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S. Keshavjee



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    MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO01.09 - A novel murine xenograft model using samples obtained by EBUS-TBNA (ID 773)

      11:10 - 11:15  |  Author(s): S. Keshavjee

      • Abstract
      • Presentation
      • Slides

      Background
      Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive approach for lymph node staging in patients with lung cancer. Although EBUS-TBNA has been utilized for various molecular testing, intrinsic characteristics of different lesions produce variability in the amount of cellular material that can be obtained. In some samples, the quantity of tumor recovered may be limited for subsequent testing. To overcome this problem, we evaluated the feasibility of establishing a murine tumor xenograft model using EBUS-TBNA samples for advanced translational research.

      Methods
      After confirmation of adequate sampling for cytopathological diagnosis during EBUS-TBNA, one additional pass was performed for this study (NCT01487603). The aspirate was stored in cell preservative solution (RPMI1640 with 10% FBS) for inoculation of the tumor for the xenograft model. The sample was transported to the laboratory on ice, then mixed with Matrigel and centrifuged. The pellet which contained tumor fragments was implanted to the subcutaneous pocket on the right flank of a NSG (NOD scid gamma) mouse. Once we confirmed the engraftment of the tumor, we passed the tumor to another mouse until 3 passages were completed. The success rate of tumor xenograft establishment was examined along with histopathology and the cellularity and cytopathologial diagnosis of the primary EBUS-TBNA samples.

      Results
      From December 2011 to June 2012, 19 patients were enrolled in this study. The cytopathological diagnoses were as follows; 12 adenocarcinoma, 3 squamous cell carcinoma, 1 large cell carcinoma NOS, and 3 small cell carcinomas. 8 out of 19 cases (42.1%) showed tumor formation. The mean duration between inoculation and tumor formation was 62.38 days (13-144 days). All engrafted tumors could be passed to the second mouse. The histological types of the engrafted tumors were 3 adenocarcinoma (3/12: 25%), 2 squamous cell carcinoma (2/3: 67%), 1 large cell carcinoma (1/1: 100%), and 2 small cell carcinomas (2/3: 67%). The tumor cellularity of primary EBUS-TBNA samples was sufficient for diagnosis and there was no correlation between engraftment and the degree of blood/lymphocyte contamination or percentage of necrosis.

      Conclusion
      EBUS-TBNA samples can be used for establishment of tumor xenograft model in immunodeficient mice. EBUS-TBNA allows minimally invasive sampling of metastatic lymph nodes in patients with advanced lung cancer which opens up possibilities for translational research. We need to continuously seek better ways to improve and standardize procurement and processing of samples obtained by minimally invasive techniques in order to optimize diagnosis and molecular analysis for improved patient care. Figure 1

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

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO14.09 - 5-year experience with accelerated induction hypofractionated hemithoracic intensity modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) (ID 2022)

      11:20 - 11:25  |  Author(s): S. Keshavjee

      • Abstract
      • Presentation
      • Slides

      Background
      Our experience in tri-modality therapy for MPM with induction chemotherapy followed by EPP and high dose hemithoracic radiation demonstrated that completion of EPP and radiation provided the best results. We therefore developed a new protocol of accelerated induction hypofractionated hemithoracic IMRT followed by EPP to deliver optimal radiation to the whole tumor bed in a short period of time. EPP is performed approximately one week after completion of radiation to limit the risk of pneumonitis. The results of Surgery for Mesothelioma After Radiation Therapy (SMART) was reviewed and compared to our previous cohort of patients undergoing induction chemotherapy followed by EPP and adjuvant hemithoracic radiation.

      Methods
      All patients undergoing EPP in our institution between 01/2001 and 06/2013 were reviewed. The SMART protocol (25 Gy in 5 daily fractions over 1 week delivered to the entire ipsilateral hemithorax by IMRT with concomitant boost of 5 Gy to volumes at high risk based on CT and PET scan findings) was started in 2008. EPP was performed 6±2 days after radiation therapy. The results of the SMART protocol were compared to the group of patients undergoing induction chemotherapy followed by EPP as part of a trimodality approach.

      Results
      A total of 111 patients underwent EPP between 01/2001 and 06/2013 with a hospital mortality of 4.5% (n=5). A total of 64 patients (81% men, 59±9 years old, 81% with epithelial histologic subtype) underwent induction chemotherapy, while 39 (82% men, 62±9 years old, 69% with epithelial histologic subtype) underwent SMART. Seven patients had no induction therapy and one had pre-operative chemo- and radiation therapy. Since 2008, the number of surgical patients undergoing SMART progressively increased from 14% in 2008 to 100% in 2013. None of the patients undergoing SMART died in hospital or within 30 days of surgery, while 4 of the 64 patients (6.4%) undergoing induction chemotherapy died in hospital after EPP (p=0.1). Patients undergoing SMART tended to have a greater proportion of ypN2 disease on final pathology than patients completing induction chemotherapy before EPP (58% vs 41%, respectively; p=0.09). After a median follow-up of 16 months after the start of therapy, the 3-year survival was significantly better in patients with epithelial disease undergoing SMART (n=27) compared to patients with epithelial disease undergoing induction chemotherapy and EPP (n=52) (79% 3-year survival vs 30% 3-year survival, respectively; p=0.04). In contrast, the 3-year survival of patients with biphasic disease was similar between patients undergoing SMART (n=12) or induction chemotherapy and EPP (n=12) (20% vs 8%, respectively; p=0.8). Multivariate survival analysis using Cox regression model demonstrated that epithelial histologic subtype (p=0.0003), the absence of ypN2 disease (p=0.007) and SMART (p=0.03) were predictors of better survival.

      Conclusion
      Over the past 5 years, accelerated hemithoracic IMRT followed by EPP has become our preferred approach for surgically resectable MPM. Surgery for mesothelioma after radiation therapy was feasible with no operative mortality in 39 patients. Although comparison with our historical cohort of patients has limitations, our current protocol provides very encouraging results in patients with epithelial disease with a 3 year survival of 79%.

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    P1.07 - Poster Session 1 - Surgery (ID 184)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P1.07-026 - VATS reduces surgical risk of lobectomy for high risk patients with early non-small cell lung cancer (ID 2039)

      09:30 - 09:30  |  Author(s): S. Keshavjee

      • Abstract

      Background
      Patients considered to be at increased risk from surgery may be offered nonsurgical therapies for early stage non-small cell lung cancer (NSCLC). However, video assisted thoracic surgery (VATS) is associated with lower morbidity and thus may permit anatomic resection for patients considered increased risk.

      Methods
      Our institutional database was queried to find all patients who received lobectomy for early stage NSCLC between 2002-2010. Patients were grouped into cohorts of standard (SR, n=536) or increased risk (IR, n=72) using the ACOSOG Z4099/RTOG 1021 eligibility criteria. Morbidity and mortality were compared based on risk group and surgical method.

      Results
      Median age was 72 and 67 years for IR and SR respectively. Most patients were stage I (IR: 83.3%; SR: 84.5%). Although IR patients had increased overall and pulmonary complications compared to SR (overall: p=0.0004; pulmonary: p<0.0001), there were no differences between the subset of IR patients who had VATS resections and SR patients resected by either open or VATS techniques (overall: p=0.7697; pulmonary: p=0.3219) [Table 1]. Survival at 5 years was significantly lower for IR patients resected by open techniques (46.2%; p=0.0028) but those resected by VATS (61.2%) had similar survival to SR patients resected by either VATS (65.1%) or open techniques (64.3%; p=0.83) [Figure 1]. There was no significant difference in operative mortality between the IR and SR groups (IR: 1.4%; SR: 0.4%; p=0.2832).

      Table 1: Post-operative complications stratified by risk subgroup and surgical method
      Increased risk (%) Standard Risk (%) Increased Risk with VATS resection (%)
      Overall Complications 33.3 16.2 18.2
      Pulmonary Complications 30.6 11.8 18.2
      Figure 1 Figure 1: Overall survival following lobectomy for NSCLC, stratified by risk group and surgical method

      Conclusion
      Surgical morbidity and mortality are reduced in patients at increased risk from lobectomy when resected by VATS offering them equivalent outcomes to standard risk patients.

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    P1.15 - Poster Session 1 - Thymoma (ID 189)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      P1.15-009 - Outcomes and Predictors of Recurrence in Patients Treated with Risk-adapted, Post-operative Radiotherapy (RT) for Thymoma - A Single Institution, 30 Year Retrospective Study (ID 3124)

      09:30 - 09:30  |  Author(s): S. Keshavjee

      • Abstract

      Background
      Thymoma is a rare epithelial cell tumour of the thymus, with an incidence of 0.15 per 100 000 persons. Thymic carcinomas comprise a distinct subset and have a greater propensity for capsular invasion and distant metastases when compared to thymomas. Resection is the standard of care for localized disease but local recurrence is generally incurable, thus post-operative RT is often employed for high risk cases. The optimal dose of RT has not been established, nor whether lower doses can be utilized in a risk-adapted fashion for cases where RT is recommended but the aggressiveness of the disease/risk of recurrence is felt to be at the lower end of the spectrum. Use of lower dose RT may help reduce the chances of late RT toxicity. Our institution employs such a risk adapted strategy and we present here our long term results.

      Methods
      Princess Margaret Cancer Center radiation and surgical oncology databases were queried from 1983-2012. Retrospective analyses using electronic patient records and Mosaiq radiotherapy database were performed to assess demographic data, clinical presentation and treatment. Descriptive statistics were used to report demographic data. Time to event analyses and correlation of outcomes with demographic and treatment variables are planned.

      Results
      Details on 104 patients treated with post-operative radiotherapy from 1983-2012 were available. The mean age was 52, range 29-73. Of patients assessed, 55/104 were male. Masaoka-Koga stage was assessed: 6% of patients were stage I, 31% IIA, 21% IIB, 27% III, 10% IV and 6% unknown. The most common WHO grade was B2 (37%) followed by B1 (16%). Complete surgical resection (R0) was obtained in 72% patients, R1 in 21%, R2 in 2% and 5% unknown. Radiotherapy doses ranged from 40 Gy – 66 Gy delivered in daily 2 Gy fractions; 57% patients were deemed low risk (typically R0 resection and WHO grade B2 or lower) and received 40Gy while 36% received between 45-66Gy. Neoadjuvant or adjuvant chemotherapy was delivered to 13% of all patients. The mean follow up period was 9.4 years, range 0.5-25.5 years, during which 22% patients experienced relapse. Of these, 43% experienced regional recurrence, defined as an intrathoracic relapse in an area not-contiguous with the thymic bed or original tumour; 39% local (intrathoracic relapse contiguous with original disease or thymic bed), and 17% distant recurrence defined as extrathoracic or intraparenchymal pulmonary nodules. For patients that experienced relapse, the median time to relapse was 8.7 years (range 1.3-18.3 years). Of the 59 patients who received 40 Gy/20 fractions, 8 developed local relapse (13.5%). Overall survival and multivariable analyses will be reported as will assessment of long term toxicities.

      Conclusion
      Risk-adapted RT prescription for patients with resected thymoma appears efficacious, and may result in an improved therapeutic ratio for these patients. Long-term, randomized controlled trials are required to further identify patients that are best suited to this approach.

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    P1.22 - Poster Session 1 - Epidemiology, Etiology (ID 166)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P1.22-011 - Assessment of the accuracy and reliability of health related behavioural data obtained from patient-reported surveys (PRS) compared with electronic patient records (EPR) in lung cancer patient population (ID 2948)

      09:30 - 09:30  |  Author(s): S. Keshavjee

      • Abstract

      Background
      Cigarette smoking, alcohol consumption and presence of co morbidities are important factors that affect health status and mortality in patients diagnosed with lung cancer. While the gold standard for presence or absence of co-morbidities is EPR, the gold standard for obtaining accurate data pertaining to health-related behaviours is by PRS. The purpose of this study is to ascertain, whether in the absence of patient self-reported data, health related behavioural data pertaining to cigarette smoking and alcohol consumption abstracted from EPR provides an accurate and reliable surrogate.

      Methods
      731 lung cancer patients completed a PRS pertaining to information on their lifetime tobacco use, alcohol consumption and whether or not they had been diagnosed with certain co-morbid conditions. Relevant smoking, alcohol consumption and co-morbidity data was collected independently from EPR. Kappa coefficient analysis was used to assess the agreement.

      Results
      Results can be seen in Table 1. Ever/never status for smoking showed almost perfect agreement (k=0.95) between PRS and EPR and surpassed all other health behavioural measures and all co-morbidity agreement values. The calculation of pack-years from EPR and PRS showed substantial agreement (k=0.77); However, categorizing the smoking status into current/ former / never, resulted in only moderate agreement (k=0.47). Alcohol ever/ never status agreement was moderate (0.44) with high sensitivity (0.90) but low specificity (0.50). The lung related co-morbidities like emphysema (k=0.41) and chronic bronchitis (k=0.28) showed fair agreement but with substantial missing data through EPR.

      Table 1
      Health Behaviour N Missing Data in EPR Agreement (k) 95% CI (P value) Se Sp
      Smoking (E/N) 709 0 0.95 (0.79, 0.89) 0.995 0.94
      Smoking (Pkyrs)* 606 81(11%) 0.77 P<0.0001
      Smoking (C/F/N)** 705 4(0.5%) 0.47 (0.41, 0.51)
      Alcohol (E/N) 575 150(20.5%) 0.44 (0.36, 0.52) 0.9 0.5
      Comorbidity
      Emphysema 589 126(17.2%) 0.41 (0.33, 0.49) 0.41 0.95
      Chronic Bronchitis 601 94(12.8%) 0.28 (0.19, 0.37) 0.39 0.88
      *Spearman correlation coefficient
      **Weighted kappa

      Conclusion
      In the absence of PRS data, EPR provides a reliable surrogate for ever/ never smoking status and moderately reliable for lifetime smoking exposure in this lung cancer population. However current/ former/ never smoking status and ever/ never alcohol status cannot be reliably ascertained from medical records. Missing EPR data related to smoking pack years, alcohol consumption and lung co-morbidities is concerning and suggests more systematic or synoptic reporting by physicians would improve opportunities for research

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-038 - Long-term outcome after resection of non-small cell lung cancer invading the thoracic inlet (ID 2929)

      09:30 - 09:30  |  Author(s): S. Keshavjee

      • Abstract

      Background
      Non-small cell lung cancer (NSCLC) of the thoracic inlet accounts for less than 5% of all lung cancers. Due to the lack of efficient treatment and the complexity of the anatomical structures commonly invaded, these tumors were deemed historically unresectable and fatal. In this study, we reviewed our surgical experience and long-term outcome after resection of NSCLC invading the thoracic inlet

      Methods
      All consecutive patients from a single center who underwent resection of NSCLC invading the thoracic inlet were reviewed with data retrieved retrospectively from the charts.

      Results
      A total of 65 consecutive patients with a median age of 61 years (range 32 to 76) underwent resection of NSCLC invading the thoracic inlet from 1991 to 2011. Tumors were located in the previously described (Reference) five zones of the thoracic inlet as follows: zone 1 or anterolateral (n=5, 8%), zone 2 or anterocentral (n=7, 11%), zone 3 or posterosuperior (n=12, 18%), zone 4 or posteroinferior (n=22, 34%) and zone 5 or inferolateral (n=7, 11%). Fifty-two (80%) patients had induction therapy, mostly two cycles of cisplatin-etoposide and 45 Gy of concurrent radiation. All patients underwent en bloc resection of the lung and chest wall. Lobectomy was performed in 60 patients (92%). A median of three ribs were resected (range 1 to 5) and included the first rib in all patients. Twenty-four patients (37%) had an additional vertebral resection of up to five levels (median 3). Considering the most extended vertebral resection, total vertebrectomy with anterior-posterior spinal stabilization was required in 6 patients (25%), hemi-vertebrectomy with posterior spinal stabilization in 15 (62%), and partial vertebrectomy without stabilization in 3 (13%). Arterial resections were performed in seven patients (11%) and included subclavian artery (n=5), vertebral artery (n=1) and combination of sublclavian and carotid arteries (n=1).The median postoperative length of stay was 11 days (range 4 to 173). Postoperative morbidity and mortality were 46% and 6%, respectively. Pathologic response to induction treatment was complete (n=19) or near complete (n=12) in 31 patients (49%). Pathologic stages were 0 in 19 patients (29%), IB in 1 (2%), IIB in 28 (43%), IIIA in 15 (23%) and IIIB in 2 (3%) patients. After a median follow-up of 20 months (range 0 to 193), 34 patients were alive without recurrence. The overall 3- and 5-year survivals reached 58% and 52%, respectively. Results of the Cox regression and log-rank/Breslow tests identified the site of tumor (zone 1/3 vs 2/4/5, p=0.050) and the response rate to induction treatment (complete/near complete vs partial, p=0.004) as significant predictors of survivals. A trend toward shorter survival was found in case of arterial resection (p=0.063).

      Conclusion
      Survival after resection of NSCLC invading the thoracic inlet in highly selected patients reached 52% after five years. Tumor location within the thoracic inlet and pathologic response to induction therapy were significant predictors of survivals. Reference: de Perrot M, Rampersaud R. Surgical approaches to apical thoracic malignancies. J Thorac Cardiovasc Surg. 2012 Jul;144(1):72-80.

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    P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.12-015 - Surgery for Early Non-Small Cell Lung Cancer with Preoperative Erlotinib (SELECT): A Correlative Biomarker Study (ID 2529)

      09:30 - 09:30  |  Author(s): S. Keshavjee

      • Abstract

      Background
      Erlotinib has demonstrated major activity in EGFR mutation positive NSCLC, but may also benefit those with wild type tumours. We conducted a single-arm trial of pre-operative erlotinib in early stage NSCLC to assess radiologic and functional response as well as correlation with known and investigational biomarkers.

      Methods
      Patients with clinical stage IA-IIB NSCLC received erlotinib 150 mg daily for 4 weeks followed by surgical resection. Tumor response was assessed using pre- and post-treatment CT and PET imaging. Tumor genotype was established using Sequenom MassARRAY analysis. EGFR, PTEN, cMET and AXL expression levels were determined by immunohistochemistry. Pre- and post-treatment circulating markers/ligands for EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR ECD) were measured by ELISA. Tumor MET copy number by FISH and VeriStrat® analysis of pre-treatment serum samples is ongoing. Secondary endpoints included pathological response, toxicity and progression-free survival.

      Results
      Twenty-five patients were enrolled; 22 received erlotinib treatment with a median follow up of 4.4 years (range 2.2 to 6.4 years). Histology was predominantly adenocarcinoma (15) with smaller numbers of squamous cell carcinoma (7). PET response (25% SUV reduction) was observed in 2 patients (9%), both with confirmed squamous carcinoma histology. All patients met criteria for stable disease by RECIST and several experienced minor radiographic regression with histologic findings of fibrosis/necrosis, including 2 with squamous histology. The presence of an EGFR activating mutation was detected in two adenocarcinoma cases; one patient experienced minor radiographic response to treatment (exon 19 deletion) and the other stable disease (L858R). High pre-treatment serum levels of TGF- α correlated with tumor growth or primary resistance to erlotinib therapy (p=0.04), whereas high post-treatment soluble EGFR levels correlated with tumor response (p=0.02). Expression of EGFR, PTEN, cMET and AXL did not correlate significantly with tumor response.

      Conclusion
      Erlotinib appears to demonstrate some activity in EGFR wild-type tumors including those with squamous histology. These findings support that certain EGFR wild-type patients may respond to EGFR TKIs. Further research is needed to characterize these patients and elucidate the predictive ability of potential biomarkers such as TGF- α, EGFR copy number and others.