Journal of Cancer Therapy, 2013, 4, 6-15 Published Online October 2013 (
Intraperitoneal Chemotherapy as a Multimodal Treatment
for Gastric Cancer Patients with Peritoneal Metastasis
Sachio Fushida*, Katsunobu Oyama, Jun Kinoshita, Tomoya Tsukada, Kouichi Okamoto,
Hidehiro Tajima, Itasu Ninomiya, Hirohisa Kitagawa, Takashi Fujimura, Tetsuo Ohta
Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan.
Email: *fushida@staff,
Received June 30th, 2013; revised July 29th, 2013; accepted August 6th, 2013
Copyright © 2013 Sachio Fushida et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Peritoneal metastasis of gastric cancer is mainly caused by the dispersion of free cancer cells from the serosal surface of
the invaded stomach, from surgically transected lymphatic channels, and from tumor cell-containing blood from the
primary lesion into the peritoneal cavity. Intraperitoneal chemotherapy (IPC) combined with surgery has performed for
the prevention and treatment of peritoneal metastasis in gastric cancer. The efficacy of this technique is influenced by
the pharmacokinetic advantage achievable with the anticancer drug, timing of administration, combination with hyper-
thermia, and tumor volume. The pharmacokinetic advantage for peritoneal cavity exposure relative to peripheral circu-
lation by intraperitoneal delivery for drugs including cisplatin (10-fold advantage), mitomycin C (20- to 30-fold advan-
tage), docetaxel (500-fold advantage), and paclitaxel (1000-fold advantage) has been confirmed. To avoid uneven drug
distribution in the peritoneal cavity and the re-growth of residual tumor, it seems to be reasonable to perform IPC pe-
rioperatively; however, early perioperative intraperitoneal chemotherapy (EPIC) has a relatively high morbidity rate
compared with intraoperative IPC. Hyperthermia has both cytotoxicity of itself and a synergistic effect with anticancer
drugs, especially mitomycin C. In the adjuvant setting, patients with either hyperthermic intraperitoneal chemotherapy
(HIPEC) or EPIC showed a significant improvement of survival compared to those with surgery alone. In addition, ex-
tensive intraoperative peritoneal lavage (EIPL) seems also to be a reasonable method to reduce free cancer cells in the
peritoneal cavity. For the treatment of peritoneal metastasis, cytoreductive surgery which achieves R0 or R1 resection
followed by IPC has demonstrated a survival benefit, whereas gross residual tumor (R2) treated by IPC has shown poor
prognosis. Extensive cytoreductive surgery, such as peritonectomy, followed by IPC achieved long-term survival for
selected patients, though this aggressive procedure led to high morbidity and mortality rates. It seems that combined
chemotherapy (systemically and intraperitoneally) followed by conversion surgery can be expected to be a powerful
procedure for the patients with gross peritoneal tumors.
Keywords: Peritoneal Metastasis; Gastric Cancer; Intraperitoneal Chemotherapy
1. Introduction
One of the most characteristic features of gastric cancer
and the most frequent causes of death from this disease is
peritoneal metastasis. In a recent multicentric prospective
study [1], the median survival time was 3.1 months for
gastric cancer patients. For two decades now, the treat-
ment of peritoneal metastasis has consisted of systemic
chemotherapy with sequential methotrexate (MTX) and
5-FU, or IPC with mitomycin C (MMC), cisplatin, OK-
432, and other agents. Sequential MTX and 5-FU have
been widely used as systemic chemotherapy because of
their high efficacy against poorly differentiated adeno-
carcinoma, persistent high concentrations in ascites, and
tendency to have low-grade toxicity [2,3]. However, gas-
tric cancer is only moderately sensitive to chemotherapy,
and peritoneal metastasis is known to be relatively resis-
tant to systemic chemotherapy due to the poor blood
supply and oxygenation of cancer cells in the peritoneum.
Therefore, in those days to enhance the efficacy of anti-
cancer drugs, IPC has been generally accepted as re-
gional intensive chemotherapy for the prevention and
treatment of peritoneal metastasis.
IPC with MMC or carbon-adsorbed MMC has been
reported to improve the survival of gastric cancer pa-
*Corresponding author.
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Intraperitoneal Chemotherapy as a Multimodal Treatment for Gastric Cancer Patients with Peritoneal Metastasis 7
tients by preventing peritoneal recurrence [4], but the
efficacy of these therapies in patients with peritoneal
metastasis has not been established.
Intraperitoneal (IP) cisplatin treatment has been per-
formed safely and effectively in ovarian cancer by many
investigators [5,6].
The usefulness of IP cisplatin must be confirmed by
controlled clinical studies, but a multicenter randomized
trial, JCOG 9206-2 (Japan Clinical Oncology Group),
which was comparing adjuvant IP cisplatin with no IP
treatment, could not reveal the superiority of IP cisplatin
Moreover, although even three large randomized
phase III trials comparing IP versus intravenous (IV) cis-
platin-based chemotherapy have shown a survival benefit
of IPC, this approach has not been accepted as a standard
treatment for gynecologic tumors [8-10].
HIPEC has been developed since 1980 [11] and MMC
is the most frequently used chemotherapeutic agent in
anticipation of its synergy effect with hyperthermia [12].
The efficacy of IPC seems to be affected mainly by the
extent of the peritoneal tumor and ascites. Most of posi-
tive results were obtained for patients without peritoneal
metastasis in an adjuvant setting or for patients with mi-
croscopic residual tumor [13-22].
Until recently, systemic chemotherapy was regarded as
less effective than IPC against peritoneal metastasis;
however, novel drugs, such as S-1 and taxanes, are ex-
pected to produce a good outcome despite the existence
of the blood-peritoneal barrier.
S-1 is a novel oral dehydropyrimidine derivative of 5-
FU [23,24]. The response rate for S-1 in gastric cancer is
over 40%, and S-1 has the potential to prolong survival
in advanced gastric cancer [25,26]. Moreover, S-1, unlike
other fluoropyrimidine agents, is effective even against
peritoneal metastasis. This was confirmed using a mouse
model developing peritoneal metastasis of gastric cancer
[27]. Although the detailed mechanism is unknown, S-1
appears to supply the peritoneal tumor with 5-fluor-
ouracil via the systemic and intraperitoneal circulation.
Considering the efficacy and survival benefit of S-1 in
patients with peritoneal metastasis, which have been
documented by many case reports and other reports [28,
29], it will be necessary to include S-1 in the regimen of
a randomized study for treatment of peritoneal metasta-
Taxanes such as docetaxel and paclitaxel bind to tubu-
lin, leading to microtubule stabilization, mitotic arrest
and, subsequently, cell death [30,31]. The activity of tax-
anes may depend on the property of killing tumor cells in
the absence of wild-type p53 function [32], unlike other
drugs requiring wild-type p53, and taxanes may therefore
be effective against gastric cancer cells, which frequently
have p53 mutations [33,34]. Furthermore, these com-
pounds have high sensitivity against poorly differentiated
adenocarcinoma, which is a common type of peritoneal
tumor, and some of these compounds, when administered
intravenously, are transported into the peritoneal cavity
[35,36]. These findings suggest that taxanes are also can-
didates for first-line drugs for peritoneal metastasis.
Because of the large body of data showing the efficacy
for peritoneal metastasis of either S-1 or taxanes admin-
istered as systemic chemotherapy, oncologists may not
be very likely to consider IPC.
This article will briefly review the current status of
IPC, with a particular focus on pharmacokinetics, treat-
ment timing, and tumor volume and combination ther-
apy. It is hoped that this review will help renew the in-
terest of oncologists in IPC.
2. Rationale for Intraperitoneal
Administration of anticancer drug into the peritoneal
cavity is one of the types of regional therapy, and its
merit is that it exposes peritoneal lesions to high concen-
trations of drugs for more prolonged periods than sys-
temic treatment [37]. The agents for intraperitoneal ad-
ministration are required to be effective against the target
tumor and to show enhanced cytotoxicity with either
increased drug concentration or exposure duration. If an
individual tumor has not responded to systemic therapy,
even 10-fold or higher increases in drug concentration
are not expected to achieve a good outcome via regional
therapy [38].
3. Pharmacokinetics and Local Toxicity
The pharmacokinetic properties of many anticancer
agents have been examined, following intraperitoneal
administration in phase I studies [38] (Table 1). Ideal
agents for intraperitoneal delivery have a high ratio of
either peak peritoneal drug concentration or area under
the peritoneal concentration versus time curve (AUC)
relative to systemic concentration, i.e., they have a low
peritoneal clearance and a high plasma clearance. Such a
pharmacokinetic advantage for peritoneal cavity expo-
sure is favored by high molecular weight, water solubil-
ity, high solution volume, and easy ionization. The phar-
macokinetic advantage has been reported to range from
10-fold for cisplatin [39] and carboplatin [40], to as high
as 1000-fold for paclitaxel [41].
Because MMC, which is commonly used intraperito-
neally, is rapidly absorbed through capillary walls in the
subperitoneum due to its low solubility in water, MMC
has only a 20 - 30-fold pharmacokinetic advantage and
disappears from the blood within 3 hours [42].
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Intraperitoneal Chemotherapy as a Multimodal Treatment for Gastric Cancer Patients with Peritoneal Metastasis
Table 1. Area under the curve ratios of intraperitoneal ex-
posure to systemic agent [38].
Drugs Area under the curve ratio
5-Fluorouracil 250
Carboplatin 10
Cisplatin 7.8
Docetaxel 550
Doxorubicin 230
Etoposide 65
Gemcitabin 500
Mitomycin C 23.5
Oxaliplatin 16
Paclitaxel 1000
Cisplatin, whose molecular weight is relatively low, is
also rapidly absorbed from subperitoneal capillaries and
transported into the systemic circulation. Pharmacoki-
netic studies confirmed that the plasma AUC is similar
after IP or IV cisplatin. Furthermore, adverse effects after
IP cisplatin and are also similar to those after IV cisplatin,
and include effects such as emesis, nephrotoxicity, and
neurotoxicity, and there are minimal local adverse events.
Considered together, these findings indicate that IP cis-
platin may exert anticancer effects both regionally and
systemically [38]. However, it has been shown that cis-
platin seems to be useful for patients with microscopic
residual tumor but not for the patients with macroscopic
residual tumor. Therefore, it is necessary to search for
some other highly effective agent for IP in gastric cancer.
Paclitaxel is retained in the peritoneal cavity at cyto-
toxic concentrations for at least 7 days, implying that
very limited amounts of paclitaxel enter the systemic
compartment after IP [43]. This is reasonable considering
the fact that the dose-limiting factor for paclitaxel is ab-
dominal pain from direct peritoneal irritation. These
findings suggest that the cytotoxic activity of IP pacli-
taxel may be exerted by direct penetration into the re-
gional tumor alone.
In contrast, docetaxel has a pharmacokinetic advantage
of two logs associated with its intraperitoneal delivery,
and the systemic AUC after intraperitoneal administra-
tion is 2 times greater than that after standard intravenous
administration [44,45]. These data indicate that docetaxel
occupies a position between cisplatin and paclitaxel from
the pharmacokinetic viewpoint (Figure 1). Paclitaxel and
docetaxel have rather similar chemical and physiological
characteristics, and the pharmacokinetic difference be-
tween them seems to be attributable to the differential
absorption in solubility [44]. The injection preparation of
paclitaxel, Taxol, contains a high concentration of Cre-
mophor EL as the surfactant vehicle, which suppresses
Figure 1. Anticancer effect according to pharmacokinetic
the permeation of the anticancer drug into tissues and
cells, and this may explain why intraperitoneally admin-
istered Taxol shows lower systemic transportation than
that of Taxotere, which contains a low concentration of
Polysorbate-80 as the surfactant [46].
In the selection of anticancer drugs for IPC, it is nec-
essary to consider to not only pharmacokinetic advantage
but also local toxicity due to administrated drug. Drugs
which possess serosa-damaging activity should be avoid-
ed to use because their drugs, such as MMC and adria-
mycin, would induce the encapsulated chemical peritoni-
tis, which represent for peritoneal fibrosis and intestinal
adhesion, associated with poor delivery (Fi gure 2).
4. The Treatment Schedule of Perioperative
The issue of when IPC should be administered is also
important with respect to the treatment efficacy. Sautner
et al. [47] reported that adjuvant IP cisplatin between
postoperative day 10 and 28 dose not improve long-term
survival. This means that the best time to perform che-
motherapy is just after cytoreduction surgery because the
remaining cancer burden is the smallest at that time. The
growth of cancer cells shed into the peritoneal cavity is
protected by the forming a connective tissue matrix and
is stimulated by cytokines in the healing surgical wound
[48]. Moreover, the delaying initiation of IPC after sur-
gery leads to poor delivery of anticancer agents caused
by peritoneal adhesion. For these reasons and for con-
venience, most surgeons perform intraoperatively in Ja-
pan. On the other hand, early postoperative intraperito-
neal chemotherapy (EPIC), which is performed for 5 - 7
days from postoperative day 1 with 5-FU, MMC or cis-
platin [17,49], is also performed in western countries and
Korea. EPIC had not been performed until Sugarbaker
reported this strategy [50], because it was feared that
early postoperative chemotherapy might increase the rate
of morbidity. Yu et al. [17] reported that there was a sig-
nificant increase in the incidence of intraabdominal
bleeding and intraabdominal sepsis in the EPIC group
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Intraperitoneal Chemotherapy as a Multimodal Treatment for Gastric Cancer Patients with Peritoneal Metastasis 9
Figure 2. Encapsulated chemical peritonitis after intraperi-
toneal administration of mitomycin.
compared with the control group, although most of these
complications could be managed conservatively.
5. Infusion Methods
Intraperitoneally injected drugs are usually distributed
unevenly because of the anatomical complexity of the
peritoneal cavity. It is considered that about 1000 ml of
solution is necessary to adequately distribute the drug
into the peritoneal cavity (Figure 3(a)), while excess
volume causes a poor outcome due to the low concentra-
tion of dissolved agents. For patients with massive as-
cites, it is better to carry out peritoneal lavage with phy-
siologic saline or potassium hydroxide, which dissolves
mucinous retention. Alpha 1-acid glycoprotein in the as-
cites also reduces the anticancer effect by binding some
agents, such as cisplatin and taxanes [51,52].
An intraperitoneal catheter provides an easy method
for repeated administration of anticancer drugs, perito-
neal lavage, and/or cytological examination (Figure
3(b)), although possible intraperitoneal catheter compli-
cations include catheter infection, blocked catheter, and
bowel complications. Makhija et al. [53] analyzed com-
plications associated with the use of IP chemotherapy at
Memorial Sloan Kettering Cancer Center and reported
that out of 411 patients, catheter malfunction occurred in
32 (7.8%) and catheter-induced sepsis occurred in 14
(3.4%). In gastric cancer, an implanted intraperitoneal
access port (Bardport; C.R. Bard, Inc., NJ, USA) has
been used generally for IPC. Emoto et al. previously de-
scribed that although 20.6% of 131 gastric cancer pa-
tients with peritoneal metastases experienced port com-
plications, complications were controllable and chemo-
therapy was not terminated by complications [54]. Thus,
IPC using a port might be safe and feasible under appro-
Figure 3. (a) MRI showed equal distribution of fluid with
1L of saline containing anticancer agent; (b) Intraperitoneal
access port and its implanted view subcutane ously.
priate management.
6. Combination with Hyperthermia
In the 1980s, HIPEC was reported [55] as a safe treat-
ment for peritoneal metastasis, and it is currently under
evaluation. Hyperthermia has been developed as an anti-
cancer therapy and has been employed clinically for its
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Intraperitoneal Chemotherapy as a Multimodal Treatment for Gastric Cancer Patients with Peritoneal Metastasis
direct cytotoxic effect [56] and synergy with some types
of chemotherapeutic agents. The detailed mechanisms by
which hyperthermia enhances the cytotoxicity of MMC
are unclear but include increased cellular accumulation
of MMC, increased activation of MMC, and altered re-
pair of DNA damage caused by MMC [57].
It is important to note that HIPEC is not a very pow-
erful treatment for patient with macroscopic residual tu-
mors, and that it has the disadvantage of requiring com-
plicated procedures to maintain the appropriate tempera-
ture. Therefore, cytoreductive surgery followed by HIPEC
might be recommended in that situation. A recent phase
III study showed that patients treated with CRS plus
HIPEC had superior survival than those treated with CRS
alone, and the median survival time (MST) for CRS plus
HIPEC was 11.0 months [58].
7. Prophylactic (Adjuvant) Chemotherapy
In an adjuvant setting, IPC is designed to eradicate re-
sidual microscopic tumor and floating cancer cells in the
peritoneal cavity after curative resection.
Some prospective randomized studies of IPC in the
adjuvant setting have yielded various results (Table 2).
IPC with MMC or carbon-adsorbed MMC has been re-
ported to improve survival of gastric cancer patients by
preventing peritoneal recurrence [4,5], but the efficacy of
these therapies was not confirmed by the Austrian Gas-
tric Cancer Working Group [59]. Fujimura et al. [14]
have showed that patients treated with intraoperative
HIPEC with cisplatin, MMC and etoposide had longer
survival than the control group, but this result was not
confirmed by Kunisaki et al. [60]. These discrepant data
seem to be influenced by the number of free cancer cells
disseminated during surgical treatment.
Dissemination of cancer cells by surgical manipulation
of tumors with serosal invasion and leakage of lymph
containing cancer cells from the transected lymphatic
channels may be unavoidable during gastrectomy. Al-
though free cancer cells in the peritoneal cavity play an
important role in peritoneal recurrence, the sensitivity of
detecting them is often influenced by the methodology,
such as morphological cytology, immunological cytos-
taining or RT-PCR [61]. Therefore, adjuvant IPC should
be performed for patients with serosal invasion. However,
it is difficult to detect the metastatic lymph nodes as an-
other source of free cancer cells intraoperatively. Inves-
tigators [17] who recommended EPIC advocate that be-
cause the pathologic stage can be determined only post-
operatively, selective adjuvant IPC should be done post-
For the prevention of peritoneal recurrence, Shimada
and colleague [62,63] reported that extensive intraopera-
tive peritoneal lavage (EIPL) followed by IPC is useful
for eradicating free cancer cells in the peritoneal cavity
and micrometastases on the peritoneal surface. Because
free cancer cells may be reduced to almost zero using
this method, treatment evaluation would not be influ-
enced by differences of the number of free cancer cells
between patients. Although JCOG9206-2 study showed
no significant difference of survival rate between IP cis-
platin group and non-IP group [7], it was reason why that
peritoneal lavage before administration of cisplatin might
be insufficiently. On the other hand, in patients with po-
sitive peritoneal cytology and no macroscopic peritoneal
tumor, radical surgery followed by postoperative S-1
showed good results with 2-year survival rate of 46% and
5-year survival rate 26% [64]. Further investigation, in-
cluding controlled clinical trials comparing S-1 and EIPL
plus IP cisplatin followed by S-1, are needed.
8. Intraoperative Chemotherapy for
Peritoneal Carcinomatosis
Reducing tumor volume has always been considered an
important factor in achieving tumor response to chemo-
therapy. Glehen et al. [20] reported that with combined
HIPEC, patients treated with complete or sub-complete
surgery had significantly longer survival than those with
incomplete cytoreduction. Similar results were reported
by Yonemura et al. [19], who showed that postoperative
survival after cytoreductive surgery was inversely related
with the residual tumor burden. He also described that
according to peritoneal cancer index (PCI), which estab-
lished by Sugarbaker as a semiquantitative scoring sys-
tem [65] (Figure 4), it was difficult to complete cytore-
duction in the patients with PCI 6 [66]. When cytore-
ductive surgery does not result in sufficient down-staging,
the survival benefit of HIPEC remains extremely low,
and median survival does not exceed 6 to 8 months.
On the basis of these data, peritonectomy was first de-
scribed as a new cytoreductive surgery technique for
gross tumors in 1995 [67]. This procedure consists of
five steps: epigastric peritonectomy, anterolateral perito-
nectomy, subphrenic peritonectomy, omental bursa peri-
tonectomy, and pelvic peritonectomy. These extensive
treatments have been developed in order to remove all
macroscopic lesions to enhance the efficacy of HIPEC.
This aggressive treatment achieved the long term sur-
vival for selected diseases, such as pseudomyxoma peri-
tonei and some colorectal cancers [68,69]. However, the
combination of peritonectomy and HIPEC can lead to
greater mortality and morbidity rates. Improvement of
the morbidity rate of the peritonectomy procedure re-
quires more experience with this operation in not only
the surgical technique of peritonectomy but also the post-
operative intensive care of the patients [70]. At the mo-
ment, extensive cytoreductive surgery of peritoneal gross
tumors is not the standard procedure in the management
of gastric cancer. To reduce the high rate of morbidity
Copyright © 2013 SciRes. JCT
Intraperitoneal Chemotherapy as a Multimodal Treatment for Gastric Cancer Patients with Peritoneal Metastasis
Copyright © 2013 SciRes. JCT
Table 2. Intraperitoneal chemotherapy after curative resection for gastric cancer.
Author regimen hyper-thermiasurvival rate % (year)
R. Hamazoe [13]
T. Fujimura [14]
T. Takahashi [15]
S. Fujimoto [16]
W. Yu [17]
Y. Yonemura [18]
T. Sautoner [47]
H. R. Rosen [59]
C. Kunisaki [60]
61/53 (5)
68/23 (3)
38/20 (3)
69/55 (5)
54/38 (5)
61/42 (5)
17M/16M (MST)
49/56 (5)
Abbreviation: MST, median survival time; N/A, not available.
Figure 4. Peritoneal cancer index (PCI). Peritoneal cavity is divided into 13 parts, which ranges from 0 to 12. Accurate meas-
urement of each region is scored as lesion size 0 through 3. LS 0: no implant.
from extensive cytoreduction, an appropriate neoadju-
vant approach is needed prior to surgery.
9. Neoadjuvant Chemotherapy
For accurate judgment regarding whether peritoneal me-
tastasis could be expected, laparoscopy may play an im-
portant role by allowing direct observation of the perito-
neal cavity in spite of the development of imaging tech-
niques such as CT, MRI and PET. Although peritoneal
lavage cytology is also useful for the diagnosis of peri-
toneal metastasis, this cytology cannot provide informa-
tion about the degree, extent, and volume of peritoneal
metastasis. If the laparoscopic examination reveals unre-
sectable peritoneal metastasis, induction chemotherapy
would be recommended. Considering that the actual dep-
th of penetration of drugs injected intraperitoneally di-
rectly into the tumor is limited to 2 - 3 mm from the peri-
toneal surface [71], it seems to be necessary to attack
both systemically and regionally.
For the following salvage surgery, intraperitoneal drug
should have sufficient efficacy against the tumor and
should not induce peritonitis or adhesion despite repeated
administration as well as taxanes. Taxanes have high sen-
sitivity against diffuse-type adenocarcinoma, which is a
common type of peritoneal tumor. Furthermore, taxanes
are absorbed through the openings of lymphatic system,
such as the milky spots and the stomata which are im-
portant sites for the formation of peritoneal metastases
[72], due to their large molecular weight and fat solubil-
ity. The oral anticancer drug S-1 is a fluoropyrimidine
derivative, combining tegafur with two modulators. S-1
is also highly effective against gastric peritoneal metas-
tasis due to the higher concentration of 5-FU and CDHP
achieved in peritoneal tumors than in plasma. These find-
ings suggest that combination therapy of S-1 plus IP tax-
anes should be the first-line for PC.
According this sense, Ishigami et al. established IP
paclitaxel with S-1 plus IV paclitaxel and provided en-
courage results with a MST of 22.5 months and 2-year
survival rate of 78% [73]. Peritoneal metastasis is con-
sidered to be a non-measurable lesion because it is diffi-
cult to detect peritoneal metastasis by conventional ra-
diological examinations. New response criteria for treat-
ment against peritoneal metastasis were developed ac-
cording to the findings of intraperitoneal photographs
which were taken in the first and second laparoscopy
[45]. In the phase II study to evaluate efficacy of S-1 plus
IP docetaxel [74], the second staging laparoscopy after 2
cycles of combined chemotherapy showed response rate
of 52% according to the response criteria for the treat-
Intraperitoneal Chemotherapy as a Multimodal Treatment for Gastric Cancer Patients with Peritoneal Metastasis
ment of peritoneal metastasis. This study also showed a
1-year survival rate of 70.4% with MST of 16.2 months.
Peritoneal responder who underwent gastrectomy show-
ed 2-year survival rate of 48%, and non-responder who
received chemotherapy alone showed 0%. These data
suggest that IP taxane combined with oral administration
of S-1 following surgery may be a powerful candidate for
the treatment of severe peritoneal metastasis. However, it
is important to note that in the absence of data from ran-
domized trials, the efficacy of this specific multi-modal-
ity strategy remains to be established.
10. Conclusion
The development of multimodal treatment consisting of
neo-adjuvant chemotherapy, cytoreductive surgery, pe-
rioperative IPC, and adjuvant chemotherapy is expected
because chemotherapy alone is not sufficient for com-
plete remission of peritoneal metastasis. Although Yo-
nemura et al. developed the most aggressive multimodal
treatment combining neoadjuvant intraperitoneal-syste-
mic chemotherapy (NIPS), peritonectomy, HIPEC, and
EPIC [66], it is difficult to start phase III clinical trials
using this treatment because of the high morbidity and
mortality rates. In the meantime, Ishigami et al. con-
ducted a randomized phase III trial, so called PHOENIX-
GC trial, comparing combination of S-1, IV paclitaxel
and IP paclitaxel with S-1/cisplatin, which is the current
standard regimen for gastric cancer patients with perito-
neal metastasis in Japan. Most of the patients who re-
ceived this intraperitoneal and systemic chemotherapy
were underwent R0 resection and prolonged survival
with low morbidity and mortality in Phase II trial. There-
fore, the forthcoming results of PHOENIX-GC trial are
expected to revolutionize treatment of peritoneal metas-
tasis in gastric cancer.
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