Gynecologic Oncology 135 (2014) 223–230
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Impact of neoadjuvant chemotherapy cycles prior to interval surgery in patients with advanced epithelial ovarian cancer P.E. Colombo a,⁎, M. Labaki a, M. Fabbro b, M. Bertrand a, A. Mourregot a, M. Gutowski b, B. Saint-Aubert a, F. Quenet a, P. Rouanet a, C. Mollevi c a b c
Department of Surgical Oncology, Montpellier Cancer Institute (ICM), 34298 Montpellier, France Department of Medical Oncology, Montpellier Cancer Institute (ICM), 34298 Montpellier, France Department of Biostatistics, Montpellier Cancer Institute (ICM), 34298 Montpellier, France
H I G H L I G H T S • EOC patients receiving late Interval Debulking Surgery (N4 NAC-cycles) have a poor prognosis compared to patients receiving early IDS. • The impact of surgical timing is reinforced in the subgroup with complete debulking and remains independent from other prognostic factors. • The relative contribution of the therapeutic sequence compared to tumor biology and chemotherapy response on prognosis remains controversial.
a r t i c l e
i n f o
Article history: Received 30 May 2014 Accepted 3 September 2014 Available online 16 September 2014 Keywords: Epithelial ovarian cancer Neoadjuvant chemotherapy Interval surgery Number of cycles Prognosis
a b s t r a c t Objectives. Complete surgery with no macroscopic residual disease (RD) at primary (PDS) or interval debulking surgery (IDS) is the main objective of surgery in advanced epithelial ovarian cancer (EOC). The aim of this work was to evaluate the impact on survival of the number of neoadjuvant chemotherapy (NAC) cycles before IDS in EOC patients. Methods. Data from EOC patients (stages IIIC–IV), operated on between 1995 and 2010 were consecutively recorded. NAC/IDS patients were analyzed according to the number of preoperative cycles (b4 = group B1; N 4 = group B2) and compared with patients receiving PDS (group A). Patients with complete resection were specifically analyzed. Results. 367 patients were analyzed, 220 received PDS and 147 had IDS/NAC. In group B, 37 patients received more than 4 NAC cycles (group B2). Group B2 patients presented more frequently stage IV disease at diagnosis (p b 0.01) compared to groups A and B1. The rate of complete cytoreduction was higher in group B (p b 0.001). Patients with no RD after IDS and who had received more than 4 NAC cycles had poor survival (p b 0.001) despite complete removal of their tumor (relative risk of death after multivariate analysis of 3 (p b 0.001)) with an independent impact from disease stage and WHO performance status. Conclusions. Patients with advanced EOC receiving complete IDS after more than 4 cycles of NAC have poor prognosis. Despite worse prognostic factors observed in this group of patients, our study reinforces the concept of early and complete removal of all macroscopic tumors in the therapeutic sequence of EOC. © 2014 Elsevier Inc. All rights reserved.
Introduction Epithelial ovarian cancer (EOC) remains the main cause of gynecological cancer death in developed countries reflecting advanced-stage disease at clinical diagnosis and early propensity for peritoneal dissemination [1]. The standard treatment for advanced EOC consists of optimal cytoreductive surgery associated with a platinum/paclitaxel-based ⁎ Corresponding author at: Department of Surgical Oncology, Montpellier Cancer Institute (ICM), 208 Rue des Apothicaires, Parc Euromedecine, 34298 Cedex 5, Montpellier, France. Fax: +33 46 761 8501. E-mail address: [email protected] (P.E. Colombo).
http://dx.doi.org/10.1016/j.ygyno.2014.09.002 0090-8258/© 2014 Elsevier Inc. All rights reserved.
chemotherapy [1]. Despite very high initial chemosensitivity and frequent clinical complete response, the majority of patients relapses and progressively develops resistance to the various chemotherapeutic treatments [2,3]. Over the last decades, retrospective and prospective studies have established that the result of the surgical procedure, defined by the amount of residual disease (RD), was the most important factor impacting on survival [4,5]. It has been now demonstrated that a large improvement in the prognosis of EOC patients is associated with the removal of all macroscopic disease and complete surgery has become the principal goal of the surgical management of advanced EOC [6–10]. Incomplete surgery with any macroscopic RD is associated with a poor survival even with low RD (b1 cm) that appears to give a
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small and limited prognostic impact compared to larger (so-called nonoptimal) RD (N 1 cm) [10]. Neoadjuvant chemotherapy (NAC) and interval debulking surgery (IDS) have been proposed in the management of advanced EOC to increase the rate of complete surgery while reducing surgical morbidity [9,11]. Initially reserved for unresectable disease or for patients in poor general condition, the prescription of NAC and IDS has increased over the past two decades and the first debulking is now often attempted only after several cycles of chemotherapy. The noninferiority of IDS after 3 cycles of NAC compared to upfront surgery has been reported by Vergote et al. in a large phase III randomized trial including patients with advanced stages IIIC–IV EOC [9]. Nevertheless, optimal surgical timing and selection criteria for NACT and IDS remain controversial in clinical practice. In parallel, large retrospective studies and meta-analyses have observed a large survival advantage for EOC cancer patients receiving initial and complete removal of all macroscopic tumors prior to initiation of chemotherapy [12]. Furthermore, the quality of surgery was heterogeneous in the EORTC trial with large variations in surgical aggressiveness and complete resection rates among participating centers. This argument has been raised to explain the comparatively low survival observed for patients treated with upfront surgery in this study [12]. Furthermore, retrospective data have also suggested that NAC and IDS compared to primary surgery may increase the risk of developing platinum-resistant disease and less sensitive recurrent disease [13]. To date, timing of surgery in the therapeutic sequence of EOC and the selection of patients who will benefit from primary surgery or NAC-IDS remain controversial. In the case of NAC and IDS, high disparities also exist as to how many cycles of NAC should be given prior to IDS, ranging from three to six or more. For advanced or unresectable disease, some authors have recently proposed to increase the number of NAC cycles with the aim of improving the rate of complete resection [14]. Preliminary reports have mentioned that IDS could be delayed after 6 or more cycles without detrimental consequences for longterm survival [15,16]. The purpose of the present study was to evaluate the impact on survival of the number of NAC cycles before the first cytoreductive surgery in a large cohort of advanced EOC patients treated in a specialized center. Patients and methods Patients All of the patients diagnosed with an advanced primary epithelial EOC operated on at our institute between 1995 and 2010 were recorded in a prospective database. Patients with stage IIIC or IV, undergoing primary (PDS) or interval debulking surgery (IDS) were included consecutively. All patients were classified at diagnosis according to the WHO performance status. Patients with incomplete clinicopathological data, non-epithelial ovarian cancers, or stages IIIC without abdominal peritoneal carcinomatosis (retroperitoneal positive nodes only) and patients receiving their first debulking surgery in other institutions were systematically excluded from this study. Surgery Surgical staging was defined according to the International Federation of Obstetricians and Gynecologists (F.I.G.O.) staging system. The initial extent of the disease at the start of each surgical procedure was quantified using the peritoneal cancer index (PCI), derived from Jacquet and Sugarbaker [17]. Surgery was considered complete when all visible tumors were removed (no macroscopic RD) at the end of the intervention. Two groups were formed according to the time of the first cytoreductive surgery in the therapeutic sequence. Group A consisted entirely of patients who had their first debulking surgery before any chemotherapy (PDS). Group B consisted of patients receiving their
first debulking after their initial NAC (IDS). Some patients in this group may have undergone an initial exploratory laparotomy in a different hospital or an exploratory laparoscopy followed by chemotherapy before IDS at our institution. Group B was divided according to the number of NAC cycles received prior to IDS (group B1 received 4 or less NAC cycles and group B2 received more than 4 cycles before surgery). In the different groups, patients with complete resection were specifically identified and analyzed. Chemotherapy All patients were treated with a first-line platinum-based chemotherapy in combination with paclitaxel for 6–8 courses, every 3 weeks, as specified by the different ongoing protocols during the years of study. Since inclusion of patients in the current study ended in 2010 before publication of the GOG-218 and the ICON-7 trials, no patient received antiangiogenic treatment (i.e. bevacizumab) in association with this first-line chemotherapy. Observation Individual data for all patients were prospectively collected: age at diagnosis, WHO performance status, dates of surgery and chemotherapy, the presence of ascites, stage, tumor grade, histology, extent of the disease and PCI at each laparotomy, RD after primary or interval surgery, CA-125 levels before and after surgery and chemotherapy. For patients in group B, the number of cycles and the response to NAC were also recorded. Tumors were defined as refractory in the case of progressive disease during the initial therapeutic sequence and resistant when recurrence was observed in the first 6 months after the end of the initial chemotherapy. Mortality and morbidity defined by death and complications within the first 30 days after each surgical procedure were also recorded. Treatment Free Interval (TFI) corresponded to time between the end of the first-line chemotherapy and the start of a second line in the case of recurrence. Follow-up All patients were regularly evaluated at the end of the treatment for evidence of disease recurrence. Clinical examinations, tumor markers assay (CA-125) and CT-scans were performed every 4 months. The date of progression was determined by CT scan and/or CA-125 levels on two consecutive assays. Statistical analysis Statistical analysis was performed with the log-rank and χ2 tests to compare univariate prognosis factors. The Cox proportional hazard regression model was used to determine the independent contributions of the prognostic variables in a multivariate analysis. Survival curves were performed with the Kaplan–Meier method. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of diagnosis. Differences were considered statistically significant at P b 0.05. STATA 10 statistical software (Stata Corporation, College Station, Texas, USA) was used for the analysis. Results Patients and tumors (Table 1) Three hundred and sixty seven patients at stage IIIC (n = 301) or IV (n = 66) advanced EOC underwent primary surgical exploration or IDS at our institution during the indicated period and were eligible for inclusion in our study. The median age at diagnosis was 59 years (range: 21–89) and the average follow-up duration was 82 months (range: 9– 203 months). Group A, B1 and B2 patients and tumors' characteristics
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225
Table 1 Patient's characteristics (n = 367) and surgical procedures performed in groups A (at primary surgery) and B (at interval surgery (IDS)). Group A (n = 220)
Group B (n = 147) Group B1
Patients, n (%) Neoadjuvant cycles (n) Age (years) b60 ≥60 WHO PS 0–1 ≥2 Missing Median Ca-125 level at diagnosis (UI/ml) Missing FIGO stage IIIC IV Pleural Visceral Missing Histological subtype Serous (ADK) Clear-cell Endometrioid Mucinous Carcinosarcoma Other Tumor grade G1 G2–3 Missing PCI before surgerya Median Missing b17 ≥17 Supramesocolic diseasea No Yes Missing Digestive resectiona No Yes Missing Posterior pelvic exenterationa No Yes Diaphragm stripping or resectiona No Yes Splenectomya No Yes Residual diseasea Microscopic Macroscopic Missing a
220 –
(100) –
123 97
55.9 44.1
181 13 26 652 75
93.3 6.7
194 26 13 10 3
88.2 11.8 56.5 43.5
86 24 16 6 2
78.2 21.8 72.7 27.3
21 16 12 3 1
56.8 43.2 80.0 20.0
194 4 9 5 5 3
88.2 1.8 4.1 2.3 2.3 1.3
102 3 2 2 0 1
92.7 2.7 1.8 1.8 0.0 1.0
31 2 1 2 0 1
83.8 5.4 2.7 5.4 0.0 2.7
17 144 59
10.6 89.4
11 77 22
12.5 87.5
3 22 12
12.0 88.0
15.0 29 124 67
0–27
9.0 8 77 25
0–28
7.0 2 29 6
1–14,626
64.9 35.1
110 3
p Group B2
(74.8) 2–4
37 6
(25.2) 5–10
49 61
44.5 55.5
17 20
45.9 54.1
81 19 10 684 22
81.0 19.0
27 8 2 1128 8
77.1 22.9
6–21,732
75.5 24.5
A vs B
B1 vs B2
– 0.039
b0.001 0.882
b0.001
0.623
0.079
0.260
b0.001
0.011
0.358
0.575
0.638
0.947
0–26
b0.001
0.275
82.9 17.1
0.015
0.369
0.003
0.946
0.008
0.786
29–8034
51 124 45
29.1 70.9
40 46 24
46.5 53.5
9 10 18
47.4 52.6
94 118 8
44.3 55.7
63 43 4
59.4 40.6
17 13 7
56.7 43.3
138 82
62.7 37.3
81 29
73.6 26.4
26 11
171 49
77.7 22.3
84 26
76.4 23.6
34 3
0.045 70.3 29.7 0.559 91.9 8.1
210 10
95.5 4.5
104 6
94.5 5.5
37 0
100 0.0
97 123 0
44.1 55.9
67 42 1
61.5 38.5
24 13 0
64.9 35.1
0.690
0.040
0.831
0.147
b0.001
0.712
At primary surgery (group A) or at interval surgery (group B).
are shown in Table 1. Most of them presented an extended disease at the time of diagnosis. Compared to group A (PDS), patients receiving IDS (group B) were significantly older or presented more frequently a stage IV disease or a WHO performance status of 2 or more. Patients and tumor characteristics were well balanced in groups B1 and B2 except for disease stage: the percentages of stage IV patients were significantly higher in group B2 compared to group B1 (p = 0.016). Considering all patients of this study with FIGO stage IIIC and IV diseases, the median survival was 44.4 months and overall 5-year survival was 38.3%.
debulking after NAC (IDS) (group B). 110 (74.8%) patients received 4 or less neoadjuvant cycles of neoadjuvant chemotherapy (group B1) whereas 37 (25.2%) received more than 4 cycles (group B2). Most of our patients underwent aggressive surgery at the time of PDS or IDS with frequent digestive and bowel resection. The rate of complete resection and the surgical procedures performed in the different groups are detailed in Table 1. The result of surgery was complete for 44.1% in patients of group A and for 61.9% of patients in group B (p b 0.001). The percentage of complete surgery increased in groups B2 (64.9%) and B1 (61.5%).
Surgery (Table 1)
Chemotherapy
Two hundred and twenty patients had their first cytoreductive surgery before receiving chemotherapy (group A) and 147 had their first
All patients in group B were treated with a first-line platinum-based chemotherapy in combination with paclitaxel. In this group, the median
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Table 2 Prognostics factors observed for patients in group B after univariate analysis. Overall survival RR Age (years) b60 ≥60 WHO PS 0–1 ≥2 FIGO stage IIIC IV Histological subtype Serous or endometriod Other subtypes Tumor grade G1 (Bien diff) G2–3 (Moy/Peu diff) Residual disease at IDS Microscopic Macroscopic Digestive resection at IDS No Yes Posterior pelvic exenteration at IDS No Yes Diaphragm stripping or resection at IDS No Yes Extensive supramesocolic disease at IDS No Yes PCI before IDS b17 ≥17 Number of NAC cycles before IDS ≤4 N4 Response to NAC at IDS Complete microscopic response Complete macroscopic response Partial response Stable or progressive disease Sensitivity to first-line chemotherapy Refractory or resistant Platinum-sensitive TFI (Treatment Free Interval) b18 months ≥18 months
Relapse free survival CI 95%
p
RR
CI 95%
0.982 1 0.99
0.877 1 1.03
[0.65; 1.51]
[0.71; 1.50]
0.039 1 1.71
0.260 1 1.30
[1.05; 2.77]
[0.83; 2.07]
0.579 1 0.88
0.915 1 1.02
[0.55; 1.40]
[0.66; 1.57]
0.022 1 2.64
0.006 1 2.86
[1.27; 5.50]
[1.47; 5.55]
0.707 1 0.88
0.584 1 1.19
[0.44; 1.73]
[0.63; 2.26]
b0.001 1 2.57
b0.001 1 3.44
[1.68; 3.93]
[2.32; 5.10]
0.023 1 1.66
0.009 1 1.70
[1.08; 2.58]
[1.15; 2.52]
0.627 1 1.12
0.220 1 1.30
[0.71; 1.79]
[0.86; 1.96]
0.920 1 0.97
0.734 1 1.09
[0.57; 1.65]
[0.68; 1.73] b0.001
0.003 1 2.09
1 2.41
[1.27; 3.46]
[1.53; 3.80]
0.003 1 2.26
0.002 1 2.19
[1.37; 3.71]
[1.39; 3.44]
0.037 1 1.63
0.039 1 1.56
[1.05; 2.54]
[1.04; 2.35] b0.001
0.008 1 1.68 2.18 4.69
1 1.36 2.42 4.66
[0.59; 4.77] [0.87; 5.50] [1.69; 13.0]
[0.54; 3.41] [1.10; 5.30] [1.90; 11.4]
b0.001 1 0.10
b0.001 1 0.10
[0.06; 0.16]
[0.06; 0.16]
b0.001 1 0.16
b0.001 1 0.20
[0.06; 0.44]
p
[0.09; 0.42]
TFI = Time between the end of first-line chemotherapy and the start of a second line
number of NAC cycles administered was 4, with the range of cycles given between 2 and 10. This median number was selected as threshold for appropriate separation of groups B1 and B2 patients. The median number of NAC cycles was 3 in group B1 and 6 in group B2. The total number of first-line chemotherapy cycle (preoperative and postoperative lines) was higher in group B2 compared to group B1 (p = 0.008).
Selection of group B2 patients For patients treated by NAC/IDS, the main cause for prolonging NAC after 3–4 cycles and delaying IDS was determined retrospectively. A decision for a NAC with 6 cycles was arbitrarily taken on initial evaluation for 20 patients independently of chemotherapy response (in 11 cases for a stage IV disease and in the presence of diffuse peritoneal extension at initial laparoscopy for 9 patients). In 15 cases, patients were referred to our institution after more than 4 cycles initiated in other hospital with no evaluation of NAC response after 3–4 cycles. In only 2 cases,
unresectable disease was predicted on CT-scan evaluation after 3– 4 cycles in the presence of a limited response to NAC.
Global prognosis factors Prognostic factors for the whole cohort are presented in Table S1. By univariate analysis, we identified several factors that significantly predicted worse overall survival in the entire study population: age N 60 years (p = 0.037), WHO performance status of 2 or more (p = 0.001), extensive peritoneal carcinomatosis at presentation (PCI before PDS or IDS N 17) (p b 0.001) and histology consistent with clear-cell or mucinous tumors (p = 0.018). In groups A and B, the result of surgery was one of most important prognosis factors and patients with complete resection at initial or at IDS had a significantly improved survival compared to patients with any macroscopic disease (p b 0.001 [IC 1.72 – 2.92]). Patients relapsing in the first six months after the end of chemotherapy (platinum-resistant diseases) had poor survival
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227
Table 3 Prognostics factors observed for patients with no macroscopic residual disease at the end of interval surgery in group B (group B0, after univariate analysis). Overall survival RR Age (years) b60 ≥60 WHO PS 0–1 ≥2 FIGO stage IIIC IV Histological subtype Serous or endometriod Other subtypes Tumor grade G1 (Bien diff) G2–3 (Moy/Peu diff) Digestive resection at IDS No Yes Posterior pelvic exenteration at IDS No Yes Diaphragm stripping or resection at IDS No Yes Extensive supramesocolic disease at IDS No Yes PCI before IDS b17 ≥17 Number of NAC cycles before IDS ≤4 N4 Response to NAC at IDS Complete microscopic response Complete macroscopic response Partial response Stable or progressive disease Sensitivity to first-line chemotherapy Refractory or resistant Platinum-sensitive TFI (Treatment Free Interval) b18 months ≥18 months
Relapse free survival CI 95%
p
RR
CI 95%
0.948 1 0.98
1 0.83
[0.54; 1.75]
[0.50; 1.39]
0.09 1 1.90
0.297 1 1.46
[0.94; 3.85]
[0.73; 2.91]
0.510 1 1.22
0.506 1 1.21
[0.67; 2.24]
[0.69; 2.13]
0.007 1 4.79
0.019 1 0.34
[1.84; 12.5]
[1.39; 7.99]
0.878 1 0.93
0.373 1 1.49
[0.35; 2.43]
[0.59; 3.79]
0.101 1 1.67
0.027 1 1.85
[0.91; 3.06]
[1.08; 3.18]
0.821 1 0.92
0.270 1 1.39
[0.47; 1.82]
[0.78; 2.47]
0.525 1 1.28
0.489 1 1.27
[0.61; 2.67]
[0.66; 2.45]
0.051 1 1.98
0.017 1 2.10
[1.01; 3.86]
[1.16; 3.80]
0.430 1 1.67
0.522 1 1.42
[0.51; 5.50]
[0.51; 3.95]
b0.001 1 2.93
0.005 1 2.21
[1.63; 5.28]
[1.30; 3.75]
0.124 1 1.55 1.60 12.2
0.242 1 1.30 1.78 4.46
[0.54; 4.49] [0.61; 4.19] [2.25; 66.4]
[0.51; 3.30] [0.79; 4.02] [0.91; 21.8]
b0.001 1 0.07
b0.001 1 0.08
[0.03;0.16]
[0.04;0.16]
b0.001 1 0.19
0.004 1 0.29
[0.07; 0.55]
p 0.485
[0.12; 0.70]
TFI = Time between the end of first-line chemotherapy and the start of a second line.
(p b 0.001). A treatment free interval (TFI) lesser than 18 months was also associated with worse overall survival.
of 3.05 (p b 0.001, [CI: 1.69–5.50]) with an independent impact from stage and WHO performance status.
Prognosis factors in group B (Tables 2 and 3)
Discussion
For patients receiving NAC, a WHO performance status of 2 or more (p = 0.039), a macroscopic RD (p b 0.001), an extensive peritoneal carcinomatosis at IDS (PCI N 17) (p = 0.003) or an extensive supramesocolic disease at IDS, the number of NAC cycles (p = 0.037) and the response to preoperative chemotherapy (p = 0.008) were significantly associated with worse overall survival after univariate analysis. Patients receiving more than 4 cycles of neoadjuvant chemotherapy (group B2) had worse survival compared to patients in group B1 (p = 0.037). After multivariate analysis (Table 4), the impact of the number of neoadjuvant cycles remained significant (p = 0.001, OR 2.28[1.41–3.70]) and was independent from disease stage, the presence of a residual disease and from the WHO performance status. This observation was reinforced in the subgroup of patients receiving NAC and complete resection at IDS. Patients with no macroscopic disease at the end of IDS and who had received more than 4 cycles of NAC treatment had poor survival (p b 0.001) despite complete removal of their tumor (Fig. 1) with a relative risk of death after multivariate analysis
Complete resection of all macroscopic disease, whether performed as primary treatment or after NAC remains the principal objective of cytoreductive surgery in the management of advanced EOC [10]. Nevertheless, timing of surgery remains contentious and controversy persists between the proponents of aggressive primary debulking and defenders of NAC followed by IDS [9,12,18]. Furthermore, identification of patients with potential resectable disease for upfront surgery and selection of patients requiring NAC remain challenging in this pathology despite attentive preoperative imaging and development of exploratory laparoscopy. For patients receiving NAC and IDS, the number of NAC cycles that should be prescribed before the first debulking and associated with the best results on overall survival is not yet determined. To date, no randomized study has specifically addressed this point. In 2006, Bristow et al. published a large meta-analysis derived from 22 cohorts and including 834 stage IIIC–IV EOC patients treated by NAC and IDS [18]. An inverse relationship was observed between survival and the number
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Table 4 Multivariate analysis in group B (interval surgery) and in group B0 (complete interval surgery). Overall survival RR
CI 95%
All group B patients Digestive resection at IDS No 1 Yes 2.19 Sensitivity to first-line chemotherapy Refractory or resistant 1 Platinum-sensitive 0.07 Number of NAC cycles before IDS ≤4 1 N4 2.28
p b0.001
[1.39; 3.43] b0.001 [0.04; 0.13] 0.001 [1.41; 3.70]
Patients with no macroscopic RD at the end of IDS (group B0) Sensitivity to first-line chemotherapy Refractory or resistant 1 Platinum-sensitive 0.07 [0.03; 0.16] Number of NAC cycles before IDS ≤4 1 N4 3.05 [1.69; 5.50]
b0.001
b0.001
of NAC cycles: each additional chemotherapy cycle (between 3 and 6 cycles) was associated with a 4-month decrease in overall survival. According to these results, the authors recommended that IDS should be performed as early as possible in the therapeutic sequence of EOC and unresectable diseases should be reevaluated regularly during NAC for potential surgery and complete resection [18]. Nevertheless, the results of Bristow and Chi's meta-analysis have been questioned because patients treated with IDS and receiving more than 3 cycles in this compilation of retrospective studies had probably more extended diseases that could explain worse prognosis. More recently, a report from a high-volume center has mentioned that IDS could be delayed beyond 6 or more cycles without detrimental consequences on survival [15].
1.00
Probability
0.75
0.50
Stage IV 0.25
0.00
Number at risk A0 B10 B20 Stage IV
0
1
2
3
97 67 24 36
93 64 24 35
82 50 14 28
68 40 8 20
A
B1
Years
4
5
6
7
54 31 5 13
38 21 5 9
30 19 4 8
23 14 3 6
B2
Stage IV
Group A0 : patients receiving complete PDS Group B10 : patients receiving complete IDS with a number of NAC cycles ≤ 4 Group B20 : patients receiving complete IDS with a number of NAC cycles > 4 Stage IV: stage IV disease in the cohort receiving complete PDS or complete IDS Fig. 1. Kaplan–Meier survival curves for patients receiving complete surgery at PDS (group A0) or at IDS (groups B10 and B20). Stage IV: Kaplan–Meier survival curve for patients with stage IV diseases and receiving complete PDS or complete IDS is indicated in gray. Group A0: patients receiving complete PDS. Group B10: patients receiving complete IDS with a number of NAC cycles ≤4. Group B20: patients receiving complete IDS with a number of NAC cycles N4. PDS: primary debulking surgery; IDS: interval debulking surgery.
In addition, the meta-analysis by Kang and Nam in 2009 showed that the number of NAC cycles did not influence survival of EOC patients receiving NAC in their review of 21 studies published between 1989 and 2008 [19]. On the contrary, discordant results were shown in our study: an inverse relationship was observed between prognosis and the number of NAC cycles: patients receiving late IDS (after more than 4 cycles) had worse survival compared to patients treated by primary surgery or early IDS (after less than 4 cycles). This result was observed despite higher rates of complete resection in the late IDS group (group B2) and the impact of the number of NAC cycles was independent from the other prognostic factors after multivariate analysis. Interpretation of these data and of these divergent results is complex. In general, patients receiving NAC and a fortiori more cycles before surgery had worse prognostic factors with more advanced disease at the time of presentation or more resistant tumors to chemotherapy. In our group and especially in this cohort, primary surgery was preferred for resectable diseases and IDS was generally reserved for patients with unresectable disease at initial exploratory laparoscopy or in the cases of stage IV disease or poor performance status. Furthermore, group B2 patients compared to groups B1 and A had more frequently stage IV disease at diagnosis that could explain worse outcome despite appropriate chemotherapy and complete resection. In consequence, one possible explanation of the poor prognosis observed in group B2 is the potential selection-bias of diseases associated with worse clinical and biological prognostic factors. In this hypothesis group B2 possibly encompasses patients with more extended carcinomatosis at diagnosis or less chemosensitive tumors that might explain increased NAC cycles with delayed IDS and finally a worse outcome. Compared to other studies that found no difference in survival for early or late IDS, our group systematically considered upfront surgery or early IDS for advanced EOC and reserved late IDS for unresectable tumors or diseases with initial extra-abdominal extension (stages IV). In contrast, Stoeckle et al. selected patients for late IDS more systematically according to the treatment protocol during the study period and not on disease extension at presentation or on response to chemotherapy [15]. Based on this observation, selection of patients may be different and our study might incorporate patients with worse intrinsic biological patterns in group B2. Furthermore, despite worse initial prognostic factors in group B (higher percentage of stage IV and poor PS), EOC patients receiving early IDS after a limited number of NAC (group B1) had an unexpected outcome compared to patients receiving PDS (group A) (Fig. 1). As our study is not randomized, groups A and B1 cannot be compared directly but our results suggest that they have comparable long-term survival. This element was also observed in the sub-groups of patients with complete IDS and PDS (Fig. 1) and further underlines the worse prognosis observed in group B2 patients receiving late IDS. Therefore, one possible explanation is that tumor with the worse biology (group B2) were subtracted from group B explaining the relative good prognosis of group B1 patients, and more akin to those, also selected, who had upfront surgery (group A). Nevertheless, the impact of the number of NAC cycles remained statistically significant after multivariate analysis and was independent from the stage. This result can infer other worse confounding prognosis factors but possibly direct impact on outcome of the numbers of NAC cycles. In addition, overall survival in group B2 was inferior to that of all stage IV patients of our cohort (Fig. 1). Furthermore, it is possible that EOC patients receiving NAC with disease resistant to initial treatment and considered unresectable after 6 cycles were not operated on and not selected for late IDS. These patients, with the worse diseases that correspond to refractory tumors, were not included in this study and did not impact the survival outcome in the delayed IDS group (only operated patients were recorded in this database). As our study was a retrospective one, the percentage of patients with refractory tumor excluded from IDS is undetermined. In addition, group B also included a significant percentage (40%) of patients having received different
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numbers of NAC after treatment initiation in other hospitals, before referral in our institution. This subgroup had all been considered unresectable with varying degrees of tumor burden. Alternatively, it is possible that some of the patients of our cohort receiving late IDS who could have been operated on earlier suffered from a delayed debulking. One explanation of this hypothesis is the possible development of resistant tumors due to the lack of initial surgery or early IDS leading to the selection of resistant tumor cells by the repetition of NAC cycles. In the same concept, retrospective data have recently suggested that NAC/IDS compared to primary surgery may increase the risk of developing platinum-resistant disease [13]. Selection of resistant tumor cells may be more significant when more chemotherapy cycles are used prior to IDS and macroscopic resection of tumor bulk. Goldie and Coldman demonstrated 20 years ago that the rate of development of tumor resistance was related to the size of the tumor [20]. In this mathematical model, there is a major statistical chance of tumor heterogeneity with resistant clones already present within the tumor at diagnosis especially for cancers with genetic instability and a high mutation rate like EOC. Based on this theory, acquired resistance often represents outgrowth of resistant clones originally present at low frequency in the tumor at diagnosis and that have expanded under the selective pressure imposed by systemic chemotherapy. In this concept, the tumor burden receiving chemotherapy cycles probably plays an important role that is confirmed by the improved effectiveness of platinum-based chemotherapy in advanced EOC receiving optimal and complete debulking. In our point of view, surgical debulking reduces the tumor bulk in a less selective manner than chemotherapy and might reduce tumor heterogeneity and somehow limit acquired resistance. Based on this hypothesis, one possible biological explanation of the worse prognosis observed for patients receiving delayed IDS besides selection-bias and worse tumor biology is the possible lack of physical removal of resistant parts within the macroscopic disease by PDS or early IDS after a limited number of NAC. In this hypothesis, the repetition of NAC cycles before surgery may select and promote the dissemination of resistant clones in microscopic format from these unremoved macroscopic lumps. This unremovable disease could lead to chemoresistance and early recurrence despite higher rates of complete surgery in the late IDS group. There are several limitations to this current retrospective study that must be considered in interpreting the data. During this long period of time (1995–2010), upfront surgery was systematically considered in our institution for all patients and NAC/IDS was reserved for patients who were not candidate for PDS including poor PS, stage IV or unresectable disease at presentation. Resectability was assessed on the basis of clinical examination, Ct-scan and exploratory laparotomy/ laparoscopy with variations depending on period and evolution of clinical practices. The definition of resectability and the selection of patients requiring NAC have probably evolved and represent a limit to generalize the findings of the present study. Despite large size of the entire cohort, the number of patients included in the B2 group was rather limited and data obtained need to be confirmed in larger studies. As the study is retrospective, the main cause for delaying IDS after more than 4 cycles of NAC was determined a posteriori with potential confounding factors. Most of them had probably less chemosensitive disease that can explain worse survival. In conclusion, we observed that in a large series of advanced EOC patients receiving late IDS (N4 NAC-cycles) have a poor prognosis compared to patients operated on earlier. The impact of surgical timing was reinforced in the subgroups with complete surgery and remained independent from other prognostic factors. The relative contribution of the therapeutic sequence compared to tumor biology and chemotherapy response remains controversial. These discordances in recent published data reinforce the necessity to complete ongoing randomized studies comparing early and late debulking in advanced EOC. Based on the results of the present series, we believe that the concept of early and complete IDS claimed by Bristow's meta-analysis should be preferred in the management of advanced EOC pending the results of
229
ongoing controlled trials. Patients with advanced EOC receiving NAC should be evaluated regularly and IDS should be attempted as soon as possible, preferably after 4 or less cycles in order to reserve the maximum number of chemotherapy cycles on microscopic RD after IDS. These results reported in this study call into question the interest of a delayed debulking in advanced cases thought to be unresectable after 3 to 4 cycles of NAC. These patients have less chemosensitive tumors or disease associated with worse intrinsic tumor biology. In these cases, surgical debulking of remnant tumor deposits, even complete after 6 cycles or more, probably has a low impact on survival. In this subgroup, aggressiveness of surgery should be questioned while paying attention to quality of life, in view of the poor survival observed after complete late IDS. Alternative treatments such as second-line chemotherapy, antiangiogenic targeted therapies, or intensification with intraperitoneal chemotherapy or hyperthermic intraperitoneal chemotherapy in the absence of extra-abdominal extension should be discussed and evaluated in future trials. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2014.09.002. Conflicts of interest statement None declared.
Acknowledgments The authors thank Oliver Wakeli for presubmission editorial assistance. References [1] Cannistra SA. Cancer of the ovary. N Engl J Med 2004;351:2519–29. [2] Colombo PE, Fabbro M, Theillet C, Bibeau F, Rouanet P, Ray-Coquard I. Sensitivity and resistance to treatment in the primary management of epithelial ovarian cancer. Crit Rev Oncol Hematol 2014;89:207–16. [3] Friedlander M, Trimble E, Tinker A, Alberts D, Avall-Lundqvist E, Brady M, et al. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer 2011;21:771–5. [4] Colombo PE, Mourregot A, Fabbro M, Gutowski M, Saint-Aubert B, Quenet F, et al. Aggressive surgical strategies in advanced ovarian cancer: a monocentric study of 203 stage IIIC and IV patients. Eur J Surg Oncol 2009;35:135–43. [5] Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248–59. [6] Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998;69:103–8. [7] Chang SJ, Bristow RE. Evolution of surgical treatment paradigms for advanced-stage ovarian cancer: redefining ‘optimal’ residual disease. Gynecol Oncol 2012;125: 483–92. [8] Chang SJ, Bristow RE, Ryu HS. Impact of complete cytoreduction leaving no gross residual disease associated with radical cytoreductive surgical procedures on survival in advanced ovarian cancer. Ann Surg Oncol 2012;19:4059–67. [9] Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2011;363:943–53. [10] du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. 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). Cancer 2009;115:1234–44. [11] Morice P, Dubernard G, Rey A, Atallah D, Pautier P, Pomel C, et al. Results of interval debulking surgery compared with primary debulking surgery in advanced stage ovarian cancer. J Am Coll Surg 2003;197:955–63. [12] Chi DS, Musa F, Dao F, Zivanovic O, Sonoda Y, Leitao MM, et al. An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical time period as the randomized EORTC–NCIC trial of PDS vs neoadjuvant chemotherapy (NACT). Gynecol Oncol 2012;124:10–4. [13] Rauh-Hain JA, Nitschmann CC, Worley Jr MJ, Bradford LS, Berkowitz RS, Schorge JO, et al. Platinum resistance after neoadjuvant chemotherapy compared to primary surgery in patients with advanced epithelial ovarian carcinoma. Gynecol Oncol 2013;129:63–8. [14] Stoeckle E, Boubli B, Floquet A, Brouste V, Sire M, Croce S, et al. Optimal timing of interval debulking surgery in advanced ovarian cancer: yet to be defined? Eur J Obstet Gynecol Reprod Biol 2011;159:407–12. [15] Stoeckle E, Bourdarias L, Guyon F, Croce S, Brouste V, Thomas L, et al. Progress in survival outcomes in patients with advanced ovarian cancer treated by neo-adjuvant
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platinum/taxane-based chemotherapy and late interval debulking surgery. Ann Surg Oncol 2014;21:629–36. [16] da Costa Miranda V, de Souza Fede AB, Dos Anjos CH, da Silva JR, Sanchez FB, da Silva Bessa LR, et al. Neoadjuvant chemotherapy with six cycles of carboplatin and paclitaxel in advanced ovarian cancer patients unsuitable for primary surgery: safety and effectiveness. Gynecol Oncol 2014;132:287–91. [17] Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res 1996;82:359–74.
[18] Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis. Gynecol Oncol 2006; 103:1070–6. [19] Kang S, Nam BH. Does neoadjuvant chemotherapy increase optimal cytoreduction rate in advanced ovarian cancer? Meta-analysis of 21 studies. Ann Surg Oncol 2009;16:2315–20. [20] Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727–33.
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Impact of neoadjuvant chemotherapy cycles prior to interval surgery in patients with advanced epithelial ovarian cancer P.E. Colombo a,⁎, M. Labaki a, M. Fabbro b, M. Bertrand a, A. Mourregot a, M. Gutowski b, B. Saint-Aubert a, F. Quenet a, P. Rouanet a, C. Mollevi c a b c
Department of Surgical Oncology, Montpellier Cancer Institute (ICM), 34298 Montpellier, France Department of Medical Oncology, Montpellier Cancer Institute (ICM), 34298 Montpellier, France Department of Biostatistics, Montpellier Cancer Institute (ICM), 34298 Montpellier, France
H I G H L I G H T S • EOC patients receiving late Interval Debulking Surgery (N4 NAC-cycles) have a poor prognosis compared to patients receiving early IDS. • The impact of surgical timing is reinforced in the subgroup with complete debulking and remains independent from other prognostic factors. • The relative contribution of the therapeutic sequence compared to tumor biology and chemotherapy response on prognosis remains controversial.
a r t i c l e
i n f o
Article history: Received 30 May 2014 Accepted 3 September 2014 Available online 16 September 2014 Keywords: Epithelial ovarian cancer Neoadjuvant chemotherapy Interval surgery Number of cycles Prognosis
a b s t r a c t Objectives. Complete surgery with no macroscopic residual disease (RD) at primary (PDS) or interval debulking surgery (IDS) is the main objective of surgery in advanced epithelial ovarian cancer (EOC). The aim of this work was to evaluate the impact on survival of the number of neoadjuvant chemotherapy (NAC) cycles before IDS in EOC patients. Methods. Data from EOC patients (stages IIIC–IV), operated on between 1995 and 2010 were consecutively recorded. NAC/IDS patients were analyzed according to the number of preoperative cycles (b4 = group B1; N 4 = group B2) and compared with patients receiving PDS (group A). Patients with complete resection were specifically analyzed. Results. 367 patients were analyzed, 220 received PDS and 147 had IDS/NAC. In group B, 37 patients received more than 4 NAC cycles (group B2). Group B2 patients presented more frequently stage IV disease at diagnosis (p b 0.01) compared to groups A and B1. The rate of complete cytoreduction was higher in group B (p b 0.001). Patients with no RD after IDS and who had received more than 4 NAC cycles had poor survival (p b 0.001) despite complete removal of their tumor (relative risk of death after multivariate analysis of 3 (p b 0.001)) with an independent impact from disease stage and WHO performance status. Conclusions. Patients with advanced EOC receiving complete IDS after more than 4 cycles of NAC have poor prognosis. Despite worse prognostic factors observed in this group of patients, our study reinforces the concept of early and complete removal of all macroscopic tumors in the therapeutic sequence of EOC. © 2014 Elsevier Inc. All rights reserved.
Introduction Epithelial ovarian cancer (EOC) remains the main cause of gynecological cancer death in developed countries reflecting advanced-stage disease at clinical diagnosis and early propensity for peritoneal dissemination [1]. The standard treatment for advanced EOC consists of optimal cytoreductive surgery associated with a platinum/paclitaxel-based ⁎ Corresponding author at: Department of Surgical Oncology, Montpellier Cancer Institute (ICM), 208 Rue des Apothicaires, Parc Euromedecine, 34298 Cedex 5, Montpellier, France. Fax: +33 46 761 8501. E-mail address: [email protected] (P.E. Colombo).
http://dx.doi.org/10.1016/j.ygyno.2014.09.002 0090-8258/© 2014 Elsevier Inc. All rights reserved.
chemotherapy [1]. Despite very high initial chemosensitivity and frequent clinical complete response, the majority of patients relapses and progressively develops resistance to the various chemotherapeutic treatments [2,3]. Over the last decades, retrospective and prospective studies have established that the result of the surgical procedure, defined by the amount of residual disease (RD), was the most important factor impacting on survival [4,5]. It has been now demonstrated that a large improvement in the prognosis of EOC patients is associated with the removal of all macroscopic disease and complete surgery has become the principal goal of the surgical management of advanced EOC [6–10]. Incomplete surgery with any macroscopic RD is associated with a poor survival even with low RD (b1 cm) that appears to give a
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small and limited prognostic impact compared to larger (so-called nonoptimal) RD (N 1 cm) [10]. Neoadjuvant chemotherapy (NAC) and interval debulking surgery (IDS) have been proposed in the management of advanced EOC to increase the rate of complete surgery while reducing surgical morbidity [9,11]. Initially reserved for unresectable disease or for patients in poor general condition, the prescription of NAC and IDS has increased over the past two decades and the first debulking is now often attempted only after several cycles of chemotherapy. The noninferiority of IDS after 3 cycles of NAC compared to upfront surgery has been reported by Vergote et al. in a large phase III randomized trial including patients with advanced stages IIIC–IV EOC [9]. Nevertheless, optimal surgical timing and selection criteria for NACT and IDS remain controversial in clinical practice. In parallel, large retrospective studies and meta-analyses have observed a large survival advantage for EOC cancer patients receiving initial and complete removal of all macroscopic tumors prior to initiation of chemotherapy [12]. Furthermore, the quality of surgery was heterogeneous in the EORTC trial with large variations in surgical aggressiveness and complete resection rates among participating centers. This argument has been raised to explain the comparatively low survival observed for patients treated with upfront surgery in this study [12]. Furthermore, retrospective data have also suggested that NAC and IDS compared to primary surgery may increase the risk of developing platinum-resistant disease and less sensitive recurrent disease [13]. To date, timing of surgery in the therapeutic sequence of EOC and the selection of patients who will benefit from primary surgery or NAC-IDS remain controversial. In the case of NAC and IDS, high disparities also exist as to how many cycles of NAC should be given prior to IDS, ranging from three to six or more. For advanced or unresectable disease, some authors have recently proposed to increase the number of NAC cycles with the aim of improving the rate of complete resection [14]. Preliminary reports have mentioned that IDS could be delayed after 6 or more cycles without detrimental consequences for longterm survival [15,16]. The purpose of the present study was to evaluate the impact on survival of the number of NAC cycles before the first cytoreductive surgery in a large cohort of advanced EOC patients treated in a specialized center. Patients and methods Patients All of the patients diagnosed with an advanced primary epithelial EOC operated on at our institute between 1995 and 2010 were recorded in a prospective database. Patients with stage IIIC or IV, undergoing primary (PDS) or interval debulking surgery (IDS) were included consecutively. All patients were classified at diagnosis according to the WHO performance status. Patients with incomplete clinicopathological data, non-epithelial ovarian cancers, or stages IIIC without abdominal peritoneal carcinomatosis (retroperitoneal positive nodes only) and patients receiving their first debulking surgery in other institutions were systematically excluded from this study. Surgery Surgical staging was defined according to the International Federation of Obstetricians and Gynecologists (F.I.G.O.) staging system. The initial extent of the disease at the start of each surgical procedure was quantified using the peritoneal cancer index (PCI), derived from Jacquet and Sugarbaker [17]. Surgery was considered complete when all visible tumors were removed (no macroscopic RD) at the end of the intervention. Two groups were formed according to the time of the first cytoreductive surgery in the therapeutic sequence. Group A consisted entirely of patients who had their first debulking surgery before any chemotherapy (PDS). Group B consisted of patients receiving their
first debulking after their initial NAC (IDS). Some patients in this group may have undergone an initial exploratory laparotomy in a different hospital or an exploratory laparoscopy followed by chemotherapy before IDS at our institution. Group B was divided according to the number of NAC cycles received prior to IDS (group B1 received 4 or less NAC cycles and group B2 received more than 4 cycles before surgery). In the different groups, patients with complete resection were specifically identified and analyzed. Chemotherapy All patients were treated with a first-line platinum-based chemotherapy in combination with paclitaxel for 6–8 courses, every 3 weeks, as specified by the different ongoing protocols during the years of study. Since inclusion of patients in the current study ended in 2010 before publication of the GOG-218 and the ICON-7 trials, no patient received antiangiogenic treatment (i.e. bevacizumab) in association with this first-line chemotherapy. Observation Individual data for all patients were prospectively collected: age at diagnosis, WHO performance status, dates of surgery and chemotherapy, the presence of ascites, stage, tumor grade, histology, extent of the disease and PCI at each laparotomy, RD after primary or interval surgery, CA-125 levels before and after surgery and chemotherapy. For patients in group B, the number of cycles and the response to NAC were also recorded. Tumors were defined as refractory in the case of progressive disease during the initial therapeutic sequence and resistant when recurrence was observed in the first 6 months after the end of the initial chemotherapy. Mortality and morbidity defined by death and complications within the first 30 days after each surgical procedure were also recorded. Treatment Free Interval (TFI) corresponded to time between the end of the first-line chemotherapy and the start of a second line in the case of recurrence. Follow-up All patients were regularly evaluated at the end of the treatment for evidence of disease recurrence. Clinical examinations, tumor markers assay (CA-125) and CT-scans were performed every 4 months. The date of progression was determined by CT scan and/or CA-125 levels on two consecutive assays. Statistical analysis Statistical analysis was performed with the log-rank and χ2 tests to compare univariate prognosis factors. The Cox proportional hazard regression model was used to determine the independent contributions of the prognostic variables in a multivariate analysis. Survival curves were performed with the Kaplan–Meier method. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of diagnosis. Differences were considered statistically significant at P b 0.05. STATA 10 statistical software (Stata Corporation, College Station, Texas, USA) was used for the analysis. Results Patients and tumors (Table 1) Three hundred and sixty seven patients at stage IIIC (n = 301) or IV (n = 66) advanced EOC underwent primary surgical exploration or IDS at our institution during the indicated period and were eligible for inclusion in our study. The median age at diagnosis was 59 years (range: 21–89) and the average follow-up duration was 82 months (range: 9– 203 months). Group A, B1 and B2 patients and tumors' characteristics
P.E. Colombo et al. / Gynecologic Oncology 135 (2014) 223–230
225
Table 1 Patient's characteristics (n = 367) and surgical procedures performed in groups A (at primary surgery) and B (at interval surgery (IDS)). Group A (n = 220)
Group B (n = 147) Group B1
Patients, n (%) Neoadjuvant cycles (n) Age (years) b60 ≥60 WHO PS 0–1 ≥2 Missing Median Ca-125 level at diagnosis (UI/ml) Missing FIGO stage IIIC IV Pleural Visceral Missing Histological subtype Serous (ADK) Clear-cell Endometrioid Mucinous Carcinosarcoma Other Tumor grade G1 G2–3 Missing PCI before surgerya Median Missing b17 ≥17 Supramesocolic diseasea No Yes Missing Digestive resectiona No Yes Missing Posterior pelvic exenterationa No Yes Diaphragm stripping or resectiona No Yes Splenectomya No Yes Residual diseasea Microscopic Macroscopic Missing a
220 –
(100) –
123 97
55.9 44.1
181 13 26 652 75
93.3 6.7
194 26 13 10 3
88.2 11.8 56.5 43.5
86 24 16 6 2
78.2 21.8 72.7 27.3
21 16 12 3 1
56.8 43.2 80.0 20.0
194 4 9 5 5 3
88.2 1.8 4.1 2.3 2.3 1.3
102 3 2 2 0 1
92.7 2.7 1.8 1.8 0.0 1.0
31 2 1 2 0 1
83.8 5.4 2.7 5.4 0.0 2.7
17 144 59
10.6 89.4
11 77 22
12.5 87.5
3 22 12
12.0 88.0
15.0 29 124 67
0–27
9.0 8 77 25
0–28
7.0 2 29 6
1–14,626
64.9 35.1
110 3
p Group B2
(74.8) 2–4
37 6
(25.2) 5–10
49 61
44.5 55.5
17 20
45.9 54.1
81 19 10 684 22
81.0 19.0
27 8 2 1128 8
77.1 22.9
6–21,732
75.5 24.5
A vs B
B1 vs B2
– 0.039
b0.001 0.882
b0.001
0.623
0.079
0.260
b0.001
0.011
0.358
0.575
0.638
0.947
0–26
b0.001
0.275
82.9 17.1
0.015
0.369
0.003
0.946
0.008
0.786
29–8034
51 124 45
29.1 70.9
40 46 24
46.5 53.5
9 10 18
47.4 52.6
94 118 8
44.3 55.7
63 43 4
59.4 40.6
17 13 7
56.7 43.3
138 82
62.7 37.3
81 29
73.6 26.4
26 11
171 49
77.7 22.3
84 26
76.4 23.6
34 3
0.045 70.3 29.7 0.559 91.9 8.1
210 10
95.5 4.5
104 6
94.5 5.5
37 0
100 0.0
97 123 0
44.1 55.9
67 42 1
61.5 38.5
24 13 0
64.9 35.1
0.690
0.040
0.831
0.147
b0.001
0.712
At primary surgery (group A) or at interval surgery (group B).
are shown in Table 1. Most of them presented an extended disease at the time of diagnosis. Compared to group A (PDS), patients receiving IDS (group B) were significantly older or presented more frequently a stage IV disease or a WHO performance status of 2 or more. Patients and tumor characteristics were well balanced in groups B1 and B2 except for disease stage: the percentages of stage IV patients were significantly higher in group B2 compared to group B1 (p = 0.016). Considering all patients of this study with FIGO stage IIIC and IV diseases, the median survival was 44.4 months and overall 5-year survival was 38.3%.
debulking after NAC (IDS) (group B). 110 (74.8%) patients received 4 or less neoadjuvant cycles of neoadjuvant chemotherapy (group B1) whereas 37 (25.2%) received more than 4 cycles (group B2). Most of our patients underwent aggressive surgery at the time of PDS or IDS with frequent digestive and bowel resection. The rate of complete resection and the surgical procedures performed in the different groups are detailed in Table 1. The result of surgery was complete for 44.1% in patients of group A and for 61.9% of patients in group B (p b 0.001). The percentage of complete surgery increased in groups B2 (64.9%) and B1 (61.5%).
Surgery (Table 1)
Chemotherapy
Two hundred and twenty patients had their first cytoreductive surgery before receiving chemotherapy (group A) and 147 had their first
All patients in group B were treated with a first-line platinum-based chemotherapy in combination with paclitaxel. In this group, the median
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Table 2 Prognostics factors observed for patients in group B after univariate analysis. Overall survival RR Age (years) b60 ≥60 WHO PS 0–1 ≥2 FIGO stage IIIC IV Histological subtype Serous or endometriod Other subtypes Tumor grade G1 (Bien diff) G2–3 (Moy/Peu diff) Residual disease at IDS Microscopic Macroscopic Digestive resection at IDS No Yes Posterior pelvic exenteration at IDS No Yes Diaphragm stripping or resection at IDS No Yes Extensive supramesocolic disease at IDS No Yes PCI before IDS b17 ≥17 Number of NAC cycles before IDS ≤4 N4 Response to NAC at IDS Complete microscopic response Complete macroscopic response Partial response Stable or progressive disease Sensitivity to first-line chemotherapy Refractory or resistant Platinum-sensitive TFI (Treatment Free Interval) b18 months ≥18 months
Relapse free survival CI 95%
p
RR
CI 95%
0.982 1 0.99
0.877 1 1.03
[0.65; 1.51]
[0.71; 1.50]
0.039 1 1.71
0.260 1 1.30
[1.05; 2.77]
[0.83; 2.07]
0.579 1 0.88
0.915 1 1.02
[0.55; 1.40]
[0.66; 1.57]
0.022 1 2.64
0.006 1 2.86
[1.27; 5.50]
[1.47; 5.55]
0.707 1 0.88
0.584 1 1.19
[0.44; 1.73]
[0.63; 2.26]
b0.001 1 2.57
b0.001 1 3.44
[1.68; 3.93]
[2.32; 5.10]
0.023 1 1.66
0.009 1 1.70
[1.08; 2.58]
[1.15; 2.52]
0.627 1 1.12
0.220 1 1.30
[0.71; 1.79]
[0.86; 1.96]
0.920 1 0.97
0.734 1 1.09
[0.57; 1.65]
[0.68; 1.73] b0.001
0.003 1 2.09
1 2.41
[1.27; 3.46]
[1.53; 3.80]
0.003 1 2.26
0.002 1 2.19
[1.37; 3.71]
[1.39; 3.44]
0.037 1 1.63
0.039 1 1.56
[1.05; 2.54]
[1.04; 2.35] b0.001
0.008 1 1.68 2.18 4.69
1 1.36 2.42 4.66
[0.59; 4.77] [0.87; 5.50] [1.69; 13.0]
[0.54; 3.41] [1.10; 5.30] [1.90; 11.4]
b0.001 1 0.10
b0.001 1 0.10
[0.06; 0.16]
[0.06; 0.16]
b0.001 1 0.16
b0.001 1 0.20
[0.06; 0.44]
p
[0.09; 0.42]
TFI = Time between the end of first-line chemotherapy and the start of a second line
number of NAC cycles administered was 4, with the range of cycles given between 2 and 10. This median number was selected as threshold for appropriate separation of groups B1 and B2 patients. The median number of NAC cycles was 3 in group B1 and 6 in group B2. The total number of first-line chemotherapy cycle (preoperative and postoperative lines) was higher in group B2 compared to group B1 (p = 0.008).
Selection of group B2 patients For patients treated by NAC/IDS, the main cause for prolonging NAC after 3–4 cycles and delaying IDS was determined retrospectively. A decision for a NAC with 6 cycles was arbitrarily taken on initial evaluation for 20 patients independently of chemotherapy response (in 11 cases for a stage IV disease and in the presence of diffuse peritoneal extension at initial laparoscopy for 9 patients). In 15 cases, patients were referred to our institution after more than 4 cycles initiated in other hospital with no evaluation of NAC response after 3–4 cycles. In only 2 cases,
unresectable disease was predicted on CT-scan evaluation after 3– 4 cycles in the presence of a limited response to NAC.
Global prognosis factors Prognostic factors for the whole cohort are presented in Table S1. By univariate analysis, we identified several factors that significantly predicted worse overall survival in the entire study population: age N 60 years (p = 0.037), WHO performance status of 2 or more (p = 0.001), extensive peritoneal carcinomatosis at presentation (PCI before PDS or IDS N 17) (p b 0.001) and histology consistent with clear-cell or mucinous tumors (p = 0.018). In groups A and B, the result of surgery was one of most important prognosis factors and patients with complete resection at initial or at IDS had a significantly improved survival compared to patients with any macroscopic disease (p b 0.001 [IC 1.72 – 2.92]). Patients relapsing in the first six months after the end of chemotherapy (platinum-resistant diseases) had poor survival
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227
Table 3 Prognostics factors observed for patients with no macroscopic residual disease at the end of interval surgery in group B (group B0, after univariate analysis). Overall survival RR Age (years) b60 ≥60 WHO PS 0–1 ≥2 FIGO stage IIIC IV Histological subtype Serous or endometriod Other subtypes Tumor grade G1 (Bien diff) G2–3 (Moy/Peu diff) Digestive resection at IDS No Yes Posterior pelvic exenteration at IDS No Yes Diaphragm stripping or resection at IDS No Yes Extensive supramesocolic disease at IDS No Yes PCI before IDS b17 ≥17 Number of NAC cycles before IDS ≤4 N4 Response to NAC at IDS Complete microscopic response Complete macroscopic response Partial response Stable or progressive disease Sensitivity to first-line chemotherapy Refractory or resistant Platinum-sensitive TFI (Treatment Free Interval) b18 months ≥18 months
Relapse free survival CI 95%
p
RR
CI 95%
0.948 1 0.98
1 0.83
[0.54; 1.75]
[0.50; 1.39]
0.09 1 1.90
0.297 1 1.46
[0.94; 3.85]
[0.73; 2.91]
0.510 1 1.22
0.506 1 1.21
[0.67; 2.24]
[0.69; 2.13]
0.007 1 4.79
0.019 1 0.34
[1.84; 12.5]
[1.39; 7.99]
0.878 1 0.93
0.373 1 1.49
[0.35; 2.43]
[0.59; 3.79]
0.101 1 1.67
0.027 1 1.85
[0.91; 3.06]
[1.08; 3.18]
0.821 1 0.92
0.270 1 1.39
[0.47; 1.82]
[0.78; 2.47]
0.525 1 1.28
0.489 1 1.27
[0.61; 2.67]
[0.66; 2.45]
0.051 1 1.98
0.017 1 2.10
[1.01; 3.86]
[1.16; 3.80]
0.430 1 1.67
0.522 1 1.42
[0.51; 5.50]
[0.51; 3.95]
b0.001 1 2.93
0.005 1 2.21
[1.63; 5.28]
[1.30; 3.75]
0.124 1 1.55 1.60 12.2
0.242 1 1.30 1.78 4.46
[0.54; 4.49] [0.61; 4.19] [2.25; 66.4]
[0.51; 3.30] [0.79; 4.02] [0.91; 21.8]
b0.001 1 0.07
b0.001 1 0.08
[0.03;0.16]
[0.04;0.16]
b0.001 1 0.19
0.004 1 0.29
[0.07; 0.55]
p 0.485
[0.12; 0.70]
TFI = Time between the end of first-line chemotherapy and the start of a second line.
(p b 0.001). A treatment free interval (TFI) lesser than 18 months was also associated with worse overall survival.
of 3.05 (p b 0.001, [CI: 1.69–5.50]) with an independent impact from stage and WHO performance status.
Prognosis factors in group B (Tables 2 and 3)
Discussion
For patients receiving NAC, a WHO performance status of 2 or more (p = 0.039), a macroscopic RD (p b 0.001), an extensive peritoneal carcinomatosis at IDS (PCI N 17) (p = 0.003) or an extensive supramesocolic disease at IDS, the number of NAC cycles (p = 0.037) and the response to preoperative chemotherapy (p = 0.008) were significantly associated with worse overall survival after univariate analysis. Patients receiving more than 4 cycles of neoadjuvant chemotherapy (group B2) had worse survival compared to patients in group B1 (p = 0.037). After multivariate analysis (Table 4), the impact of the number of neoadjuvant cycles remained significant (p = 0.001, OR 2.28[1.41–3.70]) and was independent from disease stage, the presence of a residual disease and from the WHO performance status. This observation was reinforced in the subgroup of patients receiving NAC and complete resection at IDS. Patients with no macroscopic disease at the end of IDS and who had received more than 4 cycles of NAC treatment had poor survival (p b 0.001) despite complete removal of their tumor (Fig. 1) with a relative risk of death after multivariate analysis
Complete resection of all macroscopic disease, whether performed as primary treatment or after NAC remains the principal objective of cytoreductive surgery in the management of advanced EOC [10]. Nevertheless, timing of surgery remains contentious and controversy persists between the proponents of aggressive primary debulking and defenders of NAC followed by IDS [9,12,18]. Furthermore, identification of patients with potential resectable disease for upfront surgery and selection of patients requiring NAC remain challenging in this pathology despite attentive preoperative imaging and development of exploratory laparoscopy. For patients receiving NAC and IDS, the number of NAC cycles that should be prescribed before the first debulking and associated with the best results on overall survival is not yet determined. To date, no randomized study has specifically addressed this point. In 2006, Bristow et al. published a large meta-analysis derived from 22 cohorts and including 834 stage IIIC–IV EOC patients treated by NAC and IDS [18]. An inverse relationship was observed between survival and the number
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Table 4 Multivariate analysis in group B (interval surgery) and in group B0 (complete interval surgery). Overall survival RR
CI 95%
All group B patients Digestive resection at IDS No 1 Yes 2.19 Sensitivity to first-line chemotherapy Refractory or resistant 1 Platinum-sensitive 0.07 Number of NAC cycles before IDS ≤4 1 N4 2.28
p b0.001
[1.39; 3.43] b0.001 [0.04; 0.13] 0.001 [1.41; 3.70]
Patients with no macroscopic RD at the end of IDS (group B0) Sensitivity to first-line chemotherapy Refractory or resistant 1 Platinum-sensitive 0.07 [0.03; 0.16] Number of NAC cycles before IDS ≤4 1 N4 3.05 [1.69; 5.50]
b0.001
b0.001
of NAC cycles: each additional chemotherapy cycle (between 3 and 6 cycles) was associated with a 4-month decrease in overall survival. According to these results, the authors recommended that IDS should be performed as early as possible in the therapeutic sequence of EOC and unresectable diseases should be reevaluated regularly during NAC for potential surgery and complete resection [18]. Nevertheless, the results of Bristow and Chi's meta-analysis have been questioned because patients treated with IDS and receiving more than 3 cycles in this compilation of retrospective studies had probably more extended diseases that could explain worse prognosis. More recently, a report from a high-volume center has mentioned that IDS could be delayed beyond 6 or more cycles without detrimental consequences on survival [15].
1.00
Probability
0.75
0.50
Stage IV 0.25
0.00
Number at risk A0 B10 B20 Stage IV
0
1
2
3
97 67 24 36
93 64 24 35
82 50 14 28
68 40 8 20
A
B1
Years
4
5
6
7
54 31 5 13
38 21 5 9
30 19 4 8
23 14 3 6
B2
Stage IV
Group A0 : patients receiving complete PDS Group B10 : patients receiving complete IDS with a number of NAC cycles ≤ 4 Group B20 : patients receiving complete IDS with a number of NAC cycles > 4 Stage IV: stage IV disease in the cohort receiving complete PDS or complete IDS Fig. 1. Kaplan–Meier survival curves for patients receiving complete surgery at PDS (group A0) or at IDS (groups B10 and B20). Stage IV: Kaplan–Meier survival curve for patients with stage IV diseases and receiving complete PDS or complete IDS is indicated in gray. Group A0: patients receiving complete PDS. Group B10: patients receiving complete IDS with a number of NAC cycles ≤4. Group B20: patients receiving complete IDS with a number of NAC cycles N4. PDS: primary debulking surgery; IDS: interval debulking surgery.
In addition, the meta-analysis by Kang and Nam in 2009 showed that the number of NAC cycles did not influence survival of EOC patients receiving NAC in their review of 21 studies published between 1989 and 2008 [19]. On the contrary, discordant results were shown in our study: an inverse relationship was observed between prognosis and the number of NAC cycles: patients receiving late IDS (after more than 4 cycles) had worse survival compared to patients treated by primary surgery or early IDS (after less than 4 cycles). This result was observed despite higher rates of complete resection in the late IDS group (group B2) and the impact of the number of NAC cycles was independent from the other prognostic factors after multivariate analysis. Interpretation of these data and of these divergent results is complex. In general, patients receiving NAC and a fortiori more cycles before surgery had worse prognostic factors with more advanced disease at the time of presentation or more resistant tumors to chemotherapy. In our group and especially in this cohort, primary surgery was preferred for resectable diseases and IDS was generally reserved for patients with unresectable disease at initial exploratory laparoscopy or in the cases of stage IV disease or poor performance status. Furthermore, group B2 patients compared to groups B1 and A had more frequently stage IV disease at diagnosis that could explain worse outcome despite appropriate chemotherapy and complete resection. In consequence, one possible explanation of the poor prognosis observed in group B2 is the potential selection-bias of diseases associated with worse clinical and biological prognostic factors. In this hypothesis group B2 possibly encompasses patients with more extended carcinomatosis at diagnosis or less chemosensitive tumors that might explain increased NAC cycles with delayed IDS and finally a worse outcome. Compared to other studies that found no difference in survival for early or late IDS, our group systematically considered upfront surgery or early IDS for advanced EOC and reserved late IDS for unresectable tumors or diseases with initial extra-abdominal extension (stages IV). In contrast, Stoeckle et al. selected patients for late IDS more systematically according to the treatment protocol during the study period and not on disease extension at presentation or on response to chemotherapy [15]. Based on this observation, selection of patients may be different and our study might incorporate patients with worse intrinsic biological patterns in group B2. Furthermore, despite worse initial prognostic factors in group B (higher percentage of stage IV and poor PS), EOC patients receiving early IDS after a limited number of NAC (group B1) had an unexpected outcome compared to patients receiving PDS (group A) (Fig. 1). As our study is not randomized, groups A and B1 cannot be compared directly but our results suggest that they have comparable long-term survival. This element was also observed in the sub-groups of patients with complete IDS and PDS (Fig. 1) and further underlines the worse prognosis observed in group B2 patients receiving late IDS. Therefore, one possible explanation is that tumor with the worse biology (group B2) were subtracted from group B explaining the relative good prognosis of group B1 patients, and more akin to those, also selected, who had upfront surgery (group A). Nevertheless, the impact of the number of NAC cycles remained statistically significant after multivariate analysis and was independent from the stage. This result can infer other worse confounding prognosis factors but possibly direct impact on outcome of the numbers of NAC cycles. In addition, overall survival in group B2 was inferior to that of all stage IV patients of our cohort (Fig. 1). Furthermore, it is possible that EOC patients receiving NAC with disease resistant to initial treatment and considered unresectable after 6 cycles were not operated on and not selected for late IDS. These patients, with the worse diseases that correspond to refractory tumors, were not included in this study and did not impact the survival outcome in the delayed IDS group (only operated patients were recorded in this database). As our study was a retrospective one, the percentage of patients with refractory tumor excluded from IDS is undetermined. In addition, group B also included a significant percentage (40%) of patients having received different
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numbers of NAC after treatment initiation in other hospitals, before referral in our institution. This subgroup had all been considered unresectable with varying degrees of tumor burden. Alternatively, it is possible that some of the patients of our cohort receiving late IDS who could have been operated on earlier suffered from a delayed debulking. One explanation of this hypothesis is the possible development of resistant tumors due to the lack of initial surgery or early IDS leading to the selection of resistant tumor cells by the repetition of NAC cycles. In the same concept, retrospective data have recently suggested that NAC/IDS compared to primary surgery may increase the risk of developing platinum-resistant disease [13]. Selection of resistant tumor cells may be more significant when more chemotherapy cycles are used prior to IDS and macroscopic resection of tumor bulk. Goldie and Coldman demonstrated 20 years ago that the rate of development of tumor resistance was related to the size of the tumor [20]. In this mathematical model, there is a major statistical chance of tumor heterogeneity with resistant clones already present within the tumor at diagnosis especially for cancers with genetic instability and a high mutation rate like EOC. Based on this theory, acquired resistance often represents outgrowth of resistant clones originally present at low frequency in the tumor at diagnosis and that have expanded under the selective pressure imposed by systemic chemotherapy. In this concept, the tumor burden receiving chemotherapy cycles probably plays an important role that is confirmed by the improved effectiveness of platinum-based chemotherapy in advanced EOC receiving optimal and complete debulking. In our point of view, surgical debulking reduces the tumor bulk in a less selective manner than chemotherapy and might reduce tumor heterogeneity and somehow limit acquired resistance. Based on this hypothesis, one possible biological explanation of the worse prognosis observed for patients receiving delayed IDS besides selection-bias and worse tumor biology is the possible lack of physical removal of resistant parts within the macroscopic disease by PDS or early IDS after a limited number of NAC. In this hypothesis, the repetition of NAC cycles before surgery may select and promote the dissemination of resistant clones in microscopic format from these unremoved macroscopic lumps. This unremovable disease could lead to chemoresistance and early recurrence despite higher rates of complete surgery in the late IDS group. There are several limitations to this current retrospective study that must be considered in interpreting the data. During this long period of time (1995–2010), upfront surgery was systematically considered in our institution for all patients and NAC/IDS was reserved for patients who were not candidate for PDS including poor PS, stage IV or unresectable disease at presentation. Resectability was assessed on the basis of clinical examination, Ct-scan and exploratory laparotomy/ laparoscopy with variations depending on period and evolution of clinical practices. The definition of resectability and the selection of patients requiring NAC have probably evolved and represent a limit to generalize the findings of the present study. Despite large size of the entire cohort, the number of patients included in the B2 group was rather limited and data obtained need to be confirmed in larger studies. As the study is retrospective, the main cause for delaying IDS after more than 4 cycles of NAC was determined a posteriori with potential confounding factors. Most of them had probably less chemosensitive disease that can explain worse survival. In conclusion, we observed that in a large series of advanced EOC patients receiving late IDS (N4 NAC-cycles) have a poor prognosis compared to patients operated on earlier. The impact of surgical timing was reinforced in the subgroups with complete surgery and remained independent from other prognostic factors. The relative contribution of the therapeutic sequence compared to tumor biology and chemotherapy response remains controversial. These discordances in recent published data reinforce the necessity to complete ongoing randomized studies comparing early and late debulking in advanced EOC. Based on the results of the present series, we believe that the concept of early and complete IDS claimed by Bristow's meta-analysis should be preferred in the management of advanced EOC pending the results of
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ongoing controlled trials. Patients with advanced EOC receiving NAC should be evaluated regularly and IDS should be attempted as soon as possible, preferably after 4 or less cycles in order to reserve the maximum number of chemotherapy cycles on microscopic RD after IDS. These results reported in this study call into question the interest of a delayed debulking in advanced cases thought to be unresectable after 3 to 4 cycles of NAC. These patients have less chemosensitive tumors or disease associated with worse intrinsic tumor biology. In these cases, surgical debulking of remnant tumor deposits, even complete after 6 cycles or more, probably has a low impact on survival. In this subgroup, aggressiveness of surgery should be questioned while paying attention to quality of life, in view of the poor survival observed after complete late IDS. Alternative treatments such as second-line chemotherapy, antiangiogenic targeted therapies, or intensification with intraperitoneal chemotherapy or hyperthermic intraperitoneal chemotherapy in the absence of extra-abdominal extension should be discussed and evaluated in future trials. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2014.09.002. Conflicts of interest statement None declared.
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