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.     

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.     

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.     

Palliative chemotherapy with gemcitabine and weekly high-dose 5-fluorouracil as 24-h infusion in metastatic biliary tract and gall bladder adenocarcinomas

At present, systemic treatment is not generally recommended for advanced biliary tract and gall bladder carcinomas. In particular cases, however, it may be justified to consider systemic chemotherapy treatment. In four cases we investigated the efficacy of palliative systemic treatment in metastatic biliary tract and gall bladder adenocarcinomas. Similar to the proceedings in a phase II study for metastatic pancreas adenocarcinomas, four patients with advanced biliary tract and gall bladder adenocarcinomas received a combination treatment of gemcitabine (GEM) and weekly high-dose 5-fluorouracil (5-FU) as a 24-h infusion. Altogether, the four patients received 96 chemotherapy applications. The palliative chemotherapy was tolerated well. In one patient, leukocytopenia (toxicity grade III) and thrombocytopenia (toxicity grade III) occurred. In three patients, the palliative systemic treatment led to stable disease, partly with a significant decrease of the CA 19-9 tumor marker, and in one patient to partial remission (PR). The survival times in these four patients were 6, 10, 17 and 26 months. Even in the case of PR, a curative hemihepatectomy right could be achieved after 'downsizing'. We conclude that in the four case studies, the applied palliative combination treatment based on GEM and 5-FU proved to be effective. However, future multicenter studies will be necessary to determine the significance of palliative chemotherapy in biliary tract and gall bladder carcinomas.     

Phase II study with 5-fluorouracil and ginkgo biloba extract (GBE 761 ONC) in patients with pancreatic cancer

The aim of the study was to evaluate the efficacy and tolerability of as well as the quality of life under treatment with 5-fluorouracil (CAS 51-21-8, 5-FU) combined with parenteral GBE 761 ONC (i.e. the ginkgo biloba special extract EGb 761) in patients with pancreatic cancer. Forty-eight patients with locally or metastatic advanced pancreatic cancer were treated within a phase II study. The treatment was repeated every three weeks until progression. Response to therapy was evaluated after 2 and 4 treatment courses. Thirty-two patients were evaluable for response. Progressive disease was observed in 22 (68.8%) patients, no change in 7 (21.9%) patients and partial response in 3 (9.4%) patients (overall response = 9.4%). GBE 761 ONC was well tolerated. Adverse events which occurred during the study consisted mainly of myelosuppression and gastrointestinal symptoms and were judged as 5-FU-related or consisted of liver toxicity, respectively, and were judged as tumour-related. These results suggest a good benefit-risk ratio of the combination of 5-FU and GBE 761 ONC in the treatment of pancreatic cancer. In comparison with the results of studies with either 5-FU or gemcitabine as single agents the combination of 5-FU/GBE 761 ONC shows comparable response rates. The toxicity of the 5-FU/GBE 761 ONC combination was low. This combination therapy therefore warrants further clinical investigation, such as a controlled clinical trial against 5-FU or gemcitabine monotherapy.     

Gemcitabine combined with 5-fluorouracil for the treatment of advanced carcinoma of the pancreas

BACKGROUND: Gemcitabine is an active agent in pancreatic cancer, showing clinical synergy with 5-fluorouracil (5-FU). The aim of the study was to evaluate the safety and efficacy of the combination of gemcitabine and 5-FU in patients with advanced adenocarcinoma of the pancreas. PATIENTS AND METHODS: Forty-two patients (median age, 62 years), with advanced or metastatic pancreatic adenocarcinoma, were enrolled in the study. The combination of gemcitabine (1000 mg/m2) and 5-FU (600 mg/m2) was administered on days 1, 8 and 15 and repeated every 28 days. RESULTS: A total of 168 cycles (median 4 cycles per patient) were administered. Partial responses were observed in 6 patients (14.2%) and stable disease in 11 (26.2%). The overall clinical benefit was 40.4%. Symptom relief and improvement of performance status were observed in 18 (42.8%) patients. The median time to progression, median duration of response and the median overall survival, were 6, 7 and 13 months, respectively. The most common grade 3 to 4 toxicities were neutropenia, anaemia and diarrhoea. CONCLUSION: The combination of gemcitabine and 5-FU is an active regimen for the treatment of advanced pancreatic cancer with an acceptable toxicity profile.     

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.     

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.     

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.     

Pancreatic cancer: a review of recent advances

Pancreatic cancer is one of the most common causes of cancer-related death. Despite the advances of the molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. Overall, the 5-year survival rate is < 5% and only approximately 20% of the 10% of patients with resectable disease survive 5 years. Recently, the European Study Group for Pancreatic Cancer 1 trial demonstrated substantially increased survival from adjuvant chemotherapy with 5-fluorouracil-folinic acid and preliminary data showed prolonged disease-free survival from adjuvant gemcitabine. Current palliative therapeutic approaches mostly focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Recently, large randomised trials of combinations of gemcitabine with either capecitabine or with erlotinib demonstrated prolonged survival and 1-year survival rates of approximately 25%. The advance of molecular biology has led to the elucidation of molecular events that are important for pancreatic carcinogenesis and has provided a foundation for the development of novel chemotherapeutic and biological agents that appear to be promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

Oxaliplatin: a review of its use in combination therapy for advanced metastatic colorectal cancer

Oxaliplatin (Eloxatin) is the only platinum compound to show clinical activity in colorectal cancer. The efficacy of a combination of oxaliplatin with various schedules of fluorouracil (5-FU)/folinic acid (FA) as first- or second-line treatment for advanced metastatic colorectal cancer has been investigated in large phase III trials. FOLFOX4 (an oxaliplatin/5-FU/FA regimen) as first-line therapy (n = 795) was superior to irinotecan/5-FU/FA (IFL). Response rates were 45% vs 31%, and median progression-free survival duration was 8.7 vs 6.9 months. The survival advantage shown by FOLFOX4 over the irinotecan combination (median survival duration 19.5 vs 14.8 months) may be confounded by differences in post-study treatment but equivalent efficacy is supported by another phase III trial of oxaliplatin and irinotecan combinations. As first-line therapy, oxaliplatin added to various 5-FU/FA regimens more than doubled the response rates from 16-22.6% to 48.3-53% and the median duration of progression-free survival was significantly longer with oxaliplatin/5-FU/FA than 5-FU/FA alone (7.9-9 versus 5.3-6.2 months, respectively).In disease resistant to irinotecan-based therapies, the oxaliplatin (FOLFOX4) regimen had superior efficacy to 5-FU/FA alone in a pivotal phase III trial (n = 816). Response rates and median durations of progression-free survival were 9.6% vs 0.7% and 5.6 vs 2.6 months, respectively. An oxaliplatin-induced cumulative peripheral sensory neuropathy (evident when total dose reaches approximate, equals 800 mg/m(2)) is dose limiting. The most frequently occurring grade 3 or 4 toxicities in oxaliplatin/5-FU/FA-recipients were neutropenia (up to 48%) and neurological toxicities (up to 18%). Gastrointestinal effects (diarrhoea [ approximate, equals 12%], nausea, vomiting, or mucositis/stomatitis [up to 6%]) are manageable. Withdrawals from oxaliplatin treatment were due to neuropathy (up to 10%), diarrhoea and/or vomiting (1%) or cutaneous toxicity (1%). Conclusion: As first-line therapy for metastatic colorectal cancer, oxaliplatin with 5-FU/FA consistently improves response rates and progression-free survival compared with various regimens of 5-FU/FA alone. The significant survival advantage shown by oxaliplatin/5-FU/FA (FOLFOX4) compared with first-line therapy with irinotecan/5-FU/FA (IFL) is encouraging but may require further confirmation. Oxaliplatin/5-FU/FA produces a significantly higher response rate and longer progression-free survival than 5-FU/FA in patients failing irinotecan-based therapies, and as such is also a useful second-line treatment. Although cumulative neurotoxicity is dose limiting, oxaliplatin has a manageable tolerability profile. Oxaliplatin as first- or second-line therapy is a valuable addition to the limited, but expanding, armamentarium of cytotoxic agents useful in advanced metastatic colorectal cancer.     

Adjuvant therapy in pancreatic cancer: a critical appraisal

Adenocarcinoma of the pancreas carries a grim prognosis. Surgery is currently the only curative option, but even the few patients undergoing complete resection of early localised disease run a high risk for relapse and death. Although numerous clinical trials have been conducted during the past 20 years to find an effective adjuvant treatment, thus far no general consensus on the most appropriate regimen has been reached. In a small randomised study performed in the 1980s by the GITSG (Gastrointestinal Tumor Study Group), encouraging results were obtained with fluorouracil (5-FU)-based split-course chemoradiotherapy, but these findings were not confirmed in a randomised study initiated some years later by the EORTC (European Organisation for Research and Treatment of Cancer). More recently, the ESPAC (European Study Group for Pancreatic Cancer)-1 trial even indicated a detrimental effect of chemoradiotherapy, while chemotherapy with 5-FU was shown to have a significant positive impact on long-term survival. However, this latter finding is in contrast to earlier studies of adjuvant chemotherapy with 5-FU combinations from Norway and Japan that did not suggest a prolonged beneficial effect of 5-FU on survival. Thus, the results for adjuvant regimens based on systemic 5-FU with or without external radiotherapy are conflicting. Clinical experience with intraoperative radiotherapy or regionally targeted chemotherapy to prevent local relapse, though encouraging, is still preliminary. More recently, gemcitabine, which is the most effective single agent in advanced pancreatic cancer, has also been evaluated in the adjuvant setting. The RTOG (Radiation Therapy Oncology Group)-9704 trial demonstrated that gemcitabine is superior to 5-FU as an addition to chemoradiotherapy, but the results did not allow conclusions about the value of radiation in the combined modality approach. The Charité Onkologie CONKO-001 is a randomised trial from Germany and Austria that compared adjuvant gemcitabine with observation alone. Gemcitabine was very well tolerated and almost doubled median disease-free survival and overall survival rate at 5 years, although the advantage in overall survival failed to reach statistical significance. In summary, the available data from randomised clinical trials of adjuvant therapy suggest that (i) chemoradiotherapy has no obvious advantage compared with chemotherapy alone; and (ii) chemotherapy with gemcitabine is effective and probably offers the best benefit-risk ratio of all currently available adjuvant treatment options.     

Capecitabine in gastric cancer

Double and triplet regimens comprising a fluoropyrimidine and a platinum compound, with or without an anthracycline or taxane are accepted standards of care for advanced gastric cancer. Capecitabine, an oral fluoropyrimidine designed to selectively deliver 5-fluorouracil (5-FU) to tumor cells, is safe and effective in combination chemotherapy regimens for advanced gastric cancer, and it is noninferior to 5-FU for survival. As capecitabine is more convenient to administer than infused 5-FU, avoiding the need for central venous access and the associated risk of complications, it is also an accepted alternative to 5-FU within perioperative combination chemotherapy regimens for resectable gastric cancer.     

Available options in chemotherapy for advanced gastric cancer: the current developments in Japan

Although techniques for early diagnosis and treatment of gastric cancer have been established, standard treatment for advanced gastric cancer has not. 5-Flourouracil (5-FU) plus cisplatin containing regimens, including 5-FU plus cisplatin, epirubicin plus cisplatin and 5-FU, and docetaxel plus cisplatin and 5-FU, are considered to be the most effective regimens for advanced gastric cancer in US, Europe and Korea. In Japan, oral fluoropyrimidine S-1 is currently considered to be the first-line treatment for advanced gastric cancer. S-1-based combination therapies with other promising drugs, including cis-platin, irinotecan and taxanes, are expected to yield good results. Above all, S-1 plus cisplatin therapy showed high efficacy and expected to be a standard therapy for advanced gastric cancer. Further evaluation by well-controlled clinical trials is still required.     

Disease management considerations: disease management considerations.

Colorectal cancer is still a majorhealth and social problem. However, many important advances in treatment have been made in the last 4 to 5 years, and more optimism is now justified both among clinicians and patients. In surgically resectable disease, adjuvant chemotherapy has been clearly demonstrated as able to increase overall survival in patients with colon cancer Dukes' stage C, whereas the role of medical treatment in patients with Dukes' stage B colon cancer is still controversial. At present, the standard regimen is bolus fluorouracil (5-FU) modulated by folinic acid (leucovorin) for 6 months. For rectal cancer, the best adjuvant treatment seems to be represented by radiotherapy (better if administered preoperatively) combined with chemotherapy (usually based on modulated or continuously infused 5-FU). In advanced disease, many new drugs have recently emerged: the most active regimens are those combining an optimal modality of 5-FU administration (i.e. continuous infusion) and one of the most active innovative compounds (irinotecan or oxaliplatin). The role of the oral drugs (e.g. tegafur/uracil, capecitabine) is still under investigation as is the combination of agents excluding 5-FU. It is now recognised that first-line treatment must be offered to all suitable pa- tients, even though asymptomatic, and that a second-line therapy (chiefly with irinotecan) is of value in many patients with cancer that progresses during treatment with 5-FU. From a strategic point of view, the best sequence of drugs/regimens has not yet been defined, while the duration and timing of chemotherapy is still a matter for clinical research. Finally, there is an increasing interest in the role of biological prognostic factors as an aid to a patient-tailored therapy, both in the adjuvant setting and in advanced disease. To achieve further progress in knowledge in this field, we strongly recommended that more and more patients are included in clinical trials.     

Pancreatic cancer: a review of recent advances

Pancreatic cancer is one of the most common causes of cancer-related death. Despite the advances of the molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. Overall, the 5-year survival rate is < 5% and only ～ 20% of the 10% of patients with resectable disease survive 5 years. Recently, the European Study Group for Pancreatic Cancer 1 trial demonstrated substantially increased survival from adjuvant chemotherapy with 5-fluorouracil–folinic acid and preliminary data showed prolonged disease-free survival from adjuvant gemcitabine. Current palliative therapeutic approaches mostly focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Recently, large randomised trials of combinations of gemcitabine with either capecitabine or with erlotinib demonstrated prolonged survival and 1-year survival rates of ～ 25%. The advance of molecular biology has led to the elucidation of molecular events that are important for pancreatic carcinogenesis and has provided a foundation for the development of novel chemotherapeutic and biological agents that appear to be promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

晚期非小细胞肺癌应用吉西他滨维持治疗的疗效分析

目的比较晚期非小细胞肺癌行4周期一线含铂方案联合化疗后,单药吉西他滨维持治疗与最佳支持治疗两组之间无进展生存期（PFS）和总生存（OS）之间的差别。方法选择经过一线化疗后获得疾病控制的Ⅲb期或Ⅳ期非小细胞肺癌（NSCLC）患者62例,随机分为维持治疗组和对照观察组,维持治疗组给予吉西他滨按1g.m^-2d1、d8维持化疗,三周重复一次,直至疾病进展;对照观察组只给予最佳支持治疗,观察两组患者的PFS和OS的差别。结果维持治疗组的中位PFS为4．2月,明显优于对照观察组的2．9月,两组比较差异有显著性意义（P〈0．05）;维持治疗组和对照观察组的中位OS分别为13．7个月和11．4个月,两组比较差异无显著性意义（P〉0．05）。结论非小细胞肺癌4周期一线含铂方案联合化疗后采用单药吉西他滨维持治疗能改善PFS,副作用轻微,耐受性好。     

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.     

Novel non-operative treatment and treatment strategies in pancreatic cancer

Patients with advanced pancreatic cancer have traditionally been treated with palliative care only. The last decade has seen significant improvements in the surgical treatment of this disease but until the late 1990s there was no effective non-surgical treatment for these tumours. The introduction of gemcitabine has given clinicians treating patients with pancreatic cancer a new option. The published randomised data of gemcitabine in patients with pancreatic cancer has shown both a small survival advantage and significant improvements in quality of life indicators in these patients. These data have stimulated a resurgence of interest in pancreatic tumours and several studies have been or are currently investigating novel treatments or treatment strategies. The explosion in the molecular knowledge of cancer has led to the development of several ‘molecular designer drugs’ that have been tested in pancreatic cancer. The furthest advanced of these is a matrix metalloproteinase (MMP) inhibitor called marimastat. The first randomised data using this new class of agents is increasing and suggests that marimastat may have a role in the future treatment of patients with pancreatic cancer. Other agents such as gastrimmune, are about to enter Phase III studies and several other molecular treatment strategies are progressing from the in vitro stage towards the clinical arena. Each of these treatments and treatment regimens are discussed along with their current progress.