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Trends in the Treatment for Liver Metastasis of Colorectal Cancer in Japan

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Trendy v léčbě jaterních metastáz kolorektálního karcinomu v Japonsku

V Japonsku je frekvence výskytu jaterních metastáz před operacemi pro kolorektální karcinom 11 %. Četnost přežití radikální operace s D-3 adenektomií lymfatických uzlin je u karcinomu tlustého střeva 83,7 % a u karcinomu rekta 77,1 %. Procento rekurence jaterních metastáz do 5 let po kurativních operacích s D-3 resekcí lymfatických uzlin je 7,1 %. Nejlepší četnosti přežití byly zaznamenány u hepatektomie: 52,8 % přežívajících subjektů 3 roky po operaci a 39,2 % za 5 let po operaci. Ve frekvenci přežití nejsou mezi pacienty s anatomickou hepatektomií a pacienty s neanatomickou částečnou resekcí žádné rozdíly. V případě rekurence jaterních metastáz po kurativních operacích je vhodné provést hepatektomii, pokud nejsou detekovány žádné další metastázy v jiných orgánech a pacient je operabilní.

Chemoterapie aplikací cytostatik do arteria hepatica (HAI hepatic artery infusion) se dnes již k léčbě jaterních metastáz nepoužívá. Radiofrekvenční ablace nebo mikrovlnná koagulace mohou prodloužit dobu přežití, ale nejsou kurativními výkony.

Authors: M. Maruta 1;  K. Maeda 2
Authors place of work: Sankeikai Hattori Hospital, Nagoya, Japan 1;  Fujita Health University Hospital, Toyoake, Japan 2
Published in the journal: Rozhl. Chir., 2011, roč. 90, č. 12, s. 669-673.
Category: Monothematic special - Original

Summary

The rate of liver metastasis before surgery of colorectal cancer is 11% in Japan. The survival rate of radical surgery with D-3 lymph node adenectomy is 83.7% in colon cancer and 77.1% in rectal cancer. The percentage of recurrent liver metastasis after curative surgery with D-3 lymph node extent resection is 7.1% within 5 years. Hepatectomy has the best survival rate: 52.8% after 3 years, 39.2% after 5 years. There is no difference in patients’ survival rate between systemic anatomical hepatectomy and non-anatomical limited resection. For recurrent hepatic metastasis after curative surgery, hepatectomy should be done if no other metastasis is found in any other organ and the patient is suitable for surgery. Hepatic artery infusion chemotherapy (HAI) for metastasis of the liver is no longer used today. Radiofrequency ablation or microwave coagulation therapy may prolong the survival time but is not a curative procedure.

Registration system for colorectal cancer in Japan

A registration system for colorectal cancer was established in 1978. All cases of colorectal cancer at the 122 member hospitals of The Japanese Society for Cancer of the Colon and Rectum (JSCCR) in Japan are registered with this society.

The percentage of liver metastasis of colorectal cancer before surgery

From 1995 to 1999 there were 24 316 registered cases of colorectal cancer in Japan. Among theses cases, the rate of liver metastasis before surgery was 11.0%. In detail, metastasis limited to one lobe of the liver (H1) was 3.4%; some metastasis to both lobes (4 lesions or less) (H2) was 2.0%; numerous metastases to both lobes (5 lesions or more) (H3) was 5.6 % (fig. 1).

Fig. 1. From 1995 to 1999 there were 24 316 registered cases of colorectal cancer in Japan. Among these cases, the rate of liver metastasis before surgery was 11%. In detail, metastasis limited to one lobe of the liver (H1) was 3.4%; some metastasis to both lobes (4 lesions or less) (H2) was 2.0%; numerous metastases to both lobes (5 lesions or more) (H3) was 5.6%; and as for pulmonary metastasis, the rate was 2.0%.
Fig. 1. From 1995 to 1999 there were 24 316 registered cases of colorectal cancer in Japan. Among these cases, the rate of liver metastasis before surgery was 11%. In detail, metastasis limited to one lobe of the liver (H1) was 3.4%; some metastasis to both lobes (4 lesions or less) (H2) was 2.0%; numerous metastases to both lobes (5 lesions or more) (H3) was 5.6%; and as for pulmonary metastasis, the rate was 2.0%.

Regional lymph node resection in three categories

According to „The General Clinical and Pathological Rules for Cancer of the Colon and Rectum“ in Japan, lymph nodes must be resected extently. Regional lymph nodes are classified into three categories: paracolic nodes, colored pink; intermediate nodes, colored blue; and main nodes, colored yellow. The extent of D-2 resection is to the paracolic nodes and intermediate nodes, while that of D-3 resection is to all three node categories, as shown in (fig. 2).

Fig. 2. Regional lymph nodes are classified into three categories: paracolic nodes, colored pink; intermediate nodes, colored blue; and Main nodes, colored yellow. The extent of D-2 resection is to the paracolic nodes and intermediate nodes, while that of D-3 resection is to all three node categories, as shown in this slide.
Fig. 2. Regional lymph nodes are classified into three categories: paracolic nodes, colored pink; intermediate nodes, colored blue; and Main nodes, colored yellow. The extent of D-2 resection is to the paracolic nodes and intermediate nodes, while that of D-3 resection is to all three node categories, as shown in this slide.

Five year survival rate after curative surgery in Japan

Curative surgery with lymphadenectomy (D-3 extent radical lymphadenectomy) was performed in 21.202 cases, excluding those with liver metastasis and pulmonary metastasis. Post-operative data was gathered and analyzed for cases registered with the JSCCR for 5 years from 1991 to 1994. The 5 year survival rate was 83.7% for colon cancer and 77.1 % for rectal cancer.

The age adjusted relative 5 year survival rate in OECD countries, for the year 2009 is shown in (fig. 3). The Japanese 5 year survival rate for curative surgery was the highest in the world at 67.5%. Next was Iceland, followed by the U.S.A and Finland. The 5 year survival rate for Czech, in 2009, was 46.8%.

Fig. 3. The age adjusted relative 5 year survival rate among OECD countries, for the year 2009, is shown here. As you can clearly see, the Japanese results for curative surgery are the best in the world, with a 5 year survival rate of 67.5%; followed by Iceland with 66.1%; the U.S.A with 65.5%; and Finland with 62%. As for Czech, the rate was 46.8%.
Fig. 3. The age adjusted relative 5 year survival rate among OECD countries, for the year 2009, is shown here. As you can clearly see, the Japanese results for curative surgery are the best in the world, with a 5 year survival rate of 67.5%; followed by Iceland with 66.1%; the U.S.A with 65.5%; and Finland with 62%. As for Czech, the rate was 46.8%.

The rate of recurrent liver metastasis after curative surgery:

As for the rate of recurrent hepatic metastasis after curative surgery, among the 5 230 cases in which curative surgery was performed from the 1991 to 1996, liver metastasis was found in 373 cases (7.1%) within 5 years – 252 of 3600 cases (7.0%) in colon cancer and 121 of 1630 cases (7.4%) in rectal cancer. There was no difference in the recurrent rate between colon cancer and rectal cancer.

Treatments for liver metastasis in colorectal cancer

There are several treatments for the metastasis of colorectal cancer: (1) hepatectomy (2) hepatic arterial infusion chemotherapy (HAI) (3) radiofrequency ablation or microwave coagulation (3) systemic chemotherapy.

Hepatectomy

The so-called „Study for Establishing Treatment for Hepatic and Pulmonary Metastasis of Colorectal Cancer“, sponsored by Grant-in-Aid for Cancer Research from the Ministry of Health, Welfare and Labor of Japan, from 1998 to 2002, provides analytic data of 763 cases of hepatic metastasis, recorded at 18 hospitals and institutions in Japan. Among the 763 patients with hepatic metastasis from colorectal cancer, 585 patients underwent hepatectomy and 178 patients were given other treatments (non-resection). The survival curves are shown in (fig. 4). Hepatectomy, the upper curve, had the best survival rate: 52.8% after 3 years and 39.2% after 5 years. In cases where there was no resection of the liver, the lower curve, the 3 year survival rate was 9.2% while the 5 year survival rate was 3.4%.

Fig. 4. Among the 763 patients with hepatic metastases from colorectal cancer, 585 patients underwent hepatectomy and 178 patients were given other treatments (non-resection). The survival curves are shown here. Hepatectomy, the upper curve, had the best survival rate: 52.8% after 3 years and 39.2% after 5 years. In cases where there was no resection of the liver, the lower curve, the 3 year survival was 9.2%, while the 5 year survival rate was 3.4%.
Fig. 4. Among the 763 patients with hepatic metastases from colorectal cancer, 585 patients underwent hepatectomy and 178 patients were given other treatments (non-resection). The survival curves are shown here. Hepatectomy, the upper curve, had the best survival rate: 52.8% after 3 years and 39.2% after 5 years. In cases where there was no resection of the liver, the lower curve, the 3 year survival was 9.2%, while the 5 year survival rate was 3.4%.

Concerning the surgical procedures for liver resection, systemic anatomical hepatectomy (anatomical group) and non-anatomical limited resection (non-anatomical group) were performed from 1980 through 1999. During this period there were a total of 174 cases of hepatic metastases from colorectal cancer. Among these, 96 anatomical resections and 78 non-anatomical resections were performed. The overall 5 year survival rate of these 174 patients was 43.2 % (fig. 5). There was no significant difference in patients’ survival rate between systemic anatomical hepatectomy and non-anatomical limited resection.

Fig. 5. Concerning the surgical procedures for liver resection, systemic anatomical hepatectomy (anatomical group) and non-anatomical limited resection (non-anatomical group) were performed from 1980 through 1999. During this period there was a total of 174 cases of hepatic metastases from colorectal cancer. Among these, 96 anatomical resections and 78 non-anatomical resections were performed. The overall 5 year survival rate of these 174 patients was 43.2%. There was no significant difference in patiens’ survival rate between systemic anatomical hepatectomy and non-anatomical limited resection.
Fig. 5. Concerning the surgical procedures for liver resection, systemic anatomical hepatectomy (anatomical group) and non-anatomical limited resection (non-anatomical group) were performed from 1980 through 1999. During this period there was a total of 174 cases of hepatic metastases from colorectal cancer. Among these, 96 anatomical resections and 78 non-anatomical resections were performed. The overall 5 year survival rate of these 174 patients was 43.2%. There was no significant difference in patiens’ survival rate between systemic anatomical hepatectomy and non-anatomical limited resection.

Grading of hepatectomy when determining the prognosis

Hepatectomy is clearly the best procedure. When recurrent hepatic metastasis is found during the post-operative surveillance of patients who have undergone curative surgery for colorectal cancer, hepatectomy is performed. Cases are graded with reference to the number of liver metastasis: H1, (4 lesions or less, diameter less than 5 cm); H3, (5 lesions or more, diameter more than 5 cm ); H2, excluding H1 and H3 and number of positive lymph nodes N0, N1, N2, N3. When hepatectomy is performed, cases are graded as Grade A, Grade B or Grade C when determining the prognosis (fig.6).

Fig. 6. As you can see, hepatectomy is clearly the best procedure. When recurrent hepatic metastasis is found during the post-operative surveillance of patients who have undergone curative surgery for colorectal cancer, hepatectomy is performed. When giving a prognosis, cases are graded with reference to the number of liver metastasis: H1 - 4 lesions or less, diameter less than 5 cm; H3 - 5 lesions or more, diameter more than 5 cm; H2 - excluding H1 and H3 and the number of positive lymph nodes N0, N1, N2, N3.
Fig. 6. As you can see, hepatectomy is clearly the best procedure. When recurrent hepatic metastasis is found during the post-operative surveillance of patients who have undergone curative surgery for colorectal cancer, hepatectomy is performed. When giving a prognosis, cases are graded with reference to the number of liver metastasis: H1 - 4 lesions or less, diameter less than 5 cm; H3 - 5 lesions or more, diameter more than 5 cm; H2 - excluding H1 and H3 and the number of positive lymph nodes N0, N1, N2, N3.

Among 378 patients who were followed after undergoing hepatectomy for recurrent liver metastasis after curative surgery, 177 patients were classified as Grade A; 121 as Grade B; and 80 as Grade C. The survival curve is shown in (fig. 7). Among patients who survived 5 years after hepatectomy for recurrent liver metastasis, 52.9% were Grade A; 29.6% Grade B; and 10.4% Grade C.

Fig. 7. When hepatectomy is performed, cases are graded and given a prognosis. Among the 378 patients who were followed after undergoing hepatectomy for recurrent liver metastasis after curative surgery, 177 patients were classified as Grade A; 121 as Grade B; and 80 as Grade C. The survival curve is shown in this slide. The 5 year survival rate after hepatectomy for recurrent liver metastasis was 52.9% for Grade A, 29.6% for Grade B, and 10.4% for Grade C.
Fig. 7. When hepatectomy is performed, cases are graded and given a prognosis. Among the 378 patients who were followed after undergoing hepatectomy for recurrent liver metastasis after curative surgery, 177 patients were classified as Grade A; 121 as Grade B; and 80 as Grade C. The survival curve is shown in this slide. The 5 year survival rate after hepatectomy for recurrent liver metastasis was 52.9% for Grade A, 29.6% for Grade B, and 10.4% for Grade C.

Hepatic Arterial Infusion chemotherapy (HAI)

During the 1990’s, hepatic arterial infusion chemotherapy (HAI) was the most effective treatment for unresectable liver metastasis in synchronous or recurrent liver metastasis of the colon and rectal cancer. A catheter with port was kept in the common hepatic artery. 5FU was administered at a dose of 1000mg per square meter for 5 hours once-a-week. The therapy was repeated every week for as long as possible (fig. 8).

Fig. 8. During the 1990’s, hepatic arterial infusion chemotherapy (HAI) was the most effective treatment for unresectable liver metastasis in synchronous or recurrent liver metastasis of the colon and rectal cancer. A catheter with port was kept in the common hepatic artery. 5FU was administered at a dose of 1000mg per square meter for 5 hours once-a-week. This therapy was repeated every week for as long as possible.
Fig. 8. During the 1990’s, hepatic arterial infusion chemotherapy (HAI) was the most effective treatment for unresectable liver metastasis in synchronous or recurrent liver metastasis of the colon and rectal cancer. A catheter with port was kept in the common hepatic artery. 5FU was administered at a dose of 1000mg per square meter for 5 hours once-a-week. This therapy was repeated every week for as long as possible.

In the Japan Hepatic Arterial Infusion Therapy Study Group (JHAISG), this procedure was strictly administered, using a high dose of 5FU given intravenously 5 hours per week. The overall median survival time with HAI, calculated using the Kaplan-Meier method was 25.8 months (fig. 9). At that time, 5FU was the most effective treatment for unresectable liver metastasis. However, HAI is no longer used today.

Fig. 9. In the Japan Hepatic Arterial Infusion Study Group (JHAISG), the prescribed procedure for HAI administration was followed, with a high dose of 5FU being given intravenously 5 hours per week. As shown in this slide, the overall median survival time with HAI, calculated using the Kaplan-Meier method, was 25.8 months. At that time, 5FU was the most effective treatment for unresectable liver metastasis. However, HAI is no longer used today.
Fig. 9. In the Japan Hepatic Arterial Infusion Study Group (JHAISG), the prescribed procedure for HAI administration was followed, with a high dose of 5FU being given intravenously 5 hours per week. As shown in this slide, the overall median survival time with HAI, calculated using the Kaplan-Meier method, was 25.8 months. At that time, 5FU was the most effective treatment for unresectable liver metastasis. However, HAI is no longer used today.

Thermal coagulation therapy

Thermal coagulation therapy such as radiofrequency ablasion and microwave coagulation therapy are effective for metastasis of the liver in patients with colorectal cancer and for whom other treatments of the liver metastasis are unsuitable. The radiofrequency needle is inserted into the areas of hepatic metastasis using ultrasound.Thermal coagulation therapy is very popular for hepatoma, but not popular for liver metastasis of colorectal cancer and there is little available data for this therapy. 102 patients with metastasis of colon cancer and rectal cancer received radiofrequency ablation at the Kanto Chuo Hospital in Tokyo. Among these cases, the survival rate was 71% after 1 year; 46% after 2 years; and 21% after 3 years. (Fig. 10) Therefore, it can be said that radiofrequency ablation or microwave coagulation therapy may be effective in prolonging the prognosis of patients with non-curative hepatic metastasis.

Fig. 10. Thermal coagulation therapy is not popular for liver metastasis of colorectal cancer and there is very little available data for this therapy. 102 patients with metastasis of colon cancer and rectal cancer received radiofrequency ablation at the Kanto Chuo Hospital. Among these 102 cases, the survival rate was 71% after 1 year; 46% after 2 years; and 21% after 3 years, as shown by this survival curve. Therefore, it may be said that radiofrequency ablation or microwave coagulation therapy may be effective in prolonging the prognosis of patients with non-curative hepatic metastasis.
Fig. 10. Thermal coagulation therapy is not popular for liver metastasis of colorectal cancer and there is very little available data for this therapy. 102 patients with metastasis of colon cancer and rectal cancer received radiofrequency ablation at the Kanto Chuo Hospital. Among these 102 cases, the survival rate was 71% after 1 year; 46% after 2 years; and 21% after 3 years, as shown by this survival curve. Therefore, it may be said that radiofrequency ablation or microwave coagulation therapy may be effective in prolonging the prognosis of patients with non-curative hepatic metastasis.

Systemic chemotherapy

For cases in which resection of the liver is impossible, curability by systemic chemotherapy of FOLFOX, FOLFIRI, CPT-11 etc. has recently been reported in several cases. However, there is insufficient evidence about the long-term effectiveness or safety of this treatment.

Morito Maruta

Professor of surgery

Sankeikai Hattori Hospital

Nagoya

Japan

Zdroje

1. The Japanese Society for Cancer of the Colon and Rectum: Guidelines for the Treatment of Colorectal Cancer.Tokyo, Kanehara, 2010.

2. The Japanese Society for Cancer of the Colon and Rectum: Japanese Classification of Colorectal Carcinoma. 5th edition,Tokyo, Kanehara, 1999.

3. Health Care Quality Indicators Data 2009, OECD.

4. Tomoyuki Kato, Kenzo Yasui, Takashi Hirai, et al.: Therapeutic results for hepatic metastasis of colorectal cancer with special reference to the effectiveness of hepatectomy, Disease of Colon and Rectum, 2003; 46: 10, supple, 22–31.

5. Norihito Kokudo, Keiichiro Tada, Makoto Seki, et al.: Anatomical resection versus non-anatomical limited resection for liver metastasis from colorectal carcinoma, American J. Surg., 2001; 181: 153–159.

6. Yasuaki Arai, Yoshitaka Inaba, Yoshihito Takeuchi, et al.: Intermittent hepatic arterial infusion of high dose 5FU on a weekly schedule for liver metastasis from colorectal cancer, Cancer Chemotherapy Phalmacology 1997; 40: 520–530.

7. Yukihiro Koike: Radiofrequency ablation therapy for liver metastasis of colorectal cancer (in Japanese), Internal Medicine 2009; 104: 711–715.

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Perspectives in Surgery

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