Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

R. Stahel



Author of

  • +

    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      MO06.03 - Bevacizumab and erlotinib or bevacizumab, cisplatin and pemetrexed in patients with metastatic non-small cell lung cancer: EGFR mutation based treatment allocation and repeat biopsy at progression in the SAKK19/09 (BIOPRO) trial (ID 1862)

      16:25 - 16:30  |  Author(s): R. Stahel

      • Abstract
      • Presentation
      • Slides

      Background
      Treatment allocation by EGFR mutation and maintenance therapy are two new standards for patients (pts) with metastatic non-small cell lung cancer (NSCLC). This multicenter phase II trial (NCT01116219) for the first time prospectively tested pemetrexed and bevacizumab maintenance therapy in pts with EGFR wild type NSCLC, and included repeat biopsy at progression to study molecular mechanisms of drug resistance. Pts with EGFR mutation were treated with erlotinib and bevacizumab, based on the results of the previous SAKK19/05 trial.

      Methods
      100 pts were enrolled with metastatic nonsquamous NSCLC, sufficient material for mutation analysis and translational research, and consent to repeat biopsy at progression. Pts with EGFR wild type received 4 cycles of bevacizumab 7.5mg/kg, cisplatin 75mg/m2 (or carboplatin AUC5) and pemetrexed 500mg/m2 every 3 weeks, followed by maintenance therapy with bevacizumab and pemetrexed until progression. Pts with EGFR mutation received bevacizumab 7.5 mg/kg every 3 weeks and erlotinib 150 mg daily until progression. Pts were followed by CT-scan every 6 weeks and repeat biopsy was performed at progression. The primary endpoint was progression free survival (PFS) at 6 months. For an unpromising PFS at 6 months rate of ≤20% and a promising rate of ≥35%, 77 patients with EGFR wild type were needed to reach a power of 90% and an alpha level of 5%. Secondary endpoints were median PFS, overall survival (OS), best response rate of CR+PR (RECIST), and further biomarkers including KRAS, thymidylate synthase (TS), and multigene expression.

      Results
      Seventy-seven pts with EGFR wild type and 20 pts with EGFR mutation were evaluable, 3 pts were not evaluable. Pts on bevacizumab and chemotherapy received on average 9 cycles (range 1-25). No unexpected toxicities were observed. PFS at 6 months was 45.5% (CI: 34.1%, 57.2%), median PFS was 6.9 (CI: 4.6, 8.3) months, OS was 12.1 (CI: 8.7, 14.7) months, and best response rate of CR+PR was 62%. Sixteen pts remain on treatment. Repeat biopsy at progression was successful in 31 of 39 (79%) of patients on trial treatment, and except for one transient pneumothorax, no relevant complications occurred. KRAS mutation was associated with poor overall survival (HR 2.0, CI: 1.05, 3.88; P=0.03), but not with PFS or best response. Pts on bevacizumab and erlotinib received on average 16 cycles (range 6-37). PFS at 6 months was 70.0% (CI: 45.7%, 88.1%), median PFS was 14.0 (CI: 8.8, NA) months, median OS is not yet reached, best response rate of CR+PR was 70%, 11 pts remain on treatment. Further analysis of serial serum and tumor samples is ongoing.

      Conclusion
      Compared with the previous POINTBREAK trial of pemetrexed and bevacizumab maintenance in genetically unselected pts, this trial demonstrates almost identical survival rates in pts with EGFR wild type. KRAS mutation was prognostic, repeat biopsy at progression was feasible, and laboratory analysis is ongoing to validate TS and to develop a predictive gene signature. Firstline therapy with erlotinib and bevacizumab is promising in pts with EGFR mutation, and this combination is further tested in the ongoing ETOP 2-11 BELIEF trial.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • +

      MO10.07 - ALK immunohistochemistry and fluorescence in-situ hybridization in Lung adenocarcinomas from the ETOP Lungscape tumour cohort (ID 2267)

      16:50 - 16:55  |  Author(s): R. Stahel

      • Abstract
      • Presentation
      • Slides

      Background
      The European Thoracic Oncology Platform LungScape database contains 2614 cases of primary resected lung carcinoma from 16 centres with patient demographics, pathological tumour data and detailed clinical follow-up. A total of 1281 cases of adenocarcinoma with >2 years clinical follow-up were selected for analysis of ALK status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Test positive cases were matched, in order of importance at ratio 1:2, by stage, gender, smoking status, study centre, year of surgery and age with test negative cases -both for IHC and for FISH testing.

      Methods
      Testing was performed in all centres using the same protocol (IHC: Novocastra 5A4 clone antibody at 1:10 dilution, Novolink detection system. FISH: Abbott Vysis ALK break-apart probe). Each centre passed an external QA test using unknown cases in a tissue microarray before conducting the LungScape tumour testing. IHC was scored according to three intensity scores (1+, 2+, 3+) using ‘objective’ methodology previously described [1]. Maximum staining intensity was recorded. Any IHC staining was defined as IHC positive result. FISH preparations were assessed according to the Vysis protocol on all 82 IHCpositive cases plus their 164 IHCnegative matches.

      Results

      IHC cases, n=1281 FISH positive(264 tested)
      IHC negative 1199 (93.6%) 0 (0.0% of 164 controls) FISH specificity: 100%
      IHC 1+ 43 (3.35%) 2 (4.6% of IHC 1+)
      IHC 2+ 16 (1.25%) 6 (37.5% of IHC 2+)
      IHC 3+ 23 (1.8%) 20 (87% of IHC 3+)
      IHC any positive 82 (6.4%) 28 (34.1% of IHC+) FISH sensitivity: 34.1%
      FISH sensitivity was 87% for IHC 3+. IHCpositive/FISHnegative cases (n=54) were mostly IHC 1+ (75.9%), sometimes IHC 2+ (18.5%) and rarely IHC 3+ (5.5%). The frequency of never smokers was higher in the ALK IHCpositive group (29.3%) versus IHCnegative group (18.3%) {p=0.011}. Age, gender and tumour stage did not differ between IHC groups. The hazard of an event for IHCpositive cases decreases by 32% in relapse-free survival {RFS; p=0.03} and by 38% in either time-to-relapse {TTR; p=0.02} or overall survival {OS; p=0.016}. Multivariate models -adjusted for patient and tumour characteristics- indicated that IHC-ALK was a significant predictor for all three time-to-event outcomes (RFS, TTR, OS). In stratified Cox analysis, significantly higher OS was retained in the IHCpositive (HR=0.59, p=0.04) and FISHpositive (HR=0.34, p=0.03) cases in the matched cohorts, while conditional logistic regression yielded non-significant associations with 3-year survival status.

      Conclusion
      In this large cohort of surgically resected primary lung adenocarcinoma: ALK IHC positivity was 6.4%. IHC 3+ staining (prevalence 1.8%) showed 87% probability of ALK FISH positivity ALK IHC positivity was higher in never smokers and related to better clinical outcome ALK testing can be reliably implemented across multiple laboratories {1} Ruschoff et al. Virchows Arch. 2010;457(299-307).

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MO14 - Mesothelioma II - Surgery and Multimodality (ID 121)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
    • +

      MO14.05 - Intracavitary Cisplatin-Fibrin Chemotherapy after Resection for Malignant Pleural Mesothelioma Patients (INFLuenCe-Meso) - preliminary results (ID 2683)

      10:50 - 10:55  |  Author(s): R. Stahel

      • Abstract
      • Presentation
      • Slides

      Background
      Local mesothelioma recurrence remains a challenge even after multimodal therapy. Intracavitary chemotherapy is a promising approach to improve local tumor control. In preclinical studies we observed improved pharmacokinetic characteristics when cisplatin was loaded to a fibrin carrier and applied to the chest wall after surgery while effectiveness remained the same compared to cisplatin applied as a solution. We will present the first results of a phase I –dose-escalation-clinical study.

      Methods
      Since 11/2012 3 patients were included in the study. Cisplatin-fibrin was applied after pleurectomy/decortication (P/D) to the chest wall in a concentration of 11 mg/m[2] BSA. Blood samples were taken at several time points after the application (2, 6, 10, 24, 48 and 120 hours) to assess serum cisplatin levels and to test toxicity in the early phase until 14 days postoperatively. The concentration of total platinum was quantified by means of inductively coupled plasma sector field mass spectrometric detection. Adverse events were graded according to the CTCAE.

      Results
      Between November 2012 and March 2013 three patients (2x epithelioid, 1x biphasic) in stage II, III and stage IV were included and received P/D plus Cisplatin-Fibrin in a concentration of 11 mg/m[2]. The maximum concentration of cisplatin in the serum was below 0.3 µg/g at 2 h after application and continued to decrease over a period of 5 days (see image 1). No severe adverse events were observed. The adverse events documented were not related to cisplatin (table 1):

      Diagnosis / symptoms CTC AE grading Number of patients Related to Cisplatin
      Fatigue Grade II 2 possible
      Anemia Grade III 2 unlikely
      Nausea / vomiting Grade I 1 possible
      Increased kreatinin & urea levels Grade II 1 possible
      Increased CK levels Grade IV 1 unlikely
      Increased level of transaminases Grade III 1 unlikely
      Urinary retention Grade II 1 unlikely
      Hypotension Grade II 1 unlikely
      Pneumothorax Grade II 1 unlikely
      Figure 1

      Conclusion
      Our preliminary results show, that cisplatin-fibrin application to the chest wall and the lung surface after P/D is safe on a dose level of 11mg/m2 BSA. As no treatment related mortality and no drug related toxicity was observed we escalate the dosage to 22 mg/m2 BSA, further results including chest wall concentrations of cisplatin will be available in October.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
    • +

      P3.01-015 - <b>Outcome in pemetrexed/cisplatin-treated non-small-cell lung cancer (NSCLC) patients according to mRNA expression levels of BRCA1, TS, AEG1 and REV3 </b> (ID 1170)

      09:30 - 09:30  |  Author(s): R. Stahel

      • Abstract

      Background
      REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase x, can continue replication past DNA adducts. Depletion of REV3 sensitizes A549 lung cancer cells to cisplatin. REV3 expression is part of a gene signature that predicted pemetrexed sensitivity in 17 NSCLC cell lines. BRCA1, TS, AEG1 and RAP80 are involved in DNA damage repair through homologous recombination. The homologous recombination and TLS pathways have non-redundant functions in response to cisplatin. We hypothesized that low mRNA expression of these genes – either alone or in combination – could confer improved outcome to cisplatin/pemetrexed in NSCLC patients.

      Methods
      REV3, BRCA1, RAP80, TS and AEG1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles. Expression of each gene was correlated with outcome in 47 cisplatin/pemetrexed-treated NSCLC patients.

      Results
      63.8% male; 47% smokers; 80.9% ECOG PS 1; 80.8% adenocarcinoma. Overall response rate was 51%, with no differences according to expression levels of any of the genes. Progression-free survival (PFS) for patients with low, intermediate and high BRCA1 levels was 13.4, 5.5 and 3.9 months (m), respectively (P=0.005). Similar differences in PFS were observed according to TS (P=0.003) and AEG1 (P<0.001) expression. The hazard ratio (HR) for PFS for patients with high BRCA1 levels was 4 (P=0.002). Overall survival (OS) for patients with low, intermediate and high BRCA1 levels was 29.7, 7.4 and 6.3 m, respectively (P=0.05). Similar differences in OS were observed according to TS (P=0.005) and AEG1 (P=0.001) expression. HR for OS for patients with high BRCA1 levels was 3.6 (P=0.004). There were no differences in PFS or OS according to REV3 or RAP80 levels. However, the joint effect of BRCA1 and REV3 was significant for predictive modeling. PFS for patients with low, intermediate and high levels of both genes was 14.9, 7.2 and 2.8 m, respectively (P=0.001). OS for patients with low, intermediate and high levels of both genes was 29.7, 7.8 and 6.3 m, respectively (P=0.04).

      Conclusion
      Low BRCA1 expression predicts longer PFS and OS in pemetrexed/cisplatin-treated NSCLC p. Low TS and AEG1 levels have similar predictive value. The combination of low BRCA1 and REV3 expression confers longer PFS and OS. Analysis of these genes could be useful for customizing pemetrexed/platinum chemotherapy.

  • +

    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
    • +

      P3.06-020 - Prognostic Markers for Mesothelioma Patients Treated with Induction Chemotherapy Followed by Extrapleural pneumonectomy (ID 1879)

      09:30 - 09:30  |  Author(s): R. Stahel

      • Abstract

      Background
      Multimodal treatment provides the best outcome for some but not all malignant pleural mesothelioma (MPM) patients. Therefore the identification of prognostic markers helping to select patients remains a subject of key importance. Frequent loss of NF2 tumor suppressor gene, a regulator of Hippo pathway and mammalian target of rapamycin (mTOR) has been well documented in MPM. We recently observed loss of expression of phosphatase and tensin homologue (PTEN), a tumor suppressor gene of the phosphatidylinositol 3-kinase (PI3K)/mTOR pathway, in 62% of MPM patients. In this regard, increased activity of these pathways stemming from loss of abovementioned tumor suppressor genes may serve as potential prognosticator as well as therapeutic target. Here we aim to assess prognostic significance of PI3K/mTOR and Hippo pathways for MPM patients treated with a multimodal approach.

      Methods
      Large cohort of MPM patients uniformly treated with induction chemotherapy followed by extrapleural pneumonectomy was employed in this study. Tissue micro arrays were constructed composing of paired samples from patients (n = 153) collected pre- and post-induction chemotherapy. All tissues were evaluated for apoptotic index (cleaved caspase-3) and proliferation index (Ki-67). Expression levels of biomarkers of PI3K/mTOR (PTEN, p(phosphorylated)-mTOR and p-S6) and Hippo signaling pathway (nuclear-YAP and nuclear-Survivin) were evaluated by immunohistochemistry and correlated with overall survival (OAS) and progression free survival (PFS).

      Results
      Survival analysis showed that high p-S6 expression and high Ki-67 index in samples of treatment naïve patients was associated with shorter PFS (p = 0.02 and p = 0.04, respectively). High Ki-67 index after chemotherapy remained associated with shorter PFS (p = 0.03) and OAS (p = 0.02). Paired comparison of marker expression in samples prior and post induction chemotherapy revealed that decreased cytoplasmic PTEN as well as increased p-mTOR expression was associated with a worse OAS (p = 0.04 and 0.03, respectively). No correlation was observed between expression level of nuclear-YAP with PFS or OAS.

      Conclusion
      Ki-67 proliferation index has prognostic value for MPM patients treated with multimodality approach in when analyzed both pre- and post- induction chemotherapy specimens. Our results further reveal the prognostic significance of expression changes of PI3K/mTOR pathway components during induction chemotherapy. If confirmed, these data suggest PI3K/mTOR pathway to be a target for selected MPM patients.