REVIEW

Surgery for recurrent ovarian cancer

Florian Heitz†1, Andreas du Bois1, Christian Kurzeder1, Jacobus Pfisterer2,
Jana Barinoff1, Jacek Grabowski1, Felix Hilpert3, Sven Mahner4 & Philipp Harter1
Cytoreductive surgery is accepted as a major treatment of primary ovarian cancer. The role in
recurrent ovarian cancer remains a field of discussion and controversy, mainly owing to missing
data from prospective randomized trials and lack of universal definitions. Retrospective data
indicate that complete resection of recurrent tumor formations should be aimed for, since survival
prolongation is mainly seen for patients with no residual disease. Thus, it is most important to find
predictors of complete resection, on the one hand to offer the best therapeutic chances to patients,
but on the other hand to protect patients with limited life expectancy from additional surgical
burden. The first prospective surgical trial in recurrent ovarian cancer, AGO-DESKTOP II validated
a score (‘AGO score’) for complete resection. It was shown that patients with a good general
condition (ECOG 0), no residual disease after surgery for primary ovarian cancer and absence of
ascites in presurgical diagnostics have a 76% likelihood of undergoing complete resection. In this
article, further recent data regarding surgery for recurrent ovarian cancer are going to be discussed
and the advantages of incorporating these patients into randomized trials are highlighted.

Epithelial ovarian carcinoma is the second Currently there in no level I evidence for surgery
most common genital malignancy in females in recurrent ovarian cancer. Furthermore, the
and accounts for the majority of deaths definition of secondary cytoreductive surgery
from gynecologic malignancies. To date, no is not consistently used, and different studies 1
Department of Gynecology &
screening methods to detect ovarian cancer included different groups of patients, namely
Gynecological Oncology, Kliniken
at an early stage have been developed, thus patients with recurrent disease and those with Essen-Mitte; Huyssen-Stiftung/
approximately 60–70% of women with newly persistent disease. Moreover, even patients Knappschaft GmbH, Essen, Germany
diagnosed ovarian cancer present with advanced with either progressive disease at the end of 2
Department of Gynecology &
disease [1,2] . Nevertheless, complete clinical chemotherapy or patients with persisting, but Obstetrics, Städtisches Klinikum
remission can be achieved in approximately not progressing, ovarian cancer, as well as Solingen gGmbH, Solingen, Germany
80% of these patients with the use of maximal both patients with small residual tumors that 3
Department of Gynecology &
surgical cytoreduction and platinum-based responded to systemic treatment and patients Obstetrics, University Hospital
Schleswig-Holstein, Campus Kiel,
combination chemotherapy [1] . Today a suffering from recurrence after a disease-free
Kiel, Germany
combination of carboplatin and paclitaxel is period of some weeks or several years, have been
Department of Gynecology, University
4

the standard primary chemotherapy regime [3,4] . included [14,15] . For these subgroups, survival Medical Center Hamburg Eppendorf,
Unfortunately, upwards of 75% of patients times of up to 9 months were reported, not Hamburg, Germany
with clinical complete response will develop justifying cytoreductive surgery with a morbidity †
Author for correspondence:
recurrent disease. Recent studies have reported rate of up to 24% in this setting. Therefore, it Department of Gynecology
encouraging results in women with platinum- is necessary to have clear definitions of different & Gynecologic Oncology,
sensitive relapsed ovarian cancer (platinum-free types of surgery in ovarian cancer (Box 1) . Henricistrasse 92,
45136 Essen, Germany
interval >6 months) treated with pegylated This article focuses on cytoreductive surgery
Tel.: +49 201 1743 4021
liposomal doxorubicin [5] , paclitaxel [6] or for recurrent ovarian cancer, which is defined as
Fax: +49 201 1743 4000
gemcitabine [7] in combination with carboplatin. an operation performed in patients with recurrent
[email protected]
For patients with platinum-resistant relapsed disease after completion of primary treatment
ovarian cancer, many drugs are available (surgery with or without chemotherapy) and a
but pegylated liposomal doxorubicin [8] , period without any evidence of disease. Keywords
topotecan [9,10] or gemcitabine [11,12] are the most
commonly used as monotherapy. What should be the aim of surgery for • AGO-DESKTOP • ovarian cancer
• platinum-sensitive ovarian
recurrent ovarian cancer?
cancer • recurrent ovarian cancer
General considerations regarding The phrase of ‘optimal debulking’ has been • secondary cytoreductive surgery
surgery in recurrent ovarian cancer introduced for primary cytoreductive surgery in • surgery
While cytoreductive surgery in primary advanced ovarian cancer. Retrospective studies
epithelial ovarian cancer is considered the reported a threshold above which cytoreduction
standard of care [13] , there are still many open did not result in a more favorable outcome and part of
questions in surgery for recurrent ovarian cancer defined all lesions with a maximum diameter
and the benefit remains a matter of controversy. of ≤1 cm of the residual tumor as cut-off for

10.2217/WHE.11.52 © 2011 Future Medicine Ltd Women's Health (2011) 7(5), 529–535 ISSN 1745-5057 529
REVIEW – Heitz, du Bois, Kurzeder et al.

information regarding selection criteria and

Box 1. Surgical procedures in recurrent ovarian cancer.
proportions of patients who were not intended
Surgical procedures in ovarian cancer for cytoreductive surgery was lacking in
• This type of surgery could be performed at any time in the course of ovarian most reports. If reported, the rate of patients
cancer (e.g., to get a histological diagnosis). Second-look surgery belongs to this not being offered surgery varied between 7
group of procedures. It is an operation performed in patients who are clinically, and 64%.
biochemically and radiologically free of disease after the completion of a defined
course of chemotherapy with the purpose to confirm the response status (in
Even larger series (>100 included patients)
principle, the removal of the remaining tumor at second-look passes the border dealing with cytoreductive surgery for recurrent
of diagnostic procedures) disease provided controversial f indings
Staging laparotomy concerning the impact of the scale of surgical
• This surgery should be performed in patients with macroscopically early ovarian intervention. Eisenkop et al. [25] , Harter and
cancer limited to the ovaries or the pelvis. The aim of this surgery is the detection du Bois [23] and Sehouli et al. [26] reported a
of tumor spread significant survival benefit only for patients
Primary cytoreductive surgery with complete resection, whilst Scarabelli et
• Surgery with the aim of complete resection of all macroscopic tumors in patients al. [27] and Zang et al. [28] also indicated a benefit
with first diagnosis of ovarian cancer before any other treatment modalities for so-called optimally debulked patients with
(e.g., chemotherapy) residual disease of less than 1 cm. The sixth
Secondary surgery/interval debulking series defined residuals up to 0.5 cm as ‘optimal’
• An operation performed in patients after chemotherapy, usually two or three and found a significant prognostic benefit in
cycles, with an attempt to remove any remaining tumor that has not been patients with residuals less than 0.5 cm [29] .
removed by chemotherapy, followed by additional cycles of chemotherapy Of note, in this series only a minority of
Surgery for progressive ovarian cancer patients had residual disease between 0.1 and
• An operation with the purpose of removing obviously resistant tumors that have 0.5 cm. The Kaplan–Meier curve showed
not responded to chemotherapy and progressed during primary chemotherapy poorer prognosis for this subgroup of patients
Surgery for recurrent ovarian cancer compared with completely debulked patients
• Surgery aiming for complete resection of all macroscopic tumor in patients with and p-values that always depend on numbers
recurrent ovarian cancer after completion of primary therapy including a of events, showed no statistical difference.
subsequent period without any signs of disease Interestingly, the latter three series reported
Palliative surgery lower complete resection rates (11, 41 and
• An operation performed in patients with symptoms caused by progressive disease 42%) than Harter and Eisenkop (50 and 81%,
or sequelae from prior treatment. These operations are performed in an effort to respectively), thus raising questions about
relieve symptoms and do not aim primarily at survival prolongation
different selection criteria, different surgical
Adapted from Harter et al. [41].
approaches, and methodological proceedings.
inclusion criteria [16,17] or as stratum [3,18,19] . A recent meta-ana­lysis out of most studies for
Nowadays this paradigm has changed towards surgery in recurrent ovarian cancer found that
complete resection of all visible tumor obtaining complete resection in an additional
manifestations, owing to recently published 10% of patients increases median survival by
reports [20–22] , and the Gynecologic Cancer 3 months [24] , which was even detectable in the
Interstudy Group (GCIG) has changed the multivariate model.
official nomenclature to that effect [4] . However, In conclusion, the aim of surgery in recurrent
the concept of “optimal debulking” has not ovarian cancer should be complete resection,
been established in cytoreductive surgery for as the described benefit of so-called ‘optimal
recurrent disease. debulking’ in some series is very low and
The definition of optimal debulking is probably a false finding. Therefore, if complete
varying and ranges between “removal of all resection is not feasible, the aim of surgery
visible tumor” and “small residuals” with should change from cytoreduction to palliation
different dimensions of maximum diameters with the aim to minimize surgical comorbidity
(0.5–2.0 cm). and to start chemotherapy as soon as possible.
Complete debulking rates varied between
9 and 82% in a systematic review comprising Is it possible to predict complete
retrospective studies with more than resection in recurrent ovarian cancer?
20 patients [23] and between 9 and 100% in a The presence of symptoms, localization of
meta-ana­lysis using all published data between disease, number of disease sites and treatment-
1983 and 2007 [24] . All but one series were free interval were reported as predictive
collected retrospectively and were obviously factors for complete resection in univariate
exposed to selection bias. Unfortunately, analyses. Cancer-Antigen (CA)‑125 elevation

530 www.futuremedicine.com future science group

 Surgery for recurrent ovarian cancer – Review

was also found to be predictive in univariate Does complete resection translate

analyses, and most recently it has been shown into survival benefit in recurrent
that the rate of complete resection declines ovarian cancer?
by approximately by 3% per week after first The median survival of completely debulked
CA‑125 elevation was noticed and no surgery patients ranges from 16 to 100 months [23] and
was performed [30] . overlaps with the median survival described
Four retrospective series reported multi­ in recently reported large prospective trials in
variate analyses of predictive factors associated recurrent platinum-sensitive ovarian cancer
with favorable surgical outcome. Absence (i.e., ICON4/AGO-OVAR 2.2 [6] and the
of preoperative salvage chemotherapy, good GCIG study AGO-OVAR 2.5 [7]). These studies
performance status and a size of recurrent reported a median survival of 18 and 29 months
disease of less than 10 cm were predictors in the respective superior arms. The majority
for complete debulking [25] . In another series of series on cytoreductive surgery for recurrent
with 38 patients, the number of disease sites ovarian cancer did not report median survival
(solitary vs multiple) was an independent factor exceeding the ICON4/AGO-OVAR 2.2 results.
for complete resection [31] and absence of ascites In conclusion, the lack of randomized trials
and residual disease after primary surgery were makes it impossible to conclude whether a more
reported as predictors for complete resection [32] . favorable outcome in series with high rates of
The Descriptive Evaluation of preoperative complete debulking could be attributed to
Selection KriTeria for OPerability in recurrent biology (i.e., selection bias) or to surgical results.
OVARian cancer (DESKTOP OVAR) I
trial conducted by the Arbeitsgemeinschaft Which prognostic factors are associated
Gynäkologische Onkologie (AGO) identified with prolonged survival in patients who
a combination of predictive parameters for received cytoreductive surgery for
complete resection: good performance status recurrent ovarian cancer?
(Eastern Cooperative Oncology Group 0), Almost all series reported a relationship
no residual disease after surgery for primary between survival and surgical outcome in
ovarian cancer (alternatively, if unknown, early univariate ana­lysis. Complete debulking was
initial Fédération Internationale de Gynécologie one of the strongest predictors for survival in
et d’Obstétrique [FIGO] stage) and absence of all multivariate analyses performed. All other
ascites in presurgical diagnostics. Complete analyzed factors provided controversial results.
resection was achieved in 79% of patients Treatment-free interval before cytoreductive
scoring all these factors. If not all factors were surgery showed no significant impact on outcome
positive, a complete resection was achieved in univariate analyses in approximately half of
in only 43% [33] . The latter group could be the series, but others reported a significant role.
further differentiated: complete resection However, only few patients with rather short
was achieved in 74% of this subgroup if treatment-free survival were included in the
there was no peritoneal carcinomatosis found respective series and the proportion of patients
intraoperatively, otherwise only 26% could be with less than 6 months treatment-free survival
completely debulked [34] . ranged from 0 to 13.5%. Therefore, the data
In the subsequent AGO-DESKTOP II trial regarding a possible impact of treatment-free
the ‘AGO score’ was validated in a prospective interval periods are mainly valid for different
multicenter study. A total of 512 patients periods beyond 6 months [23] . Eisenkop et al.
with platinum-sensitive relapse were screened reported a benefit for treatment-free intervals
and 261 patients (51%) presented with good exceeding 36 months compared with shorter
performance status, complete resection at
primary surgery and absence of ascites, and Box 2. ‘AGO score’ for patients with epithelial ovarian
were defined as ‘AGO score’ positive. From cancer recurrence.
these, 129 patients (49.4%) had their first • Good performance status (ECOG 0)
relapse and underwent surgery for recurrent • No residual disease after surgery for primary treatment (alternatively, if unknown:
disease. A positive ‘AGO score’ resulted in a early initial FIGO stage)
complete resection rate of 76%, thus the score • Absence of ascites in presurgical diagnostics
was successfully validated [35] . In conclusion, If all three items are existent, a complete resection of recurrent disease is feasible in
the ‘AGO score’ (B ox 2) may help to identify 76% of all patients.
patients in whom complete resection of relapsed ECOG: Eastern Cooperative Oncology Group; FIGO: Fédération Internationale de Gynécologie et
ovarian cancer is most likely. d’Obstétrique.

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REVIEW – Heitz, du Bois, Kurzeder et al.

intervals (13–36 and 6 –12 months) [25] . that the presence of peritoneal carcinomatosis
The same applies to the series of Chi et al. is a significant negative predictor for complete
(>30 months vs 12–30 months vs 6–12 months, resection [34] .
respectively) [29] . Scarabelli et al. showed a In addition, platinum-based chemotherapy
benefit for the subgroup with a recurrence- should be administered after recovery from
free interval of 13–24 months but not for surgery to eradicate minimal residual disease.
patients with longer (>24 months) or shorter The value of hyperthermic intraperitoneal
intervals (7–12 months) [27] . The AGO- chemotherapy was looked at in a small
DESKTOP I trial showed a benefit for a retrospective ana­lysis, but results were not
treatment-free interval exceeding 6 months but convincing [36] , thus the intravenous route
no difference if intervals longer than 6 months should be the route of chemotherapy application.
were compared in the univariate ana­l ysis
(6–12 vs 12–24 vs longer than 24 months, Morbidity & mortality in surgery of
respectively). However, treatment-free interval recurrent ovarian cancer
did not remain an independent factor in the Depending on the experiences and surgical
multivariate ana­lysis [34] . A similar observation capabilities, postoperative morbidity and
was reported by Zang et al. who reported a mortality rates are varying, but complication
benefit for longer progression-free intervals rates in surgery for recurrent ovarian cancer are
in a univariate ana­lysis that could not be not significantly higher, compared with primary
confirmed by multivariate ana­lysis [28] . The debulking surgery.
influence of preoperative tumor load on surgical Mean 30‑day morbidity after primary
and prognostic outcome is still controversial. cytoreductive surgery for advanced stage ovarian
Table 1 summarizes all studies with more than cancer ranges between 22% [37] and 34% [38] ,
100 included patients with respect to the best- while the morbidity rate in a meta-analyses
reported tumor residuals, median survival and of surgery in recurrent ovarian cancer ranged
further prognostic factors. An exploratory ana­ between 0 and 88.8%, with a weighted mean
lysis of the AGO-DESKTOP I trial has shown of 19.2% [24] . In the AGO-DESKTOP II trial,

Table 1. Summary of series with >100 patients for surgery of recurrent ovarian
cancer, reporting smallest achieved residual tumor.
Study (year) n Residual Median Further factors associated with Ref.
tumor (cm) survival better prognosis
(months)
Harter et al. 267 0 45.2 <500 ml ascites, postoperative [33]
(2006) platinum containing chemotherapy,
ECOG 0
Chi et al. 157 ≤0.5 56 Single site of recurrence, longer [29]
(2006) disease-free interval
Scarabelli et al. 149 0 †
Only one chemotherapy treatment [27]
(2001) before surgery
Zang et al. 117 <1 20 No ascites, longer disease-free interval [32]
(2000)
Eisenkop et al. 106 0 44.4 Longer disease-free interval, no [25]
(2000) salvage chemotherapy before surgery,
largest size of recurrent tumor <10 cm
Oksefjell et al. 217 0 54.0 Longer disease-free interval, [42]
(2009) younger age
Tian et al. 123 0 63.2 (mean) Longer disease-free interval, largest [43]
(2010) size of recurrent tumor <10 cm; single
site of recurrence
Sehouli et al. 240 0 42.3 <500 ml ascites, <FIGO IV [26]
(2010)
†
2-year survival rates for patients with no macroscopic disease, 56% of patients had a disease-free interval of 7–12 months
and 91% had a disease-free interval of 13–24 months.
ECOG: Eastern Cooperative Oncology Group; FIGO: Fédération Internationale de Gynécologie et d’Obstétrique.

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 Surgery for recurrent ovarian cancer – Review

33% of patients had at least one complication repeatedly cited as predictors for successful
in the postoperative period [35] . Mean 30‑day surgery. The AGO-DESKTOP II trial was the
postoperative mortality in primary debulking only one that successfully prospectively validated
surgery ranges between 0.7% [39] and 2.8% [40] , a score (good performance status, complete
while the mortality rate of surgery in recurrent resection at primary surgery, absence of ascites)
ovarian cancer ranges between 0 and 5.5%, with for complete resection in a multicenter setting.
a weighted mean of 1.2% [24] , 7.8% in single Most recently, the AGO-DESKTOP III trial,
centers [26] and 0.8% in the AGO-DESKTOP II “A prospective randomized trial comparing
trial [35] . Nevertheless, these data are very prone surgery and chemotherapy versus chemotherapy
to be affected by selection and publication alone in recurrent ovarian cancer”, was launched
bias, since there is a strict definition neither for (NCT01166737) [101] . Another ongoing study
morbidity, nor for the observed time after surgery. investigating the role of cytoreductive surgery
for platinum-sensitive recurrent ovarian cancer
Future perspective is being performed by the Gynecologic Oncology
Currently, there is no level I evidence for Group (GOG) (NCT00565851) [102] . Until
cytoreductive surgery in recurrent ovarian cancer. conclusive results that define the role of surgery in
However, even the most active chemotherapy recurrent ovarian cancer are available, it is feasible
regimens provided only limited activity with to counsel patients regarding their surgical
a median survival of 29 months (ICON4/ options in recurrent ovarian cancer outside of
AGO-OVAR 2.2) and improvement is clearly clinical trials based on the ‘AGO score’ (Table 1) .
needed for these patients. The series of surgery
for recurrent disease reported survival rates of Financial & competing interests disclosure
up to 100 months in patients with complete The authors have no relevant affiliations or financial
resection, thus far exceeding the median survival involvement with any organization or entity with a finan-
rates reported after chemotherapy alone. These cial interest in or financial conflict with the subject matter
findings result from highly selected patient or materials discussed in the manuscript. This includes
cohorts and, therefore, the main question employment, consultancies, honoraria, stock ownership or
might be “How can we select suitable patients options, expert testimony, grants or patents received or
for cytoreductive surgery in recurrent ovarian pending, or royalties.
cancer?” The available information is far No writing assistance was utilized in the production of
from being conclusive, but some factors were this manuscript.

Executive summary
• Approximately 75% of patients with clinical complete response after first-line therapy will develop recurrent disease.
• Different definitions have been used to describe surgery for recurrent ovarian cancer. A reasonable definition reads as follows: “surgery
aiming for complete resection of all macroscopic tumor in patients with recurrent ovarian cancer after completion of primary therapy
including a subsequent period without any signs of disease.”
• The aim of surgery in recurrent ovarian cancer should be complete resection.
• ‘Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score’: good performance status (Eastern Cooperative Oncology Group
[ECOG] 0), no residual disease after surgery for primary ovarian cancer and absence of ascites in presurgical diagnostics.
• Prospective AGO‑DESKTOP II trial: if the ‘AGO score’ is positive, complete resection is feasible in 76% of patients with recurrent
ovarian cancer.
• Morbidity and mortality rates in recurrent ovarian cancer do not exceed rates of primary surgery, if conducted in experienced centers.

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