Alain Gelibter

Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma

Cyclooxygenase‐2 (COX‐2) is up‐regulated frequently and may constitute a promising therapeutic target in patients with pancreatic ductal adenocarcinoma (PDAC).

Gemcitabine-based combinations for inoperable pancreatic cancer: have we made real progress? : A meta-analysis of 20 phase 3 trials

Several attempts have been made at improving the efficacy of gemcitabine in advanced pancreatic cancer by combining it with other chemotherapeutic or molecularly targeted agents. However, randomized trials have produced conflicting results.

Outcome of advanced NSCLC patients harboring sensitizing EGFR mutations randomized to EGFR tyrosine kinase inhibitors or chemotherapy as first-line treatment: a meta-analysis

BACKGROUND Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are effective as first-line treatment of advanced non-small-cell lung cancer patients with EGFR mutations (EGFR-M+). PATIENTS AND METHODS We conducted a literature-based meta-analysis to quantify the magnitude of benefit with upfront EGFR TKI in EGFR-M+ patients. Meta-regression and sensitivity analyses were also carried out to identify additional predictors of outcome and to assess the influence of trial design. RESULTS Five trials (805 patients) were identified (three trials prospectively enrolling EGFR-M+ patients and two retrospective analyses of EGFR-M+ patients). TKI significantly increased progression-free survival (PFS) [hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.36-0.58, P < 0.0001] and overall response rate (ORR) (HR 2.08, 95% CI 1.75-2.46, P < 0.0001)] over chemotherapy, while significantly decreasing neutropenia. No significant difference was observed in overall survival. The rate of exon-19 mutations, female gender, and nonsmoking status were identified as additional predictors of outcome at meta-regression analysis. A significant interaction with trial design was found for both PFS (P = 0.028) and ORR (P = 0.008), suggesting a larger advantage for patients treated within prospective trials. CONCLUSIONS In EGFR-M+ patients, first-line TKI increase both PFS and ORR by ~25%, while significantly decreasing toxicity. The role of additional predictive factors and the influence of trial design on the magnitude of the observed benefit warrant further investigation.

Emerging pathways and future targets for the molecular therapy of pancreatic cancer

Introduction: Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing. Areas covered: This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-β, IGF, Hedgehog, Notch and NF-κB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer. Expert opinion: Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine–targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer.

Capecitabine and Celecoxib as Second-Line Treatment of Advanced Pancreatic and Biliary Tract Cancers

Objective: An increasing number of patients with advanced pancreatic or biliary tract cancer who progress after a gemcitabine-containing regimen are candidates for further chemotherapy. We therefore evaluated a fully oral regimen of capecitabine and celecoxib (CapCel) as second-line treatment in these patients. Methods: Thirty-five patients with documented progressive disease after first-line treatment were enrolled. Capecitabine was administered at a dose of 1,000 mg/m2 b.i.d. for 2 consecutive weeks followed by 1 week of rest; celecoxib was given continuously at 200 mg b.i.d. Progression-free survival at 3 months was the primary study endpoint. Results: The CapCel combination was associated with an overall response rate of 9% and median survival duration of 19 weeks. Sixty percent of patients were free from progression 3 months after the start of treatment. Multivariate analysis identified a positive clinical benefit response and a decline in CA 19.9 serum levels >25% compared with baseline levels as independent predictors of prolonged survival. The treatment protocol was well tolerated with negligible hematological toxicity. The most common grade 3 non-hematological toxicities were hypertransaminasemia, diarrhea and asthenia. Conclusions: The CapCel combination is a safe treatment option with moderate activity in patients with pancreatic/biliary tract cancer after failure of a previous gemcitabine-containing regimen.

Second- and third-generation aromatase inhibitors as first-line endocrine therapy in postmenopausal metastatic breast cancer patients: a pooled analysis of the randomised trials

The purpose of this study was to estimate in all randomised trials the relative risk of overall response rate (ORR), clinical benefit (CB), time to progression (TTP), overall survival (OS), and toxicity of aromatase inhibitors (AI), compared with tamoxifen (Tam) as first-line endocrine therapy in postmenopausal metastatic breast cancer (PMBC) women. Prospective randomised studies were searched through computerised queries of MEDLINE, EMBASE, and the American Society of Clinical Oncology (ASCO) abstract database. Relative risk, 95% confidence interval, and heterogeneity were derived according to the inverse variance and Mantel–Haenszel method and Q statistics. Six phase III prospective randomised trials including 2787 women were gathered. A significant advantage in ORR (P=0.042), TTP (P=0.007), and CB (P=0.001) in favour of AI over Tam was detected at the fixed effects model. These results were not significant at the random effects model, owing to the significant heterogeneity. On the contrary, no difference was registered for OS (P=0.743) with no significant heterogeneity. Regarding toxicity, Tam caused more frequently thromboembolic events (P=0.005) and vaginal bleeding (P=0.001) compared with AI. Aromatase inhibitors appear to be superior to Tam as first-line endocrine option in PMBC women. Owing to a component of variability between the six studies analysed, the random effects estimates differed from corresponding fixed ones. Investigators should assess heterogeneity of trial results before deriving summary estimates of treatment effect.

Docetaxel in advanced gastric cancer--review of the main clinical trials

The aim was to investigate the activity of docetaxel in advanced gastric cancer either as single agent or in combination with other drugs. A systematic review was carried out using the databases of Medline, Embase and CancerLit. Results from ASCO and ESMO meetings during 2002 were also included. Eight phase II trials focused on docetaxel as a single agent. Considering collectively the 262 evaluable patients enrolled in these studies, the mean response rate (RR) was 19% (CI 95% 14–24%). Docetaxel was well tolerated with a dose-limiting myelosuppression (grade 3–4 neutropenia in 36–95% of cases). Adding fluorouracil, an RR ranging from 22% to 86% was registered, due to differences in populations studied (young vs. elderly) and modalities of drug administration (continuous vs. bolus infusion). RRs for docetaxel–cisplatin combination were 56%, 37% and 36% in three phase II trials and 35% in a phase III trial. The addition of both cisplatin and fluorouracil to docetaxel did not increase toxicity. Randomized trials comparing docetaxel–cisplatin–fluorouracil with ciplatin–fluorouoracil or epirubicin–cisplatin–fluorouracil, the most commonly used regimens, are ongoing. The future results of the above phase III studies could indicate docetaxel as a key drug to improve treatment of patients with advanced gastric cancer.

EGFR Molecular Profiling in Advanced NSCLC: A Prospective Phase II Study in Molecularly/Clinically Selected Patients Pretreated with Chemotherapy

Introduction: The optimal use of epidermal growth factor receptor (EGFR)-related molecular markers to prospectively identify tyrosine kinase inhibitor (TKI)-sensitive patients, particularly after a previous chemotherapy treatment, is currently under debate. Methods: We designed a prospective phase II study to evaluate the activity of EGFR-TKI in four different patient groups, according to the combination of molecular (EGFR gene mutations, EGFR gene copy number and protein expression, and phosphorylated AKT expression, pAKT) and clinicopathological (histology and smoking habits) factors. Correlations between molecular alterations and clinical outcome were also explored retrospectively for first-line chemotherapy and EGFR-TKI treatment. Results: Patients who had progressed during or after first-line chemotherapy were prospectively assigned to EGFR-TKI treatment as follows: (G1) EGFR mutation (n = 12); (G2) highly polysomic/amplified EGFR (n = 18); (G3) EGFR and/or pAKT positive (n = 41); (G4) adenocarcinoma/bronchoalveolar carcinoma and no smoking history (n = 15). G1 and G4 had the best and second-best overall response rate (25% and 20%, respectively), whereas the worst outcome was observed in G2 (ORR, 6%; p = 0.05). Disease control was highest in G1 and G4 (>50%) and lowest in G3 (<20%) (p = 0.02). Patients selected by EGFR mutation or clinical parameters (G1 and G4) also had significantly better progression-free survival and overall survival (p = 0.02 and p = 0.01, respectively). Multivariate analysis confirmed the impact of sex, smoking history, EGFR/KRAS mutation, and pAKT on outcomes and allowed us to derive an efficient predictive model. Histology, EGFR mutations, and pAKT were independent predictors of response to first-line chemotherapy at retrospective analysis, whereas pAKT and human epidermal growth factor receptor 2 expression were the only independent predictors of progression-free survival and overall survival. Conclusions: Selection of patients based on either EGFR mutation or clinical characteristics seems an effective approach to optimize EGFR-TKI treatment in chemotherapy-pretreated non–small-cell lung cancer patients.

Molecular and Genetic Bases of Pancreatic Cancer

Pancreatic cancer remains a formidable challenge for oncologists and patients alike. Despite intensive efforts, attempts at improving survival in the past 15 years, particularly in advanced disease, have failed. This is true even with the introduction of molecularly targeted agents, chosen on the basis of their action on pathways that were supposedly important in pancreatic cancer development and progression: indeed, with the notable exception of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, that has provided a minimal survival improvement when added to gemcitabine, other agents targeting EGFR, matrix metallo-proteases, farnesyl transferase, or vascular endothelial growth factor have not succeeded in improving outcomes over standard gemcitabine monotherapy for a variety of different reasons. However, recent developments in the molecular epidemiology of pancreatic cancer and an ever evolving understanding of the molecular mechanisms underlying pancreatic cancer initiation and progression raise renewed hope to find novel, relevant therapeutic targets that could be pursued in the clinical setting. In this review we focus on molecular epidemiology of pancreatic cancer, epithelial-to-mesenchymal transition and its influence on sensitivity to EGFR-targeted approaches, apoptotic pathways, hypoxia-related pathways, developmental pathways (such as the hedgehog and Notch pathways), and proteomic analysis as keys to a better understanding of pancreatic cancer biology and, most importantly, as a source of novel molecular targets to be exploited therapeutically.

A feasibility study of gefitinib in association with capecitabine (CAP) and oxaliplatin (OXA) as first-line treatment in patients with advanced colorectal cancer (ACRC)

3748 Background: EGF-receptor (EGF-R) is commonly overexpressed in epithelial tumors including ACRC and has thus become the target of various molecular therapeutic approaches. Gefitinib (Iressa), an EGF-R tyrosine kinase inhibitor, demonstrated activity in lung and head and neck cancer, but its clinical activity in ACRC is still unknown. We designed this trial to assess the safety and efficacy of Iressa in association with CAP-OXA regimen as first-line treatment in pts affected by metastatic colorectal cancer Methods: From October 2002 21 pts were included in a two steps trial (m:f:12/9, median age 66 yrs (54-73). Actually the twelve pts planned for first safety analysis are evaluable for toxicity and response. CAP was orally administered (1000 mg/m2) twice a day continuously for 15 days and OXA was administered (120 mg/m2) as a 2-hour infusion on day 1, repeated every 3 weeks for six courses. Gefitinib has been given orally, once daily, at 250 mg, continuously from day 1.Pts on response at the end of the treatment continued to receive gefitinib until progression or unacceptable toxicity. RESULTS 40 cycles were totally administered. The most common side-effect was Diarrhea (14/40 cycles: one G4, two G3 and five G2).Acneiform skin lesion (NCI-CTC grade 1-2 in four and one pts respectively) was frequent, but often disappeared or decreased under continued therapy with Iressa. Further major side-effects included Nausea/Vomiting G1-2 in 12/40 cycles, thrombocytopenia G1-2 6/40 cycles, neutropenia G2-3 4/40 cycles. 82,5% of cycles were given at full dose, while 17,5 were given at full dose but delayed; no reduction of dose was performed. 12 pts are evaluable for efficacy according to an intent-to-treat analysis: 1 CR, 5 PR, 1 SD, 3 PD and 2 withdrawn for SAE (asthenia, diarrhea, and vomiting). CONCLUSIONS Iressa in combination with Cape and Oxa is a feasible regimen in ACRC with an acceptable toxicity profile and an interesting, although preliminary, activity. Further studies are required to assess the potential of Iressa as treatment option in ACRC. Accrual will continue up to 35 patients as planned. No significant financial relationships to disclose.