Pharmacogenetics of Fluoropyrimidine and Cisplatin
Pharmacogenetics of Fluoropyrimidine and Cisplatin
Chemotherapy plays an important role in the treatment of gastric cancer both in adjuvant or advanced settings. Recent randomized trials in Japan have proved that S-1, a novel fluoropyrimidine derivative, and cisplatin are the most promising agents. However, both the efficacy and toxicity of a given regimen vary widely among patients due to the inherited variability of genes that involve drug anabolism and catabolism. A narrow therapeutic index of antitumor agents, i.e. a given regimen being too toxic and/or less effective to some segment of patients, prevents the overall improvement of treatment outcomes. Pharmacogenetics, a research field elucidating genetic polymorphism in drug metabolizing enzymes, may contribute to identifying patients who benefit from chemotherapy or who will experience life-threatening toxicity. There are several crucial enzymes identified involving anabolism and the catabolism of fluoropyrimidine and cisplatin, including dihydropyrimidine dehydrogenase, thymidylate synthase, orotate phosphoribosyl transferase, glutathione S transferase, and excision repair cross complementary group. Various polymorphisms and ethnic variabilities of these genes have been elucidated. This review highlights variations within biological functions, detection systems, and possible clinical applications of these enzymatic polymorphisms. This knowledge provides a tool to determine an optimum regimen according to the patient's drug metabolizing characteristics. This stance will contribute to establishing individualized therapies for gastric cancer, which offers superior efficacy with a minimal chance of severe toxicity.
Gastric cancer is the fourth most common cancer, accounting for an estimated one million new cases worldwide. Although the incidence of non-cardia cancer has declined in the developed countries, the mortality of gastric cancer is consistently high regardless of the geographic areas. Against these backgrounds, chemotherapy plays an important role, and 5-fluorouracil (5FU) is the most common drug used for gastric cancer both in adjuvant and advanced settings. However, randomized trials in the past century have failed to demonstrate clear survival benefits from adjuvant chemotherapy. In addition, most chemotherapy trials in an advanced setting have also failed to yield any prolongation of median survival times that exceed 12 months.
Entering the 21st century, evidence has been accumulated in Japan concerning a survival benefit of chemotherapy against gastric cancer both in adjuvant and advanced settings. Adjuvant usage of uracil-tegafur (National Surgical Adjuvant Study of Gastric Cancer Group (NSAS-GC) trial) resulted in a significant (P = 0.017) improvement in survival rate by 13% at 5 years postoperatively. Adjuvant administration of S-1, a novel fluoropyrimidine derivative, offers significant (P = 0.003) risk reduction for death as compared with surgery alone (ACTS-GC trial). For advanced or recurrent gastric cancers, the non-inferiority of S-1 to continuous infusion of 5FU alone has been documented (JCOG9912). Subsequently, S-1 in combination with cisplatin has proved to offer significantly (P = 0.04) longer median survival times (13 months) than S-1 alone (11 months). Globally, the randomized first-line therapy in patients with advanced gastric cancer (FLAGS) trial is now ongoing to clarify whether the efficacy of S-1 plus a cisplatin combination regimen is superior to standard 5FU plus cisplatin regimen against recurrent gastric cancer. These randomized trials in this century suggest that S-1 or S-1 plus cisplatin may be promising candidates for the treatment of both adjuvant and recurrent gastric cancer, although these regimens have not yet been recognized as a global standard.
Several problems remain to be resolved in performing chemotherapy. The efficacy of chemotherapy increases with dose escalation but so does the probability of adverse events. In addition, even in the same regimen, some patients respond well while others do not. Also, in a standard dose of chemotherapy, toxic events are severe in some patients while they are minimal in others. The substantial variability in tumor responses and adverse events among patients receiving the same regimen limits the use of chemotherapy. Therefore, qualities of chemotherapy should be evaluated as a net result of efficacy and adverse events. Under these circumstances, selecting patients who are likely to be responsive or resistant to chemotherapy or who have an increased risk of severe toxicity before the commencement of treatment has been recently recognized as a major factor when considering dose modifications or alternative treatment options. Unfortunately, however, it is difficult to predict whether a given regimen will prove too active or too toxic for an individual patient. Therefore, there is a pressing need to establish tools to predict treatment efficacy or toxicity that may help to realize treatment individualization.
In order to apply the above recent exciting treatment results to maximize patient benefit, the identification of factors relevant to response to fluorouracil or cisplatin as well as factors predisposed to the development of severe toxicity has been recognized as an important field of study. When molecular factors responsible for drug clearance are decreased, residual active compounds can remain in the body longer and eventually enhance drug efficacy or increase the likelihood of adverse events. On the other hand, when molecular factors responsible for exerting cytotoxicity are decreased, the clinical manifestation is a drug resistance due to the consequent decrease in the available active drugs. These molecular factors relate with each other, i.e. some factors inhibit or weaken drug metabolizing enzymatic activities while others stimulate them. Furthermore, inherited variations of genes that code drug metabolizing enzymes can affect treatment efficacy and adverse events. In this regard, pharmacogenetics, a research field identifying inherited genetic variability which may affect treatment outcomes, could provide useful information concerning the interindividual variability of efficacy and toxicity. This review highlights current knowledge on molecular differences in pharmacologically relevant genes involved in the metabolism of 5FU and cisplatin, the most promising agents in the treatment of gastric cancer. This knowledge provides explanations for the interindividual differences in drug response and toxic events and contributes toward optimizing therapy selection on an individual basis as well as to identify patients at risk for toxic events. In order to accelerate the progress in therapy optimization more effectively for gastric cancer patients, this review includes findings of genetic variability obtained from various kinds of cancers not restricted to gastric cancer, since these achievements could be extrapolated to gastric cancer and may help to establish future individualized therapies for gastric cancer patients.
Abstract and Introduction
Abstract
Chemotherapy plays an important role in the treatment of gastric cancer both in adjuvant or advanced settings. Recent randomized trials in Japan have proved that S-1, a novel fluoropyrimidine derivative, and cisplatin are the most promising agents. However, both the efficacy and toxicity of a given regimen vary widely among patients due to the inherited variability of genes that involve drug anabolism and catabolism. A narrow therapeutic index of antitumor agents, i.e. a given regimen being too toxic and/or less effective to some segment of patients, prevents the overall improvement of treatment outcomes. Pharmacogenetics, a research field elucidating genetic polymorphism in drug metabolizing enzymes, may contribute to identifying patients who benefit from chemotherapy or who will experience life-threatening toxicity. There are several crucial enzymes identified involving anabolism and the catabolism of fluoropyrimidine and cisplatin, including dihydropyrimidine dehydrogenase, thymidylate synthase, orotate phosphoribosyl transferase, glutathione S transferase, and excision repair cross complementary group. Various polymorphisms and ethnic variabilities of these genes have been elucidated. This review highlights variations within biological functions, detection systems, and possible clinical applications of these enzymatic polymorphisms. This knowledge provides a tool to determine an optimum regimen according to the patient's drug metabolizing characteristics. This stance will contribute to establishing individualized therapies for gastric cancer, which offers superior efficacy with a minimal chance of severe toxicity.
Introduction
Gastric cancer is the fourth most common cancer, accounting for an estimated one million new cases worldwide. Although the incidence of non-cardia cancer has declined in the developed countries, the mortality of gastric cancer is consistently high regardless of the geographic areas. Against these backgrounds, chemotherapy plays an important role, and 5-fluorouracil (5FU) is the most common drug used for gastric cancer both in adjuvant and advanced settings. However, randomized trials in the past century have failed to demonstrate clear survival benefits from adjuvant chemotherapy. In addition, most chemotherapy trials in an advanced setting have also failed to yield any prolongation of median survival times that exceed 12 months.
Entering the 21st century, evidence has been accumulated in Japan concerning a survival benefit of chemotherapy against gastric cancer both in adjuvant and advanced settings. Adjuvant usage of uracil-tegafur (National Surgical Adjuvant Study of Gastric Cancer Group (NSAS-GC) trial) resulted in a significant (P = 0.017) improvement in survival rate by 13% at 5 years postoperatively. Adjuvant administration of S-1, a novel fluoropyrimidine derivative, offers significant (P = 0.003) risk reduction for death as compared with surgery alone (ACTS-GC trial). For advanced or recurrent gastric cancers, the non-inferiority of S-1 to continuous infusion of 5FU alone has been documented (JCOG9912). Subsequently, S-1 in combination with cisplatin has proved to offer significantly (P = 0.04) longer median survival times (13 months) than S-1 alone (11 months). Globally, the randomized first-line therapy in patients with advanced gastric cancer (FLAGS) trial is now ongoing to clarify whether the efficacy of S-1 plus a cisplatin combination regimen is superior to standard 5FU plus cisplatin regimen against recurrent gastric cancer. These randomized trials in this century suggest that S-1 or S-1 plus cisplatin may be promising candidates for the treatment of both adjuvant and recurrent gastric cancer, although these regimens have not yet been recognized as a global standard.
Several problems remain to be resolved in performing chemotherapy. The efficacy of chemotherapy increases with dose escalation but so does the probability of adverse events. In addition, even in the same regimen, some patients respond well while others do not. Also, in a standard dose of chemotherapy, toxic events are severe in some patients while they are minimal in others. The substantial variability in tumor responses and adverse events among patients receiving the same regimen limits the use of chemotherapy. Therefore, qualities of chemotherapy should be evaluated as a net result of efficacy and adverse events. Under these circumstances, selecting patients who are likely to be responsive or resistant to chemotherapy or who have an increased risk of severe toxicity before the commencement of treatment has been recently recognized as a major factor when considering dose modifications or alternative treatment options. Unfortunately, however, it is difficult to predict whether a given regimen will prove too active or too toxic for an individual patient. Therefore, there is a pressing need to establish tools to predict treatment efficacy or toxicity that may help to realize treatment individualization.
In order to apply the above recent exciting treatment results to maximize patient benefit, the identification of factors relevant to response to fluorouracil or cisplatin as well as factors predisposed to the development of severe toxicity has been recognized as an important field of study. When molecular factors responsible for drug clearance are decreased, residual active compounds can remain in the body longer and eventually enhance drug efficacy or increase the likelihood of adverse events. On the other hand, when molecular factors responsible for exerting cytotoxicity are decreased, the clinical manifestation is a drug resistance due to the consequent decrease in the available active drugs. These molecular factors relate with each other, i.e. some factors inhibit or weaken drug metabolizing enzymatic activities while others stimulate them. Furthermore, inherited variations of genes that code drug metabolizing enzymes can affect treatment efficacy and adverse events. In this regard, pharmacogenetics, a research field identifying inherited genetic variability which may affect treatment outcomes, could provide useful information concerning the interindividual variability of efficacy and toxicity. This review highlights current knowledge on molecular differences in pharmacologically relevant genes involved in the metabolism of 5FU and cisplatin, the most promising agents in the treatment of gastric cancer. This knowledge provides explanations for the interindividual differences in drug response and toxic events and contributes toward optimizing therapy selection on an individual basis as well as to identify patients at risk for toxic events. In order to accelerate the progress in therapy optimization more effectively for gastric cancer patients, this review includes findings of genetic variability obtained from various kinds of cancers not restricted to gastric cancer, since these achievements could be extrapolated to gastric cancer and may help to establish future individualized therapies for gastric cancer patients.
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