Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paclitaxel has shown a significant activity on esophageal cancer in a phase II trial. Irinotecan has established the single-agent efficacy on both gastric and colorectal cancer. Docetaxel has attained a significant activity on advanced gastric cancer and a 29% response rate on pancreatic cancer in a phase II trial. Tomudex has shown comparable activity to leucovorin and 5-fluorouracil in colorectal cancer.
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PMID:New systemic drugs in the treatment of gastrointestinal cancer. 886 7

It has been hypothesized that intratumoral thymidylate synthase (TS) gene expression might be used to select therapy for patients with disseminated colorectal cancer. We recently reported the results of a clinical trial in 46 patients with disseminated or recurrent colorectal cancer testing whether expression of TS within the primary tumor, as assessed by quantitative polymerase chain reaction (PCR) methodology, would predict the responsiveness of that cancer of fluoropyrimidine-based therapy. This trial demonstrated that intratumoral TS/beta-actin messenger RNA (mRNA) ratio can accurately predict which metastatic colorectal tumors will be resistant to a leucovorin-modulated 5-FU infusion and which have a high likelihood of responding to such a regimen. Results of other studies of adjuvant therapy in gastric cancer and colorectal cancer also indicated that TS expression within the tumor is predictive of response of 5-FU-based therapy. It may be possible to use this parameter prospectively to decide which patients should receive fluorinated pyrimidine therapy: Patients whose tumors express low TS levels would be likely to benefit from such therapy, whereas limited preliminary data suggest that patients whose tumors express high TS levels may benefit from irinotecan (CPT-11[Camptosar]).
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PMID:Thymidylate synthase as a predictor of response. 972 90

Irinotecan (CPT-11 [Camptosar]), an active agent in the treatment of fluorouacil-refractory colorectal cancer, has antitumor activity in upper gastrointestinal cancers. Clinical trials from Japan indicate antitumor responses in gastric and pancreatic cancers. Cisplatin (Platinol), a central agent in the treatment of upper gastrointestinal malignancies, is a logical drug to study in combination with irinotecan in upper gastrointestinal cancers. In vitro studies have shown important sequence-dependent synergy of cisplatin/irinotecan combination therapy. Irinotecan appears to prevent removal of cisplatin-induced DNA-interstrand cross-links. Initial phase I and III trials of cisplatin plus irinotecan appear to confirm this synergy, with Japanese trials in gastric cancer showing an encouraging rate of response with acceptable toxicity. A phase I trial conducted at Memorial Sloan-Kettering Cancer Center has demonstrated the safety and tolerability of weekly cisplatin and irinotecan. Currently, a phase II trial of this weekly regimen is under way in patients with metastatic or recurrent esophageal cancer. The response proportion compares favorably to standard therapy, with relatively mild toxicity. Other phase II studies, including single-agent irinotecan in esophageal cancer and the combination of cisplatin and irinotecan in gastric cancer, are being initiated at other US institutions.
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PMID:Irinotecan and cisplatin in upper gastrointestinal malignancies. 972 2

No standard chemotherapy regimen for the treatment of advanced gastrointestinal cancer exists. However, 5-fluorouracil (5-FU) is being used more frequently as a key component of combination therapy regimens for this disease, and including cisplatin (CDDP) in combination therapy regimens produces significant tumor shrinkage. Although oral formulations of 5-FU are widely used in Japan, their clinical activity and toxicity have not been thoroughly evaluated. In 1992, the Japan Clinical Oncology Group initiated a phase III study in which the survival rates of patients treated with 5-FU 800 mg/m2/day for 5 days by continuous infusion (5-FUci), 5-FUci with CDDP 20 mg/ m2/day for 5 days by infusion, or oral uracil/Ftorafur 375 mg/m2/day with weekly MMC 5 mg/m2 i.v. were compared. This study was closed with 280 patients accrued in 1997, and final analysis was made in early 1998. Irinotecan and paclitaxel are new drugs with activity against gastric cancer. Combination chemotherapy consisting of irinotecan with CDDP has also been evaluated. For treatment of metastatic colorectal cancer, the only active drug previously available in Japan was 5-FU, although 5-FU + leucovorin is the international standard regimen. Irinotecan is now approved in Japan, Europe, and the USA and is the most effective drug for 5-FU-refractory patients. The optimal irinotecan and 5-FU combination regimen is being extensively examined but further trials aimed at accumulating basic data are warranted.
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PMID:Clinical trials for advanced gastrointestinal cancers in Japan. Japan Clinical Oncology Group Gastrointestinal Oncology Study Group. 975 35

This review summarizes the results reported in preclinical and clinical trials of three novel anticancer drugs developed and tested in Japan. In phase II trials, Irinotecan, a semisynthetic analog of camptothecin, has yielded response rates exceeding 20% in non-small-cell lung cancer, small-cell lung cancer, breast cancer, gastric cancer, colorectal cancer, ovarian cancer, uterine cervical cancer, and non-Hodgkini's lymphoma. It was modestly active on pancreatic cancer and was not active on acute leukemias. Dose-limiting toxicities were leukopenia and diarrhea, and other major toxicities were nausea, vomiting, and alopecia. Amrubicin, a totally synthetic anthracycline, exhibited both higher efficacy on human tumor xenografts and cardiotoxicity milder than that of doxorubicin in preclinical studies. The dose-limiting toxicity in phase I trials was leukopenia. In phase II trials, amrubicin has shown activity equivalent to that of doxorubicin on non-Hodgkin's lymphoma, response rates exceeding 20% on non-small-cell lung cancer, and a response rate of 78.8% on untreated extensive-stage small-cell lung cancer. S-1 is an oral formulation consisting of ftorafur (an analog of 5-fluorouracil), 5-chloro-2, 4-dehydropyrimidine, which inhibits degradation of 5-fluorouracil, and potassium oxonate, which reduces gastrointestinal toxicity, at a molar ratio of 1:0.4:1. In phase I trials, dose-limiting toxicities (myelosuppression and gastrointestinal toxicities) were judged to be milder than those induced by UFT (ftorafur plus uracil). The response rates obtained in phase II trials were 40-49% on advanced gastric cancer, 35.5% on colorectal cancer, 37.5% on head and neck cancer, and 40.7% on breast cancer.
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PMID:Novel anticancer drugs in Japan. 1023 66

Metastatic gastric cancer is a relatively chemosensitive disease. With current regimens, 25% to 40% of patients can be expected to respond, and median survival of 6 to 8 months is achievable. These outcomes may be improved by the use of infusional fluorouracil (5-FU) in combination with cisplatin (Platinol) or the newer agents docetaxel (Taxotere) and irinotecan (Camptosar). Phase II studies using these approaches have reported response rates of 50% to 60% and median survival of 11 months. Chemotherapy may also have a role in earlier stages of gastric cancer. However, the value of adjuvant therapy in improving survival following successful resection has still to be demonstrated, as has the survival benefit of preoperative treatment. Nevertheless, primary chemotherapy has demonstrated a capacity to downstage disease in certain otherwise inoperable cases.
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PMID:Developments in the treatment of gastric cancer in Europe. 1120 Jan 44

The camptothecins are a maturing class of anticancer agents. In this article, we review the pharmacology and antitumor activity of the camptothecin analogues that are approved for clinical use and those investigational agents undergoing clinical evaluation. Camptothecin is a naturally occurring cytotoxic alkaloid that has a unique intracellular target, topoisomerase I, a nuclear enzyme that reduces the torsional stress of supercoiled DNA during the replication, recombination, transcription, and repair of DNA. Topotecan and irinotecan are synthetic analogues designed to facilitate parenteral administration of the active lactone form of the compound by introducing functional groups to enhance solubility. They are now well-established components in the chemotherapeutic management of several neoplasms. Topotecan has modest activity in patients treated previously with ovarian and small cell lung cancer and is currently approved for use in the United States as second-line therapy in these diseases. Preliminary evidence of activity against hematological malignancies is also promising. Irinotecan is a prodrug that undergoes enzymatic conversion to the biologically active metabolite 7-ethyl-10-hydroxy-camptothecin. It is presently the treatment of choice when used in combination with fluoropyrimidines as first-line therapy for patients with advanced colorectal cancer or as a single agent after failure of 5-fluorouracil-based chemotherapy. Encouraging preliminary results suggest that irinotecan may have an increasing role in the treatment of other solid tumors, including small and non-small cell lung cancer, cervical cancer, ovarian cancer, gastric cancer, and malignant gliomas. Several additional camptothecin analogues are in various stages of clinical development, including 9-aminocamptothecin, 9-nitrocamptothecin, 7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin, exatecan mesylate, and karenitecin. Efforts to further optimize therapeutic effectiveness through drug delivery strategies that prolong tumor exposure to these S phase-specific agents, such as improving oral bioavailability through structure modification and innovative formulation approaches, alternative parenteral dosage forms, and administration schedules, are being actively pursued. Combining camptothecins with other anticancer drugs and treatment modalities, as well as gaining a better understanding of the factors contributing to tumor sensitivity and resistance, continues to be the object of considerable interest.
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PMID:Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. 1189 91

The limited effectiveness of chemotherapy in esophageal cancer used to palliate metastatic disease or to combine with radiotherapy in locally advanced disease has prompted the evaluation of new systemic agents. Irinotecan (CPT-11, Camptosar) has shown promising activity in a number of gastrointestinal cancers, including esophageal cancer. The phase II evaluation of the combination of weekly irinotecan and cisplatin has shown encouraging response rates exceeding 30% to 50% in esophageal and gastric cancer. Novel regimens include the combination of irinotecan with mitomycin (Mutamycin), the taxanes docetaxel (Taxotere) and paclitaxel, and continuous infusion fluorouracil (5-FU). Irinotecan is an active radiosensitizer, and trials have evaluated the combination of irinotecan with concurrent radiotherapy. We completed a phase I trial combining weekly irinotecan, cisplatin, and concurrent radiotherapy in locally advanced esophageal cancer. Minimal toxicity has been observed, with no grade 3/4 esophagitis or diarrhea, and hematologic toxicity was also surprisingly minimal. Full doses of weekly irinotecan (65 mg/m2) and cisplatin (30 mg/m2) could be combined safely with concurrent radiotherapy, with a significant rate of pathologic complete response. Phase II evaluation of this chemoradiotherapy regimen as preoperative therapy is planned at single institutions and at the cooperative group level in the United States. Further phase I and II investigation of combined irinotecan, cisplatin, and concurrent radiation is ongoing with the addition of targeted agents, including celecoxib (Celebrex), cetuximab (Erbitux), and bevacizumab (Avastin). Alternative combinations of irinotecan with radiotherapy, including the addition of docetaxel and continuous infusion 5-FU, are also undergoing phase I and II evaluation.
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PMID:Irinotecan in esophageal cancer. 1456 46

Esophageal cancer is a rare but highly virulent malignancy in the United States, and adenocarcinoma of the esophagus has had the most rapid rate of increase of any solid tumor malignancy. Systemic metastatic disease is present in 50% of patients at diagnosis. In the remaining 50% presenting with local regional disease, systemic metastatic disease will develop in the vast majority of these patients. The limited efficacy and toxicity of conventional fluorouracil (5-FU)/cisplatin-based chemotherapy has prompted the evaluation of newer agents. Irinotecan (Camptosar) has shown promising single-agent activity in a number of gastrointestinal cancers, including colorectal, pancreatic, and esophagogastric cancer. The phase II evaluation of the combination of weekly irinotecan and cisplatin has shown encouraging response rates exceeding 30% to 50% in esophageal and gastric cancer. Hematologic toxicity using a schedule of 4 consecutive weeks of therapy followed by 2 weeks of rest prompted interest in a multicenter trial evaluation of a change in therapy delivery to 2 weeks on and 1 week off. Cisplatin at 30 mg/m2 was administered with irinotecan at 65 mg/m2, days 1 and 8, on an every-21-day schedule. Thirty-nine patients were entered on study, with 36 evaluable for toxicity and 31 evaluable for response. Grade 3/4 neutropenia was observed in only 22% of patients, reduced from 49% in a prior phase II trial employing 4 consecutive weeks of therapy. Confirmed major responses were observed in 36% of patients (10 of 28). A change to a day 1, day 8 schedule of weekly irinotecan and cisplatin appears to reduce hematologic toxicity but maintain antitumor activity in patients with esophageal and gastroesophageal junction cancer. A randomized phase II trial in gastric and esophageal cancer comparing weekly irinotecan and cisplatin to epirubicin, cisplatin, and 5-FU, and to infusional 5-FU in combination with irinotecan, will be conducted by the Cancer and Leukemia Group B (CALGB). A phase II trial combining this schedule of weekly cisplatin and irinotecan and concurrent radiotherapy given as preoperative therapy will also be conducted by the CALGB as a pilot trial.
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PMID:Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. 1568 30

Gastric cancer is most chemosensitive among gastrointestinal tumors. However, the role of chemotherapy in advanced disease and its advantage over best supportive care has been adequately addressed only in the last decade. First generation regimens, such as 5-Fluorouracil (5-FU), Doxorubicin, Mitomycin C (FAM) have been used until early 90's, when evidence from randomized studies came up in favour of second generation regimens, such as 5-FU, Doxorubicin, high-dose Methotrexate (FAMTX), which in turn was proven less active than a third generation regimen, such as epirubicin, cisplatin, continuous infusion 5-FU (ECF) in a randomized study. Newer treatment options came up over last years. The Swiss Group for Clinical Cancer Research has carried out a randomized three-arm phase II study with ECF or docetaxel, cisplatin (TC), or docetaxel, cisplatin, 5-FU (TCF) in advanced gastric cancer. TCF has been selected as the combination to be further evaluated in a formal comparison with ECF. Oxaliplatin is being tested in advanced gastric cancer. Two recently published phase II studies of biweekly infusional 5-FU, folinic acid, and oxaliplatin have shown a considerable therapeutic activity. Irinotecan is another drug under investigation in advanced gastric cancer, both as single agent and in combination. A randomized phase II-III study of irinotecan plus cisplatin or irinotecan plus folinic acid/5-FU has recently been completed; the latter arm was proven worth undergoing a formal comparison with a standard CF regimen. Oral fluoropyrimidines represent a suitable therapeutic option in selected groups of patients. Marimastat is a matrix metalloproteinase inhibitor, whose main toxicity is musculoskeletal. A randomized phase III study of marimastat versus placebo as maintenance therapy in advanced gastric cancer has shown a significant survival advantage for the marimastat arm, both in the total patient population and in the subgroup of patients who had previously received chemotherapy. Since a clear gold standard for advanced gastric cancer does not yet exist, the inclusion of patients in well designed clinical trials is to be considered the best treatment option.
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PMID:Gastric cancer. Treatment of advanced disease and new drugs. 1597 May 66


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