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10.1245/s10434-006-9205-7
Annals of Surgical Oncology 14:61-68 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Early Postoperative Intraperitoneal Chemotherapy Following Cytoreductive Surgery in Patients with Very Advanced Gastric Cancer

Jae-Ho Cheong, MD1,2, Jia Yun Shen, MD1,4, Chang Soo Song, MD1,2, Woo Jin Hyung, MD1,2, Jian Guo Shen, MD1,4, Seung Ho Choi, MD1 and Sung Hoon Noh, MD1,2,3

1 Department of Surgery, Yonsei University College of Medicine, Seoul 120-752, Korea
2 Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul 120-752, Korea
3 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea
4 Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China

Correspondence: Address correspondence and reprint requests to: Sung Hoon Noh, MD, Department of Surgery, Yonsei University College of Medicine, 134 Shinchon-dong Seodaemun-gu, Seoul 120-752, Korea; E-mail: sunghoonn{at}yumc.yonsei.ac.kr.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The survival of patients with stage IV gastric cancer is poor due to frequent peritoneal failure. The aim of this study was to investigate the impact of early postoperative intraperitoneal chemotherapy (EPIC) after cytoreductive surgery on the long-term survival of these patients, as determined by residual disease status.

Methods: A total of 154 patients with stage IV gastric cancer were enrolled in our study. All patients underwent potentially curative or palliative resections. After surgery, the residual disease states of the patients were recorded. All patients received EPIC.

Results: Of all 154 patients, R0 resection was achieved in 37, R1 in 56, and R2 in 61. All patients received a mean of 4.3 EPIC perfusions. After a mean followup period of 29 months, 14 patients remained alive. The median survival of all 154 patients was 11.4 months. Survival times were analyzed according to the type of residual tumor; the median survival time was 25.5 months in the R0 group, 15.6 months in the R1 group, and 7.2 months in the R2 group (p < .001). Upon multivariate analysis, the residual tumor states and the cycle of EPIC perfusion were found to be independent prognostic predictors (p < .001 and p = .018, respectively).

Conclusions: The residual tumor status is the most important predictor for the survival of very advanced gastric cancer patients who received cytoreductive surgery and EPIC. Therefore, complete cytoreductive surgery yielding R0 resection is mandatory for achieving the beneficial effects of EPIC.

Key Words: Gastric cancer • EPIC • Cytoreductive surgery • R0 resection


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The survival of patients with stage IV gastric cancer, even in the absence of distant metastases, is poor. The presence of peritoneal dissemination is the most common cause of noncurative resection, recurrence after curative surgery, and death for these patients.1–3 Thus, the treatment and prevention of peritoneal dissemination may affect the probability of long-term survival. However, there is no standard treatment or effective anticancer drugs for peritoneal dissemination. Surgery alone and systemic chemotherapy have both yielded disappointing results.4–6

A new approach that combines maximal surgical extirpation of detectable tumors and maximal regional chemotherapy has been reported to have the potential to cure selected groups of patients who have peritoneal carcinomatosis from gastrointestinal cancer.1,3 Early postoperative intraperitoneal chemotherapy (EPIC) offers potential therapeutic advantages over systemic chemotherapy.7–9 Many studies suggest that EPIC or intraoperative intraperitoneal chemotherapy (IPT), combined with cytoreductive surgery, is safe and could improve outcomes for selected groups of patients with peritoneal dissemination from gastric cancer and other malignant tumors of diverse origins, such as colorectal cancer.10–12

This study aimed to investigate the impact of EPIC on the survival of patients with very advanced gastric cancer after cytoreductive surgery, according to residual disease status.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility Criteria
The eligibility criteria were as previously described.10 Each patient was required to give a complete history and undergo a physical examination, chest X-ray, upper gastrointestinal X-ray series, computed tomography scan, ultrasonography, and an endoscopic evaluation of the esophagus and stomach. There were two levels of eligibility: Preoperatively, patients were considered candidates for IPT if they met the following criteria: (1) advanced gastric carcinoma confined to the abdominal cavity; (2) age ≤ 76 years; (3) no history of previous cancer, gastric resection, or previous cytotoxic chemotherapy; (4) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; (5) normal bone marrow function (white blood cell count ≥4000/mm3, platelet count ≥100,000/mm3, hemoglobin ≥10 g/dl); (6) normal renal function (creatinine concentration <1.5 mg/dl); (7) absence of myocardial, hepatic, and neurologic impairment; and (8) verbal and written informed consent before initiation of treatment. Patients with extra-abdominal or liver metastasis based on physical and radiologic examination were excluded.

The second level of eligibility was determined during laparotomy by assessing whether patients had (1) a resectable gastric cancer with definite serosal infiltration or involvement of adjacent structures and (2) no hepatic metastasis. Based on these eligibility criteria, a total of 154 patients were enrolled in this study between January 1993 and December 2000.

Surgery
All patients underwent gastric resection and D2 or more lymph node dissection. The need for other surgical procedures, such as combined resection of involved adjacent organs or cytoreductive surgery for peritoneal dissemination, was determined by the attending surgeon based on the extent of tumor dissemination.

Assessment of residual tumors after cytoreductive surgery was made according to both the International Union against Cancer TNM classification20 and the residual tumor size classification of Yonemura et al.12 A curative (R0) resection was defined as the absence of macroscopic residual tumors, with the specimens being free of tumor cells in the resection margins. Resections were classified as R1 when the margins of the resected specimens (i.e., the primary tumor with its regional lymph nodes and distant metastases) showed microscopic residual tumors or when the diameter of each residual tumor was less than 3 mm. They were classified as R2 when there were macroscopic residual tumors larger than 3 mm in diameter as a result of incomplete cytoreduction. The anatomical sites of residual diseases were found at the mesentery, serosal surface of both small and large intestine, pelvic peritoneum, and rectal wall in the R1 and R2 groups. Most R2 resections were a result of massive involvement of small bowel mesentery and serosal surface which hindered complete removal for fear of resultant short-gut syndrome.

After surgery, a Tenckhooff catheter and two closed-suction drains were placed into the peritoneal cavity and 15 mg MMC was applied equally to all quadrants of the abdomen just before closure of the abdominal wall. The drains were clamped in place for 24 h.

Intraperitoneal Chemotherapy and Followup
The details of EPIC and followup are as previously described.10 A total dose of 500 mg/m2 5-fluorouracil (5-FU) and 40 mg/m2 cisplatin in 0.5 L of normal saline each was introduced into the peritoneal cavity with a Tenckhoff catheter over 60 min/day for 4 consecutive days. The catheter and drains were then clamped for 23 h and no effort was made to drain the intraperitoneal cavity unless it was necessary for patient comfort and the next IPT. Intravenous hydration and antiemetic therapy were routinely given before EPIC. Twelve cycles of EPIC were planned at 4-week intervals. All patients had a complete history, physical examination, routine laboratory checks, and chest X-ray before each cycle of therapy. Radiologic studies, including ultrasonography and computed tomography, were performed every three cycles during chemotherapy. After completion of chemotherapy, patients were followed up regularly for symptoms and physical evidence of recurrence. An endoscopic examination was performed biannually.

Statistical Analysis
All statistical analyses were conducted using the statistical program SPSS 13.0 (SPSS, Inc., Chicago, IL). The pretreatment characteristics were analyzed using the two-tailed {chi}2 test, one-way analysis of variance (ANOVA), and Kruskal-Wallis test. Survival analyses were assessed using the Kaplan-Meier method and the Cox proportional hazard regression model. In all statistical analyses, p < .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients’ Characteristics
A detailed description of patients’ characteristics is given in Table 1Go. The male-to-female ratio was 1.26:1 (86:68), with a mean age of 46 (range = 18–76) years. Most of the patients had infiltrative or diffuse-type tumors (91.6%) and histologically undifferentiated tumors (86.3%). All patients had tumors with serosal infiltration (46.1%) or adjacent structure involvement (53.9%), while 138 patients (89.6%) had lymph node metastasis and 105 patients (68.2%) had localized or extensive peritoneal dissemination at the time of operation. When we compared these features according to the residual tumor, both lymph node metastasis status and peritoneal metastasis status exhibited significant differences between groups (p = .003 and p = .005, respectively) (Table 2Go).


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  		TABLE 1. Patients’ characteristics
 

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  		TABLE 2. Patients’ characteristics according to residual tumor type
 
Treatment Compliance, Morbidity, and Mortality
Among the 154 total patients, curative resection (R0) was achieved in only 37 (24.0%), although every effort was made, including extended lymph node dissection, combined resection of adjacent organs, or cytoreductive surgery for peritoneal dissemination. R1 resection was achieved in 56 patients (36.4%), and 61 patients (39.6%) received R2 resection only. A mean of 4.3 cycles (range = 1–12) of EPIC were delivered despite 12 cycles being initially planned. Only eight patients completed 12 cycles; three were in R0 group and five were in R1 group. The reasons for truncating the number of cycles were disease progression or relapse, postoperative complications, patient refusal, catheter malfunction, poor compliance, grade 4 myelosuppression, or operative mortality. The cycles of EPIC also reached a significant difference when analyzed according to the residual disease status (p = .003) (Table 2Go)

Thirty-five patients (22.7%) experienced postoperative complications. Among these, catheter problems and chemical peritonitis were most likely to relate directly to EPIC, while most others were considered to occur in combined effects of cytotoxic drugs, postoperative and EPIC itself. Only four (2.6%) patients died from treatment-related causes: three from septic shock and one from refractory salt-losing nephropathy. The details of morbidity and mortality are given in Table 3Go.


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  		TABLE 3. Morbidity and mortality
 
Outcomes
As of March 2006, the mean followup time was 29 months (95% CI = 21.9–36.1). Fourteen patients remained alive without evidence of recurrence, whereas 138 patients died due to recurrence or progression of disease. Two were lost to followup. Ten of the remaining 14 patients received R0 resections, while 4 patients received R1 resections; none were in the R2 group (p < .001). The median survival of all 154 patients was 11.4 months (95% CI = 10.0–12.9) and the overall 5-year survival rate (5-YSR) was 12.2% (Fig. 1Go).


Figure 1
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  		FIG. 1. Overall survival times for the 154 patients in our study. The median survival of all 154 patients was 11.4 months (95% CI = 10.0–12.9) and the overall 5-year survival rate (5-YSR) was 12.2%.

 
When survival was analyzed according to residual tumor status, the median survival was 25.5 months (95% CI = 12.1–39.0) in the R0 group, 15.6 months (95% CI = 10.6–20.6) in the R1 group, and 7.2 months (95% CI = 6.5–7.9) in the R2 group (p < .001) (Fig. 2Go). The 5-YSR for the R0 and R1 groups was 31.7% and 12.5%, respectively. Only one patient in the R2 group lived more than two years, with a survival time of 24.9 months. Upon multivariate analysis, the residual tumor states and the number of cycles of EPIC perfusion emerged as independent prognostic predictors (p < .001 and p = .018, respectively) (Table 4Go). Compared with the R0 group, the relative hazard ratio (HR) for the R1 group was 1.667 (95% CI = .967–2.873, p = .066) and for the R2 group it was 5.237 (95% CI = 2.859–9.595, p < .001). The number of cycles of EPIC was a favorable prognostic predictor, with a HR of .922 (95% CI = .862–.986, p = .018). Patients who received more than the mean number (4.3) of cycles of EPIC had a median survival time of 20.3 months (95% CI = 16.1–24.5), while those who received less than the mean number of cycles survived only 8.3 months (95% CI = 5.4–11.2, p < .001). Their 5-YSR was 21.7% and 7.0%, respectively (Fig. 3Go).


Figure 2
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  		FIG. 2. Survival analysis according to the type of residual tumor. Median survival was 25.5 months (95%% CI = 12.1–39.0) in the R0 group, 15.6 months (95% CI = 10.6–20.6) in the R1 group, and 7.2 months (95% CI = 6.5–7.9) in the R2 group (p < .001).

 

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  		TABLE 4. Univariate and multivariate survival analyses of clinical and pathologic factors
 

Figure 3
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  		FIG. 3. Survival analysis according to the mean number of cycles of EPIC. The median survival of patients who received more than the mean number (4.3) of cycles of EPIC was 20.3 months (95% CI = 16.1–24.5), while of that of others was 8.3 months (95% CI = 5.4–11.2) (p < .001).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The presence of peritoneal dissemination is the most common cause of death in patients with stage IV gastric cancer.1–3 Therefore, the prevention and treatment of peritoneal dissemination is the key to long-term survival. However, there is no standard treatment and no effective anticancer drugs for peritoneal dissemination. In one study, the median survival for patients with peritoneal cacinomatosis of gastric cancer treated by surgery alone was only one month.4 Systemic chemotherapy also showed disappointing results. Two meta-analyses have shown that adjuvant systemic chemotherapy does not improve survival in patients with resected gastric cancer and suggested that it could not be recommended as a routine procedure because of the lack of confirmed beneficial effects.5,6 In the past a number of studies showed the beneficial effects of IPT combined with cytoreductive surgery.10–19 In this study, the median survival of all 154 patients was 11.4 months and the overall 5-year survival rate (5-YSR) was 12.2% (Fig. 1Go). Our main finding was that residual disease status was the most important independent prognostic factor for patients with stage IV gastric cancer who underwent cytoreductive surgery and EPIC.

We observed remarkable differences between the survival rates of patients who received complete and incomplete cytoreductions. A median survival period of 25.5 months was achieved in the R0 group, whereas it was only 15.6 and 7.2 months in the R1 and R2 groups, respectively (p < .001) (Fig. 2Go). The 5-YSR reached 31.7% in the R0 group and 12.5% in the R1 group, while no patients lived more than three years in the R2 group. From multivariate analysis, the residual tumor status was the most important predictive factor for survival (p < .001) (Table 4Go). This result was consistent with the findings of many other investigators,21–23 suggesting the extremely important role of a complete cytoreduction. As such, every effort should be made to achieve a R0 resection, including extended lymph node dissection, combined resection of adjacent organs, and cytoreductive surgery for peritoneal dissemination in carefully selected patients.16,24

Interestingly, there was no significant difference in survival between the R0 and R1 groups from multivariate analysis (p = .066), where the relative HR for the R1 resection was 1.667. In contrast, the HR was 5.237 (p < .001) (Table 4Go) for the R2 group. We attributed the differences observed in these two groups to the effects of EPIC. Some researchers reported that IPT penetrates into peritoneal carcinomatosis nodules by only 2–5 mm.24,25 We assessed the residual tumors after cytoreductive surgery according to the classification of Yonemura et al.12 and set the criterion for R2 resection as a macroscopic residual tumor larger than 3 mm in diameter. By this criterion, the efficacy of EPIC might have been limited in patients who underwent R2 resection; therefore, it failed to achieve a prognosis as good as in other patients groups. However, with the R1 group, because there were only microscopic residual tumors that were no more than 3 mm in diameter, the EPIC drugs could penetrate through the residual nodules to promote drug efficacy.21–23 Recent articles18,19 showed findings similar to those in our study. The same approach was administered to peritoneal carcinomatoses originating in gynecologic cancers and was observed to yield good results, even when the largest residual tumor was nearly 1 cm in diameter compared with the 2–5-mm diameter of the gastroenteric tumors where the metastases originated. These differences in response are likely attributed to the unique biological behavior and sensitivity to the chemotherapy between the different primary diseases. However, this assumption should be further evaluated through future studies focusing on the molecular biological aspect of specific cancers.

When we compared the clinical and pathologic features of the patients according to the type of residual tumor, lymph node metastasis status and peritoneal metastasis status (PMs) showed significant differences between the groups (p = .003 and p = .005, respectively) (Table 2Go). PMs also affected the survival when univariate survival analysis was performed (p < .001) (Table 4Go). However, in the multivariate regression model, neither were independent risk factors. Thus, we thought that positive PMs might affect the prognosis by increasing the chance of noncurative resection. The R2 resection rate was only 24.5% (12/49) in patients without peritoneal dissemination compared with 46.7% (49/105) in those with peritoneal metastasis (p = .013) (Table 2Go). To prove our hypothesis, we evaluated the effect of PMs on survival in each of the R0, R1, and R2 groups. Although there was a significant difference between the survival of patients with or without peritoneal metastasis (p = .021) in the R0 group, there was no such finding in the R1 and R2 groups (p = .124 and p = .595, respectively) (Fig. 4Go). Only in subgroup analysis of the R0 group was PMs not an independent risk factor according to a multivariate analysis (p = .304), suggesting that if we achieve a complete cytoreduction, even in the patients with PMs, the outcome could be as good as those without. Furthermore, from the multivariate analysis for the R0 group alone, none of the variables in Table 4Go (except residual tumor status) emerged as an independent prognostic predictor; the closest candidate was the number of EPIC cycles (p = .063; HR = .864; 95% CI = 0.74–1.008).


Figure 4
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  		FIG. 4. Survival analyses according to peritoneal metastasis status (PMs) in each group: R0, R1 and R2. (A) This figure shows a significant difference between the survival of patients with or without peritoneal metastasis in the R0 group (p = .021). (B) In the R1 group, there was no difference between the survival of patients with or without peritoneal metastasis (p = .124). (C) In the R2 group, there was no difference between the survival of patients with or without peritoneal metastasis (p = .595).

 
For all patients, the number of EPIC cycles was found to be an independent predictor for favorable prognosis (HR = .922; p = .018) (Table 4Go). In our study, patients who received more than the mean number (4.3) of EPIC cycles had a median survival of 20.3 months, which was significantly better than the 8.3 months in the other patients; their 5-YSRs were 21.7% and 7.0%, respectively (Fig. 3Go). To our knowledge, this is the first report of such a finding, which contrasts with Sugarbaker’s results published in 1996.26 However, our data could not support the hypothesis that more cycles of EPIC could lead to a better prognosis because the number of EPIC cycles was not an independent risk factor for survival in the R0 group and it could not be ruled out that more cycles of EPIC were delivered as a result of longer survival of patients with more complete cytoreduction. The efficacy of increasing the number of cycles of IPT was inadequately investigated before, even if it was for systemic chemotherapy; the results still remained controversial. Some authors revealed no confirmed clinical advantage for an increased number of cycles of chemotherapy,27,28 while several other investigators found a significantly better outcome when more cycles of the same agents were administered, including a phase III randomized trial.29 In the current analysis, we found that the patients in the R0 group received more cycles of EPIC than other patients (Table 2Go). The reasons for discontinuing treatment, including disease progression or relapse, postoperative complications, and operative mortality,10 could have affected results. Thus, in this study it is very hard to investigate the impact of increasing the number of EPIC cycles on survival. A prospective randomized trial, therefore, should be performed to clarify this issue.

In conclusion, residual tumor status was the most important predictor for the survival of very advanced gastric cancer patients who received cytoreductive surgery and EPIC. Therefore, complete cytoreductive surgery yielding R0 resection is mandatory for achieving the beneficial effects of EPIC.


   ACKNOWLEDGMENTS
 
This work was supported by the Korea Science and Engineering Foundation (KOSEF) through the Cancer Metastasis Research Center (CMRC) at Yonsei University College of Medicine.


   FOOTNOTES
 
J.-H. Cheong and J. Y. Shen contributed equally to this work.

Received for publication July 19, 2006. Accepted for publication July 20, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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