Clin J Gastroenterol (2009) 2:331–337 DOI 10.1007/s12328-009-0105-9
CASE REPORT
A long-time survivor of alpha-fetoprotein-producing gastric cancer successfully treated by fluoropyrimidine-based chemotherapy: a case study Masatsugu Hiraki Æ Seiji Sato Æ Keita Kai Æ Takao Ohtsuka Æ Naohiko Kohya Æ Yoshihiko Kitajima Æ Yuji Nakafusa Æ Osamu Tokunaga Æ Kohji Miyazaki
Received: 25 June 2009 / Accepted: 12 August 2009 / Published online: 9 September 2009 Ó Springer 2009
Abstract A 67-year-old male with advanced gastric cancer and lymph node metastasis as well as a tumor embolus in the portal vein was treated by S-1/cisplatin therapy. The serum alpha-fetoprotein levels were elevated to 836 ng/ml at the first visit. After one course of chemotherapy, the patient showed stable disease; the serum level of alpha-fetoprotein also decreased to 626 ng/ml after a transient increase, and therefore reduction surgery was performed. A total gastrectomy with a distal pancreatectomy, splenectomy, and regional lymph node dissection was performed. The resected specimen was diagnosed to be alpha-fetoprotein-producing gastric cancer. There were no metastatic foci in the resected lymph nodes, presumably due to the preoperative chemotherapy. S-1/cisplatin therapy was continued after the operation to treat the remaining tumor embolus in the portal vein. After one course of this therapy, the tumor embolus disappeared. However, a lymph node measuring 1.5 cm in diameter appeared in the hepatoduodenal ligament. Therefore, the chemotherapy was changed to paclitaxel monotherapy. After 2 courses of paclitaxel monotherapy, the lymph node swelled, and thus 50 -deoxy-5-fluorouridine was added to the paclitaxel regimen. After 5 courses of this regimen, the lymph node swelling disappeared without any other new lesions and a total of 21 courses were performed. The patient remained stable for over 8 years without recurrence. The expression M. Hiraki (&) S. Sato T. Ohtsuka N. Kohya Y. Kitajima Y. Nakafusa K. Miyazaki Department of Surgery, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: [email protected] K. Kai O. Tokunaga Department of Pathology and Biodefense, Saga University Faculty of Medicine, Saga, Japan
of chemoresistance-related proteins was retrospectively analyzed by immunohistochemistry to evaluate the chemoresistance. The ortate phosphoribosyltransferase expression was strongly positive, and the good outcome in this case may have been associated with this result. Keywords Thymidylate synthase Dihydropyrimidine dehydrogenase Ortate phosphoribosyltransferase Chemoresistance
Introduction Fluoropyrimidine-based chemotherapy is widely used for gastric cancer, and chemoresistance-related proteins such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and ortate phosphoribosyltransferase (OPRT) are closely associated with resistance to fluoropyrimidinebased chemotherapy. Alpha-fetoprotein-producing gastric cancer (APGC) is generally considered to have poor prognosis because of the early microinvasion to the lymphatic and venous vessels and the high frequency of liver metastasis. This report presents a case of a long-time survivor of advanced APGC with a tumor embolism in the portal vein, which was successfully treated by fluoropyrimidine-based chemotherapy, and discusses the possible reasons for the favorable outcome based on an analysis of the molecular status of those chemoresistance-related proteins.
Case report A 67-year-old Japanese male was admitted with the chief complaints of body weight loss and appetite loss. The physical examination was unremarkable. Laboratory
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Fig. 1 Upper gastrointestinal series shows a type 3 lesion in the upper body of the stomach
studies on admission showed most markers were within the normal range except for slight anemia (hemoglobin, 10.4 g/ dl; normal [11.3 g/dl at our institution). The serum carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) levels were elevated to 5.3 ng/ml (normal \5.0 ng/ml) and 836 ng/ml (normal \10 ng/ml), respectively. Serum viral markers for hepatitis B and C were both negative. Endoscopic and radiological studies of the upper gastrointestinal tract demonstrated that there was a type 3 gastric cancer of 7 cm in diameter in the upper part of the stomach, which invaded 3 cm in to the esophagus (Fig. 1). Biopsy specimens revealed that the lesion was a poorly differentiated adenocarcinoma. Abdominal computed tomography (CT) demonstrated that there was thickening of the lesser curvature and posterior wall of the stomach, and lymph node swelling along the left gastric artery, common hepatic artery, and aorta (Fig. 2a), and a tumor embolus of 18 mm in diameter in the portal vein (Fig. 2b). Based on these findings, a diagnosis of advanced gastric cancer [cT3, cN3, cH0, cP0, cCY0, cM1, cStage IV (tumor embolism in the portal vein)] was made, according to the 2nd English edition of Japanese classification of gastric carcinoma [1]. We judged that preoperative chemotherapy was needed to reduce the degree of esophageal invasion and for downstaging, and therefore chemotherapy using S-1 and cisplatin was initially administered. The regimen of the chemotherapy consisted of 100 mg/day S-1 given orally for 3 weeks on day 1 to day 21, followed by 2 weeks of rest. A dose of 10 mg cisplatin was given intravenously on days 1, 8, and 15. The dosage of the cisplatin was different from the recent regimen of SPRITS trial [2], because dosage in our case was determined according to pilot study in our institution at that
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Fig. 2 CT scan demonstrates thickening of the lesser curvature and posterior wall of the stomach, lymph node swelling around the left gastric artery, common hepatic artery, and para-aortic artery (a), and a tumor embolism, 18 mm in diameter, in the portal vein (b)
time in 2001. The radiological findings demonstrated that there was no change in the size of lymph nodes and the tumor embolus in portal vein, while the esophageal invasion was slightly reduced. The serum level of AFP also decreased to 626 ng/ml after a transient increase (Fig. 3). The effect of this chemotherapy was thought to be a stable disease because no new lesions appeared and the present lesions demonstrated no change except for the 17.1% reduction in the main tumor [3]. However, we judged that reduction surgery of the tumor was possible due to the reduction of the esophageal invasion. We also intended to resect the tumor embolism in the portal vein depending on the circumstances of the operation. A total gastrectomy was performed with a distal pancreatectomy, splenectomy, and regional lymph node dissection. During the operation, we also resected the lymph nodes of the para-aorta and analyzed the intraoperative frozen-section histology. The result demonstrated that the lymph nodes were negative for cancer cells. We therefore attempted to resect the tumor embolism
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in the portal vein, aiming at curative resection. However, it was difficult to remove because of severe bleeding from the portal vein. As a result, reduction surgery was performed. The resected specimen displayed an elevated tumor with a maximum diameter of 7 cm, and central ulceration and
TS-1/cisplatin Paclitaxel operation
, 5 DFUR/Paclitaxel
2500
serum level of AFP
2000
AFP (ng/ml)
1500
1000
500
0
Fig. 3 Clinical course and changes in the serum level of alphafetoprotein (AFP)
surface erosion on the lesser curvature of the posterior wall of the stomach (Fig. 4a). The lymph node on the lesser curvature showed massive swelling. The main tumor was histologically diagnosed to be a poorly differentiated adenocarcinoma (Fig. 4b), and the cancer cells were positive for AFP (Fig. 4c). There were no metastatic foci in the resected lymph nodes, which was assumed to be an effect of the preoperative chemotherapy. The final diagnosis was stage IV [fT4, fNX, fH0, fP0, CY0, cM1 (tumor embolism in the portal vein)]. Combination chemotherapy with the same regimen of S-1 and cisplatin used originally was initiated on postoperative day 20. After one course of postoperative S-1/cisplatin combined therapy, the tumor embolus in the portal vein disappeared. However, a lymph node with a diameter of 1.5 cm appeared in the hepatoduodenal ligament after the 2nd course of S-1/cisplatin therapy. Therefore, the chemotherapy was changed to paclitaxel monotherapy, at a dose of 80 mg/m2 on days 1, 15, and 21, followed by a week of rest. After 2 courses of the paclitaxel monotherapy, the lymph node grew to 2.5 cm, and thus 50 deoxy-5-fluorouridine (50 DFUR) was added to the paclitaxel regimen. In addition to the treatment with paclitaxel, 800 mg/day 50 DFUR was orally administered for 5 days/ week for 3 weeks, followed by a week of rest. After 5 courses of the treatment, the lymph node swelling disappeared and no new lesions were observed. The regimen was
Fig. 4 Macroscopic appearance of the stomach is type 3 at the upper body of the stomach (a). Microscopically, the ulcerated lesion shows invasive proliferation of poorly differentiated adenocarcinoma (b) (9100). An immunohistochemical study demonstrates positive staining for AFP (c) (9100)
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Fig. 5 An immunohistochemical study shows that TS (a) and OPRT (b) are strongly positive, DPD is mildly positive (c) (9400)
changed to 2 weeks administration of the drugs with 2 weeks of rest, and a total of 21 courses of 50 DFUR/paclitaxel combined therapy was performed over 15 months, without any significant adverse effect except for grade 2 anemia, leucopenia, and alopecia according to the Common Terminology Criteria for Adverse Events version 4.0. Although the patient refused further treatment, he has remained well for over 8 years after his initial presentation. To evaluate the chemosensitivity of the present case, expression of TS, DPD, and OPRT in the biopsy specimen was retrospectively analyzed by immunohistochemistry (IHC) and quantitative double fluorescence immunohistochemistry (qDFIHC) as previously described [4]. IHC demonstrated relatively strong expression of TS (Fig. 5a) and OPRT (Fig. 5b) but relatively mild expression of DPD (Fig. 5c). The OPRT/TS ratio, which is considered to be S-1 sensitive when it is over 1.0, was evaluated by qDFIHC and determined to be 1.404. These findings suggest that the present case was an S-1-sensitive tumor.
Discussion The incidence of APGC ranges from 2.7% to 5.3% of gastric cancers [5–7]. APGC is characterized by deeper invasion of gastric wall, and more frequent nodal involvement, venous invasion, and liver metastasis, in
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comparison with non-APGC [6], and the survival rate of APGC patients is significantly worse than that of the stagematched non-APGC group [8]. Therefore, APGC is regarded as biologically high malignancy. On the other hand, APGC is thought to have a better response rate to chemotherapy than non-APGC [9]. Table 1 [10–25] shows the chemotherapy regimens and effects that were reported from 2000 to 2008. Recently, fluoropyrimidine-based therapy, especially S-1, has been chosen as chemotherapy for APGC. Chemotherapy for non-APGC using S-1 is administered to most patients in Japan due to its high response rate. However, no standard regimen of chemotherapy for APGC has been established. The current case showed a tumor thrombus in the portal vein. Generally, APGC tends to demonstrate liver metastasis and venous invasion in comparison with non-APGC [6]. Tumor thrombosis of the portal vein due to APGC has been reported [26–28], and successfully treated by neoadjuvant chemotherapy [28] or surgical resection [27]. The incidence of tumor thrombosis of the portal vein in APGC is unclear. However, Araki et al. [26] reported 4 cases of portal venous tumor thrombosis due to gastric cancer, 3 of which (75%) showed increased levels of AFP. Therefore, it might be necessary to consider the possibility of a tumor thrombus when treating APGC. Multiple clinical studies [4, 29–33] suggest that high expression of TS and DPD and low expression of OPRT
60
70
53
73
46
29
35
51
61
64
70
79
68
67
2002 Aoyagi [15]
2004 Hirao [16]
2005 Hirata [17]
2005 Hatta [18]
2005 Takahashi [19]
2006 Bakir [20]
2006 Bakir [20]
2006 Uesato [28]
2007 Usuba [21]
2007 Takeyama [22]
2008 Nakamura [23]
2008 Kunoki [24]
2008 Matsuo [25]
2009 Our case
IV (H1)
IV (H1)
IB (SM, N1)
IV (SS, N2, H1, M0)
IV (H1)
IV (M1, LYM)
IV (H1)
IV (T3, N3, H0, P0, M0)
IV (T3, N1, H1, P0)
IA (T1, N0, M0)
IV (T2, N3, H0, M1 (OTH))
IV (H1)
T4, N2, M0
IIIA (T3, N2, v2, ly3, H0, P0)
Male
Male
IV (T3, N3, H0, P0, CY0, M1)
IIIA (T3, N1, H0,P0, CY0, M0)
Female IV (H1)
Male
Male
Male
Male
Male
Male
Male
Female IV (H1)
Male
Female IV (T3, N3, M0)
Male
Female IIIB (T3, N2, H0, P0)
Male
Male
Male
Male
Male
(-)
Advanced
(?)
Adjuvant/ (?) recurrence (D)
Advanced
(?) (?)
Advanced
(?)
(-)
(-)
(-)
(?)
(?)
(?)
(-)
(-)
(?)
(?)
(?)
(?)
(?)
(-)
PD
Serum AFP & TPA level :
SD (P), CR (L)
PR (P), CR (L)
SD (P), PR (LN)
PR (P), PR (LN)
PD
PR (P), PR (L)
SD, serum AFP level :
CR
ND
SD (P), PR (L)
Effect
S-1/CDDP
5-FU/CDDP
5-FU/LV/ VP-16/CDDP
S-1/CDDP
S-1/TXL
UFT
S-1/CDDP
SD
PD
CR
Tumor marker level :
PD (L)
PD
PR
VP-16/EPI/CDDP PD
ADR/MMC/5-FU
S-1
S-1
S-1/CDDP
S-1
5-FU/CDDP
5-FU/CDDP
CPT11/CDDP
5-FU
5-FU/CDDP
S-1
5 DFUR/CDDP
0
Operation 1st line
Advanced
Adjuvant/ recurrence
Advanced
Advanced
Advanced
Advanced
Advanced
Advanced
Advanced
Advanced
Recurrence (D)
Advanced
Advanced
Recurrence (L)
Advanced
Advanced
Target disease
TXL
S-1
(-)
(-)
(-)
(-)
3rd line
PR (L)
PD
(-)
(-)
(-)
PD
(-)
(-)
CR
(-)
(-)
ND
PD
CR
(-)
(-)
(-)
(-)
(-)
(-)
(-)
ND
(-)
(-)
(-)
(-) CR
50 DFUR/TXL
(-)
PD
ND
PD
(-)
(-)
(-)
(-)
(-)
S-1
ND
S-1/CPT11/CDDP
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
CDDP
(-)
(-)
(-)
PD
(-)
96 m. alive
48 m. alive
18 m. alive
17 m. dead
ND
52 m. alive
12 m. live
4 m. died
4 m. died
ND
19 m. alive
ND
48 m. alive
36 m. died
19 m. alive
ND
ND
23 m. alive
11 m. alive
5 m. dead
Effect Prognosis
S-1/TXL/CDDP PR
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
Effect 4th line
TXL/CPT11/CDDP PR
(-)
(-)
CPT11
(-)
(-)
(-)
PR (P), CR (L) ND
(-)
ND
PD (Meninges)
Effect
S-1/CDDP/CPT11 PD
5-FU/TXL
UFT/5-FU/CDDP
S-1
(-)
(-)
TXL/CDDP
(-)
(-)
CPT11/MMC
(-)
(-)
ND
CPT11/CDDP
(-)
ND
MTX
2nd line
D dissemination, L liver, LN lymph node, P primary, CR complete response, PR partial response, SD stable disease, PD progressive disease, ADR adriamycin, CDDP cisplatin, CPT-11 irinotecan hydrochloride, EPI epirubicin, LV leucovorin, MMC mitomycin C, MTX methotrexate, TXL paclitaxel, VP16 etoposide
63
71
2002 Shimada [13]
70
63
2001 Moritani [12]
2002 Wakasugi [14]
67
2002 Shimada [13]
68
Age Gender Stage
2001 Inagawa [11]
Author
2000 Tsujikawa [10]
Year
Table 1 Reported cases of alpha-fetoprotein-producing gastric cancer treated with chemotherapy from 2000 to 2008
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are closely associated with resistance to fluoropyrimidinebased chemotherapy. In spite of the DPD expression in the current case, the tumor showed a good response. S-1 is recommended in patients with high DPD activity [34, 35], because S-1 is a fluoropyrimidine containing a strong DPD inhibitor. APGC has been reported to express DPD [36] and is resistant to 5-fluorouracil (5-FU). This report and the current results suggested that APGC may tend to have high DPD expression and S-1-based chemotherapy may be useful instead of other fluoropyrimidine agents. In addition, the present case demonstrated high OPRT expression in the immunohistochemical study. The good outcome in this case may have been associated with the high OPRT expression. Analysis of a biopsy specimen for expression of TS, DPD, and OPRT may therefore be useful in determining the optimal chemotherapeutic strategy. 50 -DFUR/paclitaxel combined therapy presented good response after the failure of the S-1/cisplatin combined therapy and paclitaxel monotherapy. Paclitaxel shows noncross resistance to various agents [37, 38], and enhances the efficacy of 50 -dFUrd by modulating dThdPase that converts 50 -dFUrd to 5-Fura [39]. Furthermore, patients that have received prior 5-FU-based chemotherapy show a high response rate to 50 -DFUR and paclitaxel combined therapy [38]. Therefore, sequential chemotherapy might be an effective strategy for treating APGC. The current patient had an APGC with aggressive behavior and its clinical or biological features were quite different from the common non-APGC. Aggressive sequential chemotherapy should be considered, and standard multimodal therapy against APGC is needed.
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CASE REPORT
A long-time survivor of alpha-fetoprotein-producing gastric cancer successfully treated by fluoropyrimidine-based chemotherapy: a case study Masatsugu Hiraki Æ Seiji Sato Æ Keita Kai Æ Takao Ohtsuka Æ Naohiko Kohya Æ Yoshihiko Kitajima Æ Yuji Nakafusa Æ Osamu Tokunaga Æ Kohji Miyazaki
Received: 25 June 2009 / Accepted: 12 August 2009 / Published online: 9 September 2009 Ó Springer 2009
Abstract A 67-year-old male with advanced gastric cancer and lymph node metastasis as well as a tumor embolus in the portal vein was treated by S-1/cisplatin therapy. The serum alpha-fetoprotein levels were elevated to 836 ng/ml at the first visit. After one course of chemotherapy, the patient showed stable disease; the serum level of alpha-fetoprotein also decreased to 626 ng/ml after a transient increase, and therefore reduction surgery was performed. A total gastrectomy with a distal pancreatectomy, splenectomy, and regional lymph node dissection was performed. The resected specimen was diagnosed to be alpha-fetoprotein-producing gastric cancer. There were no metastatic foci in the resected lymph nodes, presumably due to the preoperative chemotherapy. S-1/cisplatin therapy was continued after the operation to treat the remaining tumor embolus in the portal vein. After one course of this therapy, the tumor embolus disappeared. However, a lymph node measuring 1.5 cm in diameter appeared in the hepatoduodenal ligament. Therefore, the chemotherapy was changed to paclitaxel monotherapy. After 2 courses of paclitaxel monotherapy, the lymph node swelled, and thus 50 -deoxy-5-fluorouridine was added to the paclitaxel regimen. After 5 courses of this regimen, the lymph node swelling disappeared without any other new lesions and a total of 21 courses were performed. The patient remained stable for over 8 years without recurrence. The expression M. Hiraki (&) S. Sato T. Ohtsuka N. Kohya Y. Kitajima Y. Nakafusa K. Miyazaki Department of Surgery, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: [email protected] K. Kai O. Tokunaga Department of Pathology and Biodefense, Saga University Faculty of Medicine, Saga, Japan
of chemoresistance-related proteins was retrospectively analyzed by immunohistochemistry to evaluate the chemoresistance. The ortate phosphoribosyltransferase expression was strongly positive, and the good outcome in this case may have been associated with this result. Keywords Thymidylate synthase Dihydropyrimidine dehydrogenase Ortate phosphoribosyltransferase Chemoresistance
Introduction Fluoropyrimidine-based chemotherapy is widely used for gastric cancer, and chemoresistance-related proteins such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and ortate phosphoribosyltransferase (OPRT) are closely associated with resistance to fluoropyrimidinebased chemotherapy. Alpha-fetoprotein-producing gastric cancer (APGC) is generally considered to have poor prognosis because of the early microinvasion to the lymphatic and venous vessels and the high frequency of liver metastasis. This report presents a case of a long-time survivor of advanced APGC with a tumor embolism in the portal vein, which was successfully treated by fluoropyrimidine-based chemotherapy, and discusses the possible reasons for the favorable outcome based on an analysis of the molecular status of those chemoresistance-related proteins.
Case report A 67-year-old Japanese male was admitted with the chief complaints of body weight loss and appetite loss. The physical examination was unremarkable. Laboratory
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Fig. 1 Upper gastrointestinal series shows a type 3 lesion in the upper body of the stomach
studies on admission showed most markers were within the normal range except for slight anemia (hemoglobin, 10.4 g/ dl; normal [11.3 g/dl at our institution). The serum carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) levels were elevated to 5.3 ng/ml (normal \5.0 ng/ml) and 836 ng/ml (normal \10 ng/ml), respectively. Serum viral markers for hepatitis B and C were both negative. Endoscopic and radiological studies of the upper gastrointestinal tract demonstrated that there was a type 3 gastric cancer of 7 cm in diameter in the upper part of the stomach, which invaded 3 cm in to the esophagus (Fig. 1). Biopsy specimens revealed that the lesion was a poorly differentiated adenocarcinoma. Abdominal computed tomography (CT) demonstrated that there was thickening of the lesser curvature and posterior wall of the stomach, and lymph node swelling along the left gastric artery, common hepatic artery, and aorta (Fig. 2a), and a tumor embolus of 18 mm in diameter in the portal vein (Fig. 2b). Based on these findings, a diagnosis of advanced gastric cancer [cT3, cN3, cH0, cP0, cCY0, cM1, cStage IV (tumor embolism in the portal vein)] was made, according to the 2nd English edition of Japanese classification of gastric carcinoma [1]. We judged that preoperative chemotherapy was needed to reduce the degree of esophageal invasion and for downstaging, and therefore chemotherapy using S-1 and cisplatin was initially administered. The regimen of the chemotherapy consisted of 100 mg/day S-1 given orally for 3 weeks on day 1 to day 21, followed by 2 weeks of rest. A dose of 10 mg cisplatin was given intravenously on days 1, 8, and 15. The dosage of the cisplatin was different from the recent regimen of SPRITS trial [2], because dosage in our case was determined according to pilot study in our institution at that
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Fig. 2 CT scan demonstrates thickening of the lesser curvature and posterior wall of the stomach, lymph node swelling around the left gastric artery, common hepatic artery, and para-aortic artery (a), and a tumor embolism, 18 mm in diameter, in the portal vein (b)
time in 2001. The radiological findings demonstrated that there was no change in the size of lymph nodes and the tumor embolus in portal vein, while the esophageal invasion was slightly reduced. The serum level of AFP also decreased to 626 ng/ml after a transient increase (Fig. 3). The effect of this chemotherapy was thought to be a stable disease because no new lesions appeared and the present lesions demonstrated no change except for the 17.1% reduction in the main tumor [3]. However, we judged that reduction surgery of the tumor was possible due to the reduction of the esophageal invasion. We also intended to resect the tumor embolism in the portal vein depending on the circumstances of the operation. A total gastrectomy was performed with a distal pancreatectomy, splenectomy, and regional lymph node dissection. During the operation, we also resected the lymph nodes of the para-aorta and analyzed the intraoperative frozen-section histology. The result demonstrated that the lymph nodes were negative for cancer cells. We therefore attempted to resect the tumor embolism
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in the portal vein, aiming at curative resection. However, it was difficult to remove because of severe bleeding from the portal vein. As a result, reduction surgery was performed. The resected specimen displayed an elevated tumor with a maximum diameter of 7 cm, and central ulceration and
TS-1/cisplatin Paclitaxel operation
, 5 DFUR/Paclitaxel
2500
serum level of AFP
2000
AFP (ng/ml)
1500
1000
500
0
Fig. 3 Clinical course and changes in the serum level of alphafetoprotein (AFP)
surface erosion on the lesser curvature of the posterior wall of the stomach (Fig. 4a). The lymph node on the lesser curvature showed massive swelling. The main tumor was histologically diagnosed to be a poorly differentiated adenocarcinoma (Fig. 4b), and the cancer cells were positive for AFP (Fig. 4c). There were no metastatic foci in the resected lymph nodes, which was assumed to be an effect of the preoperative chemotherapy. The final diagnosis was stage IV [fT4, fNX, fH0, fP0, CY0, cM1 (tumor embolism in the portal vein)]. Combination chemotherapy with the same regimen of S-1 and cisplatin used originally was initiated on postoperative day 20. After one course of postoperative S-1/cisplatin combined therapy, the tumor embolus in the portal vein disappeared. However, a lymph node with a diameter of 1.5 cm appeared in the hepatoduodenal ligament after the 2nd course of S-1/cisplatin therapy. Therefore, the chemotherapy was changed to paclitaxel monotherapy, at a dose of 80 mg/m2 on days 1, 15, and 21, followed by a week of rest. After 2 courses of the paclitaxel monotherapy, the lymph node grew to 2.5 cm, and thus 50 deoxy-5-fluorouridine (50 DFUR) was added to the paclitaxel regimen. In addition to the treatment with paclitaxel, 800 mg/day 50 DFUR was orally administered for 5 days/ week for 3 weeks, followed by a week of rest. After 5 courses of the treatment, the lymph node swelling disappeared and no new lesions were observed. The regimen was
Fig. 4 Macroscopic appearance of the stomach is type 3 at the upper body of the stomach (a). Microscopically, the ulcerated lesion shows invasive proliferation of poorly differentiated adenocarcinoma (b) (9100). An immunohistochemical study demonstrates positive staining for AFP (c) (9100)
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Fig. 5 An immunohistochemical study shows that TS (a) and OPRT (b) are strongly positive, DPD is mildly positive (c) (9400)
changed to 2 weeks administration of the drugs with 2 weeks of rest, and a total of 21 courses of 50 DFUR/paclitaxel combined therapy was performed over 15 months, without any significant adverse effect except for grade 2 anemia, leucopenia, and alopecia according to the Common Terminology Criteria for Adverse Events version 4.0. Although the patient refused further treatment, he has remained well for over 8 years after his initial presentation. To evaluate the chemosensitivity of the present case, expression of TS, DPD, and OPRT in the biopsy specimen was retrospectively analyzed by immunohistochemistry (IHC) and quantitative double fluorescence immunohistochemistry (qDFIHC) as previously described [4]. IHC demonstrated relatively strong expression of TS (Fig. 5a) and OPRT (Fig. 5b) but relatively mild expression of DPD (Fig. 5c). The OPRT/TS ratio, which is considered to be S-1 sensitive when it is over 1.0, was evaluated by qDFIHC and determined to be 1.404. These findings suggest that the present case was an S-1-sensitive tumor.
Discussion The incidence of APGC ranges from 2.7% to 5.3% of gastric cancers [5–7]. APGC is characterized by deeper invasion of gastric wall, and more frequent nodal involvement, venous invasion, and liver metastasis, in
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comparison with non-APGC [6], and the survival rate of APGC patients is significantly worse than that of the stagematched non-APGC group [8]. Therefore, APGC is regarded as biologically high malignancy. On the other hand, APGC is thought to have a better response rate to chemotherapy than non-APGC [9]. Table 1 [10–25] shows the chemotherapy regimens and effects that were reported from 2000 to 2008. Recently, fluoropyrimidine-based therapy, especially S-1, has been chosen as chemotherapy for APGC. Chemotherapy for non-APGC using S-1 is administered to most patients in Japan due to its high response rate. However, no standard regimen of chemotherapy for APGC has been established. The current case showed a tumor thrombus in the portal vein. Generally, APGC tends to demonstrate liver metastasis and venous invasion in comparison with non-APGC [6]. Tumor thrombosis of the portal vein due to APGC has been reported [26–28], and successfully treated by neoadjuvant chemotherapy [28] or surgical resection [27]. The incidence of tumor thrombosis of the portal vein in APGC is unclear. However, Araki et al. [26] reported 4 cases of portal venous tumor thrombosis due to gastric cancer, 3 of which (75%) showed increased levels of AFP. Therefore, it might be necessary to consider the possibility of a tumor thrombus when treating APGC. Multiple clinical studies [4, 29–33] suggest that high expression of TS and DPD and low expression of OPRT
60
70
53
73
46
29
35
51
61
64
70
79
68
67
2002 Aoyagi [15]
2004 Hirao [16]
2005 Hirata [17]
2005 Hatta [18]
2005 Takahashi [19]
2006 Bakir [20]
2006 Bakir [20]
2006 Uesato [28]
2007 Usuba [21]
2007 Takeyama [22]
2008 Nakamura [23]
2008 Kunoki [24]
2008 Matsuo [25]
2009 Our case
IV (H1)
IV (H1)
IB (SM, N1)
IV (SS, N2, H1, M0)
IV (H1)
IV (M1, LYM)
IV (H1)
IV (T3, N3, H0, P0, M0)
IV (T3, N1, H1, P0)
IA (T1, N0, M0)
IV (T2, N3, H0, M1 (OTH))
IV (H1)
T4, N2, M0
IIIA (T3, N2, v2, ly3, H0, P0)
Male
Male
IV (T3, N3, H0, P0, CY0, M1)
IIIA (T3, N1, H0,P0, CY0, M0)
Female IV (H1)
Male
Male
Male
Male
Male
Male
Male
Female IV (H1)
Male
Female IV (T3, N3, M0)
Male
Female IIIB (T3, N2, H0, P0)
Male
Male
Male
Male
Male
(-)
Advanced
(?)
Adjuvant/ (?) recurrence (D)
Advanced
(?) (?)
Advanced
(?)
(-)
(-)
(-)
(?)
(?)
(?)
(-)
(-)
(?)
(?)
(?)
(?)
(?)
(-)
PD
Serum AFP & TPA level :
SD (P), CR (L)
PR (P), CR (L)
SD (P), PR (LN)
PR (P), PR (LN)
PD
PR (P), PR (L)
SD, serum AFP level :
CR
ND
SD (P), PR (L)
Effect
S-1/CDDP
5-FU/CDDP
5-FU/LV/ VP-16/CDDP
S-1/CDDP
S-1/TXL
UFT
S-1/CDDP
SD
PD
CR
Tumor marker level :
PD (L)
PD
PR
VP-16/EPI/CDDP PD
ADR/MMC/5-FU
S-1
S-1
S-1/CDDP
S-1
5-FU/CDDP
5-FU/CDDP
CPT11/CDDP
5-FU
5-FU/CDDP
S-1
5 DFUR/CDDP
0
Operation 1st line
Advanced
Adjuvant/ recurrence
Advanced
Advanced
Advanced
Advanced
Advanced
Advanced
Advanced
Advanced
Recurrence (D)
Advanced
Advanced
Recurrence (L)
Advanced
Advanced
Target disease
TXL
S-1
(-)
(-)
(-)
(-)
3rd line
PR (L)
PD
(-)
(-)
(-)
PD
(-)
(-)
CR
(-)
(-)
ND
PD
CR
(-)
(-)
(-)
(-)
(-)
(-)
(-)
ND
(-)
(-)
(-)
(-) CR
50 DFUR/TXL
(-)
PD
ND
PD
(-)
(-)
(-)
(-)
(-)
S-1
ND
S-1/CPT11/CDDP
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
CDDP
(-)
(-)
(-)
PD
(-)
96 m. alive
48 m. alive
18 m. alive
17 m. dead
ND
52 m. alive
12 m. live
4 m. died
4 m. died
ND
19 m. alive
ND
48 m. alive
36 m. died
19 m. alive
ND
ND
23 m. alive
11 m. alive
5 m. dead
Effect Prognosis
S-1/TXL/CDDP PR
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
Effect 4th line
TXL/CPT11/CDDP PR
(-)
(-)
CPT11
(-)
(-)
(-)
PR (P), CR (L) ND
(-)
ND
PD (Meninges)
Effect
S-1/CDDP/CPT11 PD
5-FU/TXL
UFT/5-FU/CDDP
S-1
(-)
(-)
TXL/CDDP
(-)
(-)
CPT11/MMC
(-)
(-)
ND
CPT11/CDDP
(-)
ND
MTX
2nd line
D dissemination, L liver, LN lymph node, P primary, CR complete response, PR partial response, SD stable disease, PD progressive disease, ADR adriamycin, CDDP cisplatin, CPT-11 irinotecan hydrochloride, EPI epirubicin, LV leucovorin, MMC mitomycin C, MTX methotrexate, TXL paclitaxel, VP16 etoposide
63
71
2002 Shimada [13]
70
63
2001 Moritani [12]
2002 Wakasugi [14]
67
2002 Shimada [13]
68
Age Gender Stage
2001 Inagawa [11]
Author
2000 Tsujikawa [10]
Year
Table 1 Reported cases of alpha-fetoprotein-producing gastric cancer treated with chemotherapy from 2000 to 2008
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are closely associated with resistance to fluoropyrimidinebased chemotherapy. In spite of the DPD expression in the current case, the tumor showed a good response. S-1 is recommended in patients with high DPD activity [34, 35], because S-1 is a fluoropyrimidine containing a strong DPD inhibitor. APGC has been reported to express DPD [36] and is resistant to 5-fluorouracil (5-FU). This report and the current results suggested that APGC may tend to have high DPD expression and S-1-based chemotherapy may be useful instead of other fluoropyrimidine agents. In addition, the present case demonstrated high OPRT expression in the immunohistochemical study. The good outcome in this case may have been associated with the high OPRT expression. Analysis of a biopsy specimen for expression of TS, DPD, and OPRT may therefore be useful in determining the optimal chemotherapeutic strategy. 50 -DFUR/paclitaxel combined therapy presented good response after the failure of the S-1/cisplatin combined therapy and paclitaxel monotherapy. Paclitaxel shows noncross resistance to various agents [37, 38], and enhances the efficacy of 50 -dFUrd by modulating dThdPase that converts 50 -dFUrd to 5-Fura [39]. Furthermore, patients that have received prior 5-FU-based chemotherapy show a high response rate to 50 -DFUR and paclitaxel combined therapy [38]. Therefore, sequential chemotherapy might be an effective strategy for treating APGC. The current patient had an APGC with aggressive behavior and its clinical or biological features were quite different from the common non-APGC. Aggressive sequential chemotherapy should be considered, and standard multimodal therapy against APGC is needed.
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