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M. Van Den Heuvel



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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-024 - Prediction of drug sensitivity in second line treatment of patients with malignant pleural mesothelioma (ID 3397)

      09:30 - 09:30  |  Author(s): M. Van Den Heuvel

      • Abstract

      Background
      In second line setting there is no standard treatment for patients with mesothelioma, since all agents tested in clinical trials failed to improve survival. An individual patient however, may actually benefit from second line treatment, considering the patient population is heterogeneous. Yet, there are no predictive markers to identify those patients likely to respond to a certain drug. We developed protocols for in vitro drug sensitivity testing with several cytotoxic agents using primary tumor cells derived from pleural fluid of our patients. Recently, we implemented a personalized second line treatment protocol. Here we will report the outcome of the pilot study.

      Methods
      Cells were isolated from pleural fluid, drawn from patients with mesothelioma for symptom relief. Diagnosis of each mesothelioma patient was confirmed by regular pathological staining. Cells were plated and incubated with a five point concentration range of 5 single drugs and 2 two-drug combinations for 72 hours. Cell viability was determined by a metabolic assay. Each concentration point was measured in triplo and a biological duplo experiment was performed to check reproducibility. The drugs used in this screen were all previously tested in clinical mesothelioma trials. Patients with pleural fluid that were fit and progressed after standard first line treatment were considered for second line chemotherapy. Choice of second line treatment was based on screening results.

      Results
      Thirty-nine mesothelioma patients had pleural fluid drawn for culture of primary tumor cells and subsequent drug sensitivity screening. Drug screens were successful in 22 patients (56%). Drug sensitivity profiles were available within two weeks after isolation of tumor cells, which is appropriate for clinical decision making. Agents tested for were cisplatin or carboplatin, pemetrexed, gemcitabine, vinorelbine, oxaliplatin, a combination of cisplatin and pemetrexed and of oxaliplatin and gemcitabine. Individual dose-response curves showed different sensitivity to the various cytotoxic agents. Ten patients were chemo-naive at the time of the drug sensitivity screen. Five of them received first line chemotherapy (cisplatin and pemetrexed). Two of them had progressive disease. Both demonstrated evident resistance to cisplatin and pemetrexed in their drug sensitivity profile. Four patients received second line treatment based on the drug sensitivity profile of their primary tumor cells. To date, treatment response is evaluated for two patients. Both patients received a combination of oxaliplatin and vinorelbine. The first patient had a clinical response. For the second patient, oxaliplatin/vinorelbine was the best option, although her in vitro profile suggested a rather resistant tumor. She was progressive and showed an unusual large amount of necrosis on repeated CT imaging. Patient three and four are currently treated with oxaliplatin and gemcitabine and gemcitabine monotherapy, respectively. Their treatment responses have to be awaited.

      Conclusion
      Personalized drug screening using primary tumor cells is feasible within a clinically relevant time period and may yield new treatment combinations with better responses.

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    P2.08 - Poster Session 2 - Radiotherapy (ID 198)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P2.08-020 - Prognositc parameters for local and regional control in locally advanced NSCLC patients treated with concurrent chemo-radiotherapy (ID 2385)

      09:30 - 09:30  |  Author(s): M. Van Den Heuvel

      • Abstract

      Background
      Traditionally, the same radiotherapy dose is prescribed to the primary tumor (PT) and involved lymph nodes (LN) for locally advanced NSCLC patients, independent of volume and metabolic activity of each lesion. On the other hand, the PT and lesions with a high [18]F-FDG uptake are often believed to have a higher recurrence rate. The purpose of this study was therefore to find prognostic parameters for the lesion control probability in locally advanced NSCLC.

      Methods
      A total of 279 patients treated between 2007 and 2011 with 24×2.75Gy IMRT and concurrent daily low dose cisplatin were included in this retrospective analysis. Patients had a staging FDG-PET scan within 6 weeks prior the start of treatment. For follow-up, CT thorax was performed 4-6 weeks after treatment and at 3-monthly intervals chest x-ray or CT scans were made up to 2 years after CCRT. Medical records of the patients were retrospectively reviewed. The PT and/or LN progression were classified based on follow-up records and scans by two physicians. The volume of each separate lesion on the planning CT and their SUVmax from the pre-RT staging PET scan were then tested as prognostic factors for disease progression using Cox proportional hazard model with patient as random effect. Data were analyzed using R, package “coxme”.

      Results
      A total of 291 PTs (8 patients had no PT, 252 had 1 PT, 18 had 2 PTs, 1 had 3 PTs) and 627 LNs (59 patients without LN, 57 had 1 LN, 57 had 2 LNs and 106 had >=3 LNs involved) were analyzed. The majority (92%) of the patients had TNM stage III and 86% patients had ≥N2. At a median follow-up of 30 months (95%CI 27-35) and median OS of 25 months (95% CI 21-29), 47 PTs had progression and 14 LNs had progression, 38% patients had systemic relapse. The log(Vol), SUVmax and lesion type (TP vs. LN) were each significant (p<0.001) as prognostic factor for progression in the univariate cox regression. In the multivariate analysis, log(Vol) remains as a significant predictor (p<0.001) with a trend toward significance for lesion type (p=0.07) (Figure 1). Figure 1

      Conclusion
      Our regimen of 66 Gy in 24fx results in excellent local-regional control in locally advanced NSCLC patients. The PT yields a significantly higher risk of progression than LNs. A larger lesion volume and higher SUVmax were associated with an increased risk of progression.