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Treatment of gastric liver metastases: first updating.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

October 2002.     Review Article

To previous article about gastric liver metastases
To the second updating

Although the likelihood of long-term survival in gastric carcinoma patients after a curative resection has increased, it still poses a challenge for clinicians to increase the survival of patients with recurrent liver disease.
With regard to synchronous or metachronous liver metastasis, hepatic resection with sufficient resection margin and intrahepatic arterial chemotherapy were reported to be effective for improving the survival time.
Hepatic resection for gastric cancer metastasis is not widely used as a therapeutic option. Occasionally, it may be considered as beneficial in single, isolated recurrences. But Ambiru et al put forward contraindications to hepatic resection in the following instances: extrahepatic disease, advanced lymph node involvement, and the inability to resect all gross metastases to the liver are generally considered absolute contraindications to curable resection ( 3 ).
Recently, Dhar et al. have reported that patients with hepatic arterial infusion chemotherapy treatment had a better survival when compared with those who had hepatic resection and systemic chemotherapy. The additional and intensive therapies may be indicated for cases of high risk for liver recurrence. These methods might offer a chance for a complete cure in gastric cancer patients ( 2 ).

As most of the patients with liver metastasis die owing to the progression of the disease, advanced and reliable diagnostic methods are worthy to identify the site of recurrence at an early stage for effective therapy. At present, there is no specific marker to identify the recurrence at an early stage.
The peritoneal surface is the most frequent site for the recurrence of gastric carcinoma, whereas liver metastasis is not so common as it happens in colorectal cancer patients. Given this fact, it remains difficult to predict liver recurrence after a curative resection.
Ohno et al. affirm that gross appearance of the primary tumor, histological type, and serum level of CEA and AFP are independently correlated with liver recurrence ( 1 ).
There have been several studies describing the relationship between liver recurrence and clinicopathological features.
Koga et al showed that hematogenous recurrence, in particular liver recurrence, develops more frequently from Borrmann type 1 or 2 and well-differentiated tumor ( 4 ).
Also, Ichiyoshi et al suggested that the incidence of hematogenous recurrence is relatively higher in cases of early gastric cancer ( 5 ).
Ohno et al. also found that liver recurrence was closely related to early stage of the disease. In this study, AFP-positive gastric cancer was over-whelmingly present in early stage of disease ( 1 ).
Koide et al reported that AFP-producing gastric cancers have high malignant potential (high proliferative activity, weak apoptosis, and rich neovascularization) compared with that of AFP-negative gastric cancers. Also it has been reported that vascular endothelial growth factor (VEGF) expression and the microvessel density of AFP-producing gastric cancers were significantly higher than that of AFP-negative gastric cancers. Therefore, the increased tumor neovascularization might be one of the important factors responsible for frequent liver metastasis in this tumor. For this reason, AFP-producing gastric cancer is associated with a poor clinical outcome and prognosis ( 6 ).
In the Ohno study, all AFP-producing pT1 cases had lymph node metastasis at initial diagnosis and this precludes any endoscopic mucosal resection ( EMR ) in these patients. The authos advocate that all patients with AFP-producing gastric cancers should undergo gastrectomy operation including an extended regional lymph node resection procedure. Unfortunately, even after a radical extended resection, patients with AFP-producing gastric cancers are at risk of liver recurrence and need close follow-up for identifying early recurrence ( 1 ).
Hematogenous recurrence was thought to occur mainly when cancer cells released from the primary site entered the vascular system and were transported to distant organs, where attachment and proliferation occurred. In regard to the stomach wall, an extensive capillary plexus is present in the submucosa, so the main locus of vascular invasion is probably the submucosal layer ( 7 ).

Ikeda et al reported that stage II and III gastric cancer patients with high preoperative CEA level had frequent liver metastasis ( 8 ).
In the Ohno et al study results from logistic regression analysis have shown that the preoperative CEA along with the AFP level is an independent risk factor for liver recurrence. CEA is usually cleared from the circulation by the liver Kupffer cells, and it might be possible that the CEA-producing tumor cells have a great affinity for the liver bed and this helps in the formation of liver metastasis ( 1 ).
Miyazono et al have shown that CEA-mRNA is detected in the blood from the portal vein, peripheral artery, and superior vena cava during gastric cancer surgery and that it predicts a high incidence of blood-borne metastasis even after curative resection. The median length of time to liver recurrence in CEA-positive patients was very short (6.2 months) ( 7 ).
Ohno et al. presume that metastasizing to the liver of CEA-positive tumor cells follows on the heels of operation. Elevation of preoperative CEA level may enable surgeons to specifically design neoadjuvant treatment even before a metastatic lesion is clinically evident ( 1 ).

Marrelli et al confirm that preoperative positivity for CEA, CA 19-9 and CA 72-4 is an indipendent risk factor for hematogenous recurrence of gastric carcinoma; this aspect should be considered in the option of using adjuvant chemotherapy after surgery for gastric cancer.
The effect of tumor marker positivity was indipendent of the presence of lymph node involvement.
Since recurrences of early stages of gastric cancer are usually hematogenous rather than locoregional or peritoneal, the results of the present study help to explain the prevalent prognostic value of tumor markers in the early stages of gastric carcinoma ( 11 ).
In a previuos study Marrelli et al. observed that preoperative positivity of tumor markers has an adverse effect on the prognosis of patients who have undegone surgery for gastric cancer, especially in stages I and II of the disease, similar to the observations of other authors as well ( 12, 14, 15 ).


1) Satoshi Ohno, Toshiyuki Fujii, Shuhei Ueda,Takeru Nakamoto, Shoichi Kinugasa, Hiroshi Yoshimura, Mitsuo Tachibana, Hirofumi Kubota, Dipok Kumar Dhar, Naofumi Nagasue. Predictive factors and timing for liver recurrence after curative resection of gastric carcinoma. The American Journal of Surgery 185 (2003) 258-263. Pub Med

2) Dhar DK, Kubota H, Yamanoi A, et al. Selective approaches to gastric cancer patients with liver metastases: role of liver directed chemotherapy. Dig Liver Dis 2001;33:614. Pub Med

3) Ambiru S, Miyazaki M, Ito H, et al. Benefits and limits of hepatic resection for gastric metastases. Am J Surg 2001;181:279 -83. . Pub Med

4) Koga S, Takebayashi M, Kaibara N, et al. Pathological characteristics of gastric cancer that develop hematogenous recurrence, with special reference to the site of recurrence. J Surg Oncol 1987;36:239 -42. Pub Med

5) Ichiyoshi Y, Toda T, Minamisono Y, et al. Recurrence in early gastric cancer. Surgery 1990;107:489 -95. Pub Med

6) Koide N, Nishio A, Igarashi J, et al. AFP-producing gastric cancer: histochemical analysis of cell proliferation, apoptosis, and angiogenesis. Am J Gastroenterol 1999;94:1658 -63. Pub Med

7) Miyazono F, Natsugoe S, Takao S, et al. Surgical maneuvers enhance molecular detection of circulating tumor cell during gastric cancer surgery. Ann Surg 2001;233:189 -94. Pub Med

8) Ikeda Y, Mori M, Kajiyama K, et al. Indicative value of carcinoembryonic antigen (CEA) for liver recurrence following curative resection of stage II and III gastric cancer. Hepato-gastroenterology 1996; 43:1281-7. Pub Med

9) Chang Y-C, Nagasue N, Kohno H, et al. Clinicopathologic features and long-term results of alfa-fetoprotein-producing gastric cancer. Am J Gastroenterol 1990;85:1480 -5.

10) Chang Y-C, Nagasue N, Abe S, et al. Comparison between the clinicopathologic features of AFP-positive and AFP-negative gastric cancers. Am J Gastroenterol 1992;87:321-5. Pub Med

11) D Marrelli, E Pinto, A De Stefano, G De Manzoni, M Farnetani, L Garosi, and F Roviello. Preoperative positivitÓ of serum tumor markers is a strong predictor of hematogenous recurrence of gastric cancer. Journ Surg Oncol 2001; 78: 253-258. Pub Med

12) Marrelli D, Roviello F, et al. Prognostic significance of CEA, CA 19-9, and CA 72-4 preoperative serum levels in gastric carcinoma. Oncology 1999; 57: 55-62. Pub Med

13) Marrelli D, Pinto E et al. Clinical utility of CEA, CA 19-9 and CA 72-4 in the follow up of patients with resectable gastric cancer. Am J Surg 2001; 181: 16-19. Pub Med

14) Nakane Y et al. Correlation of preoperative CEA levels and prognosis of gastric cancer patients. Cancer 1994; 73: 2073-2078. Pub Med

15) Kodera Y et al. The prognostic value of preoperative serum levels of CEA and CA 19-9 in patients with gastric cancer. Am J gastroenterol 1996; 91: 49-53. Pub Med

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