Surg Today (2010) 40:119–124DOI 10.1007/s00595-009-4017-6

Reprint requests to: H. ShimizuReceived: January 22, 2009 / Accepted: April 24, 2009

Usefulness of Staging Laparoscopy for Advanced Gastric Cancer

HIROKI SHIMIZU1, HIROSHI IMAMURA

2, KATSUYA OHTA2, YASUHIRO MIYAZAKI

2, TOMONO KISHIMOTO2,

MUTSUMI FUKUNAGA2, HIROKI OHZATO

2, MASAYUKI TATSUTA2, and HIROSHI FURUKAWA

2

1 Department of Surgery, Japanese Red Cross Kyoto Daiichi Hospital, 15-749 Honmachi, Higashiyama-ku, Kyoto 605-0981, Japan2 Department of Surgery, Sakai Municipal Hospital, Sakai, Osaka, Japan

AbstractPurpose. The aim of this study was to clarify the useful-ness of staging laparoscopy for planning the treatment strategy in patients with advanced gastric cancer.Methods. This was a retrospective study of patients with gastric cancer who underwent staging laparoscopy. The patients were divided into three groups according to the presence/absence of peritoneal metastasis (P) and positive peritoneal cytology (CY): P negative (0) CY0, P0CY positive (1), and P1CY1. The treatment strategy after staging laparoscopy was as follows: (1) surgery for the P0CY0 group, (2) surgery with neoadjuvant chemo-therapy (NAC) for the P0CY1 group, and (3) chemo-therapy for the P1CY1 group. Survival was estimated by the Kaplan–Meier method and statistical differences were analyzed by the log-rank test.Results. Thirty-four patients were included in this study: 11 in the P0CY0 group, 13 in the P0CY1 group, and 10 in the P1CY1 group. A gastrectomy was done in 11, 10, and no patients, respectively. The survival rate of the P0CY0 patients was signifi cantly better than that of the P0CY1 or P1CY1 patients (P = 0.0106 and 0.0031, respectively).Conclusion. Staging laparoscopy is useful for planning the treatment strategy and estimating the prognosis of patients with advanced gastric cancer.

Key words Advanced gastric cancer · Staging lapa-roscopy · Peritoneal cytology · Neoadjuvant chemother-apy · Surgery

Introduction

The only radical treatment for gastric cancer is a surgi-cal resection, but it is impossible to perform curative surgery if a patient has either peritoneal seeding or metastasis to any other organs. According to the Japa-nese classifi cation of gastric carcinoma (2nd English edition), gastric cancer patients with malignant cells detected by peritoneal cytology should be classifi ed as stage IV, the prognosis of which is extremely poor.1 Therefore, accurate staging is important when planning the treatment strategy for patients with gastric cancer. The preoperative diagnosis of local tumor invasion and metastasis to lymph nodes or the liver is not so diffi cult to make because the quality of the imaging methods, such as endoscopy, abdominal ultrasonography, and computed tomography has improved markedly. On the other hand, the preoperative diagnosis of peritoneal dissemination by noninvasive methods remains diffi cult. The Japanese National Cancer Center (Central Hospi-tal) has reported unexpected peritoneal dissemination to be found in 40%–60% of gastric cancer patients with type 4 tumors and large type 3 tumors (more than 8 cm in diameter) diagnosed as resectable by noninvasive preoperative investigations.2 There have been some reports that laparoscopy is more useful for detecting peritoneal dissemination in comparison to noninvasive examinations.3–7 It is necessary to determine the stage of advanced gastric cancer correctly to avoid unneces-sary surgical exploration and then provide chemother-apy for such patients because there have also been reports about the effi cacy of chemotherapy for patients with advanced gastric cancer.8–10

Staging laparoscopy is routinely performed in patients with locally advanced gastric cancer who have type 4 tumors, large type 3 tumors (more than 8 cm in diame-ter), or extensive lymph node metastasis (“bulky N2” disease) at our hospital. This study examined the role of a staging laparoscopic examination for estimating the

120 H. Shimizu et al.: Staging Laparoscopy for Gastric Cancer

prognosis and selecting the appropriate treatment strat-egy in patients with locally advanced gastric cancer.

Patients and Methods

Patients

Between July 2000 and December 2006, staging lapa-roscopy was performed at Sakai Municipal Hospital for 34 patients with histologically proven gastric cancer who had type 4 tumors, large type 3 tumors (more than 8 cm in diameter), or extensive lymph node metastasis (“bulky N2” disease). Their tumors were judged to be curatively resectable according to such preoperative examinations as upper gastrointestinal endoscopy, abdominal ultrasonography, and enhanced computed tomography (CT). Patients with gastric cancer that was judged to be unresectable because of the detection of distant metastasis or extensive direct invasion of adja-cent organs were excluded from the study. The patients were analyzed retrospectively after being followed until February 2008, with a median follow-up period of 401 days (range, 15–2556 days).

Staging Laparoscopy

The procedure was performed as follows: (1) the patient was placed in the supine position under general anes-thesia, (2) a small (<3 cm) subumbilical incision was made and a 12-mm disposable trocar was inserted, (3) carbon dioxide pneumoperitoneum was created with a pressure of 10–12 mmHg and the laparoscope was inserted, (4) a 5-mm needle was inserted in the lower right quadrant, (5) 100 ml of saline was used to irrigate the pouch of Douglas and then was aspirated for cyto-diagnosis, and (6) all four quadrants of the peritoneal cavity were inspected for evidence of malignant depos-its. A biopsy was performed when it was hard to judge whether peritoneal lesions were malignant or not by inspection. The cytological and histological examina-tions were performed by cytotechnologists and patholo-gists, respectively. The aspirated peritoneal lavage fl uid was stained with Papanicolaou and Giemsa stains. According to the Japanese Classifi cation of Gastric Carcinoma (2nd English edition), “CY0” is defi ned as benign/indeterminate cells on peritoneal cytology and “CY1” means detection of cancer cells by peritoneal cytology.

Treatment Strategies

After the staging laparoscopic examination, the 34 patients were classifi ed as P0CY0, P0CY1, or P1CY1 according to their peritoneal metastasis (P) and positive

peritoneal cytology (CY) status. The treatment strategy for these patients is shown in Fig. 1. The chemotherapy regimen was monotherapy or a combination of the following agents: TS-1 (an oral fl uoropyrimidine), 5-fl uorouracil, cisplatin, irinotecan, and paclitaxel.

Assessment of the Response to Chemotherapy

The response to neoadjuvant and palliative chemother-apy was assessed either after each course or after 8 weeks. The antitumor effect was evaluated according to the Japanese Research Society for Gastric Cancer cri-teria, which were established by the World Health Organization: complete response (CR) meant eradica-tion of all cancer and maintenance of a tumor-free state for 4 weeks or more; partial response (PR) meant ≥50% reduction in the size of all lesions for 4 weeks or more; no change (NC) meant <50% reduction in the size of the lesions or enlargement by <25% and maintenance of that state for 4 weeks or more; and progressive disease (PD) meant enlargement of the lesions by ≥25% or the appearance of new lesions.

Assessment of the Curativity of Gastric Resection

The curativity of a gastric resection was evaluated according to the Japanese Classifi cation of Gastric Car-cinoma (2nd English edition) based on both the surgical and pathological fi ndings: Resection A meant no resid-ual disease with a high probability of cure (satisfying all of the following: T1 or T2; N0 treated by D1–D3 resec-tion or N1 treated by D2–3 resection; M0, P0, H0, CY0, and proximal and distal margins >10 mm); Resection B

Gastric cancer patients :Type 4Type 3 (>8 cm in diameter)Bulky N2 positive

Staging Laparoscopy

P CY P CY P CYP0 0 P0 1 P1 1

Surgery with or without NAC

Surgerywith NAC Chemotherapy

Fig. 1. Treatment strategy according to peritoneal metastasis (P) and positive peritoneal cytology (CY) status. NAC, neo-adjuvant chemotherapy

H. Shimizu et al.: Staging Laparoscopy for Gastric Cancer 121

meant no residual disease, but not fulfi lling the criteria for “Resection A”; and Resection C meant defi nite residual disease.

Statistical Analysis

Survival was estimated using the Kaplan–Meier method, and statistical differences were analyzed with the log-rank test. A P value of less than 0.05 was considered to be signifi cant.

Results

Clinical Characteristics of the Patients

The patients’ clinical characteristics are shown in Table 1. There were 24 men and 10 women. The median age was 64.5 years (range, 35–75 years). The number of patients with type 4 was 17, with large type 3 was 15, and with “Bulky N2” was 20. There were 2 patients with hepatic metastasis, but we judged they were curatively resectable during the surgery for gastric cancer. Clinical staging showed stage II in 3 patients (8.8%), stage IIIA in 8 (23.5%), stage IIIB in 5 (14.7%), and stage IV in 18 (53.0%).

Outcome of Staging Laparoscopy

The median time of the examination was 37 min (range, 19–60 min). There was one complication, i.e., perfora-tion of the jejunum. The number of patients with P0CY0, P0CY1, and P1CY1 were 11, 13, and 10, respectively.

Treatment After Staging Laparoscopy and Patient Outcome

Figure 2 illustrates the outcome of all 34 patients under-going a staging laparoscopic examination. The detailed profi le of the 11 patients with P0CY0 is shown in Table 2. Seven patients underwent NAC and all of their clini-cal responses were assessed as NC or PR. All 11 patients underwent surgery (in one patient, the primary tumor was unresectable and only a gastrojejunostomy was per-formed) and in 7 patients (63.6%), the curability of surgery achieved A or B. At surgery, CY1 was found in

Table 1. Clinical characteristics of the 34 patients

Men/Women 24/10Age (years), range (median) 35–75 (64.5)Macroscopic type (1/2/3/4) 1/1/15/17

cT (1/2/3/4) 0/1/28/5cN (0/1/2/3) 4/10/10/10cH (0/1) 32/2cStage (IA/IB/II/IIIA/IIIB/IV) 0/0/3/8/5/18

Table 2. Profi le of 11 patients who were P0CY0 by staging laparoscopy

Patient no. NAC regimen Clinical response P/CY status at surgery Curative potential OS (days)

1 – – P0/CY0 B 1240 2 CPT-11+CDDP PR – –a 172 3 – – P0/CY0 A 2556 (alive) 4 TS-1 NC P0/CY1 C 461 5 – – P0/CY0 C 379 6 CPT-11+CDDP NC P0/CY0 B 1431 7 CPT-11+CDDP PR P0/CY0 B 2080 (alive) 8 CPT-11+CDDP PR P0/CY0 C 786 9 TS-1 NC P0/CY0 A 99110 TS-1+CDDP PR P0/CY0 B 53411 – – P0/CY0 B 608 (alive)

NAC, neoadjuvant chemotherapy; P, peritoneal metastasis; CY, peritoneal cytology; CPT, irinotecan; CDDP, cisplatin; PR, partial response; NC, no change; OS, overall survivala Surgery was not performed

Patients with advanced gastric carcinoma undergoing staging laparoscopy (n = 34)

P0CY0(n = 11)

P0CY1(n = 13)

P1CY1(n = 10)

Palliativesurgery (n = 2)

NAC(n =11)

Palliative chemotherapy

(n = 10)

Surgerywith NAC

(n = 7)

Surgerywithout NAC

(n = 4)

Surgery(n = 10)

BSC(n = 1)

Palliativesurgery (n = 1)

Chemotherapy only

(n = 9)

Fig. 2. Outcome of all 34 patients undergoing a staging lapa-roscopic examination. NAC, neoadjuvant chemotherapy; BSC, best supportive care

122 H. Shimizu et al.: Staging Laparoscopy for Gastric Cancer

one patient but P1 was not found. The detailed profi le of 13 patients with P0CY1 is shown in Table 3. Palliative surgery was performed in 2 of those patients without neoadjuvant chemotherapy: one because of pyloriste-nosis, the other due to uncontrollable bleeding from the primary tumor. The remaining 11 patients underwent neoadjuvant chemotherapy, and in 9 of them (81.8%) clinical responses were assessed as NC or PR. Ten patients underwent surgery but the surgery achieved a curability of B in only 2 patients. CY0 was found in 3 patients and P1 was found in 3 patients during surgery. The detailed profi le of the 10 patients with P1CY1 is shown in Table 4. All of these patients underwent che-motherapy and the clinical responses were assessed as NC or PR in 4 of them (40%). In one of them, palliative surgery was performed to allow eating.

The median survival time of the patients with P0CY0, P0CY1, and P1CY1 were 786 days (range, 172–2556 days), 393 days (range, 104–967 days), and 241 days (range, 15–924 days), respectively. The median progression-free survival time of patients with P1CY1 was 79.5 days (range, 1–841 days).

The survival curves of the patients with P0CY0, P0CY1, and P1CY1 are shown in Fig. 3. The survival rate of the patients with P0CY0 was signifi cantly better than that of patients with P0CY1 and P1CY1 (P = 0.0106 and P = 0.0031). There was no signifi cant difference in the survival rate between patients with P0CY1 and P1CY1 (P = 0.2666).

Discussion

There are several reports on the effi cacy of peritoneal lavage cytology obtained by laparotomy for patients with gastric cancer. Bonenkamp et al.11 maintained that there was a clear association between positive cytology results and serosal invasion (12% positive cytology) and lymph node infi ltration (7.5% positive cytology). Kodera et al.12 reported that a positive cytology result was asso-ciated with a greater risk for recurrence in the pattern of peritoneal carcinomatosis, and was the only signifi -cant independent prognostic factor among curatively resected patients with locally advanced gastric cancer.

Table 3. Profi le of 13 patients who were P0CY1 by standing laparoscopy

Patient no. NAC regimen Clinical response P/CY status at surgery Curative potential OS (days)

1 – – P0/CY1 C 967 2 TS-1 PD – –a 145 3 TS-1 NC P0/CY1 C 534 4 TS-1 PD P1/CY1 C 169 5 – – P1/CY1 C 104 6 TS-1+CDDP NC P0/CY0 B 290 7 TS-1+CDDP NC P0/CY0 C 478 8 TS-1+CDDP PR P0/CY1 C 395 9 TS-1+CDDP PR P0/CY1 C 46210 TS-1+CDDP NC P0/CY1 C 34111 TS-1+CDDP NC P0/CY0 B 545 (alive)12 TS-1+PTX NC P1/CY1 –b 37613 TS-1+PTX PR P0/CY1 C 393 (alive)

PTX, paclitaxel; PD, progressive diseasea Surgery was not performedb Only exploratory surgery was performed

Table 4. Profi le of 10 patients who where P1CY1 by staging laparoscopy

Patient no. Chemotherapy regimen Clinical response PFS (days) OS (days)

1 TS-1 PD 16 23 2 TS-1 PD 1 15 3 PTX PD 13 23 4 TS-1+PTX PR 211 328 5 TS-1 NC 119 177 6 5-FU PD 88 148 7 TS-1+CPT-11 PR 841 924 8 TS-1+CDDP NC 267 519a

9 TS-1 PD 41 30510 TS-1 PD 71 407 (alive)

PFS, progression-free survival; 5-FU, 5-fl uorouracila Palliative surgery was performed

H. Shimizu et al.: Staging Laparoscopy for Gastric Cancer 123

Staging laparoscopy can make it possible to perform a peritoneal cytological examination before a laparot-omy. Nakagawa et al.13 reported that they performed staging laparoscopy in patients with clinical T3 or T4 advanced gastric cancer, and unsuspected free cancer cells without peritoneal deposits (P0CY1) were found in 29.0%. In their study, 18 patients with CY1 detected by a laparoscopic examination underwent surgery after NAC and in 11 cases (61.1%), no free cancer cells were detected at surgery.

The patients were divided into three groups in the current study, namely P0CY0, P0CY1, and P1CY1, after staging laparoscopy and the treatment strategy was determined. Free cancer cells were found in 67.6%, and 38.2% of patients were classifi ed into the P0CY1 group. In 76.9% of patients with P0CY1, surgery was performed after NAC, but their survival rate was sig-nifi cantly worse than that of patients with P0CY0.

There are other reports addressing the effi cacy of staging laparoscopy.14–18 Yano et al.14 reported that unsuspected peritoneal dissemination was found in 40.6% of patients with T3–4 gastric cancer. Sotiropou-los et al.15 indicated that an unnecessary laparotomy was avoided in 31.1% of patients with T3–4, N1–2 gastric cancer. In the current study, no laparotomy was per-formed in 29.4% of patients who underwent staging laparoscopy. In conclusion, free cancer cells are fre-quently found in the peritoneal lavage from patients with locally advanced gastric cancer, and the perfor-mance of peritoneal cytology is considered to be useful to estimate their prognoses.

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1.0

0.6

0.8

P0CY0rate

(n = 11)

0.4 P1CY1 P0CY1

urvi

val (n = 13)

(n = 10)

0.2

S

0

0 500 1000 1500 2000 2500Survival time (days)

Fig. 3. Survival curves of patients with P0CY0, P0CY1, and P1CY1. Median sur-vival time: 786 days, 393 days, 241 days, respectively

124 H. Shimizu et al.: Staging Laparoscopy for Gastric Cancer

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