Download Primary debulking surgery for advanced ovarian cancer: Are you a

Gynecologic Oncology 135 (2014) 595–605
Contents lists available at ScienceDirect
Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno
Review
Primary debulking surgery for advanced ovarian cancer: Are you a
believer or a dissenter?
John O. Schorge a,⁎, Rachel M. Clark a, Susanna I. Lee b, Richard T. Penson c
a
b
c
Vincent Gynecologic Oncology Service, Massachusetts General Hospital, USA
Division of Abdominal Imaging, Massachusetts General Hospital, USA
Division of Medical Gynecologic Oncology, Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, USA
H I G H L I G H T S
• The goal of primary debulking surgery should be the complete resection of all macroscopic disease.
• Neoadjuvant chemotherapy has an emerging role in the treatment of selected patients.
• Preoperative innovations under investigation are aimed at better triaging women to upfront surgery or chemotherapy.
a r t i c l e
i n f o
a b s t r a c t
Article history:
Received 8 September 2014
Accepted 7 October 2014
Available online 12 October 2014
Nothing stirs the collective soul of primary debulking surgery (PDS) advocates like hard data suggesting equivalent outcomes of neoadjuvant chemotherapy (NAC). These opposing views have even metaphorically come to
blows at the highly entertaining “SGO Fight Night” that took place during the 2008 Annual Meeting on Women's
Cancer, replete with teams supporting each of the would-be gladiators. Decades of retrospective data supporting
the clinical benefit of PDS has recently been challenged by the publication in 2010 of a randomized phase III trial
conducted in Europe supporting the clinical efficacy of NAC. Naturally, a firestorm of criticism among believers
ensued, yet practice patterns within the United States did slowly change, suggesting an emerging block of
dissenters. Another randomized phase III European trial, as presented in abstract form in 2013, showed similar
findings. Few other topics within the field of gynecologic oncology have participants so entrenched in the
“corners” of their existing practice patterns. This review attempts to consolidate the current evidence supporting
both sides so that the patient can be declared the winner.
© 2014 Elsevier Inc. All rights reserved.
Keywords:
Primary debulking surgery
Neoadjuvant chemotherapy
Advanced ovarian cancer
Contents
Introduction . . . . . . . . . . .
Primary debulking surgery . . . .
Neoadjuvant chemotherapy (NAC)
PDS v NAC: phase III trials . . . .
Special circumstances . . . . . .
The elderly . . . . . . . . .
Obesity . . . . . . . . . . .
Stage IV disease . . . . . . .
Clinical innovations . . . . . . .
Preoperative imaging . . . . .
Minimally invasive surgery . .
Ultra-radical surgery . . . . .
Synopsis . . . . . . . . . . . .
Future strategies . . . . . . . . .
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⁎ Corresponding author at: Vincent Gynecologic Oncology Service, Massachusetts General Hospital, Harvard Medical School, Yawkey-9E, 55 Fruit St, Boston, MA 02114, USA. Fax: +1
617 726 6898.
E-mail address: [email protected] (J.O. Schorge).
http://dx.doi.org/10.1016/j.ygyno.2014.10.007
0090-8258/© 2014 Elsevier Inc. All rights reserved.
596
J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
The consistent inability to reliably detect ovarian cancer before
widespread metastases has proven to be logistically problematic and a
source of ongoing disappointment. Unfortunately, routine screening
has not been shown to meaningfully improve early detection, nor
reduce mortality in either the high-risk or general populations [1–3].
The U.S. Preventative Services Task Force currently recommends against
screening given the scant evidence for any benefit, but consistently observed harms from unnecessary interventions [4]. Symptoms of ovarian
cancer tend to be vague and are often attributed to menopause, stress,
or functional bowel problems. Substantial delays prior to diagnosis are
very common, often until an abdominal-pelvic computed tomography
(CT) scan is obtained. As a result, two-thirds of women who are newly
diagnosed with invasive epithelial ovarian cancer still present, as they
always have, with stage III–IV disease typically characterized by ascites,
carcinomatosis and omental caking.
Advanced ovarian cancer is a heterogeneous disease requiring a
disciplined sequence of treatment to consistently achieve the best outcomes. No two clinical presentations are quite the same, nor would
two different clinicians necessarily be in sync on every patient. Whether
to start with an operation, or platinum-based therapy, is not always
obvious, no matter what the pre-existing biases. Primary debulking
surgery (PDS) requires knowledge of the disease process, mastery of a
wide spectrum of different procedures, and the willingness to manage
complex postoperative sequelae. Neoadjuvant chemotherapy (NAC)
appears to involve less short-term morbidity, and has demonstrated
equivalent efficacy, at least in one published phase III trial [5]. Clinical
teams are charged with the challenging task of striking the perfect
balance between being appropriately aggressive and trying to avoid
unnecessary morbidity. The most strident advocates of either PDS or
NAC will have treated selected patients with the alternative on at least
some occasions. This intriguing frequency of crossover is well-known,
but not often stated.
Due to the complexities of providing longitudinal care for patients
with ovarian cancer, better outcomes are reported when a subspecialist
is involved [6,7]. Unfortunately, fewer than half of patients in the United
States and Europe will have that opportunity [8]. Instead, the majority
are managed by physicians not necessarily intimately familiar with
the interplay between medical and surgical management. However,
maximizing overall survival depends on the precise coordination of
both forms of treatment at a center with expertise. PDS and NAC each
have their believers and dissenters. Recently, decades of retrospective
data supporting the former has collided with phase III data supporting
the latter position. Apropos to the boxing analogy, we cannot retreat
into our corner at this point, but must be willing to go the distance
with the best currently available evidence for the benefit of all women
diagnosed with advanced ovarian cancer. Furthermore, we must look
for ways to improve our treatment paradigms.
and other retrospective data rapidly accrued thereafter to establish PDS
as the de facto standard of care for advanced ovarian cancer [11–13].
Removal of the uterus, ovaries and any other intra-abdominal
tumors as part of ovarian cancer treatment is an easy concept for
patients and their families to understand. Often there is an unrealistic
assumption that taking out the offending site of origin will stop the
spread of cancer, and that peritoneal dissemination includes a finite
number of tumors that once removed, will not return. The actual clinical
benefits of debulking have been harder to prove in a rigorous fashion.
Within the broader field of oncology, this type of aggressive surgical approach to widely metastatic disease has some parallels, especially when
complete cytoreduction can be achieved [14–17].
Several supportive, but mostly theoretical, arguments have been
proposed to justify the biological plausibility of debulking (Table 1)
[18,19]. Disseminated ovarian cancers, like other solid tumors, are
postulated to contain a small subpopulation of highly specialized cells
with self-renewal capacity and the potential to reconstitute the entire
cellular heterogeneity of a tumor. These ovarian cancer stem cells are
thought to be responsible for tumor initiation, maintenance and growth.
Presumably, ineffective targeting of this cell population is responsible
for the therapeutic failures and tumor recurrences frequently observed
[20,21]. The elimination of these chemo-resistant cells, removal of the
supportive tumor microenvironment, and potential for improved drug
delivery, are, in theory at least, other benefits of surgical cytoreduction.
Additionally, removal of bulk disease should reduce the number of
Primary debulking surgery
Joe V. Meigs, a gynecologic surgeon at the Massachusetts General
Hospital (Fig. 1), initially described ovarian tumor debulking in 1934
[9]. The initial intent was to enhance the effects of radiation therapy in
an era before modern chemotherapeutics. However, due to limited clinical benefit, the concept did not really gain traction until the mid-70s
when platinum drugs were emerging. Griffiths' (Fig. 2) landmark
study appeared to conclusively demonstrate the inverse relationship
between residual tumor diameter and patient survival [10]. Case series
603
603
Fig. 1. Joe V. Meigs.
J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605
Fig. 2. C. Tom Griffiths.
chemotherapy-treated cancer cells that will undergo spontaneous
mutations to drug-resistant phenotypes [22].
PDS is a technically challenging endeavor for a number of different
reasons. Tumor-related sequelae such as symptomatic pleural effusions
or hypoalbuminemia, especially when accompanied by co-existing
health problems, often impact the ability to recover from any major
surgical procedure. Within the peritoneal cavity, anatomical landmarks
are often encased by tumor or otherwise obliterated. Routinely, radical
pelvic dissection, bowel resection, and aggressive upper abdominal
surgery are necessary to achieve an optimal result [23]. Sound clinical
judgment is required in order to be appropriately aggressive, without
inducing a cascade of potentially disastrous complications. Despite the
accumulated evidence supporting the importance of PDS, it remains
controversial whether the better outcome is due to the surgeon's
technical proficiency or some ill-defined, intrinsic feature of the cancer
that makes the tumor implants easier to remove [24,25]. While patients
definitely do appear to benefit from one maximal debulking attempt,
the timing of the operation and what defines success have become
increasingly controversial.
Proficient cytoreduction depends on numerous factors, including
patient selection, tumor location, and surgeon expertise. To achieve a
Table 1
Theoretical arguments for debulking surgery.
Removing large necrotic masses promotes drug delivery to small tumors with good
blood supply
Removing resistant clones decreases the likelihood of early onset drug resistance
Tiny implants have a higher growth fraction that should be more chemo-sensitive
Removing cancer in specific locations, such as tumors causing a bowel obstruction,
improves the patient's nutritional and immunologic status
597
survival benefit, an optimal result was initially defined as no residual tumors individually measuring more than 2 cm in size [26]. For purposes
of uniformity, the Gynecologic Oncology Group (GOG) re-defined
optimal debulking as residual implants ≤1 cm [27]. For some decades,
this criterion served as the benchmark of success. Patients undergoing
PDS who were rendered optimal (≤ 1 cm residual disease), followed
by intraperitoneal (IP) platinum-based chemotherapy were shown to
have a median overall survival of 66 months — the longest duration
ever reported in a phase III study [28]. The clinical outcomes achieved
in this GOG trial still serve as the benchmark for comparisons with
any other sequence of treatment.
Yet one valid criticism of cytoreductive surgery is the biased, subjective assessment of gross residual disease by the surgeon at the completion of the operation. Due to tissue induration, inadequate exploration,
radiologist over-estimation, or other factors, inaccuracies of residual
tumor size are common [29,30]. Perhaps due to the inability to reliably
quantify the remaining disease, a recent sub-analysis of accumulated
data from several prospective GOG trials demonstrated that patients
with 0.1 to 1.0 cm residual disease had only marginally improved overall survival compared to patients with N1 cm residual disease for stage
III ovarian cancer. In fact, dramatic survival benefit was only achieved
with complete resection to microscopic residual disease [31]. Based on
these findings and other similar reports, there is a growing consensus
that optimal cytoreduction should be defined using a more stringent
criterion. Thus, the current goal of PDS is to achieve complete resection
with no residual disease [32].
Raising the bar for surgical success accordingly decreases the
proportion of patients with advanced ovarian cancer in which this
redefined optimal result can be accomplished, unless there is a change
in practice. For stage IIIC disease, rates of complete resection predominantly range from 15 to 30%. However, the clinical benefits appear
substantial when it can be achieved (Table 2) [33–35]. Within the last
decade, multiple institutions have demonstrated the ability to revise
their surgical paradigm in order to safely debulk to no residual disease
at a rate that approaches or exceeds 50% [36–38]. Broader incorporation
of these types of surgical improvement programs could significantly
improve outcomes. In a meta-analysis of 18 studies involving 13,257
patients, Chang et al. observed that each 10% increase in the proportion
undergoing complete cytoreduction was associated with a 2.3-month
increase in cohort median survival. Additionally, for each 10% increase
in the proportion receiving IP chemotherapy, there was a 3.9-month
increase in median cohort survival time [39]. Recently, Rosen et al.
reported an astonishing seven-year survival rate of 90% in women
undergoing PDS with no residual disease who subsequently received
IP treatment [40]. All attempts should be made to achieve complete
(hereafter defined as optimal in this review) resection, as these patients,
when treated with adjuvant platinum-based IP chemotherapy have survival measures that exceed any rates previously seen in this population
[41].
However, despite the subjective nature of classifying residual disease, there is evidence to support minimizing the amount of remaining
tumor as much as possible. Chi et al. analyzed a prospective database for
outcomes of 465 women with stage IIIC ovarian cancer who underwent
PDS. They observed a median overall survival of 33–34 months for
those with N1 cm residual disease, 48 months with 0.6–1.0 cm residual,
Table 2
Median overall survival of stage IIIC ovarian cancer patients undergoing primary
debulking surgery (months).
Study
Residual disease
Microscopic
0.1–1.0 cm
N1 cm
Aletti [33]
Chang [34]
Chi [35]
N84
86
106
34
46
59
25
37
33
598
J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605
66 months for those with ≤.5 cm, and 106 months for patients with no
gross residual disease [35]. Additionally, in a Cochrane Database review
of 11 retrospective studies, “near optimal” patients with b1 cm residual
disease collectively had better outcomes than “suboptimal” cases with
residual disease N1 cm [42].
Occasionally, a gynecologist planning to remove an adnexal mass or
a general surgeon performing abdominal surgery for presumed bowel
obstruction unexpectedly encounters widespread intra-abdominal disease. These advanced ovarian cancer patients who are unintentionally
taken for surgery typically do not get a maximal cytoreductive effort,
but are oftentimes referred postoperatively. Fortunately, upfront reoperation before the start of chemotherapy should still be feasible,
and successful, in more than half of patients with incomplete primary
surgery elsewhere [43].
If it were possible to perform PDS and consistently achieve no residual disease with limited postoperative complications, then we all would
be believers in this strategy. Despite attempts to develop such a model –
predicting successful surgery with minimal morbidity – nothing yet has
proven reproducible in a prospectively validated manner [44,45]. At
present, the reality is that most patients will have some level of remaining tumor, and many will derive limited clinical benefit. Additionally,
PDS may result in a prolonged postoperative recovery that is fraught
with complications: an observation frequently made by dissenters to
the upfront surgery paradigm. All too often, the initiation of chemotherapy may be delayed, or worse, postponed indefinitely.
Neoadjuvant chemotherapy (NAC)
Some patients are clearly too medically ill to initially undergo any
type of upfront abdominal operation, whereas others have disease
that is too extensive to be resected even by an experienced ovarian
cancer surgical team. In these circumstances, NAC is routinely used
after the diagnosis has been confirmed. Core biopsy of the primary
tumor or one of the metastases is the gold standard to prove the existence of a disseminated ovarian carcinoma. Cytological diagnosis by
fine needle aspiration may also be acceptable if the CA125/CEA ratio is
N25 (as defined in trials) [46]. Following three to four courses of treatment, the feasibility of surgery can be reassessed. In some retrospective
series, NAC followed by interval debulking has demonstrated comparable survival outcomes to those reported for primary surgery [47–50].
Fewer radical procedures may be required, the rate of achieving minimal residual disease may be higher, and patients may experience less
morbidity. Six cycles of NAC prior to surgery are another less commonly
used option. In 82 patients treated with this extended regimen, the rate
of complete resection to no residual disease was 63.7%, and 23.1% were
found to have had a clinical complete response [51]. However, a metaanalysis of 81 cohorts of 6885 patients with stage III or IV ovarian cancer
suggested that NAC in lieu of PDS is associated with an inferior overall
survival [52]. Direct comparison has historically been difficult to
perform.
Unfortunately, preoperative CA125 levels, imaging tests and physical examinations all have limitations in consistently identifying which
patients can be optimally debulked to no residual disease by a gynecologic oncologist. Invariably, the final determination cannot be made
until abdominal exploration. When it is clinically evident during surgery
that achieving b1 cm is not feasible, great discretion is required to
confirm the diagnosis, but not provoke unnecessary complications
that could delay subsequent therapy.
Two phase III trials were conducted to determine whether a second
interval debulking procedure was worthwhile after an unsuccessful initial attempt followed by a few courses of chemotherapy. A multicenter
trial conducted in Europe demonstrated a 6-month median survival
advantage in patients who were re-explored after three cycles of chemotherapy [53]. In contrast, no survival advantage was demonstrated
when a similar study was conducted in the United States [54]. These
seemingly conflicting reports are most easily explained by clarifying
who performed the first surgery. In the US trial, virtually all patients
had their initial attempt by a gynecologic oncologist, unlike the
European study where relatively few had their first surgery performed
by a subspecialist. Therefore, interval debulking appears to yield benefit
only among the patients whose primary surgery was not performed by
a gynecologic oncologist, if the first try was not intended as a maximal
resection of all gross disease, or if no upfront surgery was performed
at all [55].
PDS v NAC: phase III trials
In 1986, the GOG and separately a collaborative group in the
Netherlands each opened randomized phase III trials to test the hypothesis that primary debulking was superior to NAC in advanced ovarian
cancer. Both studies were closed due to poor accrual. One prevailing
opinion at the time was that clinicians did not want to subject their
patients to ‘substandard’ NAC treatment. Until recently, the presumed
benefits of primary surgical cytoreduction in advanced ovarian cancer
had not been rigorously tested.
The results of the randomized European Organization for Research
and Treatment of Cancer (EORTC protocol # 55971) phase III trial
were first presented in October 2008 and subsequently published in
September 2010. The data has fostered debate of how best to initially
treat women with advanced ovarian cancer. In the study, 670 patients
were randomized to PDS versus NAC. After three courses of platinumbased treatment, the 90% of NAC patients who demonstrated a response
underwent interval debulking. The authors reported a median overall
survival of 29 to 30 months, regardless of the initial assigned treatment
group. In the multivariate analysis, complete resection of all macroscopic disease at debulking surgery was identified as the strongest independent prognostic factor, but the timing of surgery did not seem to matter.
Based on the authors' interpretation of their data, NAC and interval
debulking was the preferred treatment [5].
Despite these findings, the Society of Gynecologic Oncology members queried in 2010 largely remained unconvinced. Of respondents to
a survey sent to the membership, most use NAC in less than 10% of
advanced stage ovarian cancer cases [56]. In light of the phase III data,
some European gynecologic oncologists have openly questioned what
kind of evidence would be needed to convince their US colleagues
about the superiority of the NAC approach [57]. At least two criticisms
of the trial have been suggested as reasons why the results may not be
applicable in the United States. First, the duration of patient survival in
the study was shorter than expected. The median survival (29 to
30 months) was less than half that reported for optimally debulked
stage III patients receiving postoperative intraperitoneal chemotherapy
(66 months) [28]. Additionally, only 42% of those patients randomized
to PDS had ≤1 cm of residual disease.
Since expert centers in the United States often report achieving
cytoreduction to ≤ 1 cm of residual disease at least 75% of the time, it
is feasible to think that a more aggressive initial attempt might have
led to a better outcome for the group randomized to surgery. Chi et al.
analyzed the outcomes of patients treated with PDS at the Memorial
Sloan-Kettering Cancer Center during the same time period in which
the EORTC trial was conducted, using identical inclusion criteria. Of
316 eligible patients, 285 (90%) underwent PDS. In 203 patients (71%),
≤1 cm of residual disease was achieved with an overall median overall
survival of 50 months [58]. The long-term outcomes were intriguing,
but whether this was a fair comparison has been debated [59].
A second recently presented study is also of interest. The Medical
Research Council (MRC) CHemotherapy OR Upfront Surgery (CHORUS)
trial is a phase III, non-inferiority randomized controlled study conducted in the United Kingdom and New Zealand. Five hundred fifty-two
newly diagnosed advanced ovarian cancer patients with suspected
stages III–IV ovarian cancer were enrolled between March 2004 and
August 2010. Women were randomized to undergo PDS followed by
6 cycles of chemotherapy, or NAC with interval debulking surgery
J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605
599
after 3 cycles, followed by completion chemotherapy. The primary outcome was overall survival, with secondary outcomes of toxicity and
quality of life. Complete resection was achieved in 16% of the PDS arm
versus 40% in the NAC arm. Grades 3–4 postoperative adverse events
(24% v 14%) and death (5.5% v 0.5%) within 28 days of surgery were
both more common in the PDS group. Median overall survival was
comparable between the two arms: 22.8 months for the PDS arm and
24.5 months for the NAC group [60]. Peer-review of the manuscript is
eagerly awaited as it represents another meaningful contribution to
the literature on this topic.
Ultimately, a prospective phase III trial conducted within the United
States will need to be performed to sway opinion and markedly change
the practice of gynecologic oncologists in this country. Unfortunately,
recent attempts through the GOG or with industry support have not
yet been successful in launching. Meantime, the controversy will persist
and individual patterns of care will continue. PDS is certainly the standard of care for patients with stage IIIA and IIIB ovarian cancer. PDS is
also favored for those with IIIC disease, in the absence of evidence for
unresectability or poor performance status. The treatment of stage IV
is typically individualized in current patterns of practice, but NAC is a
reasonable alternative [61].
aged ≥65 years who had PDS for stage III or IV epithelial ovarian cancer
between 1995 and 2005. The overall 30-day mortality was a sobering
8.2%. Advancing age, increasing stage, and increasing co-morbidity
score were all associated with an increase in 30-day mortality [67].
Wright et al. analyzed the SEER-Medicare database to identify women
aged ≥ 65 with stages II–IV ovarian cancer who survived at least
6 months from the date of diagnosis. A total of 9587 patients were identified who received treatment from 1991 to 2007. Interestingly, the use
of primary surgery decreased from 63.2% to 49.5% over time. In addition,
overall survival with NAC did not differ from PDS in this older population [68]. In an analysis of 28,651 women undergoing surgery for ovarian cancer from 1998 to 2007 using the Nationwide Inpatient Sample,
complication rates increased with age from 17.1% in those b50 years
of age to 31.5% in those ≥80. Morbidity was observed to be greatest in
the elderly, where the effects of age and the number of radical procedures performed had an additive effect on complication rates [69]. En
masse, the data suggests that NAC will likely continue to have a more
prominent role in the elderly. When complete cytoreduction is not
feasible during PDS, the operation should be limited in scope to avoid
unnecessary postoperative morbidity as ultra-radical procedures can
be especially poorly tolerated in this population.
Special circumstances
Obesity
The elderly
The epidemic of obesity taking place in the United States and
throughout much of the world is increasingly going to impact the treatment of ovarian cancer. While studies exploring the association
between obesity and ovarian cancer survival have yielded conflicting
results [70–74], using a body mass index (BMI) of 30 kg/m2 as the tipping point for the definition of obesity hardly seems to reflect reality.
In the current vernacular, 40 is the new 30, at least as far as the aging
process goes, and we should be able to comfortably extrapolate that
also to BMI. Kumar et al. analyzed the Mayo experience with 620 stages
IIIC–IV patients who underwent PDS between 2003 and 2011, divided
into three groups according to BMI. Women with a BMI of ≥ 40 were
found to have substantially higher rates of severe 30-day postoperative
morbidity and 90-day mortality after PDS. Although the high BMI group
had limited numbers of patients, there did not appear to be deficits in
achieving optimal cytoreduction, nor did it impact long-term oncologic
outcomes [75]. It seems obvious enough that the likelihood of postoperative complications is demonstrably higher when performing PDS in the
morbidly obese population. Even though the ability to achieve complete
cytoreduction would seem to be in jeopardy with increasing body size,
current data do not bear this out, perhaps due to a mitigating effect of
excess body weight on tumor biology [76]. Matthews et al. observed
that survival rates were similar between obese and non-obese patients
when the amount of residual disease was the same [77]. Regardless,
there is a price to be paid for aggressive PDS in the morbidly obese,
though NAC too has potential limitations in this population.
Wright et al. observed that obese patients treated with chemotherapy on a GOG protocol experienced substantially less toxicity than
normal weight women. Substandard drug dosing was thought to be
causative [78]. In an analysis of the Australian Ovarian Cancer Study of
333 patients, obese women were significantly more likely to have
received b85% of relative dose intensity of carboplatin, leading to
worse outcomes [79]. Appropriate dosing for obese patients with ovarian cancer is a must, whether as NAC or given as postoperative adjuvant
treatment. When they undergo effective and receive appropriate doses
of chemotherapy, obese patients do not have a poorer prognosis [80].
Since the likelihood of a woman developing ovarian cancer increases
with every decade, and the population is living longer than ever before,
it stands to reason that more and more women will be diagnosed later
in life. The precise meaning of the term ‘elderly’ is somewhat fluid, occasionally referring to those as young as 65 years of age, but in some studies defined as 75 years and older. While increasing age as a stand-alone
variable should not immediately lead to a more palliative approach, it is
a relevant factor as almost half of ovarian cancer patients diagnosed in
the United States each year will be at least 65 years of age. Though the
exact reasons are usually difficult to separate out and tend to be multifactorial, increasing age does adversely impact survival. As a group,
elderly patients with ovarian cancer are less likely to receive care with
a gynecologic oncologist, or to undergo PDS followed by adjuvant chemotherapy [62,63]. Some of the differences in patterns of care are likely
driven by medical co-morbidities, well-meaning physician bias and/or
individual quality of life choices.
Increasing age and co-morbid conditions are risk factors for surgical
morbidity and mortality, but the interactions have not been rigorously
analyzed. Several studies have emphasized that elderly patients are
able to tolerate an aggressive approach with relatively few complications, when adjusted for performance status. Langstraat et al. reviewed
the Mayo experience of 280 consecutive patients ≥65 years with stage
IIIC or IV ovarian cancer treated over a 10-year period. A significant
number of elderly women were able to undergo PDS and adjuvant
chemotherapy. However, median overall survival still decreased with
increasing age and the impact of residual disease was greater on older
patients. In addition, 37.5% of patients ≥75 years had significant perioperative morbidity [64]. Glasgow et al. performed a retrospective cohort
study of women ≥70 years with stage IIIC or IV disease treated at Yale,
and observed that the 42 NAC patients had similar outcomes, but significantly reduced perioperative morbidity compared to 62 women who
underwent PDS [65]. Worley et al. reviewed the outcome of 165
patients aged ≥ 70 years at their institution. Median overall survival
was similar between the 125 women who underwent PDS, compared
to the 40 receiving NAC, but readmission rates within 30 days of surgery
was dramatically higher in the PDS cohort (17.6% v 2.5%) [66].
These single institution studies highlight the caution that is indicated for elderly women, especially in the presence of other significant
co-morbidities. Thrall et al. analyzed the Surveillance, Epidemiology
and End Results (SEER) data -base to identify a cohort of 5475 women
Stage IV disease
Roughly one-third of patients with advanced ovarian cancer will
have stage IV disease at the time of their diagnosis [81]. This designation
is widely believed to be associated with a more aggressive tumor biology having significant implications on surgical outcome and response to
600
J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605
Table 3
Success rates of primary debulking surgery in stage IV ovarian cancer.
Study
Aletti [76]
Bristow [77]
Rauh-Hain [78]
Trope [79]
Winter [80]
Residual disease
Microscopic
0.1–1.0 cm
N1 cm
6%
–
8%
14%
8%
43%
30%
50%
36%
22%
51%
70%
42%
50%
70%
chemotherapy. Accordingly, the likelihood of achieving complete
cytoreduction at the time of PDS is particularly dismal (Table 3)
[82–86]. Furthermore, Winters et al. retrospectively reviewed 360
stage IV patients treated on phase III GOG protocols and did not observe
a benefit with 0.1 to 1.0 cm residual disease versus those with 1.1 to
5.0 cm residual. They concluded that ultra-radical procedures might
best be targeted to those selected patients in whom microscopic residual disease is achievable [86]. Based on the available data, this would
seem to apply to less than 1 in 10 patients.
Van Meurs et al. used data from the EORTC 55971 trial to report that
patients with stage IV disease and large (defined as N 45 mm) metastatic
tumors treated with NAC had demonstrably higher survival, compared
to an attempt at PDS followed by postoperative chemotherapy [87]. In
addition, NAC patients with stage IV disease who subsequently undergo
interval debulking surgery appear to have less peri-operative morbidity,
a higher likelihood of complete resection and shorter hospital stay [88].
In the EORTC trial, 10% of patients randomized to NAC never had a
cytoreductive attempt [5]. Another advantage of NAC in this high-risk
population appears to be the ability to better triage only responding patients to interval debulking surgery. Among this subset, aggressive
cytoreduction has been shown to be beneficial [89].
While historically the stage IV subcategory represented a range of
clinical findings lumped together, since January 2014 these have been
separated out to better reflect the disease processes [90]. It will be of
interest to see whether having stage IVA or IVB disease will have implications on the success of upfront treatment. Based on current available
evidence, the ability to achieve complete resection to no residual disease is so limited, that upfront surgery should be limited to very select
patients, while the majority should be treated with NAC.
Clinical innovations
Preoperative imaging
The ability to reliably identify patients most likely to benefit from
PDS based on imaging findings has proven to be an immense challenge.
Bristow et al. retrospectively analyzed preoperative CT scans in a
blinded fashion and correlated them with surgical outcome to develop
a predictive index model [91]. In a similar study, Dowdy et al. identified
only diffuse peritoneal thickening and large volume ascites as findings
associated with a low rate of optimal debulking [92]. These attempts,
and others like them, have not led to a paradigm shift, mainly due to
Table 4
Suidan et al. criteria associated with suboptimal primary cytoreductive surgery.
Clinical
Radiologic
Age ≥ 60 years
CA125 ≥ 500 U/mL
ASAa 3–4
Suprarenal retroperitoneal nodes N1 cm
Diffuse small bowel adhesions/thickening
Lesion(s) N1 cm small bowel mesentery
Lesion(s) N1 cm root of superior mesenteric artery
Lesion(s) N1 cm perisplenic area
Lesion(s) N1 cm lesser sac
a
American Society of Anesthesiologists Physical Status classification system.
Fig. 3. Ovarian carcinosarcoma with peritoneal carcinomatosis. Coronal image from an
abdominal-pelvic CT with oral and intravenous contrast shows a 17-cm primary right
adnexal tumor (star). Bulky tumor in the lesser sac (arrow) would suggest the inability
to perform complete cytoreductive surgery.
variations of image interpretation and surgical expertise across institutions. In a multi-institutional reciprocal validation study, high accuracy
rates of CT predictors could not be confirmed [93]. Suidan et al. have
recently reported the results of a prospective, non-randomized twocenter trial of 669 patients from 2001 to 2012 that underwent PDS for
stages III–IV ovarian, fallopian tube, and peritoneal cancer. Based on
three clinical and six radiologic criteria (Table 4, Fig. 3), they developed
a predictive model in which the suboptimal rate was directly proportional to the predictive value score [94]. These findings have yet to be
validated more broadly.
The utility of preoperative whole-body (18)F-fluorodeoxyglucose
(FDG) PET/CT is controversial. More accurate detection of supradiaphragmatic disease via imaging might understandably dissuade
clinicians from favoring PDS. While fusion PET/CT shows higher staging
accuracy than either CT or FDG-PET alone [95–97], the impacts of these
findings on rates of successful PDS have yet to be demonstrated.
Hynninen conducted a study of 41 patients undergoing preoperative
PET/CT followed by diagnostic high dose contrast-enhanced CT scan.
They observed that PET/CT was not superior to CT for the detection of
intra-abdominal disease spread, but was more effective in identifying
extra-abdominal metastases (Fig. 4) [98]. Fruscio et al. reviewed their
experience with 95 patients in which more than a quarter were clinically upstaged from stage III to stage IV by PET/CT. However, women
upstaged to IV had a similar prognosis as stage III patients, presumably
because it was the intraperitoneal tumor load that was more likely to
lead to death [99].
J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605
601
Minimally invasive surgery
Fig. 4. Stage IV high grade ovarian serous carcinoma. Axial fusion images from whole
body FDG PET-CT exam shows a hypermetabolic right adnexal primary tumor (A) and retroperitoneal adenopathy (B). Chest portion of the exam (C) reveals unsuspected left
supraclavicular adenopathy (arrow) that may impact primary treatment.
While there is as yet no clear consensus on the criteria for resectable
peritoneal lesions, radiologic imaging serves as an important roadmap
for treatment planning. The American College of Radiology's Appropriateness Criteria consensus recommendations currently rate abdominal–pelvic CT as the modality of choice for pre-treatment evaluation of
ovarian cancer patients [100]. Chest CT is also indicated should the
chest radiograph prove abnormal. Accurate interpretation requires
radiologist expertise in complex intra-abdominal anatomy, and clinical
dialogue with a gynecologic oncologist having familiarity with specific
disease sites that are likely to present particular difficulties with regard
to surgical access and technique [101]. Although CT is at present the
most predictive procedure, it is not in and of itself accurate enough to
consistently guide clinical management.
The inherent limitations in accurately correlating imaging findings
for a disease with varying levels of intraperitoneal surface implant
dissemination detected at surgery has led to evolving paradigms wherein preoperative laparoscopic evaluation of disease is used to help triage
patients toward PDS or NAC. In theory, this approach would avoid
unnecessarily morbid, suboptimal laparotomies that unduly lengthen
the time of treatment and increase overall costs. Several prospective
and retrospective studies have investigated the use of laparoscopy to
predict the outcome of debulking surgery. In a pilot study of patients undergoing laparoscopy followed by standard laparotomy, Fagotti et al.
observed that optimal debulking was achievable in 87% of cases selected
as being completely resectable by explorative laparoscopy [102]. With
this promising preliminary data, a laparoscopy-based quantitative predictive model (predictive index value [PIV]) was devised to provide an
objective score of intraperitoneal disease spread (Table 5). The PIV has
subsequently undergone initial testing and validation as a triage tool
[103,104]. To minimize the chances of inappropriately failing to perform
PDS, the best PIV cutoff was noted to be ≥8, corresponding to a positive
predictive value of 100%, or a zero percent chance of complete resection
among these investigators [105].
Fagotti et al. subsequently reported on 300 consecutive patients who
underwent staging laparoscopy. Importantly, none had complications
related to the procedure. Based on high tumor load (PIV ≥ 8), 152
(50.7%) went on to receive NAC and 57.5% had no residual disease at
the time of interval debulking. Of the 148 who underwent PDS, 62.1%
had complete resection. The authors concluded that this minimally
invasive strategy may help to meaningfully individualize treatment,
while avoiding unnecessary open surgery and its sequelae [106].
Vizzielli et al. also reported 348 consecutive advanced ovarian cancer
patients who underwent preoperative laparoscopic evaluation. All
study women received a PIV score and were stratified into three groups
based on volume of disease. In a multivariate analysis, tumor load stratified by PIV was found to be independently associated with overall survival, along with the amount of residual disease and performance status
[107].
In a multicenter trial (Olympia-MITO 13) to prospectively evaluate
the accuracy and reproducibility of staging laparoscopy at different
satellite centers, 168 patients underwent PIV scoring. Following a
short intensive training period, the technique was shown to be an accurate and reliable assessment of intraperitoneal diffusion of disease in
advanced ovarian cancer patients [108]. The LapOvCa-trial is a randomized multicenter trial including all gynecologic oncology centers in the
Netherlands and their affiliated hospitals. The purpose of this ongoing
study is to investigate whether laparoscopy is cost-effective in
predicting which patients will benefit from PDS and which patients
should be treated by NAC and interval surgery instead [109].
Whether the PIV score will be readily adaptable to gynecologic
oncologists in the United States remains an open question. Nick et al.
recently presented the triage algorithm modified from Fagotti that is
currently under investigation at the MD Anderson Cancer Center. Of
the 33 patients who underwent laparoscopy, none had an intraoperative complication, and 19 (58%) who had a PIV score b8 subsequently
underwent PDS. By the use of this approach, their rate of achieving complete resection improved from a historical rate of 44% to 84% [110].
Table 5
Fagotti laparoscopic predictive index value
(PIV) score.
Omental cake
Peritoneal/diaphragmatic carcinomatosis
Mesenteric retraction
Bowel/stomach infiltration
Spleen/liver superficial metastasis
Each positive evaluation receives a score of 2.
602
J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605
However, more data is needed. In a Cochrane Database review of seven
studies reporting on six cohorts, laparoscopy identified a broad range
(27–64%) of patients with too extensive disease to warrant laparotomy
and correspondingly between 36–73% having disease suitable for PDS.
Laparoscopy is a promising tool with minimal complications, but the
limited number of studies and unproven reproducibility at present do
not allow firm conclusions to be drawn from this data as yet [111].
Ultra-radical surgery
Extensive upper abdominal disease is often the limiting factor determining whether a patient with advanced ovarian cancer can be optimally debulked to no residual disease. While tumor in this location is
strongly indicative of aggressive tumor biology, a surgeon's experience
and willingness to employ ultra-radical procedures is correlated with
success in achieving complete resection [112,113]. Not every gynecologic oncologist is comfortable routinely performing liver resection,
splenectomy, or diaphragmatic resection, and complications may not
be trivial. However, patients referred to specialized centers where
such radical procedures are commonly performed may anticipate
higher rates of optimal debulking and improved survival, without necessarily leading to increased major morbidity [114]. Several institutions
incorporating ultra-radical techniques have reported survival rates to
improve accordingly [36–38]. Although it is still unclear what impact
ultra-radical techniques have on quality of life and morbidity, the limited available evidence suggests a measured improvement in survival
[115]. One common theme for safely expanding the ability to completely resect advanced ovarian cancer is the willingness to incorporate a
multidisciplinary surgical team, as needed, to facilitate debulking outside of the provider's typical comfort zone. In addition, having tertiary
care resources to manage the wide variety of possible postoperative
complications is critically important. Complex patients warrant treatment in a specialized center.
Synopsis
Current surgical management of ovarian cancer requires excellent
clinical judgment and technical mastery of a wide array of procedures.
Involvement of a gynecologic oncologist to oversee patient care has
proven to improve outcomes. Complete resection of all macroscopic
disease at PDS has been shown to be the single most important independent prognostic factor in advanced ovarian cancer. Therefore,
when deciding on PDS there should be a reasonable chance of leaving
no residual tumor or at least substantial cytoreduction to b1 cm at the
time of surgery [46].
The ability to clinically gauge those most likely to be completely
cytoreduced and thereby effectively triage patients toward PDS or
NAC involves a complex interplay of numerous factors, including imaging findings, physical examination, existing medical co-morbidities, and
the expertise of the surgical team. No single individual has the capacity
to make the right call in every circumstance, and even if it were the case,
it would not necessarily benefit patients outside of his/her purview. We
advocate a team approach to interpret available information and allow
the patient to make an informed decision toward initial therapy. To that
end, a consistent preoperative treatment planning conference is ideal,
with multi-disciplinary attendance, consistent imaging review and ongoing reassessment of outcome measures. In this way, co-existing factors
Table 6
Patients who appear to benefit the most from primary debulking surgery: a proposal.
Stage IIIA or IIIB disease
Stage IIIC disease with Fagotti laparoscopic score b8
Stage IIIC disease with promising multidisciplinary imaging review at ‘expert’
center routinely able to incorporate ultra-radical procedures as appropriate
Table 7
Patients who appear to benefit the most from neoadjuvant chemotherapy: a proposal.
Stage IIIC disease that is too extensive to be optimally debulked based on imaging
or laparoscopic scoring
Stage IV disease (likelihood of complete resection b10%)
Performance status too poor to undergo an attempt at surgical debulking
No access to an experienced ovarian cancer surgical team
The elderly or morbidly obese when ultra-radical procedures appear necessary
such as elderly age, morbid obesity or stage IV disease extension can all
be taken into account (Tables 6 and 7).
Further modification of current imaging techniques is unlikely to
substantially improve the triage of patients upfront. The promising
work on laparoscopic scoring needs to be replicated in the United
States with reassuring survival outcomes, otherwise it is unlikely to be
widely incorporated. Ultimately, any and all of these preoperative
methods to predict complete resection are still intimately tied to the
surgeon's ability to translate them into a successful outcome. While several institutions have demonstrated improvement in rates of achieving
optimal debulking by incorporation of ultra-radical techniques, it is
difficult to conceive of pushing the surgical limits much beyond that.
Future strategies
Rather than refining subjective clinical assessments such as imaging
or laparoscopy, it is likely that a reproducible genomics-based model
will be necessary to effectively triage patients to initial therapy. Preliminary data on a signature that predicts the success of debulking has been
proposed, but much additional work is needed before this becomes a reality [116]. It seems feasible, at least in theory, that molecular analysis of
a percutaneous core biopsy might ultimately be the most cost-effective
method for determining when or if a patient should go to surgery, and
what type of targeted therapy is likely to be most efficacious.
At a more basic level, just having access to subspecialty care continues to be a significant problem. It is an unfortunate reality that
geographic proximity to a high-volume hospital and travel distance to
receive treatment are independent predictors of guideline-adherent
care for advanced ovarian cancer. Such barriers disproportionally affect
racial minorities and women of low socio-economic status [117]. Networks that are able to successfully integrate ovarian cancer treatment
across tertiary and community hospitals need to be promoted and
expanded so that all women diagnosed can receive the same level of
care. Management of advanced ovarian cancer consistently requires a
complex, multidisciplinary team to achieve the best outcomes. Whenever feasible, patients should be encouraged to seek treatment at
these expert centers.
Whether you are a believer or a dissenter of PDS, we have very limited data to interpret. Only a randomized phase III trial of PDS versus
NAC performed in the United States with impressive rates of optimal
cytoreduction will be definitive. We should embrace this challenge of
constructing a well-designed definitive study and vigorously support
those, such as Dennis Chi, who are trying to find a way to fund such a
trial. It is telling that without substantial pharmaceutical industry
support of an agent or device, there is an impasse in conducting a trial
to answer this basic question.
Finally, since surgical paradigms have been shown to improve with
sustained effort, more transparency per provider or per institution
would be helpful in measuring where there are lessons to be learned
or improvements to be incorporated. Hopefully, the newly launched
SGO Clinical Outcomes Registry will provide this type of detailed data.
In the meantime, the gynecologic oncology community is charged
with identifying further evidence-based refinements in the approach
to upfront treatment, continuing to train fellows in the range of procedures that may be required for primary or interval debulking surgery,
and broadening the access to subspecialty care.
J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605
For the foreseeable future, most women will continue to be diagnosed with ovarian cancer after it has already spread extensively within
the peritoneal cavity. The debate on efficacy of PDS versus NAC appears
to be still in the early rounds. None of us should prematurely declare our
side the winner, nor throw in the towel on this metaphorical boxing
match, but instead work together to fight the common enemy. It is
incumbent upon all of us to continue exploring ways to establish a
structured, consistent, transparent approach to the best initial management of this disease. Hopefully, that is something that we can all believe
in, without dissent.
Conflict of interest statement
The authors have no financial disclosures to report at this time.
References
[1] Menon U, Gentry-Maharaj A, Hallett R, Ryan A, Burnell M, Sharma A, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and
stage distribution of detected cancers: results of the prevalence screen of the UK
Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol 2009;
10:327–40.
[2] Schorge JO, Modesitt SC, Coleman RL, Cohn DE, Kauff ND, Duska LR, et al. SGO
White Paper on ovarian cancer: etiology, screening and surveillance. Gynecol
Oncol 2010;119:7–17.
[3] Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO)
Cancer Screening Randomized Controlled Trial. JAMA 2011;305:2295–303.
[4] Moyer VA. Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med 2012;157:900–4.
[5] Vergote I, Trope CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery
in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943–53.
[6] Earle CC, Schrag D, Neville BA, Yabroff KR, Topor M, Fahey A, et al. Effect of surgeon
specialty on processes of care and outcomes for ovarian cancer patients. J Natl
Cancer Inst 2006;98:172–80.
[7] Engelen MJ, Kos HE, Willemse PH, et al. Surgery by consultant gynecologic oncologists improves survival in patients with ovarian carcinoma. Cancer 2006;106:
589–98.
[8] Carney ME, Lancaster JM, Ford C, et al. A population-based study of patterns of care
for ovarian cancer: who is seen by a gynecologic oncologist and who is not?
Gynecol Oncol 2002;84:36–42.
[9] Meigs JV. Tumors of the female pelvic organs. New York: Macmillen; 1934.
[10] Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian
carcinoma. Natl Cancer Inst Monogr 1975;42:101–4.
[11] Griffiths CT, Parker LM, Fuller Jr AF. Role of cytoreductive surgical treatment in the
management of advanced ovarian cancer. Cancer Treat Rep 1979;63:235–40.
[12] Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive
surgery for epithelial ovarian cancer. Obstet Gynecol 1983;61:413–20.
[13] Piver MS, Lele SB, Marchetti DL, et al. The impact of aggressive debulking surgery
and cisplatin-based chemotherapy on progression-free survival in stage III and IV
ovarian carcinoma. J Clin Oncol 1988;6:983–9.
[14] Blackham AU, Russell GB, Stewart JH, Votanopoulos K, Levine EA, Shen P. Metastatic colorectal cancer: survival comparison of hepatic resection versus cytoreductive
surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol 2014;21:
2667–74.
[15] Heng DY, Wells JC, Rini BI, Beuselinck B, Lee JL, Knox JJ, et al. Cytoreductive
nephrectomy in patients with synchronous metastases from renal cell carcinoma:
results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 2014;66:704–10.
[16] Rudloff U, Langan RC, Mullinax JE, Beane JD, Steinberg SM, Beresnev T, et al. Impact
of maximal cytoreductive surgery plus regional heated intraperitoneal chemotherapy (HIPEC) on outcome of patients with peritoneal carcinomatosis of gastric
origin: results of the GYMSSA trial. J Surg Oncol 2014;110:275–84.
[17] Salti GI, Ailabouni L, Undevia S. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal sarcomatosis. Ann Surg Oncol
2012;19:1410–5.
[18] Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol
Oncol 2000;78:269–74.
[19] Napoletano C, Bellati F, Landi R, Pauselli S, Marchetti C, Visconti V, et al. Ovarian
cancer cytoreduction induces changes in T cell population subsets reducing immunosuppression. J Cell Mol Med 2010;14:2748–59.
[20] Curley MD, Garrett LA, Schorge JO, Foster R, Rueda BR. Evidence for cancer stem
cells contributing to the pathogenesis of ovarian cancer. Front Biosci 2011;16:
368–92.
[21] Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer
2005;5:275–84.
[22] Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of
tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727–33.
[23] Eisenhauer EL, Abu-Rustum NR, Sonoda Y, et al. The addition of extensive upper
abdominal surgery to achieve optimal cytoreduction improves survival in patients
with stages IIIC–IV epithelial ovarian cancer. Gynecol Oncol 2006;103:1083–90.
603
[24] 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.
[25] Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive
surgery on recurrence-free interval and survival in small-volume stage III epithelial
ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47:
159–66.
[26] Hoskins WJ, McGuire WP, Brady MF, et al. The effect of diameter of largest residual
disease on survival after primary cytoreductive surgery in patients with suboptimal
residual epithelial ovarian carcinoma. Am J Obstet Gynecol 1994;170:974–9.
[27] Whitney CW, Spirtos N. Gynecologic Oncology Group surgical procedures manual..
www.gog.org Philadelphia, PA: Gynecologic Oncology Group; 2010 [Ref Type: Electronic Citation].
[28] Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in
ovarian cancer. N Engl J Med 2006;354:34–43.
[29] Chi DS, Ramirez PT, Teitcher JB, et al. Prospective study of the correlation between
postoperative computed tomography scan and primary surgeon assessment in
patients with advanced ovarian, tubal, and peritoneal carcinoma reported to have
undergone primary surgical cytoreduction to residual disease 1 cm or less. J Clin
Oncol 2007;25:4946–51.
[30] Sala E, Mannelli L, Yamamoto K, Griffin M, Griffin N, Grant L, et al. The value of postoperative/preadjuvant chemotherapy computed tomography in the management
of patients with ovarian cancer. Int J Gynecol Cancer 2011;21:296–301.
[31] Winter III WE, Maxwell GL, Tian C, et al. Prognostic factors for stage III epithelial
ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2007;25:3621–7.
[32] Chang SJ, Bristow RE. Evolution of surgical treatment paradigms for advancedstage ovarian cancer: redefining ‘optimal’ residual disease. Gynecol Oncol 2012;
125:483–92.
[33] Aletti GD, Dowdy SC, Gostout BS, Jones MB, Stanhope CR, Wilson TO, et al. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet
Gynecol 2006;107:77–85.
[34] Chang SJ, Bristow RE, Ryu HS. Impact of complete cytoreduction leaving no gross
residual disease associated with radical cytoreductive surgical procedures on
survival in advanced ovarian cancer. Ann Surg Oncol 2012;19:4059–67.
[35] Chi DS, Eisenhauer EL, Lang J, et al. What is the optimal goal of primary
cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)?
Gynecol Oncol 2006;103:559–64.
[36] Aletti GD, Dowdy SC, Gostout BS, et al. Quality improvement in the surgical
approach to advanced ovarian cancer: the Mayo Clinic experience. J Am Coll Surg
2009;208:614–20.
[37] Chi DS, Eisenhauer EL, Zivanovic O, et al. Improved progression-free and overall
survival in advanced ovarian cancer as a result of a change in surgical paradigm.
Gynecol Oncol 2009;114:26–31.
[38] Harter P, Muallem ZM, Buhrmann C, Lorenz D, Kaub C, Hils R, et al. Impact of a
structured quality management program on surgical outcome in primary advanced
ovarian cancer. Gynecol Oncol 2011;121:615–9.
[39] Chang SJ, Hodeib M, Chang J, Bristow RE. Survival impact of complete cytoreduction
to no gross residual disease for advanced-stage ovarian cancer: a meta-analysis.
Gynecol Oncol 2013;130:493–8.
[40] Rosen B, Laframboise S, Ferguson S, Dodge J, Bernardini M, Murphy J, et al. The
impacts of neoadjuvant chemotherapy and of debulking surgery on survival from
advanced ovarian cancer. Gynecol Oncol 2014;134:462–7.
[41] Landrum LM, Java J, Mathews CA, Lanneau Jr GS, Copeland LJ, Armstrong DK, et al.
Prognostic factors for stage III epithelial ovarian cancer treated with intraperitoneal
chemotherapy: a Gynecologic Oncology Group study. Gynecol Oncol 2013;130:12–8.
[42] Elattar A, Bryant A, Winter-Roach BA, Hatem M, Naik R. Optimal primary surgical
treatment for advanced epithelial ovarian cancer. Cochrane Database Syst Rev
2011:CD007565.
[43] Grabowski JP, Harter P, Hils R, Lorenz D, Kaub C, Barinoff J, et al. Outcome of immediate re-operation or interval debulking after chemotherapy at a gynecologic
oncology center after initially incomplete cytoreduction of advanced ovarian
cancer. Gynecol Oncol 2012;126:54–7.
[44] Aletti GD, Santillan A, Eisenhauer EL, Hu J, Aletti G, Podratz KC, et al. A new frontier
for quality of care in gynecologic oncology surgery: multi-institutional assessment
of short-term outcomes for ovarian cancer using a risk-adjusted model. Gynecol
Oncol 2007;107:99–106.
[45] Stashwick C, Post MD, Arruda JS, Spillman MA, Behbakht K, Davidson SA, et al.
Surgical risk score predicts suboptimal debulking or a major perioperative complication in patients with advanced epithelial ovarian, fallopian tube, or primary
peritoneal cancer. Int J Gynecol Cancer 2011;21:1422–7.
[46] Vergote I, Du BA, Amant F, Heitz F, Leunen K, Harter P. Neoadjuvant chemotherapy
in advanced ovarian cancer: on what do we agree and disagree? Gynecol Oncol
2013;128:6–11.
[47] Fago-Olsen CL, Ottesen B, Kehlet H, Antonsen SL, Christensen IJ, Markauskas A, et al.
Does neoadjuvant chemotherapy impair long-term survival for ovarian cancer
patients? A nationwide Danish study. Gynecol Oncol 2014;132:292–8.
[48] Lawton FG, Redman CW, Luesley DM, Chan KK, Blackledge G. Neoadjuvant
(cytoreductive) chemotherapy combined with intervention debulking surgery in
advanced, unresected epithelial ovarian cancer. Obstet Gynecol 1989;73:61–5.
[49] Schwartz PE, Chambers JT, Makuch R. Neoadjuvant chemotherapy for advanced
ovarian cancer. Gynecol Oncol 1994;53:33–7.
[50] Vergote IB, De WI, Decloedt J, Tjalma W, Van GM, van DP. Neoadjuvant chemotherapy versus primary debulking surgery in advanced ovarian cancer. Semin Oncol
2000;27:31–6.
[51] da C.M. V, de Souza Fede AB, Dos Anjos CH, da Silva JR, Sanchez FB, da Silva Bessa
LR, et al. Neoadjuvant chemotherapy with six cycles of carboplatin and paclitaxel in
604
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605
advanced ovarian cancer patients unsuitable for primary surgery: safety and effectiveness. Gynecol Oncol 2014;132:287–91.
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.
van der Burg ME, van LM, Buyse M, et al. The effect of debulking surgery after
induction chemotherapy on the prognosis in advanced epithelial ovarian cancer.
Gynecological Cancer Cooperative Group of the European Organization for
Research and Treatment of Cancer. N Engl J Med 1995;332:629–34.
Rose PG, Nerenstone S, Brady MF, Clarke-Pearson D, Olt G, Rubin SC, et al. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004;351:
2489–97.
Tangjitgamol S, Manusirivithaya S, Laopaiboon M, Lumbiganon P, Bryant A. Interval
debulking surgery for advanced epithelial ovarian cancer. Cochrane Database Syst
Rev 2013;4:CD006014.
Dewdney SB, Rimel BJ, Reinhart AJ, et al. The role of neoadjuvant chemotherapy in
the management of patients with advanced stage ovarian cancer: survey results
from members of the Society of Gynecologic Oncologists. Gynecol Oncol 2010;
119:18–21.
Vergote I, Amant F, Leunen K. Neoadjuvant chemotherapy in advanced ovarian
cancer: what kind of evidence is needed to convince US gynaecological oncologists? Gynecol Oncol 2010;119:1–2.
Chi DS, Musa F, Dao F, Zivanovic O, Sonoda Y, Leitao MM, et al. An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated
with primary debulking surgery (PDS) during an identical time period as the randomized EORTC–NCIC trial of PDS vs neoadjuvant chemotherapy (NACT). Gynecol
Oncol 2012;124:10–4.
Vergote I, Leunen K, Amant F. Primary surgery or neoadjuvant chemotherapy in
ovarian cancer: what is the value of comparing apples with oranges? Gynecol
Oncol 2012;124:1–2.
Kehoe S, Hook J, Nankivell M, et al. Chemotherapy or upfront surgery for newly
diagnosed advanced ovarian cancer: results from the MRC CHORUS trial. ASCO;
6-1-2013 [Ref Type: Abstract].
Morrison J, Haldar K, Kehoe S, Lawrie TA. Chemotherapy versus surgery for initial
treatment in advanced ovarian epithelial cancer. Cochrane Database Syst Rev
2012;8:CD005343.
Hightower RD, Nguyen HN, Averette HE, Hoskins W, Harrison T, Steren A. National
survey of ovarian carcinoma. IV: patterns of care and related survival for older
patients. Cancer 1994;73:377–83.
Uyar D, Frasure HE, Markman M, von Gruenigen VE. Treatment patterns by decade
of life in elderly women (Nor =70 years of age) with ovarian cancer. Gynecol
Oncol 2005;98:403–8.
Langstraat C, Aletti GD, Cliby WA. Morbidity, mortality and overall survival in elderly women undergoing primary surgical debulking for ovarian cancer: a delicate
balance requiring individualization. Gynecol Oncol 2011;123:187–91.
Glasgow MA, Yu H, Rutherford TJ, Azodi M, Silasi DA, Santin AD, et al. Neoadjuvant
chemotherapy (NACT) is an effective way of managing elderly women with
advanced stage ovarian cancer (FIGO Stage IIIC and IV). J Surg Oncol 2013;107:
195–200.
Worley Jr MJ, Guseh SH, Rauh-Hain JA, Williams KA, Muto MG, Feltmate CM, et al.
Does neoadjuvant chemotherapy decrease the risk of hospital readmission following debulking surgery? Gynecol Oncol 2013;129:69–73.
Thrall MM, Goff BA, Symons RG, Flum DR, Gray HJ. Thirty-day mortality after primary cytoreductive surgery for advanced ovarian cancer in the elderly. Obstet
Gynecol 2011;118:537–47.
Wright JD, Ananth CV, Tsui J, Glied SA, Burke WM, Lu YS, et al. Comparative effectiveness of upfront treatment strategies in elderly women with ovarian cancer.
Cancer 2014;120:1246–54.
Wright JD, Lewin SN, Deutsch I, Burke WM, Sun X, Neugut AI, et al. Defining the
limits of radical cytoreductive surgery for ovarian cancer. Gynecol Oncol 2011;
123:467–73.
Backes FJ, Nagel CI, Bussewitz E, Donner J, Hade E, Salani R. The impact of body
weight on ovarian cancer outcomes. Int J Gynecol Cancer 2011;21:1601–5.
Fotopoulou C, Richter R, Braicu EI, Kuhberg M, Feldheiser A, Schefold JC, et al. Impact of obesity on operative morbidity and clinical outcome in primary epithelial
ovarian cancer after optimal primary tumor debulking. Ann Surg Oncol 2011;18:
2629–37.
Kotsopoulos J, Moody JR, Fan I, Rosen B, Risch HA, McLaughlin JR, et al. Height,
weight, BMI and ovarian cancer survival. Gynecol Oncol 2012;127:83–7.
Protani MM, Nagle CM, Webb PM. Obesity and ovarian cancer survival: a systematic review and meta-analysis. Cancer Prev Res (Phila) 2012;5:901–10.
Worley Jr MJ, Guseh SH, Rauh-Hain JA, Esselen KM, Muto MG, Feltmate CM, et al.
What is the optimal treatment for obese patients with advanced ovarian carcinoma?
Am J Obstet Gynecol 2014;211:231.e1–9.
Kumar A, Bakkum-Gamez JN, Weaver AL, McGree ME, Cliby WA. Impact of obesity
on surgical and oncologic outcomes in ovarian cancer. Gynecol Oncol 2014;135:
19–24.
Pavelka JC, Brown RS, Karlan BY, Cass I, Leuchter RS, Lagasse LD, et al. Effect of
obesity on survival in epithelial ovarian cancer. Cancer 2006;107:1520–4.
Matthews KS, Straughn Jr JM, Kemper MK, Hoskins KE, Wang W, Rocconi RP. The
effect of obesity on survival in patients with ovarian cancer. Gynecol Oncol 2009;
112:389–93.
Wright JD, Tian C, Mutch DG, Herzog TJ, Nagao S, Fujiwara K, et al. Carboplatin dosing in obese women with ovarian cancer: a Gynecologic Oncology Group study.
Gynecol Oncol 2008;109:353–8.
[79] Au-Yeung G, Webb PM, DeFazio A, Fereday S, Bressel M, Mileshkin L. Impact of
obesity on chemotherapy dosing for women with advanced stage serous ovarian
cancer in the Australian Ovarian Cancer Study (AOCS). Gynecol Oncol 2014;133:
16–22.
[80] Barrett SV, Paul J, Hay A, Vasey PA, Kaye SB, Glasspool RM. Does body mass index
affect progression-free or overall survival in patients with ovarian cancer? Results
from SCOTROC I trial. Ann Oncol 2008;19:898–902.
[81] Howell EA, Egorova N, Hayes MP, Wisnivesky J, Franco R, Bickell N. Racial disparities in the treatment of advanced epithelial ovarian cancer. Obstet Gynecol
2013;122:1025–32.
[82] Aletti GD, Dowdy SC, Podratz KC, Cliby WA. Analysis of factors impacting operability in stage IV ovarian cancer: rationale use of a triage system. Gynecol Oncol 2007;
105:84–9.
[83] Bristow RE, Montz FJ, Lagasse LD, Leuchter RS, Karlan BY. Survival impact of surgical cytoreduction in stage IV epithelial ovarian cancer. Gynecol Oncol 1999;72:
278–87.
[84] Rauh-Hain JA, Growdon WB, Rodriguez N, et al. Primary debulking surgery versus
neoadjuvant chemotherapy in stage IV ovarian cancer. Gynecol Oncol 2011;120:
S12–3.
[85] Trope CG, Elstrand MB, Sandstad B, Davidson B, Oksefjell H. Neoadjuvant chemotherapy, interval debulking surgery or primary surgery in ovarian carcinoma
FIGO stage IV? Eur J Cancer 2012;48:2146–54.
[86] Winter III WE, Maxwell GL, Tian C, et al. Tumor residual after surgical cytoreduction
in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic
Oncology Group study. J Clin Oncol 2008;26:83–9.
[87] van Meurs HS, Tajik P, Hof MH, Vergote I, Kenter GG, Mol BW, et al. Which patients
benefit most from primary surgery or neoadjuvant chemotherapy in stage IIIC or IV
ovarian cancer? An exploratory analysis of the European Organisation for Research
and Treatment of Cancer 55971 randomised trial. Eur J Cancer 2013;49:3191–201.
[88] Hou JY, Kelly MG, Yu H, et al. Neoadjuvant chemotherapy lessens surgical morbidity in advanced ovarian cancer and leads to improved survival in stage IV disease.
Gynecol Oncol 2007;105:211–7.
[89] Rafii A, Deval B, Geay JF, Chopin N, Paoletti X, Paraiso D, et al. Treatment of FIGO
stage IV ovarian carcinoma: results of primary surgery or interval surgery after
neoadjuvant chemotherapy: a retrospective study. Int J Gynecol Cancer 2007;17:
777–83.
[90] Prat J. Staging classification for cancer of the ovary, fallopian tube, and peritoneum.
Int J Gynaecol Obstet 2014;124:1–5.
[91] Bristow RE, Duska LR, Lambrou NC, Fishman EK, O'Neill MJ, Trimble EL, et al. A
model for predicting surgical outcome in patients with advanced ovarian carcinoma using computed tomography. Cancer 2000;89:1532–40.
[92] Dowdy SC, Mullany SA, Brandt KR, Huppert BJ, Cliby WA. The utility of computed
tomography scans in predicting suboptimal cytoreductive surgery in women
with advanced ovarian carcinoma. Cancer 2004;101:346–52.
[93] Axtell AE, Lee MH, Bristow RE, Dowdy SC, Cliby WA, Raman S, et al. Multiinstitutional reciprocal validation study of computed tomography predictors of
suboptimal primary cytoreduction in patients with advanced ovarian cancer.
J Clin Oncol 2007;25:384–9.
[94] Suidan RS, Ramirez PT, Sarasohn DM, Teitcher JB, Mironov S, Iyer RB, et al. A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary
debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer.
Gynecol Oncol 2014;134:455–61.
[95] Kitajima K, Murakami K, Yamasaki E, Kaji Y, Fukasawa I, Inaba N, et al. Diagnostic
accuracy of integrated FDG-PET/contrast-enhanced CT in staging ovarian cancer:
comparison with enhanced CT. Eur J Nucl Med Mol Imaging 2008;35:1912–20.
[96] Pfannenberg C, Konigsrainer I, Aschoff P, Oksuz MO, Zieker D, Beckert S, et al. (18)
F-FDG-PET/CT to select patients with peritoneal carcinomatosis for cytoreductive
surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol 2009;
16:1295–303.
[97] Yoshida Y, Kurokawa T, Kawahara K, Tsuchida T, Okazawa H, Fujibayashi Y, et al.
Incremental benefits of FDG positron emission tomography over CT alone for the
preoperative staging of ovarian cancer. AJR Am J Roentgenol 2004;182:227–33.
[98] Hynninen J, Kemppainen J, Lavonius M, Virtanen J, Matomaki J, Oksa S, et al. A prospective comparison of integrated FDG-PET/contrast-enhanced CT and contrastenhanced CT for pretreatment imaging of advanced epithelial ovarian cancer.
Gynecol Oncol 2013;131:389–94.
[99] Fruscio R, Sina F, Dolci C, Signorelli M, Crivellaro C, Dell'Anna T, et al. Preoperative
18F-FDG PET/CT in the management of advanced epithelial ovarian cancer. Gynecol
Oncol 2013;131:689–93.
[100] Mitchell DG, Javitt MC, Glanc P, Bennett GL, Brown DL, Dubinsky T, et al. ACR appropriateness criteria staging and follow-up of ovarian cancer. J Am Coll Radiol 2013;
10:822–7.
[101] Nougaret S, Addley HC, Colombo PE, Fujii S, Al Sharif SS, Tirumani SH, et al. Ovarian
carcinomatosis: how the radiologist can help plan the surgical approach. Radiographics 2012;32:1775–800.
[102] Fagotti A, Fanfani F, Ludovisi M, Lo VR, Bifulco G, Testa AC, et al. Role of laparoscopy
to assess the chance of optimal cytoreductive surgery in advanced ovarian cancer:
a pilot study. Gynecol Oncol 2005;96:729–35.
[103] Brun JL, Rouzier R, Uzan S, Darai E. External validation of a laparoscopic-based score
to evaluate resectability of advanced ovarian cancers: clues for a simplified score.
Gynecol Oncol 2008;110:354–9.
[104] Fagotti A, Ferrandina G, Fanfani F, Ercoli A, Lorusso D, Rossi M, et al. A laparoscopybased score to predict surgical outcome in patients with advanced ovarian carcinoma:
a pilot study. Ann Surg Oncol 2006;13:1156–61.
J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605
[105] Fagotti A, Ferrandina G, Fanfani F, Garganese G, Vizzielli G, Carone V, et al. Prospective validation of a laparoscopic predictive model for optimal cytoreduction in
advanced ovarian carcinoma. Am J Obstet Gynecol 2008;199:642–6.
[106] Fagotti A, Vizzielli G, Fanfani F, Costantini B, Ferrandina G, Gallotta V, et al. Introduction of staging laparoscopy in the management of advanced epithelial ovarian,
tubal and peritoneal cancer: impact on prognosis in a single institution experience.
Gynecol Oncol 2013;131:341–6.
[107] Vizzielli G, Costantini B, Tortorella L, Petrillo M, Fanfani F, Chiantera V, et al. Influence of intraperitoneal dissemination assessed by laparoscopy on prognosis of
advanced ovarian cancer: an exploratory analysis of a single-institution experience.
Ann Surg Oncol 2014;21:3170–7.
[108] Fagotti A, Vizzielli G, De IP, Surico D, Buda A, Mandato VD, et al. A multicentric trial
(Olympia-MITO 13) on the accuracy of laparoscopy to assess peritoneal spread in
ovarian cancer. Am J Obstet Gynecol 2013;209:462.
[109] Rutten MJ, Gaarenstroom KN, Van GT, van Meurs HS, Arts HJ, Bossuyt PM, et al.
Laparoscopy to predict the result of primary cytoreductive surgery in advanced
ovarian cancer patients (LapOvCa-trial): a multicentre randomized controlled
study. BMC Cancer 2012;12:31.
[110] Nick AM, Ramirez PT, Rangel KM, Schmeler KM, Soliman PT, Burzawa JK, et al.
Launching personalized surgical therapy for advanced ovarian cancer. Gynecol
Oncol 2014;133:28 [Supp 1].
[111] Rutten MJ, Leeflang MM, Kenter GG, Mol BW, Buist M. Laparoscopy for diagnosing
resectability of disease in patients with advanced ovarian cancer. Cochrane Database Syst Rev 2014;2:CD009786.
605
[112] Aletti GD, Gostout BS, Podratz KC, Cliby WA. Ovarian cancer surgical resectability:
relative impact of disease, patient status, and surgeon. Gynecol Oncol 2006;100:
33–7.
[113] McCann CK, Growdon WB, Munro EG, et al. Prognostic significance of splenectomy
as part of initial cytoreductive surgery in ovarian cancer. Ann Surg Oncol 2011;18:
2912–8.
[114] Wimberger P, Lehmann N, Kimmig R, et al. 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.
[115] Ang C, Chan KK, Bryant A, Naik R, Dickinson HO. Ultra-radical (extensive) surgery
versus standard surgery for the primary cytoreduction of advanced epithelial ovarian cancer. Cochrane Database Syst Rev 2011:CD007697.
[116] Riester M, Wei W, Waldron L, Culhane AC, Trippa L, Oliva E, et al. Risk prediction for
late-stage ovarian cancer by meta-analysis of 1525 patient samples. J Natl Cancer
Inst 2014;106.
[117] Bristow RE, Chang J, Ziogas A, Anton-Culver H, Vieira VM. Spatial analysis of adherence to treatment guidelines for advanced-stage ovarian cancer and the impact of
race and socioeconomic status. Gynecol Oncol 2014;134:60–7.