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Intravenous Chemotherapy Combined with Intraperitoneal Perfusion Chemotherapy for Gastric Cancer after Radical Operation. A Review of the Literature and Systematic Meta-Analysis.
Ross Finesmith MD
Abstract
Background: Gastric cancer is a common cancer with relatively poor survival rates. Early detection improves survivability, but clinical symptoms often do not present until late stages of the disease. Gastric resection and intravenous chemotherapy are the current accepted standard treatment. Intraperitoneal chemotherapy has been utilized in other abdominal cancers with moderate success. This systematic meta-analysis included randomized control studies that compared gastric cancer outcome data between post-operative subjects that received intravenous chemotherapy alone vs those that received intravenous plus intraperitoneal chemotherapy.
Methods: MEDLINE, EMBASE, LILACS and CENTRAL databases were searched for RCTs comparing gastric cancer adjunctive treatments: intravenous chemotherapy alone vs intravenous chemotherapy plus intraperitoneal chemotherapy.
Results: A collection of 392 research papers yielded 6 studies that meet entrance criteria. Treatment following gastric resection with combined intravenous chemotherapy plus intraperitoneal chemotherapy was associated with a statistical improvement in; 1-year survival (P=0.006), risk ratio of 1.11 (95% CI 1.04, 1.17); 3-year survival (P<0.0001), risk ratio of 1.22 (95% CI 1.11, 1.35); and 5-year survival (P=0.002), risk ratio of 2.00 (95% CI 1.30, 3.09). Minimal increased risk of adverse effects was associated with the improved outcome in the combined treatment groups.
Conclusion: Meta-analysis of the qualified studies confirmed that adjunctive intraperitoneal chemotherapy following gastric resection and intravenous chemotherapy, is effective in improving 1- 5 year survival rates. There was no evidence that any one specific chemotherapeutic agent administered intraperitoneally is more effective than the others. The addition of intraperitoneal chemotherapy minimally increased the risk of adverse events during treatment.
Keywords: Gastric cancer, meta-analysis, chemotherapy, intraperitoneal chemotherapy, antineoplastic agents
Research highlights
Gastric cancer survival remains poor even after aggressive surgical resection and intravenous chemotherapy
We compiled data from 6 studies examining the efficacy and safety of adjunctive intraperitoneal chemotherapy in the treatment of gastric cancer.
We calculated the risk ratio to determine if intraperitoneal chemotherapy improves the survival outcome as an adjunctive treatment to surgery and intravenous chemotherapy.
We report that intraperitoneal chemotherapy is safe, reduces the risk of recurrence and metastasis and improves survival in subjects with gastric cancer.
Introduction
As one of the most prevalent cancers worldwide, gastric cancer is the second leading cause of
cancer related death in Asia and the third in South America and Southeast Europe. The annual global
incidence of gastric cancer is about one million and among the new cases, two-thirds from developing
countries and China contributing about 42% [1],. Gastric cancer is still considered one of the most fatal
forms of malignancy throughout the world and is the leading cancer-associated mortality in many
countries in Asia including Japan, South Korea and China [1], Active prevention, screening and
effective treatment of gastric cancer has become the focus of cancer control planning and
implementation programs in the many countries.
Currently, surgery remains the only curative approach for resectable gastric cancers. Since the
first successful surgical resection of antral gastric cancer by Billoth in 1881, the importance of surgical
resection in the comprehensive treatment of gastric cancers remains high [2]. Japan and South Korea
have reported higher survival rates for gastric cancer patients with post-surgery 5-year survival rate of
more than 50%. This has been attributed to early screening detection and advanced surgical
techniques [3]. In contrast, recent statistics have shown that western countries have 5-year survival
rates of less than 20%. [4-5] China has reported 5-year survival rates of between 20%-50% [6].
Currently in China, despite complete lymphadenectomy performed with gastric resection (D2) as the
standard treatment regimen, the recurrence rate is high as 50-70%.
Local recurrence is the main reason reported for treatment failure [7-8]. As early as 1982, studies
confirmed that the detection of partial residual or recurrence by autopsy was near 80% in gastric
cancer patients. In an attempt to improve the efficacy of treatment, auxiliary intravenous (IV)
chemotherapy was added post surgery; however, approximately 50% of patients with progressive
gastric cancers still develop recurrent metastasis. Clinicians have observed from long-term practice
that microtumor foci in the abdominal cavity are one of the main reasons for recurrence and
metastasis. Therefore, auxiliary IV chemotherapy coupled with Intraperitoneal (IP) chemotherapy
following surgery is hypothesized to reduce the abdominal microtumor foci survival and thereby
improving the gastric cancer survival [9].
IV adjuvant chemotherapy has become accepted as a component of the comprehensive
treatment of gastric cancers. In the last 40 years a large body of research has accumulated, both in
western and Asian countries, studying the utilization of postoperative IV chemotherapy in gastric
cancers. In 1993, Hermans et al., [10] for the first time performed a meta-analysis on 11 randomized
studies that were published between 1980 and 1991, comparing gastric cancer patients receiving
postoperative adjuvant chemotherapies or surgery alone. The authors reported a “slight” increase in
survival rate (OR=0.88, 95% CI=0.78-1.08), however, not statistically significant. In 1999, Earle et al.,
[11] reported a second meta-analysis also comparing trial arms receiving postoperative adjuvant
chemotherapies or surgery only. The subjects in this analysis were chosen from 13 randomized
studies performed in non-Asian countries. The combined data confirmed that postoperative adjuvant
IV chemotherapies improved survival were statistically significant (OR=0.80, 95% CI=0.66-0.97).
Subgroup analysis revealed additional improvement in subjects with positive postoperative lymph
node identification that received adjuvant chemotherapy. In 2000, Mari et al., [12] performed a meta-
analysis of 20 randomized studies conducted worldwide which included 3658 subjects, and revealed
that adjuvant IV chemotherapies reduced the mortality rate by 18% (OR=0.82, 95% CI=0.75-0.89,
P=0.001). The most recent meta-analysis, Janunger et al analyzed 3962 subjects from 21 randomized
studies and reported a similar conclusion supporting survival benefit from adjuvant chemotherapies
(OR=0.84, 95% CI=0.74-0.96) [13].
Clinical studies with multiple drugs and/or multiple strategies have been performed with the
purpose of finding drugs and/or drug combinations that give rise to best treatment efficacy with least
toxicity,. Although there is no widely accepted standard protocol for adjuvant chemotherapies, auxiliary
intravenous chemotherapy following surgical resection has been considered as a standardized
treatment modality for advanced gastric cancers in Japan, South Korea, China and the United States.
[14-15].
Hypothesized explanations that may account for continued treatment failure in gastric cancer
include: 1) cancer cells have invaded the serous layers spreading into the peritoneal; 2) during
surgery, body fluid containing cancer cells such as blood, digestive or lymph overflow into the
abdominal; 3) surgical changes in microenvironment such as disruption of the “seal” of the peritoneum,
the exposure of connective tissues, as well as the release and clot of fiber-like substance around the
surgical areas, facilitate the seeding and proliferation of cancer cells. Related studies [16-18] indicated
that positive surgical peritoneal lavage findings are an independent prognosis factor for high risk of
recurrence after radical surgery. It has been reported that the median survival time for patients with
positive in cytological peritoneal lavage is 14.8 months; while for patients with negative lavage is 98.5
months (P<0.001). The median survival time for those with abdominal metastasis post surgery is as
short as 1 month, and current standard therapy or chemotherapeutic agents have not proven effective
for metastatic abdominal gastric cancers. The large surface area of the abdominal cavity and the
presence of the peritoneal barrier prevent the infiltration of systemic IV chemotherapy to effectively
concentrate in the abdominal cavity. Therefore, IV systemic chemotherapy has shown to only
minimally reduce the incidence of recurrent abdominal metastasis in advanced gastric cancers.
Utilizing IP chemotherapy to reduce the residual microtumor load following radical surgery is
expected to further increase the survival rate of gastric cancer patients. IP administration is a
selective, locally therapeutic method with special pharmacokinetic advantages including [19-20]: a)
allowing drugs to penetrate into the portal vein through abdominal cavity absorption to increase the
drug concentration in portal vein, leading to more efficient elimination of cancer cells in portal vein and
liver parenchyma; b) drugs are readily distributed to all sections of the abdominal cavity, facilitating the
full access of drugs to suspended cancer cells; c) drugs used in IP posses pharmacokinetic
advantages such as high selectivity with locally application allowing constant and sustained high drug
concentrations in the abdominal cavity, while limiting the access to circulation so as to reduce potential
toxicity; and d) drugs can simultaneously kill the growth factors-producing inflammatory cells and
platelets in the abdominal cavity, thereby decreasing the growth of cancer cells.
In 2004, Xu et al., [21] summarized data of 11 clinical studies that included 1164 patients with
progressive gastric cancers and concluded that IP chemotherapy improves the total survival rate (OR
0.51, 95% CI 0.40-0.60). In 2007, Tristan et al., [22] summarized data of 13 clinical studies including
1648 patients with gastric cancers and reported that when compared to surgery only vs. surgery
coupled with systemic auxiliary chemotherapy, surgery coupled with IP hyperthermic chemoperfusion
(HR=0.60, 95% CI=0.43 to 0.83, P=0.002) or early postoperative IP chemotherapy, significantly
increases the survival time (HR=0.45, 95% CI=0.29-0.68, P=0.0002). In 2009, Xu et al., [23]
performed a quantitative comprehensive analysis of 12 randomized studies and found that the odds
ratio (OR) and the confidence interval (CI) was 0.52 and 0.42-0.67, respectively, confirming the
significant advantages of IP chemotherapy. Further subgroup analysis on showed that subjects
benefited significantly more from IP hyperthermic chemotherapy or IP chemotherapy with activated
charcoal. However, there were only 4 studies that meet inclusion criteria in this review.
In 2008, South Korean investigators reported a phase III randomized clinical study indicating that
D2 resection and IP chemotherapy, coupled with early postoperative auxiliary IV chemotherapy
provided survival benefit in gastric cancer patients with destructive serous tumor infiltration. [24].
Brenner et al., [25] proposed that auxiliary IV chemotherapy coupled with early postoperative IP
chemotherapy: was safe and tolerable in patients with locally aggressive gastric cancers, does not
increase the incidence of surgery-associated complications, and reduces the risk of abdominal
recurrence and liver metastasis. Chen et al., [26] performed a review on gastric cancer auxiliary
postoperative IP chemotherapy and reported; a reduction in abdominal cavity metastasis. lymph node
and liver recurrence and increases the total survival time as well as disease-free survival time.
Adjunctive postoperative IV chemotherapy coupled with IP chemoperfusion appears to reduce the
abdominal recurrence and metastasis, thereby increasing the survival time of patients with operable
gastric cancers. However, the strong evidence and ideal treatment guide for prospective randomized
clinical trials of auxiliary postoperative IV chemotherapy coupled with IP chemotherapy for locally
aggressive gastric cancers are still lacking. Therefore, we performed a systemic meta-analysis of
RCTs with the purpose of further evaluating the effectiveness and safety of adjunctive postoperative IV
chemotherapy coupled with IP chemotherapy in gastric cancer patients.
Methods Studies were assessed using the Cochrane Collaboration's methodology.
Search StrategyThis review search Medline, Embase, LILACS and the Cochrane Central Register of Controlled
Trials (CENTRAL) to search for eligible studies using the following Medical Subject Heading terms:
Search terms included: CINAHL search strategies: TX radical N2 (operation or surgery or resection),
TX Infusion* or Intravenous or drip or venous or intraperitoneal, MH "Infusions, Intravenous", TX
Infusion* or Intravenous or drip or venous or intraperitoneal, chemotherapy, Chemotherapy Adjuvant,
TX (carcin* or cancer* or neoplas* or tumour* or tumor* or cyst* or growth* or adenocarcin* or malig*
or metasta*) N5 (Intestin* or Digest* or Gastr* or gut or epigastr* or stomach*), tumor* or cyst* or
growth* or adenocarcin* or malig* or metasta*) N5 (Intestin* or Digest* or Gastr* or gut or epigastr* or
stomach*), MH "Intestinal Neoplasms+"), MH "Stomach Neoplasms".
There were no date or language restrictions in the electronic search for trials. In addition,
references sited in review articles and reported randomized controls clinical trials were searched to
identify additional eligible studies. Hand searching of journals and conference proceedings was
conducted for additional eligible studies.
Selection criteria
Types of studies
RCTs evaluating the efficacy and safety of IV and IP chemotherapeutical interventions for the
treatment of gastric cancer following gastric resection were selected based on the following criteria: 1)
RCT’s that included patients with biopsy evidence of gastric cancer; 2) studies that reported gastric
resection with adjunctive IV compared to IV plus IP as the treatment interventions for gastric cancer.
Types of participants RCTs that included patients with gastric cancer that underwent radical gastric resection with no
other previous gastric cancer surgery or chemotherapy were included in this review.
Types of interventions Studies that reported IVT combined with IPT for gastric cancer after radical operation as the
treatment intervention for gastric cancer. RCTs comparing chemotherapeutic strategies will be
included.
Types of outcome measures The main outcomes analyzed were survival at 1,3, and 5-years, frequency of metastasis and adverse
events. The different chemotherapeutic agents, or methods of administration, were compared to
determine if there were superior outcomes with specific chemotherapeutic agents.
Data extraction and management Two review authors independently assessed the study titles and abstracts of all reported RCT's
that were identified through the search process. Full text copies of all identified eligible studies were
provided to the authors. The two review authors conducted independent assessment of
methodological quality of all trials. A standardized assessment form created for this review was
completed for all studies identified in the search process. Decisions on whether the findings from
specific trials should be included were determined by consensus of the two authors
The data extraction identified the following elements: Study characteristics: Study design,
randomization method, number of participants in each study, number of withdrawals, dropouts and
number lost to follow-up, participants that have completed the study and length of treatment follow-up
assessment time period.
Participant characteristics included: demographic data (age, sex), inclusion and exclusion criteria,
presence of gastric cancer metastasis duration of gastric cancer diagnosis and report of any previous
cancer treatments.
Intervention details included: specific chemotherapeutic agent used (5-fluorouracil, cisplatin, other),
dosing, duration and timing methods of chemotherapy and treatment results for each participant.
Statistical analysisAll extracted data were entered into a data based termed Review Manager (RevMan) Version 5.2
(Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012) for statistical analysis
including odds ratio (OR) and p values.
The primary outcome of survival was analyzed. Meta-analysis of the treatment effect on survival
from trials comparing: gastric resection followed by either IVT lone or IVT with adjunctive IPT were
examined. The relative risk (95% confidence interval) of death was determined as well as the risk
difference (95% confidence interval).
Assessment of risk of bias in included studiesThe methodological quality of the eligible studies was systematically evaluated according to the
criteria in the Cochrane Handbook for Systematic Reviews of Interventions. Specific consideration of
compliance with the principal study inclusion criteria of RCTs on IVT combined with pipit for gastric
cancer after radical surgical resection was maintained. Potential sources of bias were assessed
according to the following types: selection bias (as for type of masking, methods used for randomizing
and technique of randomization utilized), treatment intervention bias (effectiveness of masking
treatment types), attrition bias (rate of drop-outs in different treatment groups, compliance with intent-
to-treat principles) and detection bias (effectiveness of masking outcome measures).
The risk of bias assessment of the studies included evaluation of the following study
characteristics; randomization method of participants, allocation concealment, blinding of participants
and study personnel, blinding of outcome assessors, incomplete outcome data and evidence of
selective reporting.
These areas were rated as "bias present", "bias not present" or "bias unable to be determined".
Studies rated, as bias present were excluded from the review. Authors attempted to be contact to
clarify study rated as “bias unable to be determined.”
Measures of treatment effect Eligible studies comparing specific combinations of IVT and IPT were classified into subcategories
depending on whether the studies used 5-fluorouracil (5-FU), mitomycin-C, an anthracycline, or
cisplatin.
Unit of analysis issues Best survival rates in terms of years and degree or seriousness of side effects.
Dealing with missing data Study authors were attempted to be contacted for missing data in eligible studies.
Assessment of heterogeneity Statistical heterogeneity, potentially due to clinical and/or methodological variability across
selected studies was assessed by visual inspection of the forest and L'Abbe plots and statistically by
means of the chi-squared test for statistical heterogeneity and the I2 test results. Identification of
potential sources of heterogeneity was identified by sub-group and sensitivity analysis. Heterogeneity
in the study results was assessed by interpretation of forest plots and by conducting a chi-square test.
Assessment of reporting biases The methodological quality of the eligible studies was systematically evaluated according to the
criteria in the Cochrane Handbook for Systematic Reviews of Interventions. Specific consideration of
compliance with the principal study inclusion criteria of RCTs on IV and IP treatment of gastric cancer
was maintained. Potential sources of bias were assessed according to the following types: selection
bias (as for type of masking, methods used for randomizing and technique of randomization utilized),
treatment intervention bias (effectiveness of masking treatment types), attrition bias (rate of drop-outs
in different treatment groups, compliance with intent-to-treat principles) and detection bias
(effectiveness of masking outcome measures).
These areas were rated as "bias present", "bias not present" or "bias unable to be determined".
Studies rated as bias present were excluded from the review. We further attempted to contact study
authors to clarify those studies rated as “bias unable to be determined”.
Forest plots and reported effect sizes were evaluated to assess for publication bias and English
language bias in the meta-analysis.
Data synthesis Meta-analysis was performed according to a random-effects model when substantial
heterogeneity of the treatment effects was determined. The meta-analysis results report from a fixed
model when there are too few eligible studies identified or if there was not substantial heterogeneity.
The primary outcome of overall survival benefits was analyzed. Meta-analysis of the treatment effect
on improved survival rate at follow-up dates, specific chemotherapeutic drug benefits including survival
data, side effects reported and frequency of treatment administered. The relative risk (95% confidence
interval) of gastric cancer recurrence or death associated with intravenous chemotherapy combined
with intraperitoneal perfusion chemotherapy treatment was determined as well as the risk difference
(95% confidence interval).
Subgroup analysis and investigation of heterogeneity Additional analysis of sources was explored when statistical heterogeneity was identified. Sub-
groups analysis was performed and included analysis of the types of chemotherapeutic agents used
(5-FU, cisplatin, other) and chemotherapy combinations used and frequency of treatments.
ResultsA total of 392 study reports were collected in search results; all identified search results are
shown in a flowchart (Fig.1). After excluding 106 duplicate reports of the same studies, 203 non-
randomized studies and 67 unrelated studies, 16 studies met our inclusion criteria. On further
inspection of these 16 RCTs, 10 had substantial missing data; therefore, 6 RCTs met inclusion criteria
for this systematic review [27-32]. See figure 1. The Shimoyama study [31] designed two arms in the
treatment group. Both arms included identical doses of IV and adjunctive IP chemotherapeutic agents,
but different doses of the oral chemotherapeutic agent, tegaful-uracil (UFT). In this meta-analysis each
of the two arms were compared to the control group independently, as 1) IVT plus IPT and low UFT
dose compared to controls and 2) IVT plus IPT and high UFT dose compared to control. Therefore, 7
different analyses were calculated in this study.
Fig 1. Flowchart of study selection.
RCTs = randomized clinical trials, n= number of research reports
A significant variation in chemotherapeutic agents was used in the 6 qualifying studies. In
addition, there was significant heterogeneity in regards to the methods and timing of the administration
of the chemotherapeutic agents used. See table 1.
Definitions: pod= post-operative day, tx=treatment(s), qweek=once a week, qmos=once a month,
(H)=hyperthermic IP chemotherapy
One study [30] did not report specific chemotherapy medications administered. The following IV
agents were utilized in the 5 remaining studies: 5-FU in 3 of the 5 studies (60%), cisplatin in 4 of 5
(80%), mitomycin-C in 2 of 5 (40%), and both adriamycin and leucovorin were used in 1 of 5 (20%) of
the studies.
The following IP agents were utilized in the 6 eligible studies: 5-FU in 2 of the 6 studies (33.3%),
cisplatin in 3 of 6 (50%), mitomycin-C in 4 of 6 (66.6%), and both adriamycin and leucovorin were used
in 1 of 6 (16.6%) of the included studies.
Survival at 1-year post-interventionFour studies [27-29,31,32], 5 comparisons, reported survival rate at 1-year. 171 of 204 subjects
(82.2%) in the control groups (surgery with IV chemotherapy only) were alive at 1 year compared to
178 of 191 survivors (93.2%) in the experimental groups (surgery with combined IV and IP
chemotherapy). This represents a statistical improvement in 1-year survival in combined IV/IP
treatment group (P=0.006) and a combined risk ratio of 1.11 (95% CI 1.04, 1.17) that supports an
increased likelihood of survival at 1 year after treatment in the experimental group subjects. See figure
2.
Insert Fig 2. Individual and combined calculated risk ratio for survival at 1-year.
CI= confidence interval, IV= intravenous, IP= intraperitoneal
Survival at 3-years post-interventionSix studies [27-32], 7 comparisons, reported survival rate at 3-years. 279 of 494 subjects (56.5%)
in the control groups (surgery with IV chemotherapy only) were alive at 3 years compared to 338 of
491 survivors (68.8%) in the experimental groups (surgery with combined IV and IP chemotherapy).
This represents a statistical improvement in 3-year survival in combined IV/IP treatment group
(P<0.0001) and a combined risk ratio of 1.22 (95% CI 1.11, 1.35) that supports an increased likelihood
of survival to 3 years after treatment in the experimental group subjects. See figure 3
Insert Fig 3. Individual and combined calculated risk ratio for survival at 3-years.
CI= confidence interval, IV= intravenous, IP= intraperitoneal
One study [28] compared relapse free survival at 3 years post intervention. 129 of 258 subjects
(50.0%) in the control groups (surgery with IV chemotherapy only) survived with no evidence of
residual gastric cancer at 3 years compared to 158 of 263 survivors (60.1%) in the experimental
groups (surgery with combined IV and IP chemotherapy). This represents a statistical improvement in
3-year relapse free survival in combined IV/IP treatment group (P=0.02) and a combined risk ratio of
1.50 (95% CI 1.06, 2.13) that supports an increased likelihood of surviving to 3 years after treatment,
with no evidence of disease in the experimental group subjects.
Survival at 5-years post-interventionThree studies [29-31], 4 comparisons, reported survival rate at 5-years. 66 of 184 subjects
(35.9%) in the control groups (surgery with IV chemotherapy only) were alive at 5 years compared to
85 of 162 survivors (52.5%) in the experimental groups (surgery with combined IV and IP
chemotherapy). This represents a statistical improvement in 5-year survival in combined IV/IP
treatment group (P=0.002) and a combined risk ratio of 2.00 (95% CI 1.30, 3.09) that supports an
increased likelihood of survival to 5 years after treatment in the experimental group subjects. See
figure 4.
Insert Fig 4. Individual and combined calculated risk ratio for survival at 5-years.
CI= confidence interval, IV= intravenous, IP= intraperitoneal
Metastasis One study [27] reported metastasis occurrences not previously documented at study entrance.
New metastasis occurred in 18 of 41 subjects (43.9%) in the control group and 9 of 44 (20.5%) in the
experimental group (surgery with combined IV and IP chemotherapy). This represents a significantly
greater risk of developing metastasis (0.3, 95% CI 0.13, 0.86). A similar rate of metastasis (39% vs
15.9%) and odds ratio (0.3, 95% CI 0.11, 0.82) was found at 3-year follow-up.
One study [29] specifically reported frequency of peritoneal metastasis at 2 years. Peritoneal
metastasis occurred in 45 of 120 subjects (37.5%) in the control group and 13 of 92 (14.1%) in the
experimental group (surgery with combined IV and IP chemotherapy). This represents a significantly
greater risk of developing peritoneal metastasis in the surgery plus IV only subjects (0.55, 95% CI
0.35, 0.87).
Adverse EffectsTwo studies [28,32] quantified and reported adverse effects from the chemotherapy regimens.
One study [28] reported peripheral edema occurred in 20 of 258 subjects (7.8%) in the control
group and 74 of 263 (28.1%) in the experimental group (surgery with combined IV and IP
chemotherapy). This represents a significantly greater risk of developing peripheral edema in the
experimental group subjects (4.66, 95% CI 2.74, 7.91).
One study [28] reported neutropenia occurred in 161 of 258 subjects (62.4%) in the control group
and 217 of 263 (82.5%) in the experimental group (surgery with combined IV and IP chemotherapy).
This represents a significantly greater risk of developing neutropenia in the experimental group
subjects (2.84, 95% CI 1.89, 4.29).
The combined rate of neuropathy from 2 studies (Yoon-Koo, Gao) was 18.6% (52 of 279 subjects)
in control groups and 58.7% (169 of 288 subjects). This represents a statistical greater rate of
neuropathy occurred in combined IV/IP treatment group (P=0.00001) and a combined odds ratio of
6.01 (95% CI 4.1, 8.79) that supports an increased likelihood of developing neuropathy in the
experimental group subjects.
No statistical difference was noted in the rate of anemia [28], thrombocytopenia [28] or bone
marrow suppression [32] between control and experimental treatment groups.
DiscussionDespite advances in early detection, radiation, gastric surgery methods and chemotherapies,
gastric cancer survival remains poor.
Directing cancer cell killing agents in close proximity to malignant cells has long been understood
as potentially a more effective directive in treating many cancer types. This approach is the main stay
of radiation therapy and has been shown to be effective in treating localized tumors. Systemic IV
chemotherapy plays a critical role in attacking the cells of the primary tumor site and destroying distant
metastatic cells throughout the body. However, there are several likely reasons why systemic
chemotherapy is insufficient in some cancer types. It may not be possible for enough of the
chemotherapeutic agent to enter a tumor mass based on the arterial and venous density of the cancer
type. In addition, the blood concentration of a chemotherapeutic agent may not be great enough to
affect the majority of cells in the tumor site.
IP chemotherapy has been utilized in the treatment of several intra-abdominal cancers. The
abdomen provides a natural reservoir to infuse, and maintain, a fluid in place for an extended amount
of time. This allows the chemotherapeutic agents to surround and “bath” a tumor burden within the
cavity. In addition, the medication is absorbed into local tissue, including the primary tumor, directly
affecting the tissue and cells it passes through. This absorption also leads to systemic absorption and
creates a blood level of the chemotherapeutic agent. Increasing numbers of abdominal cancers are
currently under study to determine the effectiveness adjunctive IP chemotherapy. Studies and meta-
analysis reports have confirmed improved survival rates utilizing IP chemotherapies in abdominal
cancers, including colorectal cancer [33,34] peritoneal carcinmatosis [35,36] ovarian cancer [37-39]
and peritoneal mesothelioma [40].
This meta-analysis systematically evaluated 6 RCTs comparing outcome of radical gastric
resection plus IV chemotherapy vs radical gastric resection plus IV chemotherapy with adjunctive IP
chemotherapy. The findings in this report confirm the benefit of improved survival rates in those
subjects treated with adjunctive IP chemotherapy.
Studies reporting survival rates at 1-year, 4 of the 5 IP groups showed improved outcome, except
for the low dose branch in the Shimoyama study. The improved outcome in the IP groups was
significant when the data of all 5 studies were combined. The most significant OR was in the high dose
Shimoyama study that utilized IV cisplatin, a single administration IP mitomycin-C, followed with high
dose tegaful-uracil (UFT) for 2 years post operatively.
The data at 3-years, in 5 of the 6 experimental groups, reported improved outcome. The
combined results showed improved outcome in the IP groups overall. Again, the most significant OR
was in the high dose Shimoyama study that utilized IV cisplatin, a single administration IP mitomycin-
C, followed with high dose tegaful-uracil (UFT) for 2 years post operatively.
The heterogeneous methods and chemotherapeutic agents varied significantly in the selected
studies. The most common IP chemotherapeutic agent was mitomycin-C, used in 4 of the 6 studies.
The survival rates at 5 years continued to show improved survival rates in the IP groups. All 4 of
the IP groups showed improved survival at 5 years and the combined analysis was statically
significant.
Relapse and metastasis data were recorded in 5 studies and [27-31] all reported higher rates in
the control groups, utilizing surgery and IV chemotherapy only.
Although survival is considered the most important outcome, adverse effects and quality of life in
survivors is also important to consider. Edema, thrombocytopenia and neutropenia were found to
occur more frequently in the IPT groups. The extent and disability related to these factors was not
reported.
The limitations of this meta-analysis are the limited number of studies that meet the RCT criteria
and the variation in the chemotherapeutic agents used both IV and IP. In addition, 2 studies utilized
adjunctive oral chemotherapy agents. This heterogeneity of methods therefore does not allow an inter-
study comparison of which chemotherapy drug was more effective that the others studied. The
inconsistent study reporting of the histological features, extent of tumor invasion and grading made
chemotherapeutic agent effectiveness analysis invalid. This meta-analysis did not analyze the
differences in treatment efficacy between IP hyperthermic chemoperfusion and non-hyperthermic
chemoperfusion or the potential relationship between the IP chemotherapy cycle numbers and the
treatment efficacy and safety since an insufficient number of studies recorded this data.
ConclusionsThis systemic meta-analysis has confirmed the improved treatment efficacy and safety of IP
chemotherapy coupled with IV chemotherapy compared to IV chemotherapy alone following gastric
resection. This report cannot report clear evidence that any one specific IP chemotherapeutic agent is
more effective that the others. Although the amount of RCTs that meet our selection criteria was
relatively small, the collective data obtained from the included studies are of great importance and
medical value. These results provide guidance for use of additional treatment options for oncologists
when managing gastric cancers and provides a framework for further investigation of gastric cancer
treatments. Additional RCTs with larger sample sizes, and more uniform consistent methodologies,
are required to confirm the treatment efficacy of gastric cancer auxiliary postoperative IV
chemotherapy coupled with IP chemotherapy.
DisclosurePublication of this article was not supported by any grants.
References[1].Yang L. Incidence and mortality of gastric cancer in China. World J Gastroenterol, 2006, 12(1): 17-
20
[2].JI Jia-fu, SHAN Fei. Comprehensive therapy of gastric carcinoma. Zhong Hua Wai Ke Za Zhi,
2011,49(3): 193-197
[3].Sasako M, Saka M, Fukagawa T, et al. Surgical treatment of advanced gastric cancer: Japanese
perspective. Dig Surg, 2007, 24(2): 101-107
[4].Zerbib P, Khoury-Helou A, Chio F, et al. Adenocarcinoma of the gastric stump. Ann Chir, 2003,
128(8): 521-525
[5].Lamb P, Sivashanmugam T, White M, et al. Gastric cancer surgery--a balance of risk and radically.
Ann R Coll Surg Engl, 2008, 90(3): 235-42
[6].Lin F, Wu WL. Surgical treatment for advanced gastric cancer. Zhong Hua Wei Chang Wai Ke Za
Zhi, 2011, 14(2): 81-83
[7].De Roover A, Detmz B, Detry O, et al. Adjuvant hyperthermic intraperitoneal preoperative
chemotherapy (HIPEC) associated with curative surgew for locally advanced gastric carcinoma.
An initial experience. Acta Chir Belg, 2006, 106(3): 297-301
[8].Wu B, Wu D, Wang M, et al. Recurrence in patients following curative resection of early gastric
carcinoma. J Surg Oncol, 2008, 98(6): 411-414
[9].Maehara Y, Hasuda S, Koga T, et al. Postoperative outcome and sites of recurrence in patients
following curative resection of gastric cancer. Br J Surg, 2000, 87(3): 353-357
[10].Hermans J, Bonenkamp JJ, Boon MC, et al. Adjuvant therapy after curative resection for gastric
cancer: meta-analysis of randomized trials. J Clin Oncol, 1993, 11(8): 1441-1447
[11].Earle CC, Maroun JA. Adjuvant chemotherapy after curative resection for gastric cancer in non-
Asian patients: revisiting a meta-analysis of randomised trials. Eur J Cancer, 1999, 35(7): 1059-
1064
[12].Mari E, Floriani I, Tinazzi A, et al. Efficacy of adjuvant chemotherapy after curative resection for
gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo
Italiano per lo Studio dei Carcinomi dell' Apparato Digerente). Ann Oncol, 2000, 11(7): 837-843
[13].Janunger KG, Hafström L, Glimelius B. Chemotherapy in gastric cancer: a review and updated
meta-analysis. Eur J Surg, 2002, 168(11): 597-608
[14].Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1,
an oral fluoropyrimidine. The New England journal of medicine, 2007, 357(18): 1810-1820
[15].GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration)
Group, Paoletti X, Oba K, Burzykowski T, et al. Benefit of adjuvant chemotherapy for resectable
gastric cancer: a meta-analysis. JAMA, 2010, 303(17): 1729-1737
[16].Burke EC, Karpeh Ms, Jr Conlon Kc, et al. Peritoneal lavage cytology in gastric cancer: an
independent predictor of outcome. Ann Surg Oncol, 1998, 5: 411-415
[17].Bentrem D, Wilton A, Mazumdar M, et al. The value of peritoneal cytology as a preoperative
predictor in patients with gastric carcinoma undergoing a curative resection. Ann Surg Oncol,
2005, 12: 347-353
[18].Chu DZ, Lang NP, Thompson C, et al. Peritoneal carcinomatosis in non-gynecologic malignancy.
A prospective study of prognostic factors. Cancer, 1989, 63(2): 364–367
[19].Pestieau SR, schnake KJ, Stuart OA, et al. Impact of carrier solutions on pharmacokinetics of
intraperitoneal chemotherapy. Cancer Chemother Pharmacol, 2001, 47(3): 269-276
[20].Ceelen WP, Hesse U Hemptinne B, et al. Hypothermic intraperitoneal chemoperfusion in the
treatment of locally advanced intra-abdominal Cancer. Br J surg, 2000, 87(8): 1006-1015
[21].Da-Zhi Xu, You-Qing Zhan, Xiao-Wei Sun, et al. Meta-analysis of intraperitoneal chemotherapy
for gastric cancer. World J Gastroenterol, 2004, 10(18): 2727-2730
[22].Tristan D. Yan, BSc MBBS, Deborah Black, et al. A Systematic Review and Meta-analysis of the
Randomized Controlled Trials on Adjuvant Intraperitoneal Chemotherapy for Resectable Gastric
Cancer. Ann Surg Oncol, 2007, 14(10): 2702-2713
[23].XU Da-Zhi, GENG Qi-Rong, LIN Tong-Yu, et al. Role of Intraperitoneal Chemotherapy After
Radical Resection of Local Advanced Gastric Cancer. Role of intraperitoneal chemotherapy after
radical resection of local advanced gastric cancer. J Fourth Mil Med Univ, 2009, 30(5): 443-446
[24].KANG Y, CH ANG H,ZANG D, et al. Postoperative adjunctive chemotherapy for grossly serosa
positive advanced gastric cancer: a randomized phase III trial of intraperitoneal cisplatin and
early mitomycin C plus long term doxifluridine plus cisplatin ( ice MFP) versus mitomycin C plus
short-term doxifluridine ( M f) ( AM C 0101) ( NC T00296322). J Clin Oncol, 2008, 26( Suppl):
4511
[25].BRENNER B, SHAHM A, KARPEH M S, et al. A phase & trial of neoadjuvant cisplatin fluorouracil
followed by post operative in traperitoneal floxuridin eleucovorin in patients with locally advanced
gastric cancer. Ann Oncol, 2006, 17( 9): 1404-1411
[26].Chunmei Shi, Baoyu Yang, Qiang Chen, et al. Retrospective analysis of adjuvant intraperitoneal
chemotherapy effect prognosis of resectable gastric cancer. Oncology, 2011, 80(5-6): 289-295
[27].
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