Role of maximal primary cytoreductive surgery in patients with advanced epithelial ovarian and tubal cancer: Surgical and oncological outcomes. Single institution experience.

Abstract

To determinate the impact of maximal cytoreductive surgery on progression free survival (PFS), overall survival (OS) rates and morbidity, in patients with advanced epithelial ovarian or fallopian tube cancer.
We reviewed all medical records of patients with stages IIIC-IV epithelial ovarian and fallopian tube cancer that were managed at our institution between January 2001 and December 2008. The following information was collected: demographics, tumor characteristics, operative information, surgical outcomes and peri-operative complication.
A total of 288 patients with advanced epithelial ovarian and fallopian tube cancer were referred to our institution between January 2001 and December 2008, 259 consecutive patients were enrolled in the study. After a median follow-up of 29.8 months, the PFS and OS were 19.9 and 57.6 months, respectively. At univariate analysis, factors significantly associated with decreased PFS included: age greater than median (>60 years), stage IV, presence of ascites >1000 cc, presence of diffuse peritoneal carcinomatosis and diameter of residual disease. This was confirmed also at multivariate analysis with age greater than 60 years (P=0.025), stage IV vs IIIC (P=0.037) and any residual disease (P=0.032) having an independent association with worse PFS.
Our study seems to demonstrate that a more extensive surgical approach is associated with prolonged disease-free interval and improved survival in patients with stages IIIC-IV epithelial ovarian and fallopian tube cancer. Moreover all patients with no residual tumor seem to have the best prognosis and in view of these results we believe that the goal of primary surgery should be considered as leaving no macroscopic disease.

Full text

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Role of maximal primary cytoreductive surgery in patients with advanced
epithelial ovarian and tubal cancer: Surgical and oncological outcomes. Single
institution experience
Michele Peirettia,⁎, Vanna Zanagnoloa, Giovanni D. Alettia, Luca Bocciolonea, Nicoletta Colomboa,
Fabio Landonia, Lucas Minigd, Roberto Biffib, Davide Radicec, Angelo Maggionia
aDivision of Gynecologic Oncology European Institute of Oncology, Milan, Italy
bDivision of Abdomino-Pelvic Surgery, European Institute of Oncology, Milan, Italy
cDivision of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
dDivision of Gynecology, Hospital Universitario Madrid Norte Sanchinarro, Madrid, Spain
a b s t r a c t a r t i c l ei n f o
Article history:
Received 4 May 2010
Available online xxxx
Keywords:
Advanced ovarian cancer
Optimal cytoreduction
Tumor residual
Survival
Objective. To determinate the impact of maximal cytoreductive surgery on progression free survival (PFS),
overall survival (OS) rates and morbidity, in patients with advanced epithelial ovarian or fallopian tube cancer.
Methods.WereviewedallmedicalrecordsofpatientswithstagesIIIC–IVepithelialovarianandfallopiantube
cancer that were managed at our institution between January 2001 and December 2008. The following
information was collected: demographics, tumor characteristics, operative information, surgical outcomes and
peri-operative complication.
Results.Atotalof288patientswithadvancedepithelialovarianandfallopiantubecancerwerereferredtoour
institutionbetweenJanuary2001andDecember2008,259consecutivepatientswereenrolledinthestudy.After
a median follow-up of 29.8 months, the PFS and OS were 19.9 and 57.6 months, respectively. At univariate
analysis,factorssignificantlyassociatedwithdecreasedPFSincluded:agegreaterthanmedian(N60 years),stage
IV, presence of ascites N1000 cc, presence of diffuse peritoneal carcinomatosis and diameter of residual disease.
This was confirmed also at multivariate analysis with age greater than 60 years (P=0.025), stage IV vs IIIC
(P=0.037) and any residual disease (P=0.032) having an independent association with worse PFS.
Conclusions. Our study seems to demonstrate that a more extensive surgical approach is associated with
prolonged disease-free interval and improved survival in patients with stages IIIC–IV epithelial ovarian and
fallopiantubecancer.Moreoverallpatientswithnoresidualtumorseemtohavethebestprognosisandinviewof
theseresultswebelievethatthegoalofprimarysurgeryshouldbeconsideredasleavingnomacroscopicdisease.
© 2010 Elsevier Inc. All rights reserved.
Introduction
Ovarian cancer is the ninth most common cancer in women and it
ranks fifth as the cause of cancer death in women.In the United States,
approximately 21,550 new cases and 14,600 deaths are estimated
annually [1,2]. In the European Union the estimated number of newly
diagnosed cases was 42,700 in 2004 with a mortality of 12/100,000
women/year [3]. Unfortunately the majority of patients with ovarian
cancer are diagnosed at an advanced stage.
Thestandardapproachtoinitialtreatmentofpatientswithadvanced
ovarian cancer (AOC) consists of primary cytoreductive surgery
followed by combination platinum-based chemotherapy. Several
authors have focused on the extent of surgery as a major determinant
of prognosis [4,5]. Furthermore the goal of surgery is to reduce the
tumor bulk as much as possible. The current definition of “optimal
cytoreduction” has been used by the Gynecologic Oncology Group
(GOG)since1986withathresholdof≤1 cmresidualdiseaseingreatest
tumor dimension [6,7], recently several reports have suggested that
there may be an additional advantage in terms of survival rate
associated with cytoreduction to no visible residual disease [8–12].
Unfortunately many women with ovarian cancer do not undergo
optimal cytoreduction, one of the main reasons being, as shown by
numerous studies, that optimal cytoreduction rate greater than 50%
often requires the incorporation of a variety of extensive upper
abdominal surgical procedures, not always performed by general
gynaecologists [13].
In these series, we describe our experience since January 2001,
when we started to incorporate extensive upper abdominal surgery
into the primary cytoreductive approach, in order to improve optimal
cytoreduction rate.
The purpose of the present study was to determine the impact of
maximal cytoreductive surgery on progression free survival, overall
Gynecologic Oncology xxx (2010) xxx–xxx
⁎ Corresponding author. Division of Gynecologic Oncology, European Institute of
Oncology, Via Ripamonti 435, 20141. Milan, Italy. Fax: +39 0294379222.
E-mail address: michele.peiretti@ieo.it (M. Peiretti).
YGYNO-973699; No. of pages: 6; 4C:
0090-8258/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygyno.2010.07.032
Contents lists available at ScienceDirect
Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno
Please cite this article as: Peiretti M, et al, Role of maximal primary cytoreductive surgery in patients with advanced epithelial ovarian and
tubal cancer: Surgical and oncological outcomes. Single institution experience, Gynecol Oncol (2010), doi:10.1016/j.ygyno.2010.07.032

Page 2

survival rates and specific morbidity correlated to different surgical
procedures, in patients with advanced epithelial ovarian or fallopian
tube cancer (stages IIIC–IV) treated in a referral cancer center.
Materials and methods
After obtaining Institutional Review Board approval, we reviewed
all medical records of patients with stages IIIC–IV epithelial ovarian
and fallopian tube cancer that were managed at our institution
between January 2001 and December 2008. Among these patients we
identified all patients whounderwentmaximalprimarycytoreductive
surgery.
This specific study period encompassed the time when we modified
our surgical approach with a more aggressive one incorporating
extensive upper abdominal procedures such as diaphragm peritonect-
omyand/orresection,splenectomy, distalpancreatectomy, partialliver
resection, cholecystectomy and gastric resection performed to achieve
optimal cytoreduction. Residual tumor was defined as maximal
dimension of single largest cancer nodule at the end of cytoreductive
surgery. In an attempt to make the study cohort as homogeneous as
possible, patients with stage IIIC disease based on nodal metastases
alone were excluded.
Exclusioncriteriaincludedpriorattemptofsurgicalcytoreductionat
another institution, histology consistent with non-epithelial ovarian
malignancies or borderline tumors and neoadjuvant chemotherapy
treatment.
Individual records were reviewed and the following data were
collected: age at surgery, date of surgery, American Society of
Anestesiology(ASA)class,primarysiteofdisease,presenceofperitoneal
carcinomatosis defined as tumor nodules covering the parietal
peritoneum of the pelvis and abdomen with/without involvement of
the mesenteric surface and bowel sierosa, histologic type and tumor
grade,pre-operativeserumCA-125level,locationandsizeofthelargest
tumor mass, the initial ascites volume (if present), all surgical
procedures performed, and size of residual disease after surgery.
We classified the residual disease as follows: none grossly visible,
grossresidual 1–5 mm, 6–10 mm, 11–20 mmand N20 mm. Thesewere
the categories of residual disease used in the statistical analysis. Post-
operativedatasuchasestimatedbloodloss,numberoftransfusedblood
units, operative time, length of hospitalization, peri-operative compli-
cations,typeofadjuvantchemotherapy,numberofcyclesandfollow-up
were also collected. All patients were staged by the International
Federation of Gynecology and Obstetrics (FIGO) system.
All statistical tests were two-sided, and differences were consid-
ered statistically significant at Pb0.05. Progression free survival (PFS)
was defined as the time interval from date of surgery to the date of the
documented first recurrence of disease. If there was no documented
recurrence, PFS was calculated from the date of surgery to the date of
last follow-up or death, whichever occurred first. OS was defined as
the time interval from date of surgery to the date of death or last
follow-up. The Kaplan–Meier method was used to estimate survival
curves and differences in survival were analyzed utilizing the log-rank
test [14]. Cox proportional hazards regression was performed to
identify independent prognostic variables for OS by univariate and
multivariate analyses [15].
Results
A total of 288 patients with advanced epithelial ovarian and
fallopian tube cancer were referredto our institution between January
2001 and December 2008; 259 consecutive patients met inclusion
criteria for the study. All these patients underwent an attempt of
maximal surgical cytoreduction unless there was unresectable disease
as determined by the attending surgeon.
The median age was 58 years (range 22 to 77 years). The final
stage of diseases (ovarian cancer 98% and fallopian tube cancer 2%)
was as follows: 199 patients (76%) had stage IIIC disease, and 60
patients (24%) had stage IV disease.
The distribution according to histological subtype was as follows:
serous — (184/259) 71%, endometrioid — (39/259) 15%, clear cell —
(8/259) 3%, mixed — (26/259) 10% and others — (2/259) 1%. The
majority of patients 76% had grade 3 tumors, while 21% had grade 1–2
tumors. Lymph node dissection (pelvic and/or para-aortic) was
performed in 184/259 (71%) of the patients and 82% of these patients
had positive lymph nodes at final pathology. Ascites was present at
the time of surgery in 73% of the patients with a volume ranging
between 100 cc and 15,000 cc and peritoneal carcinomatosis in 72%,
the majority of the patients presented the largest tumor mass in the
pelvis, with median diameter of 15 cm (3 cm and 40 cm) (Table 1).
All surgical procedures are listed in Table 2. The majority of
patients underwent hysterectomy (92%); rectosigmoid resection was
performed in 57% of the cases as part of their radical pelvic tumor
dissection. Additional bowel resections were performed in 22% of the
patients (Table 2). Diverting colostomy was performed only once
because of low rectal anastomosis while diverting ileostomy in two
cases, at operating surgeon's discretion, and the reason for diversion
wasinthese patientsthepresenceofpre-operativebowelobstruction.
Complete cytoreduction to no gross residual disease was achieved
in 44% of cases, while residual disease was ≤5 mm in 63% (Table 3).
The median EBL was 700 cc and the median operative time was
270 min, 47% of the patients was transferred to the surgical intensive
care unit post-operatively, with a median stay in the intensive care unit
of 1 day. Post-operative total parenteral nutrition (TPN) was adminis-
tered in 46% of the cases (Table 3). This practice has changed with time
Table 1
Patients and tumor characteristics.
Variable No. of patients%
Median age (range)
Primary site disease
Ovary
Fallopian tube
ASAaclass
1–2
3–4
NA
Figo stage
IIIC
IV
Tumor grade
1–2
3
N/Ab
Histologic type
Serous
Endometrioid
Clear cell
Mixed
Others
Peritoneal carcinomatosis
Yes
No
Location of largest mass
Pelvis
Omentum
Upper abdomen
Retroperitoneal node
Other
Size of largest mass (cm)
≤10
N10
Median CA125 (range)c
Median ascites (range)
58 years (22–77)
–
256
3
98
2
119
136
4
46
52
2
199
60
76
24
53
198
8
21
76
3
184
39
8
26
2
71
15
3
10
1
188
71
72
28
130
110
14
1
4
50
42
5
0.4
1.6
98
161
913 U/mL (17–52,817)
1500 cc (100–15,000)
38
62
–
–
aASA, American Society of Anesthesiologists.
bN/A, not available.
cPreoperative value.
2
M. Peiretti et al. / Gynecologic Oncology xxx (2010) xxx–xxx
Please cite this article as: Peiretti M, et al, Role of maximal primary cytoreductive surgery in patients with advanced epithelial ovarian and
tubal cancer: Surgical and oncological outcomes. Single institution experience, Gynecol Oncol (2010), doi:10.1016/j.ygyno.2010.07.032

Page 3

andrecently,sincetheintroductionofearly-feedingprotocol,wealmost
never use TPN unless the patient is significantly malnourished.
Therewasnointra-operativedeath.Peri-operativecomplicationwas
classified as minor (defined as those not requiring any kind of
intervention) and major (Table 3).
ChestX-raywasperformed onpost-operative dayone in all patients
who had undergone peritoneal diaphragmatic stripping and/or resec-
tion and those patients who complained of respiratory symptoms. Mild
pleural effusion, defined as layering fluid occupying less than one third
of a lung field on upright chest radiograph, was observed in 51 patients
of whom 75% had undergone surgery of the diaphragm. None of them
required chest tube placement while it was necessary in 14 (12% of
those who underwent diaphragmatic surgery) subjects who experi-
encedsymptomaticpleuraleffusionpost-operatively.Whileperforming
peritoneal stripping, opening of the diaphragm occurred in 40% of the
cases because of involvement of the diaphragmatic muscle.
Post-operative re-exploration for haemoperitoneum occurred in 7/
259 (3%)cases.Overall, 6 patients (4%)experienceda breakdown ofthe
colorectalanastomosis,whichwasdiagnosedfrompost-operativeday3
to post-operative day 6. Five patients were managed with surgical re-
exploration and intestinal diversion, only one had resolution of bowel
leakage with conservative management. Three fistulae were observed,
one recto-vaginal and two involving the urinary tract. All of them were
managed surgically.
The median length of hospital stay was 9 days. Post-operative
platinum-based chemotherapy was administered in all patients, 92% of
them was able to complete 5 or more cycles of platinum-based
systematic chemotherapy (Table 3).
At univariate analysis, factors significantly associated with de-
creased PFS included: age greater than median (N60 years), stage IV,
presence of ascites N1000 cc, presence of diffuse peritoneal carcino-
matosis and macroscopic residual disease (Table 4).
This was confirmed also at multivariate analysis with age greater
than 60 years (P=0.025), stage IV vs IIIC (P=0.037) and any residual
disease (P=0.032) having an independent association with worse
PFS.
In order to analyze more specifically the correlation between the
percentage of the optimal cytoreduction (i.e. residual tumor=≤1 cm)
anddifferentclinicalandpathologicalvariables,weperformedaPearson
χ2analysis and logistic regression model. At both the univariate and
multivariateanalysestheamountofascites(b1000 mL)andtheabsence
of carcinomatosis were significantly associated with optimal residual
disease. Whereas age, ASA class and CA125 greater than 750 U/mL
achieved a statistical significance at univariate analysis only.
After a median follow-up of 29.8 months, PFS and overall median
survival (OS) were 19.9 and 57.6 months respectively as shown in
Figs. 1(A–B).
Fig. 2A depicts the progression free survival curves based on the
different residual disease diameters at the end of surgery. We
observed a statistically significant difference (P=0.035) in PFS
between the group with no macroscopic residual disease (median of
25.9 months) and the other patients with any other gross residual
disease.
The median overall survival in relation to the 5 residual disease
categorieswas:notreachedforno grossresidual disease;61.3 months
for gross 1–5 mm; 42.4 months for 6–10 mm; 35.3 months for 10–
20 mm; and 42.6 months for N20 mm. Kaplan–Meier survival curves
comparing among the 5 residual disease categories revealed 2 distinct
groups: these 2 groups were: (1) no gross residual and gross ≤5 mm;
and (2) gross residual N5 mm. There was a statistically significant
difference toward improved survival in patients left with residual
disease ≤5 mm compared with those belonging to the other groups
(P=0.0048). However when we incorporated the residual tumor
group 1–5 mm with 6–10 mm one, comparing the sub-categories “no
gross residual” vs “gross 1–10 mm” there was a statistical difference
between these two groups of patients (P=0.001) (Figs. 2B–C).
Table 2
Surgical procedures.
ProcedureNo. of patients%
Hysterectomy+USO/BSO
USO/BSO
Intestinal resection
Rectosigmoid resection
Right hemicolectomy
Left hemicolectomy
Transverse colectomy
Ileo-cecal resection
Small bowel resection
Omentectomy
Appendectomy
Pelvic and/or para-aortic lymph node dissection
Diaphragm stripping/resection
Cholecystectomy
Splenectomy
Partial liver resection
Distal pancreasectomy
Gastric resection
240
19
92
8
14857
3
3
3
6
5
9
8
8
17
15
259
111
184
113
100
43
71
44
52
33
11
4
2
13
4
2
1
USO, unilateral salpingo-oophorectomy; BSO, bilateral salpino-oophorectomy.
Table 3
Surgical outcomes and peri-operative morbidity.
VariableNo. of patients%
Residual disease (mm)
None grossly visible
1–5
6–10
11–20
N20
Median length of surgery (range)
Median estimated blood loss (range)
Intra-operative units blood transfused
None
1–2
3–4
N5
Post-operative units blood transfused
None
1–2
3–4
N5
Length of hospitalization (days)
≤4
5–7
8–10
N10
Length of ICUa(days)
None
1–2
3–4
N5
Total parenteral nutrition (TPN)
Yes
No
Minor complication
Wound infection
Post-operative ileus
Mild pleural effusion
Major complication
Anastomotic Leak
Haemoperitoneumb
Pleural effusionc
Deep vein thrombosis/pulmonary embolism
Fistulas
Systematic chemotherapy platinum-based
completed ≥5 cycles
115
50
33
18
43
270 min (70–480)
700 cc (50–6000)
44
19
13
7
17
–
–
147
67
31
14
56
26
12
5
122
113
23
4
47
43
8
2
6
73
96
84
2
28
37
33
147
96
8
7
57
37
3
3
119
140
46
54
15
8
51
6
3
19
6
7
14
6
3
238
4
3
5
2.3
1
92
aIntensive Unit Care.
bAll patients required a re-intervention.
cAll patients required thoracic drain post-operatively.
3
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Please cite this article as: Peiretti M, et al, Role of maximal primary cytoreductive surgery in patients with advanced epithelial ovarian and
tubal cancer: Surgical and oncological outcomes. Single institution experience, Gynecol Oncol (2010), doi:10.1016/j.ygyno.2010.07.032

Page 4

Discussion
Historically, Meigs earlier and later Giffiths, suggested an inverse
relationship between residual tumor diameter and survival and the
latter concluded that surgery provided optimum benefits when all
gross tumor was safely excised [16,17]. This initial observation has
been confirmed by multiple subsequent studies and it became the
current treatment paradigm for patients with advanced ovarian
cancer. Bristow et al. evaluated 81 studies involving 6885 patients and
demonstrated that each 10% increase in maximal cytoreduction was
associated with a 5.5% increase in median survival time [18].
Several authors showed that the use of extensive upper abdominal
surgical procedures significantly increased the optimal primary
cytoreduction rate with a significant impact on the overall survival
[13,19,20].
Chi et al. in a recent paper [21] analyzed the influence of upper
abdomen surgery on progression free survival and overall survival in
patients with stages IIIC and IV ovarian, tubal, and peritoneal cancer.
The authors compared 2 different groups: Group 1 (control group)
consisted in 168 patients who underwent primarycytoreduction from
1/96 to 12/99, Group 2 (study group) in 210 patients who underwent
primary surgery including extensive upper abdominal procedures.
Group 2 showed a significantly higher optimal cytoreduction rate
(80% vs 46%; P=b0.001), moreover the percentage of patients left
with no grossly visible or palpable disease also increased from 11% in
Group 1 to 27% in Group 2. Five-year PFS and OS rates for Group 2 vs
Group 1 patients were 31% vs 14% and 47% vs 35%, respectively.
Similarly our surgical approach to patients with the widespread of
disease to the upper abdomen has changed since 2001 with
progressive implementation of extensive upper abdominal proce-
dures and 44% of patients left with no grossly visible/palpable disease
at the end of the primary surgery. Our analysis confirms that the
incorporation of extensive upper abdominal procedures into the
operative strategy can substantially obtain a higher rate of primary
optimal cytoreduction without significantly increasing peri-operative
morbidity and mortality. As confirmed by the fact that residual
disease ≤1 cm was 76% during the study period while it was only
48% between 1996 and 2000 (data not published). Therefore the
implementation of extensive upper abdominal procedures has
represented in our Institute the key factor in the achievement of
optimal residual disease and it was possible as a result of a
multidisciplinary approach to the treatment of ovarian cancer patients.
In Europe optimal surgical care is achieved only for a minority of
patients with advanced ovarian cancer due to the lack of a “formal”
trainingin thesurgical techniques frequently used in debulkingovarian
cancer. In fact the proportion of patients operated on by gynaecologists
with extensive surgical training varies, in Europe, between 0% and 95%.
From the data of European literature the percentage of residual disease
≤1 cm during primary debulking ranged between 37.8% and 81% [22].
Table 4
Progression free survival univariate risk estimates.
Factor No. of
patients
Relapsed no.
(%)
Hazard ratio
(95% CI)
P
value
Age
≤60
N60
ASA
1–2
3–4
Stage
IIIC
IV
Grade
1–2
3
Histology
Serous
Endometriod
Clear cell
Mixed
Ascites
≤1000 cc
N1000 cc
CA125
≤750 U/mL
N750 U/mL
Size of largest mass
≤10 CM
N10 CM
Diffuse peritoneal
carcinomatosis
No
Yes
Location of largest mass
Pelvis
Omentum
Upper abdomen
Nodes
Other
Bowel resection
No
Yes
Nodes
Negative
Positive
Residual disease
None grossly visible
1–5 mm
6–10 mm
11–20 mm
N20 mm
120
81
70 (58)
60 (74)
1 (ref)
1.62 (1.15,2.30)
0.006
94
103
52 (55)
75 (73)
1 (ref)
1.28 (0.89,1.83)0.178
158
43
97 (61)
33 (77)
1 (ref)
1.54 (1.04, 2.29)
0.032
40
154
28 (70)
95 (62)
1 (ref)
0.97 (0.63,1.47)0.965
141
33
87 (62)
22 (67)
4 (67)
16 (80)
1 (ref)
1.11 (0.67,1.78)
1.99 (0.73,5.45)
1.66 (0.97,2.84)
0.644
0.178
0.063
6
20
95
106
56 (59)
74 (70)
1 (ref)
1.52 (1.08,2.16)
0.018
90
111
54 (60)
76 (68)
1 (ref)
1.32 (0.93,1.88) 0.114
81
120
45 (56)
85 (71)
1 (ref)
1.35 (0.94,1.93) 0.107
48
154
26 (54)
114 (74)
1 (ref)
2.14 (1.31,3.51)
0.002
108
79
10
–
63 (58)
57 (72)
7 (70)
–
3 (75)
1 (ref)
1.39 (0.97,1.99)
1.39 (0.64,3.04)
na
na
0.073
0.411
4
84
117
51 (61)
79 (67)
1 (ref)
1.18 (0.83, 1.69)0.349
30
119
15 (50)
78 (66)
1 (ref)
1.72 (0.98,2.99)0.056
102
37
27
11
24
56 (55)
25 (68)
24 (89)
10 (91)
15 (62)
1 (ref)
1.55 (0.97,2.48)
1.85 (1.15,3.00)
2.12 (1.08,4.18)
1.86 (1.03,2.59)
0.070
0.012
0.029
0.019
Significant P values are capturated in bold font.
Fig. 1. Progression free survival (A) — overall survival (B).
4
M. Peiretti et al. / Gynecologic Oncology xxx (2010) xxx–xxx
Please cite this article as: Peiretti M, et al, Role of maximal primary cytoreductive surgery in patients with advanced epithelial ovarian and
tubal cancer: Surgical and oncological outcomes. Single institution experience, Gynecol Oncol (2010), doi:10.1016/j.ygyno.2010.07.032

Page 5

Therefore to overcome this limitation, while waiting for the implemen-
tation of a formal gynaecologic oncology training, the multidisciplinary
approach in high-volume hospitals seems to be the adequate choice.
In the present study at multivariate analysis an independent
association of PFS was observed with no residual disease. This
association seems more important since PFS is more influenced by
maximal cytoreductive effort than OS where other factors may have a
significant impact on the natural history of the disease. Survival data
calculatedinthepresentstudyfurthersupportthereportedobservation
that removal of all macroscopic disease has a statistically significant
survival benefit: patients with no gross residual disease had a
significantly longer PFS and OS compared to the other category groups,
in fact any left visible disease determinates a reduction survival,
therefore nogrossresidual shouldseemsto representtheabsolutegoal.
Several authors raised the criticism that the improved survival of
those patients undergoing maximal cytoredution is determinated by a
“good tumor biology”, as opposed to good surgical technique [23,24].
However, tumor biology is difficult to quantify in a clinically useful
manner and while the controversy remains as to whether it is tumor
biology or surgical skill that enables a patient to undergo optimal
cytoreduction, there is little debate that suboptimal cytoreduction
offers no survival benefit.
Moreover Eisenkop et al. have demonstrated that there are no
specific intra-abdominal tumor locations or surgical procedures that
correlate with inherent tumor biologic aggressiveness [12].
A major limitation of maximal cytoreductive surgery for ovarian
cancer is that a no residual disease must be achieved at the end of
surgery to achieve a significant impact on survival, in fact, based on
published data, if this goal is not reached, surgery does not confer any
appreciable survival benefit to patients and actually exposes them to
long operative times, significant blood loss, transfusion rate, and
therefore higher morbidity. The logical alternative claimed by suppor-
ters of “neoadjuvant” chemotherapy followed by interval debulking
surgery consists in the attempt to reduce the bulk of tumor using
chemotherapy to render the disease more amenable to subsequent
surgical resection.
Recently, Vergote [25] presented the results of a multicenter
European randomized clinical trial (EORTC 55791) on 668 stages IIIC–
IV epithelial ovarian cancer patients: 329 were randomized to
undergo primary debulking surgery (PDS) and 339 to receive
neoadjuvant chemotherapy followed by interval debulking surgery
(IDS). Optimal cytoreduction (defined by the Authors as residual
disease ≤1 cm) was achieved in 46% of the cases in the first group and
in 82% of the IDS group. Comparable percentages of patients received
6 cycles of chemotherapy (83% and 86% for PDS and IDS). Median
follow-up was 4.8 years. Progression free survival was equivalent in
both groups (12 months) and median survival times were 30 months
for patients who underwent primary surgery vs 31 months for
patients treated with neoadjuvant chemotherapy followed by IDS.
During the present study performance status or other medical
conditions that did not allow general anesthesia and an extensive
surgery were the only criteria to abort surgery and to treat patients
with neoadjuvant chemotherapy. Moreover we looked at the
correlation between different variables and the percentage of optimal
debulking at the end of primary cytoreductive surgery. Patients with
ascites N1000 mL and with peritoneal carcinomatosis were less likely
tobe optimally debulkedsuggesting thatthese factorscould represent
pre-operative selecting criteria for patients who might benefit from
adjuvant chemotherapy approach. The appropriate means to obtain
an adequate pre-operative evaluation of such parameters remain to
be established. Accordingly, Aletti et al. showed that patients with
significant dissemination of disease and poor performance status
were less likely to be optimally debulked [26].
The strengths of this study lie in the large number of patients with
comparable initial disease volumes who were treated at a single
institution in a uniform fashion.
The weaknesses lie in its retrospective nature, lack of homogeneity
regarding post-operative management after primary surgery, the
modest follow-up interval, and thefactthat extensiveupperabdominal
procedureswere progressively incorporatedin oursurgical approach in
the first 2 years of the study period (2001–2002).
In conclusion our study seems to confirm that a more extensive
surgical approach is associated with prolonged disease-free interval
and improved survival in patients with stages IIIC–IV epithelial
ovarian and fallopian tube cancer. The age greater than 60 years, stage
IV vs IIIC and any residual tumor volume other than no residual
disease were independently associated with worse PFS.
The survival curves suggest that all patients with no residual
tumor had the best prognosis and in view of these results we believe
that the gold standard of primary surgery should be considered as
Fig. 2. (A) Progression free survival and overall survival (B–C) by residual tumor.
5
M. Peiretti et al. / Gynecologic Oncology xxx (2010) xxx–xxx
Please cite this article as: Peiretti M, et al, Role of maximal primary cytoreductive surgery in patients with advanced epithelial ovarian and
tubal cancer: Surgical and oncological outcomes. Single institution experience, Gynecol Oncol (2010), doi:10.1016/j.ygyno.2010.07.032

Page 6

leaving no macroscopic tumor. In order to achieve such a goal a
multidisciplinary approach to the treatment of advanced ovarian
cancer should to be recommended.
However in view of these findings gynaecologic oncologists must
select carefully patients with advanced ovarian cancer and if complete
gross resection is not feasible other therapeutic options must be
considered.Futureresearchshouldbedirectedatrefiningthisapproach
to more effectively select patients by likelihood of optimal resection,
taking into account underlying health status and tumor dissemination.
Conflict of interest statement
The authors have no conflicts of interest to declare.
Acknowledgments
We would like to give our acknowledgments to Doctors Rosanna
Cassano and Sara Boveri for their very important contribution to
collect and analyze all the presented data.
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Please cite this article as: Peiretti M, et al, Role of maximal primary cytoreductive surgery in patients with advanced epithelial ovarian and
tubal cancer: Surgical and oncological outcomes. Single institution experience, Gynecol Oncol (2010), doi:10.1016/j.ygyno.2010.07.032