Pancreatic Cancer: Beyond Brca Mutations.

Pancreatic cancer is the fourth-leading cause of cancer-related deaths worldwide. The outcomes in patients with pancreatic cancer remain unsatisfactory. In the current review, we summarize the genetic and epigenetic architecture of metastatic pancreatic cancer beyond the BRCA mutations, focusing on the genetic alterations and the molecular pathology in pancreatic cancer. This review focuses on the molecular targets for the treatment of pancreatic cancer, with a correlation to future treatments. The potential approach addressed in this review may lead to the identification of a subset of patients with specific biological behaviors and treatment responses.

The Presence of Concomitant Mutations Affects the Activity of EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) Patients.

Recent findings suggest that a fraction of EGFR-mutant non-small-cell lung cancers (NSCLC) carry additional driver mutations that could potentially affect the activity of EGFR tyrosine kinase inhibitors (TKIs). We investigated the role of concomitant KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of 133 EGFR mutant patients, who received first-line therapy with EGFR TKIs between June 2008 and December 2014. Analysis of genomic DNA by Next Generation Sequencing (NGS) revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA, or MET, in 29/133 cases (21.8%). A p.T790M mutation was found in 9/133 tumour samples (6.8%). The progression free survival (PFS) of patients without other mutations was 11.3 months vs. 7 months in patients with other mutations (log-rank test univariate: p = 0.047). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status, and the presence of p.T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95% CI 1.04⁻2.58; p = 0.035). In contrast, no correlation was found between TP53 mutations and patients' outcome. These data suggest that a subgroup of EGFR mutant tumours have concomitant driver mutations that might affect the activity of first-line EGFR TKIs.

Cancer of the Liver Italian Program (CLIP) score for staging hepatocellular carcinoma.

AIM: To assess the prognostic ability of the Cancer of the Liver Italian Program (CLIP) score in patients with hepatocellular carcinoma after a longer follow up. METHODS: The updated survival data were derived from an analysis that was performed on two joined sets of data. The first set was collected retrospectively in 1995 and was used to perform an exploratory prognostic factor analysis (the CLIP-03 study), that produced the CLIP score. The second set of data was collected prospectively for the CLIP-01 randomized clinical trial. RESULTS: Out of 912 overall patients, analysis was performed on 650 patients whose records contained all informationregarding prognostic factors. The median survival of the whole group of patients was 17.7 months and the 5-year survival rate was 10.7%. The median survival of the patients was inversely proportional to the CLIP score: the higher the CLIP score the worse the survival. CONCLUSIONS: The CLIP score keeps good prognostic and discriminative abilities after a longer follow up and remains one the most useful prognostic system for hepatocellular carcinoma.

Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients.

PURPOSE: CXC chemokine receptor 4 (CXCR4) and vascular endothelial growth factor (VEGF) are implicated in the metastatic process of malignant tumors. However, no data are currently available on the biological relationship between these molecules in colorectal cancer. We studied whether CXCR4 and VEGF expression could predict relapse and evaluated in vitro the contribution of CXCR4 in promoting clonogenic growth, VEGF secretion, and intercellular adhesion molecule-1 (ICAM-1) expression of colorectal cancer cells. EXPERIMENTAL DESIGN: CXCR4 and VEGF were studied in colorectal cancer tissues and in Lovo, HT29, and SW620 colorectal cancer cell lines by immunohistochemistry. Correlations with baseline characteristics of patients and tumors were analyzed by chi2 test. VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1 expression was evaluated by flow cytometry. Clonogenic growth induced by CXCL12 was determined by clonogenic assays. Functional effects induced by CXCL12 were prevented by the administration in vitro of AMD3100, a bicyclam noncompetitive antagonist of CXCR4. RESULTS: Seventy-two patients, seen between January 2003 and January 2004, were studied. CXCR4 was absent in 16 tumors (22.2%); it was expressed in < or = 50% of cells in 25 (34.7%) tumors and in >50% of cells in 31 (43.0%) tumors. VEGF was absent in 17 (23.6%) tumors; it was expressed in < or = 50% of cells in 16 (22.2%) tumors and in >50% of cells in 39 (54.2%) tumors. There was a significant association between CXCR4 expression and lymph nodal status (P = 0.0393). There were significant associations between VEGF and tumor invasion (P = 0.0386) and lymph nodal involvement (P = 0.0044). American Joint Committee on Cancer stage (P = 0.0016), VEGF expression (P = 0.0450), CXCR4 expression (P = 0.0428), and VEGF/CXCR4 expression (P = 0.0004) had a significant prognostic value for disease-free survival with univariate analysis. The predictive ability of the American Joint Committee on Cancer stage and of the concomitant and high expression of VEGF and CXCR4 was confirmed by multivariate analysis. Prognosis is particularly unfavorable for patients whose primary tumors express CXCR4 and VEGF in >50% of cells (median disease-free survival in relapsed patients, 5.8 months; hazard ratio of relapse, 8.23; 95% confidence interval, 7.24-14.29). In clonogenic assays, CXCL12 (20 ng/mL/d) significantly increased the number of clones in SW620, HT29, and Lovo cells at 7 and 14 days. Again, CXCL12 was able to stimulate VEGF secretion in SW620, HT29, and Lovo cells as well as up-regulated ICAM-1. These effects were prevented by the administration of AMD3100 (1 micromol/L). CONCLUSIONS: We have shown that concomitant and high expression of CXCR4 and VEGF is a strong and independent predictor of early distant relapse in colorectal cancer. CXCR4 triggers a plethora of phenomena, including stimulation of clonogenic growth, induction of VEGF release, and ICAM-1 up-regulation. These data support the inhibition of CXCR4 to prevent the development of colorectal cancer metastasis.

Long-term survival in a patient with metastatic squamous cell lung carcinoma: A case report.

Non-small-cell lung cancer (NSCLC) is the most common malignancy in industrialized countries, with a 5-year survival rate of only ~15%, as the majority of the patients have advanced-stage disease at diagnosis and the treatment options are limited. Squamous cell carcinoma the second most frequent type of NSCLC and is closely associated with cigarette smoking. We herein present the case of a 72-year-old male smoker, diagnosed with stage IV squamous cell lung carcinoma, with a solitary brain metastasis. After the diagnosis, stereotactic radiotherapy was performed on the brain metastasis. Following radiotherapy, chemotherapy with carboplatin + paclitaxel was initiated. However, after 2 cycles of chemotherapy, disease progression in the lung was observed. Therefore, second-line treatment with pemetrexed was started, which was discontinued after 2 cycles due to further disease progression. Third-line treatment with erlotinib was then administered, with notable benefit, as the patient remains alive after 6 years of treatment with a good performance status. The mutation status of EGFR was unknown.

Pretreatment quality of life and functional status assessment significantly predict survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: a prognostic analysis of the multicenter Italian lung cancer in the elderly study.

PURPOSE: To study the prognostic value for overall survival of baseline assessment of functional status, comorbidity, and quality of life (QoL) in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy. PATIENTS AND METHODS: Data from 566 patients enrolled onto the phase III randomized Multicenter Italian Lung Cancer in the Elderly Study (MILES) study were analyzed. Functional status was measured as activities of daily living (ADL) and instrumental ADL (IADL). The presence of comorbidity was assessed with a checklist of 33 items; items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (EORTC QLQ-C30) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency. For IADL and QoL, three categories were defined using first and third quartiles as cut points. Comorbidity was summarized using the Charlson scale. Analysis was performed by Cox model, and stratified by treatment arm. RESULTS: Better values of baseline QoL (P = .0003) and IADL (P = .04) were significantly associated with better prognosis, whereas ADL (P = .44) and Charlson score (P = .66) had no prognostic value. Performance status 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted shorter overall survival. CONCLUSIONS: Pretreatment global QoL and IADL scores, but not ADL and comorbidity, have significant prognostic value for survival of elderly patients with advanced non-small-cell lung cancer who were treated with chemotherapy. Using these scores in clinical practice might improve prognostic prediction for treatment planning.

Second-line intra-arterial chemotherapy in advanced pancreatic adenocarcinoma.

The present study was conducted to evaluate activity and toxicity of the FLEC (folinic acid 100 mg/m2; 5-fluorouracil 1000 mg/m2; carboplatin 300 mg/m2; epirubicin 60 mg/m2) schedule as second-line treatment for progressive locally advanced or metastatic pancreatic cancer (LAMPC). FLEC was administered every 3 weeks with an angiographic catheter introduced into the tumor vascular bed. Thirty-two patients were enrolled. Twenty patients had a PS of 2. Twenty-five patients had metastatic disease to liver. Seven (21.9%) partial responses were observed (WHO criteria). Fifteen patients (46.9%) had stable disease and ten patients (31.2%) had progressive disease. The median OS from the diagnosis was 11.8 months. PS (p=0.0308) and pain (WHO scale, p=0.0222; analogic scale, p=0.0446) significantly improved after therapy. No patient discontinued treatment because of toxicity (NCI-CTC criteria). The current study shows that intraarterial chemotherapy is a good therapeutic option in second-line treatment of LAMPC.

Stop Flow in abdominal and pelvic cancer relapses.

To determinate MTD, DLT and safe doses for phase II study, a dose finding study with Mitomycin and Adriamycin Stop-Flow administration was carried out. A phase II study focused on resectability of pelvic colorectal relapses is in progress. From November 1995, 84 pts, 52 male and 32 female (94 treatments), with advanced not resectable abdominal (14 pts) or pelvic (70 pts) relapses, and resistant to previous systemic chemotherapy, were enrolled in the study. 46 pts entered the phase I-early phase II study, while subsequently 38 pts were recruited in ongoing phase II study. Safe dose were: MMC 20 mg/mq and ADM 75 mg/mq. The phase II study focused on colorectal relapses registered very promising responses: 90% pain control, 1 pCR and 26 PR / 63 (OR 43%), 8 NC (13%) 9/27 responder patients (33%) obtained a complete resectability of colorectal relapses. Stop-Flow is a safe and feasible technique very useful as a palliation treatment.

[Thrombotic thrombocytopenic purpura in patient with metastatic occult adenocarcinoma. A case report]. / Un caso di porpora trombotica trombocitopenica in paziente con adenocarcinoma metastatico.

In the past two decades, in addition to idiopathic thrombotic thrombocytopenic purpura (TTP) more cases of secondary TTP have been identified, perhaps due to an enthusiasm for cure potential with an availability of exchange-plasmapheresis. An early diagnosis is important, because the evaluation of patients with suspected thrombotic thrombocytopenic purpura is difficult since the diagnostic criteria, thrombocytopenia, microangiopathic haemolytic anemia and no other clinically apparent etiology are not specific.

[Screening of hepatocellular carcinoma: role of the alpha-fetoprotein (AFP) and ultrasonography]. / Lo screening del carcinoma epatocellulare.

Even if there are no definitive evidence that hepatocellular carcinoma (HCC) screening in high-risk groups improves survival, many physicians screen high-risk population by various strategies, alpha-fetoprotein (AFP) and liver ultrasonography are the most widely used tools. AFP sensitivity and specificity depend on the cut-off value chosen. In cirrhotic patients, using a cut-off level of 20 ng/mL, sensitivity is only around 60% and positive predictive value ranges from 9% to 50%, depending on HCC prevalence. Sensitivity and specificity are much higher (94.1% and 99.9%, respectively) in hepatitis B carriers, but positive predictive value is only 5%. The performance of ultrasonography as a screening tool varies widely depending on the experience of the examiner and the technology used. Recent studies generally indicate a 60% sensitivity or higher, a specificity greater than 90%, and a positive predictive value of 70%. Based on the estimated HCC doubling time, the recommended screening interval is 6 months, although a 1 year interval seems as effective. Currently, HCC screening with AFP only is not recommended except when ultrasonography is either not available or of poor quality. Ultrasonography seems more efficient as a screening tool. Pathology assessment of liver explants in living donor transplantation programs will provide more precise and reliable information regarding the value of AFP and ultrasonography as HCC screening tools.

The role of chemotherapy in locally advanced, metastatic and recurrent cervical cancer.

Cervical cancer is among the major health problems world-wide although advances in screening programs. Surgery and radiotherapy are the treatment modalities of choice for early and locally advanced cervical cancer. However, the role of chemotherapy in this setting has been better investigated in the latest years. To improve loco-regional control in locally advanced disease, authors have tested both neo-adjuvant chemotherapy and concurrent chemoradiotherapy. From 1999 NCI clinical announcement, concurrent cisplatin-based chemoradiation is considered the treatment of choice for cervical cancer patients requiring radiation therapy. Neo-adjuvant chemotherapy is reaching encouraging results in IB bulky-IIA cervical cancer, but further investigation are ongoing in locally advanced cervical setting. The optimal treatment for patients with metastatic or recurrent cervical cancer is still undefined and chemotherapy is used with palliation intent. Cisplatin remains the most active cytotoxic agents, although combinations of cisplatin with paclitaxel, topotecan, vinorelbine, have shown encouraging results in phase II and in early phase III studies. This paper reviews the role of chemotherapy in the management of patients with locally advanced, metastatic and recurrent cervical cancer. Studies discussed in this paper were selected trough a search in the med-line database performed in October 2003.

Transcatheter arterial procedures in the treatment of patients with hepatocellular carcinoma: a review of literature.

BACKGROUND: Transcatheter arterial procedures (TAP) have been widely used to treat hepatocellular carcinoma (HCC) in several clinical settings (advanced and neoadjuvant), and contraindications and secondary effects have been clearly described. However, it is still unclear which patients should be selected for treatment, which procedures should be used, in particular whether or not to add an antiblastic agent to embolization, and if the treatment provides a survival advantage in patient with HCC. METHODS: We conducted a Medline search for all study reports published until May 2002. Data from randomised studies were evaluated in detail. RESULTS: Data on the use of TAP for the treatment of unresectable HCC mainly come from retrospective studies that are difficult to compare because of the lack of standardized procedures. Some prognostic systems have been proposed in order to improve the selection of the patients that can benefit from treatment. While the effects in terms of tumour response are clearly documented, the results in terms of survival are still unclear. CONCLUSIONS: The real impact of TAP on survival remains to be determined in all clinical settings. The very few published prospective randomised trials are underpowered and cannot provide any definitive conclusions. Thus, there is an urgent need for prospective controlled trials in order assess the impact of TAP on survival and to compare different procedures.

Carboplatin plus vinorelbine plus G-CSF in elderly patients with extensive-stage small-cell lung cancer: a poorly tolerated regimen. Results of a multicentre phase II study.

PURPOSE AND METHODS: A multicentre phase II trial (single-stage design) was undertaken to test the activity and toxicity of carboplatin (AUC 5 according to Calvert, day 1) plus vinorelbine (25 mg/m(2) days 1 and 8) with lenograstim support, every 3 weeks in the first line treatment of elderly patients, aged 65 or more, affected by extensive small-cell lung cancer (SCLC). The primary end-point of the trial was the objective response rate. Twenty-three responses among 37 patients were considered necessary to proceed to a phase III trial. RESULTS: Twenty-eight patients were enrolled (median age 70 years). Treatment was remarkably toxic. Three patients died while on treatment. Eleven patients (39.3%, 95% exact confidence interval (CI): 21.5-59.4) had an objective response, that was complete in 2 cases. Median time to progression was 5.1 months (95% CI: 3.3-6.7). Median survival was 7.9 months (95% CI: 4.8-14.4). CONCLUSION: Carboplatin plus vinorelbine is poorly tolerated and not sufficiently active to warrant phase III comparison with standard chemotherapy regimens in elderly patients with extensive SCLC.

Pancreatic involvement from heavily pretreated small cell lung cancer successfully treated with transcatheter intra-arterial chemotherapy: a case report with local and systemic disease control.

This is a case report on pancreatic metastases from small cell lung cancer successfully treated by transcatheter arterial infusion of chemotherapy. The patient showed partial regression of pancreatic and thoracic disease. To our knowledge this is the first reported case of small cell lung cancer with pancreatic involvement treated with the transcatheter arterial infusion procedure; it represents an example of integrated treatments that may be considered for patients with pancreatic involvement from small cell lung cancer even if heavily pretreated.

CD40 activation as potential tool in malignant neoplasms.

BACKGROUND: CD40, a cell surface molecule, is expressed on B-cell malignancies and many different solid tumors. It is capable of mediating diverse biological phenomena such as the induction of apoptosis in tumors and stimulation of the immune response. It has thus been studied as a possible target for antitumor therapy. The general aim of this review is to focus the attention of clinical oncologists on the involvement of CD40 in tumors and the rationale of CD40-activation-based therapies in new, biologically oriented antitumor protocols. METHODS: A Medline review of published papers about the role of CD40 activation in cancer therapy. RESULTS: Many authors have shown that CD40 activation promotes apoptotic death of tumor cells and that the presence of the molecule on the surface of carcinoma lines is an important factor in the generation of tumor-specific T-cell responses that contribute to tumor cell elimination. The CD40 ligand (CD40L) is the natural ligand for CD40; it is expressed primarily on the surface of activated T lymphocytes. Preclinical studies suggest that CD40-CD40L interaction could be useful for cytotoxicity against CD40-expressing tumors and for immune stimulation. Tumor inhibition was observed when tumor cells were treated with agonistic anti-CD40 monoclonal antibodies or with the soluble form of CD40L. The results of the first phase I clinical trial to treat cancer patients with subcutaneous injection of recombinant human CD40L have been recently reported. Immunohistochemical studies have revealed that detection of CD40 in primary cutaneous malignant melanoma and lung cancer may have a negative prognostic value. Interestingly, up-regulation of CD40 was observed in the tumor vessels of renal carcinomas and Kaposi's sarcoma, suggesting possible involvement of CD40 in tumor angiogenesis. Recently, it has also been shown that CD40 engagement on endothelial cells induces in vitro tubule formation and expression of matrix metalloproteinases, two processes involved in the neovascularization and progression of tumors. CONCLUSIONS: CD40 activation represents an exciting target for hematological malignancies and solid tumors expressing the molecule, but its functional role in cancer development still remains unclear and controversial.

Phase I-II trial of gemcitabine-based first-line chemotherapies for small cell lung cancer in elderly patients with performance status 0-2: the G-STEP trial.

INTRODUCTION: Treatment of elderly patients with small cell lung cancer (SCLC) is based on scanty evidence. METHODS: Patients with extensive SCLC, age >70 years, and performance status 0-2 were eligible for a study looking for optimal two-drug combination of gemcitabine (Gem) with vinorelbine (Vin), etoposide (Eto), cisplatin (Cis), or carboplatin (Car). Gemcitabine dose was the same (1000 mg/m2, days 1-8) in all combinations. A two-stage minimax flexible design for response was applied to GemVin combination (Vin 25 mg/m2, days 1-8). For GemCar, GemCis, GemEto, a phase I-II Bayesian design was applied, looking for the optimal dose of the partner drugs. Objective response rate ≥ 60% and unacceptable toxicity ≤ 25% were required to define a combination worthy of further studies. RESULTS: Median age of 78 eligible patients was 74 years. GemVin produced a 36.7% objective response rate. GemEto and GemCis arms were found not sufficiently active. GemCar produced 16 responses (14 with area under the curve [AUC] 3.5 and 2 with AUC 4.0) in 26 patients (61.5%) and 6 cases of unacceptable toxicity (3 at each Car dose). CONCLUSIONS: In elderly patients with extensive SCLC, GemVin, GemEto, and GemCis are not enough active and do not merit further studies. Gem plus Car might deserve further attention.

Italian Survey on adjuvant treatment of non-small cell lung cancer (ISA).

BACKGROUND: A recent pooled analysis of randomized trials indicated significant improvement in overall survival from cisplatin-based adjuvant chemotherapy for non-small cell lung cancer (NSCLC), depending on disease stage (only in stages II and III) and PS (≤ 1). Post-operative radiotherapy (RT) is optional for pN2 tumours. PATIENTS AND METHODS: To evaluate opinions and daily clinical practice of Italian Oncologists about adjuvant treatment of NSCLC, a 46-item questionnaire was delivered via e-mail. RESULTS: Seventy-eight physicians from 68 Centers (out of 98 contacted) returned their questionnaire. Seventy-four, 86, 94, and 78% of them give the indication for adjuvant chemotherapy for stage IIA, IIB, IIIA, and IIIB disease, respectively and 14% in stage IB disease. Stage, PS, and age are taken into consideration evaluating adjuvant approach by 97, 95 and 73%, respectively. Cisplatin-vinorelbine (64%) and cisplatin-gemcitabine (33%), for 4 cycles (81%), are the preferred regimens, while 32% use different regimens. Ninety-two percent indicate RT in pN2 disease and/or positive resection margins. Real Number of patients Needed to Treat (NNT) is probably not completely known/understood and/or used by physicians. CONCLUSIONS: A substantial adherence between clinical daily practice in Italy and scientific progresses is described in this paper, even with some discordances regarding the most appropriate adjuvant chemotherapy regimen.

Prospective clinical trials of biotherapies in solid tumors: a 5-year survey.

PURPOSE: To review the content and quality of prospective clinical trials of biotherapies in solid tumors. METHODS: Data were collected from the literature between 1990 and 2002 on general study characteristics, patient and disease factors, study methodology, and factors related to completeness of reporting. Quality of phase II studies was evaluated by an ad hoc questionnaire. Descriptive statistics, contingency tables, and the chi-square test were applied. RESULTS: A total of 334 studies were selected, of which about three quarters were multicenter, with 42.5% reporting phase I, 42.2% phase II or I/II, and 11.9% phase III or II/III studies. Only 13.7% were randomized, and a study design emphasizing statistical analysis was lacking in as many as one third. The assessment of biological endpoints was stated as the primary or secondary goal in half of these studies. Melanoma (17.1%), renal carcinoma (11.1%), gastrointestinal neoplasms (11.1%), and lymphomas (6.3%) were the most studied diseases. Immunotherapies accounted for 182 studies; the remaining 152 reported other biotherapies. Patients with (1) advanced disease (P = 0.003), (2) heavily pretreated neoplasms (P < 0.0001), (3) poor performance status (PS < 2) (P < 0.0001), were more frequently enrolled in studies of biotherapy. Biotherapies were less frequently evaluated in phase III studies (7/152) compared with immunotherapies (33/182) (P < 0.0001). A statistical study design was more frequently identified in biotherapy trials (127/152) compared with immunotherapy trials (98/182) (P < 0.0001). Biological endpoints were less frequently evaluated in phase III studies in both biotherapies (100% no vs 0% yes) and immunotherapies (81.8% no vs 18.2% yes) (P = 0.01, for biotherapies; P < 0.0001, for immunotherapies). Phase I immunotherapy studies more frequently applied biological or molecular criteria for patient selection (41.1%) than phase II (29.3%) and III (3.1%) studies (P < 0.0001). CONCLUSIONS: The very wide diversity in modalities of conducting and reporting clinical trials of biotherapies of solid tumors and the presence of some methodological pitfalls suggest that the methodological standards for conducting and publishing clinical trials in biotherapies should be improved to enhance the reliability of the body of published data.

Individualized chemotherapy for elderly patients with nonsmall cell lung cancer.

Approximately one third of all patients with nonsmall cell lung cancer (NSCLC) are over the age of seventy. Elderly patients tolerate chemotherapy poorly because of impaired organ function and comorbidities. For this reason, these patients are often not considered eligible for aggressive cisplatin-based chemotherapy. A multidimensional geriatric evaluation is important to plan appropriate treatments. At present, there are no indications for adjuvant and neoadjuvant chemotherapy. Combined chemoradiotherapy in locally advanced disease increases toxicity and seems determine no survival advantage as compared with radiation therapy alone. In advanced disease, single-agent vinorelbine proves to be active and well-tolerated, and compared with best supportive care, improves survival and perhaps quality of life. Gemcitabine is active and also well tolerated. Taxanes are in advanced phase of evaluation. A phase III randomized trial showed that polychemotherapy with gemcitabine and vinorelbine does not improve any outcome as compared with single-agent chemotherapy with vinorelbine or gemcitabine. In clinical practice, single-agent chemotherapy should remain the standard treatment. The choice of the drug should be based on the toxicity profile of each drug and type of comorbid conditions. In the near future, new therapeutic strategies and biologic agents could improve present results.