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Surgery for recurrent ovarian cancer: Options and limits
Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2016) 1e8
Contents lists available at ScienceDirect
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Surgery for recurrent ovarian cancer: Options and limits J. Sehouli, Professor *, J.P. Grabowski, Dr Department of Gynecology, European Competence Center for Ovarian Cancer, Charit e-University Medicine of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
Keywords: recurrent ovarian cancer surgery
Cytoreductive surgery is the backbone of the multimodal therapy in primary ovarian cancer patients. Despite the effect of various tumor biological factors such as grading and histological subtype, the surgical outcome is the most important prognostic factor for both progression free- and overall survival. In contrast, the management of recurrent situation has long remained a subject of an emotional international discussion. To date, only few prospective studies have focused on the effect of surgery in relapsed ovarian cancer. The available retrospective data associate complete cytoreduction with prognosis improvement. However, the selection of patients eligible for surgery in recurrent situation is the essential issue. The establishment of predictive factors for complete tumor resection and defining the patient group with recurrent disease who might profit from this approach are crucial. The available predictors of complete resection depend on the results of primary surgery and the current patient's situation. Women who underwent primary complete cytoreduction are in good performance status, and those who have only minimal ascites volume (less than 500 ml) in the recurrent situation have 76% likelihood of undergoing complete resection and survival prolongation. Moreover, the complete cytoreduction in the tertiary cytoreductive approach has been evaluated and showed a potential positive influence on patients' survival. This review concentrates on the recent data and highlights the need of further randomized trials to develop and incorporate operative standards in recurrent ovarian cancer. © 2016 Published by Elsevier Ltd.
Compre* Corresponding author. Department of Gynecology, European Competence, Center for Ovarian Cancer, Charite -University Medicine of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. hensive Cancer Center, Charite E-mail address: [email protected] (J. Sehouli). http://dx.doi.org/10.1016/j.bpobgyn.2016.10.009 1521-6934/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: Sehouli J, Grabowski JP, Surgery for recurrent ovarian cancer: Options and limits, Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/ 10.1016/j.bpobgyn.2016.10.009
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Introduction Epithelial ovarian cancer (EOC) is a gynecologic malignancy that accounts for approximately 150,000 deaths occurring worldwide annually [1]. Around 70% of EOC cases are diagnosed as an advanced International Federation of Gynecology and Obstetrics (FIGO) stage, resulting in poor 5-year survival rates [2]. Despite the high remission rate reaching 80%, most of the patients develop recurrence [2]. The standard therapy in primary ovarian cancer is surgery followed by systemic chemotherapy with carboplatinum plus paclitaxel. In recurrent situation, an operative approach remains a subject of the international emotional discussion. Several effective chemotherapy regimens dependent on the platinum-free interval are commonly used, despite the fact that most of these regimens have failed to improve the overall survival (OS). In phase III trials with chemotherapies alone or in combination with targeted therapies, only a minority underwent salvage surgery prior to the trials [3e10]. Therefore, a subgroup analysis of the cohort of patients who were operated before entering these trials was statistically insufficient. Retrospective studies of multicenter cohorts report a potential survival benefit after complete cytoreduction in patients with platinum-sensitive first relapse patients [11]. However, the selection of patients eligible for the surgery is an essential issue. The palliative/salvage approach versus cytoreduction attempt, direct systemic therapy, or best supportive care should be well considered. Therefore, it is necessary to have clear definitions of different clinical situations as well as types and objectives of surgery in relapsed ovarian cancer. The decision between the surgical approach and/or systemic treatment should be a result of clinical situation, general condition, and patient's perception and preferences. The goal of the surgery should be discussed with the patient in detail and should be fully transparent. Patients seem to decide between surgery and chemotherapy, which is not true. In most situations, it is more likely that the decision is made between surgery plus systemic platinum-based chemotherapy and systemic platinum-based chemotherapy alone. In our opinion, no surgery with the goal of influencing the progression-free survival or OS can be indicated without defining the total cancer treatment strategy, including the systemic approach. This review concentrates on the recent data and highlights the need of further randomized trials to develop and incorporate operative standards in recurrent ovarian cancer. Surgery and recurrent ovarian cancer The benefit of surgery on progression-free survival and OS in recurrent ovarian cancer remains debatable. The available data are based on various collectives in different clinical situations. The enrolment of patients with recurrence as well as patients with persistent or progressive disease in trials was not an uncommon proceeding [12]. Consequently, moderate survival rates and relatively high morbidity revealed the surgical approach as controversial [13]. The different patient selection and definition of relapse and surgical outcome limit the interpretation of the available literature significantly (12) Defined subgroups and nomenclature used with regard to surgical approach remain a subject of discussion. The Gynecologic Cancer InterGroup has introduced the current definition of optimal debulking as a complete resection of all visible tumor manifestations in primary ovarian cancer [14e18]. This nomenclature is also usually used with regard to secondary cytoreductive surgery; however, published data are lacking. The pattern of tumor spread in relapse situation shows peritoneal carcinomatosis with the involvement of the upper abdomen in many patients. Our working group presented the differences in tumor spread between primary and recurrent situation in a prospective study. The highest tumor burden in primary ovarian cancer was localized in the lower abdomen in comparison to the recurrent situation in which it was localized in the upper abdomen [19]. Consequently, the higher complexity of surgical approach in these cases requires experienced gynecologist oncologist, developed infrastructure, interdisciplinary cooperation, established logistic processes, and quality management. The typical change in the tumor pattern from the lower into the upper part of the abdomen must be always considered for the planning of any surgery in relapsed ovarian cancer (Fig. 1e3).
Please cite this article in press as: Sehouli J, Grabowski JP, Surgery for recurrent ovarian cancer: Options and limits, Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/ 10.1016/j.bpobgyn.2016.10.009
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Fig. 1. En-bloc tumor resection. Multivisceral approach with inv resection of the bowel, peritoneal carcinomatosis, and omental-cake.
Fig. 2. En-bloc peritoneum resection.
The indication for surgery in the recurrent disease is salvage operation to remedy the symptoms and (or) cytoreduction with the aim of complete tumor resection. The complete cytoreduction rates range between 9% and 100% in patients with recurrent ovarian cancer [20,21]. However, surgery was not offered for 7e64% women. Several studies analyzed the association between recurrence-free interval and benefit of secondary surgery with different results [19,20,22e24]. Eisenkop et al. found the recurrence-free interval as the most important prognostic factor in patients with relapse in addition to residual tumor after surgery. Age, CA125 level, symptoms, ascites, and grade were found to be significant factors in this analysis [18]. Complete cytoreduction is associated with significant survival benefits [20,23e25]. However, according to other authors, only those patients who underwent surgery with residuals of up to 1 cm benefitted from the surgical approach [26,27]. Nevertheless, the latter group showed poorer prognosis than completely operated patients. The recent analysis of Feldheiser et al. showed that cytoreductive surgery does not seem to be more challenging in terms of perioperative management compared to that at the primary situation [28]. Please cite this article in press as: Sehouli J, Grabowski JP, Surgery for recurrent ovarian cancer: Options and limits, Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/ 10.1016/j.bpobgyn.2016.10.009
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Fig. 3. Resection of liver metastasis.
The surgery in eligible patients with relapsed ovarian cancer should be complete tumor resection. In the remaining cases, the surgical approach should be as short as possible and limited to the most necessary procedures. Predictive factors of complete cytoreduction The complexity of surgery in the recurrent situation forces very precise selection of patients for this approach. Fleming et al showed that the rate of complete resection declines approximately by 3% a week without surgery, after first CA125 elevation was noticed [29]. A multicenter, retrospective study titled the Descriptive Evaluation of pre-operative Selection Kriteria for Operability in recurrent €kologische Onkologie (AGO) evaluated OVARian cancer (DESKTOP) of the Arbeitsgemeinschaft Gyna the surgery value in patients with recurrent ovarian cancer [30]. An analysis of a total of 267 patients revealed a group of women who mostly benefit from a secondary cytoreduction. Those women who underwent complete tumor resection have significantly better progression-free survival and OS (median OS 45.2 months vs. 19.7 months for patients with residuals >10 mm, p < 0.0001). Furthermore, in a multivariate analysis, ascites over 500 ml in the recurrent situation and complete primary cytoreduction were found to be the independent prognostic factors. Consequently, the combination of complete primary cytoreduction, minimal ascites (<500 ml) at recurrence, and good performance status constituted the so-called AGO Score. Score-positive patients are those who fulfill all three criteria (Table 1). Meeting all three criteria helps to identify women in whom complete resection of recurrent ovarian cancer is most likely. The subsequent prospective DESKTOP II trial validated the AGO Score for a total 516 patients, among whom 51% were classified as score-positive. The rate of complete macroscopic cytoreduction achieved was 76%, and the mortality rate of surgery was 0.8% [11]. The “AGO Score” has been recently evaluated on 209 patients who underwent secondary surgery in a single-center retrospective analysis [31]. Of these patients, 70 women had at least one negative
Table 1 AGO Score “positive”. AGO Score “positive” e Good performance status e Complete resection at primary surgery e Absence of ascites
Please cite this article in press as: Sehouli J, Grabowski JP, Surgery for recurrent ovarian cancer: Options and limits, Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/ 10.1016/j.bpobgyn.2016.10.009
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criterion. A total of 127 women in “AGO Score”-positive group received complete cytoreduction. Interestingly, 48.5% of patients with one negative criterion also underwent surgery with no residual disease. The progression-free survival was 22 months in AGO-positive patients who were tumor free and 21 months in the AGO-negative patients with complete resection. Morbidity and mortality were also comparable. This study confirms the validation trials and reveals a chance for eligibility in selected “score negative” patients. Nevertheless, it must be underlined that the AGO score is only validated for a positive enhancement of the patient cohort with the optimal surgical outcome. A negative AGO score (e.g., ascites more than 500 mL) will not exclude the chance of surgery without any postoperative residuals. Furthermore, the treatment-free interval for the selection of the best patients for salvage surgery is not clear. Various series discuss a treatment-free interval ranging from 6 months to 36 months despite clear evidence for a “real cut off” [32]. Fotopoulou et al. reported a series of 37 patients (median age, 58 years; range, 22e71 years) who underwent salvage surgery [32]. Of these patients, 3 (8.1%) had primary and 34 (91.6%) had relapsed EOC. Twenty-one patients (56.8%) had a residual intestinal length of less than 1 m (median 70 cm; range, 10e180 cm). One-month mortality and major morbidity rates were 10% and 51%, respectively. Median OS was 5.6 months (range, 0.1e49 months). Salvage palliative surgery because of bowel symptoms resulting in short bowel syndrome is associated with high morbidity rates and low OS. Therefore, this approach should optimally be performed only in a multidisciplinary setting with adequate infrastructure. In the absence of acute abdomen or intestinal perforation, conservative management should be favored. Surgery versus chemotherapy in recurrent ovarian cancer The median survival of platinum-sensitive recurrent ovarian cancer patients who underwent complete cytoreduction in available publications does not exceed the outcome of those women who received upfront systemic therapy [4,5,20,21]. Nevertheless, even the most effective chemotherapy provided only limited effect with a median of 29 months [4]. Furthermore, Bristow et al reported that complete cytoreduction in recurrent ovarian cancer translates into additional 3 months OS [21]. The comparison between additional relapse surgery and direct chemotherapy in patients with recurrent platinum-sensitive ovarian cancer was investigated in a randomized, multicenter prospective DESKTOP III trial. The results of this trial are highly anticipated. Tertiary surgery In the last decades, surgical treatment of epithelial ovarian cancer developed in the direction of complete tumor resection because it has been proved as the most relevant prognostic factor for survival improvement. Consequently, the radicality throughout the multivisceral approach increased [16,33e35]. AGO DESKTOP III study, a randomized prospective surgical study, aims at an evidencebased assessment of the surgical benefit of secondary cytoreduction. Postoperative tumor residuals appear to be a highly significant prognostic factor at primary cytoreduction as well as at secondary tumor debulking. Nevertheless, it remains unclear whether this factor retains its prognostic significance in the tertiary setting [22,23,36e39]. The available data regarding tertiary cytoreductive surgery (TCS) are limited and based mainly on single center, low-cohort experiences [40e45]. In 2011, an evaluation of clinical outcome of a series of 135 consecutive patients who underwent tertiary surgery for relapsed ovarian cancer was published [45]. In 53 patients (39.3%), a complete tumor resection was achieved. The 30-day operative mortality rate was 6%. A total of 78 patients (57.8%) died, while 52 patients (38.5%) suffered from further relapse within the median follow-up period of 9.6 months (range, 0.1e75 months). Median OS was 19.1 months, with 37.8, 19.0, and 6.9 months for patients without any residual tumor masses, with residual tumors less than 1 cm, and with residual tumors larger than 1 cm, respectively. Complete tumor resection was identified as the main predictor of survival. The multivariate analysis identified tumor involvement of the middle abdomen and peritoneal carcinomatosis as the independent predictors of complete tumor resection. The predictive value of ascites and peritoneal carcinomatosis should be investigated by future multicenter prospective trials to select patients suitable for TCS. Please cite this article in press as: Sehouli J, Grabowski JP, Surgery for recurrent ovarian cancer: Options and limits, Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/ 10.1016/j.bpobgyn.2016.10.009
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Fotopoulou et al conducted the largest multicenter study to date and reported that residual tumor retains its high effect on OS and progression-free survival even in the tertiary setting of ovarian cancer. The high complete resection rates are obtainable in specialized gynecologic oncology centers. The clinicopathologic characteristics such as stage, age, and histology, which have been shown to be of significant predictive value at initial disease, do not appear to be of any prognostic significance in the tertiary setting [46]. However, a prospective clinical trial should be performed to confirm definitely the value of TCS in recurrent ovarian cancer. Summary The prediction of likelihood of complete resection in recurrent ovarian cancer was reported as feasible. This approach based on the score assessment and selection of eligible patients might be applied outside of clinical trials. However, the conclusive results that define the role of surgery in recurrent ovarian cancer are highly anticipated. With regard to tertiary cytoreduction, postoperative residual mass retains its strong effect on the overall prognosis. Similar to the primary situation, the postoperative systemic treatment also appears to have a strong effect on survival even in the tertiary situation. Nevertheless, prospective data are still awaited.
Practice points Complete cytoreduction in recurrent ovarian cancer improves the prognosis Predictive factors of complete cytoreduction are available Surgery in recurrent ovarian cancer is possible in specialized gyn-oncological centers
Research agenda effect of surgery in recurrent ovarian cancer predictive factors of complete cytoreduction in recurrent ovarian cancer salvage surgery in recurrent ovarian cancer
Conflict of interest No potential conflict of interest has been reported by the authors.
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Contents lists available at ScienceDirect
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Surgery for recurrent ovarian cancer: Options and limits J. Sehouli, Professor *, J.P. Grabowski, Dr Department of Gynecology, European Competence Center for Ovarian Cancer, Charit e-University Medicine of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
Keywords: recurrent ovarian cancer surgery
Cytoreductive surgery is the backbone of the multimodal therapy in primary ovarian cancer patients. Despite the effect of various tumor biological factors such as grading and histological subtype, the surgical outcome is the most important prognostic factor for both progression free- and overall survival. In contrast, the management of recurrent situation has long remained a subject of an emotional international discussion. To date, only few prospective studies have focused on the effect of surgery in relapsed ovarian cancer. The available retrospective data associate complete cytoreduction with prognosis improvement. However, the selection of patients eligible for surgery in recurrent situation is the essential issue. The establishment of predictive factors for complete tumor resection and defining the patient group with recurrent disease who might profit from this approach are crucial. The available predictors of complete resection depend on the results of primary surgery and the current patient's situation. Women who underwent primary complete cytoreduction are in good performance status, and those who have only minimal ascites volume (less than 500 ml) in the recurrent situation have 76% likelihood of undergoing complete resection and survival prolongation. Moreover, the complete cytoreduction in the tertiary cytoreductive approach has been evaluated and showed a potential positive influence on patients' survival. This review concentrates on the recent data and highlights the need of further randomized trials to develop and incorporate operative standards in recurrent ovarian cancer. © 2016 Published by Elsevier Ltd.
Compre* Corresponding author. Department of Gynecology, European Competence, Center for Ovarian Cancer, Charite -University Medicine of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. hensive Cancer Center, Charite E-mail address: [email protected] (J. Sehouli). http://dx.doi.org/10.1016/j.bpobgyn.2016.10.009 1521-6934/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: Sehouli J, Grabowski JP, Surgery for recurrent ovarian cancer: Options and limits, Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/ 10.1016/j.bpobgyn.2016.10.009
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Introduction Epithelial ovarian cancer (EOC) is a gynecologic malignancy that accounts for approximately 150,000 deaths occurring worldwide annually [1]. Around 70% of EOC cases are diagnosed as an advanced International Federation of Gynecology and Obstetrics (FIGO) stage, resulting in poor 5-year survival rates [2]. Despite the high remission rate reaching 80%, most of the patients develop recurrence [2]. The standard therapy in primary ovarian cancer is surgery followed by systemic chemotherapy with carboplatinum plus paclitaxel. In recurrent situation, an operative approach remains a subject of the international emotional discussion. Several effective chemotherapy regimens dependent on the platinum-free interval are commonly used, despite the fact that most of these regimens have failed to improve the overall survival (OS). In phase III trials with chemotherapies alone or in combination with targeted therapies, only a minority underwent salvage surgery prior to the trials [3e10]. Therefore, a subgroup analysis of the cohort of patients who were operated before entering these trials was statistically insufficient. Retrospective studies of multicenter cohorts report a potential survival benefit after complete cytoreduction in patients with platinum-sensitive first relapse patients [11]. However, the selection of patients eligible for the surgery is an essential issue. The palliative/salvage approach versus cytoreduction attempt, direct systemic therapy, or best supportive care should be well considered. Therefore, it is necessary to have clear definitions of different clinical situations as well as types and objectives of surgery in relapsed ovarian cancer. The decision between the surgical approach and/or systemic treatment should be a result of clinical situation, general condition, and patient's perception and preferences. The goal of the surgery should be discussed with the patient in detail and should be fully transparent. Patients seem to decide between surgery and chemotherapy, which is not true. In most situations, it is more likely that the decision is made between surgery plus systemic platinum-based chemotherapy and systemic platinum-based chemotherapy alone. In our opinion, no surgery with the goal of influencing the progression-free survival or OS can be indicated without defining the total cancer treatment strategy, including the systemic approach. This review concentrates on the recent data and highlights the need of further randomized trials to develop and incorporate operative standards in recurrent ovarian cancer. Surgery and recurrent ovarian cancer The benefit of surgery on progression-free survival and OS in recurrent ovarian cancer remains debatable. The available data are based on various collectives in different clinical situations. The enrolment of patients with recurrence as well as patients with persistent or progressive disease in trials was not an uncommon proceeding [12]. Consequently, moderate survival rates and relatively high morbidity revealed the surgical approach as controversial [13]. The different patient selection and definition of relapse and surgical outcome limit the interpretation of the available literature significantly (12) Defined subgroups and nomenclature used with regard to surgical approach remain a subject of discussion. The Gynecologic Cancer InterGroup has introduced the current definition of optimal debulking as a complete resection of all visible tumor manifestations in primary ovarian cancer [14e18]. This nomenclature is also usually used with regard to secondary cytoreductive surgery; however, published data are lacking. The pattern of tumor spread in relapse situation shows peritoneal carcinomatosis with the involvement of the upper abdomen in many patients. Our working group presented the differences in tumor spread between primary and recurrent situation in a prospective study. The highest tumor burden in primary ovarian cancer was localized in the lower abdomen in comparison to the recurrent situation in which it was localized in the upper abdomen [19]. Consequently, the higher complexity of surgical approach in these cases requires experienced gynecologist oncologist, developed infrastructure, interdisciplinary cooperation, established logistic processes, and quality management. The typical change in the tumor pattern from the lower into the upper part of the abdomen must be always considered for the planning of any surgery in relapsed ovarian cancer (Fig. 1e3).
Please cite this article in press as: Sehouli J, Grabowski JP, Surgery for recurrent ovarian cancer: Options and limits, Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/ 10.1016/j.bpobgyn.2016.10.009
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Fig. 1. En-bloc tumor resection. Multivisceral approach with inv resection of the bowel, peritoneal carcinomatosis, and omental-cake.
Fig. 2. En-bloc peritoneum resection.
The indication for surgery in the recurrent disease is salvage operation to remedy the symptoms and (or) cytoreduction with the aim of complete tumor resection. The complete cytoreduction rates range between 9% and 100% in patients with recurrent ovarian cancer [20,21]. However, surgery was not offered for 7e64% women. Several studies analyzed the association between recurrence-free interval and benefit of secondary surgery with different results [19,20,22e24]. Eisenkop et al. found the recurrence-free interval as the most important prognostic factor in patients with relapse in addition to residual tumor after surgery. Age, CA125 level, symptoms, ascites, and grade were found to be significant factors in this analysis [18]. Complete cytoreduction is associated with significant survival benefits [20,23e25]. However, according to other authors, only those patients who underwent surgery with residuals of up to 1 cm benefitted from the surgical approach [26,27]. Nevertheless, the latter group showed poorer prognosis than completely operated patients. The recent analysis of Feldheiser et al. showed that cytoreductive surgery does not seem to be more challenging in terms of perioperative management compared to that at the primary situation [28]. Please cite this article in press as: Sehouli J, Grabowski JP, Surgery for recurrent ovarian cancer: Options and limits, Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/ 10.1016/j.bpobgyn.2016.10.009
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Fig. 3. Resection of liver metastasis.
The surgery in eligible patients with relapsed ovarian cancer should be complete tumor resection. In the remaining cases, the surgical approach should be as short as possible and limited to the most necessary procedures. Predictive factors of complete cytoreduction The complexity of surgery in the recurrent situation forces very precise selection of patients for this approach. Fleming et al showed that the rate of complete resection declines approximately by 3% a week without surgery, after first CA125 elevation was noticed [29]. A multicenter, retrospective study titled the Descriptive Evaluation of pre-operative Selection Kriteria for Operability in recurrent €kologische Onkologie (AGO) evaluated OVARian cancer (DESKTOP) of the Arbeitsgemeinschaft Gyna the surgery value in patients with recurrent ovarian cancer [30]. An analysis of a total of 267 patients revealed a group of women who mostly benefit from a secondary cytoreduction. Those women who underwent complete tumor resection have significantly better progression-free survival and OS (median OS 45.2 months vs. 19.7 months for patients with residuals >10 mm, p < 0.0001). Furthermore, in a multivariate analysis, ascites over 500 ml in the recurrent situation and complete primary cytoreduction were found to be the independent prognostic factors. Consequently, the combination of complete primary cytoreduction, minimal ascites (<500 ml) at recurrence, and good performance status constituted the so-called AGO Score. Score-positive patients are those who fulfill all three criteria (Table 1). Meeting all three criteria helps to identify women in whom complete resection of recurrent ovarian cancer is most likely. The subsequent prospective DESKTOP II trial validated the AGO Score for a total 516 patients, among whom 51% were classified as score-positive. The rate of complete macroscopic cytoreduction achieved was 76%, and the mortality rate of surgery was 0.8% [11]. The “AGO Score” has been recently evaluated on 209 patients who underwent secondary surgery in a single-center retrospective analysis [31]. Of these patients, 70 women had at least one negative
Table 1 AGO Score “positive”. AGO Score “positive” e Good performance status e Complete resection at primary surgery e Absence of ascites
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criterion. A total of 127 women in “AGO Score”-positive group received complete cytoreduction. Interestingly, 48.5% of patients with one negative criterion also underwent surgery with no residual disease. The progression-free survival was 22 months in AGO-positive patients who were tumor free and 21 months in the AGO-negative patients with complete resection. Morbidity and mortality were also comparable. This study confirms the validation trials and reveals a chance for eligibility in selected “score negative” patients. Nevertheless, it must be underlined that the AGO score is only validated for a positive enhancement of the patient cohort with the optimal surgical outcome. A negative AGO score (e.g., ascites more than 500 mL) will not exclude the chance of surgery without any postoperative residuals. Furthermore, the treatment-free interval for the selection of the best patients for salvage surgery is not clear. Various series discuss a treatment-free interval ranging from 6 months to 36 months despite clear evidence for a “real cut off” [32]. Fotopoulou et al. reported a series of 37 patients (median age, 58 years; range, 22e71 years) who underwent salvage surgery [32]. Of these patients, 3 (8.1%) had primary and 34 (91.6%) had relapsed EOC. Twenty-one patients (56.8%) had a residual intestinal length of less than 1 m (median 70 cm; range, 10e180 cm). One-month mortality and major morbidity rates were 10% and 51%, respectively. Median OS was 5.6 months (range, 0.1e49 months). Salvage palliative surgery because of bowel symptoms resulting in short bowel syndrome is associated with high morbidity rates and low OS. Therefore, this approach should optimally be performed only in a multidisciplinary setting with adequate infrastructure. In the absence of acute abdomen or intestinal perforation, conservative management should be favored. Surgery versus chemotherapy in recurrent ovarian cancer The median survival of platinum-sensitive recurrent ovarian cancer patients who underwent complete cytoreduction in available publications does not exceed the outcome of those women who received upfront systemic therapy [4,5,20,21]. Nevertheless, even the most effective chemotherapy provided only limited effect with a median of 29 months [4]. Furthermore, Bristow et al reported that complete cytoreduction in recurrent ovarian cancer translates into additional 3 months OS [21]. The comparison between additional relapse surgery and direct chemotherapy in patients with recurrent platinum-sensitive ovarian cancer was investigated in a randomized, multicenter prospective DESKTOP III trial. The results of this trial are highly anticipated. Tertiary surgery In the last decades, surgical treatment of epithelial ovarian cancer developed in the direction of complete tumor resection because it has been proved as the most relevant prognostic factor for survival improvement. Consequently, the radicality throughout the multivisceral approach increased [16,33e35]. AGO DESKTOP III study, a randomized prospective surgical study, aims at an evidencebased assessment of the surgical benefit of secondary cytoreduction. Postoperative tumor residuals appear to be a highly significant prognostic factor at primary cytoreduction as well as at secondary tumor debulking. Nevertheless, it remains unclear whether this factor retains its prognostic significance in the tertiary setting [22,23,36e39]. The available data regarding tertiary cytoreductive surgery (TCS) are limited and based mainly on single center, low-cohort experiences [40e45]. In 2011, an evaluation of clinical outcome of a series of 135 consecutive patients who underwent tertiary surgery for relapsed ovarian cancer was published [45]. In 53 patients (39.3%), a complete tumor resection was achieved. The 30-day operative mortality rate was 6%. A total of 78 patients (57.8%) died, while 52 patients (38.5%) suffered from further relapse within the median follow-up period of 9.6 months (range, 0.1e75 months). Median OS was 19.1 months, with 37.8, 19.0, and 6.9 months for patients without any residual tumor masses, with residual tumors less than 1 cm, and with residual tumors larger than 1 cm, respectively. Complete tumor resection was identified as the main predictor of survival. The multivariate analysis identified tumor involvement of the middle abdomen and peritoneal carcinomatosis as the independent predictors of complete tumor resection. The predictive value of ascites and peritoneal carcinomatosis should be investigated by future multicenter prospective trials to select patients suitable for TCS. Please cite this article in press as: Sehouli J, Grabowski JP, Surgery for recurrent ovarian cancer: Options and limits, Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/ 10.1016/j.bpobgyn.2016.10.009
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Fotopoulou et al conducted the largest multicenter study to date and reported that residual tumor retains its high effect on OS and progression-free survival even in the tertiary setting of ovarian cancer. The high complete resection rates are obtainable in specialized gynecologic oncology centers. The clinicopathologic characteristics such as stage, age, and histology, which have been shown to be of significant predictive value at initial disease, do not appear to be of any prognostic significance in the tertiary setting [46]. However, a prospective clinical trial should be performed to confirm definitely the value of TCS in recurrent ovarian cancer. Summary The prediction of likelihood of complete resection in recurrent ovarian cancer was reported as feasible. This approach based on the score assessment and selection of eligible patients might be applied outside of clinical trials. However, the conclusive results that define the role of surgery in recurrent ovarian cancer are highly anticipated. With regard to tertiary cytoreduction, postoperative residual mass retains its strong effect on the overall prognosis. Similar to the primary situation, the postoperative systemic treatment also appears to have a strong effect on survival even in the tertiary situation. Nevertheless, prospective data are still awaited.
Practice points Complete cytoreduction in recurrent ovarian cancer improves the prognosis Predictive factors of complete cytoreduction are available Surgery in recurrent ovarian cancer is possible in specialized gyn-oncological centers
Research agenda effect of surgery in recurrent ovarian cancer predictive factors of complete cytoreduction in recurrent ovarian cancer salvage surgery in recurrent ovarian cancer
Conflict of interest No potential conflict of interest has been reported by the authors.
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Please cite this article in press as: Sehouli J, Grabowski JP, Surgery for recurrent ovarian cancer: Options and limits, Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/ 10.1016/j.bpobgyn.2016.10.009