INVITED REVIEW ARTICLE
Nagoya J. Med. Sci. 75. 3 ~ 10, 2013
GASTRIC CANCER WITH MINIMAL PERITONEAL
METASTASIS: IS THIS A SIGN TO GIVE UP OR
TO TREAT MORE AGGRESSIVELY?
Department of Surgery II (Department of Gastroenterological Surgery),
Nagoya University Graduate School of Medicine, Nagoya, Japan
Peritoneal metastasis from gastric cancer is often undetectable by routine imaging studies. Even a
microscopic metastasis detected only by cytologic examination of the peritoneal washes denotes a dismal
prognosis, and surgery is ruled out as futile for patients who turn out to be cytology-positive by staging
laparoscopy. On the other hand, recent developments in cancer chemotherapy have improved the outcome of
the cytology-positive population to the point where a certain proportion of these patients survive for 5 years
through a straightforward strategy of radical surgery followed by chemotherapy. Thus, there is certainly a
role for surgeons in patients with minimal peritoneal metastasis, both in clinical practice and in clinical
trials where multimodal treatment strategies including surgery are to be explored. Even in this category
of patients, surgery in combination with various types of chemotherapy remains the only hope for a cure.
Key Words: Gastric cancer, Peritoneal metastasis, Cytology, Peritoneal carcinomatosis, D2 dissection
In the Far East, the most common pattern of disease failure after curative resection of gastric
carcinoma is reported to be peritoneal carcinomatosis.1,2) Cancer cells that are exfoliated from
the serosal surface of the stomach and scattered into the peritoneal cavity are considered to be
responsible for this fatal condition.3 Detection of free cancer cells in the peritoneal cavity through
various methods has therefore been attempted to understand the risk for recurrence.3-5) Moreover,
conventional cytologic examination of the peritoneal washes through Papanicolaou staining has
become mandatory in Japan as a tool for the prediction of prognosis and, ultimately, one of the
key components of the staging system.6) Patients with viable cancer cells in the peritoneal cavity
are bound to harbor micrometastases on the peritoneal surface and are at a high risk of suffering
from peritoneal carcinomatosis. Such a status is defined as CY1, and cancer diagnosed as CY1
through laparotomy or staging laparoscopy is invariably classified into Stage IV by the Japanese
Classification of Gastric Carcinoma.6) Treatment options recommended by the Japanese Treatment
Guidelines for Gastric Cancer for Stage IV gastric cancer are chemotherapy, radiotherapy, sup-
Received: November 9, 2012; accepted: November 14, 2012
Corresponding author: Yasuhiro Kodera, MD, PhD, FACS
Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku,
Nagoya, Aichi 466-8550, Japan
Phone: 81-52-744-2232, FAX 81-52-744-2255, e-mail address: firstname.lastname@example.org
portive care, and palliative surgery that includes gastrectomy to circumvent bleeding, and by-pass
surgery or ileostomy for those with obstruction of the gastrointestinal tract. However, it does not
include gastrectomy with curative intent. These facts point to the notion that a CY1-stage patient
is no longer eligible for surgery with curative intent, despite the absence of any macroscopic
evidence of disease. This notion could be accepted in countries where morbidity and mortality
from gastric cancer surgery cannot be dismissed as negligible,7) but the prognosis of curatively
resected gastric cancer in general remains dismal.8) Medical professionals under such circum-
stances should seek out any useful criteria so as to avoid futile and toxic modes of treatment,
and cytologic examination could be useful in that regard. On the contrary, such a notion has
been perceived as regrettable in Japan, where gastrectomies have been performed safely, and have
generally provided relatively favorable outcomes. This article provides an overview of current
treatment strategies for minimal peritoneal disease in gastric cancer in Japan.
OUTCOME OF PATIENTS WITH CY1 STATUS
The dismal prognosis of CY1 disease had been well-documented not only in the West but
also in the Far East.3,9) Several researchers have reported that the chance of survival of CY1
patients is equivalent to that of patients with macroscopic peritoneal deposits.10) The accuracy of
cytologic examination may be an issue for debate, as it has been questioned by Leake et al. in
their review article.11) This study featured several investigators who adopted immunostaining and
RT-PCR techniques, in addition to the conventional cytologic examination, to more sensitively
detect minimal cancer cells. It is apparent that the weakness in the conventional cytologic
examination lies in its relatively low sensitivity, an area where techniques such as RT-PCR could
do better.3) Given its high specificity, however, conventional cytologic examination remains useful
in identifying patients for whom some fundamental considerations are necessary to establish the
treatment strategy, such as delivering highly toxic treatments or making serious decisions such
as ruling out surgery.
LINITIS PLASTICA-TYPE GASTRIC CANCER AS A PARTICULARLY
AGGRESSIVE DISEASE ENTITY
The authors have looked specifically at the outcomes of linitis plastica-type gastric cancer.12)
This diffusely invasive type of cancer usually requires total gastrectomy that has a detrimental
effect on the quality of life of the patients, while it rarely induces massive hemorrhage or gastric
outlet disease until relatively late in the course of the disease. Through the analysis of peritoneal
washes from 47 consecutive patients suffering from linitis plastica, the authors found that 43%
of patients who were deemed operable by the preoperative imaging technique were CY1 at
surgery.12) By using the RT-PCR technique, the likelihood of detecting free cancer cells in the
same population rose to 83%. This figure turned out to be even more accurate than what was
provided after conventional cytologic examination, since as much as 77% of the same popula-
tion was found at surgery or during the follow-up to suffer from peritoneal carcinomatosis.12)
Fukagawa et al. found that the prognosis of the linitis plastica-type was outstandingly dismal
even among patients who were diagnosed as CY1.9) The authors made it a rule at around year
2000 to perform staging laparoscopy for all patients with linitis plastica, and to avoid surgery
not only for those with peritoneal deposits but also for those with the CY1 status.13)
TREATMENT FOR CY1 GASTRIC CANCER
EFFECT OF NOVEL ANTICANCER AGENTS AGAINST MINIMAL DISEASE
IN THE PERITONEAL CAVITY
The recent introduction of more effective anticancer drugs into the clinic have changed the
picture of CY1 disease in the Far East.14-16) Tegafur-gimeuracil-oxo (S-1), an oral fluoropyrimidine,
has shown its potential to treat intraperitoneal micrometastasis in a phase III adjuvant trial,
ACTS-GC, where the incidence of peritoneal carcinomatosis has declined considerably after
curative surgery for Stage II/III gastric cancer through administration of S-1, compared with
treatment by surgery alone.17) While this phase III trial was on-going, the authors conducted a
phase II trial to test postoperative S-1 after radical surgery for CY1-stage gastric cancer (CY1
cancer is classified as Stage IV and is ineligible for the ACTS-GC trial), with no other signs
of incurable disease. Forty-seven patients were accrued, among whom 14 patients had linitis
plastica-type cancer. The two-year survival rate, this study’s primary endpoint, was as high as
46%, and was significantly superior to the historical control.18) Further follow-up has shown that
26% of patients survived for 5 years. Five-year survival data in this study cannot be dismissed
as trivial, given that patients with gastric cancer who are treated by chemotherapy alone rarely
survive for 5 years. Thus, radical surgery could be recommended for patients with CY1 as the
sole non-curative factor, provided that adequate chemotherapy is given perioperatively. Patients
with linitis plastica did suffer from an inferior prognosis, but there were long-term survivors even
among this population (Fig. 1). Patients who had a small number of visible peritoneal deposits
in addition to the CY1 status were also eligible for this study, provided that these deposits
were resected along with the stomach to leave the CY1 status as the only non-curative factor.
Surprisingly, survival of this subset of patients was not inferior to that of the patients who had
no visible peritoneal deposits (Fig. 2). Thus, a proposal could be made to define the CY1 status
as “optimally debulked gastric cancer.” Surgery to downsize the tumors could be meaningful
Fig. 1 Survival curves for patients entered onto the CCOG0301 trial (a phase II trial testing radical surgery
followed by postoperative chemotherapy with S-1 for patients positive for peritoneal washing cytology),
stratified by whether or not the primary cancer was linitis plastica-type. Difference between survival
curves as assessed by Logrank test was not significant (p=0.1527).
only when chemotherapy has sufficient power to control minimal disease. Arguably, surgery to
dissect all tumors >1 cm in diameter is considered to be a useful part of multimodal therapy
for ovarian cancer (optimally debulked ovarian cancer), which is generally more sensitive to
chemotherapy. In case of gastric cancer, the size of residual disease will have to be microscopic
to expect benefits from chemotherapy, but if all macroscopic disease could be removed through
surgery, there is some hope.
COMBINATION CHEMOTHERAPY AFTER RADICAL SURGERY
FOR GASTRIC CANCER
The combination of S-1 with cisplatin,19) in addition to showing superior overall survival in
the advanced/metastatic setting than S-1 monotherapy,20) has shown in a subset analysis of the
same phase III trial a remarkable efficacy against peritoneal disease. An attempt to treat Stage IV
patients by S-1/CDDP following gastric resection, however, was a failure, showing poor relative
drug intensity due to adverse events and patient refusal.21) Adverse reactions such as nausea,
anorexia and general fatigue were found to be intolerable during the early postoperative period
for patients who underwent gastrectomy. Takahari et al. have shown that compliance could be
improved considerably through treating patients with S-1 only in the first cycle, and adding
CDDP in the subsequent cycles.22) The difficulty in administering the S-1/CDDP combination
shortly after surgery prompted other investigators to perform staging laparoscopy, to detect CY1
and P1 patients and treat them preoperatively.23) Survival of patients whose cytologic examina-
tion turned negative after the preoperative S-1/CDDP generally did well, while the prognosis
of those with no effect against the CY1 status was poor. Preoperative treatment combined with
laparoscopy is therefore a useful option that enables the selection of appropriate patients to be
sent for radical surgery, but its prognostic effect in the intention-to-treat population as a whole
remains to be elucidated.
Fig. 2 Survival curves for patients entered onto the CCOG0301 trial (a phase II trial testing radical surgery
followed by postoperative chemotherapy with S-1 for patients positive for peritoneal washing cytology),
stratified by the presence or absence of macroscopic peritoneal deposits. Difference between survival
curves as assessed by Logrank test was not significant (p=0.4770).
TREATMENT FOR CY1 GASTRIC CANCER
INTRAPERITONEAL ADMINISTRATION OF CISPLATIN
Before the advent of S-1, several investigators looked at intraperitoneal (IP) administration
of anticancer drugs for the treatment and prevention of peritoneal carcinomatosis. Taxanes have
been found to not readily absorb into the blood stream when given IP,24) and the ratio of drug
concentration between the peritoneal cavity versus peripheral blood is thus kept outstandingly
high for a prolonged period. On the contrary, cisplatin was found to be absorbed into the
blood stream quite promptly upon IP. As this finding implicates, the attempt to incorporate IP
cisplatin, given on the day of surgery with one postoperative course of intravenous 5FU/CDDP
and followed by UFT in T4-stage cancer (CY0), was an utter failure, and the survival curve
was identical to that of the surgery alone group.25) Although compliance with the lengthy oral
UFT treatment was reportedly poor, almost all patients should have had IP CDDP, since it had
to be administered during surgery. Another Korean group has shown in their phase III trial that
an adjuvant “treatment A” containing IP CDDP showed a significantly longer survival than the
“treatment B,” which contained no IP CDDP. However, since the patients in the treatment A
group were also given intravenous mitomycin C on the day of surgery, followed by a longer
postoperative course of the capecitabine/CDDP combination instead of a shorter treatment with
capecitabine alone in the treatment B, IP CDDP could not be interpreted as the only reason for
improvement of survival in this population. We concluded from these and other studies that a
single dose of IP CDDP is insufficient to show efficacy, although it is not possible to discard
at this stage the theory that repeated administration of CDDP through IP reservoir is effective.
INTRAPERITONEAL ADMINISTRATION OF PACLITAXEL AND
ONGOING RANDOMIZED TRIAL
More recently, several investigators turned to paclitaxel and made sporadic efforts claiming
that this drug is effective when given as IP.26) However, these attempts did not follow the
general rules, i.e., a dose-finding study should be conducted first, followed by a phase II study
to evaluate its efficacy (since most patients suffer from cancer with non-measurable lesions, the
primary endpoint needs to be survival) and safety. Moreover, IP paclitaxel has not been formally
approved by the Ministry of Health, Labor and Welfare in Japan, and its use, along with other
government-approved modes of treatment, will result in either the investigator or the patient
paying all medical expenses for the treatments given, outside of the social insurance system.
To overcome this critical situation, the authors used the “kodo iryo (meaning “high standard
medical practice”)” system, whereby the details and current status of the unapproved treatment,
including the known safety profile and the advantage and disadvantage of providing such a
drug or technique, need to be fully reported to the Ministry. When the Ministry of Health,
Labor and Welfare grants the “kodo iryo,” the cost of treatment other than the new technique
will be covered by the insurance, while expenses needed for the new treatment could either be
paid by the patients or the investigators. Medical practice performed using the “kodo iryo” will
need to be scientifically designed, and generate evidence aimed at the future incorporation of
the new treatment into general practice. Moreover, IP paclitaxel against peritoneal disease, with
no validated surrogate endpoint to show efficacy, must take a form of randomized trial to be
regarded as “evidence-generating.”
Motivated further by the result of a phase III study in ovarian cancer with peritoneal metasta-
ses, where the IP group had a significantly prolonged survival over the intravenous administration
(IV) group,27) the authors consulted the government and were eventually permitted to use the
“kodo iryo” system to conduct a multi-institutional randomized phase II trial to test the efficacy of
IP paclitaxel following gastrectomy (the INPACT trial). In this trial, IP paclitaxel was compared
to postoperative IV paclitaxel, given by the same schedule to eradicate micrometastasis in patients
with particularly high risks for developing peritoneal carcinomatosis, such as linitis plastica-type,
those with a minimal number of peritoneal deposits resected, and those with a CY1 status.28) In
both treatment arms, a choice of either the S-1/CDDP combination or S-1 monotherapy was to
be given after 7 doses of either the IP or IV paclitaxel, depending on the patients’ condition. A
sequential use of IV paclitaxel with S-1 or S-1/CDDP merits further explanation. The sequential
IV paclitaxel/S-1 combination is the new test arm being explored in a pivotal phase III trial,
testing new modes of systemic adjuvant chemotherapy for patients with serosa-positive gastric
cancer.29) The final results of this trial are expected to be publicized in the early 2013.
In the meantime, Ishigami et al. conducted a phase I/II study with a combination of S-1,
IV paclitaxel and IP paclitaxel to control peritoneal carcinomatosis from gastric cancer. The
combination was successful with a one-year survival rate of 78% and a median survival time of
23.6 months, for a group of previously untreated patients with extensive peritoneal metastases.30)
They also were able to use the “kodo iryo” system to conduct a randomized phase III trial,
and compared this combination in the first-line setting with S-1/CDDP, the current standard, in
patients with previously untreated gastric cancer and gross peritoneal metastases (the PHOENIX-
GC trial). Patients with minimal peritoneal metastases were also eligible for the PHOENIX-GC
trial, and this intraperitoneal and systemic treatment delivered in combination with surgery could
be extremely promising for eradicating minimal peritoneal disease.
HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY
The most aggressive treatment that could be proposed for selected cancer patients with
peritoneal disease would be hyperthermic intraperitoneal chemotherapy (HIPEC), in which
patients receive intraperitoneal perfusion of a heated solution containing anticancer drugs.31) This
technique was attempted in the 1980’s by several Japanese groups to treat gastric cancer with
peritoneal metastasis, alone and in combination with surgery ranging from gastrectomy to total
peritonectomy. Unfortunately, variations in the drugs and devices used, the quality of surgery,
and other factors evidenced in various case series reported at the time prevented a majority of
surgeons from being convinced that this modality was efficacious. In addition, the toxicity and
complexity of the treatment did not allow HIPEC to be recognized as a candidate for standard
treatment. More recently, this modality was used to treat tumors of the peritoneal origin by
specialists in peritoneal surface malignancy, and some of these specialists began to expand the
indication of HIPEC to include peritoneal metastases from cancers of the colorectal and ovarian
origin. Gastric cancer, with its tendency to aggressively metastasize throughout hematogenous
and lymphatic pathways in addition to peritoneal dissemination, may be the last cancer to benefit
from this modality. Nevertheless, addition of HIPEC after surgery for CY1-stage gastric cancer
could lead to the elimination of minimal residual disease in the peritoneal cavity.
Prognosis of gastric cancer patients with free cancer cells in the peritoneal cavity had been
extremely poor. However, around 25% of these patients can live for 5 years following radical
gastrectomy plus chemotherapy, available as of 2012. Further trials are now being conducted
TREATMENT FOR CY1 GASTRIC CANCER
to explore the potential of repeated intraperitoneal chemotherapy for this population in Japan.
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