[show abstract][hide abstract] ABSTRACT: Platinum agents such as cisplatin and carboplatin are DNA-damaging agents with activity in breast cancer (BC), particularly in the triple negative (TN) subgroup. The utility of platinum agents, in addition to standard neoadjuvant chemotherapy (NAC), is controversial. To assess the activity of platinum agents in patients with TNBC treated with NAC, we performed a systematic review and meta-analysis of all published studies. A search of PubMed, EMBASE, the Web of Science, SCOPUS, and the Cochrane Central Register of Controlled Trials was performed to identify studies that investigated platinum-based NAC in patients with TNBC. Random effect models were adopted to estimate the summary risk ratio (RR), and the publication bias was evaluated using a funnel plot and Egger's regression asymmetry test. The primary endpoints were the pooled rate of the pathologic complete response (pCR) and the RR to obtain a pCR in patients treated versus not treated with NAC containing platinum agents. 28 studies were included (six randomized controlled trials and 22 retrospective or prospective studies) for a total of 1,598 TNBC patients. Overall, the pooled rate of pCR in patients treated with platinum-based NAC was 45 %. In randomized trials, NAC containing cisplatin or carboplatin significantly increased the rate of pCR compared with nonplatinum agents (RR = 1.45, 95 % CI 1.25-1.68; P < 0.0001). Compared with non-TN, TNBCs were associated with a threefold increase in the pCR rate when treated with platinum-based NAC (RR 3.32, 95 % CI 2.39-4.61; P < 0.0001). In conclusion, pCR rates increase significantly with the addition of cisplatin or carboplatin in TNBC compared with NAC containing no platinum drugs. TN status is a predictor of benefit from platinum-based NAC.
Breast Cancer Research and Treatment 02/2014; · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background
Gemcitabine monotherapy is the cornerstone of treatment for advanced pancreatic cancer. To date, no clear survival benefit has been found when combination chemotherapy has been compared with gemcitabine alone, except in a few studies. This meta-analysis compared the efficacy of polychemotherapy with gemcitabine alone in advanced pancreatic cancer.
Randomised trials comparing combination chemotherapy with gemcitabine alone were identified through electronic searches of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials. Overall survival, reported as the hazard ratio at the 95% confidence interval, was the primary outcome measure.
29 trials (19 phase III and 10 small randomised trials) that included 8421 patients were identified. Overall, polychemotherapy significantly improved overall survival (hazard ratio = 0.87; 95% CI, 0.81–0.93; P < 0.0001), progression-free survival (hazard ratio = 0.77; 95% CI, 0.70–0.84; P < 0.00001), and response rate (risk ratio = 1.71; 95% CI, 1.42–2.07; P < 0.00001) compared with gemcitabine alone.
Compared with gemcitabine monotherapy, combinations of two or more drugs (particularly those with novel agents or associated with >20% response rates and triplets) improved outcomes and response rate in advanced pancreatic cancer, and they could be considered a new standard of care in advanced settings.
Digestive and Liver Disease 01/2014; · 3.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: The significance of KRAS in advanced colorectal cancer (CRC) treated with bevacizumab (B) is not well understood. We conducted a systematic review and pooled analysis of published trials with the aim to assess the predictive and prognostic role of KRAS status in patients treated with B. We performed a systematic search of PubMed, EMBASE, Web of Science, and Cochrane Register of Controlled Trials. The primary endpoints included objective response rate (RR), progression-free survival (PFS), and overall survival (OS). The odds ratio (OR) for RR and hazard ratios (HRs) were calculated or extracted by published data either using a fixed effect model or a random effect model. A total of 12 studies were included. A total of 2,266 patients were analysed (54 % were KRAS wt). The pooled RRs for KRAS wild-type (wt) versus mutated (mut) patients were 54.8 and 48.3 %, respectively (OR 1.42, P = 0.02). Median PFS was significantly longer in KRAS wt patients compared with that in KRAS mut patients (HR = 0.85; 95 % confidence interval (CI) 0.74-0.98; P = 0.02). Similarly, median OS was significantly better in wt KRAS patients compared with that in mut KRAS patients (HR = 0.65; 95 % CI 0.46-0.92; P = 0.01). This pooled analysis of 12 published studies shows that KRAS wt status is a good prognostic factor for B-based chemotherapy. Also, KRAS wt CRC is associated with a better RR with B plus chemotherapy than mut counterpart.
Medical Oncology 09/2013; 30(3):650. · 2.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: The sole agents pemetrexed (PEM), docetaxel and anti-EGFR agents are approved second-line therapies for non-small cell lung cancer (NSCLC) after failure with cisplatin-based doublets. The potential usefulness of platinum-based doublets as rechallenge for second-line chemotherapy has not yet been established.
Studies that enrolled NSCLC platinum pre-treated patients were identified using electronic databases (MEDLINE and EMBASE). Pemetrexed and taxanes (TAXs)-based platinum combinations were considered. A systematic review was conducted using Comprehensive Meta-Analysis (version 2.2.064) software to calculate the event rate of response and 95% confidence interval. Median weighted progression-free survival (PFS) and overall survival (OS) time for PEM and TAXs-based doublets were compared by two-sided Student's t test. We tested for significant heterogeneity by Cochran's chi-square test and I(2) index.
Eleven studies published between 1999 and 2012 were included in this analysis with a total of 607 patients enrolled; 468 were treated with PEM-doublets and 139 with TAXs-doublets. The overall response rate was 27.5% with a higher response rate of 37.8% (range, 29.7-46.7%) for TAXs-based treatment vs. 22% (range, 13.4-34.1%) for PEM-based combinations; (p<0.0001). Median PFS and OS were 3.9 and 8.7 months with weighted PFS of 3.9 vs. 5.3 months (p<0.0001) and similar OS for PEM vs. TAXs-based doublets.
With the limitations of small and not randomised trials included, this pooled analysis shows that NSCLC patients who relapsed after a first-line platinum-based chemotherapy obtain a tumour response of 27% from a platinum rechallenge containing PEM or TAXs. Response rate and median PFS appear better with TAXs-than with PEM-doublets.
Lung cancer (Amsterdam, Netherlands) 07/2013; · 3.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Five years of adjuvant hormonal therapy is the standard of care in early breast cancer (BC) expressing oestrogen receptors (ER+). Prolonged duration of adjuvant endocrine therapy is implemented to prevent recurrence and death; in particular, its carryover effect may prevent very late events. This meta-analysis compares the efficacy of 5 years of hormonal therapy alone with that of additional years of hormonal therapy, in patients with early BC. Randomised trials comparing 5 years versus more than 5 years of hormonal therapy in BC were identified by electronic searches of PubMed, EMBASE, ISI Web of Science and the Cochrane Central Register of Controlled Trials. Meta-analysis was performed using the fixed- or random-effects models. The primary endpoints were overall survival (OS), BC-specific survival (BCSS) and relapse-free survival (RFS) reported as odds ratios (ORs) and 95 % confidence interval (CI). Eight trials, including 29,138 patients, were identified. Overall, in ER+ BCs, extended endocrine therapy beyond 5 years of tamoxifen significantly improved OS (OR, 0.89; 95 % CI 0.80-0.99; P = 0.03), BCSS (OR, 0.78; 95 % CI 0.69-0.9; P = 0.0003) and RFS (OR 0.72; 95 % CI 0.56-0.92; P = 0.01) compared with 5 years of hormonal therapy alone. Loco-regional and distant relapses were reduced by 36 and 13 %, respectively. Compared with 5 years of tamoxifen, additional adjuvant endocrine therapy reduced risk of death and relapse of ER+ BC by ~10 and 30 %, respectively. This strategy should be considered in patients free of disease after 5 years of hormonal therapy.
Breast Cancer Research and Treatment 07/2013; · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Introduction: Cetuximab and irinotecan are effective agents in advanced colorectal cancer (CRC) after either irinotecanor oxaliplatin-based first-line chemotherapy. Here, the efficacy of this combination in patients with the KRAS wild-type gene as second- or further-line therapy is reviewed and data are collected in a pooled analysis. Methods: Studies that enrolled pretreated CRC patients for second-line therapy or beyond were identified using electronic databases (PubMed and EMBASE). A systematic analysis was conducted using Comprehensive Meta Analysis (versión 2.2.064) to calculate the event rate of response and the 95% confidence interval. The weighted median overall survival (OS) and progression-free survival (PFS) were also calculated with NCSS 2007 software. We tested for significant heterogeneity using Cochran's chi-square test and the I2 index. Results: Twenty-five studies published between 2007 and 2012 were eligible for this analysis, with a total of 1,712 KRAS wild-type patients enrolled. The overall response rate was 31.9% with similar response rates of 28.7% for second-line treatment and 31.1% for third or further lines. The overall weighted median OS and PFS were 12.5 and 6 months with a weighted OS of 11.56 and 12.2 months for second- and further-line CRC settings, respectively.
In metastatic KRAS wild-type CRC patients pretreated with one or more lines of therapy, cetuximab plus irinotecan-based chemotherapy is an active treatment. Response rates and survival outcomes appear similar in second-line therapy or beyond.
[show abstract][hide abstract] ABSTRACT: Neoadjuvant chemotherapy before radical cystectomy (RC) is the preferred initial option for muscle-invasive bladder cancer (BCa). As in rectal and breast cancer, pathologic downstaging is associated with increased overall survival (OS).
We conducted a meta-analysis to determine whether pathologic complete response (pCR) (pT0N0M0) after neoadjuvant chemotherapy is associated with a better outcome in muscle-invasive BCa.
A systematic search was conducted in PubMed, Web of Science, Cochrane Collaboration's Central register of controlled trials, and Embase for publications reporting outcomes of patients with and without pCR. All patients underwent neoadjuvant cisplatin-based polychemotherapy and RC. The primary outcome reported as relative risk (RR) was OS. Secondary end points were recurrence-free survival (RFS) and cancer-specific survival other than distant and locoregional RFS. A meta-analysis was performed using the fixed effects model or random effects model. Overall heterogeneity for RFS and OS was assessed with forest plots and the Q test.
A total of 13 trials were included, for a total of 886 patients analysed after neoadjuvant chemotherapy and RC, without any postoperative treatment. The pCR rate was 28.6%. Patients who achieved pCR in the primary tumour and the lymph nodes presented an RR for OS of 0.45 (95% confidence interval [CI], 0.36-0.56; p<0.00001). The number needed to treat to prevent 1 death was 3.7 (absolute risk difference: -26%). The summary RR for RFS was 0.19 (95% CI, 0.09-0.39; p<0.00001).
Patients with BCa who achieved pCR (pT0N0M0 stage) after neoadjuvant chemotherapy have a better OS and RFS than do patients without pCR.
[show abstract][hide abstract] ABSTRACT: Irinotecan and infusional bolus 5-fluorouracil (5-FU)-based chemotherapy (FOLFIRI [5-fluorouracil, folinic acid, irinotecan]) + bevacizumab (FOLFIRI-B) is 1 of the cornerstones of first-line treatment of advanced colorectal cancer (CRC). However, bevacizumab was approved for use after the AVF2107 trial that included a bolus 5-FU schedule (IFL [irinotecan + 5-FU + leucovorin]). No randomized trials have been published comparing FOLFIRI and FOLFIRI-B. The aim of this review is to pool all published data on the activity and efficacy of FOLFIRI-B as first-line therapy in treating advanced CRC in prospective and retrospective studies. We performed a systematic review, through PubMed and EMBASE, of all prospective and retrospective published studies exploring the efficacy of FOLFIRI-B as first-line chemotherapy in patients with advanced CRC. Pooled estimates of the response rate (RR) and weighted median of progression-free survival (PFS) and overall survival (OS) from all FOLFIRI-B-related studies were calculated. Rates of metastasectomy and bevacizumab-related severe toxicities were reported. A total of 29 studies (8 randomized controlled trials, 1 phase IV trial, 2 phase II trials, 4 observational studies, 4 prospective nonrandomized cohort studies, and 10 retrospective case series) were retrieved for a total of 3502 patients. Overall, the pooled RR (n = 22 publications) was 51.4%. Median PFS and OS (n = 25 and 20 publications) were 10.8 months (95% confidence interval [CI], 8.9-12.8) and 23.7 months (95% CI, 18.1-31.6), respectively. The pooled rate of surgical resection of metastases (any site of surgery: n = 7 publications) was 9.3% (range, 3.6%-24%), and rate of liver resections (liver surgery only: n = 7 publications) was 18% (range 8%-25%). Grade 3-4 bevacizumab-related toxicities were also comparable with larger phase III trials. FOLFIRI-B is used worldwide as upfront treatment for stage IV CRC. This indication is confirmed by robust data about RR, PFS, and survival obtained, which this pooled analysis of 29 trials also found. FOLFIRI-B remains 1 of the referent combinations when bevacizumab is considered as first-line therapy.
Clinical Colorectal Cancer 06/2013; · 1.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: Irinotecan and infusional 5-fluorouracil-based chemotherapy (FOLFIRI) plus bevacizumab (FOLFIRI-B) is one of the most effective treatments of advanced colorectal cancer (CRC). However, this schedule is regarded more extensively as first-line therapy and its efficacy has not been proven in phase III randomised trials in oxaliplatin-pretreated patients. We have performed a systematic review through PubMed and EMBASE, including all prospective and retrospective publications exploring the efficacy of FOLFIRI-B as second-line chemotherapy in advanced CRC patients pretreated with oxaliplatin and not with B. Pooled estimates of the response rates (RR), weighted medians of progression-free survival (PFS), and overall survival (OS) from all FOLFIRI-B-containing arms were calculated. A total of 11 studies (one randomised phase II trial, two phase II trials, two observational studies, two prospective non-randomised collections, and four retrospective case series) were retrieved giving a total of 435 patients. Overall, the pooled RR (n = 11 publications) was 26 %. Median PFS and OS (n = 11 and 10 publications, respectively) were 8.3 and 17.2 months. FOLFIRI-B is a reasonable and effective option for stage IV CRC pretreated with oxaliplatin and not exposed to B during first-line treatment. Its activity seems better than historical FOLFIRI-based second-line trials.
Medical Oncology 03/2013; 30(1):486. · 2.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cisplatin-based chemotherapy is frequently used to treat advanced gastric cancer (GC). Although it leads to increased overall survival (OS) when added to single agents or chemotherapy doublets, toxicity is also generally increased. The purpose of this meta-analysis study was to compare the efficacy of fchemotherapy with and without cisplatin in patients with advanced GC.
Randomised trials that compared first-line cisplatin-based chemotherapy with regimens in which cisplatin was replaced by other agents were identified by electronic searches of PubMed, EMBASE, the Web of Science, and the Cochrane Central Register of Controlled Trials. Meta-analysis was performed using a fixed or random effects model. OS, reported as a hazard ratio (HR) and a 95% confidence interval (CI), was the primary outcome measure.
Fourteen trials (5 phase III and 9 phase II), including 2,981 patients, were identified. Overall, chemotherapy regimens without cisplatin significantly improved OS (HR, 0.79; 95% CI, 0.68-0.92; p = 0.003), progression-free survival (PFS) (HR, 0.77; 95% CI, 0.66-0.90; p = 0.001), and response rate (RR) (OR, 1.25; p = 0.004) when compared to cisplatin-containing regimens. A subgroup analysis according to histology, site of the primary tumour and extent of disease was not possible due to lack of data.
Compared with cisplatin-based doublets and triplets, combinations in which cisplatin was replaced by new drugs improved outcome and RRs in randomised trials for advanced GC and therefore should be strongly considered in the metastatic setting. A limitation of this meta-analysis is that we cannot identify a subgroup of patients (according to histology, site of primary tumour or burden of metastatic disease) which could derive greater benefit from cisplatin-free chemotherapy.
PLoS ONE 01/2013; 8(12):e83022. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: The only approved agents for second-line therapy in unselected non-small-cell lung cancer are docetaxel and pemetrexed (chemotherapies) and erlotinib (targeted therapies). Several new molecular drugs have now entered clinical trials and are being compared with approved agents (e.g., vandetanib). Alternative pathways are also being explored to overcome resistance to established agents (c-MET and ALK inhibitors), and predictive factors are now crucial for the selection of drug and of patients (e.g., EGFR mutations). Better patient selection permits second-line treatment to be tailored according to disease identity, which confers a particular benefit in certain subgroups of patients. In this review, the authors examine existing trials comparing targeted therapies with the standard of care as second-line therapy for advanced non-small-cell lung cancer.
[show abstract][hide abstract] ABSTRACT: INTRODUCTION: The typical class side effect of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (panitumumab and cetuximab) is a cutaneous maculopapular rash, although hypomagnesemia is also described to be a frequent adverse event. The purpose of our meta-analysis is to evaluate the frequency and the relative risk of hypomagnesemia in patients treated with cetuximab or panitumumab in randomized trials. AREA COVERED: Eligible studies included prospective randomized Phase III controlled trials in which cetuximab or panitumumab were compared with standard anti-neoplastic therapy or best supportive care. Summary incidence rates and relative risks with 95% confidence intervals were calculated. EXPERT OPINION: The overall incidence of hypomagnesemia was 17% among the patients who received the treatment, whose risk of developing hypomagnesemia turned out to be significantly increased compared with the patients treated with control medication, with an overall relative risk of 5.83 (p < 0.00001), where 3.87 refers to cetuximab and 12.55 to panitumumab. The addition of anti-EGFR monoclonal antibodies to standard anticancer therapy showed a significantly increased risk of hypomagnesemia compared with controls. The risk seems to be even higher for panitumumab, probably correlated with the increased risk of other adverse events (e.g., diarrhea and dehydration). Hypomagnesemia does not seem to be linked with any serious complications.
Expert Opinion on Drug Safety 08/2011; 11 Suppl 1:S9-19. · 2.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Malignant ascites is defined as a condition in which fluid containing cancer cells accumulates in the abdomen. The cancers most commonly associated to ascites are ovarian (37%), pancreato-biliary (21%), gastric (18%), oesophageal (4%), colorectal (4%), and breast (3%). Treatment of malignant ascites remains a challenge. In the majority of patients systemic chemotherapy is ineffective and diuretics and paracentesis are still the only approaches, but new promising option are appearing, as cytoreductive debulking surgery and intraperitoneal (IP) or intravenous biological (target) therapies. More promising, after the recognition of potential epithelial targets as Epithelial Cell Adhesion Molecule (EpCAM), are the trifunctional antibodies able to bind these cell adhesion molecules and, at the same, time the immune system cells. These agents have been developed for malignant ascites with the aim also to prolong the need for subsequent paracentesis. So patients with malignant ascites may look at the future with hope and growing optimism.
Critical reviews in oncology/hematology 08/2011; 79(2):144-53. · 5.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: As of today, advanced non-small cell lung cancer is still an incurable disease. However, recent researches on the biology of adenocarcinoma have led to considerable progress in the treatment of this subgroup of patients. The administration of bevacizumab and pemetrexed as first-line therapy, erlotinib in the maintenance phase and erlotinib again combined with vandetanib as second-line therapy, gives patients with lung adenocarcinoma new hope. In particular, in metastatic adenocarcinoma with an EML4-ALK fusion oncogene, crizotinib (a selective, ATP-competitive, small molecule, orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases), led to a response rate of 64%, which is similar to the results achieved in chronic myeloid leukemia and GIST with imatinib. Overall, the application of all available active therapies during the natural history of adenocarcinoma may lead to a survival benefit that was unimaginable only a few years ago. This article reviews the main studies on molecular targeted therapies in various lines of treatment of advanced lung adenocarcinoma.
Current Medicinal Chemistry 03/2011; 18(11):1640-50. · 4.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Anti-epidermal growth factor receptor monoclonal antibodies (panitumumab [P] and cetuximab [C]) are approved and effective only in KRAS wild-type patients with advanced colorectal cancer. The purpose of our meta-analysis is to evaluate the real effects of C and P in KRAS wild-type patients treated in randomized trials.
Eligible studies included prospective, randomized, and controlled trials in which either C or P had been added to standard antineoplastic therapy or best supportive care and data for KRAS wild-type patients only had been calculated. Six thousand three hundred ninety-five patients' tumor samples have been analyzed (total wild-type n = 3,254; experimental arm n = 1,608; control arm n = 1,646). Relative risks (RRs) with 95% confidence intervals (CIs) for response rate were calculated, as well as hazard ratios (HRs)for progression-free survival (PFS) and overall survival.
The overall RR of response rate is 1.69 (p = 0.003) in all trials. The overall HRs for PFS and survival are 0.65 (p = 0.0006) and 0.84 (p = 0.03), respectively, and both are significant. The HRs for PFS and survival in C trials are 0.64 and 0.79, respectively, and 0.65 and 0.87, respectively, in P trials, although only the results achieved in P trials are significant (p = 0.0007 and p = 0.03). Both response rate (RR = 10.94) and PFS (HR = 0.51) have increased more in pretreated patients than in first-line trials.
The addition of anti-EGFR monoclonal antibodies to standard anticancer therapy in KRAS wild-type colorectal cancer showed an overall significantly increased risk of objective response rate and increased progression-free and overall survival. Only the results achieved in P randomized trials are significant, and the strongest results have been achieved in pretreated patients.
International Journal of Colorectal Disease 02/2011; 26(7):823-33. · 2.24 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this meta analysis was to evaluate the benefit of adding concomitant trastuzumab to neoadjuvant(anthracycline and taxane-based) chemotherapy, which was assessed based on two published randomized controlled trials. The eligible patients were randomized to receive either neoadjuvant chemotherapy alone or with concurrent administration of trastuzumab. Relative risks(RRs) with 95% confidence intervals of pathologically complete response in breast and nodes, relapse-free survival, overall survival, and cardiotoxicity were calculated.The RR of obtaining a pathologically complete response in breast and nodes was 2.07 in the experimental arms(1.41–3.03; P = 0.0002; P for heterogeneity 0.63; fixed effect model). The RR of being disease free was 0.67 in favor of the experimental arms (0.48–0.94; P = 0.02; P for heterogeneity 0.22; fixed affect model). The RR of being alive was 0.67 in favor of the experimental arms (0.39–1.15;P= 0.15). The RR of a cardiac event was 1.09 in the arms treated with chemotherapy and concomitant trastuzumab, but that is not significant (0.6–1.98; P =0.77). The addition of concomitant trastuzumab to neoadjuvant chemotherapy doubles the risk of obtaining a pathologically complete response in both breast and nodes compared with controls. Trastuzumab significantly reduces the risk of relapse and does not increase the risk of cardiotoxicity,despite being associated with anthracyclines. The largest benefit was observed in a locally advanced patient study.
[show abstract][hide abstract] ABSTRACT: A 57-year-old woman presented with metastatic renal cell carcinoma (RCC). She was enrolled in a clinical study, in which she received two cycles of neoadjuvant sunitinib therapy followed by cytoreductive nephrectomy. Her primary tumor and rib metastasis showed a good response to neoadjuvant therapy; however, after surgery, the patient developed neurologic symptoms, including flaccid paraparesis with paresthesia and hypoesthesia. MRI of the brain and spine revealed a leptomeningeal lesion at the T12-L1 space, which was presumed to have progressed during the 3-week treatment-free perioperative period. The patient underwent radiation therapy for the intramedullary lesion 1 month later, and sunitinib therapy was subsequently reinstated. After 6 months, her extracranial lesions remained stable and the intramedullary lesion was undetectable on MRI.
CT of the chest and abdomen, bone scan, kidney and liver function tests, measurement of serum levels of calcium, electrolytes and lactate dehydrogenase, CBC, MRI of the brain and spine.
Progression of a central nervous system metastasis linked to the interruption of neoadjuvant sunitinib therapy.
Neoadjuvant sunitinib therapy followed by cytoreductive nephrectomy for the primary RCC; radiation therapy for the intramedullary lesion, followed by reinstatement of sunitinib therapy owing to a good clinical response observed in the extracranial lesions.
[show abstract][hide abstract] ABSTRACT: Advanced pancreatic cancer is usually treated with first-line gemcitabine (GEM) (alone or in combination). More recently, GEM has become an established part of an adjuvant therapy based on two recently-reported randomized trials. There remains unresolved the problem of second-line therapy in patients relapsed during or after adjuvant or first-line GEM-based treatment. As of today, platinum analogues in combination with fluoropyrimidine or with GEM represent the most common schedule in clinical practice with data from single-centre or multicentric phase II studies. In 2008, for the first time, a randomized phase III trial conducted on good performance status GEM-refractory patients (CONKO 003) confirmed their benefit in progression-free and overall survival by adding oxaliplatin to a bolus 5-FU/folinic acid schedule. Other agents (irinotecan, taxanes, antifolates, biological) have been tested, although only dismal results have been achieved, as they turned out to be too toxic in combination and to have too low activity when used as single agents. Which the optimal candidate is for second-line therapies, is debatable. Good performance status and discrete progression-free survival since the beginning of the GEM therapy (more than 6 months?) are likely to be the best indicators of subsequent line benefit. The benefit of biological agents is unknown, also given the poor results achieved in the first-line treatment. In summary, as of today, there is one randomized study that confirms the benefit of second-line chemotherapy for the treatment of GEM-relapsed pancreatic cancer. Current data indicate 5-FU plus a platinum agent (oxaliplatin) as the standard of care for PS 0-1 patients. Ongoing clinical trials will clarify whether there is obviously a place for improvement and for other agents. At present, even though no data on benefits in unfit patients (Karnofsky < 70) are available, a fluopyrimidine agent still remains a reasonable treatment option.