The role of surgery in the management of epithelial ovarian cancer.
ABSTRACT Epithelial ovarian cancer is the most deadly gynecologic cancer in the United States. Multiple modalities of therapy are utilized in the management of the disease. The role of surgery remains important in the treatment of this disease and is described herein.
Medline and PubMed were utilized to search the English language medical literature up to March 2010. A broad range of studies and quality of data were analyzed, including prospective studies, case control analyses, and meta-analyses. When possible, the highest level of evidence was reviewed and presented.
For the medically fit patient, optimal cytoreductive surgery positively impacts survival. For some highly selected patients, there is a role for a minimally invasive approach. In the recurrent setting, factors such as interval to recurrence and the distribution of disease will determine the utility of secondary cytoreductive surgery. A subgroup of patients may benefit from palliative surgical procedures in the recurrent setting.
Despite advances in the use of chemotherapy and biologic agents, surgery remains an important modality in the diagnosis and treatment of ovarian cancer.
- SourceAvailable from: Fabio Landoni[show abstract] [hide abstract]
ABSTRACT: No randomised trials have addressed the value of systematic aortic and pelvic lymphadenectomy (SL) in ovarian cancer macroscopically confined to the pelvis. This study was conducted to investigate the role of SL compared with lymph nodes sampling (CONTROL) in the management of early stage ovarian cancer. A total of 268 eligible patients with macroscopically intrapelvic ovarian carcinoma were randomised to SL (N=138) or CONTROL (N=130). The primary objective was to compare the proportion of patients with retroperitoneal nodal involvement between the two groups. Median operating time was longer and more patients required blood transfusions in the SL arm than the CONTROL arm (240 vs 150 min, P<0.001, and 36 vs 22%, P=0.012, respectively). More patients in the SL group had positive nodes at histologic examination than patients on CONTROL (9 vs 22%, P=0.007). Postoperative chemotherapy was delivered in 66% and 51% of patients with negative nodes on CONTROL and SL, respectively (P=0.03). At a median follow-up of 87.8 months, the adjusted risks for progression (hazard ratio [HR]=0.72, 95%CI=0.46-1.21, P=0.16) and death (HR=0.85, 95%CI=0.49-1.47, P=0.56) were lower, but not statistically significant, in the SL than the CONTROL arm. Five-year progression-free survival was 71.3 and 78.3% (difference=7.0%, 95% CI=-3.4-14.3%) and 5-year overall survival was 81.3 and 84.2% (difference=2.9%, 95% CI=-7.0-9.2%) respectively for CONTROL and SL. SL detects a higher proportion of patients with metastatic lymph nodes. This trial may have lacked power to exclude clinically important effects of SL on progression free and overall survival.British Journal of Cancer 09/2006; 95(6):699-704. · 5.08 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Background: In order to analyze the prognostic role of node involvement in advanced ovarian cancer, we have analyzed data from a randomized clinical trial on advanced ovarian cancer. Cases were 456 women who entered a randomized multicentric clinical trial comparing two cisplatin-based schemes of treatment after cytoreductive surgery for advanced stage III-IV ovarian cancer. They underwent selective pelvic and/or paraortic lymphadenectomy. A total of 161 (35.3%) cases had positive nodes. The frequency of positive nodes was statistically significantly higher in FIGO stage IV than in stage III. Also grade 3 tumors were more likely to have positive nodes than grade 1-2 tumors. No association was observed between nodal status and response to chemotherapy. The 3-year survival was 46.2 (standard error (SE) = 3.4 based on 147 deaths) and 44.6 (SE = 4.4, based on 84 deaths), respectively, in negative and positive node groups. The corresponding values, when the analysis was performed considering only subjects with residual tumor <1 cm or absent, after first-line cytoreductive surgery were 66.2 (SE = 5.7) and 62.4 (SE = 9.6). We did not find any association between nodal status and survival. Particularly, nodal status was not a prognostic factor for survival in the subgroup of women with residual tumor <1 cm or absent after cytoreductive surgery.Gynecologic Oncology 08/1999; 74(1):7-11. · 3.93 Impact Factor
- CancerSpectrum Knowledge Environment 12/2005; 97(21):1621; author reply 1621-3. · 14.07 Impact Factor
22 Cancer Control January 2011, Vol 18, No.1
present with advanced metastatic disease at diagnosis.
Initial evaluation includes a thorough history and physi-
cal examination, imaging studies, assessment of tumor
markers (CA-125), possible biopsies, and/or colonoscopy.
Cytotoxic chemotherapy has an important role in
the treatment of this disease, in the neoadjuvant, adju-
vant, and recurrent setting. For the medically fi t patient,
surgery also has an important role in the management
of ovarian cancer for diagnosis, primary therapy, and
treatment of recurrent disease.
This paper focuses on the role of surgery in the
management of EOC. Although fallopian tube cancer and
primary peritoneal cancer are not specifi cally addressed,
these diseases are thought to be similar to EOC and are
treated in a manner identical to EOC.
Terms that should be defi ned prior to proceeding
include primary cytoreduction, interval cytoreduction,
secondary cytoreduction, neoadjuvant chemotherapy,
Epithelial ovarian cancer (EOC) remains the most deadly
gynecologic cancer in the United States. In 2010, approxi-
mately 21,880 new cases and 13,850 deaths occurred.1
There is no proven screening test for this disease. Many
women present with vague symptoms, including abdomi-
nal bloating, change in bowel or bladder habits, early sati-
ety, or abdominal pain. For these reasons, many patients
From the Department of Obstetrics and Gynecology at the Univer-
sity of South Florida, Tampa, Florida (IR), and the Department of
Women’s Oncology at the H. Lee Moffi tt Cancer Center & Research
Institute, Tampa, Florida (HSC, SMA).
Submitted May 17, 2010; accepted September 9, 2010.
Address correspondence to Sachin M. Apte, MD, MS, Department of
Women’s Oncology, Moffi tt Cancer Center, 12902 Magnolia Drive,
MCC-GYNPROG, Tampa, FL 33612. E-mail: Sachin.Apte@moffi tt.org
No signifi cant relationship exists between the authors and the
companies/organizations whose products or services may be ref-
erenced in this article.
J. L. Munro. Arctic Whalers. Mixed media on canvas, 24? × 36?.
Surgery remains key in the diagnosis,
staging, and management of
The Role of Surgery in the Management of
Epithelial Ovarian Cancer
Ingrid Ramirez, MD, Hye Sook Chon, MD, and Sachin M. Apte, MD, MS
Background: Epithelial ovarian cancer is the most deadly gynecologic cancer in the United States. Multiple
modalities of therapy are utilized in the management of the disease. The role of surgery remains important in
the treatment of this disease and is described herein.
Methods: Medline and PubMed were utilized to search the English language medical literature up to March
2010. A broad range of studies and quality of data were analyzed, including prospective studies, case control
analyses, and meta-analyses. When possible, the highest level of evidence was reviewed and presented.
Results: For the medically fi t patient, optimal cytoreductive surgery positively impacts survival. For some highly
selected patients, there is a role for a minimally invasive approach. In the recurrent setting, factors such as
interval to recurrence and the distribution of disease will determine the utility of secondary cytoreductive surgery.
A subgroup of patients may benefi t from palliative surgical procedures in the recurrent setting.
Conclusions: Despite advances in the use of chemotherapy and biologic agents, surgery remains an important
modality in the diagnosis and treatment of ovarian cancer.
January 2011, Vol 18, No.1Cancer Control 23
and adjuvant chemotherapy. Primary cytoreduction
refers to the initial surgical excision of tumor and tumor-
involved organs prior to chemotherapy. According to the
Gynecologic Oncology Group (GOG), optimal surgical
cytoreduction is defi ned as residual tumor less than 1
cm. Interval cytoreduction is performed on patients who
have previously received neoadjuvant chemotherapy.
Secondary cytoreduction refers to the surgical manage-
ment of recurrent ovarian cancer. Cytoreduction and
debulking are terms that are used interchangeably. Neo-
adjuvant chemotherapy is the administration of chemo-
therapy prior to cytoreductive surgery. This is reserved
for those patients in whom optimal cytoreduction is not
possible because of either the distribution of disease
or poor performance status. Adjuvant chemotherapy is
administered after surgery in appropriate patients. Pa-
tients usually receive 6 cycles of adjuvant platinum and
Role of Surgery
Surgical evaluation is indicated for most women with
known or suspected EOC. Surgery is generally recom-
mended, provided there are no medical contraindications
and the distribution of disease is deemed resectable on
preoperative evaluation. The goals of the initial surgery
are to obtain a pathologic diagnosis, accurately determine
the extent of disease and, when feasible, optimally cyto-
reduce the ovarian cancer. For patients with suspected
EOC, the usual differential diagnosis includes uterine,
fallopian tube, primary peritoneal, or metastatic cancers
from the gastrointestinal tract or breast.
Accurate surgical staging is particularly important for
apparent early-stage disease, ie, women with an ovarian
cancer that appears grossly confi ned to the ovary. Ap-
proximately 25% to 30% of women with apparent early-
stage disease will be upstaged upon thorough surgical
staging. Treatment is often driven by the surgical stage, as
expressed by the International Federation of Gynecology
and Obstetrics (FIGO) staging system (Table). Precise
surgical staging is critical for the patient in terms of both
therapy and prognosis. Women with a true stage I, well-
differentiated EOC may be observed; however, those
with more advanced disease are generally treated with
chemotherapy. Due to a lack of effective screening and
insidious symptoms, the majority of women will pre-
sent with advanced disease. In the setting of advanced
disease, the goal of the initial surgical effort is to achieve
optimal cytoreduction. Intraperitoneal chemotherapy
is considered for some patients with advanced disease
who have undergone optimal cytoreductive surgery. A
careful preoperative assessment is mandatory to deter-
mine patient fi tness for surgery. The surgeon must take
Table. — Carcinoma of the Ovary: FIGO Nomenclature (Rio de Janeiro 1988)
Stage IGrowth limited to the ovaries.
IA Growth limited to one ovary: no ascites present containing malignant cells. No tumor on the external surface; capsule intact.
IBGrowth limited to both ovaries: no ascites present containing malignant cells. No tumor on the external surfaces; capsules intact.
IC*Tumor either stage IA or IB, but with tumor on surface of one or both ovaries, or with capsule ruptured, or with ascites present
containing malignant cells, or with positive peritoneal washings.
Stage IIGrowth involving one or both ovaries with pelvic extension.
IIA Extension and/or metastases to the uterus and/or tubes.
IIBExtension to other pelvic tissues.
IIC* Tumor either stage IIA or IIB, but with tumor on surface of one or both ovaries, or with capsule(s) ruptured, or with ascites present
containing malignant cells, or with positive peritoneal washings.
Stage III Tumor involving one or both ovaries with histologically confi rmed peritoneal implants outside the pelvis and/or positive retroperitoneal
or inguinal nodes. Superfi cial liver metastases equals stage III. Tumor is limited to the true pelvis but with histologically proven
malignant extension to small bowel or omentum.
IIIATumor grossly limited to the true pelvis, with negative nodes, but with histologically confi rmed microscopic seeding of abdominal
peritoneal surfaces, or histologic proven extension to small bowel or mesentery.
IIIBTumor of one or both ovaries with histologically confi rmed implants, peritoneal metastasis of abdominal peritoneal surfaces, none
exceeding 2 cm in diameter; nodes are negative.
IIICPeritoneal metastasis beyond the pelvis > 2 cm in diameter and/or positive retroperitoneal or inguinal nodes.
Stage IV Growth involving one or both ovaries with distant metastases. If pleural effusion is present, there must be positive cytology to allot a
case to stage IV. Parenchymal liver metastasis equals stage IV.
* In order to evaluate the impact on prognosis of the different criteria for allotting cases to stage IC or IIC, it would be of value to know if rupture of the
capsule was spontaneous, or caused by the surgeon; and if the source of malignant cells detected peritoneal washings, or ascites.
From Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. Int J Gynecol Obstet. 2006;95(suppl 1):S163. Reprinted with permission
by Elsevier. http://www.sciencedirect.com/science/journal/00207292.
24 Cancer ControlJanuary 2011, Vol 18, No.1
into consideration a variety of factors, such as perfor-
mance status, nutrition, medical comorbidities, impend-
ing bowel obstruction, and patient age. The patient must
undergo a careful and thorough consent process and
must understand the risks, benefi ts, and radicality of the
possible procedures involved.
The staging procedure is usually performed via a verti-
cal incision, and a thorough exploration is performed
to assess the extent of disease. All peritoneal surfaces
and organs are palpated, including the diaphragm, liver,
spleen, gall bladder, small and large intestine, and mes-
entery. The retroperitoneum is carefully evaluated for
bulky adenopathy. A frozen section is obtained, usually of
a portion of involved omentum or adnexa. An assessment
is made regarding whether a patient can be debulked
optimally. If so, attention should fi rst be placed on the
area of most concern so that it can be rendered free of
disease. Also, potential sites of bowel obstruction must
be carefully evaluated and addressed.
In the absence of gross extra-ovarian disease, multiple
peritoneal biopsies are obtained, along with a pelvic and
para-aortic lymphadenectomy. An omentectomy, hyster-
ectomy, and bilateral salpingo-oophorectomy are also per-
formed. For women with early-stage ovarian cancer, sys-
tematic lymphadenectomy is part of the complete staging
procedure. Nearly one-fourth of patients with apparent
early-stage ovarian cancer who undergo this procedure
are upstaged to stage IIIC due to the presence of node
metastases.2 However, in patients with advanced-stage
EOC, the role and benefi t of systematic lymphadenectomy
are unclear. In a study of 456 women with advanced
stage III/IV ovarian cancer, no correlation between nodal
status and survival was noted. In addition, nodal status
was not a prognostic factor for optimally cytoreduced
patients with advanced-stage EOC.3 In another trial, 427
women with stage III/IV ovarian cancer were random-
ized to either systemic lymphadenectomy vs resection of
bulky nodes.4 No statistical difference in the 5-year overall
survival rate (48.5% vs 47%, respectively) was noted. Sys-
temic lymphadenectomy, however, was associated with
increased progression-free survival compared to the no-
lymphadenectomy arm: 31.2% vs 21.6%. Therefore, the
recommendation is to resect bulky tumor-involved nodes
in advanced-stage ovarian cancer.
The cornerstones of the initial management of EOC are
staging and surgical cytoreduction. For patients with
advanced-stage ovarian cancer, the optimal cytoreduc-
tive rate has been shown to vary from 17% to 87%.5-16 To
achieve an optimal surgery, a variety of procedures may
need to be performed, such as splenectomy, diaphragm
stripping, partial hepatic resection, partial bladder or
ureteral resection, or bowel resection.
In the 1970s, Griffi ths et al17,18 described an associa-
tion between overall survival and cytoreduction of bulky
disease. In a study of 102 patients with stage II and III
EOC, residual disease ? 1.5 cm was identifi ed as a poor
prognostic indicator. Hoskins et al19 also reported on the
size of residual disease and overall survival in patients
with stage III ovarian cancer. Patients with suboptimal
cytoreduction (? 1 cm) but with smaller diameter re-
sidual disease (? 2 cm) still had an increased overall
survival compared with those who had larger volume
residual disease (? 2 cm). Since then, multiple studies
have consistently shown that the volume of residual
disease remaining after cytoreductive surgery inversely
correlates with survival.5,19-22
The term optimal cytoreduction has recently
become a topic of controversy since the defi nition has
now evolved to also include maximal cytoreductive
efforts, with the end goal of complete resection of all
visible disease. No residual disease at the completion
of surgery has consistently been shown to result in im-
proved overall survival and progression-free survival.
Although studies have described optimal cytoreduction
by different criteria, for example, ? 2 cm or ? 0.5 cm,
to date, no prospective randomized control trials have
defi ned the degree of residual disease that has the best
Based on current retrospective studies, the recom-
mendation for complete resection of all visible disease is
becoming more widely accepted as it has been shown to
improve overall survival.23 Chi et al21 reported that the
amount of residual disease was recognized as a signifi cant
prognostic factor. In that study, 465 patients with stage
IIIC EOC who had undergone primary cytoreductive
surgery were identifi ed from a prospective database.
The amount of residual disease was categorized into
fi ve distinct groups: no gross residual, gross ? 0.5 cm,
0.6–1.0 cm, 1–2 cm, and ? 2 cm residual. The median
overall survival rates in the fi ve groups were as follows:
106 months for no gross, 66 months for gross ? 0.5 cm,
48 months for 0.6–1.0 cm, 33 months for 1–2 cm, and 34
months for ? 2 cm. In a study of 3,126 patients, du Bois
et al24 also demonstrated improved overall and progres-
sion- free survival with complete resection. The patients
with complete resection had a median survival of 99.1
months, whereas the median survival for patients with
0.1 to 1 cm and ? 1 cm residual disease was 36.2 and
29.6 months, respectively.
The fi ndings from the above studies reiterate the
importance of optimal cytoreduction at the time of
primary surgery for EOC. In addition, although the
GOG defi nes optimal cytoreduction as residual disease of
? 1 cm, data from more recent studies suggest that
overall and progression-free survival are improved to a
greater extent when maximal cytoreduction is achieved.
These fi ndings of increased overall survival with maximal
cytoreduction have led many to advocate for complete
January 2011, Vol 18, No.1Cancer Control 25
resection with the end goal of no residual disease.
However, maximal cytoreduction may be associated
with signifi cant perioperative morbidity, as aggressive
surgical techniques such as diaphragmatic stripping may
have to be employed to obtain an optimal cytoreduction.
Nevertheless, surgery by either optimal cytoreduction or
maximal cytoreduction before chemotherapy has been
shown consistently to improve survival in patients with
advanced EOC. In addition to the improved survival with
cytoreduction, surgery improves some of the symptoms
associated with advanced-stage EOC, such as bloating,
abdominal distention, or abdominal pain.
After primary cytoreductive surgery, adjuvant platinum
and taxane-based chemotherapy is used in the majority
of women with advanced ovarian cancer. Optimal de-
bulking is thought to maximize the effi cacy of chemo-
therapy. Chemotherapeutic drugs exert their maximum
effects on small tumors that are well perfused and there-
fore mitotically active. Large tumor size is associated
with poor perfusion, a greater chance of sublethal cel-
lular damage, and the emergence of multidrug-resistant
clones. Chemotherapy can be administered by intrave-
nous or intraperitoneal routes. In EOC, the peritoneum
is the focus of tumor metastasis. The intraperitoneal
route allows for direct exposure to chemotherapeu-
tic agents and has been shown to increase overall and
progression-free survival in advanced ovarian cancer
compared with intravenous chemotherapy.25-27 In a
recent study by Armstrong et al,27 429 optimally de-
bulked patients were randomized to receive intravenous
paclitaxel followed by either intravenous cisplatin on
day 2 (intravenous group) or intraperitoneal cisplatin
on day 2 and intraperitoneal paclitaxel on day 8 (in-
traperitoneal group). Among 415 eligible patients, the
median progression-free survival and overall survival in
the intraperitoneal group vs the intravenous group were
23.8 vs 18.3 months and 65.6 vs 49.7 months. However,
intraperitoneal chemotherapy is associated with more
side effects and thus has a higher discontinuation rate.
Nonetheless, in this study, despite the discontinuation
rate (only 42% of the patients in the intraperitoneal
group completed the assigned six cycles), a survival
benefi t was shown. Most of the complications with
intraperitoneal chemotherapy were catheter related,
such as infection, leakage near the port, access diffi cul-
ties, blocked catheter, and leakage of fl uid through the
vagina.28 Other adverse events included abdominal
pain, nephrotoxicity, fatigue, hematologic disorders, and
neuropathy. Despite these adverse effects, intraperito-
neal chemotherapy should be considered for adjuvant
chemotherapy in optimally cytoreduced patients with
advanced-stage ovarian cancer, as it has consistently
been shown to confer a clinical advantage with in-
creased overall survival.
Achieving optimal debulking is not always feasible. Limit-
ing factors may include extensive upper abdominal or
retroperitoneal disease, large tumor burden in bowel
mesentery, or porta hepatis. Selection criteria often used
to determine which patients cannot be optimally cyto-
reduced include presence of stage IV disease, massive
ascites, bulky omental disease with splenic involvement,
and suprarenal lymphadenopathy. If optimal debulking
is not possible, then the operation is generally limited to
a bilateral salpingo-oophorectomy and/or omentectomy
to prove the site of origin and to address potential sites
of bowel obstruction.
Clinical models have been developed to try to iden-
tify those patients who will have a low probability of
optimal cytoreductive surgery. Computed tomography
(CT) scans have been evaluated to determine their pre-
dictive value in identifying unresectable disease. Nelson
et al29 assessed the likelihood of resectability based on
CT fi ndings. The CT fi ndings predictive of unresectabil-
ity included the presence of an omental cake extending
to the spleen, a diaphragm coated by tumor extending
to the liver serosa, lesions ? 2 cm in the suprarenal
para-aortic lymph nodes and porta hepatis, parenchy-
mal liver disease, pulmonary metastases, and enlarged
pericardial lymph nodes. With these criteria, the likeli-
hood of resectability was accurately predicted in 23 of
24 patients. Bristow et al30 also used CT radiographic
features for predicting the outcome of cytoreductive
surgery in advanced ovarian cancer. The authors identi-
fi ed 13 radiographic features corresponding to certain
anatomic locations that have traditionally made optimal
cytoreductive surgery diffi cult, such as extensive upper
abdominal disease. Forty-one patients with stage III/IV
EOC who had undergone primary surgical cytoreduc-
tion were identifi ed. Their preoperative CT scans were
reviewed and, based on certain radiographic features and
performance status, the patients were assigned a score.
In this study, a Predictive Index score ? 4 was indica-
tive of poor likelihood to undergo optimal cytoreduc-
tion. However, more recent studies have contradicted
these fi ndings.31 Axtell et al32 analyzed preoperative CT
scans from 65 patients with stage III/IV ovarian cancer
who had undergone primary cytoreduction. Fourteen
radiologic criteria were chosen as possible pertinent
predictors of suboptimal cytoreduction, including large-
volume ascites, pleural effusion, diffuse peritoneal thick-
ening, omental caking, omental extension to spleen or
stomach, suprarenal lymph nodes ? 1 cm, infrarenal or
inguinal lymph nodes ? 2 cm, and tumor implants ? 2
cm (located on bowel mesentery, peritoneum, diaphragm,
liver, or porta hepatis). Only diaphragmatic disease ? 2
cm and large bowel mesentery implants ? 2 cm were
noted to be statistically signifi cant predictors of subopti-
mal cytoreductive outcome. However, the utility of this
fi nding is limited because half of the patients with ?
26 Cancer ControlJanuary 2011, Vol 18, No.1
2-cm disease in the diaphragm and large bowel actually
underwent optimal cytoreduction. In addition, when
these criteria were applied to two previously published
patient cohorts (patients who underwent primary cyto-
reduction at Johns Hopkins Medical Institute30 and the
Mayo Clinic33), the sensitivity, specifi city, and accuracy
of these positive predictors were all noted to decrease.
CT scans should thus be used with caution when trying
to identify those patients who are not likely to achieve
optimal cytoreduction. Clinical judgment must be exer-
cised when deciding whether to proceed with primary
cytoreductive surgery, as no clinical model has yet ac-
curately predicted disease resectability.
In addition, the above clinical models did not take
into account the surgeon as an independent predictive
factor of surgical outcome. In a study by Aletti et al,34
certain preoperative and intraoperative factors were
analyzed to identify a correlation with optimal residual
disease. The variables analyzed were patient age, perfor-
mance status, CA-125 level, ascites volume, carcinomato-
sis, diaphragm and mesentery involvement, and surgeon
tendency. Only performance status, carcinomatosis, and
surgeon tendency were independently associated with
optimal cytoreduction. These fi ndings were consistent
with the belief that resectability of tumor is highly depen-
dent on surgical skills. This study also demonstrated that
any proposed model to preoperatively identify patients
unlikely to have optimal cytoreduction must take into
account surgeon tendency as a predictive factor.
Preoperative CA-125 level also has been evaluated as
a predictor for primary optimal cytoreduction in patients
with advanced ovarian cancer. Despite initial positive
results from Chi et al35 regarding the preoperative pre-
dictability of CA-125 for optimal cytoreduction, the same
group recently reported that there was no threshold
CA-125 level that accurately predicted cytoreductive
outcome after their change in surgical paradigm that
incorporated extensive upper abdominal procedures to
attain optimal debulking.36 It is a general consensus that,
currently, CA-125 level does not appear to be a signifi cant
predictor of tumor resectability.
In addition to cytoreduction and surgeon skill, a
patient’s specifi c tumor biology likely plays a role in re-
sectability of disease and survival. The reasoning is that
certain tumor cells have the ability to escape cell repair
mechanisms, making them inherently more aggressive.
For example, the “biological aggressiveness” of certain
tumors may decrease long-term survival due to tumor-
dependent characteristics, such as rapid development
of chemoresistance, despite optimal cytoreduction. A
study by Hacker et al37 showed that large-volume ascites
or large tumor burden (? 10 cm), despite cytoreduction,
was a poor prognostic factor. Heintz et al38 found that
ascites, large tumor diameter, and peritoneal carcinoma-
tosis were poor prognostic factors despite cytoreduction.
The above studies support the idea that initial tumor
burden may be in itself an indicator of tumor biological
The majority of women will receive adjuvant che-
motherapy after suboptimal debulking. Whether these
women would benefi t from another attempt at debulking
is unclear. A report by van der Burg et al39 described
the fi ndings of a European Organisation of Research and
Treatment of Cancer (EORTC) study in which 278 evalu-
able patients with suboptimal tumor debulking (residual
tumor ? 1 cm) were randomly assigned, after three cycles
of cyclophosphamide and cisplatin, to either undergo a
secondary attempt at debulking or continue with another
three cycles of chemotherapy. Those with progressive
disease after neoadjuvant chemotherapy were excluded
from the study. The secondary attempt at debulking was
performed on 140 patients and was well tolerated: 65%
of patients had residual disease ? 1 cm after neoadjuvant
chemotherapy, and optimal cytoreduction was achieved
in 45% of patients in this group. Median survival time was
26 months for those undergoing a secondary attempt and
20 months for those in the non-secondary attempt group
(P = .04). Overall, after adjustments were made for all
other prognostic factors, surgery reduced the risk of death
by 33% (95% confi dence interval, 10% to 50%; P = .008). A
second study showed results contradictory to the EORTC
study. In GOG 152, Rose et al40 reported on 425 patients
with advanced EOC who had been suboptimally debulked
(residual tumor ? 1 cm) at primary surgery, received
three cycles of paclitaxel and cisplatin chemotherapy, and
then were randomized to secondary attempt at debulking
or no surgery followed by chemotherapy in both groups.
Patients receiving secondary attempt at debulking had a
median survival time of 32 months compared with 33
months for those receiving chemotherapy alone. There
was no difference in progression-free survival time (10.5
and 10.8 months, respectively). Unlike the EORTC trial,
GOG 152 had inclusion criteria for a maximal surgical
effort at the time of primary surgery. It is apparent that
patients who have had a maximal but suboptimal primary
cytoreductive surgical effort do not benefi t from a sec-
ondary attempt at debulking. Therefore, women who
have undergone an attempted cytoreduction by a surgeon
trained in the aggressive management of this disease are
unlikely to benefi t from a second attempt for debulking
surgery after chemotherapy.
Neoadjuvant Chemotherapy Followed by
Interval Debulking Surgery
For patients with suspected advanced ovarian cancer, the
general recommendation is for primary surgical cytore-
duction followed by chemotherapy. However, when this
is not advisable, patients are usually treated initially with
neoadjuvant platinum and taxane-based chemotherapy
prior to cytoreductive surgery. These patients may have
signifi cant pre-existing medical comorbidities or severe
malnutrition and thus be at high risk for perioperative