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.     

Therapeutic strategies in neoadjuvant therapy of non-small cell lung cancer: benefits of gemcitabine

Stages of non-small cell lung cancer (NSCLC) that are potential candidates for surgical resection have been treated in several ways: surgery alone is curative in only two-thirds of cases and post-operative radiotherapy (RT) provides only weak control of advanced-stage disease. Since metastatic recurrence is due to the presence of micrometastases, chemotherapy (CT) can be envisaged, even at an early stage of the disease--first with the CT/RT induction combination, which improves survival (median survival: 15 months) and the resection rate (70%). Recent studies on neoadjuvant therapy have evaluated the usefulness of different induction CT regimens. Among these, the gemcitabine/cisplatin study protocol (GC), set up in a phase II study for patients with stage IIIA N2 NSCLC, was very effective [objective response (OR): 70.2%; median survival: 19 months] and should be promising for stages IB and II. Other studies involving platinum analogs have shown good OR rates inducing a high resection rate and a reduction in the spread to mediastinal lymph nodes. Major studies are ongoing, one of which compares GC + surgery versus surgery alone (stages IB-IIIA); the other regimen aims to evaluate GC versus paclitaxel/carboplatin as well as two induction strategies.     

Gemcitabine and urothelial tumours

Since 1985, standard chemotherapy of metastatic urothelial tumours has been based on a combination of methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC protocol). Two major lessons have been learned from the use of M-VAC, namely, clear evidence of chemo-sensitivity, and an absence of chemo-curability associated with notable toxicity. Three phase II studies using gemcitabine monotherapy have demonstrated promising efficacy with an objective response rate of 22-28%, and a satisfactory toxicity profile. Three further phase II studies have confirmed the efficacy of gemcitabine in association with cisplatine (GC protocol), with a response rate of 42-66%, of which 18-28% were complete responses. The main adverse effects were haematological, including neutropenia, or grade 3 or 4 thrombocytopenia without any symptoms of fever or significant haemorrhage. Current research with gemcitabine in the treatment of urothelial tumours is aimed at optimising administration of the GC protocol, investigating the use of gemcitabine in association with other cytotoxic agents such as taxanes, or expanding the use of this drug as adjuvant therapy. The results of a phase III study to compare the efficacy and toxicity of the M-VAC and GC protocols are eagerly awaited.     

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.     

Systemic chemotherapy in patients with advanced transitional cell carcinoma of the urothelium and impaired renal function

Cisplatin is the backbone of chemotherapeutic regimens used in the treatment of advanced transitional cell carcinoma of the urothelium. However, about 50% of patients cannot be administered cisplatin because of impaired renal functions. A review of the different approaches that have been developed in this patient population was performed through a Medline search from 1 January 1998 to 31 December 2010. Twenty-six studies including 25 phase II and one randomized phase II/III studies were analyzed. All regimens, except one, were based on gemcitabine and/or carboplatin and/or paclitaxel. Only five (20%) out of 25 phase II studies actually include homogeneous patients with an impaired renal function defined by a creatinine clearance below 60 ml/min. One hundred and eight patients with a median creatinine clearance ranging from 28 to 48 ml/min received four different chemotherapy regimens including one to four drugs. The results showed the response rates to vary from 24 to 56% and survival to range from 7 to 15 months. No standard chemotherapy can be recommended from literature data. Future randomized studies will have to solve the following questions: what is the optimal definition of cisplatin eligibility? Which platinum salt should be used? Is a platinum salt necessary? How many drugs should be delivered?     

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.     

Multi-targeted antifolate therapy roe non-small cell lung cancer and mesothelioma

Multi-targeted antifolate (MTA) is an anti-metabolite with useful activity in the treatment of non-operable patients presenting with non-small cell lung cancer. Its good efficacy and tolerability profile as first-line therapy was demonstrated in phase II studies of MTA as monotherapy. The use of MTA as second-line therapy with or without a platinum analog also provides good results. It should be observed that, in combination with cisplatin (C), docetaxel or gemcitabine (G), MTA presents synergistic efficacy: two phase II protocols have shown that the MTA/C combination as first-line therapy presented high efficacy (objective response: 39-45%) and low toxicity. These results are promising and also seem to be observed in an ongoing phase II study evaluating MTA/G. In the treatment of mesothelioma, promising activity was observed for the MTA/C combination, and this activity is under evaluation in ongoing phase II and phase III studies.     

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.     

Malignant pleural mesothelioma

PURPOSE The etiology, diagnosis, staging, and management of malignant pleural mesothelioma (MPM) are reviewed, with an emphasis on clinical trials of newer approaches to first-line, second-line, and adjuvant chemotherapy. SUMMARY: In the past decade, more effective chemotherapy regimens have been developed for patients with MPM, a rapidly progressing disease linked to a history of asbestos exposure in about 70% of cases. Patients with MPM often require multimodal treatment with surgery, radiotherapy, and adjuvant or neoadjuvant (presurgical) chemotherapy. The current standard of first-line chemotherapy for MPM is cisplatin or carboplatin in combination with pemetrexed, an antifolate compound that has been shown to increase the cytotoxic effects of platinum-based drugs. In Phase II and III clinical trials, combination therapy with pemetrexed and either cisplatin or carboplatin yielded some of the highest rates of tumor response (21-41%) and overall survival (about 12-14 months) reported to date. Dual-agent neoadjuvant chemotherapy (cisplatin plus gemcitabine or pemetrexed) followed by radical surgery with or without radiotherapy has been reported to yield median survival of up to 23-29 months in small clinical trials, but larger randomized controlled studies are needed to better define the role of neoadjuvant therapy in MPM management. Other chemotherapeutic agents that have been used against MPM, with variable results, include gemcitabine, vinorelbine, taxanes, anthracyclines, and molecular-targeted agents. CONCLUSION: Treatment approaches for MPM include surgery, radiation, and systemic chemotherapy. MPM carries a poor prognosis, but recent studies of pemetrexed and platinum analogue combination therapies have demonstrated improved response rates over other treatments.     

The addition of erlotinib to gemcitabine and cisplatin does not appear to improve median survival in metastatic pancreatic cancer

Metastatic pancreatic cancer carries a poor prognosis, with median survival on the order of several months. There is evidence that combining gemcitabine with either erlotinib or cisplatin may be superior to single agent gemcitabine in patients with good performance (PS 0–1). We retrospectively compared outcomes of patients treated with either the three drug regimen of gemcitabine, cisplatin, and erlotinib (GCE) or the doublet of gemcitabine and cisplatin (GC) in order to assess the potential benefit of erlotinib. We also evaluated the role of erlotinib among smokers and non-smokers. We retrospectively analyzed 145 patients who presented between 2006 and 2009 with previously untreated metastatic pancreatic cancer initially treated at the M.D. Anderson cancer center with either GC or GCE. Information on tumor characteristics and overall survival time (OS) was collected by medical record review. Kaplan-Meier curves were used to estimate OS. Log rank tests were used to compare OS between groups. The Cox proportional hazards regression model was used to evaluate the ability of patient prognostic variables or treatment group to predict OS. A total of 71 patients were treated with GC, while 74 were treated with GCE. Cox analyses found no significant difference in overall survival (median 5.5 vs. 8.0 months, respectively, p-value?=?0.1). Small sampling numbers may have contributed to this result. One year survival was 23 % in the GCE group and 13 % in the GC group. Patients with poor performance status (PS?=?2–3) had worse survival as compared to patients with better performance status (PS?=?0–1, p?=?0.001). As in earlier studies, patients treated with more lines of therapy tended to have better survival (p <0.0001), and CA19-9 was found to be a significant predictor for OS (p?=?0.001). No statistical evidence of a survival difference was found between smokers and non-smokers in both treatment groups (p?=?0.72). In conclusion, though there was a trend towards improved survival with the addition of erlotinib to gemcitabine and cisplatin, this does not reach statistical significance.     

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.     

New options in the treatment of non-small cell lung cancer

The options for treating non-small cell lung cancer (NSCLC) were expanded by the introduction of the taxanes. As a single agent, docetaxel produced response rates ranging from 15 to 22% in evaluable patients in the second-line setting, with median duration of responses ranging from 5.6 to 7.5 months. To confirm the results observed in the phase II studies, a phase III trial was conducted. Three-hundred and seventy-three patients with advanced NSCLC who had failed prior platinum-based chemotherapy were randomized to receive docetaxel 100 mg/m2, docetaxel 75 mg/m2 or a reference arm consisting of vinorelbine or ifosfamide. Efficacy, safety and quality of life (using the Lung Cancer Symptom Scale) were assessed. Data from this study are forthcoming and may confirm the benefits provided by the inclusion of docetaxel in the second-line treatment of NSCLC. Docetaxel is also an active single agent in the first-line setting, with response rates ranging from 24 to 38% in evaluable patients, with a median survival of 6-13 months. Based on the single-agent activity, it was logical to evaluate the efficacy of docetaxel in combination with other active agents. As such, docetaxel has been studied in with numerous other agents such as vinorelbine, gemcitabine, platinums, etc. Notably cisplatin and carboplatin has shown promising rates of response and response duration in phase II trials. These combinations have now entered randomized phase III study.     

Gemcitabine and cisplatin chemotherapy is an active combination in the treatment of platinum-resistant ovarian and peritoneal carcinoma

The treatment of recurrent ovarian cancer with the combination of gemcitabine and cisplatin chemotherapy has recently been shown to be an active regimen. But the majority of positive responses have been observed in patients considered either platinum-sensitive or who have had extended platinum-free intervals. The purpose of our study was to review our experience with this regimen in women with platinum-resistant ovarian and peritoneal carcinoma with more recent exposure to platinum. We studied twenty-two patients who had relapsed within six months of their most recent platinum-based regimen and were treated with gemcitabine (450–600 mg/m²) and cisplatin (30 mg/m²) on days 1 and 8 of a 21-day cycle. The overall response rate was 64% (95% C.I. 42–85%) with seven (32%) complete and seven (32%) partial responses. The median progression-free interval was 6.7 months for responding patients and 3.9 months for the entire study group. Median survival for responders was 15.8 months compared to 8.8 months for non-responders. Overall survival was 11.4 months. Grade 3 or 4 toxicity was encountered in 59% of treatments. We conclude from this limited review that the combination of gemcitabine and cisplatin chemotherapy is an active regimen in platinum-resistant ovarian and peritoneal carcinoma and warrants consideration in the management of patients with recurrent disease.     

Phase II study of gemcitabine in combination with cisplatin in patients with locally advanced and/or metastatic pancreatic cancer

The present phase II trial was performed to assess the efficacy and toxicity of polychemotherapy with gemcitabine and cisplatin in patients with locally advanced or metastatic carcinoma of the pancreas. Sixteen patients received six courses of an i.v. cytotoxic regimen consisting of gemcitabine (1000 mg/m2, days 1, 8 and 15) and cisplatin (35 mg/m2, days 1, 8 and 15) administered in 28-day intervals. Complete remission (CR) occurred in one patient (6%), partial remission (PR) in four patients (25%) and stable disease in seven patients (44%), whereas four patients (25%) developed progressive disease resulting in an overall response rate of 31%. Mean duration of responses (CR+PR) was 3.6 (range 0.7-8.5) months and mean time to progression was 7.4 (range 3.8-12.6) months. After a mean observation period of 11.5 months the overall survival was 9.6 months with 12 patients (75%) still being alive, which compares favorably with historical data of the administration of gemcitabine alone. The performance status improved in three (19%) and stabilized in eight (50%) out of 16 patients for 4 weeks or longer. Treatment-associated toxicity included alopecia of WHO grade III in all cases, leukopenia of WHO grades I and II in 10 patients (63%), grade III in five patients (31%), and thrombocytopenia grades I and II in four patients (25%), and grades III and IV in 10 patients (63%). We conclude that the administered dosage and schedule of gemcitabine and cisplatin in patients with locally advanced or metastatic cancer of the pancreas constitutes an active cytotoxic regimen associated with moderate toxicity.     

Combined chemotherapy with cytotoxic and targeted compounds for the management of human malignant pleural mesothelioma

Human malignant pleural mesothelioma (hMPM) is an aggressive asbestos-associated cancer, the incidence of which is increasing and which, despite progress in diagnosis and therapy, continues to have a poor prognosis. Asbestos fibers induce aberrant cell signaling, leading to proto-oncogene activation and chemoresistance. In this review, we discuss the evolution of pharmacological management of hMPM up to the most recent advances. Monotherapy with single cytotoxic drugs achieves modest objective response rates, seldom reaching 30%. However, combination regimens using novel drugs and standard molecules are showing gradually improving responses and clinical benefits. Phase II/III studies have identified pemetrexed, a multitarget folate pathway inhibitor in combination with platinum derivatives, and the cisplatin/gemcitabine association as front-line chemotherapy for hMPM. Detailed knowledge of molecular mechanisms of signal transduction and neoangiogenesis in hMPM should aid in the design and screening of other promising compounds such as more efficacious receptor tyrosine kinase inhibitors.     

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.     

Increasing-dose gemcitabine plus low-dose cisplatin in metastatic non-small cell lung cancer

Gemcitabine, a pyrimidine analog active in non-small cell lung cancer (NSCLC), is widely used with cisplatin. The potential activity of the combination has not been fully assessed: gemcitabine is not used at its maximum tolerated dose (MTD) and cisplatin shows a clearly dose-related toxicity. This trial was designed to assess the MTD and dose-limiting toxicity (DLT) of low-dose cisplatin and increasing gemcitabine dose. CHEMOTHERAPY: cisplatin 50 mg/m2 on day 1, gemcitabine starting at 1400 mg/m on days 1 and 8 every 21 days. Subsequent levels were increased by 200 mg/m2. Forty-two patients with metastatic NSCLC were enrolled (37 males; median age 61 years; squamous cell carcinoma 19 patients; performance status 2, in 13 patients; 18 patients had significant weight loss). MTD was found to be 2600 mg/m2 because of DLT in three of six patients: two neutropenic fever and one massive bleeding. Overall toxicity was generally mild consisting mainly of neutropenia. Asthenia was the most common non-hematological effect. Overall response rate was 19 out of 41 patients (46.3%) and median survival was 31 weeks. We conclude that the recommended dose for a phase II dose is gemcitabine 2400 mg/m2 days 1 and 8 as a 30-min infusion when given with cisplatin 50 mg/m2.     

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.