J Cancer Res Clin Oncol (2008) 134:187–192 DOI 10.1007/s00432-007-0268-z

ORIGINAL PAPER

Palliative gastrectomy and chemotherapy for stage IV gastric cancer Sheng-Zhang Lin · Hong-Fei Tong · Tao You · Yao-Jun Yu · Wei-Jun Wu · Cong Chen · Wei Zhang · Bing Ye · Chun-Ming Li · Zhi-Qiang Zhen · Jia-Rong Xu · Jun-Liang Zhou

Received: 27 August 2006 / Accepted: 11 June 2007 / Published online: 5 July 2007 © Springer-Verlag 2007

Abstract Purpose To investigate the value of palliative gastrectomy and chemotherapy in a large series of patients with stage IV gastric cancer. Methods A total of 389 patients were identiWed in survival analysis. Among which, 183 cases received palliative gastrectomy (PG) and 206 cases received unresectable operation, 184 cases received palliative chemotherapy (PC) and 205 cases did not receive chemotherapy. The survival advantages of patients, based on treatments modality, were also analyzed in patients with liver metastasis, peritoneal dissemination and lymph node metastasis. Results The 1-year, 3-year, 5-year survival rate of those patients who were treated with PG + PC were 85.7% (96/ 112), 32.1% (36/112), and 8.9% (10/112), which were far better than those who were not. For those patients with liver metastasis, peritoneal dissemination, and/or N3 lymph node metastasis, survival advantages were also present if treated with this multimodality approach. Conclusion The survival time and palliative duration were signiWcantly longer in patients after PG than after non-resection operations. Postoperative chemotherapy prolonged the survival time of patients after palliative surgery. PG combined with adjuvant chemotherapy may improve survival in patients with stage IV gastric cancer, even with liver metastasis, peritoneal dissemination, and lymph node metastasis. Keywords

Gastric cancer · Surgery · Chemotherapy

S.-Z. Lin (&) · H.-F. Tong · T. You · Y.-J. Yu · W.-J. Wu · C. Chen · W. Zhang · B. Ye · C.-M. Li · Z.-Q. Zhen · J.-R. Xu · J.-L. Zhou Department of General Surgery, Second AYliated Hospital, Wenzhou Medical College, Wenzhou 325027, China e-mail: [email protected]

Abbreviations PG Palliative gastrectomy PC Palliative chemotherapy UO Unresectable operation NC No chemotherapy DFS Disease-free survival OS Overall survival

Introduction According to the latest global estimation-GLOBOCAN 2002, gastric cancer ranks the third among the most common cancers in incidence rate and the second in mortality rate in men, while in women, it is the Wfth most common cancer in incidence and the fourth in mortality (Parkin et al. 2005). In 2005, in terms of incidence rates, gastric cancer ranks the third among the most common cancers in China (after cancers of lung and liver in men and after cancers of breast and lung in women) (Yang et al. 2005). Despite improved clinical outcomes associated with earlier diagnosis, more accurate staging, and decreased surgical morbidity and mortality, the overall prognosis of gastric cancer remains poor because many patients are incurable at the Wrst presentation (Swan and Miner 2006). Thus, palliative strategies and symptom management remain essential component in the total care of the patient with gastric cancer (Miner and Karpeh 2004). There is insuYcient evidence nowadays to recommend palliative gastrectomy (PG) and chemotherapy (PC) as a rational approach for stage IV gastric cancer (Kakeji et al.1998). In the present study, we investigate the value of PG and PC in a large series of patients with stage IV gastric cancer by comparison with unresectable operation (UO) and no chemotherapy (NC).

123

188

Patients and methods

J Cancer Res Clin Oncol (2008) 134:187–192 Table 1 Clinicopathological characteristics of the patients Variable

PG (n = 183)

UO (n = 206)

P value

M/F ratio

143/40

147/59

0.125

From January 1994 to January 2001, 413 patients with histopathologically diagnosed stage IV gastric cancer received surgical treatment at the Department of Surgery of Second Hospital aYliated to Wenzhou Medical College. Stage IV gastric cancer was deWned based on American Joint Commission on Cancer (AJCC, 6th edition), as M1 or T4N1–3M0 (AJCC 2003). All of the patients were given informed consent and followed up till January 2006. Three patients who died within 30 days after operation and 21 patients missed or died of unrelated diseases during follow-up were excluded and the remain 389 (94.2%) cases were identiWed in survival analysis. The mean age of the patients was 62 years old (range 24–84 years). Among which, 183 cases received PG (subtotal gastrectomy, total gastrectomy, or multiorgan resection ) and 206 cases received UO (by-pass or laparotomy exploration only), 184 cases received PC (oral, intravenous, or intraperitoneal, Xuorouracil-based combinations), and 205 cases did not receive chemotherapy (NC). The indications for PG were judged individually by attending surgeons based on patients’ general health, performance status, symptoms, extent of disease, and feasibility of resection. The clinicopathological characteristics of the patients are shown in Table 1.

Age (mean)

60

63

Statistical analysis

Patients and their clinicopathological characteristics

Fisher’s exact test was used to compare qualitative data. Continuous variables were transformed into dichotomous variables before the survival analysis. Student’s t-test was used for mean comparisons. Patients’ survival was calculated from the data of operation to the data of death or to the data of point, which was the major clinical endpoint. Survival curves were estimated according to the method of Kaplan–Meier and compared with a log-rank test. To identify the factors that might be of independent signiWcance in inXuencing the disease-free survival or overall survival (OS), a Cox stepwise proportional risk regression model was Wtted. All statistical calculations were performed with Stata (version 9) statistical software. A P-value <0.05 was considered signiWcantly.

Results The 1-year, 3-year, 5-year survival rate for PG group were 80.3% (147/183), 20.8% (38/183), and 6.0% (11/183), while the 1-year survival rate for UO group was only 33.5% (69/206) (P = 0.000), and there was no 3-year survival in UO group. Among PG group, the 1-year, 3-year,

123

Histological type

0.339 0.245

DiVerentiated

79 (43%)

77 (37%)

UndiVerentiated

104 (57%)

129 (63%)

Depth of invasion (T) T1

0

T2

5 (2.7%)

T3

43 (23.5%)

T4

135 (73.8%)

Lymph node metastasis (N)

0.557

N0–2

150 (82.0%)

164 (79.6%)

N3

33 (18.0%)

42 (20.4%)

M0

48 (26.2%)

50 (24.3%)

M1

135 (73.8%)

156 (75.7%)

No

118 (64.5%)

116 (56.3%)

Yes

65 (35.5%)

90 (43.7%)

Distant metastasis (M)

0.657

Liver metastasis

0.100

Peritoneal dissemination

0.536

No

69 (37.7%)

84 (40.8%)

Yes

114 (62.3%)

122 (59.2%)

No

71 (38.8%)

113 (54.9%)

Yes

112 (61.2%)

93 (45.1%)

Chemotherapy

0.002

When complete data were not available for comparison, the area is left blank PG palliative gastrectomy, UO unresectable operation

5-year survival rate for those patients received PC were 85.7% (96/112), 32.1% (36/112), and 8.9% (10/112), which were much higher than that of patients did NC [the 1-year, 3-year, 5-year survival rate were 71.8% (51/71) (P = 0.021), 2.8% (2/71) (P = 0.000), and 1.4% (1/71) (p = 0.037)]; and among UO group, the 1-year survival rate for PC group and NC group were 52.7% (49/93) and 17.7% (20/113, p = 0.000). (Table 2) The survival time of the patients based on treatment modality is shown in Fig. 1. For those patients with liver metastasis, the treatment modality was only associated with 1-year survival rate of the patients. The 1-year survival rate of UO and NC groups were lower to be 25.6% (23/90) and 30.2% (26/86) than that of PG and PC groups [the 1-year survival rate were 53.9% (35/65) (P = 0.000) and 46.4% (32/69) (P = 0.021)] (Table 3). For those patients with peritoneal dissemination, the 1-year, 2-year, 3-year survival rate of PG group were 70.2% (80/114), 37.7% (43/114), and 12.3% (14/114), which were

J Cancer Res Clin Oncol (2008) 134:187–192

189

Table 2 Survival time of patients with stage IV gastric cancer based on treatments modality Survival time

Palliative surgery

PG

PG

UO

P

Yes

147 (80.3%)

69 (33.5%)

No

36 (19.7%)

137 (66.5%)

1-Year

UO

PC

NC

96 (85.7%)

51 (71.8%)

16 (14.3%)

20 (28.2%)

P

0.000

2-Year 92 (50.3%)

20 (9.7%)

No

91 (49.7%)

186 (90.3%)

3-Year

NC

49 (52.7%)

20 (17.7%)

44 (47.3%)

93 (82.3%)

10 (10.8%)

10 (8.9%)

83 (89.2%)

103 (91.1%)

0.000

0.000 71 (63.4%)

21 (29.6%)

41 (36.6%)

50 (70.4%)

0.000

0.646

0.000

NA

Yes

38 (20.8%)

0 (0%)

36 (32.1%)

2 (2.8%)

0 (0%)

0 (0%)

No

145 (79.2%)

206 (100%)

76 (67.9%)

69 (97.2%)

93 (100%)

113 (100%)

Yes

21 (11.5%)

0 (0%)

19 (17.0%)

2 (2.8%)

0 (0%)

0 (0%)

No

162 (88.5%)

206 (100%)

93 (83.0%)

69 (97.2%)

93 (100%)

113 (100%)

4-Year

0.000

5-Year

P

0.021

0.000

Yes

PC

0.003

0.000

NA

0.037

NA

Yes

11 (6.0%)

0 (0%)

10 (8.9%)

1 (1.4%)

0 (0%)

0 (0%)

No

172 (94.0)

206 (100%)

102 (91.1%)

70 (98.6%)

93 (100%)

113 (100%)

PG palliative gastrectomy, UO unresectable operation, PC palliative chemotherapy, NC no chemotherapy

Kaplan-Meier survival estimates, by treatment modality 1.00

0.75

0.50

UO+NC

0.25

UO+PC

PG+NC

PG+PC

0.00 0

20

40

60

Survival time (mon)

Fig. 1 Survival time of patients with stage IV gastric cancer based on treatments modality. PG palliative gastrectomy, UO unresectable operation, PC palliative chemotherapy, NC no chemotherapy

Table 3 Survival time of patients with liver metastasis based on treatments modality

Survival time

much higher than that of UO group [the 1-year, 2-year, 3-year survival rate were 14.8% (18/122) (P = 0.000), 5.7% (7/122) (P = 0.000), and 0% (0/122) (P = 0.000)]; the 1-year, 2-year, 3-year survival rate of PC group were 53.3% (56/105), 33.3% (35/105), and 14.5% (14/105), which were also higher than that of NC group [the 1-year, 2-year, 3-year survival rate were 32.1% (42/131) (P = 0.001), 11.5% (15/131) (P = 0.000), and 0% (0/131) (P = 0.000)] (Table 4). For those patients with N3 lymph node metastasis, the 1-year, 2-year survival rate of PG group were 66.7% (22/33) and 33.3%(11/33), which were much higher than that of UO group [the 1-year, 2-year survival rate were 19.1% (8/42) (P = 0.000) and 2.4% (1/42) (P = 0.000)], while no signiWcant diVerence was found of the 3-year, 4-year survival rate between the two groups (P = 0.256, P = 0.256 ); The survival rate of PC group showed a little higher than that of

Liver metastasis PG

UO

PC

NC

Yes

35 (53.9%)

23 (25.6%)

32 (46.4%)

26 (30.2%)

No

30 (46.1%)

67 (74.4%)

37 (53.6%)

60 (69.8%)

Yes

10 (15.4%)

7 (7.8%)

10 (14.5%)

7 (8.1%)

No

55 (84.6%)

83 (92.2%)

59 (85.5%)

79 (91.9%)

1-Year

PG palliative gastrectomy, UO unresectable operation, PC palliative chemotherapy, NC no chemotherapy

P 0.000

2-Year

P 0.021

0.135

0.208

123

190 Table 4 Survival time of patients with peritoneal dissemination based on treatments modality

J Cancer Res Clin Oncol (2008) 134:187–192

Survival time

Peritoneal dissemination PG

UO

P

Yes

80 (70.2%)

18 (14.8%)

No

34 (29.8%)

104 (85.2%)

1-Year

Yes

43 (37.7%)

7 (5.7%)

No

71 (62.3%)

115 (94.3%)

49 (46.7%)

89 (67.9%)

35 (33.3%)

15 (11.5%)

70 (66.6%)

116 (88.5%)

0.000

0.000

14 (12.3%)

0 (0%)

14 (14.5%)

0 (0%)

No

100 (87.7%)

122 (100%)

91 (85.5%)

131 (100%)

Yes

2 (1.8%)

0 (0%)

2 (1.9%)

0 (0%)

No

112 (98.2%)

122 (100%)

103 (98.1%)

131 (100%)

4-Year

0.142

The eVective and appropriate use of palliative surgical interventions in patients with gastric cancer remains controversial. In 1958, Lawrence and McNeer demonstrated that palliative gastric resections eVectively relieve symptoms in patients with incurable gastric cancer (Lawrence Jr and McNeer 1958). Since palliative gastrectomies are associated with signiWcant perioperative morbidity and mortality, the authors recommend deliberate palliative resection only in carefully selected patients with severe symptoms (Monson et al. 1991; Sarela et al. 2004). Some other series,

Survival time

P 0.001

Yes

Discussion

0.113

however, showed total gastrectomy could improve symptom relief and survival data without increasing complication rates, and proposed that it should be performed whenever technically possible (Ouchi et al. 1998; MedinaFranco et al. 2004). In our study with a large series of stage IV gastric cancer cases, we also found a more favorable outcome for patients having a resection than for those not being resected. The 1-year, 3-year, 5-year survival rate for PG group were 80.3, 20.8, and 6.0%, while the 1-year survival rate for UO group was only 33.5%, and there was no 3-year survival in UO group. PG may be a worthwhile palliative procedure for advanced gastric cancer. As long as the primary tumor can be removed with reasonable risk of mortality and morbidity, every attempt should be made to resect the tumor. Chemotherapy in advanced gastric cancer is an important issue because the majority of patients with gastric

Lymph node metastasis (N3) PG

UO

Yes

22 (66.7%)

8 (19.1%)

No

11 (33.3%)

34 (80.9%)

1-Year

P

PC

NC

16 (44.4%)

14 (35.9%)

20 (55.6%)

25 (64.1%)

7 (19.4%)

7 (18.0%)

29 (80.6%)

32 (82.0%)

0.000

2-Year Yes

11 (33.3%)

1 (2.4%)

No

22 (66.7%)

41 (97.6%)

0.632

0.256

0.295

Yes

1 (3.0%)

0 (0%)

1 (2.8%)

0 (0%)

No

32 (97.0%)

42 (100%)

35 (97.2%)

39 (100%)

4-Year

P 0.450

0.000

3-Year

123

42 (32.1%)

0.000

NC group, but no statistically signiWcant survival advantage was present in PC group comparing with NC group (Table 5).

PG palliative gastrectomy, UO unresectable operation, PC palliative chemotherapy, NC no chemotherapy

56 (53.3%) 0.000

3-Year

Table 5 Survival time of patients with N3 lymph node metastasis based on treatments modality

NC

0.000

2-Year

PG palliative gastrectomy, UO unresectable operation, PC palliative chemotherapy, NC no chemotherapy

PC

0.256

0.295

Yes

1 (3.0%)

0 (0%)

1 (2.8%)

0 (0%)

No

32 (3.0%)

42 (100%)

35 (97.2%)

39 (100%)

J Cancer Res Clin Oncol (2008) 134:187–192

cancer develop metastases during the course of their disease (Wohrer et al. 2004). Traditionally, although responses to chemotherapy have been reported in up to 60% of patients in phase II trials, most patients developed drug resistance within few months. These disappointing results together with the toxic eVects derived from chemotherapy prompted to several investigators to evaluate the beneWt of chemotherapy in terms of survival and/or quality of life compared with best supportive care alone. While some randomized phase III studies conducted during the last decade showed chemotherapy should be oVered to patients with metastatic gastric cancer in good general conditions, even in those patients with asymptomatic disease (Sastre et al. 2006). In our study, among PG group, the 1year, 3-year, 5-year survival rate for those patients received PC were much higher than that of patients did NC; while among UO group, signiWcant diVerence was found only in 1-year survival rate. Adjuvant chemotherapy resulted in a signiWcant survival beneWt in patients with stage IV gastric cancer, especially combined with palliative resection. Removing the primary tumor might reduce tumor burden and leave the patients more responsive to adjuvant modalities. In summarize, using Kaplan–Meier survival estimates, the OS of patients who were treated with multimodality approach (PG + PC group) was far better for those who were not (Table 2; Fig. 1). Palliative gastrectomy has been considered neither prolongs life nor improves the quality of survival in patients with GC and synchronous liver metastasis (Doglietto et al. 1999). Hepatic artery infusion chemotherapy or systemic chemotherapy, the same, has not achieved satisfactory results for patients with hepatic metastasis from GC (Wang et al. 1996; Maehara et al. 1991). In present study, the treatment modality was found only associated with 1-year survival rate of the patients with liver metastasis (Table 3). We noticed that hepatic metastasis of patients survived more than 1 year were mostly single or located only in one lobe of the liver, which could be resected with a adequate tumorfree margins. So PG may not be beneWcial to prolonging life in the patients with synchronous liver metastasis except a few selected patients who adequate hepatic resection is possible. This result was same as a previous report (Miyazaki et al. 1997) documented that hepatic resection for synchronous or metachronous hepatic metastasis from GC after gastrectomy may improve the prognosis in patients with a solitary metastasis if adequate tumor-free margins (10 mm) can be obtained. Peritoneal dissemination from primary gastric cancer occurs in 10–20% of patients. No deWnite surgical policy has been established for the treatment of patients with simultaneous peritoneal metastasis (Otani et al. 1995). Most of these patients have very poor prognosis and may die within 1 year irrespective of whether they undergo

191

surgery or postoperative chemotherapy (Ohno et al. 1994). But in our study of stage IV patients with peritoneal metastasis, the 1-year, 2-year, 3-year survival rate of PG group were 70.2, 37.7, and 12.3%, of PC group were 53.3, 33.3, and 14.5% (Table 4). PG and PC resulted in a signiWcant survival beneWt for patients with peritoneal dissemination. So we advised that gastrectomy with peritonectomy to eliminate all visible implants combined with PC, especially perioperative intraperitoneal chemotherapy, should be used in patients with gastric cancer and peritoneal dissemination. Lymph node metastasis is known to be one of the most important prognostic factors of advanced gastric cancer. Therefore, radical resection together with extended lymphadenectomy is required to improve the prognosis of these patients (Kodera et al. 1997; Takeno et al. 2001). In our study, for those stage IV patients with N3 lymph node metastasis, the 1-year, 2-year survival rate of PG group were still higher to be 66.7 and 33.3%, and were much higher than that of UO group. The survival rate of PC group showed a little higher than that of NC group, but no statistically signiWcant survival advantage was present in PC group comparing with NC group (Table 5). So, patients with stage IV gastric carcinoma, even with N3 lymph node metastasis, might have beneWted from aggressive surgery with curative intent combine with adjuvant chemotherapy. In conclusion, the survival time and palliative duration were signiWcantly longer in patients after PG than after nonresection operations. Postoperative chemotherapy prolonged the survival time of patients after palliative surgery. PG combined with adjuvant chemotherapy may improve survival in patients with stage IV gastric cancer, even with liver metastasis, peritoneal dissemination, and lymph node metastasis.

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