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A. Dingemans



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    MO03 - Thymic Malignancies (ID 123)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO03.09 - Detection of Human Polyomavirus 7 in thymomas (ID 1829)

      10:30 - 12:00  |  Author(s): A. Dingemans

      • Abstract
      • Presentation
      • Slides

      Background
      Thymomic pathologies are associated with the autoimmune disease myasthenia gravis (MG). The thymomagenesis have been studied extensively but the etiology of human thymoma remains poorly understood. Based on the consistent finding that murine polyomavirus induces thymomas in mice we tested the presence of Human Polyomavirus 7 (HPyV7) in human thymic epithelial tumors.

      Methods
      We applied HPyV7 DNA Fluorescence in situ hybridization (FISH), DNA PCR and immunohistochemistry (IHC) in 37 thymomas (19 female, 18 male; mean age 58.3 years; range 34 – 82 years). Of these, 26 were previously diagnosed with MG. In addition, 2 thymic carcinomas, 20 follicular hyperplasia and 20 fetal thymus tissues were tested for HPyV7.

      Results
      HPyV7 FISH revealed specific nuclear hybridization signals within the thymoma cells of 23 thymomas (62.2%). Fifteen thymomas revealed strong to very strong hybridization signals, whereas 8 revealed only weak positivity. With one exception the HPyV7 FISH data highly correlated with the HPyV7 DNA-PCR data. IHC showed the presence of HPyV7 on the translational level and immunohistochemical double stainings confirmed the presence of HPyV7 in the epithelial thymoma cellular compartment. One thymus carcinoma was HPyV7 positive the other negative. All fetal thymus tissues were tested HPyV7 negative. The follicular hyperplasia results are pending.

      Conclusion
      We conclude that HPyV7 is frequently present in human thymic epithelial tumors and absent in fetal thymic tissues. No convincing association on HPyV7 and MG could be found. In as much HPyV7 is of relevance to human thymomagenesis remains to be established.

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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.07 - Early onset body weight loss during concurrent chemo-radiotherapy for non-small cell lung cancer is not due to dysphagia or reduced calorie intake (ID 3409)

      10:30 - 12:00  |  Author(s): A. Dingemans

      • Abstract
      • Presentation
      • Slides

      Background
      Increased treatment-associated esophagitis could be responsible for concurrent chemo-radiotherapy (CT-RT)-induced weight loss in patients with non-small cell lung cancer (NSCLC). However, based on clinical observations, we hypothesized that weight loss already starts early after initiation of concurrent CT-RT and might therefore be not solely dependent on decreased intake due to esophagitis symptoms.

      Methods
      In a retrospective cohort, the onset and frequency of weight changes and their association with esophagitis grade ≥2 were assessed in patients with NSCLC treated with concurrent (n=102) or sequential (n=92) CT-RT. The findings in the retrospective cohort were validated in a prospective study in which weight loss and esophagitis grade ≥2 was assessed over a longer time period and additional data on nutritional intake, muscle strength and quality of life was obtained of patients treated with concurrent CT-RT (n=9).

      Results
      In the retrospective cohort, both the number of patients with weight loss and the magnitude of weight loss was significantly higher in concurrent than sequential treated patients in week 2, 3 and 4 of (CT-)RT (p<0.05). Longitudinal data analysis showed no significant associations between weight loss and grade esophagitis ≥2 in patients treated with concurrent CT-RT (p=0.10). In the prospective cohort, a similar pattern of ‘early’ weight loss was observed in the first weeks of concurrent CT-RT (p<0.05). This early weight loss was not accompanied by significant decreases in nutritional intake but muscle strength did already decline in this early stage (p<0.05). In the following weeks of concurrent CT-RT, the weight further decreased and reached its minimum at the end of treatment (p<0.05), while the number of patients with grade esophagitis ≥2 increased during this time period. During the later part of concurrent CT-RT, dietary intake was significantly lower and patients became more reliant on supplemental nutrition (p<0.05). Although the weight increased again in the weeks after concurrent CT-RT, it had still not reached the baseline level after 4 weeks post treatment (p<0.05).

      Conclusion
      Weight loss is a common complication of concurrent CT-RT for locally advanced NSCLC, starts early after initiation of CT-RT and is not dependent of esophagitis. It is presumably caused by active catabolism as this ‘early’ weight loss is accompanied by decreased muscle strength, despite stable dietary intake. In the later weeks of treatment, concurrent CT-RT is characterized by a further decline in body weight, decreased dietary intake and higher reliance on nutritional support. In this phase the occurrence of radiation-induced esophagitis grade ≥2 increases. In the weeks following concurrent CT-RT, partial recovery of body weight takes place but this is still not complete after 4 weeks post CT-RT. The sustained weight loss during and following concurrent CT-RT might have major negative consequences as weight loss in patients with underlying malignant disease might has been associated with higher mortality, lower treatment responses and decreases in quality of life. Though the origin of weight loss during concurrent CT-RT seems to be different in the subsequent phases, more aggressive supportive nutritional support throughout the treatment course seems conceivable to prevent negative energy balances and optimize concurrent CT-RT management.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-015 - EGFR mutated patients: different pattern and outcome of metastatic bone disease and brain metastases? (ID 1596)

      09:30 - 16:30  |  Author(s): A. Dingemans

      • Abstract

      Background
      Bone and brain are frequent and problematic sites of metastasis in metastatic non-small cell lung cancer (mNSCLC). Conflicting studies exist whether patients with EGFR mutations develop brain metastases (BM) more often or have a longer survival after diagnosis of mNSCLC than EGFR/KRAS wild type (WT) or KRAS+ patients. For metastatic bone disease (MBD) this is not known. In this retrospective matched control study we compared in EGFR+, KRAS+ and WT patients time from mNSCLC to development of MBD/BM, skeletal related events (SREs) and subsequent survival.

      Methods
      In this retrospective case-control study all EGFR+ patients diagnosed at two molecular pathology departments were selected (VUMC 01-11-2004 to 01-01-2012, MUMC 01-10-2008 to 01-08-2012). For every EGFR+ patient a consecutive KRAS+ and WT mNSCLC patient was selected. Patients with another malignancy within 2 years of mNSCLC diagnosis or no follow up were excluded. Data regarding age, gender, histology, performance score, treatment, MBD and BM diagnosis, SRE and subsequent survival were collected.

      Results
      222 patients were included: 73 EGFR+, 76 KRAS+ and 73 WT (table 1). Respectively 56.2%, 51.3% and 50.7% had MBD (p=0.768) of which respectively 41.5%, 25.6% and 40.5% were diagnosed during follow up (p=0.262). Time to MBD was (mean, [SD]) respectively 13.4 [±10.6], 20.7 [±17.8], 16.8 [±9.6] months (p=0.360). Post MBD survival was (median, [95% confidence interval (CI)]) 15.0 [11.0-19.0], 7.1 [1.3-12.8], 3.2 [0.0-8.3] months respectively (p=0.008). Time to 1[st] SRE was not significantly different (p=0.164). Respectively 28.8%, 39.5% and 34.2% had BM (p=0.444) of which 76.2%, 60.0% and 48.0% were diagnosed during follow up (p=0.148). Mean time to BM was 20.3 [±11.7], 10.8 [±9.3], 14.3 [±10.8] months respectively (EGFR+-KRAS+ p=0.013, EGFR+-WT p=0.176). Post BM survival was 11.0 [2.2-19.8], 6.9 [0-14.1], 12.5 [5.6-19.5] months respectively (p=0.969). Results did not change significantly when patients with only best supportive care were excluded nor when in the EGFR+ group only exon 19/21 patients were included.

      table: patient characteristics and results bone and brain metastasis
      Characteristics EGFR+ N = 73 KRAS+ N = 76 Wildtype N = 73 p-value
      Female N (%) 51 (72.6) 44 (57.9) 29 (39.7) 0.001
      Mean age, years (range) 59.6 (29.3-90.7)
      60.6 (35.1-83.3)
      		62.5 (39.6– 81.8) 0.228
      Never smoker N (%) 29 (45.3) 2 (2.7) 10 (15.2) <0.001
      WHO PS 0-2 N (%) 63 (98.4) 72 (97.3) 60 (92.3) 0.270
      Adenoca N (%) 67 (91.8) 63 (84.0) 55 (76.4) 0.209
      1[st] line no treatment 1[st] line chemo 1[st] line EGFR-TKI 3 ( 4.1) 23 (31.5) 47 (64.4) 10 (13.2) 64 (84.2) 2 ( 2.6) 14 (19.2) 54 (74.0) 5 ( 6.8) 0.069 <0.001 <0.001
      MBD N (%) Yes - at diagnosis - during follow up No 41 (56.2) -24 (58.5) -17 (41.5) 32 (43.8) 39 (51.3) -29 (74.4) -10 (25.6) 37 (48.7) 37 (50.7) - 22 (59.5) - 15 (40.5) 36 (49.3) 0.768 0.262
      SRE+ N (%) 22 (53.7) 23 (59.0) 21 (55.3) 0.887
      BM N (%) Yes -at diagnosis -during follow up No 21 (28.8) - 5 (23.8) -16 (76.2) 52 (72.2) 30 (39.5) -12 (40.0) -18 (60.0) 46 (60.5) 25 (34.2) - 13 (52.0) - 12 (48.0) 48 (65.8) 0.444 0.148

      Conclusion
      Incidence of MBD or BM was not different between EGFR+, KRAS+ and WT patients. Time from diagnosis of mNSCLC to MBD, 1[st] SRE or post-BM survival did not differ. However, survival after MBD was significantly longer in EGFR+ patients. This stresses the impact of bone management in these patients and probably warrant more intense screening for MBD. In EGFR+ patients BM remain a serious event with short survival. This should stimulate investigators to search for BM specific treatments in order to prolong survival post BM in EGFR+ patients.

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    P1.08 - Poster Session 1 - Radiotherapy (ID 195)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P1.08-022 - Number of pathologic nodes in regions closest to the oesophagus is the strongest predictor for esophagitis in small cell lung cancer patients treated with concurrent chemo-radiation: an analysis of 170 patients. (ID 2711)

      09:30 - 16:30  |  Author(s): A. Dingemans

      • Abstract

      Background
      Radiation esophagitis grade III caused by chemo-radiation for small-cell lung cancer is a burden for patients and thus of concern to radiation oncologists. Neutropenia and radiation dose to the esophagus are known treatment factors influencing the rate of esophagitis during treatment, but currently the only factors that can be discussed with the patient at diagnosis are the choice of concurrent versus sequential chemo-radiation and the radiation dose fractionation schedule. In order to build predictive models to more accurately tailor treatment and advise patients on treatment options, more prognostic factors known at the moment of diagnosis are needed.

      Methods
      Analysis of all patients in our prospective database with stage I-III SCLC referred for concurrent chemo-radiotherapy between 5-2004 and 1-2012. All patients were PET-staged and received 45 Gy in 1.5 Gy fractions twice daily to the tumour and PET-or pathologically proven positive lymph nodes. Chemotherapy consisted of carboplatin-etoposide given concurrently with radiotherapy. All pathological lymph node regions were noted for each patient. Based on the Mountain Dressler atlas, the lymph node regions closest to the oesophagus were designated ``high risk`` regions for esophagitis, namely: 1R, 1L, 3P, 4L, 7, 8 and 9. Toxicity was scored according to CTC AE 3.0. Univariate analysis was done using the Chi-square test, reporting for p-value the Fischer exact Test for small numbers of events. Multivariate analysis was done using logistic regression. .

      Results
      170 patients were included in the present analysis. Thirty-seven (20%) patients developed grade III esophagitis. In univariate analysis the number of nodal regions (0, 1-4, ≥5) (p=0.02) and the number of high risk nodal regions (0, 1-2, ≥3) (p=0.001) had a significant effect on the risk of grade III esophagitis whereas the location of the primary tumour or having a T4 tumour did not. In multivariate analysis including age, gender and T4 tumour, the number of pathological nodal stations lost significance. In the multivariate analysis using age, gender, T4 tumour and the ``high risk`` count (0, 1-2, ≥3 areas) having nodes in ≥3 high risk areas was the only significant factor (p=0.002), with a hazard ratio (HR) of 7.4 for developing oesophagitis grade III (95% CI for HR: 2.2-25.2). The absolute rates of esophagitis grade III were: 5/51 (10%), 19/91 (21%), 12/28 (43%) for patients with respectively 0, 1-2 and ≥3 pathological high risk nodal areas.

      Conclusion
      In this series of stage I-III small cell lung cancer treated with radical chemo-radiation, the strongest predictor for esophagitis grade III known at diagnosis is the presence of nodal disease in ``high-risk regions`` 1R, 1L, 3P, 4L, 7, 8 and 9. Analysis of the correlation of this finding with the dose to the esophagus (Dmax/ Dmean) is ongoing and will also be presented at the conference.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.11-022 - Retrospective Longitudinal Chart Review of Patients with Advanced Non-Small Cell Lung Cancer in the Netherlands: A Quantification of Disease Burden (ID 1855)

      09:30 - 16:30  |  Author(s): A. Dingemans

      • Abstract

      Background
      The availability of novel therapeutic regimens has led to increase in duration of treatment and utilization of healthcare in non-small cell lung cancer (NSCLC). Although medical resource use and costs were assessed in previous studies, characterization of disease burden exclusively for advanced-stage, in real-world setting is scarce. The aims of our study were to quantify medical costs of stage IIIB/IV NSCLC and identify components of care, that are likely to alter in light of new developments, in Dutch clinical practice.

      Methods
      A retrospective longitudinal chart review was performed to obtain healthcare utilization of patients, age ≥18 years, with stage IIIB/IV NSCLC (based on the sixth edition of tumor-node-metastasis classification) who received first- and subsequent-line of systemic anti-cancer therapy (SACT). As part of the LUng Cancer Economics and Outcomes Research (LUCEOR), a multi-country retrospective patient chart review, two academic and two non-academic Dutch hospitals participated in the study. Patients who deceased before April 2010 were included. The components of care, from the initiation of first-line SACT until death, were quantified by twelve distinct categories. Total and monthly medical costs attributable to each component were calculated and expressed in 2012 US dollars. Outcomes were fit with statistical models to compare trends. Potential predictors of lifetime NSCLC costs and variability were examined.

      Results
      A total of 134 patients, 65% (87/134) males, of age 63 ± 9.7 (mean ± SD) years were included. While 34% (46/134) of patients were presented with adenocarcinoma, the proportion of large-cell carcinoma, squamous cell carcinoma and NSCLC not otherwise specified were 33% (44/134), 29% (39/134) and 4% (5/134), respectively. The clinical stage at the start of first-line SACT were 28% (37/134) IIIB and 72% (97/134) IV. Aside from the relatively small subset of patients (12%, 16/134) harboring oncogenic drivers, platinum-based combination chemotherapy regimens were the mainstay of treatment. For a median survival of 7.1 months (95% CI 5.9-8.1), total lifetime costs were averaged to $39,992 ± $20,928 per patient. The influential cost-drivers across all lines of therapy were hospitalizations ($15,521± $16,511) and SACT ($11,628± $7,583), mainly platinum-based gemcitabine or docetaxel. Monthly costs per patient were amounted to $11,932± $14,571. The degree of associations between predictors and outcomes were observed for clinical stage of disease at the start of SACT, administration of prior treatment and smoking history. Although clinically imperative, age and gender were not predictors of variability of healthcare costs at alpha ≤0.05.

      Conclusion
      Real-world medical costs, in particular hospital admissions and SACT, are substantial in the management of stage IIIB/IV NSCLC in the Netherlands. In a molecularly enriched patient population, biomarker-driven treatments are expected to result in higher likelihood of clinical benefit. Consequently, the average hospitalization costs and long-term management of treatment-related events are likely to reduce. Future research assessing the quantification of disease burden based solely on molecularly targeted agents in daily practice is encouraged. These results may collectively inform decision-making of registration, reimbursement and pricing of interventions in NSCLC.

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      P1.11-023 - Molecular Screening in Advanced Non-Small Cell Lung Cancer: A Systematic Review of Cost-Effectiveness Analyses for First-Line Therapy (ID 1931)

      09:30 - 16:30  |  Author(s): A. Dingemans

      • Abstract

      Background
      Novel molecularly targeted therapies are increasingly licensed in conjunction with companion diagnostics to stratify patients with oncogenic aberrations and to help improve patients' likelihood of clinical benefit. Cost-effectiveness analyses (CEAs) are now expected to examine the value of molecular screening as well as traditional costs and benefits of therapeutic choices. The aim of this study was to assess the impact of first-line predictive biomarker screening on the cost-effectiveness of molecularly targeted agents in locally advanced or metastatic non-small cell lung cancer (NSCLC).

      Methods
      A systematic literature review was performed using MEDLINE, EMBASE and NHS EED. CEAs of epidermal growth factor receptor (EGFR)-, Kirsten RAS (KRAS)-, and anaplastic lymphoma kinase (ALK)-guided screening prior to first-line treatment were appraised according to a priori eligibility criteria. The impact of screening guided patient management was quantified by incremental cost-effectiveness ratios (ICERs) and expressed in 2013 US dollars. Sensitivity analyses were explored to examine the influence of extracted parameters on the ICERs. Methodological quality of the studies was assessed by standardized checklists.

      Results
      Based on the explicit test-treat combined strategy, eight CEAs met the inclusion criteria. Although six EGFR- and two ALK-guided diagnostic-therapeutic pairings were reviewed, none of the retrieved CEAs explored the potential benefits of KRAS mutation screening on the molecularly targeted agents in the front-line setting. Country-specific decisions regarding utilization of healthcare were conducted from the perspectives of the United States, England and Wales, France, Singapore and China. Efficacy data including biomarker prevalence (ALK: 1.6-4.4%, EGFR: 16.6-60%), sensitivity of the test (ALK: 67-100%, EGFR: 92-100%), specificity of the test (ALK: 93-100%, EGFR: 96-100%) and Quality-Adjusted Life Years (QALY) gained (ALK: 0.009-0.014, EGFR: 0.04-0.5) were extracted. Base-case costs for ALK- and EGFR-guided screening were $98-$1,421 and $105-$516, respectively. The ICERs of EGFR-guided test-treat strategy ranged from being less costly/more effective to unlikely to be cost-effective (ICER range: dominant-$160,123/QALY gained). The ICERs of ALK-guided strategy ranged from likely to be cost-effective to unlikely to be cost-effective (ICER range: $59,240-$213,869/QALY gained). Sensitivity analyses revealed that ICERs of molecularly enriched patient groups were profoundly dependent on the monthly costs of targeted agents (erlotinib, gefitinib, crizotinib) and duration of treatment. Conversely, at low biomarker frequencies, ICERs were influenced by the cost of the screening test. Test specificity, the proportion of advanced NSCLC patients correctly identified as not having EGFR/ALK positivity, was more influential than the test sensitivity. Although clinically imperative, re-biopsy and subsequent therapy were not explored. Furthermore, critical assessment of the CEAs revealed that justification of preferred methods, transparency of input parameters and generalizability of results affected quality.

      Conclusion
      This study investigates indications of cost-effective screening of 'actionable' molecular aberrations and highlights the impact of clinical and cost parameters on the ICERs. While advancements in mechanisms of resistance and histological transformations will shed light on the future of lung cancer care, CEAs of novel diagnostic-therapeutic pairings will continue to help informed decision-making of all stakeholders.

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    P2.04 - Poster Session 2 - Tumor Immunology (ID 154)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.04-001 - Myeloid derived suppressor cells (MDSC) are increased in patients with advanced non-squamous lung cancer (aNSQ) compared to healthy controls and early stage non-squamous lung cancer (eNSQ) and are related to the WHO performance status. Subanalysis of the NVALT12 study (ID 1802)

      09:30 - 16:30  |  Author(s): A. Dingemans

      • Abstract

      Background
      Background: recent evidence shows a role for immunotherapy via checkpoint antibodies in a subgroup of patients with non-small cell lung cancer (NSCLC). We have recently published the complex interplay between tumors and the immune system[1]. The modulating effect of the tumor on the immune system, mainly immunosuppressive, is challenging. MDSC are described to play a major role in this tumor associated immune suppression by inhibiting cytotoxic Tcell function. The aim of the present study is to relate the number of MDSC to two well-known prognostic factors in NSCLC: stage of the disease and WHO performance status.

      Methods
      Methods: MDSC were determined in peripheral blood mononucleair cell fractions of 195 treatment-naive NSCLC patients (185 stage IV (aNSQ), 10 stage I-III(eNSQ), and 20 healthy controls (HC)). WHO performance status was determined by experienced investigators prior to the start of treatment. In this abstract the relation between clinical data and polynucleair MDSC are presented. Flowcytometric analysis was performed within 5 hours after the blood was drawn. MDSC were characterized as CD16low,CD11b+,CD14-,HLA-DR-,CD15+, and CD33+.

      Results
      Results: A large variation in the number of MDSC was observed in patients with NSCLC, also in the same stage of the disease and WHO performance status. In a subgroup of patients with eNSQ high MDSC levels were found, but also in patients with aNSQ low levels of MDSC were found. For the group as a whole, however, an increased number of MDSC was found in patients with aNSQ compared to HC and eNSQ (p<.001, in both comparisons). Comparison of the limited number of patients with of eNSQ and HC no statistical difference was found but there is a tendency for an increase in the number of MDSC per stage of NSCLC. The number of MDSC increased with worse WHO performance status ( p=0.05 between 0 and 2). Whether the number of MDSC has prognostic or predictive value to response to chemotherapy in all patients is subject of current research. Follow up data in all patients with response to chemotherapy, progression free survival and overall survival are at present collected.

      Conclusion
      Conclusion: Peripheral blood MDSC levels are increased in patients with aNSQ compared to eNSQ and HC. MDSC are increased in patients with worse WHO performance status. The number of MDSC shows large variation between patients with similar stage of the disease, showing the complex interplay between tumor and immune system. 1 Aerts JG, Hegmans JP, Cancer Research 2013

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-004 - Oligometastatic non-small cell lung cancer: a simulation expert multidisciplinary tumor board. (ID 1122)

      09:30 - 16:30  |  Author(s): A. Dingemans

      • Abstract

      Background
      Series on aggressive local treatment in selected patients with oligometastatic non-small cell lung cancer (NSCLC) are mostly retrospective, and prospective data are scarce (De Ruysscher et al, JTO 7:1547-1555, 2012). Although a precise definition is lacking, ‘oligometastatic NSCLC’ is considered an intermediate biologic state of restricted metastatic capacity with a limited number of metastases. The turning point between oligometastatic and polymetastatic is merely based on personal opinion and situated somewhere between 1 and 5 distant metastases. In the absence of clear definitions or clinical practice recommendations, a treatment decision is mainly driven by the opinion of each local multidisciplinary tumor board (MDTB).

      Methods
      As the consideration of and the treatment modality for oligometastatic NSCLC is a controversial area in respiratory oncology, in preparation of a recent dedicated workshop, we simulated a MDTB with international experts in the field. Multiple disciplines from 7 different centers participated in the MDTB, including pathology (1), nuclear medicine physician (1), thoracic surgery (3), radiation oncology (3), and respiratory oncology (3). Participants were asked to assess an electronic file describing 10 clinical ‘oligometastatic NSCLC’ cases, with 2 simple questions per case: 1. Do you consider this case ‘oligometastatic’ (Yes/No) and 2. What is your preferred treatment proposal.

      Results
      A full response was returned by all 11 specialists taking part in the simulated MDTB. Only 1 case was considered ‘oligometastatic NSCLC’ by all MDTB members. The presented cases were considered by a median of 78% (range 36-100%) of responders as true oligometastatic disease. Despite the fact that each responder gave only one treatment proposal, a median of 4 different treatment proposals (range 2-6) was made per case. Except for brain metastases, most team members would treat the locoregional thoracic disease before the distant metastases. No preference towards neo-adjuvant or adjuvant chemotherapy could be found. The option for surgery or radiation therapy as part of a combined modality treatment was mainly driven by the physicians’ preference.

      Conclusion
      Our simulated MDTB shows that oligometastatic NSCLC is an entity with many unanswered questions, and thus a major challenge for clinicians. Patients with oligometastatic NSCLC are in the need of 1. discussion at an experienced multidisciplinary tumor board to select patients for a radical combined modality approach; 2. multidisciplinary prospective research protocols to set better definitions of oligometastic NSCLC, evaluate the validity of a radical approach, and to optimize therapeutic modalities.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-037 - A phase II study of sorafenib and metformin in patients with stage IV non-small cell lung cancer (NSCLC) with a KRAS mutation (ID 2701)

      09:30 - 16:30  |  Author(s): A. Dingemans

      • Abstract

      Background
      Previously we reported a phase II study of sorafenib, a multi tyrosine kinase inhibitor, in advanced NSCLC patients with a KRAS mutation [1]. While sorafenib was found active in this group of patients, progression free survival (PFS) and overall survival (OS) were disappointing. Concurrent inhibition of multiple pathways may improve treatment outcome. Metformin is a save and well known antidiabetic drug. It has been described that metformin has inhibitory effects against mTOR, downstream of PI3K. An in vitro study of our group has shown synergistic effects of sorafenib and metformin which provided the rationale for this study [2]. In a post hoc analysis of the previous study, metformin users appeared to be among the longest survivors.

      Methods
      Patients with advanced NSCLC with a KRAS mutation, pretreated with platinum containing chemotherapy were included. Other inclusion criteria were: ECOG performance score (PS) 0-1, adequate organ reserve, creatinine clearance >60 ml/min and provided written informed consent according to local IRB regulations. A tumor biopsy was mandatory to confirm the presence of a KRAS mutation, prior to start of treatment. Treatment consisted of sorafenib 400 mg BID and metformin 1000 mg BID until disease progression or unacceptable toxicity. Dose reductions and discontinuations were specified per protocol in the face of CTC toxicities grade 3 and 4. Primary endpoint: disease control rate (DCR) at 6 weeks according to RECIST version 1.1. Secondary endpoints: duration of response, progression free survival (PFS), overall survival and treatment related toxicities. A 2-stage design was implemented (Simon's optimal design; p0=50%, p1=70%, alpha=0.05, beta=0.20) for a total of 45 evaluable patients.

      Results
      Fifty-five patients were included between 1[st] of July 2012 and 1[st] of June 2013. Median age was 60 (range 34-77) years, 28 female (51 %), ECOG PS 0/1/2 16/32/1, all patients had stage IV disease. Of 47 patients disease evaluation after 6 weeks was available (Fig. 1). Two patients had a partial response, 23 stable disease and 22 patients had progressive disease. DCR was 53%. Results of secondary endpoints will be available at time of the conference.

      Conclusion
      This preliminary analysis suggests that the addition of metformin did not improve DCR, compared to previous reported results of sorafenib monotherapy in pretreated stage IV NSCLC patients with a KRAS mutation. [1] Dingemans AM et al. Clin Cancer Res. 2013 Feb 1;19(3):743-51 [2] Groenendijk FH et al. EJC. 2012 Nov; 48 (suppl. 6): p 48 Figure 1

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-029 - Progression of radiation induced esophageal stenosis in a non-small cell lung cancer (NSCLC) patient treated with sorafenib (ID 1882)

      09:30 - 16:30  |  Author(s): A. Dingemans

      • Abstract

      Background
      Sorafenib is an orally available multikinase inhibitor with antiproliferative and anti-angiogenic activity. Reported oral adverse events of any grade are stomatitis/mucositis (11-38%, mostly ≤ CTC-AE grade 2), oral mucosal pain and dysphagia in the absence of clinical lesions. Sorafenib is under investigation in NSCLC. We report a patient who developed symptomatic progression of an esophageal stenosis during sorafenib treatment.

      Methods
      not appicable

      Results
      Case: A 67-year old male presented at the outpatient clinic with dysphagia CTC-AE grade 3. He was diagnosed with a cT3N3M1a (oligometastatic adenocarcinoma, KRAS mutated) NSCLC in January 2011 for which he was treated with concurrent chemoradiotherapy. Treatment was complicated with grade 3 radiation esophagitis (confirmed with duodenogastroscopy) for which he was treated with a feeding tube and proton pump inhibition. Because of remaining grade 1 dysphagia, duodenogastroscopies were performed in August 2011 and February 2012. A stable relative stenosis of the upper esophagus was found, easy to pass with the duodenogastroscope. Because of progressive disease he was subsequently treated with erlotinib/ pemetrexed (September 2011, study) and docetaxel monotherapy (August 2012). February 2013 he progressed again with subsequent participation in a phase II study with sorafenib 400 mg BID and metformin 1000 mg BID. Within three weeks he developed dysphagia for solid foods. A chest computed tomography showed no external compression of the esophagus and no tumor progression. Duodenogastroscopy revealed a stenosis with ulceration in the upper part of the esophagus, passing the stenosis was only possible with a baby-duodenogastroscope. Because of swallowing problems, sorafenib was temporarily stopped and placement of a percutaneous feeding tube was planned. However, two days after stopping sorafenib, his dysphagia completely resolved and food passage was normal. So, ten days later sorafenib was restarted with dose reduction (200 mg BID). After restarting sorafenib his dysphagia returned with grade 3 within six weeks. Again, sorafenib was temporarily stopped and in a couple of days his dysphagia resolved. After another restart of sorafenib at the latter dose he again developed dysphagia, but this time manageable.

      Conclusion
      We present a patient who developed a grade 3 stenosis of the esophagus during treatment with sorafenib which clinically resolved shortly after stopping sorafenib but reoccurred after rechallenge with sorafenib at a lower dose. Dysphagia resolved again after stopping the sorafenib with again complaints after restarting. No other explanation was found (e.g. progression of malignancy, external compression). 1.5 year before, after concurrent chemoradiotherapy, he was diagnosed with a relative stenosis of the upper esophagus, but this remained stable until sorafenib treatment was started. He scored 8/13 points on the Naranjo score, making sorafenib a probable cause of the stenosis. The underlying mechanism is unknown. A possible explanation is sorafenib inhibition of the VEGF and MAP-kinase pathway. These pathways are both involved in the process of mucosal defense and repair, and it could be that blocking this pathway combined with sensitization by previous irradiation caused progression of the stenosis. This case stresses the importance of being aware of unusual side effects of medication and taking into account possible interactions with previous treatments.