Gemcitabine-based Treatment Research Articles

RRM1 expression is associated with the outcome of gemcitabine-based treatment of non-small cell lung cancer patients--a short report.

RRM1 is the large subunit of ribonucleotide reductase (RNR), which catalyzes the rate-limiting step in the production of deoxyribonucleotides (dNTPs) and is essential for DNA synthesis and repair. Through a meta-analysis of observational studies, we evaluated whether RRM1 expression levels are associated with the clinical outcome of gemcitabine-containing treatment regimens in patients with advanced non-small cell lung cancer (NSCLC). A literature search was conducted using the PubMed, Embase, Web of Science, Wanfang and Chinese National Knowledge Infrastructure databases from inception to September 2014. A meta-analysis was conducted to pool eligible studies, and pooled analyses were performed using fixed effects models. A total of 12 studies encompassing 593 NSCLC patients met our search criteria and were, therefore, included. Pooled analyses revealed that patients with low/negative RRM1 expression levels exhibited significantly higher response rates (OR: 0.35, 95% CI 0.24-0.51) and better survival rates (OR: 0.41, 95% CI 0.23-0.75) than those with high/positive RRM1 expression levels. Subgroup analyses did not reveal any significant heterogeneity in outcome regarding the RRM1 assessment methods used or the ethnicities of patient populations studied. The meta-analysis reported here indicates that RRM1 expression is associated with the response rate and overall survival rate of advanced NSCLC patients treated with gemcitabine-based chemotherapy. Additional phase III randomized trials are required to confirm our current findings.

Gemcitabine-Based Treatment in Poor-Prognosis Patients with Relapsed and Refractory Hodgkin Lymphoma and Non-Hodgkin Lymphoma--a Multicenter Polish Experience.

The treatment of patients with relapsed or refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) remains challenging. Gemcitabine is acytidine analog with awide spectrum of antitumor activity. Gemcitabine treatment is widely used to treat patients with certain solid tumors and relapsed/refractory hematological malignancies. There are several reports indicating that this compound is active in lymphoid malignancies. In patients with relapsed or refractory HL and NHL, gemcitabine has demonstrated efficacy as asingle agent and in combination with other cytostatics. The aim of the study was to analyze the efficacy and toxicity of gemcitabine-based chemotherapy in patients with relapsed or refractory lymphomas. The study evaluated 68 heavily pretreated patients with relapsed/refractory HL and NHL. The median age of the patients was 36years. All the patients received gemcitabine-based chemotherapy (gemcitabine monotherapy or gemcitabine in combination with other cytostatics). The overall response rate was 46%. Complete response was achieved by 21% of the patients and partial response by 25%. Out of those who responded to gemcitabine treatment, 26patients proceeded to autologous stem cell transplant. Toxicities connected with gemcitabine therapy occurred in 44% of the patients and included grade 3/4 neutropenia, thrombocytopenia and anemia. The results suggest that gemcitabine-based salvage chemotherapy is effective and well tolerated in patients with relapsed/refractory HL and NHL.

714P - Fixed Dose Rate Gemcitabine and S-1 Combination Therapy (Fgs) As Salvage Chemotherapy for Gemcitabine-Refractory Advanced Pancreatic Cancer

ABSTRACT Aim: No standard salvage chemotherapy regimens has been established for patients with advanced pancreatic cancer after failure of gemcitabine-based treatment. Although a phase I/II clinical trial of FGS was conducted, the number of patients enrolled was small and the efficacy and safety of FGS is still not well known. Methods: We retrospectively reviewed 67 patients who received FGS as salvage chemotherapy at our institution from March 2009 to Mach 2014. The selection criteria in this study was progressive disease under gemcitabine-based chemotherapy, ECOG performance status Results: Sixty-six patients were selected for the analysis. Twenty-two patients of them had received FGS as third line treatment. The overall responce rate was 12% and the disease control rate was 45%. The median progression-free survival time was 2.7 months and the median overall survival time was 6.0 months. The common grade 3/4 toxicities were leukopenia (11%), neutropenia (15%), diarrhea (3%), anorexia (2%) and fatigue (2%). Univariate analysis showed that performance status of >0, presence of ascites, serum carcinoembryonic antigen level of > 10 ng/ml, serum albumin level of 500 IU/L and serum C-reactive protein level of > 1.0 mg/dl were significantly associated with a poor prognosis. Multivariate analysis identified serum C-reactive protein level of > 1.0 mg/dl and serum albumin level of Conclusions: FGS as salvage chemotherapy for patients with gemcitabine-refractory advanced pancreatic cancer is marginally effective and well tolerated in a practical setting. These results suggest FGS is of value to be further investigated in a clinical trial in patients with gemcitabine-refractory pancreatic cancer. Disclosure: All authors have declared no conflicts of interest.

P0218 Metastatic pancreatic carcinoma and experience with FOLFIRINOX: A cross-sectional analysis from a developing country

Background Pancreatic cancer is the fourth leading cause of cancer-related deaths, with median survival ranging from 3 to 6 months for metastatic disease. Palliative chemotherapy has been the backbone of treatment in advanced stage disease and has evolved over time. Data pertaining to the disease is scarce from our part of the world, where treatment poses a significant challenge due to lack of resources. Methods Retrospective chart review was performed for all patients presenting with stage IV pancreatic carcinoma at a tertiary care hospital in Karachi, Pakistan between January 2008 and December 2012. Data was collected using a pre-designed, coded questionnaire that covered patient characteristics, treatment, and outcome. Findings One hundred and one patients were eligible. Mean age was 56.7 ± 12.8 years, male to female ratio was 2:1, and most patients had a good performance status. More than half of the tumours were located in the head (57%, n = 58) and almost all were adenocarcinomas (95%, n = 96). 58% (n = 59) received first-line chemotherapy, of which 49% (n = 29) received gemcitabine-based therapy and 39% (n = 23) received fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). Median progression-free survival for gemcitabine-based treatment was 2.9 months (interquartile range [IQR] 1.6–5.6), compared with 7.3 months (IQR 4.5–9.2) for FOLFIRINOX (p = 0.02). Median overall survival was 4.9 months (IQR 2.3–9.5) for first-line gemcitabine-based treatment and 10.5 months (IQR 7.0–13.2) for first-line FOLFIRINOX therapy (p = 0.002). Patients who received FOLFIRINOX had better survival across all subgroups. Inpatient admissions and dose reductions were more frequent with FOLFIRINOX, but the difference between the two regimens was not statistically significant. FOLFIRINOX was successfully administered as outpatient therapy for some patients. Interpretation FOLFIRINOX remains a suitable first-line option in patients with metastatic pancreatic cancer and good performance status, even in a resource-poor country where diagnostic and supportive-care facilities may be suboptimum and cost is a limitation.

Berbamine Enhances the Antineoplastic Activity of Gemcitabine in Pancreatic Cancer Cells by Activating Transforming Growth Factor‐β/Smad Signaling

Drug-resistance to gemcitabine chemotherapy in pancreatic cancer is still an unsolved problem. Combinations of other chemotherapy drugs with gemcitabine have been shown to increase the efficacy of gemcitabine-based treatment. In this study, the effect of berbamine on the antitumor activity of gemcitabine was evaluated in human pancreatic cancer cell lines Bxpc-3 and Panc-1, and the underlying mechanisms were explored. Our results demonstrated that berbamine exhibited a time- and dose-dependent inhibitory effect in the pancreatic cancer cell lines. Berbamine enhanced gemcitabine-induced cell growth inhibition and apoptosis in these cells. Combined treatment of berbamine and gemcitabine resulted in down-regulation of anti-apoptotic proteins (Bcl-2, Bcl-xL) and up-regulation of pro-apoptotic proteins (Bax, Bid). More importantly, berbamine treatment in combination with gemcitabine activated the transforming growth factor-β/Smad (TGF-β/Smad) signaling pathway, as a result of a decrease in Smad7 and an increase in transforming growth factor-β receptor II (TβRII) expression. Changes in downstream targets of Smad7, such as up-regulation of p21 and down-regulation of c-Myc and Cyclin D1 were also observed. Therefore, berbamine could enhance the antitumor activity of gemcitabine by inhibiting cell growth and inducing apoptosis, possibly through the regulation of the expression of apoptosis-related proteins and the activation of TGF-β/Smad signaling pathway. Our study indicates that berbamine may be a promising candidate to be used in combination with gemcitabine for pancreatic cancer treatment.

Outcome and patterns of care in advanced biliary tract carcinoma (ABC): experience from two tertiary institutions in the United Kingdom.

The ABC-02 trial has defined the standard therapy for patients with advanced biliary tract cancer (ABC); however, outcome in an unselected patient population in the UK has not been described. We aimed to investigate the outcome of a series of patients with ABC from two large UK cancer networks. We retrospectively reviewed all cases of ABC presenting to two UK cancer networks over a nine-year period. Overall survival (OS) and factors influencing OS were assessed. Four hundred and two patients were available for analysis. The median OS was 6.2 months. On univariate analysis, age ≥70 years (P = 0.047), advanced disease stage (P <0.001), gall bladder primary (P = 0.033), poor performance status (P <0.001) and lack of chemotherapy (P <0.001) were associated with worse outcome. Survival was superior in the 36.4% of patients who received palliative chemotherapy (12.5 vs 4.3 months; P <0.001). On multivariate analysis of patients who had chemotherapy, those who did not receive fluoropyrimidine-based regimens (HR = 5.12; P = 0.022) or gemcitabine-based regimens (HR = 5.01; P = 0.021) had a higher mortality, whereas the effect of platinum-containing regimens was of borderline significance (HR = 2.23; P = 0.086). Sites, age, and multi-agent regimens were not significant. This is one of the largest retrospective studies reporting outcome of palliative chemotherapy for ABC. It confirms the benefit of palliative chemotherapy in an unselected group of patients. Fluoropyrimidine-based regimens appear to be as effective as gemcitabine-based treatments.

Updated use of first-line chemotherapy for advanced pancreatic cancer: FOLFIRINOX versus gemcitabine.

6607 Background: Pancreatic cancer (PC) is the fourth leading cause of death in the United States. It is estimated that 45,220 patients will be diagnosed in 2013 and 38,460 will die (Siegel, CA Cancer J Clin 2013). Gemcitabine has long been the standard of care chemotherapy. Recent advances in treatment created a combination regimen (oxaliplatin, irinotecan, leucovorin, fluorouracil [FOLFIRINOX]) for patients with good Karnofsky performance status (PS) (Conroy, NEJM 2011). This retrospective analysis was conducted as an update to results reported at ASCO 2012 (Ginsburg Arlen, JCO 2012) to evaluate characteristics and overall survival (OS) of patients receiving FOLFIRINOX and gemcitabine-based treatments in a large outpatient community setting. This is the largest study describing FOLFIRINOX patients to date. Methods: Patients with advanced PC treated within The US Oncology Network entered into the iKnowMed (iKM) database between June 2010 and November 2012 were included. Patterns of treatment were characterized by the median age at diagnosis, sex, PS, and first-line metastatic chemotherapy prescribed. The primary endpoints of the analysis were OS and uptake of FOLFIRINOX within the network. Results: Compared to ASCO 2012 results, 1,000 additional patients were identified in iKM. Of the 1,714 total patients, 24% received FOLFIRINOX (up from 13% in 2012) and 76% gemcitabine-based therapy (87% in 2012). Increased utilization of FOLFIRINOX for patients with good PS began in June 2010. For all patients (55% male), the median age at diagnosis was 67 years and the majority (85%) had a PS of 70% or greater. The OS was significantly longer for FOLFIRINOX (9.6 mos) versus gemcitabine (6.3 mos) (p&lt;0.0001). This held true for PS of 70% or greater patient given FOLFIRINOX (9.6 mos) versus gemcitabine (7 mos) (p&lt;0.0001). Conclusions: Utilization of FOLFIRINOX has continued to expand after the publication of phase III trials. Our data in a community setting supports a survival advantage for FOLFIRINOX. Although the magnitude of benefit may be smaller in the community, we agree that FOLFIRINOX should become a standard of care for good PS patients.

Locally advanced pancreatic cancer.

Treatment of locally advanced pancreatic cancer is palliative, based on chemotherapy and according to response, chemoradiotherapy can be applied. The authors summarize three abstracts (#LBA146, #256 and #303) presented on the 2013 ASCO Gastrointestinal Cancers Symposium, which were focused on treatment of locally advanced pancreatic cancer. A discussion is presented about the different chemotherapy or chemoradiotherapy regimens, that move away from gemcitabine-based treatment, and the effort to find less toxic, but efficient therapeutic combinations.

Stage II Trial of Capecitabine Joined Together with Thalidomide in Second-Line Medicine of Progressed Pancreatic Growth

Abstract Background: To assess the viability and averageness of capecitabine joined together with thalidomide in patients with propelled pancreatic disease (APC) who have beforehand accepted gemcitabine-based treatment. Systems: what added up to 31 patients were enrolled prospectively in Shandong Tumor Hospital from May 2007 to April 2009. Capecitabine was offered to patients twice a day at a dosage of 1,250 mg/m2 for 14-days then emulated by 7-day rest. Thalidomide was controlled 100 mg/day without interference until sickness movement or event of inadmissible poisonous quality. Results: Two patients put forth fractional reaction (PR), eleven patients indicated stable ailment (SD) and eighteen patients exhibited continuous illness (PD). The average without movement survival (PFS) was 2.7 months (95% expectancy interim (CI), 2.4-3.3) and the average generally speaking survival (OS) was 6.1 months (95% CI, 5.3-6.9). In the subgroup examination, PFS had a huge distinction between the serum CA19-9 level diminishing >25% and diminishing <25%, with 3.0 months (95% CI, 2.5-3.6) and 2.5 months (95% CI, 1.8-3.2), (Log Rank=0.02), separately. Hematological poisonous quality incorporated leukocytopenia, frailty and neutropenia. Non-hematological toxicities incorporated loose bowels, skin rash, nausea/vomiting, hand-foot syndrome, weariness, discombobulation, languor and clogging. Conclusion: Capecitabine joined together with thalidomide is a generally tolerated second line regimen, in patients with APC obstinate to gemcitabine.

Use of first-line chemotherapy for advanced pancreatic cancer: FOLFIRINOX versus gemcitabine.

e16536 Background: Pancreatic cancer (PC) is the fourth leading cause of death in the United States. It is estimated that 43,920 patients will be diagnosed in 2012 and 37,390 will die (Siegel, CA Cancer J Clin, 2012). Gemcitabine has long been the standard of care chemotherapy. Recent advances in treatment options have led to the utilization of a combination regimen (oxaliplatin, irinotecan, leucovorin, fluorouracil [FOLFIRINOX]) in patients with good Karnofsky performance status (PS). This regimen was compared to single-agent gemcitabine, presented at ASCO 2010 and recently published (Conroy, NEJM, 2011). This retrospective analysis was conducted to evaluate characteristics and overall survival (OS) of patients receiving FOLFIRINOX and gemcitabine-based treatments in a large outpatient community setting. Methods: Patients with advanced PC treated within The US Oncology Network and entered into the iKnowMed (iKM) database between June 2010 and November 2011 were included. Patterns of treatment were characterized by the median age at diagnosis, sex, PS, and first-line metastatic chemotherapy prescribed. The primary endpoints of the analysis were OS and uptake of FOLFIRINOX within the network. Results: Of the 717 patients identified within the iKM database, 13% received FOLFIRINOX and 87% gemcitabine-based therapy. Increased utilization of FOLFIRINOX for patients with good PS began in June 2010. For all patients (54% male), the median age at diagnosis was 67 years and the majority of patients (89%) had a PS of 70% or greater. The OS was significantly longer for FOLFIRINOX (8.4 months) versus gemcitabine (6.4 months) (p=0.036). OS was also significantly longer for PS of 70% or greater given FOLFIRINOX (9.0 months) versus gemcitabine (6.7 months) (p=0.022). After controlling for PS, the use of gemcitabine led to a shorter OS (HR 1.4; 95% CI: 1.02-2.01). Conclusions: Utilization of FOLFIRINOX has rapidly been adopted in patients with good PS after the publication of phase III trials. Our data in a community setting supports a survival advantage for FOLFIRINOX. Although the magnitude of benefit may be smaller in the community setting, we agree that should FOLFIRINOX become a standard of care for good PS patients.

EGFR mutations as a predictive marker of cytotoxic chemotherapy

BackgroundEpidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) are important predictive markers for the response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Whether EGFR mutations can also predict the clinical outcomes in NSCLC patients receiving chemotherapy has not yet been established. MethodsWe included 217 locally advanced/metastatic NSCLC cases in our study cohort. Each patient had received platinum doublet chemotherapy as a first line treatment, and had been screened for an EGFR mutation. ResultsThe subject cohort comprised 80 EGFR wild type and 137 EGFR-mutated lung cancer patients. Gemcitabine-based and taxane-based regimens were administered in 131 (60.4%) and 86 (39.6%) cases, respectively. Among the patients with a wild type EGFR, there was no significant difference in the response rate (RR), disease control rate (DCR), or progression-free survival (PFS) between gemcitabine-based and taxane-based therapies. Among the patients with EGFR mutations, no difference in RR was observed between gemcitabine-based and taxane-based treatments. On the other hand, the DCR and PFS associated with taxane-based therapy were superior when compared with the gemcitabine-based treatments. When we analyzed patients with an EGFR exon 19 deletion, the PFS of the taxane treated cases was better than that of the gemcitabine treated cases (5.3months vs 3.7months, P=0.012). ConclusionsOur current data indicate that lung cancer patients with EGFR-mutations had longer PFS with taxane than gemcitabine when receiving a platinum-based doublet regimen. The predictive meaning of EGFR mutations for cytotoxic chemotherapy should be further investigated.

Su2031 Comparison Outcomes for Unresectable Hilar Cholangiocarcinoma Treated With Definitive Photodynamic Therapy(PDT)Combined With Gemcitabine-Based Chemotherapy and Conservative Treatment

Su2031 Comparison Outcomes for Unresectable Hilar Cholangiocarcinoma Treated With Definitive Photodynamic Therapy(PDT)Combined With Gemcitabine-Based Chemotherapy and Conservative Treatment

Inferior Survival of Advanced Pancreatic Cancer Patients Who Received Gemcitabine-Based Chemotherapy but Did Not Participate in Clinical Trials

Background: Advanced pancreatic cancer, even when treated, is highly lethal. The best choice of gemcitabine-based therapy and the prognostic factors affecting the success of treatment remain uncertain. Methods: We identified 159 of 1,475 patients with pancreatic cancer diagnosed in our institution and receiving gemcitabine-based chemotherapy between January 1995 and June 2007. Univariate and multivariate analyses were used to evaluate the prognostic significance of various clinical parameters for overall survival (OS). Results: The median survival after gemcitabine-based therapy was 5.4 months; 89.9% (n = 143) had ductal adenocarcinoma, 55.3% (n = 88) with stage IV. Gemcitabine alone was given to 60 (38%) patients, and gemcitabine with high-dose infusional fluorouracil (5-FU) with (n = 25) or without (n = 39) oxaliplatin was given to 64 (40%) patients. All regimens correlated with OS (p = 0.042) but not with the response rate (RR; p = 0.3). The overall RR was 11.1%, and all responders had a good performance status (PS). The RRs to gemcitabine with infusional 5-FU, and gemcitabine with oxaliplatin and infusional 5-FU were 5.3 and 20.8%, respectively. In a multivariate analysis, old age, advanced stage, poor PS and no enrollment in clinical trials were associated with inferior survival. Conclusions: The outcome for patients who did not participate in clinical trials, regardless of gemcitabine-based treatment, is still bleak.

Biweekly gemcitabine–paclitaxel, gemcitabine–carboplatin, or gemcitabine–cisplatin as first-line treatment in metastatic breast cancer after anthracycline failure: a phase II randomized selection trial

The primary objective of this multicenter, open-label, randomized, parallel, phase II selection trial was to compare the objective tumor response to biweekly (every 2 weeks) gemcitabine/paclitaxel, gemcitabine/carboplatin, and gemcitabine/cisplatin as first-line treatment for metastatic breast cancer. Eligible patients with stage IV disease who relapsed after anthracycline failure were randomly assigned in a 1:1:1 ratio to gemcitabine (2,500 mg/m2) plus paclitaxel 150 mg/m2 (n = 49); plus carboplatin, area under the curve = 2.5 mg/mL × min (n = 47); or plus cisplatin 50 mg/m2 (n = 51). Study therapy continued up until a maximum of 8 cycles and follow-up continued for 24 months. All patients were analyzed for efficacy and one patient was excluded from the safety analyses. The objective response was 26.5% [95% confidence interval (CI) 14.9-41.1] for gemcitabine/paclitaxel, 17.0% (95% CI 7.6-30.8) for gemcitabine/carboplatin, and 15.7% (95% CI 7.0-28.6) for gemcitabine/cisplatin. The adjusted odds ratio for tumor response was 0.33 (95% CI 0.10-1.06), P = 0.063 for gemcitabine/carboplatin versus gemcitabine/paclitaxel; 0.26 (95% CI 0.08-0.86), P = 0.027 for gemcitabine/cisplatin versus gemcitabine/paclitaxel; and 0.77 (95% CI 0.24-2.52), P = 0.671 for gemcitabine/cisplatin versus gemcitabine/carboplatin. There were no significant differences in overall survival or progression-free survival (P > 0.05). Grade 3 or 4 drug-related adverse events varied between groups and the majority of deaths (94.9%; 74/78) were related to disease progression. The gemcitabine-based treatments had comparable activity and tolerability. Similar survival characteristics and different toxicity profiles suggested that gemcitabine-platinum may be evaluated further in patients after anthracycline failure.

S-1 Monotherapy as Second-line Treatment for Advanced Pancreatic Cancer after Gemcitabine Failure

No standard salvage chemotherapy regimen has been established for patients with advanced pancreatic cancer after failure of gemcitabine-based treatment. Although a Phase II study of S-1 monotherapy was conducted in patients with gemcitabine-refractory advanced pancreatic cancer, the number of patients enrolled was small. We retrospectively reviewed 84 consecutive patients who received S-1 monotherapy as a second-line treatment after gemcitabine failure at the Shizuoka Cancer Center between May 2004 and April 2008. The selection criteria in this study were age 20-75 years, ECOG performance status <or=2 and preserved organ functions. S-1 was administered orally twice a day at a dose of 40 mg/m(2) for 28 days, followed by 14-day rest. Fifty-two patients were selected for the analysis. Out of the 47/52 patients with measurable lesions, only 2 patients (4%) showed a partial response and 15 patients (32%) showed stable disease. The median progression-free survival was 2.1 months and the median overall survival was 5.8 months, with a 1-year survival rate of 12%. The common grade 3/4 toxicities were diarrhea (8%), anorexia (6%), fatigue (6%), anemia (6%) and leucopenia (4%). S-1 monotherapy is marginally effective and well tolerated in the second-line setting in patients with gemcitabine-refractory advanced pancreatic cancer.

Quality-of-Life Assessment in Phase III Clinical Trials of Gemcitabine in Non-Small-Cell Lung Cancer

Health-related quality-of-life (QOL) endpoints in clinical trials provide decision makers with a more comprehensive picture of a specific treatment than activity-related endpoints alone. Such endpoints are increasingly being reported in cancer clinical trials. We reviewed phase III clinical trials that involved gemcitabine in the treatment of unresectable non-small-cell lung cancer. A systematic literature search was undertaken and 16 phase III clinical trials were found in which gemcitabine therapy was included in a treatment arm and QOL was an endpoint. Twelve of the 16 trials compared a gemcitabine-based treatment with a non-gemcitabine-based treatment. Not all data were reported in the trials, and the findings are mixed. However, a review of these 12 trials generally shows that gemcitabine-containing chemotherapy treatments had either no different or more favourable QOL outcomes than non-gemcitabine-containing chemotherapy treatments. Ten of the 16 trials that were reviewed had a primary endpoint or objective that was not QOL. Of these ten trials, only four concluded that one treatment arm could be therapeutically favoured over another in terms of the non-QOL primary endpoint. Two of the trials reported no difference in QOL and two reported that QOL favoured the arm that was therapeutically favoured. Many more trials will need to be conducted in order to conclude that gemcitabine-containing arms are associated with a more desirable QOL than non-gemcitabine-containing arms and that QOL necessarily favours the therapeutically favoured arm in the treatment of non-small-cell lung cancer.

Two-drug gemcitabine-based first-line treatment of elderly patients (pts) with small cell lung cancer (SCLC): The G-STEP program

7089 Background: Trials testing chemotherapy for elderly pts with SCLC are scanty. Gemcitabine (Gem) is active and well tolerated. The G-STEP program looked for optimal 2-drug combination of G with either vinorelbine (Vin), etoposide (Eto), cisplatin (Cis), or carboplatin (Car). Methods: Extended stage SCLC pts, aged &gt;70 years, PS 0–2, were eligible. Dose of G was 1,000 mg/m2, dd 1&amp;8, every 3 weeks in all the four combinations. As safety data in the elderly were already available for Gem+Vin (Vin dose 25 mg/m2, dd 1&amp;8), a two-stage minimax flexible design was applied with response as end-point: ≥13 responses/30 pts required at 1st stage, with p0=0.40, p1=0.60, α and β=0.10. For Gem+Car, Gem+Cis, Gem+Eto a phase 1–2 Bayesian design to select optimal dose was applied (Thall &amp; Russell, Biometrics, 1998), with 3 possible outcomes for each patient: “active” (response and no unacceptable toxicity [UT]), “inactive” (no response, no UT), or “toxic” (UT independently of response). A response rate [RR] ≥60% and a rate of UT ≤25% were acceptable. Dose levels to explore were: Car: AUC 3.5 / 4 / 4.5, d1; Cis: 50 / 60 / 70 mg/m2, d1; Eto: 60 / 70 / 80 mg/m2, dd 1,2,3. Results: From May 2000 to September 2005, 78 eligible pts were enrolled; median age was 74 years (42% of pts older than 75yrs). In the whole group, median progression-free survival and overall survival were 20.3 weeks (95% CI 17.6 - 24.1) and 33.7 weeks (95% CI 23.7 - 41.6), respectively. Study of Gem+Vin was closed for inactivity after 1st stage with 11 responses / 30 pts (RR 36.7%, 95% exact CI: 19.9–56.1). Gem+Eto arm was closed after 10 pts (5 inactive and 5 toxic) because too high probability (0.994) of inactivity. Gem+Cis arm was closed after 12 pts (2 active, 5 inactive, 5 toxic) because too high probability (0.988) of inactivity. With Gem+Car (December 2005: 2 pts ongoing, 24 analysed: 12 active, 6, inactive and 6 toxic), RR in the 20 pts receiving Car at AUC 3.5 was 60% (95% exact CI: 36.1–80.9). Conclusions: The combination of gemcitabine and carboplatin seems promising for future trials in elderly patients with extended SCLC. The G-STEP program was supported by GIOGER. No significant financial relationships to disclose.

Incorporating novel agents with gemcitabine-based treatment of NSCLC

First-line treatment with a two-drug combination chemotherapy regimen comprising of a platinum-based agent with a third-generation agent has been the accepted standard of care in most countries for the treatment of advanced non-small-cell lung cancer (NSCLC). Previously, the addition of a third agent to standard chemotherapy regimens has failed to improve survival in the majority of randomized trials that have been conducted. However, recent findings suggest that the addition of the novel targeted agent bevacizumab to a standard paclitaxel/carboplatin regimen significantly improves survival. The addition of novel agents to gemcitabine-based regimens is therefore a logical approach to improving the treatment of advanced NSCLC. Several trials of gemcitabine-based regimens with bevacizumab are ongoing.

A prospective randomized study of gemcitabine with doxifluridine versus paclitaxel with doxifluridine in concurrent chemoradiotherapy for locally advanced pancreatic cancer

The objective of this study was to compare the efficacy and toxicity of gemcitabine-based concurrent chemoradiotherapy (CCRT) with paclitaxel-based CCRT in patients with locally advanced pancreatic cancer. A total of 48 patients who had received no prior therapy were enrolled. The patients were treated with 4500 cGy radiation in 25 fractions over 5 weeks concomitant with gemcitabine 1000 mg/m(2)/week/intravenously (IV) and doxifluridine 600 mg/m(2)/day/by mouth (PO), or paclitaxel 50 mg/m(2)/week/IV and doxifluridine 600 mg/m(2)/day/PO. After a 4-week rest, the responses were evaluated and maintenance therapies (operation or chemotherapy) (gemcitabine 1000 mg/m(2)/week/IV and doxifluridine 600 mg/m(2)/day/PO) were conducted. The median survival was 12 months in the gemcitabine group vs. 14 months in the paclitaxel group. The response rate was 13.6% vs. 25%, and the median time to progression was 12 months vs. 12.5 months, respectively. The positive rate of the clinical benefit response was 59.1% vs. 41.7%, respectively. Toxicities were acceptable in both groups. In this trial, we demonstrated that the gemcitabine-based CCRT and the paclitaxel-based CCRT in combination of doxifluridine are clearly acceptable treatment strategy, and appear more effective than the 5 fluorouracil-based CCRT for locally advanced pancreatic cancer with comparable tolerability. Furthermore, the paclitaxel-based CCRT showed similar efficacy and toxicities to the gemcitabine-based treatment when it was combined with 5-fluorouracil.