ARTICLE
Auteur(s) : N
Carrabin1, F Mithieux1, P
Meeus1, O Trédan2, J-P Guastalla2,
T Bachelot2, SI Labidi2, I
Treilleux3, M Rivoire1, I
Ray-Coquard2
1Centre Léon-Bérard, Department of Surgical
Oncology, 28, rue Laennec, 69008 Lyon, France
2Centre Léon-Bérard, Department of Medical
Oncology
3Centre Léon-Bérard, Department
of Cytopathology
Article reçu le 1 Novembre 2009, accepté le 8 Février 2010
Introduction
Epithelial ovarian cancer is the second most common gynecologic
malignancy in France [1] and in Europe. It is also the most lethal
of all gynecologic malignancies, with a high mortality to incidence
ratio [2]. Most patients present with advanced disease at the time
of diagnosis, whereas dissemination of the cancer is often limited
to the peritoneal cavity [3] for much of its natural history.
Complete surgical cytoreduction provides a substantial survival
benefit for patients with locoregional disease, both at primary
surgery [4-6] and, as reported more recently, at recurrence [7].
However, even after complete surgical cytoreduction, the majority
of patients with advanced epithelial ovarian cancer ultimately
experience tumor recurrence [8]. Many adjuvant treatments with
intravenous cytotoxic agents have proved effective in ovarian
cancer, particularly platinum compounds and taxanes [9].
On the basis of these observations, new aggressive procedures
have been developed, and surgical efforts have been made to improve
survival rates. Considering that intraperitoneally administered
agents are associated with significantly increased drug exposure in
the peritoneal cavity as compared to systemic agents [10], and that
hyperthermia is both tumoricidal in itself [11] and likely to
increase the cytotoxicity of platinum [12], it was proposed to
combine hyperthermic intraperitoneal chemotherapy (HIPEC) and
cytoreductive surgery (CRS) [13], as previously done for many other
tumors spreading within the peritoneal cavity, such as colorectal
or gastric tumors [14-16]. Ovarian carcinoma that develops slowly
in the peritoneal cavity and involves only the peritoneum and
adjacent intra-abdominal organs appeared ideally suited for
locoregional therapy. Only few studies, with relatively small
numbers of patients, have tested CRS and HIPEC in this disease
[17-21], and they usually report the use of adjuvant chemotherapy
after CRS + HIPEC.
To date, there is no scientific evidence to support the use of
HIPEC as a standard therapy in ovarian cancer. The objectives of
our study were to evaluate the feasibility and long-term results of
HIPEC without adjuvant chemotherapy in stage IIIC ovarian cancer
patients.
Materials and methods
This is an observational study designed in 2003 and is based
on data from the medical records of consecutive patients with
ovarian cancer.
Patient selection
Inclusion criteria were FIGO (International Federation of
Gynecology and Obstetrics) stage IIIC ovarian cancer in relapse,
FIGO stage IIIC ovarian cancer with suboptimal cytoreduction
following primary surgery and platinum-taxane based chemotherapy
(three to nine cycles) and with evidence of persistent peritoneal
involvement, WHO performance status ≤ 2, age ≤ 70 years, and
fully informed consent to undergo HIPEC.
Exclusion criteria were cancer histology other than serous or
poorly differentiated carcinoma, evidence of nonresectable disease
at preoperative evaluation, and anesthesiologic risk
contraindicating HIPEC.
Preoperative evaluation
Preoperative assessment identified patients with potentially
unresectable disease. Preoperative workup included clinical
examination, thoracic, and abdominal CT scan and evaluation of
serum Ca 125 level. Complete information about the procedure
was given to the patients, and each decision of HIPEC was discussed
and approved at a multidisciplinary consultation meeting.
Treatment plan and drug administration
Intravenous chemotherapy
HIPEC was performed in two clinical situations: ovarian cancer with
nonoptimal cytoreduction at primary surgery (completion of initial
treatment) and ovarian cancer in relapse.
All patients with nonoptimal cytoreduction at primary surgery
received adjuvant intravenous chemotherapy after the first surgery,
and CRS + HIPEC were performed next in case of evidence of
persistent peritoneal involvement as a completion of initial
treatment.
Patients with recurrence and with evidence of widespread disease
on preoperative evaluation received intravenous chemotherapy before
HIPEC to facilitate surgical resection. When preoperative
evaluation indicated complete cytoreduction, no intravenous
chemotherapy was given.
No patient received adjuvant chemotherapy after HIPEC.
Surgical procedure
Careful abdominal exploration was performed through a midline
incision from xiphoid to pubis, under general anesthesia.
The goal of the surgical procedure was the removal of all
macroscopically visible tumor nodules from the visceral or parietal
peritoneum. After exploration of the abdominal cavity, the
peritoneal cancer index (PCI) was calculated as described by
Sugarbaker [22], and the feasibility of complete CRS was evaluated.
When the procedure was considered unfeasible, the HIPEC option was
rejected at that stage. When necessary, total or partial resection
of an involved organ was performed. Intestinal anastomoses were
performed before the HIPEC procedure.
Cytoreduction scoring
The completeness of cytoreduction (CC) was scored as proposed
during the fifth international consensus meeting on peritoneal
surface malignancies treatment [23], with CC0 corresponding to
no residual disease, CC1 to residual nodules less than
2.5 mm in diameter, CC2 to residual nodules between
2.5 mm and 2.5 cm, and CC3 to residual nodules
greater than 2.5 cm.
HIPEC procedure
HIPEC was performed as an open procedure at the end of surgery
using the coliseum technique [22]. After suspension of the anterior
abdominal wall using a Bookwalter retractor system (Aesculap inc.,
Le Locle, Switzerland), two inflow drains and three outflow
drains were inserted into the abdominal cavity. Six temperature
probes were placed in different parts of the abdomen (right and
left subdiaphragmatic areas, mesenteric roots, Douglas pouch,
inflow, and outflow drains) to allow good control of the
temperature during HIPEC. The abdominal cavity was filled with a 5%
glucose solution heated at 41-43 °C using a heat exchanger,
two roller pumps, and a heater/cooler unit (Performer LRT, RanD
S.r.l. Medolla, Italy).
HIPEC consisted of oxaliplatin (460 mg/m2) for
30 min. The temperature recorded by each probe was monitored
every 5 min during the procedure and an average of all
measurements was calculated. Total operative duration, blood loss,
and need for transfusion were recorded at the end of surgery.
Post-HIPEC management
All patients were admitted postoperatively to an intensive care
unit for at least 24 h, and then transferred to the general
surgery unit.
Toxicity and postoperative complications were evaluated using
the CTCAE scale, version 3.0. [24]. All documented grade
3-5 side effects were recorded, and relation with CRS or HIPEC
was reported when possible. Hematological toxicity was evaluated
every 48 h during hospital stay by complete blood count and
basic metabolic panel tests.
Hospital discharge, grade 3-5 complications, and
reoperation were documented in the patients’ medical records.
Follow-up, evaluation of response, and survival
Routine follow-up was performed every 4 months during the
first 2 years, and then every 6 months thereafter. It
included clinical examination, Ca 125 measurement, and a CT
scan of the thorax and abdomen at every follow-up visit.
All patients undergoing ostomy surgery were reoperated for
laparotomy closure within 6 months. A surgical
exploration including systematic peritoneal biopsy was performed at
that time.
Recurrence and progression were evaluated using the Response
Evaluation Criteria in Solid Tumors (RECIST) and Rustin’s criteria.
[25, 26] Recurrent carcinomatosis was diagnosed when patients
presented clinical evidence of peritoneal carcinomatosis (ascites,
digestive occlusion, and so on) or when peritoneal carcinomatosis
was visible on a CT scan.
When recurrence was diagnosed, an adapted treatment was given as
decided by the multidisciplinary consultation meeting (number of
chemotherapy lines, radiotherapy, and iterative surgical
resection). The time and type of recurrence, the nature of
treatment, and date of death were recorded.
Median follow-up was calculated from the date of HIPEC to the
date of last visit or date of death.
Statistical analysis
Survival rates and time to progression were analyzed by the
Kaplan-Meier method using SAS® version 9.1. Overall survival (OS),
disease-free survival (DFS) and carcinomatosis-free survival (CFS)
were calculated from the date of HIPEC to, respectively, the date
of death (OS), the date of relapse (DFS), and the date of
carcinomatosis recurrence (CFS) or, in the absence of any event, to
the date of last follow-up. Survival estimates were calculated
using the Kaplan-Meier method [27]. Differences in survival
estimates were assessed by the log-rank test [28]. Median follow-up
was estimated by the reversed Kaplan-Meier method.
Results
Patient characteristics
Twenty-two patients were included between September 2003 and
September 2007. The median age was 49 years (range 29-63).
Patient characteristics are summarized in table
1.
HIPEC was performed for completion of initial treatment in
12 patients with stable disease after nonoptimal CRS followed
by platinum-taxane based chemotherapy and for the treatment of
recurrent disease in 10 patients (6 patients in first
relapse, 2 in second relapse and 2 in third relapse).
Nine patients with recurrent disease were platinum-sensitive
(disease-free interval >6 months) and one was
platinum-refractory (disease-free interval <6 months). All
patients were previously treated with chemotherapy (1 to
3 lines).
Table 1 Patient characteristics.
|
Patient
|
Age (years)
|
Histology
|
HIPEC indication
|
Disease stage
|
PCI
|
HIPEC performed
|
|
1
|
49
|
SA
|
CIT
|
SD
|
7
|
yes
|
|
2
|
29
|
SA
|
CIT
|
SD
|
9
|
yes
|
|
3
|
49
|
SA
|
CIT
|
SD
|
3
|
yes
|
|
4
|
48
|
PDA
|
CIT
|
SD
|
3
|
yes
|
|
5
|
49
|
SA
|
CIT
|
SD
|
5
|
yes
|
|
6
|
48
|
SA
|
CIT
|
SD
|
1
|
yes
|
|
7
|
44
|
SA
|
CIT
|
SD
|
6
|
yes
|
|
8
|
53
|
SA
|
CIT
|
SD
|
13
|
yes
|
|
9
|
42
|
SA
|
CIT
|
SD
|
4
|
yes
|
|
10
|
52
|
SA
|
CIT
|
SD
|
9
|
yes
|
|
11
|
48
|
SA
|
First relapse
|
PS
|
14
|
yes
|
|
12
|
50
|
SA
|
Second relapse
|
PS
|
1
|
yes
|
|
13
|
46
|
PDA
|
First relapse
|
PS
|
6
|
yes
|
|
14
|
61
|
SA
|
First relapse
|
Platinum refractory
|
18
|
yes
|
|
15
|
49
|
SA
|
Third relapse
|
PS
|
9
|
yes
|
|
16
|
63
|
PDA
|
First relapse
|
PS
|
3
|
yes
|
|
17
|
63
|
SA
|
First relapse
|
PS
|
6
|
yes
|
|
18
|
42
|
SA
|
Third relapse
|
PS
|
4
|
yes
|
|
19
|
60
|
SA
|
First relapse
|
PS
|
15*
|
no
|
|
20
|
41
|
SA
|
CIT
|
SD
|
0**
|
no
|
|
21
|
48
|
SA
|
CIT
|
SD
|
19*
|
no
|
|
22
|
44
|
SA
|
Second relapse
|
PS
|
29*
|
no
|
HIPEC procedures
Four of the 22 patients (18%) did not receive HIPEC because of
operative findings. HIPEC had then been planned for completion of
initial treatment in two cases and for the treatment of recurrent
disease in two cases. In three patients, lesions were considered
not completely removable, and in one patient surgical exploration
revealed no macroscopic or microscopic evidence of lesion.
Table 2 shows the
characteristics of the HIPEC procedure in the 18 patients
treated for completion of initial treatment or for recurrent
disease: PCI, CC rate, proportion of patients undergoing organ
resection and stoma, HIPEC temperature, length of surgery,
estimated blood loss, and time to hospital discharge. Median PCI
score was 6 (range 1-18). CC score after CRS was 0 or
1 for all patients. Respectively, 70% and 75% of the patients
undergoing HIPEC for completion of initial treatment or for
recurrent disease had bowel resection, and 30% and 75% required a
stoma. The median total length of surgery was 395 min (range
145-600) and the median blood loss was 250 ml (range 50-1500).
Five patients (28%) were transfused with red blood cells during the
surgical procedure.
Table 2 Characteristics in patients undergoing CRS +
HIPEC for completion of initial treatment or for recurrent
disease.
|
PCI at surgical exploration
|
CC score
|
Bowels resection
|
Ostomy surgery
|
Splenectomy
|
HIPEC average temperature (°C)
|
Length of surgery (min)
|
Blood loss (ml)
|
Hospital discharge(days)
|
|
Median (range)
|
Number of patients (%)
|
Median [range]
|
|
Completion of initial treatment n = 10
|
5.5 (1-13)
|
CC0 = 8 CC1 = 2
|
7 (70%)
|
3 (30%)
|
4 (40%)
|
42 [41.7-44]
|
382 [180-480]
|
200 [50-700]
|
18 [13-29]
|
|
Recurrent disease n = 8
|
6 (1-18)
|
CC0 = 8 CC1 = 0
|
6 (75%)
|
6 (75%)
|
4 (50%)
|
42 [41.5-43]
|
480 [145-600]
|
450 [50-1500]
|
22.5 [13-65]
|
|
Total n = 18
|
6 (1-18)
|
CC0 = 16 CC1 = 2
|
13 (72%)
|
9 (50%)
|
8 (44%)
|
42 [41.5-44]
|
395 [145-600]
|
250 [50-1500]
|
21 [13-65]
|
Toxicity
Ten patients (55.6%) had at least one grade 3-4 toxicity
(3 of them had two), including 3 (16.7%) patients
requiring reoperation. No death occurred in the first postoperative
month. Table 3 shows the different
grade 3-4 complications observed. No grade
3-4 leucopoenia, no grade 3-4 glomerular filtration
impairment or creatinine elevation was observed.
Table 3 Complications observed (according to the CTCAE
v3.0 classification [24]).
|
Category
|
Adverse event
|
Severity grade
|
Number of cases n (%)
|
Patient number
|
|
Blood/bone marrow
|
Low hemoglobin
|
3
|
2 (11)
|
11, 6
|
|
Gastrointestinal
|
Anastomotic leak (rectum)
|
3
|
1 (5)
|
16
|
|
Fistula (pancreas)
|
4
|
1 (5)
|
14
|
|
Hemorrhage/bleeding
|
Hematoma (liver)
|
4
|
1 (5)
|
8
|
|
Hematoma (retroperitoneal)
|
3
|
1 (5)
|
10
|
|
Infection
|
Sepsis with normal absolute neutrophil count
|
3
|
1 (5)
|
5
|
|
Metabolic/laboratory findings
|
Hyponatremia
|
3
|
1 (5)
|
1
|
|
Pulmonary/upper respiratory
|
Pleural effusion
|
3
|
3 (17)
|
14, 10, 18
|
|
Pneumonitis
|
4
|
1 (5)
|
9
|
|
Vascular
|
Phlebitis
|
3
|
1 (5)
|
8
|
Survival
Median patient follow-up was 38 months (CI 95%, 23.8-39.2).
Survival analysis did not include patients in whom HIPEC was not
performed because of operative findings. Overall survival, DFS and
CFS are shown in figure
1. The median OS was not reached, but OS rates at
2 and 3 years were, respectively, 92% (CI 95%,
67-99) and 83% (CI 95%, 54-95). The median CFS was 16.2 months
(CI 95%, 9.3-22.7), and the median DFS was 11.3 months (CI
95%, 9.3-17.6). Figure
2 shows the DFS curves of patients treated for completion
of initial treatment or for recurrent disease, with median
durations of 16.9 months (CI 95%, 10.2-23.2) and
10 months (CI 95%, 4.5-11.3). Patients receiving HIPEC for
recurrent disease relapsed significantly earlier than patients
receiving HIPEC for completion of initial treatment (p = 0.03).
Fifteen patients relapsed after HIPEC. Four patients developed
distant metastases (abdominal skin n = 2 and distant lymph
node n = 2), eight patients showed a locoregional relapse
(carcinomatosis n = 5, locoregional lymph node n = 1, and
carcinomatosis and locoregional lymph node n = 2), and three had
both locoregional relapse and distant lymph node involvement.
All the patients who relapsed received chemotherapy, with a
median of two lines (range 1-5). Two patients received
radiotherapy, and six had iterative surgery.
Discussion
No randomized studies testing HIPEC in patients with ovarian cancer
have been published to date because of poor patient accrual, and
phase II studies often mix different disease stages, different
HIPEC drugs, and different adjuvant strategies [29, 30].
Descriptive studies with strictly described patients, long
follow-up, and precise outcome are needed. With a follow-up of
38 months, our study provides useful information about HIPEC
in two clinical situations: completion of initial treatment after
suboptimal surgery followed by chemotherapy and at the time of
disease recurrence. The drug used for HIPEC was oxaliplatin.
Single-agent oxaliplatin has demonstrated efficacy [31], associated
with a favorable toxicity profile [10], in platinum-pretreated
ovarian cancer patients.
Numerous phase I studies have reported on the feasibility of
HIPEC in ovarian cancer [18, 32]. Our study confirms these earlier
reports with no mortality but with an important 55.6% rate of grade
3-4 toxicities. In this study, we only recorded major toxic
events (grade 3-5) and not minor toxicities. We used the CTCAE
version 3.0 grading system to record toxicity in our patients,
as it was the classification system adopted by an international
panel of experts for assessing complications related to HIPEC and
CRS [24]. Up to now, only few studies have used this classification
system to assess toxicity [17, 18, 32, 33], and comparison between
the different toxicity grading systems is difficult [32]. In
addition, only few other studies have reported on the use of
oxaliplatin for HIPEC in ovarian cancer. A prospective study
by Fagotti et al. [33] using the same grading system has found
28% of major complications, which is much lower than the rate
reported here. In their study, HIPEC was associated with no grade
3-4 metabolic complication, whereas we observed one patient
with grade 3 hyponatremia, and grade 3-4 hemorrhagic
complications occurred in two patients after treatment with an
isotonic solution of oxaliplatin 460 mg/m2. Elias
et al. have reported a higher rate of hemorrhagic
complications with hypotonic intraperitoneal oxaliplatin compared
to the administration of an isotonic solution [34]. In our study,
oxaliplatin 460 mg/m2 was associated to a
relatively high rate of grade 3-4 toxicities (55%) and is
unreasonable to propose this treatment without scientific evidence
of its clinical benefit. This is the reason why randomized phase
III studies are urgently needed.
The cytoreduction preceding HIPEC is a time-consuming procedure,
with a median duration of 395 min in our experience. For
efficient operating theatre organization, treatment planning should
be done carefully, based on clinical and radiological findings, to
avoid wasting time on cancelled interventions. The objective of CRS
should be a residual lesion size of 2.5 mm or less
(CC0 or CC1 cytoreduction) prior to HIPEC, according to
the expert consensus reached during the fifth international
consensus meeting on peritoneal surface malignancies treatment
[29]. Even though no consensus has yet been reached regarding the
indication for HIPEC in case of suboptimal CRS [35], we chose not
to use it in patients with suboptimal cytoreduction. We based our
decision on evidences that the diffusion of intraperitoneally
administered drugs into peritoneal tumors reaches a maximum of
2.5-5 mm, even when treatment is associated with hyperthermia
[36-38], and that the benefits of HIPEC after suboptimal
cytoreduction are limited in terms of outcome [17, 18, 39-41].
However, both peritoneal carcinomatosis and CC remain difficult to
ascertain preoperatively, even with modern imaging techniques [42,
43]. In our study, minimal preoperative assessment with a CT scan,
serum CA 125 measurement, and complete physical examination
failed to predict operative findings in 4 of the
22 patients (18%). Other authors advise systematic
laparoscopic evaluation of peritoneal carcinomatosis before
planning surgery for HIPEC to avoid unnecessary laparotomy [44]. We
now perform systematic FDG-Pet/CT (Fluorodeoxyglucose-Positron
emission tomography with computed tomography) imaging for the
preoperative staging.
With a median follow-up of 38 months, the median OS was not
reached in our study. The 3-year OS rate was 83%. A literature
analysis shows similar values with median OS durations ranging from
24 months to 64 months [18-20] and 2-year survival rates
between 55% and 60% [17, 45]. However, due to the large
heterogeneity of the populations studied, comparison with our
results is difficult.
In our study, the median DFS of patients undergoing HIPEC for
recurrent disease was 10 months. Other studies using HIPEC at
time of recurrence have reported post-HIPEC DFS durations between
10 and 40 months [17, 18, 21, 33, 39]. In patients
undergoing HIPEC for completion of initial treatment (evidence of
persistent disease after first suboptimal surgery followed by
chemotherapy), the median DFS was 16.9 months in our study
versus 40.6 months in the study reported by Ryu et al. of
HIPEC for second look or interval debulking in patients with
residual disease less than 1 cm [19]. However, it is not known
how many patients were in each group. Indeed, survival is expected
to be different whether HIPEC is performed at the time of second
look surgery for consolidation after complete prior cytoreduction
and adjuvant chemotherapy or used for interval surgery after
sub-optimal prior surgery and chemotherapy.
As shown in table 4, most authors are
inclined to give adjuvant chemotherapy after HIPEC, even if its
tolerance is not known. Fagotti et al. [33], who have used
oxaliplatin HIPEC in association with adjuvant chemotherapy in a
population similar to our patient population (recurrent disease
surgery in platinum-sensitive patients), have found a median DFS of
10 months. We did not use adjuvant chemotherapy after HIPEC,
but we also observed a median DFS of 10 months in patients
with recurrent disease. No scientific evidence supports the benefit
of systemic chemotherapy after HIPEC. Furthermore, the effects of
systemic chemotherapy may interfere with those of HIPEC after
complete cytoreduction, and the survival reported in phase II
studies may be associated to either HIPEC or adjuvant
chemotherapy.
In a recent meta analysis, Bristow et al. [7] have
identified only two parameters associated with OS improvement in
patients with recurrent ovarian cancer: year of treatment and
complete CRS at the time of recurrence. Up to now, no compelling
evidence has emerged about the use of HIPEC in ovarian cancer due
to the lack of phase III trials, but results of observational and
retrospective comparative studies are encouraging. As in our study,
HIPEC is always associated with a maximal surgical effort toward
complete cytoreduction, thus making it difficult to differentiate
between the effects of peritoneal chemotherapy and those of CRS.
The apparent survival benefit reported in observational studies of
HIPEC could also be due to the maximal cytoreductive effort made
before the intraperitoneal hyperthermic administration of the
cytotoxic agent. Furthermore, the intraperitoneal hyperthermic
administration of cytotoxic agents after CRS is associated with
increased toxicity as compared with maximal CRS alone [32, 46]. In
addition, numerous targeted cancer therapies based on the new
understanding of molecular pathways within normal and malignant
cells are currently in clinical trial [47]; these therapies might
well modify the place of HIPEC in the treatment of ovarian cancer.
All these observations suggest the need for randomized phase III
trials of CRS with and without HIPEC in ovarian cancer.
In conclusion, HIPEC is feasible but is associated with a high
rate of grade 3-5 complications and should therefore be
administered by trained clinicians. The treatment is associated
with a DFS of 11 months, but median OS is still not reached in
selected cases after a 38-month median follow-up. The outcome of
stage III ovarian cancer remains poor, but the combination of CRS
and HIPEC could be an interesting therapeutic option. No consensus
has yet been reached about indication, drugs, and doses for HIPEC.
Randomized phase III studies are needed to determine the exact
therapeutic value of the combination of CRS and HIPEC compared to
CRS alone and the therapeutic value of adjuvant chemotherapy after
HIPEC.
Table 4 Results of other studies.
|
Authors year [Ref]
|
Patient n
|
Cancer stage: n
|
Disease status: n
|
Agent
|
Cytoreduction: n (%)
|
Adjuvant chemotherapy
|
Median DFS in months
|
Median OS in months
|
Five years OS rate
|
|
Ryu, 2004 [19]
|
57
|
Ic-II: 22 III: 35
|
Second LS/IDS
|
Carboplatin Interferon α
|
R0-R1: 48 (84%) R2: 9 (16%)
|
NR
|
Stage III: 26 III + R0-R1: 40
|
NR
|
Stage III: 53%
|
|
Piso 2004 [40]
|
19
|
III: 14 IV: 5
|
PS: 9 RDS: 11
|
Cisplatin mitoxantron
|
R0: 9 (47%) R1-R2:10 (53%)
|
Yes - n = 9 No - n = 10
|
NR
|
R0: 28 R1-R2: 20
|
15%
|
|
Zanon 2004 [45]
|
30
|
III-IV
|
PS: 8 RDS: 22
|
Cisplatin
|
CC0-CC1: 23 CC2: 7
|
NR
|
CC0-CC1: 24 CC2: 4
|
CC0-CC1: 37 CC2: 11
|
NR
|
|
Gori 2005 [30]
|
29
|
IIIB-IIIC
|
Second LS
|
Cisplatin
|
CC0
|
NR
|
57
|
64
|
NR
|
|
Reichmann 2005 [41]
|
13
|
III-IV
|
PS: 9 RDS: 4
|
Cisplatin
|
CC0-CC1: 11 CC2:2
|
NR
|
15
|
NR
|
NR
|
|
Rufian, 2006 [20]
|
33
|
III: 33
|
PS: 19 RDS: 14
|
Paclitaxel
|
R0: 17 (52%) R1: 11 (33%) R2: 5 (15%)
|
Yes
|
PS: 25 RDS: 31
|
PS: 38 RDS: 57
|
NR
|
|
Raspagliesi 2006 [21]
|
40
|
III-IV
|
Second LS: 13 RDS: 27
|
Cisplatin Mitomycin Doxorubicin
|
CC0: 33 CC1: 7
|
NR
|
Mean: 24
|
26
|
15%
|
|
Helm 2007 [18]
|
18
|
I: 2 III: 13 IV: 3
|
RDS: 18
|
Cisplatinum Mitomycin C
|
CC0: 11 (61%) CC1: 4 (22%) CC2:3 (17%)
|
Yes - n = 12 No - n = 6
|
10
|
31
|
NR
|
|
Cotte 2007 [17]
|
81
|
I-II: 7 III: 71 IV: 3
|
RDS: 77 IDS: 4
|
Cisplatin
|
CCR0: 45 (55%) CCR1: 20 (25%) CCR2: 16 (20%)
|
Yes - n = 43 No - n = 38
|
CCR0: 27 CCR1:NR CCR2:NR
|
CCR0: 55 CCR1:17 CCR2: 5
|
NR
|
|
Di Giorgio 2008 [39]
|
47
|
III-IV
|
PS: 22 RDS: 18 IDS: 4 Second LS: 3
|
Cisplatin
|
CC0: 30 (64%) CC1: 12 (25%) CC2: 5 (11%)
|
Yes - n = 45 No - n = 2
|
CC0: 24 CC1: 13 CC2: 6
|
CC0: 26 CC1: 13 CC2: 12
|
17%
|
|
Fagotti 2009 [33]
|
25
|
II: 2 III:21 IV:2
|
RDS
|
Oxaliplatin
|
CC0: 23 CC1: 2
|
Yes
|
10
|
NR
|
NR
|
|
Present study
|
18
|
IIIc
|
IDS: 10 RDS: 8
|
Oxaliplatin
|
CC0: 16 CC1: 2
|
No
|
IDS: 17 RDS: 10
|
>38
|
NR
|
Acknowledgments
The authors gratefully acknowledge C. Ferlay for support with
statistical analyses and M.D. Reynaud for editorial assistance.
Conflict of interest. None.
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