Successful paclitaxel-based chemotherapy for an alpha-fetoprotein-producing gastric cancer patient with multiple liver metastases
© Takeyama et al; licensee BioMed Central Ltd. 2007
Received: 21 March 2007
Accepted: 16 July 2007
Published: 16 July 2007
Alpha-fetoprotein (AFP)-producing gastric cancer is known to frequently cause multiple liver metastases and to have an extremely poor prognosis.
A 64-year-old Japanese man admitted to our hospital was diagnosed with gastric cancer with liver metastases. He underwent a total gastrectomy with splenectomy, and pathological stage IV disease according to the classification proposed by the Japanese Gastric Cancer Association was assigned. The histological diagnosis was poorly differentiated adenocarcinoma, and tumor production of AFP was confirmed by immunohistochemical staining. Following surgery, the patient received combination chemotherapy consisting of TS-1 and paclitaxel. Initially, AFP levels decreased dramatically and computed tomography (CT) revealed regression of liver metastases. However, multiple new liver metastases appeared and serum AFP levels increased after 5 months. A regimen of 5-FU plus paclitaxel followed by paclitaxel monotherapy was used next. Serum AFP levels once again decreased and CT showed regression or disappearance of liver metastases. The patient currently has a very good quality of life, and is receiving weekly paclitaxel monotherapy as an outpatient. No progression of liver metastases has been observed to date.
We consider this rare case to have significant value with respect to treatment of AFP-producing gastric cancer with multiple liver metastases, and propose that combining surgery with chemotherapeutic agents such as paclitaxel may lead to a better prognosis in such cases.
Alpha-fetoprotein (AFP), which was initially identified from human fetal tissue, is normally produced in the fetal liver and yolk sac . Since Bourreille et al., first reported a patient with gastric tumors that produced AFP, a considerable number of such patients have been identified . AFP-producing gastric cancer is known to frequently cause multiple liver metastases and to have an extremely poor prognosis [3–6]. It has been reported that AFP-producing gastric cancer has high proliferative activity, weak apoptotic activity, and rich neovascularization compared with AFP-negative gastric cancer . It is likely that these biological observations reflect the aggressive clinical behavior of AFP-producing gastric cancers.
There is no standard chemotherapy available for this disease, although the following regimens have demonstrated efficacy in a small number of cases: EAP (etoposide [ETP], adriamycin, and cisplatin [CDDP]), FAP (5-fluorouracil [5-FU], epirubicin [EPI], and CDDP), and FAP (5-FU, adriamycin, and CDDP) [7–9]. The therapeutic efficacy of irinotecan hydrochloride (CPT-11) and paclitaxel [10, 11] in this disease state has also been recently reported.
In this report, we describe a case with AFP-producing gastric cancer that responded to combination 5-FU/paclitaxel chemotherapy followed by a bi-weekly course of paclitaxel monotherapy.
AFP-producing gastric cancers should be divided in to three subtypes: 1) hepatoid type; 2) yolk sac tumor-like type; and 3) fetal gastrointestinal type . The hepatoid type was the most common one of AFP-producing gastric cancer, and they were described as hepatoid adenocarcinoma that means primary gastric cancer that are characterized by both hepatoid differentiation and the production of AFP [14, 15]. Our case had the tumor that was classified as having a hepatoid subtype. Unfortunately, most hepatoid type tumor tends to be highly malignant . AFP-producing gastric cancer has a high proliferative activity, weak apoptosis, and rich neovascularization . Recent reports described that some factors associated with mitosis, cell movement, proliferative activity, and tumor progression such as Ki-67, hepatocyte growth factor (HGF) and its receptor, c-Met, vascular endothelial growth factor (VEGF) and its isoform VEGF-C, were found to be highly expressed in AFP-producing gastric cancer and might contribute to the poor prognosis and drug resistance of this tumor [4, 16, 17].
Few successful treatment options exist for AFP-producing gastric cancer. While surgical resection is considered to be somewhat effective, approximately 50% of patients who undergo curative resection of the primary tumor eventually die due to recurrence, most of them with multiple liver metastases . Indeed, AFP-producing gastric cancer is associated with a high incidence of multiple liver metastases, which render resection impossible. Moreover, AFP-producing gastric cancer is reported to respond poorly to a number of chemotherapy regimens. The use of various chemotherapeutic protocols that are active in other types of cancer have been reported, although their efficacy in gastric cancer is controversial [7–11]. Some investigators have reported that AFP-producing gastric cancer can be treated successfully with preoperative (i.e., neoadjuvant) combination chemotherapy with EPI, 5-FU, and leucovorin (LV) . Kochi et al., have also reported the use of a combination chemotherapy regimen consisting of 5-FU, LV, ETP, and CDDP (designated as the FLEP regimen) for inoperable stage IV gastric cancer [20, 21]. FLEP chemotherapy was more effective for stage IV AFP-producing gastric cancer than for stage IV non-AFP-producing gastric cancer, and it improved the prognosis of AFP-producing gastric cancer due to downstaging.
TS-1 has shown superior results in the treatment of gastric cancer both as monotherapy and in combination with other agents. In a phase II clinical trial in Japan, single administration of TS-1 yielded a higher response rate (46.5%, 60/129 cases), longer median survival time (MST; 8.1 months), and lower incidence of adverse events compared to historical controls (e.g., 5-FU, methotrexate + LV, CDDP). It has proven to be one of the most promising new anti neoplastic agents . However, in poorly differentiated gastric cancer, the agents described above are only effective in a small proportion of patients. Several case reports have demonstrated the efficacy of TS-1 monotherapy against malignant ascites. The novel antimitotic agent paclitaxel inhibits cell division by promoting tubulin polymerization and stabilizing microtubules . This agent has been used as second-line treatment in patients with gastric cancer, particularly for cases refractory to first-line drugs (i.e., CDDP, 5-FU) or who experience recurrence following surgery.
As monotherapy, paclitaxel has been shown to result in a response rate of 26% in gastric cancer patients with previously treated by surgery and 21% in those with prior chemotherapy. Remarkably, paclitaxel is the only monotherapy shown to increase MST to longer than 300 days in patients with advanced and recurrent gastric cancer, regardless of prior treatment history . Recently, some cases responding to paclitaxel treatment were reported. Chiba et al., reported the case of AFP-producing hepatoid adenocarcinoma in association with Barrett's esophagus with multiple liver metastases responding to paclitaxel/CDDP . Hirashima et al., reported the successful bi-weekly paclitaxel treatment of an AFP-producing gastric cancer , however, there was no English literature which described the efficacy of paclitaxel for AFP-producing gastric cancers.
In our patient, we first used TS-1 and paclitaxel combination chemotherapy. Initially, the patient's AFP levels dramatically decreased and CT showed regression of metastatic liver tumors; however, multiple new liver metastases appeared and serum AFP levels increased after 5 months. Furthermore, the patient suffered an ileus due to peritonitis carcinomatous. Consequentially, we used combination 5-FU and paclitaxel chemotherapy with subsequent paclitaxel monotherapy as second-line treatment. This regimen resulted in the disappearance or reduction in size of many liver metastases, and greatly improved the patient's quality of life. The most significant toxicity, leukopenia, was effectively controlled with granulocyte colony-stimulating factors.
To our knowledge, this is the first case report in the English literature of an AFP-producing gastric cancer associated with multiple liver metastases that was successfully treated with paclitaxel. We consider this rare case to be of significant value with respect to the treatment of AFP-producing gastric cancer with multiple liver metastases. We feel that combining surgery with chemotherapy such as paclitaxel will lead to a better prognosis in such cases. We also believe that our protocol is an effective and safe treatment for liver metastases associated with AFP-producing gastric cancer. Nevertheless, further clinical evaluation of this regimen in advanced AFP-producing gastric cancer with liver metastases is required.
Written consent was obtained from the patient for publication of study.
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