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Optimal timing of interval debulking surgery in advanced ovarian cancer: yet to be defined?
European Journal of Obstetrics & Gynecology and Reproductive Biology 159 (2011) 407–412
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Optimal timing of interval debulking surgery in advanced ovarian cancer: yet to be defined? Eberhard Stoeckle a,*, Benjamin Boubli a, Anne Floquet b, Ve´ronique Brouste c, Marie Sire b, Sabrina Croce d, Laurence Thomas e, Fre´de´ric Guyon a a
Department of Surgery, Institut Bergonie´, Regional Cancer Centre, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France Department of Medical Oncology, Institut Bergonie´, Regional Cancer Centre, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France Department of Biostatistics, Institut Bergonie´, Regional Cancer Centre, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France d Department of Pathology, Institut Bergonie´, Regional Cancer Centre, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France e Department of Radiotherapy, Institut Bergonie´, Regional Cancer Centre, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 February 2011 Received in revised form 12 April 2011 Accepted 11 July 2011
Objectives: Interval debulking surgery (IDS) following neo-adjuvant chemotherapy (NAC) is a treatment option in advanced ovarian cancer. It is recommended to perform IDS early, after 3 cycles of NAC, but late IDS (after 6 cycles) may yield better results. Delaying IDS, however, harbours the risk of loosing the opportunity for debulking surgery. Study design: Retrospective comparison of two groups of patients with advanced ovarian carcinoma (stages IIC–IV) treated by platinum-based chemotherapy (CT) having undergone early IDS (after 3.6 cycles, group 1, n = 33) or late IDS (after 6.3 cycles, group 2, n = 104). Contemporary patients who had undergone standard treatment by primary debulking surgery (PDS) + CT (group 3, n = 446) and those treated by CT alone (group 4, n = 64 patients) served as internal controls. Results: Prognosis in IDS patients (groups 1 + 2) was comparable to that in PDS patients (group 3). Only a few patients in group 4 potentially had lost an opportunity for debulking surgery. Groups 1 and 2 were well-matched concerning usual prognostic factors. Surgery extent and post-operative outcomes were similar in both. In contrast, complete cytoreductions were significantly more frequent in late than in early IDS (group 2 vs.1: 58% vs. 36%, p = 0.03) and survival was not inferior in the late IDS group compared to the early IDS group with 37 vs. 22 months, respectively (p = 0.09). Conclusion: Late IDS yields higher complete resection rates than early IDS and should be evaluated prospectively for outcome in further trials. ß 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Advanced ovarian carcinoma Cytoreductive surgery Interval debulking surgery Neo-adjuvant chemotherapy Ovarian neoplasm Timing of surgery
1. Introduction Treatment in advanced ovarian cancer combines cytoreductive, debulking surgery and platinum-based chemotherapy. The definition of optimal cytoreductive surgery has evolved over time. Historically, it was based on the size of residual nodules [1], declining progressively from 3 cm to 2 cm [2,3] with up to a recent date a most accepted diameter of 1 cm [4]. In a meta-analysis, Bristow et al. have shown that any 10% incremental increases of optimal cytoreductions to residual nodules <2 cm enhanced the median survival of a patient cohort by 5.5% [3]. Some authors have proposed to consider the weight of residual disease [5]. We have shown that the number of residual nodules was also an important determinant of outcome, reclassifying a former optimal category
* Corresponding author. Tel.: +33 5 56 33 32 16; fax: +33 5 56 33 78 57. E-mail address: [email protected] (E. Stoeckle). 0301-2115/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2011.07.014
(residual tumors <2 cm) into a suboptimal group when their residual nodules were numerous [6]. However, the best outcome was observed after resection to no residual disease [6]. Recent reports suggest that only complete resections should be considered optimal [7–12]. In order to obtain better resection rates, and hopefully better outcome, different treatment strategies have been developed. In Europe mainly, where initial experience with more radical primary debulking surgery (PDS) gave mitigated results [13], effort focused on interval debulking surgery (IDS), primarily conceived as a supplementary time of debulking after PDS and several courses of chemotherapy (CT) [14]. Later, IDS constituted the sole surgical moment after neo-adjuvant chemotherapy (NAC) [5]. The validity of this concept has been confirmed recently in an EORTC/ Intergroup trial, comparing NAC (3) + IDS + CT (3) to PDS + CT (6). In this trial, to which our centre has contributed, survival was similar in both arms (30 vs. 29 months, respectively), but morbidity was lower in the neo-adjuvant arm [15]. In contrast
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to the former European experience, showing benefit from adding IDS to primary surgery and NAC [14], findings of a Gynaecologic Oncology Group trial in the US did not confirm this benefit [16]. The authors concluded that one surgical session might be sufficient if performed properly by a gynaecologic oncologist, preferably during PDS. Accordingly, some groups in the US first, and then outside the US developed recently radical PDS, reporting improved survivals of up to 58 months [7,9,10,12,17,18]. The debate whether and when to prefer the neo-adjuvant treatment to the standard approach with PDS is not closed and precise selection criteria remain to be determined [19]. However, when neo-adjuvant chemotherapy is chosen, its ideal number of courses before IDS may also be discussed. At conception, IDS was fixed empirically to be performed after three cycles of chemotherapy [14]. At that time a mathematical model (Goldie and Goldman) predicted that resistant tumor clones may arise when chemotherapy was prolonged. The fear was to miss the opportunity for debulking surgery because of tumor progression during prolonged chemotherapy. Early timing of IDS was then reconducted in the neo-adjuvant EORTC/Intergroup trial [15]. At Institut Bergonie´, treatment policy at the considered treatment period was the standard approach with the aim to achieve optimal PDS. If optimal debulking by standard, not radical surgery [20] was deemed unachievable, the neo-adjuvant option was taken. Because of the more restrictive definitions of optimal surgery over time [6], the indication for neo-adjuvant treatment increased. Timing of IDS depended on ongoing treatment protocols at different periods: In the early period, IDS was indicated after 6 cycles of NAC. Afterwards, according literature data [14] and then through our own, limited participation to the EORTC/Intergroup trial [15], we performed IDS early after 3 (or 4) cycles. In the last period, however, we re-introduced late IDS. This change was motivated by the feeling that surgery was easier at late IDS, and the impression, that higher resection rates were obtained at late IDS in comparison to early IDS. By consequence, timing of IDS depended on the actual treatment protocol prescriptions, but not on response to neo-adjuvant chemotherapy, hence avoiding a major bias in patient selection. Therefore, we judged possible to perform a retrospective comparison between early and late IDS testing the hypothesis that late IDS may yield higher resection rates, and maybe, better outcome than early IDS. In the present paper therefore we compare two groups of patients treated by NAC, one with early IDS, the other with late IDS. Because it has been argued that prolonging NAC beyond three cycles might be harmful [21], we investigated another group of contemporary patients treated by neo-adjuvant chemotherapy with no further surgery, trying to estimate the importance of loss of opportunity for debulking in them. Finally, because during the 28-year-period several changes in treatment occurred, we established a fourth group of contemporary patients treated by PDS and CT, serving as an internal reference for outcome after standard treatment. 2. Materials and methods 2.1. Patient’s selection and definitions After Institutional Review Board acceptance, patient charts fulfilling the selection criteria were extracted from our institutional database. Research criteria were: study period 1980–2007, primary invasive epithelial ovarian cancer, advanced stages IIC–IV, platinum-based chemotherapy regimens. A total of 647 patients fulfilled the research criteria. Patients selected to the NAC + IDS groups had to comply with the following criteria: no primary surgery or diagnostic surgery only comprising biopsy or maximally one diagnostic excisional procedure, e.g. a unilateral salpingooophorectomy. When more than one diagnostic procedure was
done, patients were excluded in order not to select those with a second debulking surgery or second-look surgery. All patients had measurable disease. All underwent NAC using platinum-based chemotherapy followed by IDS. Two groups of IDS-patients were established: early IDS with 4 cycles of NAC (group 1; n = 33) and late IDS with 5 cycles of NAC (group 2; n = 104). The two other groups were: a reference group of patients treated with the standard treatment by PDS + CT (group 3; n = 446) and a group of patients treated by CT alone (group 4; n = 64). 2.2. Statistics and follow-up Patient charts were registered in a Medlog (R) (Information Analysis Corp., Crystal Bay, NV 60606) database. Pearson’s chi2 and Fisher’s exact test were used to compare qualitative variables. Actuarial overall survival was estimated by the Kaplan–Meier method and comparison of survival data was performed by the logrank test. The SPSS 12.0 statistical software was used (SPSS, Inc., Chicago, IL). Patients were regularly followed-up at our centre. Follow-up was calculated with the inverse Kaplan–Meier method. Median follow-up was 86 months (range: 49–122), 149 months (range: 127–171) and 88 months (no ranges because of few survivors) in patients with IDS (early + late), PDS and CT alone, respectively. 3. Results 3.1. Patient characteristics (Table 1) The characteristics of the two IDS groups are comparable concerning age (p = 0.16), FIGO stage (p = 0.57), histology (p = 1) and tumor grade (p = 0.38, Table 1). Owing to evolving treatment practice at our centre, late IDS was more frequent in the 1990s whereas early IDS was more frequent in the 2000s. This difference was not significant. As expected, patients in group 3 (judged operable) had better tumor characteristics than IDS patients (judged inoperable). They were significantly younger than patients with late IDS (58 vs. 62 years, p = 0.001), had less advanced disease than the combined IDS patients (stages IIIC + IV: 348/446 = 78% vs. 129/137 = 94%) and had fewer serous/undifferentiated carcinoma (353/446 = 79% vs. 123/137 = 90%). Patients in group 4 showed significantly worse characteristics in comparison to all other groups: they were older (median age: 67 versus 60 years, p < 0.0001) and had more advanced disease (stage IV: 51% vs. 24%). Of note, information about performance status was not available in the database. 3.2. Medical treatments and treatment results (Table 2) Treatment evolved during the study period with important changes in 1997 including notably the introduction of taxane use and the abandon of consolidation whole abdominal radiotherapy. In combined IDS patients, the taxane use was 55% (75/137 patients) with a nonsignificant difference between early and late IDS (68% vs. 52%). Median numbers of pre-operative and total cycles of chemotherapy were 3.6 and 6.3 in early IDS and 6.3 and 8.0 in late IDS. Different types of consolidation chemotherapy were used over the years, but are not detailed in the database. Treatments and their results are summarized. 3.3. Type of surgery and disease status at interval debulking The extent of surgery was equivalent between early and late IDS (Table 3). Significant morbidity, defined by needing prolonged or new hospitalization or re-operation, was similar between the two groups (15 vs. 13%). At opening the abdomen, no visible tumor was
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Table 1 Patient and tumor characteristics. Group
1 Early IDS
2 Late IDS
3 PDS
4 CT alone
Total
Patients, n (%) Median age (range)
33 (5) 60 (41–87)
104 (16) 62 (22–88)
446 (69) 58 (17–86)
64 (10) 67 (27–88)
647 (100) 60 (17–88)
Stage FIGO, n (%) IIC–IIIB IIIC IV
1 (3) 23 (70) 9 (27)
7 (7) 65 (62) 32 (31)
98 (22) 248 (56) 100 (22)
3 (5) 28 (44) 33 (51)
109 (17) 364 (56) 174 (27)
Histology, n (%) Serous Endometrioid Undifferentiated Mucinous Clear cell Other
29 1 1 1 1 0
(88) (3) (3) (3) (3) (0)
90 6 3 4 0 1
(86) (6) (3) (4) (0) (1)
330 59 23 20 8 6
(74) (13) (5) (5) (2) (1)
44 3 10 3 2 2
(69) (5) (15) (5) (3) (3)
493 69 37 28 11 9
(76) (11) (6) (4) (2) (1)
Grade, n (%) G1 G2 G3 NP
5 6 19 3
(15) (18) (58) (9)
7 28 55 14
(7) (27) (53) (13)
46 118 225 57
(10) (27) (50) (13)
3 11 29 21
(5) (17) (45) (33)
61 163 328 95
(9) (25) (51) (15)
Treatment period 1980–89 1990–99 2000–07
9 (27) 2 (6) 22 (67)
29 (28) 22 (21) 53 (51)
137 (31) 185 (41) 124 (28)
21 (33) 16 (25) 27 (42)
196 (30) 225 (35) 226 (35)
Early IDS: 3.6 courses of neo-adjuvant chemotherapy – interval debulking – postop. chemo/or radiotherapy. Late IDS: 6.3 courses of neo-adjuvant chemotherapy – interval debulking – postop. chemo/or radiotherapy. PDS: primary debulking surgery – 6 courses of chemotherapy – consolidation (chemo/or radiotherapy). CT alone: first-line chemotherapy with no further surgery.
seen in 6% and 26% of early and late IDS patients, respectively. After completion of surgery, those rates rose to 36% and 58% respectively. These differences are significant (Table 3).
patients (37 vs. 22 months) without reaching significance (Table 4B and Fig. 2, p = 0.09). 4. Comments
3.4. Final outcome (Table 4) A constant progress in overall survival was observed in all patient categories with an approximately 10 months gain in median survival every decade (Table 4A). At last follow-up, the numbers of patients alive were 6, 34, 83 and 3 in early IDS, late IDS, PDS and CT-alone groups, respectively. Overall survival was worst in group 4. It was identical between the PDS group and the combined IDS patients (32 vs. 30 months, Fig. 1), and there was a trend to better survival in late IDS patients compared to early IDS
Our results confirm that resection rates are higher in late IDS than in early IDS. This difference does not seem to result from surgery because complementary resections reached a comparable 30% gain in both (from 26% to 58% and from 6% to 36%, respectively), but may be a direct effect of prolonging neoadjuvant chemotherapy. Higher resection rates, however, did not result in significantly better survival, but at least survival in late IDS was not inferior to that in early IDS, suggesting that prolonging chemotherapy was not prejudicial.
Table 2 Delivered treatments and primary treatment results. Group
1 Early IDS
2 Late IDS
3 PDS
4 CT alone
All
Patients, n (%)
33 (5)
104 (16)
446 (69)
64 (10)
647 (100)
21 (68)
54 (52)
151 (36)
26 (45)
252 (39)
3.6 (3–4) 6.3 (3–9) 5 (15)
6.3 (5–14) 8.0 (5–17) 30 (29)
8.0 (1–19)a 137 (31)
4.6 (1–12) 1 (2)
173 (27)
9 (9) 10 (10) 84 (81) 1 (1)
79 (18) 36 (8) 322 (72) 9 (2)
31 (48) 11 (17) 16 (25) 6 (10)
124 (19) 64 (10) 443 (68) 16 (3)
First-line chemotherapy Taxane use, n (%) Mean number of cycles NAC (range) Total (range) Radiotherapy
p = 0.12 Final combined treatment response Progression Stabilization or PR < 50 PR > 50 or CR NS
5 (15) 7 (21) 21 (64) 0 (0)
PR < 50: partial response <50%. PR > 50: partial response 50%. CR, complete response; NS, not specified. a In 309 PDS patients receiving consolidation chemotherapy instead of radiotherapy.
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Table 3 Extent of surgery at interval debulking and rates of complete remissions. Group
1 Early IDS
2 Late IDS
Patients, n (%) Median incision Total abdominal hysterectomy Bilat./unilateral salpingo-oophorectomy Omentectomy Para-aortic lymph node assessment Pelvic lymph node assessment Appendectomy Bowel resection Other surgery Significant morbiditya Infection Hemorrhage Bowel obstruction VTEb Needing reoperation Comprising death
33 (24) 32 (97) 27 (82) 25 (76) 25 (76) 16 (49) 19 (58) 20 (61) 6 (18) 6 (18) 5 (15) 3 1 1 0 1 (3) 1 (3)
104 (76) 102 (98) 93 (89) 85 (82) 78 (76) 49 (47) 57 (55) 67 (65) 15 (14) 15 (14) 13 (13) 8 4 0 1 7 (7) 2 (2)
Complete remissionc at surgery, n (%) Complete remission after surgery, n (%)
2 (6) 12 (36)
27 (26) 60 (58)
p-Value
Interval Debulking Surgery Primary Debulking Surgery
0.02 0.03
a Significant morbidity: comprising prolonged or new hospitalization, reoperation, death. b Venous thrombo embolic events. c Complete remission: no visible tumor.
Fig. 1. Overall survival in patients with advanced ovarian cancer stages IIC–IV treated by platinum-based chemotherapy according to timing of debulking surgery: primary debulking surgery (group 3; n = 446) vs. interval debulking surgery (groups 1 + 2; n = 137).
Selection criteria, however, may have biased our findings. First, patients with sustained response to chemotherapy might have been selected for late IDS whereas ill responders might have been allocated preferentially to early IDS. This potential bias is not sustained by our treatment policy, because indications for early or late IDS depended on the treatment protocols applying at the respective periods and not on response to neo-adjuvant chemotherapy. Comparable patient and surgery characteristics (Tables 1 and 3) support this affirmation. Minor, not significant treatment differences between early and late IDS were observed, favouring indistinctly one or the other group with respectively fewer total courses of chemotherapy (6.3 vs. 8 cycles), less radiotherapy (15% vs. 29%), higher taxane use (68% vs. 52%), more recent treatment period (Tables 1 and 2). Second, patients progressing during neo-adjuvant chemotherapy might have been lost to IDS. To evaluate this risk, we established group 4 including patients treated by neo-adjuvant chemotherapy without further surgery. In this group of patients with primarily inoperable disease, 65% of them had tumor
progression or minor response, unsuitable to cytoreductive surgery (Table 2). This is a group with platinum-resistant or refractory disease. If surgery had been tried, a recent study suggests that complete resection would have been achieved in less than a fifth of those patients [22]. Only a quarter of the patients had sufficient tumor response allowing considering surgery. Why they had not been operated cannot be retrieved retrospectively, but there are indices for low operability: probable poor performance status due to age (half of the patients were aged 67–88 years, Table 1), knowing that at that time measures to correct frail conditions in geriatric patients were not available. Furthermore, half of the patients had stage IV disease, frequently inaccessible to optimal surgery. Another information is that in half of the patients chemotherapy had to be stopped at 4.6 cycles. That means early tumor progression precluding many of these patients even from early IDS. The only alternative to surgery here was second-line chemotherapy or palliation.
Table 4 Survival outcome. (A) According treatment period in all patients Period
Patients (n)
5-y OS (%)
Median survival (months, CI)
p-Value
1980–1989 1990–1999 2000–2007
196 225 226
21% 25% 33%
19 (15–23) 30 (25–34) 40 (35–46)
p = 0.001
(B) According treatment group Group
1 Early IDS
2 Late IDS
3 PDS
4 CT alone
Total
Patients, n (%) 5-y OS Median survival (range), in months
33 (5) 17% 22 (13–31)
104 (16) 29% 37 (27–46)
446 (69) 29% 32 (28–36)
64 (10) 6% 9 (7–12)
647 (100) 26% 28 (25–32)
p = 0.09 p = 0.6 p = 0.2 5-y OS, five-year overall survival. CI, confidence interval.
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Early Interval debulking (early IDS, n= 33) Late interval debulking surgery (late IDS, n= 104)
Fig. 2. Overall survival in patients with advanced ovarian cancer stages IIC–IV treated by platinum-based chemotherapy according to timing of interval debulking surgery after neo-adjuvant chemotherapy: early interval debulking surgery (after 3.6 cycles; group 1, n = 33) vs. late interval debulking surgery (after 6.3 cycles; group 2, n = 104), median survival: 22 vs. 37 months (p = 0.09).
The median overall survival of 30 months in this series of patients with neo-adjuvant treatment compares unfavourably to better survivals reported in recent series with the standard approach [7,9,10,12,17,18]. However, survival data should be looked on at same treatment periods. As others [10,19] we have observed constant progress in outcome in patients over time, with approximately a 10 month gain in survival every decade (Table 4A). Presently, we have established group 3 in order to look for outcome in patients treated in a standard manner in our institution at the same time. What we found were completely superposing survival curves (Fig. 1). This was a surprise because group 3 patients had more favourable tumor characteristics than IDS patients (Table 1). Furthermore, with roughly close tumor characteristics (stages IIIC/IV: 94% vs. 100%) survival in our combined IDS group was identical to that reported in the neo-adjuvant EORTC/Intergroup trial with 30 months in both [15]. The latter was hampered of course by its multicentricity, but favoured by chemotherapy (taxane use: 100% vs. 55%) and treatment period (1998–2006 vs. 1980–2007) in comparison to our series. This observation sustains the validity of the neo-adjuvant concept and underlines the pertinence of our patient selection. In the EORTC/Intergroup trial comparing PDS to early IDS, despite higher resection rates in the IDS arm, survival did not differ between the two arms [15]. This apparent paradox may be explained by differences in the respective treatment impacts according timing of surgery. In the neo-adjuvant setting possibly the efficacy of chemotherapy overruled the impact of the surgical effort. If this hypothesis applied, increasing the intensity of chemotherapy, e.g. through prolonged NAC, consequently might have resulted in prolonged survival. Data concerning late IDS after prolonged NAC are limited. Consecutive series of patients treated by 5 or 6 cycles of NAC report median survivals of 13, 23 and 46 months, depending on treatment periods [23–25]. Two series compared retrospectively late to early IDS. Ansquer et al. [26] in a cohort of 54 patients observed differences in complete remission rates between early and late IDS (45% versus 61%) but not in survival (both 22 months). Loizzi et al. in a case– control study of 30 patients, did not find any difference either in response rates or in survival (median survival: 32 months) between 18 patients with 3 cycles and 12 patients with >3 cycles [27].
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In a review of 27 series of patients treated by NAC + IDS, we did not find arguments in the literature supporting the hypothesis that early IDS was superior to late IDS [28]. In contrast, Bristow and Chi reviewing 22 series of patients in a meta-analysis concluded that every further cycle of chemotherapy beyond 3 cycles was associated with a decrease in median survival of 4.1 months [21]. A recent meta-analysis by Kang and Nam [29] in 21 patient cohorts taking into account most of the series included in the precedent analysis, found that independent predictors for survival were year of publication, the percentage of taxane use, and, the rate of optimal surgery. The number of cycles of neo-adjuvant chemotherapy, however, was not prognostic, in contradiction to Bristow et al. Several arguments support the interest of late IDS: (1) higher debulking rates; (2) higher treatment intensity because of the absence of treatment interruption during the surgical period. The duration of treatment interruption depends on the importance of cytoreductive surgery, ranging from 9 to 24 days according to the extent of primary debulking in one series [10] and on postoperative morbidity likely to prolong hospital stay up to 40 days [9]. After IDS, delays of 24 days before resuming chemotherapy have been reported [14,16]. (3) Biological evidence supports prolonged NAC. Pro-apoptotic factors in ascitic fluids and tumor specimen showed to be more effective after 6 than 3 cycles of NAC in patients treated for ovarian cancer [30]. Combined to our findings, these data suggest that it would be worthwhile to evaluate the optimal timing of IDS and test the hypothesis that late interval debulking surgery might be better. Conflict of interest statement None of the authors declared any conflict of interest regarding the subject of this study. Acknowledgement This paper has not been supported by any funding. References [1] Griffiths CT, Fuller F. Intensive surgical and chemotherapeutic management of advanced ovarian cancer. Surg Clin North Am 1978;58:131–42. [2] Omura G, Blessing J, Ehrlich C, et al. A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. Cancer 1986;57:1725–30. [3] 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. [4] Omura GA, Brady MF, Homesley HD, et al. Long follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 1991;9:1138–50. [5] Vergote I, de Wever I, Tjalma W, Van Gramberen M, Decloedt J, van Dam P. Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients. Gynecol Oncol 1998;71: 431–6. [6] Stoeckle E, Paravis P, Floquet A, et al. Number of residual nodules, better than size, defines optimal surgery in advanced epithelial ovarian cancer. Int J Gynecol Cancer 2004;14:779–87. [7] Eisenkop SM, Spirtos NM, Friedman RL, et al. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90: 390–6. [8] Wimberger P, Lehmann N, Kimmig R, Burges A, Meier W, du Bois A. Prognostic factors for complete debulking in advanced ovarian cancer and its impact on survival. An exploratory analysis of a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol 2007;106:69–74. [9] Scholz H, Tasdemir H, Hunlich T, Turnwald W, Both A, Egger H. Multivisceral cytoreductive surgery in FIGO stages IIIC and IV epithelial ovarian cancer: results and 5-year follow-up. Gynecol Oncol 2007;106:591–5. [10] Eisenhauer EL, Abu-Rustum NR, Sonoda Y, Aghajanian C, Barakat RR, Chi DS. The effect of maximal surgical cytoreduction on sensitivity to platinum– taxane chemotherapy and subsequent survival in patients with advanced ovarian cancer. Gynecol Oncol 2008;108:276–81.
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Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Optimal timing of interval debulking surgery in advanced ovarian cancer: yet to be defined? Eberhard Stoeckle a,*, Benjamin Boubli a, Anne Floquet b, Ve´ronique Brouste c, Marie Sire b, Sabrina Croce d, Laurence Thomas e, Fre´de´ric Guyon a a
Department of Surgery, Institut Bergonie´, Regional Cancer Centre, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France Department of Medical Oncology, Institut Bergonie´, Regional Cancer Centre, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France Department of Biostatistics, Institut Bergonie´, Regional Cancer Centre, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France d Department of Pathology, Institut Bergonie´, Regional Cancer Centre, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France e Department of Radiotherapy, Institut Bergonie´, Regional Cancer Centre, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 February 2011 Received in revised form 12 April 2011 Accepted 11 July 2011
Objectives: Interval debulking surgery (IDS) following neo-adjuvant chemotherapy (NAC) is a treatment option in advanced ovarian cancer. It is recommended to perform IDS early, after 3 cycles of NAC, but late IDS (after 6 cycles) may yield better results. Delaying IDS, however, harbours the risk of loosing the opportunity for debulking surgery. Study design: Retrospective comparison of two groups of patients with advanced ovarian carcinoma (stages IIC–IV) treated by platinum-based chemotherapy (CT) having undergone early IDS (after 3.6 cycles, group 1, n = 33) or late IDS (after 6.3 cycles, group 2, n = 104). Contemporary patients who had undergone standard treatment by primary debulking surgery (PDS) + CT (group 3, n = 446) and those treated by CT alone (group 4, n = 64 patients) served as internal controls. Results: Prognosis in IDS patients (groups 1 + 2) was comparable to that in PDS patients (group 3). Only a few patients in group 4 potentially had lost an opportunity for debulking surgery. Groups 1 and 2 were well-matched concerning usual prognostic factors. Surgery extent and post-operative outcomes were similar in both. In contrast, complete cytoreductions were significantly more frequent in late than in early IDS (group 2 vs.1: 58% vs. 36%, p = 0.03) and survival was not inferior in the late IDS group compared to the early IDS group with 37 vs. 22 months, respectively (p = 0.09). Conclusion: Late IDS yields higher complete resection rates than early IDS and should be evaluated prospectively for outcome in further trials. ß 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Advanced ovarian carcinoma Cytoreductive surgery Interval debulking surgery Neo-adjuvant chemotherapy Ovarian neoplasm Timing of surgery
1. Introduction Treatment in advanced ovarian cancer combines cytoreductive, debulking surgery and platinum-based chemotherapy. The definition of optimal cytoreductive surgery has evolved over time. Historically, it was based on the size of residual nodules [1], declining progressively from 3 cm to 2 cm [2,3] with up to a recent date a most accepted diameter of 1 cm [4]. In a meta-analysis, Bristow et al. have shown that any 10% incremental increases of optimal cytoreductions to residual nodules <2 cm enhanced the median survival of a patient cohort by 5.5% [3]. Some authors have proposed to consider the weight of residual disease [5]. We have shown that the number of residual nodules was also an important determinant of outcome, reclassifying a former optimal category
* Corresponding author. Tel.: +33 5 56 33 32 16; fax: +33 5 56 33 78 57. E-mail address: [email protected] (E. Stoeckle). 0301-2115/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2011.07.014
(residual tumors <2 cm) into a suboptimal group when their residual nodules were numerous [6]. However, the best outcome was observed after resection to no residual disease [6]. Recent reports suggest that only complete resections should be considered optimal [7–12]. In order to obtain better resection rates, and hopefully better outcome, different treatment strategies have been developed. In Europe mainly, where initial experience with more radical primary debulking surgery (PDS) gave mitigated results [13], effort focused on interval debulking surgery (IDS), primarily conceived as a supplementary time of debulking after PDS and several courses of chemotherapy (CT) [14]. Later, IDS constituted the sole surgical moment after neo-adjuvant chemotherapy (NAC) [5]. The validity of this concept has been confirmed recently in an EORTC/ Intergroup trial, comparing NAC (3) + IDS + CT (3) to PDS + CT (6). In this trial, to which our centre has contributed, survival was similar in both arms (30 vs. 29 months, respectively), but morbidity was lower in the neo-adjuvant arm [15]. In contrast
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to the former European experience, showing benefit from adding IDS to primary surgery and NAC [14], findings of a Gynaecologic Oncology Group trial in the US did not confirm this benefit [16]. The authors concluded that one surgical session might be sufficient if performed properly by a gynaecologic oncologist, preferably during PDS. Accordingly, some groups in the US first, and then outside the US developed recently radical PDS, reporting improved survivals of up to 58 months [7,9,10,12,17,18]. The debate whether and when to prefer the neo-adjuvant treatment to the standard approach with PDS is not closed and precise selection criteria remain to be determined [19]. However, when neo-adjuvant chemotherapy is chosen, its ideal number of courses before IDS may also be discussed. At conception, IDS was fixed empirically to be performed after three cycles of chemotherapy [14]. At that time a mathematical model (Goldie and Goldman) predicted that resistant tumor clones may arise when chemotherapy was prolonged. The fear was to miss the opportunity for debulking surgery because of tumor progression during prolonged chemotherapy. Early timing of IDS was then reconducted in the neo-adjuvant EORTC/Intergroup trial [15]. At Institut Bergonie´, treatment policy at the considered treatment period was the standard approach with the aim to achieve optimal PDS. If optimal debulking by standard, not radical surgery [20] was deemed unachievable, the neo-adjuvant option was taken. Because of the more restrictive definitions of optimal surgery over time [6], the indication for neo-adjuvant treatment increased. Timing of IDS depended on ongoing treatment protocols at different periods: In the early period, IDS was indicated after 6 cycles of NAC. Afterwards, according literature data [14] and then through our own, limited participation to the EORTC/Intergroup trial [15], we performed IDS early after 3 (or 4) cycles. In the last period, however, we re-introduced late IDS. This change was motivated by the feeling that surgery was easier at late IDS, and the impression, that higher resection rates were obtained at late IDS in comparison to early IDS. By consequence, timing of IDS depended on the actual treatment protocol prescriptions, but not on response to neo-adjuvant chemotherapy, hence avoiding a major bias in patient selection. Therefore, we judged possible to perform a retrospective comparison between early and late IDS testing the hypothesis that late IDS may yield higher resection rates, and maybe, better outcome than early IDS. In the present paper therefore we compare two groups of patients treated by NAC, one with early IDS, the other with late IDS. Because it has been argued that prolonging NAC beyond three cycles might be harmful [21], we investigated another group of contemporary patients treated by neo-adjuvant chemotherapy with no further surgery, trying to estimate the importance of loss of opportunity for debulking in them. Finally, because during the 28-year-period several changes in treatment occurred, we established a fourth group of contemporary patients treated by PDS and CT, serving as an internal reference for outcome after standard treatment. 2. Materials and methods 2.1. Patient’s selection and definitions After Institutional Review Board acceptance, patient charts fulfilling the selection criteria were extracted from our institutional database. Research criteria were: study period 1980–2007, primary invasive epithelial ovarian cancer, advanced stages IIC–IV, platinum-based chemotherapy regimens. A total of 647 patients fulfilled the research criteria. Patients selected to the NAC + IDS groups had to comply with the following criteria: no primary surgery or diagnostic surgery only comprising biopsy or maximally one diagnostic excisional procedure, e.g. a unilateral salpingooophorectomy. When more than one diagnostic procedure was
done, patients were excluded in order not to select those with a second debulking surgery or second-look surgery. All patients had measurable disease. All underwent NAC using platinum-based chemotherapy followed by IDS. Two groups of IDS-patients were established: early IDS with 4 cycles of NAC (group 1; n = 33) and late IDS with 5 cycles of NAC (group 2; n = 104). The two other groups were: a reference group of patients treated with the standard treatment by PDS + CT (group 3; n = 446) and a group of patients treated by CT alone (group 4; n = 64). 2.2. Statistics and follow-up Patient charts were registered in a Medlog (R) (Information Analysis Corp., Crystal Bay, NV 60606) database. Pearson’s chi2 and Fisher’s exact test were used to compare qualitative variables. Actuarial overall survival was estimated by the Kaplan–Meier method and comparison of survival data was performed by the logrank test. The SPSS 12.0 statistical software was used (SPSS, Inc., Chicago, IL). Patients were regularly followed-up at our centre. Follow-up was calculated with the inverse Kaplan–Meier method. Median follow-up was 86 months (range: 49–122), 149 months (range: 127–171) and 88 months (no ranges because of few survivors) in patients with IDS (early + late), PDS and CT alone, respectively. 3. Results 3.1. Patient characteristics (Table 1) The characteristics of the two IDS groups are comparable concerning age (p = 0.16), FIGO stage (p = 0.57), histology (p = 1) and tumor grade (p = 0.38, Table 1). Owing to evolving treatment practice at our centre, late IDS was more frequent in the 1990s whereas early IDS was more frequent in the 2000s. This difference was not significant. As expected, patients in group 3 (judged operable) had better tumor characteristics than IDS patients (judged inoperable). They were significantly younger than patients with late IDS (58 vs. 62 years, p = 0.001), had less advanced disease than the combined IDS patients (stages IIIC + IV: 348/446 = 78% vs. 129/137 = 94%) and had fewer serous/undifferentiated carcinoma (353/446 = 79% vs. 123/137 = 90%). Patients in group 4 showed significantly worse characteristics in comparison to all other groups: they were older (median age: 67 versus 60 years, p < 0.0001) and had more advanced disease (stage IV: 51% vs. 24%). Of note, information about performance status was not available in the database. 3.2. Medical treatments and treatment results (Table 2) Treatment evolved during the study period with important changes in 1997 including notably the introduction of taxane use and the abandon of consolidation whole abdominal radiotherapy. In combined IDS patients, the taxane use was 55% (75/137 patients) with a nonsignificant difference between early and late IDS (68% vs. 52%). Median numbers of pre-operative and total cycles of chemotherapy were 3.6 and 6.3 in early IDS and 6.3 and 8.0 in late IDS. Different types of consolidation chemotherapy were used over the years, but are not detailed in the database. Treatments and their results are summarized. 3.3. Type of surgery and disease status at interval debulking The extent of surgery was equivalent between early and late IDS (Table 3). Significant morbidity, defined by needing prolonged or new hospitalization or re-operation, was similar between the two groups (15 vs. 13%). At opening the abdomen, no visible tumor was
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Table 1 Patient and tumor characteristics. Group
1 Early IDS
2 Late IDS
3 PDS
4 CT alone
Total
Patients, n (%) Median age (range)
33 (5) 60 (41–87)
104 (16) 62 (22–88)
446 (69) 58 (17–86)
64 (10) 67 (27–88)
647 (100) 60 (17–88)
Stage FIGO, n (%) IIC–IIIB IIIC IV
1 (3) 23 (70) 9 (27)
7 (7) 65 (62) 32 (31)
98 (22) 248 (56) 100 (22)
3 (5) 28 (44) 33 (51)
109 (17) 364 (56) 174 (27)
Histology, n (%) Serous Endometrioid Undifferentiated Mucinous Clear cell Other
29 1 1 1 1 0
(88) (3) (3) (3) (3) (0)
90 6 3 4 0 1
(86) (6) (3) (4) (0) (1)
330 59 23 20 8 6
(74) (13) (5) (5) (2) (1)
44 3 10 3 2 2
(69) (5) (15) (5) (3) (3)
493 69 37 28 11 9
(76) (11) (6) (4) (2) (1)
Grade, n (%) G1 G2 G3 NP
5 6 19 3
(15) (18) (58) (9)
7 28 55 14
(7) (27) (53) (13)
46 118 225 57
(10) (27) (50) (13)
3 11 29 21
(5) (17) (45) (33)
61 163 328 95
(9) (25) (51) (15)
Treatment period 1980–89 1990–99 2000–07
9 (27) 2 (6) 22 (67)
29 (28) 22 (21) 53 (51)
137 (31) 185 (41) 124 (28)
21 (33) 16 (25) 27 (42)
196 (30) 225 (35) 226 (35)
Early IDS: 3.6 courses of neo-adjuvant chemotherapy – interval debulking – postop. chemo/or radiotherapy. Late IDS: 6.3 courses of neo-adjuvant chemotherapy – interval debulking – postop. chemo/or radiotherapy. PDS: primary debulking surgery – 6 courses of chemotherapy – consolidation (chemo/or radiotherapy). CT alone: first-line chemotherapy with no further surgery.
seen in 6% and 26% of early and late IDS patients, respectively. After completion of surgery, those rates rose to 36% and 58% respectively. These differences are significant (Table 3).
patients (37 vs. 22 months) without reaching significance (Table 4B and Fig. 2, p = 0.09). 4. Comments
3.4. Final outcome (Table 4) A constant progress in overall survival was observed in all patient categories with an approximately 10 months gain in median survival every decade (Table 4A). At last follow-up, the numbers of patients alive were 6, 34, 83 and 3 in early IDS, late IDS, PDS and CT-alone groups, respectively. Overall survival was worst in group 4. It was identical between the PDS group and the combined IDS patients (32 vs. 30 months, Fig. 1), and there was a trend to better survival in late IDS patients compared to early IDS
Our results confirm that resection rates are higher in late IDS than in early IDS. This difference does not seem to result from surgery because complementary resections reached a comparable 30% gain in both (from 26% to 58% and from 6% to 36%, respectively), but may be a direct effect of prolonging neoadjuvant chemotherapy. Higher resection rates, however, did not result in significantly better survival, but at least survival in late IDS was not inferior to that in early IDS, suggesting that prolonging chemotherapy was not prejudicial.
Table 2 Delivered treatments and primary treatment results. Group
1 Early IDS
2 Late IDS
3 PDS
4 CT alone
All
Patients, n (%)
33 (5)
104 (16)
446 (69)
64 (10)
647 (100)
21 (68)
54 (52)
151 (36)
26 (45)
252 (39)
3.6 (3–4) 6.3 (3–9) 5 (15)
6.3 (5–14) 8.0 (5–17) 30 (29)
8.0 (1–19)a 137 (31)
4.6 (1–12) 1 (2)
173 (27)
9 (9) 10 (10) 84 (81) 1 (1)
79 (18) 36 (8) 322 (72) 9 (2)
31 (48) 11 (17) 16 (25) 6 (10)
124 (19) 64 (10) 443 (68) 16 (3)
First-line chemotherapy Taxane use, n (%) Mean number of cycles NAC (range) Total (range) Radiotherapy
p = 0.12 Final combined treatment response Progression Stabilization or PR < 50 PR > 50 or CR NS
5 (15) 7 (21) 21 (64) 0 (0)
PR < 50: partial response <50%. PR > 50: partial response 50%. CR, complete response; NS, not specified. a In 309 PDS patients receiving consolidation chemotherapy instead of radiotherapy.
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Table 3 Extent of surgery at interval debulking and rates of complete remissions. Group
1 Early IDS
2 Late IDS
Patients, n (%) Median incision Total abdominal hysterectomy Bilat./unilateral salpingo-oophorectomy Omentectomy Para-aortic lymph node assessment Pelvic lymph node assessment Appendectomy Bowel resection Other surgery Significant morbiditya Infection Hemorrhage Bowel obstruction VTEb Needing reoperation Comprising death
33 (24) 32 (97) 27 (82) 25 (76) 25 (76) 16 (49) 19 (58) 20 (61) 6 (18) 6 (18) 5 (15) 3 1 1 0 1 (3) 1 (3)
104 (76) 102 (98) 93 (89) 85 (82) 78 (76) 49 (47) 57 (55) 67 (65) 15 (14) 15 (14) 13 (13) 8 4 0 1 7 (7) 2 (2)
Complete remissionc at surgery, n (%) Complete remission after surgery, n (%)
2 (6) 12 (36)
27 (26) 60 (58)
p-Value
Interval Debulking Surgery Primary Debulking Surgery
0.02 0.03
a Significant morbidity: comprising prolonged or new hospitalization, reoperation, death. b Venous thrombo embolic events. c Complete remission: no visible tumor.
Fig. 1. Overall survival in patients with advanced ovarian cancer stages IIC–IV treated by platinum-based chemotherapy according to timing of debulking surgery: primary debulking surgery (group 3; n = 446) vs. interval debulking surgery (groups 1 + 2; n = 137).
Selection criteria, however, may have biased our findings. First, patients with sustained response to chemotherapy might have been selected for late IDS whereas ill responders might have been allocated preferentially to early IDS. This potential bias is not sustained by our treatment policy, because indications for early or late IDS depended on the treatment protocols applying at the respective periods and not on response to neo-adjuvant chemotherapy. Comparable patient and surgery characteristics (Tables 1 and 3) support this affirmation. Minor, not significant treatment differences between early and late IDS were observed, favouring indistinctly one or the other group with respectively fewer total courses of chemotherapy (6.3 vs. 8 cycles), less radiotherapy (15% vs. 29%), higher taxane use (68% vs. 52%), more recent treatment period (Tables 1 and 2). Second, patients progressing during neo-adjuvant chemotherapy might have been lost to IDS. To evaluate this risk, we established group 4 including patients treated by neo-adjuvant chemotherapy without further surgery. In this group of patients with primarily inoperable disease, 65% of them had tumor
progression or minor response, unsuitable to cytoreductive surgery (Table 2). This is a group with platinum-resistant or refractory disease. If surgery had been tried, a recent study suggests that complete resection would have been achieved in less than a fifth of those patients [22]. Only a quarter of the patients had sufficient tumor response allowing considering surgery. Why they had not been operated cannot be retrieved retrospectively, but there are indices for low operability: probable poor performance status due to age (half of the patients were aged 67–88 years, Table 1), knowing that at that time measures to correct frail conditions in geriatric patients were not available. Furthermore, half of the patients had stage IV disease, frequently inaccessible to optimal surgery. Another information is that in half of the patients chemotherapy had to be stopped at 4.6 cycles. That means early tumor progression precluding many of these patients even from early IDS. The only alternative to surgery here was second-line chemotherapy or palliation.
Table 4 Survival outcome. (A) According treatment period in all patients Period
Patients (n)
5-y OS (%)
Median survival (months, CI)
p-Value
1980–1989 1990–1999 2000–2007
196 225 226
21% 25% 33%
19 (15–23) 30 (25–34) 40 (35–46)
p = 0.001
(B) According treatment group Group
1 Early IDS
2 Late IDS
3 PDS
4 CT alone
Total
Patients, n (%) 5-y OS Median survival (range), in months
33 (5) 17% 22 (13–31)
104 (16) 29% 37 (27–46)
446 (69) 29% 32 (28–36)
64 (10) 6% 9 (7–12)
647 (100) 26% 28 (25–32)
p = 0.09 p = 0.6 p = 0.2 5-y OS, five-year overall survival. CI, confidence interval.
E. Stoeckle et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 159 (2011) 407–412
Early Interval debulking (early IDS, n= 33) Late interval debulking surgery (late IDS, n= 104)
Fig. 2. Overall survival in patients with advanced ovarian cancer stages IIC–IV treated by platinum-based chemotherapy according to timing of interval debulking surgery after neo-adjuvant chemotherapy: early interval debulking surgery (after 3.6 cycles; group 1, n = 33) vs. late interval debulking surgery (after 6.3 cycles; group 2, n = 104), median survival: 22 vs. 37 months (p = 0.09).
The median overall survival of 30 months in this series of patients with neo-adjuvant treatment compares unfavourably to better survivals reported in recent series with the standard approach [7,9,10,12,17,18]. However, survival data should be looked on at same treatment periods. As others [10,19] we have observed constant progress in outcome in patients over time, with approximately a 10 month gain in survival every decade (Table 4A). Presently, we have established group 3 in order to look for outcome in patients treated in a standard manner in our institution at the same time. What we found were completely superposing survival curves (Fig. 1). This was a surprise because group 3 patients had more favourable tumor characteristics than IDS patients (Table 1). Furthermore, with roughly close tumor characteristics (stages IIIC/IV: 94% vs. 100%) survival in our combined IDS group was identical to that reported in the neo-adjuvant EORTC/Intergroup trial with 30 months in both [15]. The latter was hampered of course by its multicentricity, but favoured by chemotherapy (taxane use: 100% vs. 55%) and treatment period (1998–2006 vs. 1980–2007) in comparison to our series. This observation sustains the validity of the neo-adjuvant concept and underlines the pertinence of our patient selection. In the EORTC/Intergroup trial comparing PDS to early IDS, despite higher resection rates in the IDS arm, survival did not differ between the two arms [15]. This apparent paradox may be explained by differences in the respective treatment impacts according timing of surgery. In the neo-adjuvant setting possibly the efficacy of chemotherapy overruled the impact of the surgical effort. If this hypothesis applied, increasing the intensity of chemotherapy, e.g. through prolonged NAC, consequently might have resulted in prolonged survival. Data concerning late IDS after prolonged NAC are limited. Consecutive series of patients treated by 5 or 6 cycles of NAC report median survivals of 13, 23 and 46 months, depending on treatment periods [23–25]. Two series compared retrospectively late to early IDS. Ansquer et al. [26] in a cohort of 54 patients observed differences in complete remission rates between early and late IDS (45% versus 61%) but not in survival (both 22 months). Loizzi et al. in a case– control study of 30 patients, did not find any difference either in response rates or in survival (median survival: 32 months) between 18 patients with 3 cycles and 12 patients with >3 cycles [27].
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In a review of 27 series of patients treated by NAC + IDS, we did not find arguments in the literature supporting the hypothesis that early IDS was superior to late IDS [28]. In contrast, Bristow and Chi reviewing 22 series of patients in a meta-analysis concluded that every further cycle of chemotherapy beyond 3 cycles was associated with a decrease in median survival of 4.1 months [21]. A recent meta-analysis by Kang and Nam [29] in 21 patient cohorts taking into account most of the series included in the precedent analysis, found that independent predictors for survival were year of publication, the percentage of taxane use, and, the rate of optimal surgery. The number of cycles of neo-adjuvant chemotherapy, however, was not prognostic, in contradiction to Bristow et al. Several arguments support the interest of late IDS: (1) higher debulking rates; (2) higher treatment intensity because of the absence of treatment interruption during the surgical period. The duration of treatment interruption depends on the importance of cytoreductive surgery, ranging from 9 to 24 days according to the extent of primary debulking in one series [10] and on postoperative morbidity likely to prolong hospital stay up to 40 days [9]. After IDS, delays of 24 days before resuming chemotherapy have been reported [14,16]. (3) Biological evidence supports prolonged NAC. Pro-apoptotic factors in ascitic fluids and tumor specimen showed to be more effective after 6 than 3 cycles of NAC in patients treated for ovarian cancer [30]. Combined to our findings, these data suggest that it would be worthwhile to evaluate the optimal timing of IDS and test the hypothesis that late interval debulking surgery might be better. Conflict of interest statement None of the authors declared any conflict of interest regarding the subject of this study. Acknowledgement This paper has not been supported by any funding. References [1] Griffiths CT, Fuller F. Intensive surgical and chemotherapeutic management of advanced ovarian cancer. Surg Clin North Am 1978;58:131–42. [2] Omura G, Blessing J, Ehrlich C, et al. A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. Cancer 1986;57:1725–30. [3] 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. [4] Omura GA, Brady MF, Homesley HD, et al. Long follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 1991;9:1138–50. [5] Vergote I, de Wever I, Tjalma W, Van Gramberen M, Decloedt J, van Dam P. Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients. Gynecol Oncol 1998;71: 431–6. [6] Stoeckle E, Paravis P, Floquet A, et al. Number of residual nodules, better than size, defines optimal surgery in advanced epithelial ovarian cancer. Int J Gynecol Cancer 2004;14:779–87. [7] Eisenkop SM, Spirtos NM, Friedman RL, et al. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90: 390–6. [8] Wimberger P, Lehmann N, Kimmig R, Burges A, Meier W, du Bois A. Prognostic factors for complete debulking in advanced ovarian cancer and its impact on survival. An exploratory analysis of a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol 2007;106:69–74. [9] Scholz H, Tasdemir H, Hunlich T, Turnwald W, Both A, Egger H. Multivisceral cytoreductive surgery in FIGO stages IIIC and IV epithelial ovarian cancer: results and 5-year follow-up. Gynecol Oncol 2007;106:591–5. [10] Eisenhauer EL, Abu-Rustum NR, Sonoda Y, Aghajanian C, Barakat RR, Chi DS. The effect of maximal surgical cytoreduction on sensitivity to platinum– taxane chemotherapy and subsequent survival in patients with advanced ovarian cancer. Gynecol Oncol 2008;108:276–81.
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