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.     

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.     

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.     

Neoadjuvant strategies in the treatment of non-small cell lung cancer

The prognosis of patients with resectable non-small cell lung cancer (NSCLC), other than stage IA disease, remains disappointing, with 5 year survival rates ranging from 40-55%. For the past 15-20 years, several phase II trials have investigated the efficacy of chemotherapy and chemoradiotherapy prior to surgery in the management of stage IIIA NSCLC, with encouraging results. Phase III trials comparing surgery alone with chemotherapy plus surgery have confirmed the efficacy of this multimodality approach. Gemcitabine, one of the new agents with significant activity against NSCLC, has undergone extensive clinical testing in combination with cisplatin in this setting. In 47 patients with stage IIIA disease, induction with gemcitabine/cisplatin was well tolerated and yielded a response rate of >70%. Downstaging of the mediastinal lymph nodes occurred in 53% of patients. Preliminary data from another study employing mitomycin C, ifosfamide and cisplatin in resectable NSCLC suggest that there are favourable effects of induction treatment, especially in early-stage disease. With the availability of chemotherapeutic combinations such as gemcitabine/cisplatin, which are both effective and well tolerated, combination therapy is likely to become a major advance in the treatment of patients with early-stage (IB, II) NSCLC.     

The role of gemcitabine alone and in combination in the treatment of pancreatic cancer

Pancreatic cancer, one of the most frequently reported gastrointestinal tumors, has a 5-year survival of less than 5%. Despite representing only 2-3% of the total cancer incidence, it is the fifth leading cause of cancer death. This is because it is commonly only diagnosed at an advanced stage. Until recently the traditional therapy for patients with advanced disease was palliative 5-fluorouracil (5-FU)-based chemotherapy. However, the novel antinucleoside gemcitabine (Gemzar) has demonstrated a survival benefit over 5-FU, and an improvement in disease-related symptoms and quality of life in patients with advanced disease. This review presents an overview of the clinical studies of gemcitabine, either alone or in combination, with other chemotherapeutic agents and/or radiation therapy, in the treatment of these patients. A comparison of these studies is made with those using alternative treatment regimens. The data suggest that gemcitabine in combination with biomodulated 5-FU should be considered the standard palliative treatment to which other new drug combinations or combined modality chemoradiation regimens should be compared.     

Tirofiban: an investigational plateletglycoprotein IIb/IIIa receptor antagonist

Introduction: Fluoropyrimidines with oxaliplatin or irinotecan plus bevacizumab is the standard chemotherapy combination in patients with advanced colorectal cancer (CRC). Gemcitabine acts synergistically with fluoropyrimidines to enhance the binding of thymidylate synthase and increase inhibition of DNA synthesis. The objective of this review is to evaluate the literature for evidence of efficacy and safety of fluoropyrimidine plus gemcitabine (FG) in patients with advanced CRC. Methods: Relevant studies were identified in PubMed, Ovid, Cochrane database and the American Society of Clinical Oncology abstracts using the following search terms: gemcitabine, fluorouracil, capecitabine and colorectal cancer. Only studies using the FG combination were selected. Results: Forty-two advanced CRC patients were evaluated in two Phase I studies and the maximum tolerated dose of gemcitabine was 900 – 1,000 mg/m² weekly with either bolus 5-fluorouracil (5-FU) or capecitabine. A total of 216 advanced CRC patients were evaluated in six Phase II studies. Gemcitabine (750 – 1,250 mg/m²) with either 5-FU (continuous infusion or bolus) or capecitabine was administered as first-line therapy in two studies and as third-line therapy in three studies. The range reported for overall response rate was 30 – 38.3%, median time to progression was 4 – 8.3+ months and median survival was 9.8 – 18+ months. The most commonly reported grade 3 – 4 toxicities were neutropenia, thrombocytopenia and mucositis. Conclusions: Fluoropyrimidine plus gemcitabine is clinically active in patients with refractory CRC demonstrating prolonged median time to progression and acceptable toxicity only when bolus 5-FU was not used. Studies are underway to evaluate the combinations of FG with other chemotherapy or targeted agents. Meanwhile, FG may be considered for patients with advanced CRC who are refractory to primary treatment without other options or who are not eligible for clinical studies.     

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.     

Lung cancer in the elderly: current and future chemotherapeutic options

Lung cancer is a prevalent malignancy disproportionately affecting the elderly, and in our aging societies will only increase in magnitude. Physicians typically assume that elderly lung cancer patients will have poorer prognoses. This belief is in part based on certain physiological changes of aging affecting the kidneys, liver, and bone marrow. However, there are no data to clearly support or refute increased toxicity from chemotherapy or a lessened therapeutic effect in the elderly based on these changes, although it is a field worthy of further study. Retrospective studies of treatment of elderly non-small cell and small cell lung cancer patients do not suggest a worse prognosis based on advanced age alone. Clinicians are hampered by the lack of clinical trials focusing on or even including the elderly, despite the increased incidence of lung cancer in the elderly. Phase II studies in elderly non-small cell lung cancer patients concentrate on newer agents (vinorelbine and gemcitabine) alone or combined with platinum compounds in hopes of more favourable toxicity profiles. Phase III trials have demonstrated survival benefits, quality of life improvements, and acceptable toxicity profiles for vinorelbine compared to best supportive care alone and the combination of vinorelbine and gemcitabine compared to vinorelbine alone. Data are also sparse for elderly small cell lung cancer patients. Phase II studies focused on single agent oral etoposide also in hopes of lessening toxicity. However, phase III trials have shown improvement in survival and quality of life for multiagent intravenous chemotherapy compared to oral etoposide. Given the existing data, altering therapy for lung cancer patients based on age alone would not be warranted. Given the prevalence of the disease, future studies need to include an appropriate number of elderly patients with continued emphasis on quality of life in addition to survival.