITY
FIG.2. Probability of CR in observed CR group.
The broad range of survival rates for patients with
NSGCT is very large and clearly related to the occurrence of a complete remission with the first treatment.'-3,12Our study has used a logistic regression analysis to analyze the impact of prognostic factors on the
obtention of a complete remission and a Cox regression
model to analyze the impact of prognostic factors on the
survival. Both analyses has shown the significance of the
level of serum HCG and the level of serum AFP. Since
both factors are related to the CR and survival, we de-
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No. 3
PROGNOSTIC FACTORS
IN TESTISCANCER
*
DrOZ
et d.
567
TABLE
4. Relative Risk of Death
TABLE
3. Survival Analysis for Prognosis Factors
Using Log-Rank Test
AFP
Variables
HCG (mIU/ml)
510
10-6000
>6000
AFP (ng/ml)
530
30- 1000
>loo0
Abdominal mass
( < l o cm)
No
Yes
Histopathologic
characteristics
Choriocarcinoma
component
No choriocarcinoma
component
Lung mtastasis
No
5 2 cm and <5/lung
>2 cm and/or >5/
lung
Visceral mtastasis
No
Yes
Protocol
T78
T79
T82
2-yr
survival
rates
No. of
patients
HCG
P value
<10
10-6000
26000
0.72 (0.10)
0.64 (0.08)
0.36 (0.11)
22
38
21
0.004
0.63 (0.08)
0.67 (0.10)
0.37 (0.13)
42
22
17
0.036
0.67 (0.07)
0.50 (0.08)
47
37
0.042
0.54 (0.08)
46
0.66 (0.09)
38
0.60 (0.07)
31
21
0.50 (0.09)
32
0.60 (0.06)
0.57 (0.19)
76
8
0.168
18
41
25
0.812
<30
30- 1000
2 1000
1
1.89
4.46
1.21
2.27
5.38
2.84
5.36
12.68
~
HCG: human chorionic gonadotropin; AFP: alpha-fetoprotein.
0.210
0.446
good prognosis was chosen to be 0.50. Using this cutoff
point they achieved an overall correct prediction of 83%,
56% of non-CR, and 94% of CR. When the cutoff point
of 70% was used, the overall correct prediction is 79%,
84% of non-CR, and 77% of CR. When a cutoff point of
50% is used in our study, the results are an overall correct prediction of 75% with 55% of non-CR and 88% of
CR. The results of this study are very similar to ours,
even though our study was based on only 84 patients.
The choice of a particular cutoff point in defining
good and poor prognostic patients depends on the treatment strategy to be adopted and the balance between
treatment efficacy and toxicity. Bajorin et al. tested
three models on their data and came to the conclusion
that all of them overestimated poor-risk patientsz2
The model developed at Indiana University" uses a
clinicobiological classification issued from the M. D.
Anderson
A European Organization for Research on the Treatment of Cancer (EORTC) study"
also used a logistic regression model and identified four
group of patients according to the combination of the
following prognostic factors: presence of trophoblastic
component, level of HCG, presence of lung metastasis,
and size and number of the lung metastasis.
Our model is based on the HCG and AFP serum
levels. These markers, when elevated or nonelevated, are
closely related to the histologic component of the tumor,
and their level is correlated to the tumor burden.z3Nevertheless, the assessment of a predicted CR value is
closely dependent on the quality of the markers dosage.
The same method of dosage is warranted for the reproductibility of this model. We emphasize the interest in
defining prognostic subgroups of patients with numeri-
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HCG human chorionic gonadotropin; AFP: alpha-fetoprotein.
fine obtaining of a CR as a unique outcome of interest.
The probability of a CR greater than 70% adequately
separates the patients in two prognostic subgroups. No
advantage is noted when an intermediate subgroup with
a predicted CR rate between 0.30 and 0.70 is individualized (Table 5). Our predictive model has been tested on
a population of 29 patients and the CR predictive rate
also was valid in that population.
The prognostic factors were first described in 1975.5
These factors were obtained by an univariate analysis of
different variables. Since 1983 four multivariateanalysis
were r e p ~ r t e d . ~ "The
~ - ' ~Cox regression model performed by the Medical Research Council Working Party
on Testicular Tumors'* revealed three prognosticgroups
identified by combination of the following variables:
tumor volume, serum AFP, and serum HCG. The first
multivariate logistic regression analysis was published in
1983.7It gives a continuous spectrum of predicted CR
according to three prognostic factors: logarithm of
serum HCG level and serum LDH level and the number
of involved sites. The cutoff point between poor and
TABLE
5. Observed Versus Predicted Response
With Three Subgroups
~~
~
Probability of CR
Observed response
Complete remission
Yes
No
CR: complete remission.
530%
3 1%-69%
270%
3
14
10
10
37
7
568
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CANCERAugust 1 1988
cal measurements instead of clinical assessment, which
could be difficult to define according to the workup of
patients.
Currently, no model could be considered as universal,
as has recently been pointed out.24It is thus highly recommended to take the greatest care in the interpretation
of all published results concerning the treatment of
poor-prognosis patients. The model presented in this
study currently is being used in our institution to enroll
previously untreated patients in a prospective clinical
trial for the treatment of NSGCT according to prognostic factors. Good prognostic patients are treated with
standard chemotherapy whereas poor prognostic patients are treated with high-dose chemotherapy followed
by autologous bone marrow transplantation after two
cycles of conventional intensive chemotherapy.*’ This
trial validates the model and measures the efficacy and
the toxic cost of intensified treatment in poor-prognosis
patients.
Vol. 62
cancer: Response to treatment and prognostic correlations. A Southwest Oncology Group study. Eur J Cancer 1980 16:1359- 1 366.
9. Von Eyben FE, Jacobsen GK, Pedersen H et al. Multivariate
analysis of risk factors in patients with metastatic testicular germ cell
tumors treated with vinblastine and bleomycin. Invasion Metastasis
1982; 2:125-135.
10. Stoter G, Sylvester R, Sleijfer DT et a/. Multivariate analysis of
prognostic factors in patients with disseminated nonseminomatous
testicular cancer: Results from an European Organisation for Research
on Treatment of Cancer Multi-Institutional Phase 111 study. Cancer
Res 1987; 47:2714-2718.
1 1. Birch R, Williams S, Cone A et a/. Prognostic factors for favorable outcome in disseminated germ cell tumors. J Clin Oncol 1986;
4~400-407.
12. Medical Research Council Working Party on Testicular
Tumors. Prognostic factors in advanced nonseminomatous germ cell
testicular tumors: Results ofa multicentric study. Lance? 1985; 1:8-11.
13. Javadpour N, Young JD. Prognostic factors in nonseminomatous testicular cancer. J Urol 1986; 135:497-499.
14. Lange PH, Vogelzang NJ, Goldman A, Kennedy BJ, Fraley EE.
Marker half-life analysis as a prognostictool in testicular cancer. J Uro/
1982; 128:708-711.
15. Mostofi FK, Sobin LH. Histological Typing of Germ Cell
Tumors, no. 16. Geneva: World Health Organization, 1977.
16. Droz JP, Kramar A, Piot G et al. Treatment of advanced germ
cell tumors of the testis: Gustave Roussy Institute experience (1979198 1). Forty-one cases (Submitted for publication).
17. Wartelle M, Kramar A, Jan P, Kruger D. PIGAS: An interactive
statistical database management system. In: Proceedings of the International Workshop on Statistical Database Management, 1983;
124- 132.
18. Anderson S , Auquier A, Hauck WW, Oakes D, Vandaele W,
Weisburg HI. Logit analysis. In: Statistical Methods for Comparative
Studies. New York John Wiley and Sons, 1980; 161-273.
19. Kaplan EL, Meir P. Non parametric estimation from incomplete observations. J A m Stat Assoc 1958; 53:457-48 1 .
20. Mantel N, Haenszel W. Statistical aspects of the analysis of data
from retrospective studies of disease. J Nut/ Cancer Inst 1959; 22:7 19748.
21. Cox DR. Regressions models and life tables (with discussion). J
R Stat SOCSer 1972; B34: 187-220.
22. Bajorin D, Katz A, Bosl GJ, Myers WPL. Comparison of eligibility criteria of studies assigning germ cell tumor (GCT) patients (pts)
to good risk (GR) and poor risk (PR) categories (Abstr). Proc Am Soc
Clin Oncol 1986; 5: 104.
23. Droz JP, Sancho-Garnier H, Caillaud JM, Amiel JL, Brule G.
Prognostic factors in advanced stages of non-seminomatous germ cell
testicular tumors (Abstr). Proceedings of the 2nd European Conference on Clinical Oncology and Cancer Nursing, 1983; 153.
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Int JAndrol 1987; 10:225-237.
25. Droz JP, Pic0 JL, Ghosn M eta/.Preliminary results ofa modulated protocol of treatment for advanced stage of nonseminomatous
germ cell tumors based on prognostic factors (Abstr). Proceedings of
the 14th International Cancer Congress, 1986; Karger, Basel, 205.
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