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E. Smit

Moderator of

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    MS20 - Small Cell Lung Cancer (ID 37)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Medical Oncology
    • Presentations: 4
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      MS20.1 - The Clinical Challenge of Small Cell Lung Cancer (ID 551)

      14:00 - 15:30  |  Author(s): S. Almokadem, C. Belani

      • Abstract
      • Presentation
      • Slides

      Abstract
      Small cell lung cancer represents about 12% of new case of lung cancer in the USA. It has a unique presentation and natural history compared to other types of lung cancer and is highly responsive to first-line treatment. Unfortunately, the cancer typically relapses after a short period of time and exhibits resistance to cytotoxic and targeted therapeutic agents with a poor median survival. The last 2 decades witnessed significant improvement in our understanding of the molecular basis of small cell lung cancer with identification of several potential therapeutic targets leading to application and evaluation of novel chemotherapeutic, targeted and immunotherapeutic agents in a large number of clinical trials. In this presentation, we will summarize the data from the recent and ongoing clinical trials in this disease and understand the challenge that it poses. However, the results have overall been disappointing and the combination of a platinum compound with etoposide remains the most effective treatment for this patient population. Despite the advent of new cytotoxic and targeted agents, which have shown significant activity in other types of cancer including non-small cell lung cancer, their use in SCLC has not had any impact on survival. The differences in efficacy observed with agents such as amrubicin and irinotecan in patients from different ethnic or racial groups indicate the importance of the understanding the tumor genetic makeup and individualizing treatment regimens. The landscape of genetic alterations of SCLC is more complex than in other types of cancer. To date, no specific mutation, abnormal fusion protein secondary to chromosomal translocation or aberrant signal transduction pathway has been validated and proven to be critical for the continuation of the carcinogenesis process and survival of the SCLC tumor cells. SCLC remains one of the most challenging tumors to treat with our current standard of care. The recent advances in sequencing and high throughput technologies have started to yield useful information about the molecular abnormalities of SCLC. We need to refine the recently acquired knowledge of SCLC biology and apply that knowledge in innovative clinical trials to have a breakthrough in the treatment of SCLC.

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      MS20.2 - Small Cell Cancer Biology: Recent Insights (ID 552)

      14:00 - 15:30  |  Author(s): D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS20.3 - Optimal Radiotherapy for SCLC (ID 553)

      14:00 - 15:30  |  Author(s): C. Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Abstract
      Whilst the incidence of small cell lung cancer (SCLC) has reduced over the last 20 years, the prognosis of the disease remains poor. Major advances in SCLC include improvements in radiotherapy (RT) techniques, the use of prophylactic cranial irradiation (PCI) for all stages of SCLC and the improved integration of chemotherapy and RT. It is unlikely that future advances in the treatment of SCLC will relate to standard chemotherapy. The role of thoracic RT is well established in the management of stage I-III SCLC [1,2,3,4]. There is increasing evidence in the literature in favour of early concurrent chemo-radiotherapy (CTRT), and a gold standard of care for patients with a good performance status is twice-daily thoracic RT (45 Gy in 3 weeks) with concurrent cisplatin and etoposide [5]. Although current clinical trials are exploring the efficacy of new chemotherapeutic strategies, essential questions related to the optimisation of thoracic RT remain unanswered. These questions include i) optimal total dose, ii) fractionation, iii) timing and sequencing of radiation, iv) volume of irradiation, v) concurrent chemotherapy/targeted therapy combinations, and vi) the importance of the time between the start of any treatment to end of RT. PCI reduces the incidence of brain metastases and improves survival in all stages of SCLC [6,7]. As a result of the implementation of best standard of care the 5 year survival of stage I-III SCLC patients has increased from less than 10% with chemotherapy alone to 25-30% with early concurrent CTRT and PCI. It is crucial that patients with SCLC are given the opportunity to participate in clinical research in order to continue to improve the survival of this disease. Clinical trials aiming to establish a standard dose/fractionation in the stage I-III setting include the European/Canadian CONVERT and the US intergroup (CALGB 30610/RTOG 0538) studies. The results of the CREST study investigating the role of thoracic RT in stage IV SCLC are eagerly awaited. Molecular studies are ongoing aiming to gain improved insight into the molecular biology of SCLC, discover and/or validate candidate biomarkers for response, resistance to or toxicity of systemic treatment and radiation. There is now a concerted effort within the research community to understand the molecular mechanisms that underpin the molecular pathways in cancer. It is hoped that this understanding will lead to the development of targeted therapies that will not only prove efficacious, but also less toxic than more conventional treatments. In combination with newer techniques such as conformal RT and better imaging, it is hoped that the rates of long term survivors will increase significantly in the future. References 1 Bayman NA, et al. Radiotherapy for small-cell lung cancer-Where are we heading? Lung Cancer. 2009;63(3):307-14. 2 Sørensen M, et al. ESMO Guidelines Working Group. Small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Supplement 5):v120–v125. 3 Stahel R, et al. 1st ESMO Consensus Conference in lung cancer; Lugano 2010: small-cell lung cancer. Ann Oncol. 2011;22(9):1973-80. 4 Pignon JP, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327:1618-22. 5 Turrisi AT, et al. Twice daily compared to once-daily thoracic radiotherapy in limited-stage small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265-71. 6 Auperin A, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341(7):476-84. 7 Slotman B, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;357(7):664-72.

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      MS20.4 - New Treatments for SCLC (ID 554)

      14:00 - 15:30  |  Author(s): A. Adjei

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MO24 - NSCLC - Chemotherapy III (ID 110)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO24.08 - Survival outcomes among NSCLC patients in Europe receiving platinum-based therapies as first-line treatment: results from the FRAME observational study (ID 1944)

      10:30 - 12:00  |  Author(s): E. Smit

      • Abstract
      • Presentation
      • Slides

      Background
      FRAME was a European non-interventional prospective observational study of patients with advanced or metastatic non-small cell lung cancer (NSCLC) initiating platinum-based therapies as first-line treatment (FLT).

      Methods
      Patients were enrolled between April 2009 and February 2011. Consenting adult NSCLC (Stage III/IV) patients initiating FLT with a platinum-based doublet chemotherapy, with or without an additional targeted agent, were eligible for the study. The choice of FLT was left to physician discretion, as per routine clinical practice. The primary objective of FRAME was to evaluate overall survival (OS) among different platinum-based treatment cohorts in patients with and without additional targeted therapy. Secondary objectives included the evaluation of OS in patients with different histological subtypes of NSCLC. Survival outcomes were assessed using Kaplan-Meier analysis, and unadjusted estimates are presented.

      Results
      A total of 1564 eligible patients from 11 EU countries were observed. Patient cohorts were: pemetrexed + platinum, gemcitabine + platinum, vinorelbine + platinum, taxanes + platinum and other therapy + platinum. Table 1 shows a subset of baseline patient characteristics, which varied across several parameters in the treatment cohorts, including age, performance status (PS), stage and histology. The median OS across the 4 main treatment cohorts was 10.3 months (95% CI: 9.5-11.2). A subset of overall survival estimates in the different treatment cohorts is shown in Table 1.

      Table 1. Select baseline patient characteristics and overall survival
      Baseline Patient Characteristics Overall Survival Estimates (unadjusted)
      Treatment Cohort[a] Age ≥70 Years (%) ECOG PS of 2/3 (%) Stage IV (%) Non-squamous Histology (%) All patients Median OS in Months (95% CI) Non-squamous Median OS in Months (95% CI) Non-squamous Cisplatin[b] Median OS in Months (95% CI)
      Pemetrexed + Platinum[b ](n=569) 23 18 86 97 10.7 (9.4-12.3) [n=569] 10.6 (9.4-12.0) [n=553] 11.6 (9.9-13.8) [n=374]
      Gemcitabine + Platinum[b] (n=360) 35 11 74 56 10.0 (8.4-11.8) [n=360] 8.4 (7.0-10.6) [n=201] 8.4 (6.7-10.8) [n=107]
      Taxanes + Platinum[b ](n=295) 36 23 75 64 9.1 (8.0-11.3) [n=295] 8.1 (7.4-10.1) [n=189] 9.6 (7.1-14.1) [n=44]
      Vinorelbine + Platinum[b] (n=300) 28 15 67 53 10.7 (8.9-12.8) [n=300] 10.1 (8.0-13.1) [n=160] 9.9 (7.2-13.4) [n=91]
      [a]A fifth cohort, the ‘other’ + platinum cohort contained a small number of subjects (n=40) and it was not included in the analyses presented here [b]Cisplatin is the platinum agent in the EMA approved prescription drug label

      Conclusion
      This observational study of first-line treatment for advanced NSCLC provides data describing patients and their survival outcomes in a real-world European practice setting between 2009 and 2012.

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    MS15 - Extending the Limits of Combined Modality Treatment for NSCLC (ID 32)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Combined Modality
    • Presentations: 1
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      MS15.1 - Targeted Therapy in Combined Modality Therapy for Intrathoracic NSCLC with Activating Mutations (ID 526)

      14:00 - 15:30  |  Author(s): E. Smit

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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): E. Smit

      • 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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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-046 - EML4-ALK monitoring of crizotinib response in blood platelets and plasma of NSCLC patients (ID 3267)

      09:30 - 16:30  |  Author(s): E. Smit

      • Abstract

      Background
      The discovery of various genetic alterations that underlie lung cancer has opened-up a new era in the development of specifically targeted therapies employing specific alteration-dependent inhibitors. In the vast majority of NSCLC patients genetic alterations occur in EGFR (20-25%), BRAF (3%), and ALK (3-10%), seemingly in a predominant mutual exclusive manner. Hence, patient stratification for EGFR, KRAS, BRAF, and ALK alterations is becoming common practice among oncologists. The mutational status of NSCLC patients is considered dynamic and can change in due course of the disease and selection in response to therapy. Longitudinal monitoring of the mutational status of NSCLC patients is of crucial importance to tailor targeted therapy by adapting treatment regimens according to mutational status. However, technical challenges associated with serial tumor biopsy constitute a major challenge in longitudinal molecular monitoring and targeted treatment of NSCLC patients. Blood-based assays may overcome such limitations and allow for frequent assessment of the mutational status.

      Methods
      Here, tumor tissue, platelets, and/or plasma of NSCLC patients were collected and analyzed for the presence of translocated ALK using FISH, IHC, and/or RT-PCR. Monitoring of EML4-ALK in platelets and plasma was performed by RT-PCR on EML4-ALK positive patients treated with crizotinib and correlated to the clinical response as measured by serial radiographic CT.

      Results
      From a multicenter cohort of NSCLC patients we identified EML4-ALK positive patients by FISH, IHC, and RT-PCR, for blood platelet and/or plasma isolation. In blood platelets of ALK positive NSCLC patients (n=24) and ALK negative control subjects (n=54) we demonstrated an EML4-ALK test sensitivity of 70-80% and specificity of 100%. We detected EML4-ALK in plasma of ALK positive NSCLC patients (n=22), however with inferior sensitivity of 20-30%. In addition, longitudinal EML4-ALK monitoring in blood platelets of an ALK positive NSCLC patient correlated with the crizotinib response.

      Conclusion
      We demonstrate here that blood platelets of NSCLC patients are a biosource for the detection of the EML4-ALK translocation and may proof useful for longitudinal monitoring of ALK inhibitors in NSCLC patients, with superior outcome over plasma.

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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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      P2.08-012 - Treatment of Multiple Primary Lung Cancers (MPLC) with stereotactic ablative radiotherapy (SABR) (ID 1394)

      09:30 - 16:30  |  Author(s): E. Smit

      • Abstract

      Background
      Multiple primary lung cancers (MPLC) are not an uncommon clinical presentation, with an incidence in the surgical literature of 1-8%. ESMO guidelines state that synchronously detected lesions should be treated as multiple primary tumors, and a curative approach for both lesions has been associated with improved survival in the surgical series. However, many patients with MLCP are elderly and have multiple co-morbidities, which can render them unfit to undergo surgery for both lesions. We analyzed clinical outcomes in such patients who were treated with SABR.

      Methods
      SABR was performed in 62 patients diagnosed with MPLC at the VUmc from 2003 – 2012. Staging included a mandatory FDG-PET scan, and all patients were discussed in a multi-disciplinary tumor board. A pathological diagnosis was available for both lesions in 3%, and for one lesion in 48%. Invasive nodal staging was performed in 13% of patients. SABR was used as a single modality for both lesions (n=56), or in combination with surgery for the second lesion (n=6). SABR was delivered to a total dose of 54-60 Gray (Gy) in 3-8 fractions, depending on tumor size and location. Clinical outcome, including survival, patterns of relapse and toxicity (CTC v4.0) was evaluated. A sub-analysis was performed for ipsilateral and bilateral lung lesions.

      Results
      Median overall survival was 31 months, with an actuarial survival of 56% at 2 years. Overall lesion local control rate was 84% at 2 years. Local control correlated significantly with number of fractions (p=0.013) and lesion location (p=0.004) on univariable Cox regression analysis. Lesion control at 2 years for bilateral lesions was 92% versus 74% for ipsilateral lesions (p=0.009). Regional failures at two years were observed in 13% (n=6) of all patients, and in 0% versus 31% in patients with respectively bilateral and ipsilateral lesions. Of the patients who developed a subsequent regional recurrence, only one had undergone EUS/EBUS prior to treatment, and others did not as pre-treatment FDG-PET-scans showed no nodal uptake. Distant failures were observed in 27% of all patients, at two years. No grade ≥3 early toxicity was observed. Late grade 3 toxicity was reported in 3 patients (5%), consisting of pneumonitis (n=1), rib fracture (n=1) and chest wall pain (n=1). No grades 4-5 late toxicity was reported.

      Conclusion
      Curative treatment of MPLC using SABR, either alone or combined with surgery, can lead to long-term survival with limited toxicity. The disappointing local control rates observed after SABR for ipsilateral double lesions merits further investigation. The higher rate of nodal recurrences in patients presenting with multiple ipsilateral lesions suggests that systematic nodal staging may be appropriate in such cases.

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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): E. Smit

      • 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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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-002 - Resource utilization of NSCLC patients receiving platinum-based therapies across Europe; results from the FRAME observational study (ID 183)

      09:30 - 16:30  |  Author(s): E. Smit

      • Abstract

      Background
      FRAME was a non-interventional, prospective observational study of advanced or metastatic non-small cell lung cancer (NSCLC) patients initiating first-line treatment (FLT) with platinum-based therapies in a routine practice setting across 11 European countries.

      Methods
      Patient enrollment occurred between April 2009 and February 2011. Consenting adults with Stage IIIB or IV NSCLC receiving platinum-based doublet chemotherapy with or without an additional targeted agent as FLT were eligible for this study. Patients were under routine treatment for NSCLC by their doctors and treatment choice and resource use were at the discretion of the treating physician. Secondary objectives of the study included determining resource use during FLT. Hospitalizations, outpatient visits, concomitant therapy use, transfusions and the use of colony stimulating factors (CSFs) are reported here. Cohorts were not adjusted for multivariate parameters prohibiting statistical comparisons.

      Results
      Evaluable patients (n=1564) were categorized into 4 main cohorts based on their FLTs: pemetrexed + platinum (n=569), gemcitabine + platinum (n=360), taxanes + platinum (n=295) or vinorelbine + platinum (n=300). Forty of the evaluable patients received other platinum-doublet treatments and were excluded from the analyses presented here.Across the four main cohorts, 55% of patients were hospitalized.A majority (61%) of hospitalizations were preplanned (71% in the pemetrexed cohort, 45% in the gemcitabine cohort, 67% in the taxanes cohort and 53% in the vinorelbine cohort). Among the unplanned hospitalizations, 54% were related to an adverse event (54% in the pemetrexed cohort, 54% in the gemcitabine cohort, 55% in the taxanes cohort, and 55% in the vinorelbine cohort). The mean (95%-confidence interval) duration of hospitalizations was 13 days (11.6 to 14.6) for pemetrexed (median=9 days), 11 days (9.4 to 12.8) for gemcitabine (median=7 days),17 days (14.0 to 19.7) for taxanes (median=12 days), and 13 days (11.3 to 15.0) for vinorelbine (median=9 days). Nearly half of patients (47%) were seen in an outpatient setting with most outpatient visits (82%)planned for scheduled treatments. Nineteen percent of patients received ≥1 transfusion (16% in the pemetrexed cohort, 24% in the gemcitabine cohort, 15% in the taxanes cohort and 24% in the vinorelbine cohort). Nearly all (94%) of these patients received packed red blood cells. Nineteen percent of patients received ≥1 colony stimulating factor (CSF), which included G-CSF (69%), or erythropoietin (39%). During therapy, 82% of patients used antiemetics and antinauseants, 58% used steroids, 40% used analgesics, and 24% used antibiotics. Twenty-eight percent of patients received radiation during FLT and most often radiation was delivered concurrently with chemotherapy (66% overall, 66% in the pemetrexed cohort, 54% in the gemcitabine cohort, 68% in the taxanes cohort, and 73% in the vinorelbine cohort).

      Conclusion
      The FRAME study provides unique, real-life data reflecting prospectively collected information on resource use not accessible in a clinical trial setting. This study revealed several important findings regarding real-world resource use during NSCLC therapy including data on hospitalizations, outpatient visits, transfusions, concomitant treatments, and radiation.

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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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      P3.11-013 - Treatment with high-dose, weekly erlotinib in EGFR-mutated NSCLC-patients with extra-cranial progressive disease (ID 1350)

      09:30 - 16:30  |  Author(s): E. Smit

      • Abstract

      Background
      Progression of disease (PD) in advanced NSCLC patients with an EGFR mutation (EGFR+) treated with tyrosine kinase inhibitors (TKI) is inevitable. Therapeutic options for these patients are lacking. Several patients with acquired TKI-resistance who were treated with high-dose, weekly erlotinib (‘pulsatile erlotinib’) for leptomeningeal metastases showed an evident thoracic response (1). We initiated this trial to evaluate the effect of pulsatile erlotinib on advanced, EGFR+ NSCLC patients with TKI-resistance.

      Methods
      This study was developed as a prospective, mono-center, open-label, single-arm phase II trial. Primary endpoint was objective response rate (ORR). Secondary endpoints were PFS, toxicity and safety. Eligibility criteria included histologically confirmed stage IV, non-squamous, EGFR+ NSCLC-patients who progressed on TKI (erlotinib or gefitinib) in standard dose. Biopsy was obtained before treatment initiation. Patients were treated with erlotinib 1500mg weekly. Response was assessed according to RECIST 1.1. Simon’s 2-stage optimal design was applied (2).

      Results
      Eleven patients were enrolled. Patient characteristics and pathological results are depicted in table 1. When 10 patients were assessed to have PD or stable disease, the trial was discontinued, according to predefined criteria. Objective response rate (ORR) was 9,1%. Median PFS was 1.6 months (95% CI, 0.9-2.0 months). One biopsy revealed KRAS mutation, whereas earlier biopsies had shown exon 18 + exon 20 mutation. A second primary tumour is not excluded in this case. Patients received pulsatile erlotinib as 3[rd] -6[th] treatment. At time of analysis, one patient remains on treatment. One patient had clinical benefit lasting for 3 months beyond PD. There were no deaths during the study. Toxicity was mainly grade 1-2.

      Table 1: PATIENT CHARACTERISTICS N = 11
      Median Range
      Age (years) 57 (32-75)
      Frequency (%)
      Sex female 11 (100%)
      male 0 (0%)
      Smoking Non-smoker 7 (63,6%)
      Previous smoker 3 (27,3%)
      Current smoker 1 (9,1%)
      Performance score PS 0 4 (36,4%)
      PS 1 5 (45,5%)
      PS 2 2 (18,2%)
      Ethnicity Caucasian 11 (100%)
      Stage IV - metastatic 11 (100%)
      Histology Adenocarcinoma 10 (90,9%)
      1 (9,1%)
      Mutation EGFR-exon 19 2 (18,2%)
      EGFR-exon 21 1 (9,1%)
      EGFR exon 19 + T790M 3 (27,3%)
      EGFR exon 21 + T790M 2 (18,2%)
      KRAS 1 (9,1%)
      No mutation 1 (9,1%)
      No biopsy 1 (9,1%)

      Conclusion
      Despite some individual successes with pulsatile erlotinib treatment of EGFR+ NSCLC patients, this trial failed to meet its primary endpoint and was discontinued prematurely. Pulsatile erlotinib was safe and toxicity was manageable. Further investigation of this treatment for this indication is not recommended.

  • +

    P3.18 - Poster Session 3 - Pathology (ID 177)

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

      P3.18-021 - <strong>Array CGH is useful in the evaluation of patients with synchronic or metachronic tumors</strong> (ID 3380)

      09:30 - 16:30  |  Author(s): E. Smit

      • Abstract

      Background
      Synchronic or metachronic tumors may develop in patients with a lung tumor. Determining whether these tumors originate from the same clone or are separate lesions may be challenging. Clinical, morphological and immunohistochemical criteria are often not distinctive. The aim of our study was to investigate comparative genomic hybridization (array CGH) analysis for the evaluation of clonality in patients with metachronic or synchronic tumors, having at least one intrathoracic tumor localization.

      Methods
      A database was constructed of consecutive patients (n=77) referred by clinicians or pathologists for assessment of clonality by array CGH from 2007 till 2012. All cases with at least one intrathoracic tumor were selected. The array CGH patterns were analyzed by a visual comparison of CGH patterns performed by two investigators and by two mathematical models on the raw data. One model uses a log likelihood ratio as described previously[1], the other a Pearson correlation between the segmented values. Clonality cut-off and p-values were set according to copy number profiles from individual patients, which are therefore by definition non-clonal. The results of the visual evaluation and the mathematical approach were correlated. A control group was formed by the specimens of one lung tumor from every patient in the database, which were all compared, using the mathematical models. 1. Ostrovnaya I, Seshan VE, Olshen AB, et al. Clonality: an R package for testing clonal relatedness of two tumors from the same patient based on their genomic profiles. Bioinformatics. 2011;27:1698-1699.

      Results
      Specimens of 77 patients were referred for analysis. Samples of 14 cases were not suited to array CGH due to insufficient material or bad quality of DNA. The remaining 63 cases comprised of 142 samples. In 8 patients DNA from more than 2 tumors was compared. In the mathematical model the outcome of 3 cases was missing, 23 cases were determined clonal, 22 non-clonal, 5 with clonal as well as non-clonal tumors and 10 were undetermined. In the negative control group > 96% of cases were scored as non-clonal. The visual analysis determined 40 cases clonal, 14 non-clonal, 1 with clonal as well as non-clonal tumors and 8 were undetermined. 46 cases were available for comparing the outcomes of the mathematical and visual evaluation, as for 3 cases data were missing and in 14 cases the outcome was undetermined. The concordance rate for clonal and non-clonal tumors between visual analysis and the mathematical approach was 35 out of 46 (76%). In 4 cases in which the visual judgment was clonal, the mathematical model determined clonal as well as non-clonal samples. In 7 cases discordance was noted: the visual outcome was clonal and the mathematical non-clonal.

      Conclusion
      Array CGH is a useful approach for evaluating clonality of synchronic or metachronic tumors.