Novel combination chemotherapy in the treatment of non-small cell lung cancer

Treatment of patients with advanced non-small cell lung cancer (NSCLC) remains a vexing problem and long-term survival beyond 5 years is extremely rare. Five new agents, paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan, have been introduced for the treatment of NSCLC and investigated extensively both preclinically and clinically. Monotherapy with one of these agents has produced survival benefits over the best supportive care in Phase III studies. Combination chemotherapy with a new agent and platinum produced a higher response rate than conventional cisplatin-based chemotherapy and improved survival was observed in some randomised trials. There was little difference in efficacy and toxicity between the chemotherapeutic regimens with a new agent and a platinum in Phase III trials, suggesting the clinical utility of these regimens is similar. Many trials have focused on regimens containing two new agents, with or without platinum. Preliminary results of Phase III trials of three drug combinations versus two drug combinations suggested the former to be more promising, in terms of response rates and survival. Whether the era of platinum-based chemotherapy in the treatment of NSCLC should continue or not must be determined by Phase III trials, evaluating the use of a platinum agent with one of the new agent combinations. These aggressive chemotherapeutic combinations will hopefully improve survival and quality of life for patients with advanced NSCLC.     

Erlotinib: a new therapeutic approach for non-small cell lung cancer

Although treatment with cytotoxic agents has produced modest survival improvement in patients with stage III and IV non-small cell lung cancer (NSCLC), it appears that a plateau has been reached with currently available chemotherapeutic regimens. Increasing knowledge regarding the properties of malignant neoplasms has identified a number of potential therapeutic targets. The epidermal growth factor receptor (EGFR) is one of these targets. Preclinical models have revealed that tumour growth can be inhibited by monoclonal antibodies directed against EGFR and EGFR-specific tyrosine kinase inhibitors. Erlotinib (Tarceva?; OSI Pharmaceuticals, Genentech and Roche), a quinazoline derivative with good oral absorption, is one of several EGFR tyrosine kinases that has been studied in clinical trials. In a Phase I study, mild diarrhoea and mild rash were the most common toxicities. At a dose of 200 mg/day, diarrhoea was the dose-limiting toxicity. The observation that EGFR overexpression is relatively common in NSCLC led to a Phase II trial of erlotinib at the maximum-tolerated dose (150 mg/day) in previously treated NSCLC patients. Erlotinib produced a 12% response rate and there was no apparent relationship between response and tumour EGFR levels. More recent reports suggest that patients who develop a rash have higher responses. Based on its single agent activity, erlotinib has been evaluated in two Phase III trials which compared erlotinib plus chemotherapy to chemotherapy alone in previously untreated NSCLC patients. Erlotinib has also been compared to placebo in a Phase III trial which was limited to advanced stage NSCLC patients whose disease had progressed after two previous chemotherapy regimens. The optimum use of erlotinib in NSCLC will be determined by the results of the completed and future Phase III trials.     

Taxanes for advanced non-small cell lung cancer

The emergence of novel chemotherapeutic agents with promising anticancer activity in non-small cell lung cancer (NSCLC) during the 1990s has led to an expanded role for chemotherapy in the management of this disease. The taxanes (paclitaxel and docetaxel) are novel microtubule stabilising agents, and have become an integral part of several commonly-used chemotherapy regimens in NSCLC. Taxanes inhibit the growth of lung cancer cell lines, exhibit synergistic interaction with other chemotherapy agents and enhance the efficacy of radiation in vitro. When used in low doses (metronomic dosing), they have important antiangiogenic properties. Several Phase II and III clinical trials have established the efficacy of the taxanes, as single agents and when used in combination with a platinum compound, in the treatment of advanced NSCLC. The use of a taxane in combination with a platinum compound has become an acceptable standard for patients with advanced or metastatic NSCLC. In addition to its efficacy in the first-line therapy of NSCLC, docetaxel is also the FDA-approved second-line agent for recurrent or relapsed NSCLC in the US. Several ongoing trials are comparing the efficacy of combining molecularly targeted agents with taxane-based regimens for the treatment of advanced NSCLC.     

Taxanes for advanced non-small cell lung cancer

The emergence of novel chemotherapeutic agents with promising anticancer activity in non-small cell lung cancer (NSCLC) during the 1990s has led to an expanded role for chemotherapy in the management of this disease. The taxanes (paclitaxel and docetaxel) are novel microtubule stabilising agents, and have become an integral part of several commonly-used chemotherapy regimens in NSCLC. Taxanes inhibit the growth of lung cancer cell lines, exhibit synergistic interaction with other chemotherapy agents and enhance the efficacy of radiation in vitro. When used in low doses (metronomic dosing), they have important antiangiogenic properties. Several Phase II and III clinical trials have established the efficacy of the taxanes, as single agents and when used in combination with a platinum compound, in the treatment of advanced NSCLC. The use of a taxane in combination with a platinum compound has become an acceptable standard for patients with advanced or metastatic NSCLC. In addition to its efficacy in the first-line therapy of NSCLC, docetaxel is also the FDA-approved second-line agent for recurrent or relapsed NSCLC in the US. Several ongoing trials are comparing the efficacy of combining molecularly targeted agents with taxane-based regimens for the treatment of advanced NSCLC.     

Erlotinib: a new therapeutic approach for non-small cell lung cancer

Although treatment with cytotoxic agents has produced modest survival improvement in patients with stage III and IV non-small cell lung cancer (NSCLC), it appears that a plateau has been reached with currently available chemotherapeutic regimens. Increasing knowledge regarding the properties of malignant neoplasms has identified a number of potential therapeutic targets. The epidermal growth factor receptor (EGFR) is one of these targets. Preclinical models have revealed that tumour growth can be inhibited by monoclonal antibodies directed against EGFR and EGFR-specific tyrosine kinase inhibitors. Erlotinib (Tarceva trade mark; OSI Pharmaceuticals, Genentech and Roche), a quinazoline derivative with good oral absorption, is one of several EGFR tyrosine kinases that has been studied in clinical trials. In a Phase I study, mild diarrhoea and mild rash were the most common toxicities. At a dose of 200 mg/day, diarrhoea was the dose-limiting toxicity. The observation that EGFR overexpression is relatively common in NSCLC led to a Phase II trial of erlotinib at the maximum-tolerated dose (150 mg/day) in previously treated NSCLC patients. Erlotinib produced a 12% response rate and there was no apparent relationship between response and tumour EGFR levels. More recent reports suggest that patients who develop a rash have higher responses. Based on its single agent activity, erlotinib has been evaluated in two Phase III trials which compared erlotinib plus chemotherapy to chemotherapy alone in previously untreated NSCLC patients. Erlotinib has also been compared to placebo in a Phase III trial which was limited to advanced stage NSCLC patients whose disease had progressed after two previous chemotherapy regimens. The optimum use of erlotinib in NSCLC will be determined by the results of the completed and future Phase III trials.     

Paclitaxel: a hope for advanced non-small cell lung cancer?

Recent studies have shown that paclitaxel (Taxol); Bristol-Myers Squibb Co., Princeton, NJ) is an active agent in the treatment of advanced non-small cell lung cancer (NSCLC). Early trials in patients with advanced NSCLC utilised a 24 h infusion schedule and reported objective tumour responses in 21 - 24% of patients. Shorter infusion schedules have equivalent efficacy, and combined results from 14 separate trials of single agent paclitaxel in advanced NSCLC show an overall tumour response rate of 26%. Alternative schedules of paclitaxel from the traditional regimen every three weeks are under active investigation, but it is premature to assess whether these will yield improved efficacy for patients with advanced NSCLC. A single multicentre randomised trial of paclitaxel versus best supportive care in advanced NSCLC showed a significant survival advantage for the chemotherapy arm. Two large randomised Phase III trials have shown that paclitaxel and cisplatin is modestly more effective than cisplatin and podophyllotoxin combinations. The addition of cisplatin or carboplatin to paclitaxel results in higher response rates than for each of the drugs as single agents, but it is unclear whether the combinations yield superior survival or quality of life compared to single agent paclitaxel, or to other paclitaxel-containing regimens.     

Role of platinum agents in the management of advanced pancreatic cancer

Pancreatic cancer, one of the most common gastrointestinal tumors, has a 5-year survival rate of < 5%. Since 1997, when gemcitabine showed superior clinical benefit to single-agent 5-fluorouracil, it has remained the only standard chemotherapy approved by the US FDA for the treatment of advanced pancreatic cancer. Numerous new agents, both cytotoxic and targeted, have been tested against and in combination with this standard. Many combination therapy regimens showed encouraging results in Phase II settings, which led to > 12 randomized Phase III trials in the last decade. Some trials showed improved response rates or progression-free survival, but there was no clear improvement in survival. Among these combinations, the combination of gemcitabine plus platinum agents showed improved progression-free survival or time-to-tumor progression, but failed to demonstrate a survival advantage over gemcitabine. This combination has regained attention after a recent pooled analysis and a meta-analysis suggested a survival benefit of gemcitabine-platinum doublets when compared with single agent gemcitabine. There are preclinical data showing synergism between gemcitabine and platinum agents. Hence, this review covers the role of platinum doublets in the treatment of metastatic pancreatic cancer.     

Role of platinum agents in the management of advanced pancreatic cancer

Pancreatic cancer, one of the most common gastrointestinal tumors, has a 5-year survival rate of < 5%. Since 1997, when gemcitabine showed superior clinical benefit to single-agent 5-fluorouracil, it has remained the only standard chemotherapy approved by the US FDA for the treatment of advanced pancreatic cancer. Numerous new agents, both cytotoxic and targeted, have been tested against and in combination with this standard. Many combination therapy regimens showed encouraging results in Phase II settings, which led to > 12 randomized Phase III trials in the last decade. Some trials showed improved response rates or progression-free survival, but there was no clear improvement in survival. Among these combinations, the combination of gemcitabine plus platinum agents showed improved progression-free survival or time-to-tumor progression, but failed to demonstrate a survival advantage over gemcitabine. This combination has regained attention after a recent pooled analysis and a meta-analysis suggested a survival benefit of gemcitabine-platinum doublets when compared with single agent gemcitabine. There are preclinical data showing synergism between gemcitabine and platinum agents. Hence, this review covers the role of platinum doublets in the treatment of metastatic pancreatic cancer.     

Gefitinib in non-small cell lung cancer

Gefitinib (Iressa), an orally-active tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is the first approved molecular-targeted drug for the management of patients with advanced non-small cell lung cancer (NSCLC). Two Phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib in advanced NSCLC patients who received < or = 2 (IDEAL1) or > or = 2 (IDEAL2) previous chemotherapy regimens. The response rate and disease control rate in IDEAL1 and -2 was 18/12% and 54/42%, respectively. The median survival time and one-year survival rate in both studies were approximately 7 months and 30%, respectively. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Disappointingly, in chemotherapy-naive patients with advanced NSCLC, gefitinib 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/cisplatin or paclitaxel/carboplatin) did not produce prolonged survival, compared with chemotherapy alone in two large, randomised, placebo-controlled, multi-centre Phase III trials (INTACT [Iressa NSCLC Trial Assessing Combination Treatment]-1 and -2). Furthermore, in a recent randomised, placebo-controlled, Phase III trial (ISEL: IRESSA Survival Evaluation in Lung cancer), gefitinib failed to prolong survival compared with placebo in patients with advanced NSCLC who had failed one or more lines of chemotherapy. Subgroup analysis of ISEL suggested improved survival in patients of Asian origin and non-smokers. In addition, subset analyses of IDEAL and several retrospective studies have indicated that female gender, adenocarcinoma histology (especially bronchial alveolar carcinoma), non-smoker status and Asian ethnicity are factors which predict to response to gefitinib. Two types of somatic mutation clustered around the ATP binding pocket in the tyrosine kinase domain of the EGFR gene have been reported as possible surrogate biological markers for predicting response to gefitinib. Appropriate patient selection by clinical characteristics or genetical information is needed, both for future clinical trials of gefitinib and its routine use in the clinic among patients with advanced NSCLC.     

Chemotherapy for advanced gastric cancer: across the years for a standard of care

Chemotherapy is of crucial importance in advanced gastric cancer patients, in order to obtain palliation of symptoms and improve survival. The most extensively studied drugs as single agents are 5-fluorouracil, cisplatin, doxorubicin, epirubicin, mitomycin C and etoposide. Newer chemotherapeutic agents include the taxanes (docetaxel and paclitaxel), oral fluoropyrimidines (capecitabine and S-1), oxaliplatin and irinotecan. Randomised trials comparing monotherapy with combination regimens have consistently shown increased response rates in favour of combination regimens, whereas only marginally improved survival rates were usually found. Several combination therapies have been developed and have been examined in Phase III trials. However, in most cases, they have failed to demonstrate a survival advantage over the reference arm. There is no internationally accepted standard of care, and uncertainty remains regarding the choice of the optimal chemotherapy regimen. The objective of this article is to review the present literature available on major Phase II – III clinical trials, in which patients suffering from advanced gastric cancer were treated with cytotoxic chemotherapy.     

Chemotherapy for advanced gastric cancer: across the years for a standard of care

Chemotherapy is of crucial importance in advanced gastric cancer patients, in order to obtain palliation of symptoms and improve survival. The most extensively studied drugs as single agents are 5-fluorouracil, cisplatin, doxorubicin, epirubicin, mitomycin C and etoposide. Newer chemotherapeutic agents include the taxanes (docetaxel and paclitaxel), oral fluoropyrimidines (capecitabine and S-1), oxaliplatin and irinotecan. Randomised trials comparing monotherapy with combination regimens have consistently shown increased response rates in favour of combination regimens, whereas only marginally improved survival rates were usually found. Several combination therapies have been developed and have been examined in Phase III trials. However, in most cases, they have failed to demonstrate a survival advantage over the reference arm. There is no internationally accepted standard of care, and uncertainty remains regarding the choice of the optimal chemotherapy regimen. The objective of this article is to review the present literature available on major Phase II - III clinical trials, in which patients suffering from advanced gastric cancer were treated with cytotoxic chemotherapy.     

Gefitinib in non-small cell lung cancer

Gefitinib (Iressa^TM), an orally-active tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is the first approved molecular-targeted drug for the management of patients with advanced non-small cell lung cancer (NSCLC). Two Phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib in advanced NSCLC patients who received ≤ 2 (IDEAL1) or ≥ 2 (IDEAL2) previous chemotherapy regimens. The response rate and disease control rate in IDEAL1 and -2 was 18/12% and 54/42%, respectively. The median survival time and one-year survival rate in both studies were ~ 7 months and 30%, respectively. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Disappointingly, in chemotherapy-naive patients with advanced NSCLC, gefitinib 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/cisplatin or paclitaxel/carboplatin) did not produce prolonged survival, compared with chemotherapy alone in two large, randomised, placebo-controlled, multi-centre Phase III trials (INTACT [Iressa NSCLC Trial Assessing Combination Treatment]-1 and -2). Furthermore, in a recent randomised, placebo-controlled, Phase III trial (ISEL: IRESSA Survival Evaluation in Lung cancer), gefitinib failed to prolong survival compared with placebo in patients with advanced NSCLC who had failed one or more lines of chemotherapy. Subgroup analysis of ISEL suggested improved survival in patients of Asian origin and non-smokers. In addition, subset analyses of IDEAL and several retrospective studies have indicated that female gender, adenocarcinoma histology (especially bronchial alveolar carcinoma), non-smoker status and Asian ethnicity are factors which predict to response to gefitinib. Two types of somatic mutation clustered around the ATP binding pocket in the tyrosine kinase domain of the EGFR gene have been reported as possible surrogate biological markers for predicting response to gefitinib. Appropriate patient selection by clinical characteristics or genetical information is needed, both for future clinical trials of gefitinib and its routine use in the clinic among patients with advanced NSCLC.     

Gemcitabine in non-small cell lung cancer

Gemcitabine is considered to be one of the most active drugs in the treatment of non-small cell lung cancer (NSCLC). When used as a single agent, gemcitabine yielded response rates consistently > 20%, with a uniformly good tolerance profile. Preclinical data indicated synergism between gemcitabine and platinum compounds, such as cisplatin or carboplatin. The gemcitabine-cisplatin combination is considered one of the reference regimens for advanced NSCLC and the recommended schedule is gemcitabine 1000 - 1250 mg/m(2) on days 1 - 8 and cisplatin 70 - 80 mg/m(2) on days 1 or 2. In order to avoid many of the non-haematological toxicities associated with cisplatin, several trials evaluated the gemcitabine-carboplatin combination. Previous trials using the 28-day schedule showed unacceptable haematological toxicity. Recent studies demonstrated the activity and feasibility of gemcitabine-carboplatin combination using a 21-day schedule, with carboplatin administered on day 1 and gemcitabine on days 1 and 8. Gemcitabine can be combined with one of the other new agents, such as the taxanes or vinorelbine, to create novel non-platinum-doublets. Although encouraging, the available data are still conflicting and non-platinum-based combinations are not indicated outside clinical trials. Three-drug combinations increased toxicity and failed to demonstrate any advantage over standard doublets in advanced NSCLC. Gemcitabine is active and well tolerated in elderly patients and represents a reasonable therapeutic option. Although no Phase III trials have been conducted to compare gemcitabine to the best supportive care or docetaxel in pretreated NSCLC, gemcitabine alone or in combination with vinorelbine or one of the taxanes can be considered a valid option for second-line treatment in patients who had a previous response or who achieved stable disease with a platinum-containing regimen. Gemcitabine is considered the most radiopotentiating agent available amongst the newer agents we have in terms of activity and toxicity, but the routine use of gemcitabine in combination with radical thoracic radiotherapy, although promising, is not yet recommended. Further testing of gemcitabine-based combinations with concurrent radiation is underway.     

Vandetanib for the treatment of non-small-cell lung cancer

INTRODUCTION: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways. AREAS COVERED: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens. EXPERT OPINION: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

Bevacizumab as first-line treatment for advanced non-small cell lung cancer

Bevacizumab is a humanized monoclonal antibody (mAb) to vascular endothelial growth factor (VEGF), a major proangiogenic factor in advanced solid tumors. Phase I and II trial results suggested that this agent was well tolerated and could be combined with standard regimens in various solid tumors. An initial randomized phase II trial in advanced non-small cell lung cancer (NSCLC) yielded positive results regarding the potential efficacy of this agent in combination with carboplatin and paclitaxel (CbP). It also identified a safety signal in patients with squamous histology, who appear to have a higher rate of serious and potentially life-threatening pulmonary hemorrhage. Because of this observation, patients with predominantly squamous histology were excluded from the pivotal phase III trials, as were patients with brain metastases and a history of significant hemoptysis. Two phase III trials comparing a standard platinum-based doublet with or without bevacizumab have been reported in advanced NSCLC, both of which met their primary endpoints. The trial reported by the Eastern Cooperative Oncology Group (ECOG 4599) was the first to show an overall survival benefit, as well as a benefit in response rates and progression-free survival resulting from the addition of bevacizumab to CbP. Certain toxicities were increased when bevacizumab was added to CbP, including neutropenia, febrile neutropenia, thrombocytopenia, bleeding (including pulmonary hemorrhage), hypertension and proteinuria. Bevacizumab is the first targeted therapeutic agent to improve survival in advanced NSCLC when added to standard chemotherapeutic regimens.     

Alogliptin benzoate for the treatment of type 2 diabetes

Docetaxel (Taxotere?, Aventis Pharma), a semisynthetic taxane targeting the β-subunit of tubulin, has broad spectrum anticancer activity including non-small cell lung cancer (NSCLC). It is synergistic with platinum and radiation in preclinical models and has been tested clinically in every stage of NSCLC. Docetaxel–platinum combinations have an efficacy comparable to other newer-agent platinum doublets as first-line therapy in advanced NSCLC, and has been approved for use in this setting. Docetaxel was initially approved for NSCLC in the second-line setting following two Phase III trials demonstrating improved survival and quality of life. Ongoing clinical trials are investigating how best to combine docetaxel with thoracic radiotherapy in locally advanced disease. Preliminary studies evaluating docetaxel in the pre-operative setting have also been completed. Ongoing studies are focused on confirming the results observed with consolidation docetaxel in locally advanced NSCLC (SWOG 9504) and docetaxel in combination with molecularly targeted agents. This paper will review the pharmacology, preclinical, clinical and pharmacoeconomic data supporting the use of docetaxel in the treatment NSCLC.     

The current status of docetaxel for advanced non-small cell lung cancer

Docetaxel is an active single agent in both first- and second-line therapy of patients with advanced non-small cell lung cancer (NSCLC). Randomized trials versus best supportive care have documented an improvement in overall survival for docetaxel therapy in both settings. Docetaxel also produced a significant 1-year survival rate improvement when compared with vinorelbine or ifosfamide as second-line therapy. Docetaxel has been extensively investigated in phase I/II studies in combination with cisplatin, carboplatin, irinotecan and gemcitabine. Substantial activity has been demonstrated. In a randomized phase II trial comparing docetaxel plus cisplatin with docetaxel plus gemcitabine, the efficacy of the two regimens was almost identical (response rates 32 and 34%; 1-year survival rates 42 and 38%). However, the combination of docetaxel with gemcitabine was associated with significantly less grade III/IV neutropenia, diarrhea and nausea/vomiting. Three drug regimens combining docetaxel with, for example, gemcitabine and carboplatin or with ifosfamide and cisplatin, are producing very high response rates in phase II trials. Whether three-drug combinations including docetaxel will result in an improved outcome for patients with advanced NSCLC remains to be determined.     

Docetaxel in non-small cell lung cancer: a review

Docetaxel (Taxotere, Aventis Pharma), a semisynthetic taxane targeting the beta-subunit of tubulin, has broad spectrum anticancer activity including non-small cell lung cancer (NSCLC). It is synergistic with platinum and radiation in preclinical models and has been tested clinically in every stage of NSCLC. Docetaxel-platinum combinations have an efficacy comparable to other newer-agent platinum doublets as first-line therapy in advanced NSCLC, and has been approved for use in this setting. Docetaxel was initially approved for NSCLC in the second-line setting following two Phase III trials demonstrating improved survival and quality of life. Ongoing clinical trials are investigating how best to combine docetaxel with thoracic radiotherapy in locally advanced disease. Preliminary studies evaluating docetaxel in the pre-operative setting have also been completed. Ongoing studies are focused on confirming the results observed with consolidation docetaxel in locally advanced NSCLC (SWOG 9504) and docetaxel in combination with molecularly targeted agents. This paper will review the pharmacology, preclinical, clinical and pharmacoeconomic data supporting the use of docetaxel in the treatment NSCLC.     

Trastuzumab-based combination therapy for breast cancer

Trastuzumab, a humanised monoclonal antibody directed against the extracellular domain of HER-2, has been shown to be active against HER-2-overexpressing metastatic breast cancer, either as single agent or when used in combination with chemotherapy. In preclinical models, trastuzumab has shown additive and even synergistic anti-tumour activity with the most active chemotherapeutic agents used in the treatment of breast cancer. In a large, randomised, Phase III trial, the combination of trastuzumab plus chemotherapy was shown to improve response rate and survival. The high incidence of cardiotoxicity seen with the combination of trastuzumab plus anthracycline drugs prompted carrying out of several clinical studies combining trastuzumab with other chemotherapeutic agents, including docetaxel, vinorelbine, platinum salts, gemcitabine and capecitabine. This article summarises the available data on trastuzumab-based combinations for breast cancer.     

Capecitabine in advanced gastric cancer

Since the routine introduction of chemotherapy for advanced gastric cancer in the early 1990s, median survival for gastric cancer has improved from 3 months, with best supportive care alone, to > 11 months in recently reported Phase III trials of triplet chemotherapy. Capecitabine is an orally-active fluoropyrimidine, which is selectively metabolised to fluorouracil in tumour cells. The combinations of platinum compounds and capecitabine have been evaluated in two recent, large, Phase III trials demonstrating non-inferiority in efficacy compared with platinum plus continuous infusion fluorouracil. In view of the convenience and flexibility of patients in adjusting dosage when encountering toxicities, capecitabine is replacing continuous infusion fluorouracil as the backbone of combination chemotherapy in advanced gastric cancer patients. Future trials evaluating biologicals are now incorporating capecitabine combinations as control arms in both advanced disease and peri-operative settings in gastric cancer.