Download Role of surgical outcome as prognostic factor in advanced epithelial

Original Article
Role of Surgical Outcome as
Prognostic Factor in Advanced
Epithelial Ovarian Cancer: A
Combined Exploratory Analysis of 3
Prospectively Randomized Phase 3
Multicenter Trials
By the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe
Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux
Pour les Etudes des Cancers de l’Ovaire (GINECO)
Andreas du Bois, MD1, Alexander Reuss, MD2, Eric Pujade-Lauraine, MD3, Philipp Harter, MD1,
Isabelle Ray-Coquard, MD4, and Jacobus Pfisterer, MD5
BACKGROUND: Primary surgery followed by platinum-taxane based chemotherapy has been the standard
therapy in advanced ovarian cancer. However, the prognostic role of complete and so-called optimal and
suboptimal debulking and its interaction with biological factors has not been not fully defined. METHODS:
Exploratory analysis was conducted of 3 prospective randomized trials (AGO-OVAR 3, 5, and 7) investigating platinum-taxane based chemotherapy regimens in advanced ovarian cancer conducted between 1995
and 2002. RESULTS: A total of 3126 patients were analyzed. Approximately one-third each fulfilled criteria
for complete resection (group A), small residual tumor burden of 1-10 mm (group B), or macroscopic residual disease exceeding 1 cm in diameter (group C). Multivariate analysis showed improved progression-free
and overall survival for group A with complete resection compared with groups B or C (P < .0001). The
impact of so-called optimal debulking as in group B showed a smaller prognostic impact compared with
group C. Further independent prognostic factors for overall survival were age, performance status, grade,
FIGO stage, and histology, namely the mucinous subtype. An interaction between residual tumor and some
biologic factors was demonstrated. CONCLUSIONS: The goal of primary surgery should be complete
Corresponding author: Andreas du Bois, MD, Department of Gynecology & Gynecologic Oncology, Dr. Horst Schmidt Klinik, Ludwig-Erhard-Str.
100, D-65199 Wiesbaden, Germany; Fax: þ49 611 43 2672; [email protected]
1
Department of Gynecology & Gynecologic Oncology, Dr. Horst Schmidt Klinik, HSK Wiesbaden, Germany (AGO-OVAR); 2Coordinating Centre for
Clinical Trials (KKS), University Marburg (AGO-OVAR statistical centre), Germany; 3Department of Oncology, Hôpital Hôtel-Dieu, Paris, France
(GINECO); 4Department of Oncology, Centre Léon Bérard and EA SIS 4129 Lyon, France (GINECO); 5Department of Gynecology & Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany (AGO-OVAR)
We thank all members of the AGO study group and of GINECO who enrolled patients in the underlying clinical studies. Furthermore, we appreciate
the continuing support of the staff of AGO-OVAR and GINECO including statistical offices, monitors, and study secretariats, namely Gabriele Elser
from AGO-OVAR and Benedicte Votan from GINECO. Finally, we thank the sponsors of the original trials and the German Cancer Society for
support.
Received: July 22, 2008; Revised: September 9, 2008; Accepted: September 18, 2008
C 2009 American Cancer Society
Published online: February 2, 2009, V
DOI: 10.1002/cncr.24149, www.interscience.wiley.com
1234
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Surgical Outcome as Prognostic Factor/du Bois et al
resection. The prognostic impact of tumor biology seemed to be partially overruled by residual tumor and
C 2009
further evaluation of biologic factors should stratify for residual tumor. Cancer 2009;115:1234–44. V
American Cancer Society.
KEY WORDS: ovarian cancer, prognostic factors, surgery, surgical, outcome.
Epithelial ovarian cancer is the fifth most frequent
cause of cancer death in women and remains the leading
cause of gynecologic cancer-related deaths in the US and
Europe.1,2 The mainstay of treatment of advanced ovarian
cancer is primary surgery aiming at complete resection followed by platinum and paclitaxel chemotherapy.3 Until
today, no predictors are available indicating which
patients will respond to chemotherapy and, therefore,
should be exposed to this therapy. However, response
rates are high and regarding the obvious lack of any reliable selection criteria currently all patients receive postoperative chemotherapy. Outcome of chemotherapy mainly
depends on chemosensitivity, a factor currently not
amendable to any influence by the therapist. As homogenous the medical treatment is, as heterogeneous are its
results. Surgical treatment is much more individualized,
and its performance and outcome depends on both resectability of the tumor and patients condition to tolerate
extensive surgical procedures. A further source of heterogeneity is surgical skill, infrastructure, and capacity.4,5
Surgical outcome is to a far greater extent variable and
amendable for being influenced by the therapists.
Surgical outcome in ovarian cancer is usually classified according to the amount of postoperative residual
tumor. A complete resection is regarded if no macroscopically visible tumor is left. If any visible tumor remains
after surgery, it is classified according to its largest diameter. Operations that ended up with residuals up to 1 cm
largest diameter had been formerly classified as ‘‘optimal
debulking’’ whereas those resulting in any larger residual
tumor had been defined as ‘‘suboptimal debulking’’. The
prognostic value of complete and/or optimal debulking
has been reported on several occasions and been confirmed in a meta-analysis.6 Furthermore, a prospectively
randomized trial had shown a significant impact of optimal debulking on further outcome.7 Earlier analysis of
prospectively randomized trials by the Gynecologic Oncology Group (GOG) had indicated that optimal debulking cannot overrule other prognostic factors such as age,
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March 15, 2009
grade, or preoperative tumor spread as indicated by Fédération Internationale de Gynécologie et d’ Obstétrique
(FIGO) substage.8 However, these analyses were based
on older classifications and included mainly patients
with small residual tumor (so-called optimal debulking).
Data analyzing the impact of different surgical outcomes including complete resection in large patient
cohorts treated homogeneously with postoperative platinum-taxan combination chemotherapy are sparse.
Therefore, we performed this exploratory analysis aiming at a better understanding of the impact of surgery
alongside with other prognostic factors in advanced epithelial ovarian cancer.
MATERIALS AND METHODS
The data set was retrieved from the latest 3 prospectively
randomized phase 3 trials in advanced epithelial ovarian
cancer coordinated and performed by the AGO-OVAR
together with GINECO, a French multicenter study
group. All trials were fully published and details were
reported elsewhere.9-11 The inclusion criteria were similar
in all 3 trials and 18 þ -year-old patients after given written consent were enrolled if they had previously untreated
epithelial ovarian cancer FIGO stage IIB-IV.12 Patients
were randomly assigned to 1 of 2 treatment arms consisting of either carboplatin or cisplatin and paclitaxel or to
the comparisons of carboplatin-paclitaxel versus the same
combination added by a third drug in the experimental
arms (epirubicine or topotecan). All patients were scheduled to receive at least 6 courses platinum-taxan intravenously every 3 weeks. None of the trials showed any
significant difference for the different treatment arms
with respect to progression-free or overall survival. Therefore, we combined the data sets for this analysis.
Data were retrieved from the original case report
forms. Quality controls included data source verification
by monitoring, double data entry and in-house monitoring in the central study office. Surgical and pathology
reports were reviewed in almost all patients, central pathology review was performed in only a subset. All
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Original Article
patients were followed until death or end of preplanned
observation period. As indicated in the original protocols,
CA 125 rise without any clinical sign of relapse was not
counted as progression, but commonly induced radiological investigations (CT scans).
Some of the originally enrolled patients were
excluded from this analysis. Mainly, these patients had
been defined as ineligible in the original study reports. In
addition, we excluded patients from this exploratory analysis if metric data about intra- and postoperative findings
or details about surgical procedures were not completely
documented.
Subgroups according to surgical outcome included
patients with complete resection and no visible residuals
postoperatively (group A), patients with small postoperative residuals and largest diameter 1-10 mm (group B),
and patients with residual tumor exceeding 10 mm in
largest diameter (group C). The measurements of residual
tumor diameter were provided by the primary surgeon
and documented postoperatively in the original case
report form. This item was monitored in all patients and
surgical reports and pathology reports were checked for
any implausibilities. We used this commonly reported
classification of residual tumor sizes both for comparability and adherence to the stratification rules in the original
study protocols. Furthermore, we performed a pretest if
any other cutoffs would produce more meaningful separation of prognostic subgroups. For this purpose, Martingale residuals were used to explore the functional form of
the effect of residual tumor size as a continuous variable,
and Akaike (AIC) and Schwarz Bayesian (SBC) information criteria were used to evaluate different categorizations
of this variable.13,14 This analysis did not suggest different
cutoffs (data not shown).
Postoperative chemotherapy was assigned by central
randomization stratified by center and stratum. Stratum 1
contained patients with FIGO stage IIB-III and postoperative residual tumor size of 0-1 cm (so-called ‘‘optimal
debulking’’), stratum 2 contained patients with either
FIGO stage IV disease or residual tumor size larger than
1 cm. Overall survival and progression-free survival were
calculated from the day of randomization in the original
trial. Time-to-recurrence (TTR) was calculated from the
day the last platinum chemotherapy was administered or
the day of the sixth course in patients receiving more than
6 courses. Progression-free (PFS) and overall survival
1236
(OS) after occurrence of recurrence was calculated from
the day on which the first recurrence or progression or
death without prior diagnosis of recurrence was observed.
Cox regression models and Kaplan-Meier estimates
were used to explore the impact of different covariates on
OS and PFS. All statistical analyses were performed using
SAS statistical software (version 9.1.3, SAS Institute,
Cary, NC).
RESULTS
The 3 randomized phase 3 trials had enrolled 3388
patients with advanced epithelial ovarian cancer between
1995 and 2002. Fifteen patients were excluded and classified as ineligible due to violation of inclusion criteria of
the original protocols. Furthermore, 247 patients were
excluded from this exploratory analysis because of missing
details regarding surgery or surgical outcome. The
remaining 3126 patients represent 92.3% of the originally
randomized population and were the basis of this analysis.
At the time point of this analysis, 1837 of the included
patients (58.8%) had died, and further 538 patients
(17.2%) had experienced a relapse. A total of 1289
patients (41.2%) were still living after a median observation period of 53.9 months. The median PFS and OS for
the whole group were 18.2 (95% confidence interval [CI]:
17.3-19.1) and 44.1 (95% CI, 42.3-46.4) months. The
corresponding 5-year PFS and OS rates were 22.6% and
39.0%.
Patient characteristics are displayed for the whole
cohort in Table 1. Approximately one-third each fulfilled
criteria for complete resection (group A), small residual
tumor burden of 1-10 mm (group B), or macroscopic residual disease exceeding 1 cm diameter (group C). A pelvic and/or para-aortic lymphadenectomy was performed
in 43.9% of patients. Lymphadenectomy was only recommended for suitable patients without large residual tumor
but not demanded as inclusion criteria in any protocol.
Univariate analysis revealed age, performance status,
initial FIGO stage, histological grade, presence of large
volume ascites ( 500 mL), and postoperative residual tumor as significant prognostic factors for OS and PFS (Table 2). The different platinum-taxan regimens did not
show any significant impact on OS, as already stated in
the original analyses of all 3 studies (data not shown).
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Surgical Outcome as Prognostic Factor/du Bois et al
Table 1. Baseline Characteristics*
Characteristics
Parameter
No.
%
1190
1592
326
18
38.1
50.9
10.4
0.6
105
172
171
366
1779
530
3
3.4
5.5
5.5
11.7
56.9
17.0
0.1
1557
618
588
363
49.8
19.8
18.8
11.6
244
998
1702
182
7.8
31.9
54.4
5.8
2296
272
147
396
14
73.4
8.7
4.7
12.7
0.4
1046
975
1105
33.5
31.2
35.3
1174
1181
771
58.9
37.6
37.8
24.7
[19.6-83.6]
Performance status
ECOG 0
ECOG 1
ECOG 2
Missing
Stage
FIGO IIB
FIGO IIC
FIGO IIIA
FIGO IIIB
FIGO IIIC
FIGO IV
Missing
Chemotherapy regimen
Carboplatin-paclitaxel (TC)
TC-Topotecan (TC-TOP)
TC-epirubicine (TEC)
Cisplatin-paclitaxel (PT)
Histological grading
G1
G2
G3
Missing
Histological subtype
Serous/papillary
Endometrioid
Mucinous
Others
Missing
Postoperative residual tumor size
0 mm (microscopic)
1-10 mm
>10 mm
Ascites >500 mL
No
Yes
Missing†
Age, y, median [range, y]
ECOG indicates Eastern Cooperative Oncology Group; FIGO, Fédération
Internationale de Gynécologie et d’Obstétrique.
* TC indicates carboplatin AUC 5 þ paclitaxel 175 mg/m2 (OVAR 5, OVAR
7) or AUC 6 þ 185 mg/m2 (OVAR 3) d1 iv q21. PT is cisplatin 75 mg/m2 þ
paclitaxel 185 mg/m2 (OVAR 3) d1 iv q21. TEC is TC AUC5/175 mg/m2 þ
epirubicine 60 mg/m2 (OVAR 5) d1 iv q 21. TC-TOP is TC AUC5/175 mg/m2
d1 q 21 x 6 followed by topotecan 1,25 mg/m2 (OVAR 7) d1-5 q 21 x 4.
y this variable was not documented in the AGO-OVAR 3 study.
Compared with the most common serous-papillary
histotype both the mucinous and endometrioid histological subtype showed a significantly different outcome. The
mucinous subtype predicted an inferior OS (hazards ratio
[HR], 1.76, 95% CI, 1.43-2.15), whereas the endomeCancer
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trioid subtype predicted a superior OS (HR, 0.77, 95%
CI, 0.64-0.91). However, only the mucinous histotype
remained a significant adverse prognostic factor in the
multivariate model. Furthermore, the 3 different surgical
outcome groups differed significantly among each other
with respect to both OS and PFS.
The most striking difference was observed between
complete resection and any macroscopic residual tumor
(Fig. 1A,B). Median survival in group A without any visible residual tumor was 99.1 months (95% CI, 83.5 to -),
the corresponding median survival durations for group B
with residual tumor 1-10 mm and group C with residuals
>10 mm were 36.2 (95% CI, 34.6, 39.4) and 29.6 (95%
CI, 27.4, 32.2) months, respectively (log rank test: P <
.0001). The hazard reduction associated with complete
resection versus any residual tumor were very similar for
PFS and OS and were 66% for PFS compared with 68%
for OS.
A stratified analysis of residual tumor analyzing
patients with FIGO IIB-IIIB, FIGO IIIC, or FIGO IV
separately, revealed a similar relative impact of complete
resection for all groups with different preoperative tumor burden (Fig. 2A,B). The corresponding hazard
reductions for PFS and OS in these 3 groups were
63%/63% in FIGO IIB-IIIB, 61%/64% in FIGO IIIC,
and 47%/51% in FIGO IV, respectively. Comparing
small residuals 1-10 mm to larger residual disease
showed a consistent impact of so-called optimal debulking only for FIGO III (Table 3). However, based on
the available database we could not reliably dissect stage
FIGO IV into subgroups (eg, positive pleural effusion
vs others) for this analysis.
Taken together, these analyses indicate that complete surgical debulking improves prognosis in any FIGO
substage in advanced ovarian cancer but cannot completely overrule the prognostic impact of preoperative tumor burden (as indicated by different FIGO stages).
A similar observation concerned other preoperative
prognostic factors: The stratified analysis among the 3
most common histological subtypes: serous-papillary,
endometrioid, and mucinous did not show any hint for
more or less impact of residual tumor depending on different histological subtypes. The hazard reductions for
complete debulking with respect to PFS and OS were
67%/69%, 67%/70%, and 70%/69% for the serous,
endometrioid, and mucinous subtypes, respectively.
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Table 2. Univariate and Multivariate Cox Regression Models for Overall and Progression-free Survival*
Univariate Analysis
Parameter
Multivariate Analysis
HR
95% CI
P
HR
95% CI
P
1.23
1.76
2.24
2.50
0.77
1.76
2.70
1.34
1.95
(1.17,
(1.54,
(1.99,
(1.99,
(0.64,
(1.43,
(2.37,
(1.21;
(1.76,
1.29)
2.01)
2.53)
3.13)
0.91)
2.15)
3.07)
1.49)
2.16)
<.0001
<.0001
<.0001
<.0001
.0029
<.0001
<.0001
<.0001
<.0001
1.13
1.36
1.45
1.74
0.94
2.38
2.12
1.20
1.36
(1.08,
(1.18,
(1.28,
(1.37,
(0.79,
(1.94,
(1.85,
(1.08,
(1.22,
1.18)
1.56)
1.65)
2.21)
1.13)
2.93)
2.43)
1.33)
1.51)
<.0001
<.0001
<.0001
<.0001
.5030
<.0001
<.0001
.0006
<.0001
1.17
1.51
2.18
2.33
0.76
1.53
2.52
1.36
1.80
(1.12, 1.22)
(1.33, 1.71)
(1.97, 2.42)
(1.93, 2.81)
(0.65, 0.89)
(1.27, 1.84)
(2.26, 2.81)
(1.24, 1.50)
(1.64;1.98)
<.0001
<.0001
<.0001
<.0001
.0004
<.0001
<.0001
<.0001
<.0001
1.07
1.15
1.46
1.66
0.91
2.02
2.03
1.25
1.28
(1.02,
(1.02,
(1.31,
(1.36,
(0.78,
(1.67,
(1.81,
(1.14,
(1.16,
1.11)
1.31)
1.63)
2.01)
1.06)
2.44)
2.27)
1.37)
1.41)
.0019
.0280
<.0001
<.0001
.2165
<.0001
<.0001
<.0001
<.0001
Overall Survival
Age [10 y]
ECOG 2 vs 0-1
FIGO IIIC-IV vs IIB-IIIB
Grading G2/3 vs G1
Endometrioid vs serous histology
Mucinous vs serous histology
Tumor residuals 1-10 mm vs 0 mm
Tumor residuals > 10 mm vs 1-10 mm
Ascites > 500 mL (intraop.) yes vs no
Progression-Free Survival
Age [10 y]
ECOG 2 vs 0-1
FIGO IIIC-IV vs IIB-IIIB
Grading G2/3 vs G1
Endometrioid vs serous histology
Mucinous vs serous histology
Tumor residuals 1-10 mm vs 0 mm
Tumor residuals >10 mm vs 1-10 mm
Ascites > 500 mL (intraop.) yes vs no
HR indicates hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; FIGO, Fédération Internationale de Gynécologie et
d’Obstétrique; intraop, intraoperative finding.
* Both univariate and multivariate models are stratified by study (OVAR 3, 5, and 7).
The reverse approach was used to analyze if any biologic prognostic marker possesses more or less potential in
subgroups defined by postoperative tumor burden. The
stratified analysis of the 3 subgroups A-C defined by surgical resection status showed different penetration of
prognostic factors depending on the amount of residual
postoperative tumor (Table 4). Age, performance status,
mucinous histology, grading, ascites, and FIGO stage
showed a significant prognostic impact in patients without any macroscopic residual tumor both for OS and
PFS. A stepwise decline impact of some biologic factors
was observed in patients with small residual disease up to
1 cm and above 1 cm maximum diameter. Analysis of OS
showed no impact of histologic grade in patients with residual disease. Furthermore, only FIGO stage and mucinous histology retained their prognostic impact for PFS in
both subgroups with macroscopic residual disease. A
reverse separate analysis of the mucinous and serous subtypes showed that only complete debulking and to some
extent performance status had any significant prognostic
impact in the latter poor prognostic histotype (Table 5).
These analyses indicated that postoperative residual tumor overrules most of the biological prognostic factors in
1238
patients not completely debulked. Only FIGO stage,
again a surrogate for tumor burden, remained a significant
prognostic factor in any subgroup defined by surgical outcome and only mucinous histology seemed to be such a
strong biologic factor that its significant impact on outcome could be observed in any surgically defined
subgroup.
Further complexity was observed when we analyzed
the interaction between primary surgical outcome, timeto-recurrence, and overall or progression-free survival after recurrence in the subgroup of patients who developed
recurrence or died within the observation period. Not
only the incidence but also the time pattern of recurrences
(or progression) showed significant differences with
respect to primary surgical outcome (Table 6). The median times to recurrence in patients who experienced recurrence, progression, or death were 15.5, 10.1, and 7.8
months after complete (microscopic residuals only), socalled optimal (residuals 1-10 mm), and suboptimal primary debulking, respectively (log rank: P < .0001). Furthermore, both PFS and OS after progression differed
significantly according to the different time periods before
occurrence of recurrence or progression, thus adding to
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Surgical Outcome as Prognostic Factor/du Bois et al
FIGURE 2. (A) Overall and (B) progression-free survival
according to Fédération Internationale de Gynécologie et d’
Obstétrique (FIGO) stage and size of residual tumor.
FIGURE 1. (A) Overall and (B) progression-free survival
according to size of residual tumor.
the survival benefit observed after complete debulking
(Fig. 3A,B).
DISCUSSION
Many earlier series evaluating prognostic factors in ovarian cancer were comprised of retrospective single institution series and sometimes limited by both rather small
patient numbers and/or heterogeneous treatment pattern.
This report was based on patients who had been prospectively enrolled in 3 consecutive randomized phase 3 trials
which had used almost identical inclusion criteria. Furthermore, all patients were treated in member centers of
cooperative study groups and received systemic treatment
comprised of the currently regarded most effective drugs
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in ovarian cancer, namely platinum and paclitaxel. Therefore, series such as this and similar reports from other cooperative study groups15-17 may help to better understand
the impact of prognostic factors in patients exposed to
current state-of-the-art therapy. This might help to better
select patients for future trials or at least adjusting analysis
of future trials thus avoiding bias by imbalances of patient
distribution regarding possibly important prognostic profiles. Furthermore, understanding of potential interaction
of factors related to patient characteristics, tumor biology,
and therapy-related variables might help to select patient
cohorts suitable for evaluation of new biologic factors or
even therapies by avoiding planning studies in cohorts in
whom strong prognostic factors might overrule potential
alterations of biologic profiles or course of disease in specific subgroups.
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Table 3. Impact of Tumor Resection on Outcome in Different FIGO Stages (Preoperative Tumor Burden)
Initial
FIGO
stage
No Macroscopic
Residual Tumor
Any
Residual
Tumor
No. of
Patients
PFS
(mo)
No. of
Patients
PFS
(mo)
FIGO IIB-IIIB
FIGO IIIC
FIGO IV
497
486
63
91.7
35.0
19.2
317
1293
467
19.1
14.5
12.1
Initial FIGO
stage
Residual tumor
1-10 mm
FIGO IIB-IIIB
FIGO IIIC
FIGO IV
205
613
156
22.2
15.9
13.5
HR*
(95% CI)
No
Residual
Tumor
Any
Residual
Tumor
HR*
(95% CI)
OS (mo)
0.37 (0.31; 0.45)
0.39 (0.35; 0.45)
0.53 (0.39; 0.72)
108.6
81.1
54.6
48.3
34.2
24.6
0.37 (0.30; 0.47)
0.36 (0.31; 0.42)
0.49 (0.34; 0.70)
Residual tumor
>10 mm
HRy
(95% CI)
Residuals
1-10 mm
Residuals
>10 mm
HRy
(95% CI)
112
680
311
0.73 (0.56; 0.95)
0.78 (0.70; 0.88)
0.84 (0.69; 1.03)
52.3
35.6
26.2
41.0
30.7
23.9
0.75 (0.55; 1.01)
0.80 (0.70; 0.91)
0.86 (0.69; 1.07)
16.7
13.7
11.5
HR indicates hazard ratio; CI, confidence interval; PFS, progression-free survival; OS, overall survival; FIGO, Fédération Internationale de Gynécologie et
d’Obstétrique.
* Reference class for HR is ‘‘Any residual tumor’’; PFS and OS (mo), median.
y Reference class for HR is ‘‘residual tumor > 10 mm’’; PFS and OS (mo), median.
Table 4. Multivariate Cox Regression Models of Overall Survival and Progression-free Survival for Subgroups According to
Different Sizes of Residual Postoperative Tumor
No Residual Postop
Tumor
Parameter
Residual Tumor
1-10 mm
Residual Tumor
>10 mm
HR
95% CI
P
HR
95% CI
P
HR
95% CI
P
1.24
1.78
1.41
2.19
0.84
1.97
1.92
(1.11,
(1.24,
(1.13,
(1.45,
(0.61,
(1.26,
(1.52,
1.37)
2.55)
1.75)
3.30)
1.16)
3.08)
2.41)
<.0001
.0016
.0024
.0002
.2867
.0028
<.0001
1.12
1.47
1.49
1.57
0.95
2.76
1.18
(1.03,
(1.16,
(1.20,
(1.00,
(0.69,
(1.90,
(0.96,
1.21)
1.87)
1.85)
2.46)
1.30)
4.02)
1.45)
.0068
.0013
.0003
.0524
.7328
<.0001
.1178
1.10
1.22
1.48
1.46
0.97
2.29
1.31
(1.02,
(1.01,
(1.16,
(0.99,
(0.73,
(1.70,
(1.10,
1.18)
1.47)
1.90)
2.15)
1.29)
3.10)
1.56)
.0103
.0365
.0019
.0569
.8355
<.0001
.0023
1.17
1.53
1.52
2.13
0.84
1.53
1.70
(1.08,
(1.11,
(1.28,
(1.56,
(0.65,
(1.05,
(1.39,
1.27)
2.11)
1.81)
2.91)
1.09)
2.25)
2.07)
.0002
.0091
<.0001
<.0001
.1794
.0282
<.0001
1.02
1.14
1.47
1.26
0.86
2.17
1.19
(0.95,
(0.91,
(1.22,
(0.89,
(0.64,
(1.52,
(1.00,
1.09)
1.42)
1.77)
1.79)
1.15)
3.11)
1.43)
.5969
.2567
<.0001
.1910
.3002
<.0001
.0515
1.06
1.09
1.41
1.38
0.94
2.16
1.19
(0.99,
(0.91,
(1.13,
(0.97,
(0.72,
(1.62,
(1.02,
1.13)
1.30)
1.75)
1.96)
1.22)
2.87)
1.40)
.0912
.3486
.0022
.0693
.6312
<.0001
.0273
Overall Survival
Age [10 y]
ECOG 2 vs 0-1
FIGO IIIC-IV vs IIB-IIIB
Grading G2/3 vs G1
Endometrioid vs serous
Mucinous vs serous
Ascites, yes vs no
Progression-Free Survival
Age [10 y]
ECOG 2 vs 0-1
FIGO IIIC-IV vs IIB-IIIB
Grading G2/3 vs G1
Endometrioid vs serous
Mucinous vs serous
Ascites, yes vs no
HR indicates hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; FIGO, Fédération Internationale de Gynécologie et
d’Obstétrique.
We found a tremendous impact of surgical outcome
after initial debulking surgery in advanced ovarian cancer
with both impact on progression-free and overall survival.
This had already been reported before and was confirmed
in more recent analysis.8,14 However, we could not confirm, that the impact of complete debulking was only limited to better prognosis ovarian cancer as had been
postulated by another European group.15 Our results fit
1240
well with a recently reported observation of the GOG
indicating a significant impact of complete tumor resection even in FIGO IV disease.16 Furthermore, we
observed this strong impact of surgical outcome in all
prognostic subgroups with respect to initial FIGO substages of advanced ovarian cancer (ie, different preoperative tumor burden). An earlier analysis of the GOG had
suggested that the impact of optimal debulking could not
Cancer
March 15, 2009
Surgical Outcome as Prognostic Factor/du Bois et al
Table 5. Multivariate Cox Regression Models of Overall and Progression-free Survival for Serous and Mucinous Ovarian
Cancer
Serous Histology
Parameter
Mucinous Histology
HR
95% CI
P
HR
95% CI
P
1.15
1.22
1.50
1.67
2.16
1.16
1.36
(1.09,
(1.05,
(1.29,
(1.26,
(1.84,
(1.03,
(1.20,
1.22)
1.43)
1.75)
2.21)
2.54)
1.31)
1.55)
<.0001
.0117
<.0001
.0004
<.0001
.0141
<.0001
1.18
1.98
1.10
1.95
2.40
1.01
1.43
(0.98,
(1.01,
(0.65,
(0.99,
(1.35,
(0.62,
(0.85,
1.43)
3.87)
1.88)
3.84)
4.29)
1.65)
2.40)
.0773
.0456
.7131
.0523
.0031
.9559
.1801
1.09
1.06
1.50
1.60
2.07
1.22
1.25
(1.04,
(0.92,
(1.32,
(1.26,
(1.81,
(1.10,
(1.12,
1.14)
1.23)
1.71)
2.03)
2.37)
1.36)
1.40)
.0006
.4325
<.0001
.0001
<.0001
.0003
<.0001
1.12
1.52
1.22
1.69
2.51
1.09
1.42
(0.95,
(0.79,
(0.74,
(0.92,
(1.46,
(0.69,
(0.88,
1.32)
2.92)
2.03)
3.12)
4.30)
1.72)
2.31)
.1925
.2144
.4355
.0915
.0008
.7221
.1488
Overall Survival
Age [10 y]
ECOG 2 vs 0-1
FIGO IIIC-IV vs IIB-IIIB
Grading G2/3 vs G1
Residual tumor 1-10 mm vs 0 mm
Residual tumor >10 mm vs 1-10 mm
Ascites, yes vs no
Progression-Free Survival
Age [10 y]
ECOG 2 vs 0-1
FIGO IIIC-IV vs IIB-IIIB
Grading G2/3 vs G1
Residual tumor 1-10 mm vs 0 mm
Residual tumor >10 mm vs 1-10 mm
Ascites, yes vs no
n indicates number of data sets in univariate model; HR, hazard ratio; CI, confidence interval; ECOG indicates Eastern Cooperative Oncology Group; FIGO,
Fédération Internationale de Gynécologie et d’Obstétrique.
Table 6. Time Pattern and Frequency of Recurrence in Relation to Surgical Outcome After Primary Debulking Surgery in
Advanced Ovarian Cancer*
Time to Recurrence in Patients With Recurrence or Death
Alive Without
Recurrence
0-6 Months
6-12 Months
‡12 Months
Outcome 1st OP
No.
(%)
No.
(%)
No.
(%)
No.
(%)
No residuals
Residuals 1-10 mm
Residuals >10 mm
All
483
158
110
751
46.2
16.2
10.0
24.0
93
213
376
682
8.9
21.8
34.0
21.8
120
263
321
704
11.5
27.0
29.0
22.5
350
341
298
989
33.5
35.0
27.0
31.6
OP indicates operation (surgery).
* All percentages were calculated by rows; chi-square: P < .0001 for the 3 categories of initial surgical outcome and the 3 recurrence interval categories.
overrule preoperative tumor load8 and more recently,
some investigators restarted to challenge if radical surgery
switching small macroscopic residuals to microscopic
residuals has any significant impact on outcome at all or if
the course of disease is determined by preoperative tumor
spread and biologic profiles.18,19 We found comparable
effects of surgical debulking in all different subgroups
defined by biologic tumor characteristics such as histology
or different preoperative tumor loads. Nevertheless, biologic factors, especially histological type mucinous carcinoma remained an independent strong prognostic factor
and both factors seemed to contribute independently to
patients’ outcome in our series.
Cancer
March 15, 2009
More recently, the definitions of desirable surgical
outcome switched from so-called optimal debulking with
variable residuals up to 1 or 2 cm20,21 to microscopic
residuals only.22-25 Our data confirmed the rationale
behind this development. So-called optimal debulking
resulting in small but macroscopic postoperative tumor
residuals had some impact in our series, but was far less
important than the impact of complete resection without
any macroscopic residual. More interestingly, the prognostic power of variables related to tumor biology or
patient characteristics vanished with increasing negative
prognostic impact of large residual tumor lesions. This
might have an impact on planning of future trials. New
1241
Original Article
FIGURE 3. (A) Overall and (B) progression-free survival after
occurrence relapse/progression stratified for time-to-recurrence 0-6 versus 6-12 versus 12 months or longer following
the last or sixth course of primary platinum-paclitaxel
chemotherapy.
treatment approaches with potential interference with
biologic factors may be overlooked in study populations
dominated by the impact of residual tumor in cohorts not
completely debulked.
Our analysis in the subgroup with mucinous ovarian
cancer raise the question if surgical approaches should be
reconsidered in this poor-prognostic subgroup who did
not show any benefit from so-called optimal debulking.
In our analysis, only complete debulking had an impact
on outcome in mucinous ovarian cancer. However, this
result was based on only 147 patients with that histotype
and should be re-evaluated by others.
The achievement of complete resection showed an
impact on the course of disease even after occurrence of
recurrent disease. A similar interaction of outcome of primary surgery and treatment for relapsed disease was al1242
ready observed in a recent analysis of surgery for recurrent
ovarian cancer.26 The limitations of our analysis hampered us to further analyze this issue because we had not
documented details regarding treatment for recurrence in
the original studies.
The main limitation of our approach is that we
could not analyze data regarding the infrastructure and
surgical skills of all member institutions contributing to
the original studies. Therefore, we cannot rule out that
not only surgical outcome was determined by the patients
choice of institution for primary therapy but also those
therapists who performed better surgery tended to provide
superior treatment for relapsed disease. Many reports
have already reported different surgical outcomes associated to therapist characteristics such as specialization,
study participation, and hospital volume.4,5,27 In summary, these reports as well as our data reconfirming the
utmost importance of complete surgical resection question the current practice of treating ovarian cancer.
Another limitation was based on the original study designs
demanding upfront surgery only. Therefore, our results
might not be valid for patients receiving neoadjuvant
chemotherapy followed by interval debulking surgery.
Some retrospective series have already suggested that the
role of complete macroscopic resection after neoadjuvant
chemotherapy might not be comparably strong than after
primary debulking.28-30
What information could be gathered for prognostic
factors not related to therapy? Mucinous histology was a
strong prognostic factor not correctable by any therapeutic intervention. The particularly poor outcome in the
mucinous adenocarcinoma subgroup has been reported
by others as well and may indicate a need for different
studies addressing specific questions for this subtype.31 At
least, future trials should stratify for histology to avoid
bias by maldistribution of mucinous tumors. Others have
reported an impact of other histotypes as well. Clear cell
tumors had been associated with an impaired prognosis32
and transitional cell tumors have been reported to have a
better prognosis.33 However, both mentioned subtypes
were too rare for separate analysis in our population, thus
suggesting intergroup approaches to elucidate if further
histological differentiation should be suggested in future
studies. In our study, endometrioid ovarian cancer
showed a trend for better prognosis; however, this could
not be confirmed in the multivariate analysis. In addition,
Cancer
March 15, 2009
Surgical Outcome as Prognostic Factor/du Bois et al
other histological factors such as grading played only a
role as prognostic factor in completely debulked patients
thus indicated a limited value as prognostic factor in unselected cohorts. The same accounted for patient-related
factors such as age or performance status. However, all
analysis of patient related factors in collectives based on
prospective clinical studies are limited by study selection
bias. Patients with impaired performance status and elderly patients are systematically underrepresented in ovarian cancer trials34 and sincere analysis of these factors
would need epidemiological studies.
In summary, our analysis confirmed the outstanding
importance of surgical debulking and its impact on prognosis in advanced ovarian cancer. The factor should be
regarded at least as stratification factor in future clinical
trials. The AGO Study Group has already changed their
stratification module, dividing patients in cohorts with
complete resection versus those with any residual tumor.
Conflict of Interest Disclosures
None of the authors declared any conflict of interest regarding
the subject of this study. However, the included prospectively
randomized international phase 3 studies were supported by
Bristol-Myers-Squibb, Pfizer, and Glaxo-SmithKline.
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