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Original Article · Originalarbeit

Editor's Choice - Free Access

Interval Debulking Surgery in Patients with Federation of Gynecology and Obstetrics (FIGO) Stage IIIC and IV Ovarian Cancer

Keyver-Paik M.-D.a · Zivanovic O.a · Rudlowski C.a · Höller T.b · Wolfgarten M.a · Kübler K.a · Schröder L.a · Mallmann M.a · Pölcher M.c · Kuhn W.a

Author affiliations

aBonn University Medical Center, Department of Obstetrics and Gynecology, Center for Integrated Oncology Köln-Bonn, Bonn, bInstitute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, cDepartment of Obstetrics and Gynecology, Rotkreuzklinikum München, Germany

Corresponding Author

Dr. med. Mignon-Denise Keyver-Paik

Zentrum für Geburtshilfe und Frauenheilkunde

Universitätsklinikum Bonn

Sigmund-Freund-Str. 25, 53105 Bonn, Germany

mignon-denise.paik@ukb.uni-bonn.de

Related Articles for ""

Onkologie 2013;36:324-332

Abstract

Background: The feasibility of neoadjuvant chemotherapy (NAC) and the outcome in patients with Federation of Gynecology and Obstetrics (FIGO) IIIC and IV ovarian cancer were assessed. Patients and Methods: 67 patients undergoing interval debulking surgery (IDS) and ≥ 4 courses of platinum-based NAC were analyzed for survival, perioperative morbidity and mortality. Results: The median follow-up was 30 months. The median progression-free survival (PFS) was 17 months, the overall survival (OS) 34 months. The PFS of patients without residual disease (n = 23; 34.3%) was 31 months (p = 0.003), the OS 65 months (p = 0.001). PFS and OS were significantly longer in patients with no residual disease than in patients with 1-10 mm (n = 34; 47.9%) (p = 0.005 and p = 0.0001, respectively) residual disease. No survival benefit was seen for patients with 1-10 mm compared to > 1 cm (n = 12; 16.9%) residual disease (PFS p = 0.518; OS p = 0.077). 1 patient (1.4%) died; 12 patients needed interventional treatment or operation (16.9%) within the first 30 days postoperatively. Out of these, 5 patients (7.0%) had residual or lasting disability. Conclusions: NAC and IDS are safe and feasible in this series of patients with unfavorable prognosis. IDS does not change the goal of complete cytoreduction and therefore does not compensate for a less radical surgical approach.

© 2013 S. Karger GmbH, Freiburg


Schlüsselwörter

Neoadjuvant

Ovarialkarzinom

Operatives Staging

Überleben

Systemische Therapie

Intervalldebulking

Zusammenfassung

Hintergrund: Die Anwendbarkeit von neoadjuvanter Chemotherapie (NAC) und das Behandlungsergebnis bei Patientinnen mit Ovarialkarzinom FIGO (Federation of Gynecology and Obstetrics) IIIC und IV wurden analysiert. Patienten und Methoden: 67 Patientinnen mit Intervalldebulking (IDS) und ≥ 4 Zyklen einer Platin-basierten NAC wurden hinsichtlich Überleben, perioperativer Morbidität und Mortalität analysiert. Ergebnisse: Das mediane Follow-up war 30 Monate. Das mediane progressionsfreie Überleben (PFS) betrug 17 Monate, das Gesamtüberleben (OS) 34 Monate. Patientinnen ohne postoperativen makroskopischen Tumorrest (n = 23; 34,3%) hatten ein PFS von 31 Monaten (p = 0,003) und ein OS von 65 Monaten (p = 0,001). Dies war signifikant länger als bei Patientinnen mit einem postoperativen Tumorrest von 1-10 mm (n = 34; 47,9%) (p = 0,005 bzw. p = 0,0001). Der Vergleich zwischen Patientinnen mit einem Tumorrest zwischen > 0 and 1-10 mm und > 1 cm (n = 12; 16,9%) ergab keinen signifikanten Unterschied (PFS p = 0,518; OS p = 0,077). Es kam zu 1 perioperativen Todesfall (1,4%), 12 Patientinnen (16,9%) erlitten höhergradige Komplikationen in den ersten 30 postoperativen Tagen, 5 (7,0%) von ihnen mit einem bleibenden Schaden. Schlussfolgerungen: NAC und IDS sind bei dem hier untersuchten Patientinnenkollektiv mit eingeschränkter Prognose sicher. Die postoperative makroskopische Tumorfreiheit bleibt auch in diesem Therapiekonzept das Ziel, ein weniger radikaler chirurgischer Ansatz ist nicht gerechtfertigt.

Introduction

Since early ovarian cancer is mostly silent in symptoms, more than 70% of patients present with advanced-stage International Federation of Gynecology and Obstetrics (FIGO) III/IV disease. At this stage, the 5-year survival rates are 36% for FIGO IIIC and 18% for FIGO IV disease [1].

Currently, the standard treatment for advanced stages usually involves primary cytoreductive surgery followed by a combination of platinum- and taxane-based adjuvant chemotherapy. Apart from the FIGO stage, cytoreduction to no macroscopic residual disease has proven to be the most important prognostic factor for survival [2,3,4,5,6]. Primary surgery therefore aims for a complete resection of all visible tumor. The importance of this goal has been emphasized since the definition of ‘optimal cytoreduction' in 2010 moved from its former meaning of a cytoreduction to f 1 cm to no residual disease [7]. Tumor resection with > 1 cm of residual disease (15-30% of patients) places these patients at risk of the morbidities of the cytoreductive attempt without survival benefit [6,8].

To this date, the biggest debate concerning treatment of advanced ovarian cancer is on the sequence of surgical treatment and chemotherapy.

Neoadjuvant chemotherapy (NAC) reduces the tumor burden before surgery. Patients with platinum-resistant disease would be identified and spared an extensive surgical procedure on the basis of their poor outcome. Although biobanking has firmly been implemented by most clinicians today, NAC offers the additional opportunity, as seen in other tumor entities, to directly investigate the molecular effects of chemotherapy on the tumor [9]. Already, different groups with experience in NAC have started building extensive biobanks with paired tissues before and after chemotherapy, trying to understand vessel growth, immune response or tumor regression during treatment [10,11,12,13]. However, other groups have suggested that NAC is associated with worse prognosis and chemoresistance in comparison to the standard approach [14,15].

All patients in this analysis were FIGO IIIC or IV patients with ascites of at least 500 ml as a sign of gross peritoneal involvement. The purpose of this study was to evaluate the feasibility and outcome of the neoadjuvant approach in this subset of patients.

Patients and Methods

Inclusion of Patients

The Consolidated Standards of Reporting Trials (CONSORT) diagram (fig. 1) gives details of the patients included in this report. All patients diagnosed with primary epithelial ovarian cancer receiving NAC between 2002 and 2008 were recorded. 71 patients with FIGO IIIC and IV disease and ≥ 500 ml of ascites treated according to a prospective protocol were included in this analysis. 4 patients who did not receive at least 4 cycles of platinum-based chemotherapy were included in the morbidity and mortality analysis but were not included in the analysis of survival data, since treatment was not considered complete.

Fig. 1

CONSORT diagram. OvCa = ovarian cancer, pt = patient.

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Patient data was collected retrospectively from clinical data files. The American Society of Anesthesiologists (ASA) status of patients was used as a surrogate marker for the overall performance status of a patient. Perioperative morbidity and follow-up information was collected and analyzed. 2 out of the 71 patients were lost to follow-up. The median follow-up was 30 months.

Statistical Methods

The Kaplan-Meier method was used for univariate analysis on survival data. Multivariate analysis was carried out using the Cox regression model. Statistical tests were done at the level of 5% for α two-sided. An α-level of 10% was used as the entry level for the Cox regression. All data was analyzed using IBM SPSS statistics 18.0 software from IBM SPSS, Chicago, IL, USA.

Results

Patient Data

The clinical characteristics are summarized in table 1. The majority of patients presented with FIGO IIIC, and ASA II or III status. Histological confirmation was done by laparoscopy in 60 (84.5%), by laparotomy in 8 (11.3%) and by cytology in 3 (4.2%) cases. 68 patients (95.8%) presented with serous carcinomas; most histologies (69 patients) were grade 3 and 2 in differentiation.

Table 1

Patient data

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The majority of patients received 3 or 2 chemotherapy cycles preoperatively. 64 patients (90.2%) were treated with a combination therapy of carboplatin and paclitaxel or docetaxel, 5 received single-agent carboplatin, 2 patients received other platinum-based combinations.

As outlined in the CONSORT diagram (fig. 1), patients included in this analysis were treated at our institution within prospective studies (PRIMOVAR and SOROVAR) or treated outside of clinical trails according to our protocol [16,17].

Perioperative Data

All surgical procedures in our cancer center are carried out by board-certified surgeons. The goal of surgery was complete cytoreduction. The perioperative data is shown in table 2. A total of 35 patients (49.3%) received at least 1 bowel resection, which was mostly large bowel. In 2 patients (2.8%), primary enterostomy or colonostomy was performed. 21 of the 71 patients (29.6%) were treated including extensive upper abdominal surgery, with the diaphragm as the most common site of tumor localization. 36 (50.7%) patients underwent systematic paraaortic and pelvic lymphonodectomy; the procedure was omitted in 38 patients when adequate cytoreduction could not be achieved. We achieved cytoreduction to a residual tumor of u 1 cm in 58 patients (81.7%); 24 patients (33.8%) were completely cytoreduced.

Table 2

Surgical data

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Perioperative Morbidity and Mortality

Anastomotic leak and peritonitis was diagnosed in 4 patients (5.6%). Enterostomy or colonostomy was performed in all 4 cases. 1 patient died of sepsis and respiratory failure as a result of this complication. 1 patient suffered myocardial infarction on postoperative day 1. A percutaneous transluminal coronary angioplasty was performed and antiplatelet therapy caused abdominal hemorrhage, leading to revision. 1 patient developed laparostoma and was discontinued from chemotherapy.

Survival Data

In the analysis, 67 patients were included; 56 patients had developed recurrent disease at the time of the last follow-up and 45 patients had died (table 1).

The median progression-free survival (PFS) for all patients was 17 months (12-23 months, 95% confidence interval (CI)), the overall survival (OS) was 34 months (25-42 months, 95% CI) (fig. 2).

Fig. 2

Survival data of FIGO IIIC and FIGO IV patients: Kaplan-Meier function of 67 patients treated with at least 4 courses of platinum-based chemotherapy and receiving surgery with (a) a PFS of 17.4 months and (b) an OS of 33.5 months.

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Univariate analysis (tables 3 and 4) showed no significant influence of ASA status, FIGO stage or positive lymph nodes on the survival (both PFS and OS) of the patients. Both PFS and OS were significantly longer in patients with no residual tumor versus patients with any postoperative tumor size (p = 0.03 and 0.01, respectively) and significantly longer than after debulking to a residual tumor of 1-10 mm (p = 0.005 and 0.0001, respectively) (fig. 3). No statistical benefit could be detected when comparing patients with a residual tumor size of 1-10 mm to patients with a tumor size of > 1 cm (PFS p = 0.518; OS p = 0.077) (figure not shown).

Table 3

Survival data, Kaplan-Meier univariate analysis of prognostic markers: PFS (months)

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Table 4

Survival data, Kaplan-Meier univariate analysis of prognostic markers: OS (months)

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Fig. 3

Survival data of FIGO IIIC and FIGO IV patients: Kaplan-Meier function of 67 patients treated with at least 4 courses of platinum-based chemotherapy and receiving surgery in the subset analysis of completely cytoreduced patients (n = 24) against patients with a residual tumor of 1-10 mm (n = 34) or all patients without complete cytoreduction (n = 43). (a) PFS of 30.8 months (p = 0.005), (b) OS of 65.2 months (p = 0.0001).

http://www.karger.com/WebMaterial/ShowPic/184323

Multivariate analysis was performed for PFS and OS. The odds ratio of being alive was 3.2 times increased if a complete resection of all visible tumor could be achieved, compared to any other residual tumor size (p = 0.001). Debulking to 1-10 mm again showed no benefit over a residual tumor of > 1 cm (p = 0.157) (figure not shown).

Intention-to-treat analysis for all 71 patients showed a PFS of 18 months and an OS of 30 months. The 1-, 2- and 5-year survival rates of PFS and OS are shown in table 5.

Table 5

Survival rates (1-, 2- and 5-year) depending on the postoperative tumor residuals

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Discussion

This trial demonstrates that NAC in advanced ovarian cancer patients with stage FIGO IIIC and IV and unfavorable prognosis is safe and feasible. The perioperative complication and mortality rates and the survival rate have to be compared to treatment results of patients with surgical debulking followed by adjuvant chemotherapy. We registered 16.9% of severe perioperative morbidity, in which insufficiency of bowel anastomosis represented the major part with 5.6% (n = 4). The mortality rate was 1.4% (1 patient). This is a description of a single-center experience, but our findings are consistent with those in the literature [18].

Sehouli et al. [19] recently described a rate of 5.3% of bowel insufficiencies and fistulae in a group of 372 patients, 3% in the subgroup of interval debulking surgery (IDS) patients and 5.6% in the group of primary debulking surgery (PDS) patients. Death within 30 days occurred in 2.8%. Other, mostly retrospective, trials have also been able to show less morbidity of patients receiving NAC with better resection rates, with either longer survival of patients under IDS treatment or equivalent survival rates [20,21]. Surwit et al. [22] also associated NAC with reduced morbidity and similar outcome. Lee et al. [21] concluded from a series of 40 patients that NAC provided a higher rate of optimal cytoreduction, equivalent survival and reduced morbidity. Therefore, NAC may be a valuable alternative treatment for these patients. NAC certainly seems safe on the background of this data.

Vergote et al. [23], in the European prospective randomized trial on ovarian cancer patients, did not show a direct comparison of morbidity in IDS and PDS. It was criticized that primary progression under platinum-based chemotherapy may have led to omitting surgery, and therefore morbidity and mortality would be biased in favor of the NAC arm. If this should indeed be the case, in our opinion, this is a very strong point in favor of NAC; thus, we would spare those patients who do not benefit from extensive surgery.

Residual tumor size has emerged as the one most important prognostic factor for patients with ovarian cancer. Vergote et al. [23] reported an overall rate of complete cytoreduction of 19.4% in the PDS arm versus 51.2% in the IDS arm, and a rate of patients with a residual tumor of < 1 cm of 41.6% in the PDS arm and 80.7% in the IDS arm. However, the trial was hindered by significantly different tumor resection rates when comparing participating nations. Nevertheless, higher rates of successful reduction of tumor after neoadjuvant chemotherapy were also described by other groups during the last 20 years of tumor debulking in ovarian cancer. Lawton et al. [24] in 1989 described 28 out of 36 patients who were debulked during their chemotherapy treatment. 89% of these patients were optimally cytoreduced to ≤ 2 cm, with a favorable postsurgical morbidity rate. Onnis et al. [25] described 88 patients treated with NAC and compared these to 284 patients treated in the same period by upfront surgery. Debulking was optimal (≤ 2 cm) in 42% of the patients treated by NAC versus 29% of the patients treated with the standard sequence of surgery followed by chemotherapy. NAC significantly reduces the tumor burden before surgery and therefore increases the feasibility of cytoreduction at the time of surgery [26]. We reached a rate of cytoreduction to 0-10 mm (formally defined as ‘optimal') of 82% and a rate for complete cytoreduction of 34%.

For patients in the EORTC-GCG/NCIC-CTG trial (European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group/National Cancer Institute of Canada-Clinical Trials Group), better rates of optimal debulking in the IDS group failed to turn into a survival benefit [23]. This is in contrast to many findings in adjuvant trials where it was clearly shown that ‘optimal cytoreduction' to ≤ 1 cm of residual disease would turn into a survival benefit of patients compared to those with greater residuals after surgery [27,28]. Therefore, residual disease after NAC might not have the same significance as in PDS. Le et al. [29] found a significant improvement of PFS when comparing the outcome of patients with macroscopically no residual tumor to the outcome of those with any residual tumor. There was, however, no significant difference between outcomes in patients with any residual disease after IDS, using < 1, 1-2 and > 2 cm as cut-offs.

In this analysis, there was no significant survival difference when comparing patients with any macroscopic residual disease, whether the disease was 1-10 mm or greater. In this series of FIGO IIIC and FIGO IV patients, PFS was 30.8 months when comparing patients with no macroscopic disease after IDS to patients with any residual disease (15 months, p = 0.03). OS for patients without residual disease was 65.2 months compared to 24.7 months if any residual disease was present (p = 0.01). Our findings support the theory that cytoreduction to a residual disease of 1-10 mm after NAC might not have the same biological significance as after primary debulking and that complete tumor resection must be the goal and leads to prolonged survival time.

Another point for discussion, besides the biological significance of residual tumor in IDS and PDS, are issues of practical difficulties with tumor resection after NAC. In 2012, Luyckx et al. [30] retrospectively analyzed 527 patients with FIGO IIIC and IV disease from 7 French gynecologic oncology units. All patients had at least received 6 courses of platinum-based chemotherapy in either a PDS or IDS setting. They found a complete resection rate of 65% (PDS) and 74% (IDS), respectively (p < 0.05), but the PFS in IDS was significantly lower than in the PDS group. It has been argued that chemotherapy-induced tissue changes make it impossible for the surgeon to recognize residual tumor, and Luyckx et al. [30] hypothesize ‘that a proportion of the patients who relapsed after complete cytoreduction based on palpation only or on incomplete visualization actually had remaining unidentified disease'. For both PDS- and IDS-treated patients together, the PFS in the analysis of Luyckx et al. [30] was 17.9 months. This PFS is similar to our findings here, only with a rate of complete resection of 34%.

The EORTC-GCG/NCIC-CTG trial showed equivalent survival rates in PDS versus IDS with a PFS of 12 months and an OS of 29 versus 30 months in a group of patients consisting of 75.7% FIGO IIIC and 24.3% FIGO IV patients of a median age of 62 versus 63 years, respectively [23]. The relatively poor outcome of the patients in both arms of the trial has been largely attributed to the poor rates of successful cytoreduction in this trial. We found a median PFS of 17 months and a median OS of 34 months. du Bois et al. [31] reported a PFS in a large multicenter trial administering adjuvant cisplatin and paclitaxel versus carboplatin and paclitaxel of 17 versus 19 months and an OS of 43 versus 44 months. This AGO (Arbeitsgemeinschaft Gynäkologische Onkologie) trial included stages from IIB onwards, only 54.9% of FIGO IIIC and 17.1% of FIGO IV patients compared to 85.5% FIGO IIIC and 15.5% FIGO IV stages in this analysis [31]. Chi et al. [32] report an OS of 54 months in a group of 210 FIGO IIIC and IV patients, of which 55% had ascites > 500 ml and were receiving adjuvant therapy [32]. Subgroup analysis of these patients is not available.

In this series, only FIGO IIIC and IV ovarian cancer patients with ascites of at least 500 ml as surrogate for gross peritoneal involvement and unfavorable prognosis underwent NAC. The outcome, at least for completely cytoreduced patients, seems to be promising. Further investigation in prospective trials is needed.

Conclusions

We found neoadjuvant chemotherapy and IDS to be safe and feasible in this series of patients. Keeping in mind the limits of this single-center analysis, our data supports the goal of complete cytoreduction at the time of IDS. Neoadjuvant treatment cannot lead to evasion of radical surgical treatment of advanced-stage ovarian cancer patients.

Disclosure Statement

There are no financial disclosures or conflicts of interest from any of the authors.


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Author Contacts

Dr. med. Mignon-Denise Keyver-Paik

Zentrum für Geburtshilfe und Frauenheilkunde

Universitätsklinikum Bonn

Sigmund-Freund-Str. 25, 53105 Bonn, Germany

mignon-denise.paik@ukb.uni-bonn.de


Article / Publication Details

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Published online: May 21, 2013
Issue release date: June 2013

ISSN: 2296-5270 (Print)
eISSN: 2296-5262 (Online)

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References

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