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.

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