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.     

Meta-analysis of randomised trials comparing gemcitabine-based doublets versus gemcitabine alone in patients with advanced and metastatic pancreatic cancer

OBJECTIVE: To evaluate the impact on overall survival at 6, 12 and 18 months of gemcitabine-based doublets compared with gemcitabine alone in patients with advanced and metastatic pancreatic cancer. METHODS: We conducted a systematic review and meta-analysis of published data on the use of gemcitabine-based doublets compared with gemcitabine alone in chemotherapy-naive patients with advanced and metastatic pancreatic cancer treated in randomised controlled phase II-III trials with overall survival as the principal or secondary endpoint. To this end, a literature search was performed using Cochrane methodology. The relative risks with 95% confidence intervals were estimated based on adjusted number of deaths and patients at risk according to the extent of follow-up and censoring. Twenty-three randomised clinical trials including 5886 patients met the inclusion criteria. In these trials, 2932 patients were randomly assigned to receive gemcitabine-based doublets and 2954 patients to receive gemcitabine alone. RESULTS: Gemcitabine-based doublets were associated with small but significant reductions in the risk of death at 6, 12 and 18 months of 8% (95% CI 3, 13), 4% (95% CI 2, 7) and 3% (95% CI 1, 5), respectively (p<0.005 for all timepoints). No heterogeneity between studies was observed. Subgroup analyses showed an overall survival benefit for gemcitabine-based doublets in clinical trials testing the same planned dose intensity of gemcitabine in comparative arms, using platinum salt-based protocols and with survival as the primary endpoint. CONCLUSION: This meta-analysis of data obtained from randomised controlled phase II-III trials of patients with advanced pancreatic cancer showed a small but significant improvement in overall survival for patients receiving gemcitabine-based doublets compared with gemcitabine alone.     

Cytotoxic chemotherapy for pancreatic cancer: Advances to date and future directions

Chemotherapy remains the mainstay of treatment for pancreatic cancer as most patients present with advanced disease, which precludes locoregional treatment. However, the efficacy of chemotherapy is limited. Gemcitabine is the only agent that improves symptoms and confers a modest survival advantage. Many combination therapy regimens have been studied in phase II settings. Eleven randomised phase III trials have been conducted to compare gemcitabine-containing regimens with gemcitabine monotherapy since gemcitabine became available clinically. The combination of gemcitabine plus capecitabine has demonstrated a survival advantage over gemcitabine, whereas gemcitabine plus oxaliplatin and gemcitabine plus cisplatin have shown improved progression-free survival or time to tumour progression but failed to demonstrate a survival advantage over gemcitabine. The search for effective therapy for advanced pancreatic cancer continues. Gemcitabine in combination with cytotoxic agents or molecular targeted agents hold promise.     

Combination therapy versus single agent chemotherapy in non-small cell lung cancer

There is proven evidence of improved symptom control with platinum-based chemotherapy in the palliation of non-small cell lung cancer, and small but definite improvements in progression-free and overall survival when compared with best supportive care. The newer chemotherapy agents vinorelbine, gemcitabine, docetaxel and paclitaxel all have single agent activity, and in combination with cisplatin these provide superior quality of life and/or survival compared with the single agents, albeit with some increase in haematological toxicity. Doublet chemotherapy consisting of a new agent combined with platinum, cisplatin by preference where tolerated, has become the standard of care for advanced disease. The use of a functional assessment of fitness, rather than chronological age alone, is appropriate in the treatment of elderly patients. Although in this group there is evidence that doublets are superior to single agents, treatment should be undertaken with caution. In the second line setting where patients are unlikely to tolerate combination therapy, single agents have proven superiority over best supportive care. Patients with poor performance status (PS2) without comorbidity may tolerate combination therapy, but currently available evidence is insufficient to allow a definitive recommendation for combination or single-agent chemotherapy.     

Combination therapy versus single agent chemotherapy in non-small cell lung cancer

There is proven evidence of improved symptom control with platinum-based chemotherapy in the palliation of non-small cell lung cancer, and small but definite improvements in progression-free and overall survival when compared with best supportive care. The newer chemotherapy agents vinorelbine, gemcitabine, docetaxel and paclitaxel all have single agent activity, and in combination with cisplatin these provide superior quality of life and/or survival compared with the single agents, albeit with some increase in haematological toxicity. Doublet chemotherapy consisting of a new agent combined with platinum, cisplatin by preference where tolerated, has become the standard of care for advanced disease. The use of a functional assessment of fitness, rather than chronological age alone, is appropriate in the treatment of elderly patients. Although in this group there is evidence that doublets are superior to single agents, treatment should be undertaken with caution. In the second line setting where patients are unlikely to tolerate combination therapy, single agents have proven superiority over best supportive care. Patients with poor performance status (PS2) without comorbidity may tolerate combination therapy, but currently available evidence is insufficient to allow a definitive recommendation for combination or single-agent chemotherapy.     

Role of gemcitabine in the treatment of advanced non-small cell lung cancer: review of the main phase II and phase III trials

Marked advances in the treatment of non-small cell lung cancer (NSCLC) have been made thanks to new agents. Among these agents, gemcitabine appears to be a major compound in advanced stage NSCLC chemotherapy. To start with, several phase III trials (conducted in Europe and in the USA) studied the gemcitabine/cisplatin combination (GC): US study protocois compared GC to cisplatin alone, to the standard treatment (etoposide/cisplatin) or to platinum/taxane doublets; in these studies, as a result of treatment with GC, a higher survival rate was observed. A study conducted in Italy, which is undergoing analysis, observes GC versus paclitaxel/carboplatin versus cisplatin/vinorelbine. In addition, in newer clinical protocols, it was observed that gemcitabine combined with taxanes or with vinorelbine demonstrated efficacy at least equal to that of combinations with platinum analogs. Newer agents acting on epithelial growth factor are also undergoing evaluation.     

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.     

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.     

Recent developments in the pharmacological treatment of advanced pancreatic cancer

Metastatic pancreatic cancer is one of the leading causes of cancer-related death in North America and Europe. The high mortality rate associated with pancreatic cancer is related to the fact that the vast majority of patients develop incurable, metastatic disease. Such patients have, in the past, had few treatment options. In recent years, however, the systemic administration of gemcitabine has been accepted as a standard first-line treatment for patients with advanced pancreatic cancer. While treatment with gemcitabine has been shown to result in both clinical benefit and in prolongation of survival, objective tumour responses following therapy with gemcitabine are relatively uncommon and median survival times remain short. Current efforts have, therefore, focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Several such combinations appear to be associated with higher objective response rates than single-agent gemcitabine and have been well-tolerated in early clinical trials. Ongoing, prospectively randomised clinical trials will help better define the efficacy of these new combinations and will determine if they result in a significant benefit when compared to gemcitabine monotherapy. A number of novel chemotherapeutic and biological agents also appear promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

Recent developments in the pharmacological treatment of advanced pancreatic cancer

Metastatic pancreatic cancer is one of the leading causes of cancer-related death in North America and Europe. The high mortality rate associated with pancreatic cancer is related to the fact that the vast majority of patients develop incurable, metastatic disease. Such patients have, in the past, had few treatment options. In recent years, however, the systemic administration of gemcitabine has been accepted as a standard first-line treatment for patients with advanced pancreatic cancer. While treatment with gemcitabine has been shown to result in both clinical benefit and in prolongation of survival, objective tumour responses following therapy with gemcitabine are relatively uncommon and median survival times remain short. Current efforts have, therefore, focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Several such combinations appear to be associated with higher objective response rates than single-agent gemcitabine and have been well-tolerated in early clinical trials. Ongoing, prospectively randomised clinical trials will help better define the efficacy of these new combinations and will determine if they result in a significant benefit when compared to gemcitabine monotherapy. A number of novel chemotherapeutic and biological agents also appear promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

State-of-the art treatment of locally advanced and metastatic non-small cell lung cancer

Despite the poor mortality figures from lung cancer, advances have been observed in the treatment of advanced (stages IIIB and IV) non-small cell lung cancer (NSCLC). In the first instance, such advances have been achieved thanks to chemotherapy (CT) consisting of platinum-based compounds (results demonstrated in several phase III studies) and then thanks to newer cytotoxic agents such as gemcitabine. Used as monotherapy, gemcitabine provides a marked benefit compared to the standard treatment consisting of etoposide/cisplatin (EC) (21% objective response, 39% survival at 1 year). A good efficacy profile of this agent in combination with platinum analogs was also observed in randomized phase III studies, confirming the significant higher survival obtained with the gemcitabine/cisplatin (GC) combination (in GC versus C protocols and that comparing four doublets of CT). Results observed with G without platinum analogs are comparable to those of treatment with a platinum agent. Other studies conducted with triplets of CT need to be confirmed. Newer non-cytotoxic agents have also been studied: the anti-vascular endothelial growth factor monoclonal antibody with or without CT may prolong survival; docetaxel improves overall survival outcomes compared to palliative therapy. In locally advanced stages, advances have been made possible by radiochemotherapy (RT/CT): several phase II and phase III studies using EC and RT have been conducted. Lastly, in induction treatments, CT appears to provide improvement.     

Conventional chemotherapy of advanced pancreatic cancer

The vast majority of patients with pancreatic cancer present with locally advanced unresectable or metastatic disease, and in this setting only a palliative treatment can be offered. Single-agent gemcitabine has been considered the standard chemotherapy for patients with advanced pancreatic cancer since the results of a pivotal phase III trial showing superior clinical benefit compared to bolus 5-fluorouracil were published in 1997. In recent years, many randomized trials have attempted to improve results obtained with gemcitabine exploring a different schedule (fixed dose rate) of its administration, or testing the addition of one or more drugs to gemcitabine. Unfortunately, none of these trials produced a statistically significant and clinically relevant improvement in overall survival compared to the standard. A randomized phase III trial has recently shown a survival advantage using a combination of more drugs (FOLFIRINOX: irinotecan, oxaliplatin, folinic acid and 5-fluorouracil) compared to single-agent gemcitabine, suggesting that regimens without gemcitabine can be successfully used in patients with advanced pancreatic cancer. FOLFIRINOX was associated with worse toxicity than gemcitabine, and the available data suggest that this regimen may be considered for patients with metastatic pancreatic cancer who are fit enough to withstand potential side effects. The best option for these patients remains the enrolment in prospective clinical trials. Improvements in the treatment of the advanced disease will possibly derive from new combinations or from new drugs, but certainly from a better knowledge of the multiple molecular pathways implicated in pancreatic carcinogenesis and in invasion and metastasis.     

Economic evaluation of gemcitabine alone and in combination with cisplatin in the treatment of nonsmall cell lung cancer

OBJECTIVE: To evaluate the cost effectiveness of gemcitabine in the treatment of nonsmall cell lung cancer (NSCLC). METHODS: Gemcitabine was compared with best supportive care and gemcitabine/cisplatin was compared with three standard chemotherapies and four other novel chemotherapy combinations. Costs and effectiveness measures were based on resource and outcome data from previously reported clinical trials. All direct costs associated with NSCLC treatment were included and adjusted to year 2000 values. PERSPECTIVE: UK National Health Service. RESULTS: Gemcitabine plus best supportive care was associated with an incremental cost per progression-free life year gained of pound sterling5228 compared with best supportive care alone. In comparison with standard chemotherapies, gemcitabine/cisplatin was associated with an incremental cost per progression-free life year gained of pound sterling1751 versus etoposide/cisplatin and cost per 1-year survival gain of pound sterling5681 versus mitomycin/vinblastine/platinum. Incremental cost per tumour response was pound sterling2032 relative to etoposide/cisplatin, pound sterling5169 relative to mitomycin/ifosfamide/cisplatin and pound sterling6240 relative to mitomycin/vinblastine/platinum. Compared with four novel (newer) combination chemotherapies gemcitabine/ cisplatin showed cost savings in each case, with the same or better outcome. Thus, gemcitabine/cisplatin showed improved cost effectiveness and dominance. Sensitivity analyses showed the results were robust to variations to the values of key parameters. CONCLUSION: Gemcitabine alone or in combination with cisplatin was assessed to be a cost-effective or cost-saving therapy when compared with best supportive care, standard chemotherapy regimens and novel chemotherapy combinations. Chemotherapy regimens containing gemcitabine therefore represent good value for money and efficient use of healthcare resources in the treatment of advanced NSCLC.     

Emerging drugs in pancreatic cancer

Improving survival in patients with pancreatic cancer remains a formidable challenge. For the few patients with localised stages of the disease, intra-operative radiotherapy, adjuvant chemoradiotherapy and neo-adjuvant therapies remain non-validated and the survival benefit conferred by 5-fluorouracil-folinic acid adjuvant chemotherapy over radical surgery alone is still a matter of debate. Gemcitabine has recently emerged as the standard single agent in advanced stages of the disease and pharmacokinetic refinements such as the use of a fixed-dose infusion rate may further improve still rather modest result figures. At present, most efforts deal with the development of more effective doublet or triplet therapies, combining gemcitabine with either conventional cytotoxic drugs--the most promising being oxaliplatin--or more innovative, targeted therapeutic agents. Among these agents, matrix metalloprotease inhibitors and farnesyltransferase inhibitors have already undergone Phase III trials, alone or in combination with gemcitabine, with rather disappointing results. However, preclinical and Phase I and II studies of cyclooxygenase-2 or lipoxygenase inhibitors, various immunotherapeutic approaches and several tyrosine kinase inhibitors or monoclonal antibodies against growth factors or their receptors are encouraging and may provide some hope for patients with pancreatic cancer.     

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.     

A review of erlotinib and its clinical use

Erlotinib is an orally available, reversible tyrosine kinase inhibitor of the epidermal growth factor receptor. Encouraging activity as a single agent and in combination with other targeted agents has been demonstrated in Phase II trials in many tumour types. Erlotinib has an established role in the treatment of advanced, refractory non-small cell lung cancer-based on a pivotal trial demonstrating a survival advantage over best supportive care. In a Phase III trial, the addition of erlotinib to gemcitabine improved survival in advanced pancreatic cancer. The toxicity profile of erlotinib includes diarrhoea and rash, with no haematological side effects. Predictive factors for response include the presence of a rash, epidermal growth factor receptor expression and mutation status. This article reviews the current clinical status of erlotinib.     

New directions in the management of advanced pancreatic cancer: a review

Complete surgical resection is the only potentially curative option for pancreatic cancer. However, most patients have advanced/metastatic disease at the time of diagnosis, or will relapse after surgery. Systemic chemotherapy is only palliative. Gemcitabine-based therapy is an acceptable standard for unresectable locally advanced/metastatic pancreatic cancer, but average median survival is only 6 months. The addition of other chemotherapies (including other antimetabolites, platinum, and topoisomerase I inhibitors) or targeted therapies (farnesyl transferase inhibitors, metalloproteinase inhibitors, cetuximab and bevacizumab) to gemcitabine has failed to improve outcome. The combination of gemcitabine and erlotinib, a small-molecule tyrosine kinase inhibitor of the human epidermal growth factor receptor, was recently approved by the US/European authorities for use in advanced disease. In a phase III trial, the combination demonstrated a significant improvement in overall survival compared with gemcitabine monotherapy. Positive efficacy results have also been observed in a phase III trial, favoring the addition of capecitabine to gemcitabine compared with gemcitabine alone. This review focuses on the recent developments in systemic treatment, and discusses how novel agents might be incorporated into future treatment strategies for pancreatic cancer.     

Anti-angiogenic agents in pancreatic cancer: a review

Pancreatic cancer is the fourth leading cause of cancer related death in the United States, with a 5-year survival of less than five percent. Since the majority of patients have locally advanced or metastatic disease at the time of diagnosis, there has been little progress made to extend survival. For over ten years, chemotherapy with gemcitabine has been standard treatment for those patients with advanced pancreatic cancer, prolonging survival by only 5-6 months. To improve upon this modest benefit, several investigations have explored other strategies aimed at curbing pancreatic cancer growth. Because pancreatic cancer has been found to have a profoundly hypoxic environment with high vascular in-growth, several agents have been developed to target the angiogenesis process. Major emphasis has been placed on anti- vascular endothelial growth factor (VEGF) models and the epidermal growth factor receptor (EGFR) signaling pathway. Over the past several years, a number of phase II and phase III trials have combined gemcitabine with these novel treatments, with the hope of prolonging survival in patients with pancreatic cancer. This review will discuss these therapies and their potential application in a clinical setting.     

Tyrosine kinase inhibitors and gemcitabine: new treatment options in pancreatic cancer?

Pancreatic cancer (PCa) is one of the most lethal malignancies in humans. Gemcitabine is the current standard chemotherapy of advanced PCa but it is still far from optimal and novel therapeutic strategies are urgently needed. For the near future, tyrosine kinase inhibitors (TKIs) hold great promise as a therapeutic strategy. Tyrosine kinases (TKs) play a pivotal role in intercellular signal transduction and regulate crucial processes of tumor cells such as proliferation, migration, survival and angiogenesis. Several TKs--such as EGFR, VEGFR, PDGFR and Src--are known to be overexpressed or constitutively activated in PCa. Hence, blocking receptor tyrosine kinases (RTKs) and non-receptor, cytoplasmic tyrosine kinases (CTKs) represents a rational approach to treat PCa. In particular, cetuximab and erlotinib, the monoclonal antibodies against EGFR-1 (ErbB-1) showed promising activity in Phase II and Phase III trials and their combination with gemcitabine resulted in synergistic antitumor activity. In addition, small antiangiogenic molecules such as VEGFR-2 inhibitors, PDGFR inhibitors and multiple receptor targeting agents are under active investigation. Association of chemoresistance with the activity of certain tyrosine kinases (e.g. ErbB-1 and Src) has been described for pancreatic cancer and makes a strong case for combining gemcitabine with TKIs. Combinations of different TKIs might also be used to target the cancer cell micro-environment. Detailed molecular characterization of tumor cells and combinations of appropriate TKIs with cytotoxic agents such as gemcitabine are expected to lead to improved therapy of pancreatic cancer.     

Pancreatic cancer: the evolving role of systemic therapy

Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the US. The outcome for patients with pancreatic cancer has not essentially altered over the past few decades. Several new drugs with activity against pancreatic cancer have recently been identified for use in palliative settings. Of these, gemcitabine is the most widely used agent against the disease, but its benefit is very modest. Pilot Phase II studies combining gemcitabine with 5-fluorouracil (5-FU), irinotecan, docetaxel or cisplatin show improved outcomes that need to be confirmed in randomised studies. Concurrent administration of gemcitabine and external beam radiation therapy (EBRT) for locally advanced pancreatic cancer is feasible and is currently undergoing efficacy evaluations. Current research in pancreatic cancer involves newer dosing schedules of gemcitabine, and combinations of gemcitabine with novel agents. Ultimately, better understanding of the molecular biology of pancreatic neoplasia will identify potential cellular targets for future development of new agents for pancreatic cancer.