Stefan Boeck

Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer.

BackgroundSingle-agent gemcitabine (GEM) is a standard treatment for advanced and metastatic pancreatic cancer. This study examines the question whether GEM-based combination chemotherapy can further improve treatment efficacy.MethodsA meta-analysis was performed to evaluate randomized trials comparing GEM versus GEM+X (X = cytotoxic agent). Fifteen trials including 4465 patients were eligible for an analysis of overall survival, the primary end-point of this investigation.ResultsThe meta-analysis revealed a significant survival benefit for GEM+X with a pooled hazard ratio (HR) of 0.91 (95% CI: 0.85 – 0.97, p = 0.004). The overall test for heterogeneity resulted in p = 0.82 (I2 = 0%). The analysis of platinum-based combinations indicated a HR of 0.85 (95% CI: 0.76 – 0.96, p = 0.010), while for fluoropyrimidine-based combinations the HR was 0.90 (95% CI: 0.81 – 0.99, p = 0.030). No risk reduction was observed in the group of trials combining GEM with irinotecan, exatecan or pemetrexed (HR = 0.99). A meta-analysis of the trials with adequate information on baseline performance status (PS) was performed in five trials with 1682 patients. This analysis indicated that patients with a good PS had a marked survival benefit when receiving combination chemotherapy (HR = 0.76; 95% CI: 0.67 – 0.87; p < 0.0001). By contrast, application of combination chemotherapy to patients with an initially poor PS appeared to be ineffective (HR = 1.08; 95% CI: 0.90 – 1.29, p = 0.40).ConclusionThe meta-analysis of randomized trials indicated a significant survival benefit when GEM was either combined with platinum analogs or fluoropyrimidines. Based on a preliminary subgroup analysis (representing 38% of all patients included in this meta-analysis), pancreatic cancer patients with a good PS appear to benefit from GEM-based cytotoxic combinations, whereas patients with a poor PS seem to have no survival benefit from combination chemotherapy.

Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR

The epidermal growth factor receptor (EGFR) plays an important role in tumorigenesis and tumor progression of colorectal cancer (CRC). As a result, the EGFR has evolved as a relevant target in the treatment of metastatic CRC. KRAS serves as a mediator between extracellular ligand binding and intracellular transduction of signals from the EGFR to the nucleus. The presence of activating KRAS mutations has been identified as a potent predictor of resistance to EGFR-directed antibodies such as cetuximab or panitumumab. These agents should therefore be applied only in tumors with a wild-type status of the KRAS gene. Further parameters of resistance are lack of EGFR amplification, PTEN loss or BRAF mutation. However, they are less well studied or associated with less consistent data and therefore require prospective analyses before integration into clinical decision making. Future studies need to identify patterns of single or multiple mutations to further increase the power of patient selection for anti-EGFR therapy. While molecular parameters help to predict treatment efficacy upfront, skin toxicity has been accepted as an independent predictor of response during exposure to anti-EGFR therapy.

Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer

In pancreatic cancer (PC) accurate determination of treatment response by imaging often remains difficult. Various efforts have been undertaken to investigate new factors which may serve as more appropriate surrogate parameters of treatment efficacy. This review focuses on the role of carbohydrate antigen 19-9 (CA 19-9) as a prognostic tumor marker in PC and summarizes its contribution to monitoring treatment efficacy. We undertook a Medline/PubMed literature search to identify relevant trials that had analyzed the prognostic impact of CA 19-9 in patients treated with surgery, chemoradiotherapy and chemotherapy for PC. Additionally, relevant abstract publications from scientific meetings were included. In advanced PC, pretreatment CA 19-9 levels have a prognostic impact regarding overall survival. Also a CA 19-9 decline under chemotherapy can provide prognostic information for median survival. A 20% reduction of CA 19-9 baseline levels within the first 8 weeks of chemotherapy appears to be sufficient to define a prognostic relevant subgroup of patients (‘CA 19-9 responder’). It still remains to be defined whether the CA 19-9 response is a more reliable method for evaluating treatment efficacy compared to conventional imaging.

Randomized, Multicenter, Phase II Study of CO-101 Versus Gemcitabine in Patients With Metastatic Pancreatic Ductal Adenocarcinoma: Including a Prospective Evaluation of the Role of hENT1 in Gemcitabine or CO-101 Sensitivity

PURPOSE Gemcitabine requires transporter proteins to cross cell membranes. Low expression of human equilibrative nucleoside transporter-1 (hENT1) may result in gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). CO-101, a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1. We conducted a randomized controlled trial to determine whether CO-101 improved survival versus gemcitabine in patients with metastatic PDAC (mPDAC) with low hENT1. The study also tested the hypothesis that gemcitabine is more active in patients with mPDAC tumors with high versus low hENT1 expression. PATIENTS AND METHODS Patients were randomly assigned to CO-101 or gemcitabine, after providing a metastasis sample for blinded hENT1 assessment. An immunohistochemistry test measuring tumor hENT1 was developed. To dichotomize the population, an hENT1 cutoff value was defined using primary PDAC samples from an adjuvant trial, and a high/low cutoff was applied. The primary end point was overall survival (OS) in the low hENT1 subgroup. RESULTS Of 367 patients enrolled, hENT1 status was measured in 358 patients (97.5%). Two hundred thirty-two (64.8%) of 358 patients were hENT1 low. There was no difference in OS between treatments in the low hENT1 subgroup or overall, with hazard ratios (HRs) of 0.994 (95% CI, 0.746 to 1.326) and 1.072 (95% CI, 0.856 to 1.344), respectively. The toxicity profiles in both arms were similar. Within the gemcitabine arm, there was no difference in survival between the high and low hENT1 subgroups (HR, 1.147; 95% CI, 0.809 to 1.626). CONCLUSION CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1. Metastasis hENT1 expression did not predict gemcitabine outcome.

Systemic treatment of advanced pancreatic cancer

Pancreatic cancer belongs to the most malignant gastrointestinal cancers and, in its advanced stage, remains a deadly disease for nearly all affected patients. Treatment of metastatic adenocarcinoma of the pancreas not only involves chemotherapy and targeted therapy, but also requires attention to accompanying comorbidities as well as frequently intensive supportive treatment and psychosocial support. Gemcitabine-based combinations with fluoropyrimidines and platin analogs have essentially failed to provide a substantial prolongation of survival and may constitute a treatment option only in patients with a good performance status. Among targeted therapies, only the EGFR tyrosine kinase inhibitor erlotinib has shown activity which is marginal in the overall population, but clinically relevant in patients developing skin rash. New avenues of polychemotherapy are presently explored since the gemcitabine-free FOLFIRINOX-regimen (infusional 5-fluorouracil/folinic acid plus irinotecan and oxaliplatin) was shown to be markedly superior to gemcitabine in selected good-performance patients. Pancreatic cancer is notably characterized as a hypovascular tumor rich in desmoplastic stromal tissue. An innovative approach to treatment therefore focuses on peritumoral fibroblasts and aims to induce a depletion of the stroma either by inhibition of the hedgehog pathway or by targeting SPARC (secreted protein acidic and rich in cysteine) via application of albumin-bound paclitaxel.

Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104)

Objective AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine. Methods 281 patients with PC were randomly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib. In case of treatment failure (eg, disease progression or toxicity), patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was time to treatment failure (TTF) after 1st- and 2nd-line therapy (TTF2; non-inferiority design). KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the randomised patients. Results Of the 274 eligible patients, 43 had locally advanced and 231 had metastatic disease; 140 (51%) received 2nd-line chemotherapy. Median TTF2 was estimated with 4.2 months in both arms; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine, respectively (HR 1.02, p=0.90). TTF for 1st-line therapy (TTF1) was significantly prolonged with gemcitabine/erlotinib compared to capecitabine/erlotinib (3.2 vs 2.2 months; HR 0.69, p=0.0034). Skin rash was associated with both TTF2 (rash grade 0/1/2–4:2.9/4.3/6.7 months, p<0.0001) and survival (3.4/7.0/9.6 months, p<0.0001). Each arm showed a safe and manageable toxicity profile during 1st- and 2nd-line therapy. A KRAS wild-type status (52/173 patients, 30%) was associated with an improved overall survival (HR 1.68, p=0.005). Conclusion Both treatment strategies are feasible and demonstrated comparable efficacy; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib. Trial registration number This study was registered at ClinicalTrials.gov, number NCT00440167. Significance of this study What is already known on this subject? Gemcitabine-based chemotherapy remains an international standard of care for patients with non-resectable, advanced pancreatic cancer (PC). Anti-EGFR treatment with the tyrosine kinase inhibitor erlotinib, as well as chemotherapy intensification by application of the FOLFIRINOX regimen, both significantly improved overall survival in randomised phase 3 trials. The optimal (sequential) regimen for the use of gemcitabine, erlotinib and the oral fluoropyrimidine capecitabine remains unclear in advanced PC. Molecular predictors for the efficacy of anti-EGFR treatments in PC have not been defined up to now. What are the new findings? The sequential use of gemcitabine, erlotinib and capecitabine is safe and equally effective in PC; gemcitabine appears to be more effective in 1st- and 2nd-line therapy than capecitabine and therefore remains the preferred combination partner for erlotinib. Skin rash is strongly correlated with efficacy outcome measures in PC patients treated with erlotinib. KRAS wild-type status appears to be associated with improved overall survival in patients treated with erlotinib in this AIO study. Significance of this study How might it impact on clinical practice in the foreseeable future? The benefit of adding erlotinib to chemotherapy is restricted to patients that experience skin rash during treatment; non-rash patients are characterised by a very poor outcome and need to be offered novel treatment strategies. Second-line salvage chemotherapy is effective and safe in selected PC patients. KRAS could serve as the first biomarker for improved survival in erlotinib-treated patients; the predictive value of KRAS for erlotinib efficacy remains to be defined prospectively.

Neoadjuvant treatment of borderline resectable and non-resectable pancreatic cancer

Neoadjuvant therapy is increasingly becoming a valid treatment option for patients with locally advanced pancreatic cancer (LAPC). In borderline resectable disease, neoadjuvant therapy is employed to improve the probability of margin-clear resections. In non-metastatic, non-resectable pancreatic cancer, treatment primarily aims to induce disease control, but may achieve conversion to surgical resectability in some patients. Several treatment modalities including chemotherapy, chemoradiotherapy (CRT) or the sequential use of both have been investigated in numerous, mostly small and non-randomized studies. Nevertheless, there is a consistent finding that neoadjuvant therapy can induce resectability in up to 30%-40% of LAPC patients. Once resection has been achieved, overall survival appears to be comparable to that observed for primarily resectable patients. Thus, patient selection evolves as an important aspect of neoadjuvant therapy; retrospective analyses identified induction chemotherapy as an appropriate tool to define LAPC patients who may benefit most from subsequent treatment with CRT. The clinical importance of induction chemotherapy may further increase once highly active protocols such as the FOLFIRINOX or the gemcitabine plus nab-paclitaxel regimen are introduced into novel multimodality treatment concepts.

The Role of Adjuvant Chemotherapy for Patients with Resected Pancreatic Cancer: Systematic Review of Randomized Controlled Trials and Meta-Analysis

Background: In patients undergoing surgery for resectable pancreatic cancer prognosis still remains poor. The role of adjuvant treatment strategies (including chemotherapy and chemoradiotherapy) following resection of pancreatic cancer remains controversial. Methods: A Medline-based literature search was undertaken to identify randomized controlled trials that evaluated adjuvant chemotherapy after complete macroscopic resection for cancer of the exocrine pancreas. Five trials of adjuvant chemotherapy were eligible and critically reviewed for this article. A meta-analysis (based on published data) was performed with survival (median survival time and 5-year survival rate) being the primary endpoint. Results: For the meta-analysis, 482 patients were allocated to the chemotherapy group and 469 patients to the control group. The meta-analysis estimate for prolongation of median survival time for patients in the chemotherapy group was 3 months (95% CI 0.3–5.7 months, p = 0.03). The difference in 5-year survival rate was estimated with 3.1% between the chemotherapy and the control group (95% CI –4.6 to 10.8%, p > 0.05). Conclusion: Currently available data from randomized trials indicate that adjuvant chemotherapy after resection of pancreatic cancer may substantially prolong disease-free survival and cause a moderate increase in overall survival. In the current meta-analysis, a significant survival benefit was only seen with regard to median survival, but not for the 5-year survival rate. The optimal chemotherapy regimen in the adjuvant setting as well as individualized treatment strategies (also including modern chemoradiotherapy regimens) still remain to be defined.

Risk factors for surgical complications in distal pancreatectomy.

BACKGROUND Pancreatic fistula (PF) represents a major complication after distal pancreatectomy. In a consecutive series of 110 patients, risk factors for the incidence of PF and surgical morbidity were identified. METHODS Patients having undergone distal pancreatectomy between 2003 and 2007 were identified. Clinicopathologic parameters as well as perioperative data were correlated with the incidence of PF and overall surgical morbidity using univariate and multivariate models. RESULTS In 72 patients (65%), malignant disease was present. Splenectomy and multivisceral resection were performed in 84 (76%) and 47 (42%) patients, respectively. Overall major surgical morbidity was 18%, and 12 patients (11%) developed PFs. A body mass index > 25 kg/m(2) was the only independent significant predictive factor for PF. Malignancy, splenectomy, multivisceral resection, transfusion, comorbidity, and stapler use did not show statistical significance. For overall surgical morbidity, there was no significant indicator. CONCLUSIONS A body mass index > 25 kg/m(2) contributes to the incidence of PF after distal pancreatectomy. Other parameters did not show a significant influence on PF or on overall surgical morbidity.

EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104

Background:We aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in pancreatic cancer (PC) patients treated with the anti-EGFR agent erlotinib within the phase 3 randomised AIO-PK0104 study.Methods:AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC; primary study end point was the time-to-treatment failure after first- and second-line therapy (TTF2). Translational analyses were performed for KRAS exon 2 mutations, EGFR expression, PTEN expression, the EGFR intron 1 and exon 13 R497K polymorphism (PM). Biomarker data were correlated with TTF, overall survival (OS) and skin rash.Results:Archival tumour tissue was available from 208 (74%) of the randomised patients. The KRAS mutations were found in 70% (121 out of 173) of patients and exclusively occurred in codon 12. The EGFR overexpression was detected in 89 out of 181 patients (49%) by immunohistochemistry (IHC), and 77 out of 166 patients (46%) had an EGFR gene amplification by fluorescence in-situ hybridisation (FISH); 30 out of 171 patients (18%) had a loss of PTEN expression, which was associated with an inferior TTF1 (first-line therapy; HR 0.61, P=0.02) and TTF2 (HR 0.66, P=0.04). The KRAS wild-type status was associated with improved OS (HR 1.68, P=0.005); no significant OS correlation was found for EGFR–IHC (HR 0.96), EGFR–FISH (HR 1.22), PTEN–IHC (HR 0.77), intron 1 (HR 0.91) or exon 13 R497K PM (HR 0.83). None of the six biomarkers correlated with the occurrence of skin rash.Conclusion:The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study; it remains to be defined whether this association is prognostic or predictive.