Treatment Of Metastatic Gastric Cancer Research Articles

Cathepsin S Mediates Gastric Cancer Cell Migration and Invasion via a Putative Network of Metastasis-Associated Proteins

Cancer progression is governed by multifaceted interactions of cancer cells with their microenvironment and one of these ways is through secreted compounds. Substances released by gastric cancer cells have not being profiled in a proteome-wide manner. ITRAQ-based tandem mass spectrometry was employed to quantify proteins secreted by HFE145 normal, MKN7 well-differentiated, and MKN45 poorly differentiated gastric cancer cell lines. The expression levels of 237 proteins were found to be significantly different between normal and cancer cells. Further examination of 16 gastric cell lines and 115 clinical samples validated the up-regulation of CTSS expression in gastric cancer. Silencing CTSS expression suppressed the migration and invasion of gastric cancer cells in vitro. Subsequent secretomics revealed that CTSS silencing resulted in changes in expression levels of 197 proteins, one-third of which are implicated in cellular movement. Proteome-wide comparative secretomes of normal and gastric cancer cells were produced that constitute a useful resource for gastric cancer research. CTSS was demonstrated to play novel roles in gastric cancer cell migration and invasion, putatively via a network of proteins associated with cell migration, invasion, or metastasis. Cathepsin S is member of a large group of extracellular proteases, which are attractive drug targets. The implicated role of CTSS in gastric cancer metastasis provides an opportunity to test existing compounds against CTSS for adjuvant therapy and/or treatment of metastatic gastric cancers.

FOLFOX6 as first-line treatment in metastatic gastric cancer: Preliminary results of a phase II trial.

4091 Background: In metastatic gastric cancer, the superiority of a 3-drug regimen compared with a two drug regimen in terms of response rates (RR) and survival has not been definitely demonstrated...

Phase II Study of Irinotecan, High-dose 5-fluorouracil, and Leucovorin Combination Chemotherapy in Taxane and Cisplatin-based Chemotherapy-refractory Metastatic Gastric Cancer

This phase II study evaluated the efficacy and safety of combination chemotherapy with irinotecan, highdose 5-fluorouracil (5-FU), and leucovorin as a second line of treatment in metastatic gastric cancer refractory to taxane and cisplatin-based chemotherapy. Eligible criteria were as follows: histologically confirmed adenocarcinoma of the stomach previously treated with taxane and cisplatin, age≥18 years, Eastern Clinical Oncology Group (ECOG) performance status of 1 or less, and adequate organ function. Irinotecan (150 mg/m 2 ) and leucovorin (200 mg/m 2 ) were given on day 1, followed by a 400-mg/m 2 bolus infusion of 5-FU and then 2,400 mg/m 2 5-FU as a 48-hour continuous infusion. This cycle was repeated every 2 weeks until disease progression or unacceptable toxicities. Thirty-seven patients were enrolled. The patients’ median age was 55 years (range, 27∼73 years), and the ECOG performance status of all patients was 1. All patients were evaluable for safety and survival, and 29 patients (78.3%) were evaluable for tumor response. The overall response rate was 17.2% [95% confidence interval (CI): 3.5∼30.9%]. The median progression-free survival and overall survival were 4.3 months (95% CI: 2.1∼6.6) and 10.6 months (95% CI: 7.1∼14.1). Greater than grade 3 hematological toxicities were neutropenia in 9 (24.3%), febrile neutropenia in 1 (2.7%), and thrombocytopenia in 1 (2.7%) patient. The major nonhematological toxicity was asthenia, but most patients showed grade 1 or 2. Greater than grade 3 nonhematological toxicities were elevated AST/ALT in 4 (10.8%), hyperbilirubinemia in 2 (5.4%), and nausea in 2 (5.4%) patients. This study showed that combination chemotherapy with irinotecan, high dose 5-FU, and leucovorin is well tolerated and active in patients with cancer refractory to taxane and cisplatin.

Future perspectives of chemotherapy for advanced gastric cancer

According to the results of two recent randomized studies of treatment for metastatic gastric cancer in Japan, S-1 could replace infusional 5-fluorouracil and S-1 plus cisplatin showed a significant survival advantage over S-1 monotherapy, with a favorable toxicity profile. However, no globally accepted standards have been established yet and we have to wait for the results of other ongoing international studies, including studies of S-1 and its combinations, to achieve such standards. There are two major approaches to achieve further progress in the treatment of advanced gastric cancer. The first is to optimize the use of conventional cytotoxic agents (regimens) in the continuum of treatment for this disease. Several randomized studies of such regimens as second-line treatments are being planned in Japan, for which definitions of eligibility criteria and primary endpoints should be fully discussed in the design of the protocols. The second approach is to incorporate new active agents, particularly molecular targeting agents. Several molecular targeting agents that have shown survival advantages in patients with other tumor types are now under investigation for the treatment of gastric cancer in international randomized studies, including Japan and Korea. The next generation of targeting agents is also being evaluated in early clinical studies. Biological research has become essential for developing new targeting agents. For such biological studies, the tumor tissues of gastric cancer are easily obtainable via endoscopy, and such studies may constitute new frontiers in biological therapy. We expect that these studies will provide not only further clinical advantages but that they will also lead to tailored medicine.

3546 POSTER (XELOX)Capecitabine plus Oxaliplatin: clinical efficacy and safety in first-line treatment for metastatic gastric cancer

3546 POSTER (XELOX)Capecitabine plus Oxaliplatin: clinical efficacy and safety in first-line treatment for metastatic gastric cancer

Chemoimmunotherapy in the treatment of metastatic gastric cancer

Docetaxel, capecitabine and 5-fluorouracil have been shown to be active in the treatment of metastatic gastric adenocarcinoma. Consistent with this finding, the aim of this study was to test this combination in a clinical trial. Forty-one patients with metastatic gastric adenocarcinoma and a median age of 64 years were recruited for the study. The treatment was based on the administration of docetaxel 60 mg/m2 every 4 weeks, leucovorin 200 mg/m2, 5-fluorouracil 400 mg/m2 bolus, and capecitabine 1000 mg/m2 twice daily on days 1 and 2 every 2 weeks. Patients achieving a clinical benefit were treated, as maintenance immunotherapy, with low-dose interleukin-2 and 13-cis-retinoic acid. The primary end point of this phase II study was the response rate. The secondary end points relied on the evaluation of the immunological parameters, toxicity, and progression-free survival and overall survival. The overall response rate in the 41 evaluable patients was estimated to be 49%. Median progression-free and overall survival was 9.5 and 21.1 months, respectively. Grade 3 and 4 hematological toxicities were neutropenia and thrombocytopenia in 44 and 5% of patients, respectively. A sustained improvement of evaluated immunological parameters with a negligible toxicity profile was observed in the 27 patients treated with interleukin 1-2/13-cis-retinoic acid. Docetaxel in combination with leucovorin, 5-fluorouracil and capecitabine followed by low-dose interleukin 1-2 and 13-cis-retinoic acid is well tolerated, and shows a significant activity in patients with metastatic gastric adenocarcinoma.

Treatment of Metastatic or Recurrent Gastric Cancer with Weekly 24-hour Infusion of Cisplatin and High-Dose 5-Fluorouracil/Leucovorin in an Outpatient Setting

Objective: There is no general agreement over a standard chemotherapy regimen for metastatic or recurrent gastric cancer. We evaluated, retrospectively, the activity and toxicity of weekly 24-hour infusion of cisplatin with high-dose 5-fluorouracil/leucovorin (P-HDFL) in an outpatient setting. Materials and Methods: Patients with metastatic or recurrent gastric cancer, treated in an outpatient setting from May 2001 to July 2005, were analyzed retrospectively. The regimen consisted of continuous infusion cisplatin 25mg/m^2, 5-fluorouracil 2000 mg/m^2 and leucovorin 200mg/m^2 on day 1, 8 and 15 every 4 weeks. The treatment was continued for a maximum of six cycles unless the disease progressed or intolerable toxicities occurred. Results: Twenty-one patients received this regimen: 16 men and 5 women, median age 56 years (range 27-71). A median of 4.3 cycles was administered. Seven of 21 patients (33.3%) achieved an objective partial response. Stable disease was observed in 6 patients (28.6%) and progressive disease in 8 patients (38.1%). The median survival was 7.7 months (95% confidence interval, 6.2-12.8 months). Digestive and hematological toxicities were low and no severe renal insufficiency was observed. The most common toxicity was elevated liver enzymes (11 patients, 52%), of whom three had≥grade 3 toxicity: 1 of them died of hepatic failure. Conclusion: Our results show that outpatient P-HDFL therapy leads to a fairly comparable outcome with various regimens of 5-fluorouracil/cisplatin. This outpatient regimen could be a reasonable alternative that combines advantages in respect of patient activity, mild to moderate toxicity, convenience of dosing and minor expenditure.

Prediction of clinical outcome of fluoropyrimidine-based chemotherapy for gastric cancer patients, in terms of the 5-fluorouracil metabolic pathway

Fluoropyrimidines are widely used in chemotherapy regimens for metastatic gastric cancer. Interindividual variation in the enzyme activity of the 5-fluorouracil (FU) metabolic pathway can affect the extent of 5-FU metabolism and affect the efficacy of 5-FU based chemotherapy. In this review, the role of the genetic factors affecting the therapeutic efficacy of fluoropyrimidines is discussed, with a special emphasis on enzymes involved in the 5-FU metabolic pathway. The gene expressions of thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase are discussed in relation to the efficacy of fluoropyrimidine treatment for metastatic gastric cancer. These candidate genes, along with others yet to be identified, could allow accurate prediction of the clinical outcome in patients receiving fluoropyrimidine-based chemotherapy in the future. Well-designed and large prospective studies, which include relevant pharmacogenetic parameters, are needed to confirm the values required to predict clinical outcome.

Phase I trial of docetaxel, oxaliplatin and capecitabine (TEX) in patients with metastatic gastric cancer

14051 Background: Combination regimens of 3 active drugs have shown promising activity in treatment of metastatic gastric cancer (GC). Docetaxel (D) combined with cisplatin and 5-FU (CF) yielded superior overall survival and response rates when compared to standard CF. However, toxicity profile showed the need for development of less toxic modifications. In this phase I trial, D was combined with oxaliplatin (Ox) and capecitabine (Cape) in order to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) in patients (pts) with metastatic GC. Methods: Pts had to have metastatic or locally advanced GC, adequate organ function, ECOG PS 0–2, no prior chemotherapy. Four dose levels were planned planned for the TEX regimen: D 35–40 mg/m2, Ox 70 mg/m2 d1 and d88, with Cape 800–1000 mg/m2 bid d1–14 q d22. Toxicity was assessed 3-weekly whereas CT scans were repeated 9-weekly. Results: 14 pts were enrolled: 9m/5f, age 64 (42–76) yrs, ECOG PS 1 [0–2]. All pts. had distant metastatis, 10 no gastrectomy. On dose level 1 (D 35 mg/m2, Ox 70 mg/m2, Cape 800 mg/m2) 3 pts were included initially. 1 pt. had grade 4 bleeding from primary tumor site after 2nd administration and therefore was excluded. For safety reasons, 6 more pts. were enrolled - without further DLT. On dose level 2 (D 40 mg/m2, Ox 70 mg/m2, Cape 800 mg/m2), diarrhea and mucositis grade 3 occurred as DLT in 2/2 patients. Level 1 was determined as MTD and 5 more pts were included to a total of 12 with toxicity displayed at the table. Out of 10 pts with measurable disease, 3 had a PR, 4 more had disease stabilization. Median PFS of all pts (5 censored) is 3.9+ (1–9.3+) mos. whereas median OS is not yet reached. Conclusion: TEX can safely be administered without higher graded toxicity in pts with GC. Preliminary efficacy results indicate promising activity that merits further testing in a phase II trial. [Table: see text] [Table: see text]

Low rate of progressive disease in metastatic gastric cancer using tandem chemotherapy with four active compounds

14069 Background: Taxanes and irinotecan have significantly increased the therapeutic options in the treatment of metastatic gastric cancer. However, the potential of all active substances is highest in first - line treatment. The rate of second remissions is low and survival after relapse is short. We performed a phase II study incorporating 5FU, irinotecan, cisplatin and docetaxel in a tandem protocol for first line treatment of patients with metastastic adenocarcinoma of stomach or cardia. Methods: Chemonaive patients received a 30-minute infusion of irinotecan 80 mg/m2 followed by IV bolus leucovorin 20 mg/m2 and infusional 5FU 2000 mg/m2 over 24 hours on days 1, 8 and 15. The second block included docetaxel 25 mg/m2 over 60 minutes followed by a 30-minute infusion of cisplatin 40 mg/m2 on days 29, 36 and 43. Patients were scheduled to receive two complete cycles. Primary objective was evaluation of remission rate. Further objectives were toxicity and overall survival. Results: 32 patients were included, 25 patients are currently evaluable. The median age was 56 years (36 - 72), 10 female and 15 male patients. 10/25 (40%) patients achieved a partial remission, 3 of these 10 patients had a very good partial remission. 13 (52%) patients had stable disease, and 2 (8%) patients progressed early. Main toxicities grade ≥ 3 were diarrhea (8/50 cycles), nausea and vomiting (3/50), neutropenia (2/50), anemia (1/50) and renal insufficiency (1/50). The median survival time was 11.7 months. Conclusions: This treatment schedule includes the four most active substances in the treatment of metastastic gastric cancer in a tandem protocol. Only 2/25 patients had progressive disease under therapy. Toxicity was moderate. Dose intensication may further increase the remission rate. No significant financial relationships to disclose.

Phase II study of docetaxel and irinotecan combination chemotherapy in metastatic gastric carcinoma

The current treatment for metastatic gastric cancer (MGC) consists of cisplatin and/or fluorouracil (5-FU) based combination chemotherapy, but cisplatin-based regimens are associated with considerable toxicity. We evaluated the efficacy and safety of a noncisplatin-, non-5-FU-containing regimen, docetaxel/irinotecan in MGC. Chemo-naive patients with MGC received docetaxel (30 mg m−2) and irinotecan (70 mg m−2) on days 1 and 8 every 3 weeks. The 48 eligible patients (median age 56 years) received a median of four cycles of docetaxel/irinotecan (range 1–18). Of the 46 patients in whom efficacy could be evaluated, 21 showed a partial response (response rate=45.7%; 95% confidence interval (CI) 31.3–60.1%). At a median follow-up of 15.0 months, the median time to progression was 4.5 months (95% CI 3.8–5.2 months) and overall survival was 8.2 months (95% CI, 5.8–10.6 months). Grade 3/4 neutropenia developed in 57.4% of patients, and febrile neutropenia/neutropenic infection in 19.1%. Nonhaematological toxicities were moderate; grade 3/4 diarrhoea occurred in 19.1% of patients, however, was manageable by a dose reduction. There was one possible treatment-related death. In conclusion, weekly docetaxel/irinotecan is a promising outpatient regimen in MGC, with appropriate dose modification.

Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer

Oxaliplatin plus fluorouracil/folinic acid (5-FU/FA) every 2 weeks has shown promising activity in advanced gastric cancer. This study assessed the efficacy and safety of weekly oxaliplatin plus 5-FU/FA (FUFOX regimen) in the metastatic setting. Patients with previously untreated metastatic gastric cancer received oxaliplatin (50 mg m−2) plus FA (500 mg m−2, 2-h infusion) followed by 5-FU (2000 mg m−2, 24-h infusion) given on days 1, 8, 15 and 22 of a 5-week cycle. The primary end point of this multicentre phase II study was the response rate according to RECIST criteria. A total of 48 patients were enrolled. Median age was 62 years and all patients had metastatic disease, with a median number of three involved organs. The most common treatment-related grade 3/4 adverse events were diarrhoea (17%), deep vein thrombosis (15%), neutropenia (8%), nausea (6%), febrile neutropenia (4%), fatigue (4%), anaemia (4%), tumour bleeding (4%), emesis (2%), cardiac ischaemia (2%) and pneumonia (2%). Grade 1/2 sensory neuropathy occurred in 67% of patients but there were no episodes of grade 3 neuropathy. Intent-to-treat analysis showed a response rate of 54% (95% CI, 39–69%), including two complete responses. At a median follow-up of 18.1 months (range 11.2–26.2 months), median survival is 11.4 months (95% CI, 8.0–14.9 months) and the median time to progression is 6.5 months (95% CI, 3.9–9.2 months). The weekly FUFOX regimen is well tolerated and shows notable activity as first-line treatment in metastatic gastric cancer.

Randomised phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF) vs 5-fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer

An open-label randomised comparison of efficacy and tolerability of irinotecan plus high-dose 5-fluorouracil (5-FU) and leucovorin (LV) (ILF) with etoposide plus 5-FU/LV (ELF) in patients with untreated metastatic or locally advanced gastric cancer. One cycle of ILF comprised six once-weekly infusions of irinotecan 80 mg m−2, LV 500 mg m−2, 24-h 5-FU 2000 mg m−2, and ELF comprised three once-daily doses of etoposide 120 mg m−2, LV 300 mg m−2, 5-FU 500 mg m−2. In all, 56 patients received ILF and 58 ELF. Median age was 62 years, Karnofsky performance 90%, and disease status was comparable for both arms. The objective clinical response rates after 14 weeks treatment (primary end point) were 30% for ILF and 17% for ELF (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.29–1.13, P=0.0766). Overall response rates over the entire treatment period for ILF and ELF were 43 and 24%, respectively (RR 0.56, 95% CI 0.33–0.97; P=0.0467). For ILF and ELF, respectively, median progression-free survival was 4.5 vs 2.3 months, time to treatment failure was 3.6 vs 2.2 months (P=0.4542), and overall survival was 10.8 vs 8.3 months (P=0.2818). Both regimens were well tolerated, the main grade 3/4 toxicities being diarrhoea (18%, ILF) and neutropenia (57%, ELF). The data from this randomised phase II study indicate that ILF provides a better response rate than ELF, and that ILF should be investigated further for the treatment of metastatic gastric cancer.

Chemotherapy for Metastatic Gastric Cancer: Results from Clinical Trials in Asia

Chemotherapy for metastatic gastric cancer surely has a survival benefit compared to best supportive care. In the recent decades, some phase III trials have been conducted for metastatic gastric cancer all over the world. However, no chemotherapy regimen has shown a survival benefit with 5-FU alone, and there is no standard treatment. Recently, not a few anti-tumor agents have been developed, including irinotecan, oral pyrimidines, Taxane, and molecular target agents. Many phase I and II trials conducted in Asia have shown their activity both as single agents and in combination. Moreover, phase III trials including these new agents are underway, and some of them are expected to prolong survival and establish a standard treatment for metastatic gastric cancer.

Irinotecan for the treatment of gastric cancer

First-line therapy for metastatic gastric cancer has progressed from the use of 5-fluorouracil (5-FU) in the late 1960s through to an array of combination therapies such as cisplatin/5-FU, FAM (5-FU, doxorubicin, mitomycin), FAMTX (substituting methotrexate for mitomycin) and more recently ECF (epirubicin, cisplatin, 5-FU). Systemic chemotherapy has been shown to prolong survival compared with best supportive care alone, but the median survival for patients is still in the region of 9 months. This is because although gastric cancer is a chemosensitive disease with over 40% of patients showing a response, these responses are of short duration. Furthermore, it is difficult to consider one of the many frequently used regimens as a generally accepted standard for the treatment of these patients. Irinotecan (Campto ®, CPT-11) is one of a group of new drugs showing activity in the treatment of gastric cancer, which include docetaxel, paclitaxel, oral fluoropyrimidines and oxaliplatin. Many phase II studies of irinotecan alone or in combination with cisplatin and/or 5-FU showed promising efficacy for the first and second line treatment. Eagerly awaited results of randomised phase III studies with irinotecan are expected to set new standards in the treatment of metastatic gastric cancer.

Fatal deep vein thrombosis after allogeneic reduced intensity hematopoietic stem cell transplantation for the treatment of metastatic gastric cancer

A 61-year-old man received reduced intensity stem cell transplantation (RIST) for the treatment of metastatic gastric cancer. The cytoreductive course of RIST was uneventful until day 0, when fever suddenly developed and his performance status deteriorated. Edema developed in the bilateral lower extremities by day 7, which was diagnosed by Doppler ultrasonography as deep vein thrombosis (DVT) involving the femoral veins to the inferior vena cava. While the edema improved with anticoagulation treatment, gastrointestinal graft-versus-host disease (GVHD) followed on day 13. Diarrhea subsided spontaneously, but hypoalbuminemia persisted, with the subsequent development of oliguria and jaundice on day 18. He died of sepsis on day 30, without any evidence of cancer progression. This case demonstrates that DVT is a potentially significant problem following RIST for solid tumors.

Advances in systemic treatment of metastatic gastric cancer

Gastric carcinoma is a frequent malignancy throughout the world and endemic in many of its regions. Advanced gastric carcinoma is often diagnosed. Patients with advanced gastric cancer have a median survival of 6-8 months and chemotherapy is palliative. Even in patients with resectable disease 5-year survival is generally poor. Chemotherapy is usually accepted as standard treatment for advanced disease. None of existing chemotherapy regimens has been established as standard, and chemotherapy within the controlled clinical trials is still the best option for advanced gastric cancer patients. In some trials a response rate of more than 50% has been achieved for multidrug regimens. It seems that the important story in gastric cancer is not told by focusing on the response rates in serial phase II or even phase III trials. In this disease, the success with respect to high response rates has been virtually canceled out by the fact that tumor shrinkage seems to be evanescent. There has not yet been a regimen reported that leads to a 50% survival probability at one year. A 2-year survival rate of 14% is considered noteworthy as a "long-term survival". Toxicity including nausea, vomiting, asthenia, anorexia, neutropenia, and treatment related morbidity, in patients with gastric cancer remain substantial issues, especially with multidrug therapy. Among the newer agents, oral fluoropyrimidines, taxanes, irinotecan and oxaliplatin appear to be relevant candidates for improved palliation and extension of survival. Further clinical studies are certainly needed to define the optimal role for these drugs. Gastric carcinoma has a variety of molecular abnormalities. Many of these molecules can be targeted theoretically, however, practical applications are yet to be fully developed. Limited number of studies has been done using specific targets against gastric carcinoma.

TREATMENT OF PATIENTS WITH METASTATIC GASTRIC-CANCER BY CONTINUOUS-INFUSION OF 5-FLUOROURACIL, CISPLATIN AND ETOPOSIDE

The therapeutic effectiveness of continuous infusion of 5-fluorouracil and cisplatin, and etoposide (FEP) for treatment of metastatic gastric cancer was examined. Studies were made on 17 patients with gastric cancer with distant metastases. 5-fluorouracil (300 mg/m(2)/day) and cisplatin (80 mg/m(2)/day) were administered by continuous intravenous infusion for 120 and 24 hours, respectively; etoposide (60 mg/m(2)/day) was injected intravenously over a 2 hour period on days 2, 3 and 4. These chemotherapy treatments were repeated every 28 days. Partial, but not complete, remission was seen in four patients (24%). The treatment increased the survival times of patients with differentiated or Borrmann 2 or 3 type cancer, but not significantly. In many cases the treatment caused myelosuppression, but side effects were usually mild or moderate. It is concluded that infusion of 5-fluorouracil, etoposide and cisplatin is effective and well tolerated.